 Combination of selected opioids with muscarine antagonists for treating urinary incontinence
专利摘要:
The present invention provides a combination of a compound of group A (particularly an opioid) with a compound of group B (particularly an antimuscarinic agent and other significant peripherally functional substances) for the manufacture of a medicament for treating urinary or incontinence with increased urgency. It relates to the use of. The invention also relates to a corresponding agent for treating urinary or incontinence with increased urgency and a method of treating urinary or urinary incontinence with increased urgency. 公开号:KR20040044953A 申请号:KR10-2004-7004002 申请日:2002-09-18 公开日:2004-05-31 发明作者:크리스토프토마스 申请人:그뤼넨탈 게엠베하； IPC主号:
专利说明:
Combination of selected opioids with muscarine antagonists for treating urinary incontinence [1] The present invention provides compounds of Group A (particularly opioids) and Group B compounds (particularly antimuscarinics and other significant peripherals) for the manufacture of medicaments for the treatment of an increased urge to urinate or urinary incontinence. And a corresponding agent for treating urinary or urinary incontinence with increased urgency and methods of treating urinary or urinary incontinence with increased urgency. [2] Urinary incontinence is the unconscious excretion of urine. Urinary incontinence occurs uncontrolled when the pressure in the bladder exceeds the pressure needed to close the urethra. The cause of urinary incontinence may be, on the one hand, an incontinence due to an increase in bladder internal pressure (eg, symptoms due to detrusor muscle instability), and on the other hand, a decrease in sphincter pressure (such as symptoms following childbirth or surgical procedures). It can be tension incontinence. The detrusor muscle is a coarse bundle of multiple bladder wall roots. The detrusor muscle contracts to induce urination of the urine, and the sphincter closes the muscles of the urethra. Mixed types of these incontinences and the above mentioned sunrise incontinence or reflective incontinence (eg, incontinence following spinal cord injury) occur. Thus, urgent urination and increasing urination cycles are all possible symptoms of benign prostatic hyperplasia (eg, incontinence). Further details on these symptoms are given in the literature (Chutka, D. S. and Takahashi, P. Y., 1998, Drugs 560: 587-595). [3] "Decreased urination" is a condition in which urine excretion (urination) is required, because the bladder muscle tension is increased by reaching (or exceeding) the maximum bladder capacity. This tension stimulates urination. Urgently increased urination is understood in particular to mean premature urinary urination or even urgently increased urination, sometimes accompanied by pain. As a result, the frequency of urination increases significantly. These causes can be, in particular, inflammation of the bladder, neurological bladder disease and bladder tuberculosis. But the cause is not yet fully identified. [4] Urination and urinary incontinence with increasing urgency are recognized to be quite unpleasant and therefore there is a need to improve patients with the symptoms for as long as possible. [5] Urination with increased urgency and especially urinary incontinence is usually treated with a medicament using a substance involved in the reflexes of the lower urinary tract (Wein, A. J., 1998, Urology 51 (Suppl. 21): 43-47). Drugs that act to inhibit the detrusor muscle that regulate the internal pressure of the bladder are common. These agents include, for example, parasympathetic stimulants such as oxybutynin, propiberine or tolterodine, tricyclic antidepressants such as imipramine or muscle relaxants such as flavoxates. Other agents, particularly agents that increase resistance to the urethra or bladder neck, exhibit affinity for α-adrenergic receptors such as ephedrine and β-adrenergic receptors such as clenbutanol, or hormones such as oestradiol. [6] The reference precisely describes the therapeutics and methods of treatment used, in particular for antimuscarinic agents and other substances with peripheral action. See KE Andersson et al., "The pharmacological treatment of urinary incontinence", BJU International (1999). ), 84, 923-947] [7] Certain diarylmethylpiperazines and diarylmethylpiperidine are also described in WO 93/15062. In tramadol, a positive effect on bladder function has also been demonstrated in a rat model for peristaltic contraction of the bladder (WO 98/46216 to Nippon-Shinyaku). There is further research on the characteristics of opioid side effects on urine retention, among which are weak opioids such as diphenoxylates (Fowler et al., 1987 J. Urol 138: 735738) and meperidine (Doyle). and Briscoe, 1976 Br J Urol 48: 329-335]}, mixed opioid agonists / opioid antagonists {eg buprenopine [Malinovsky et al., 1998 Anesth Analg 87: 456-461; Drenger and Magora, 1989 Anesth Analg 69: 348-353], pentazosin (Shimizu et al. (2000) Br. J. Pharmacol. 131 (3): 610-616] and nalbuphine (Malinovsky et al., 1998, loc. cit.]} and potent opioids {eg, morphine [Malinovsky et al., 1998, loc. cit .; Kontani und Kawabata, (1988); Jpn J Pharmacol. Sep; 48 (1): 31] and fentanyl (Malinovsky et al., 1998, loc. cit.]} affects bladder function. Nevertheless, these studies generally work at analgesic activity concentrations. [8] In the measures raised herein, it should be noted that, in contrast to the many situations in which a medicament is generally administered for a fairly long time, and in contrast to many situations in which analgesics are administered, the patient is very unpleasant but not unbearably unpleasant. Thus, even if a higher amount of analgesic is administered, it is desired to prevent side effects if the patient does not want to replace one pain with another. In addition, most of the analgesic effects in the permanent treatment of incontinence are also undesirable. [9] It is therefore an object of the present invention to be beneficial in the treatment of urinary or incontinence with increased urgency, preferably at the same time showing little side effects and / or analgesic effects as compared to substances known in the art at active dosages. To develop substances or combinations of substances, in particular for the treatment of urinary incontinence. [10] Surprisingly, group A comprising opioids and other substances which can act centrally and interact with opioid receptors and whose effects can be counteracted by naroxone or in particular substances acting by opioid receptors, in particular μ-receptors It has been found that a combination of a compound of and a compound of group B comprising a compound of and a compound of group B comprising a muscarinic antagonist and other substances active in urinary incontinence and having a pronounced peripheral action is excellent in bladder function. Also quite unusually, since these combinations show significant activity even at very low dosages, it has already been demonstrated that small amounts of the active compound in combination can be administered. As a result, in therapeutic use, the side effects that occur when high doses are required are significantly reduced, and the effects of the peripheral antimuscarinic and central opioid or μ-receptor effects that act remarkably directly on the bladder or bladder root system. The combination maintains the therapeutic action completely. [11] The present invention therefore provides the use of an active compound combination of at least one group A compound and at least one group B compound for the manufacture of a medicament for the treatment of urinary or incontinence with increased urgency. [12] The compound of group A is selected from groups (a) to (e), [13] Group (a) may comprise tramadol, O-demethyltramadol or O-demethyl-N-mono-demethyl-tramadol, optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers). ) Or in the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) and any of their acid or base forms or salts thereof (particularly physiologically acceptable salts) in any desired mixing ratio, Or in the form of solvates (particularly hydrates) thereof, [14] Group (b) is codeine, dextrosepropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphine, pentidine (meperidine), tilidine, tramadol, biminol, butorpanol, Dextromoramide, dezosin, diacetylmorphine (heroin), hydrocodone, hydromorphone, ketobemidone, levometadon, levomethadyl acetate [1-α-acetylmethol (LAAM)], levorpanol, Morphine, nalopine, oxycodone, pentazosin, pyritramide, alfentanil, buprenopine, etopin, fentanyl, remifentanil or serfentanil, optionally in their racemic form, their pure stereoisomers (especially enan Thiomers or diastereomers) or mixtures of stereoisomers (especially enantiomers or diastereomers) in any desired mixing ratio and acids or bases thereof or salts thereof (especially physiologically) Allowed Salt) or solvates (particularly hydrates) thereof, [15] Group (c) may optionally contain the 1-phenyl-3-dimethylamino-propane compounds of formula I in their racemic form, their pure stereoisomers (in particular enantiomers or diastereomers) or any desired mixtures. In the form of mixtures of ratio stereoisomers (especially enantiomers or diastereomers) and their acid or base forms or salts thereof (especially physiologically acceptable salts), or solvates thereof In the form of (carb), [16] Group (d) may be selected from the 6-dimethylaminomethyl-1-phenylcyclohexane compounds of formula (II), optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers) or any desired In the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) in mixed ratios and in the form of their acids or bases or salts thereof (particularly physiologically acceptable salts), or solvates thereof ( Particularly, in the form of hydrates), [17] (e) the group may contain the 6-dimethylaminomethyl-1-phenyl-cyclohexane compound of formula III, optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers) or any desired In the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) and acids or bases thereof or salts thereof (particularly physiologically acceptable salts), or solvates thereof (Especially in the form of hydrates), [18] The at least one group B compound is an antimuscarinic agent such as atropine, oxybutynin, propiberine, propanetellin, emepronium, trophypichet, tolterodine, darfenacin and α, α-diphenylacetic acid As well as 4- (N-methylpiperidyl) esters, as well as dulocetin, imipramine and desmopressin, which are optionally in their racemic form, their pure stereoisomers (especially enantiomers or Diastereomers) or mixtures of stereoisomers (especially enantiomers or diastereomers) in any desired mixing ratio, and their acid or base forms or salts thereof (especially physiologically acceptable) Salt) or solvates (particularly hydrates) thereof. [19] [20] In Formula I above, [21] X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), [22] R 1 is selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-4 -alkyl, [23] R 2 and R 3 , at each occurrence, are independently selected from H, or branched or unbranched, saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted C 1-4 -alkyl, [24] R 2 and R 3 together form an unsubstituted, mono- or polysubstituted saturated C 4-7 -cycloalkyl radical, [25] R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, [26] R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring. [27] [28] In Formula II above, [29] X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), [30] R 1 is selected from C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 -C 6 H 5 , OC 1-4 -alkyl, Cl and F, [31] R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are each independently of the other H; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, [32] R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring. [33] [34] In Formula III above, [35] X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), [36] R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, [37] R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring, provided that R 9 , R 11 and R 13 correspond to H, one of R 10 and R 12 corresponds to H and the remaining groups correspond to OCH 3 , X cannot be OH. [38] Surprisingly, it has been found that the combinations of the above-mentioned substances show a significant positive effect, which is important for urinary or urinary incontinence with increasing urgency at certain physiological parameters. It means that each of these compounds can significantly alleviate the symptoms of the patient. [39] In the scope of the present invention, an alkyl radical or cycloalkyl radical is understood to be a branched or unbranched, saturated or unsaturated (non-aromatic) cyclic hydrocarbon which may be monosubstituted. In this category, C 1-2 -alkyl is C 1 -alkyl or C 2 -alkyl; C 1-3 -alkyl is C 1 -alkyl, C 2 -alkyl or C 3 -alkyl; C 1-4 -alkyl is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl or C 4 -alkyl; C 1-5 -alkyl is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl or C 5 -alkyl; C 1-6 -alkyl is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl or C 6 -alkyl; C 1-7 -alkyl is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl or C 7 -alkyl; C 1-8 -alkyl is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl, C 7 -alkyl or C 8 -alkyl; C 1-10 -alkyl is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl, C 7 -alkyl, C 8 -alkyl, C 9- Alkyl or C 10 -alkyl; C 1-18 -alkyl is C 1 -alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl, C 6 -alkyl, C 7 -alkyl, C 8 -alkyl, C 9- Alkyl, C 10 -alkyl, C 11 -alkyl, C 12 -alkyl, C 13 -alkyl, C 14 -alkyl, C 15 -alkyl, C 16 -alkyl, C 17 -alkyl or C 18 -alkyl. And C 3-4 -cycloalkyl is C 3 -cycloalkyl or C 4 -cycloalkyl; C 3-5 -cycloalkyl is C 3 -cycloalkyl, C 4 -cycloalkyl or C 5 -cycloalkyl; C 3-6 -cycloalkyl is C 3 -cycloalkyl, C 4 -cycloalkyl or C 5 -cycloalkyl or C 6 -cycloalkyl; C 3-7 -cycloalkyl is C 3 -cycloalkyl, C 4 -cycloalkyl or C 5 -cycloalkyl, C 6 -cycloalkyl, or C 7 -cycloalkyl; C 3-8 -cycloalkyl is C 3 -cycloalkyl, C 4 -cycloalkyl or C 5 -cycloalkyl, C 6 -cycloalkyl, or C 7 -cycloalkyl or C 8 -cycloalkyl; C 4-5 -cycloalkyl is C 4 -cycloalkyl or C 5 -cycloalkyl; C 4-6 -cycloalkyl is C 4 -cycloalkyl, C 5 -cycloalkyl or C 6 -cycloalkyl; C 4-7 -cycloalkyl is C 4 -cycloalkyl, C 5 -cycloalkyl, C 6 -cycloalkyl or C 7 -cycloalkyl; C 5-6 -cycloalkyl is C 5 -cycloalkyl or C 6 -cycloalkyl; C 5-7 -cycloalkyl is C 5 -cycloalkyl, C 6 -cycloalkyl or C 7 -cycloalkyl. The term "cycloalkyl" also includes saturated cycloalkyl in which one or two carbon atoms are replaced with heteroatoms, S, N or O. However, cycloalkyls also include monosaturated or polysaturated, preferably monosaturated cycloalkyls (unless the cycloalkyl is an aromatic system, there are no heteroatoms in the ring). Preferred alkyl radicals and cyclicalkyl radicals are 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, cyclo Butyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl and cyclooctyl, and also adamantyl, CHF 2 , CF 3 or CH 2 OH, as well as pyrazolinone oxopyrazolinone, [1,4] Dioxane or dioxane. [40] Unless defined otherwise, in the context of the present invention with respect to alkyl and cycloalkyl, the term “substituted” means at least one (or optionally several) by F, Cl, Br, I, NH 2 , SH or OH. As understood by substitution of hydrogen radical (s), and in the case of polysubstitution, the terms "polysubstituted" or "substituted" are understood to mean being different and substituted several times with different or the same substituents at the same atom, eg For example, CF 3 is substituted three times at the same C atom or at —C (OH) —CH═CH—CHCl 2 at different C atom positions. Particularly preferred substituents herein are F, Cl and OH. For cycloalkyls, the hydrogen radical is also OC 1-3 -alkyl or C 1-3 -alkyl (in each case mono- or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl, i- Propyl, CF 3 , methoxy or ethoxy. [41] (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- ; (CH 2 ) 1-4 are —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, and —CH 2 —CH 2 —CH 2 —CH 2 —; (CH 2 ) 4-5 is understood as meaning -CH 2 -CH 2 -CH 2 -CH 2 -and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2- . [42] Aryl radicals are understood to be ring systems that contain at least one aromatic ring, but do not contain heteroatoms in only one ring of the rings. Examples of aryl radicals are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which are unsubstituted or mono- or polysubstituted. [43] Heteroaryl radicals are understood to be heterocyclic ring systems that include at least one unsaturated ring that contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur and may be mono- or polysubstituted. . Examples of heteroaryl radicals, which may be mentioned from heteroaryl groups, are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2 , 5-thiadiazole, benzothiadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline. [44] In this category relating to aryl and heteroaryl, “substituted” is defined by R 23 , OR 23 and halogen, preferably F and / or Cl, CF 3 , CN, NO 2 , NR 24 R 25 , C 1- Understood as the substitution of aryl or heteroaryl by 6 -alkyl (saturated), C 1-6 -alkoxy, C 3-8 -cycloalkoxy, C 3-8 -cycloalkyl or C 2-6 -alkylene , [45] Wherein the R 23 radical is H or C 1-10 -alkyl, preferably an C 1-6 -alkyl, aryl or heteroaryl radical or an aryl or heteroaryl radical bonded by a C 1-3 -allylene group ( Wherein these aryl or heteroaryl radicals may not be substituted by themselves by aryl or heteroaryl radicals), [46] R 24 and R 25 radicals are the same or different and are H or C 1-10 -alkyl, preferably bonded by a C 1-6 -alkyl, aryl or heteroaryl radical or C 1-3 -allylene group Aryl or heteroaryl radicals, wherein these aryl or heteroaryl radicals cannot be substituted by themselves by aryl or heteroaryl radicals, or [47] R 24 and R 25 radicals together are CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 26 CH 2 CH 2 or (CH 2 ) 3-6 , [48] The R 26 radical is H or C 1-10 -alkyl, preferably an aryl or heteroaryl radical bonded by a C 1-6 -alkyl, aryl or heteroaryl radical or a C 1-3 -allyylene group, wherein These aryl or heteroaryl radicals may not be substituted by themselves by aryl or heteroaryl radicals). [49] The term "salt" in the context of the present invention is understood in the sense of any form of the active compound according to the invention, which is in ionic form or charged, combined with a counterion (cation or anion) or present in solution. The term is also understood to mean complexes of other molecules and ions with active compounds, in particular complexes by ionic interactions. [50] The term "physiologically acceptable salts (particularly with cations or bases)" in the scope of the present invention is generally an (unprotonated) acid, preferably at least, especially when used in humans and / or mammals. It is understood in the sense of a salt of at least one compound according to the invention as a physiologically acceptable anion with one inorganic cation. Particularly preferred salts are alkali metals and alkaline earth metals, in particular monosodium salts, disodium salts, monopotassium salts, dipotassium salts, magnesium salts or calcium salts. [51] Also within the scope of the present invention the term "physiologically acceptable salts (particularly with anions or acids)" is generally protonated (eg nitrogen), at least when used in humans and / or mammals, at least It is understood in the sense of a salt of at least one compound according to the invention as a physiologically acceptable cation with one anion. In particular within the scope of the present invention the salts are understood in the sense of salts of specially active compounds with physiologically acceptable acids or salts formed with physiologically acceptable acids, especially when used in humans and / or mammals. do. Examples of physiologically acceptable salts of particular acids include hydrochloride, hydrobromide, sulfate, methanesulfonate, formate, acetate, oxalate, succinate, malate, tartarate, mandelate, fumarate, lactate, Citrate, glutamate, 1,1-dioxo-1,2-dihydro 1b6-benzo [d] isotriazole-3-one salt (saccharate), monomethyl sebacate, 5-oxo-proline salt, hexane -1-sulfonate, nicotinate, 2-aminobenzoate, 3-aminobenzoate, 4-aminobenzoate, 2,4,6-trimethyl-benzoate, α-riponate, acetylglycine salt, acetylsalicylate Hypofurite and / or aspartate. Hydrochloride is particularly preferred. [52] In the scope of the present invention, suitable salts for each use described and for each drug described are those of particular active compounds with inorganic or organic acids and / or sugar substituents such as saccharin, cyclate or acesulfame. Salt. Hydrochloric acid is however particularly preferred. [53] Compounds of group (c) and methods for their preparation are known from WO 44 26 245 A1 and US Pat. No. 6,248,737. Compounds of group (d) and methods for their preparation are known from German Patent Publication Nos. 195 25 137 A1, US Pat. Nos. 5,733,936 and RE37355E. [54] In a preferred embodiment, the compounds of group A for use according to the invention comprise tramadol, (+)-tramadol, (+)-O-demethyltramadol and (+)-O-demethyl-N- in the (a) group. From mono-demethyl-tramadol, preferably from tramadol and (+)-tramadol, particularly preferably from tramadol. [55] In a preferred embodiment, the compounds of group A for use according to the invention comprise in the group (b) codeine, dextrosepropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphine, fentidine (meth) Ferridine), tilidine, biminol, butropanol, dezosin, nalopin, pentazosin and buprenopine, preferably codeine, dextrosepropoxyphene, dihydrocodeine, meptazinol, nalbuphine, tili Dine and buprenopine. [56] In a preferred embodiment, the compounds of group A for use according to the invention are selected from [57] X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F, OC (O) CH 3 and H, and / or [58] R 1 is saturated or unsaturated, branched or unbranched C 1-4 -alkyl, preferably CH 3 , C 2 H 5 , C 4 H 9 and tert-butyl, in particular CH 3 and C 2 H 5 Selected from [59] R 2 and R 3 , in each case, independently of each other H or saturated or unsaturated, branched or unbranched C 1-4 -alkyl, preferably H, CH 3 , C 2 H 5 , i-propyl And tert-butyl, in particular H and CH 3 , preferably R 3 is H, [60] R 2 and R 3 together form a saturated, unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted C 5-6 -cycloalkyl radical, in particular cyclohexyl, [61] R 9 to R 13 should be H, Cl, F, OH, CF 2 H, CF 3 or unsaturated or branched, with each occurrence of 3 or 4 of R 9 to R 13 independently of each other; Or unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably Or selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, [62] In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H while the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably Is selected from OH, CF 2 H, OCH 3 and SCH 3 , or [63] If R 9 and R 13 are H and R 11 corresponds to OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is also H and the remaining radicals are OH, OCH 3 , Cl or F , Preferably Cl, [64] When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or [65] When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H and the remaining radicals are selected from compounds according to formula I, selected from OH, OC 2 H 5 and OC 3 H 7 . [66] In this category, compounds of formula (I) in which R 3 is H are in the form of diastereoisomers having the relative arrangement of formula (Ia), in particular used as mixtures in which the content of such diastereomers is higher than the content of other diastereomers, Used as pure diastereomers and / or [67] Compounds of formula (I) are used in the form of (+)-enantiomers, in particular as mixtures of racemic compounds with a higher content of (+)-enantiomers than (-)-enantiomers, or pure (+)-enan Particular preference is given to compounds of group (c) which are used as thiomers. [68] [69] In this category, [70] (2RS, 3RS) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, [71] (2R, 3R) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, [72] (+)-(2R, 3R) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, [73] (2RS, 3RS) -3- (3,4-Dichlorophenyl) -l-dimethylamino-2-methyl-pentan-3-ol, [74] (2RS, 3RS) -3- (3-Difluoromethyl-phenyl) -1-dimethylamino-2-methyl-pentan-3-ol, [75] (2RS, 3RS) -1-Dimethylamino-2-methyl-3- (3-methylsulfanyl-phenyl) -pentan-3-ol, [76] (3RS) -1-Dimethylamino-3- (3-methoxy-phenyl) -4,4-dimethyl-pentan-3-ol, [77] (2RS, 3RS) -3- (3-Dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl) -phenol, [78] (1RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl) -phenol, [79] (+)-(1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl) -phenol, [80] (+)-(1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl) -phenol, [81] (1R, 2R) -3- (3-Dimethylamino-1-ethyl-2-methyl-propyl) -phenol, [82] (-)-(1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, [83] (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, [84] (+)-(1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, [85] (+)-(1R, 2R) -Acetic acid 3-dimethylamino-1-ethyl-1- (3-methoxy-phenyl) -2-methyl-propyl ester, [86] (1RS) -1- (1-dimethylaminomethyl-cyclohexyl) -1- (3-methoxy-phenyl) -propan-1-ol, [87] (2RS, 3RS) -3- (4-Chlorophenyl) -1-dimethylamino-2-methyl-pentan-3-ol, [88] (+)-(2R, 3R) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl) -phenol, [89] (2RS, 3RS) -4-Dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol and [90] The compound of Group A selected from (+)-(2R, 3R) -4-dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol, preferably their hydrochlorides Particular preference is given to use. [91] In a preferred embodiment, the compounds of group A for use according to the invention are selected from [92] X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F and H, and / or in particular OH, [93] R 1 is selected from C 1-4 -alkyl, CF 3 , OH, OC 1-4 -alkyl, Cl and F, preferably OH, CF 3 , and CH 3 , [94] R 9 to R 13 should be H, Cl, F, OH, CF 2 H, CF 3 or unsaturated or branched, with each occurrence of 3 or 4 of R 9 to R 13 independently of each other; Or unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably Or selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, [95] In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH, CF 2 H, OR 14 and SCH 3 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 , or [96] When R 9 and R 13 are H and R 11 is OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is also H and the remaining radicals are OH, OCH 3 , Cl or F, preferably Is Cl, [97] When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or [98] When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H, or the remaining radicals are selected from OH, OC 2 H 5 and OC 3 H 7 , [99] Very particularly preferably, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH and OR 14 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 , selected from compounds according to formula II, selected from compounds according to formula II. [100] In this category, the compounds of formula (II) are in the form of diastereoisomers having the relative arrangement of formula (IIa), in particular used as mixtures in which the content of said diastereomers is higher than the content of other diastereomers, or as pure diastereomers. Used and / or [101] Compounds of formula (II) are used in the form of (+)-enantiomers, in particular as mixtures of racemic compounds in which the content of (+)-enantiomers is higher than the content of (-)-enantiomers, or pure (+) Particular preference is given to compounds of group (c) which are used as enantiomers. [102] [103] In this category, [104] (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, [105] (+)-(1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, [106] (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxy-phenyl) -cyclohexane-1,3-diol, [107] (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, [108] (+)-(1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl) -phenol and [109] (1RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl) -phenol, preferably a compound of group A selected from their hydrochlorides Is particularly preferred. [110] In a preferred embodiment, the compounds of group A for use according to the invention are selected from the group (e) [111] X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F and H, in particular F and H, [112] R 9 to R 13 are independently branched from each other, in each case H, Cl, F, OH, CF 2 H, CF 3 or saturated or unbranched, while three or four of R 9 to R 13 must be H; Unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably H , Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, [113] In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH, CF 2 H, OR 14 and SCH 3 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 , or [114] When R 9 and R 13 are H and R 11 is OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is H and the other radicals are OH, OCH 3 , Cl or F, Preferably Cl, [115] When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or [116] When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H, and the remaining radicals are selected from OH, OC 2 H 5 and OC 3 H 7 , [117] Very particularly preferably when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH and OR 14 , in particular OH and OC 1-3 -alkyl, preferably from compounds according to formula III, selected from compounds according to formula III, selected from OH and OCH 3 . [118] In this category, the compounds of formula III are in the form of diastereoisomers having the relative arrangement of formula IIIa and are used as mixtures in which the content of such diastereomers is higher than the content of other diastereomers, or as pure diastereomers. / Or [119] Compounds of formula III are used in the form of (+)-enantiomers, in particular as mixtures of racemic compounds in which the content of (+)-enantiomers is higher than the content of (-)-enantiomers, or pure (+) Particular preference is given to compounds of group (c) which are used as enantiomers. [120] [121] In this category, [122] (+)-(1R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) -phenol, [123] (+)-(1S, 2S) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol or [124] (1S, 2S) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol or [125] (-)-(1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol, [126] (1R, 2R) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol, [127] (-)-(1R, 2R)-[2- (3-methoxy-phenyl) -cyclohexylmethyl] -dimethylamine and [128] Particular preference is given to the use of compounds of group A selected from (1R, 2R)-[2- (3-methoxy-phenyl) -cyclohexylmethyl] -dimethylamine, preferably their hydrochlorides. [129] For a particularly preferred use, group B is selected from darfenacin, dulocetin, oxybutynin and tolterodine, preferably from dulocetin, oxybutynin and tolterodine, preferably oxybutynin and tolte Selected from rodin. [130] Although the use according to the invention shows only low levels of side effects, for example, in addition to the combination of compounds of group A and compounds of group B, morphine antagonists, in particular naloxone, naltrexone and / or levalophane It may also be advantageous to prevent certain forms of addiction to the use of. [131] The invention also provides active compound combinations of at least one group A compound with at least one group B compound. [132] The compound of group A is selected from groups (a) to (e), [133] Group (a) may comprise tramadol, O-demethyltramadol or O-demethyl-N-mono-demethyl-tramadol, optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers). ) Or in the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) and any of their acid or base forms or salts thereof (particularly physiologically acceptable salts) in any desired mixing ratio, Or in the form of solvates (particularly hydrates) thereof, [134] Group (b) is codeine, dextrosepropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphine, pentidine (meperidine), tilidine, tramadol, biminol, butorpanol, Dextromoramide, dezosin, diacetylmorphine (heroin), hydrocodone, hydromorphone, ketobemidone, levometadon, levomethadyl acetate [1-α-acetylmethol (LAAM)], levorpanol, Morphine, nalopine, oxycodone, pentazosin, pyritramide, alfentanil, buprenopine, etopin, fentanyl, remifentanil or serfentanil, optionally in their racemic form, their pure stereoisomers (especially enan Thiomers or diastereomers) or mixtures of stereoisomers (especially enantiomers or diastereomers) in any desired mixing ratio and in the form of their acids or bases or salts thereof (especially physiological Huh Salts), or in the form thereof, [135] Group (c) may optionally contain the 1-phenyl-3-dimethylamino-propane compounds of formula I in their racemic form, their pure stereoisomers (in particular enantiomers or diastereomers) or any desired mixtures. In the form of mixtures of ratio stereoisomers (especially enantiomers or diastereomers) and their acid or base forms or salts thereof (especially physiologically acceptable salts), or solvates thereof In the form of (carb), [136] Group (d) may be selected from the 6-dimethylaminomethyl-1-phenylcyclohexane compounds of formula (II), optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers) or any desired In the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) in mixed ratios and in the form of their acids or bases or salts thereof (particularly physiologically acceptable salts), or solvates thereof ( Particularly, in the form of hydrates), [137] (e) the group may contain the 6-dimethylaminomethyl-1-phenyl-cyclohexane compound of formula III, optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers) or any desired In the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) and acids or bases thereof or salts thereof (particularly physiologically acceptable salts), or solvates thereof (Especially in the form of hydrates), [138] The at least one group B compound is an antimuscarinic agent such as atropine, oxybutynin, propiberine, propanetellin, emepronium, trophypichet, tolterodine, darfenacin and α, α-diphenylacetic acid As well as 4- (N-methylpiperidyl) esters, as well as dulocetin, imipramine and desmopressin, which are optionally in their racemic form, their pure stereoisomers (especially enantiomers or Diastereomers) or mixtures of stereoisomers (especially enantiomers or diastereomers) in any desired mixing ratio, and their acid or base forms or salts thereof (especially physiologically acceptable) Salt) or solvates (particularly hydrates) thereof. [139] Formula I [140] [141] In Formula I above, [142] X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), [143] R 1 is selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-4 -alkyl, [144] R 2 and R 3 , at each occurrence, are independently selected from H, or branched or unbranched, saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted C 1-4 -alkyl, [145] R 2 and R 3 together form an unsubstituted, mono- or polysubstituted saturated C 4-7 -cycloalkyl radical, [146] R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, [147] R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring. [148] Formula II [149] [150] In Formula II above, [151] X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), [152] R 1 is selected from C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 -C 6 H 5 , OC 1-4 -alkyl, Cl and F, [153] R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, [154] R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring. [155] Formula III [156] [157] In Formula III above, [158] X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), [159] R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, [160] R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) forms a 4 or OCH = CHO ring, provided that R 9 , R 11 and R 13 correspond to H, one of R 10 and R 12 corresponds to H and the remaining groups correspond to OCH 3 , X cannot be OH. [161] In the active compound combinations, the compounds of group A in the group (a) are treated with tramadol, (+)-tramadol, (+)-O-demethyltramadol and (+)-O-demethyl-N-mono-demethyl- Particularly preferred is the case from tramadol, preferably from tramadol and (+)-tramadol, particularly preferably from tramadol. [162] In the active compound combinations, the compounds of group A are selected from the group (b): codeine, dextropropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphine, pentidine (meperidine), tilly Dean, Biminol, Butropanol, Dezosin, Nalopin, Pentazosin and Buprenopine, preferably Codeine, Dextrosepropoxyphene, Dihydrocodeine, Cetazinol, Nalbuphine, Tilidine and Buprenopine Particularly preferred is the case selected from. [163] In the active compound combinations, the compound of group A is selected from group (c) [164] X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F, OC (O) CH 3 and H, and / or [165] R 1 is saturated or unsaturated, branched or unbranched C 1-4 -alkyl, preferably CH 3 , C 2 H 5 , C 4 H 9 and tert-butyl, in particular CH 3 and C 2 H 5 Selected from [166] R 2 and R 3 , in each case, independently of each other H or saturated or unsaturated, branched or unbranched C 1-4 -alkyl, preferably H, CH 3 , C 2 H 5 , i-propyl And tert-butyl, in particular H and CH 3 , preferably R 3 = H, [167] R 2 and R 3 together form a saturated, unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted C 5-6 -cycloalkyl radical, in particular cyclohexyl, [168] R 9 to R 13 should be H, Cl, F, OH, CF 2 H, CF 3 or unsaturated or branched, with each occurrence of 3 or 4 of R 9 to R 13 independently of each other; Or unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably Or selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, [169] In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H while the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , preferably Is selected from OH, CF 2 H, OCH 3 and SCH 3 , or [170] If R 9 and R 13 are H and R 11 corresponds to OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is also H and the remaining radicals are OH, OCH 3 , Cl or F , Preferably Cl, [171] When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or [172] When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H and the remaining radicals are selected from compounds according to formula I, selected from OH, OC 2 H 5 and OC 3 H 7 Is particularly preferred. [173] In this category, the compounds of formula (I) in which R 3 is H are in the form of diastereoisomers having the relative arrangement of formula (Ia), in particular mixtures of which the content of the diastereomers is higher than the content of other diastereomers, or pure parts Stereoisomers and / or [174] The compound of formula (I) is a mixture of racemic compounds having a higher content of (+)-enantiomers than the (+)-enantiomer form, in particular (-)-enantiomer, or a pure (+)-enantiomer Particular preference is given to the case of compounds of group (c). [175] Formula Ia [176] [177] In this category, the compounds of group A [178] (2RS, 3RS) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, [179] (2R, 3R) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, [180] (+)-(2R, 3R) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, [181] (2RS, 3RS) -3- (3,4-Dichlorophenyl) -l-dimethylamino-2-methyl-pentan-3-ol, [182] (2RS, 3RS) -3- (3-Difluoromethyl-phenyl) -1-dimethylamino-2-methyl-pentan-3-ol, [183] (2RS, 3RS) -1-Dimethylamino-2-methyl-3- (3-methylsulfanyl-phenyl) -pentan-3-ol, [184] (3RS) -1-Dimethylamino-3- (3-methoxy-phenyl) -4,4-dimethyl-pentan-3-ol, [185] (2RS, 3RS) -3- (3-Dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl) -phenol, [186] (1RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl) -phenol, [187] (+)-(1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl) -phenol, [188] (+)-(1R, 2R) -3- (3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl) -phenol, [189] (1R, 2R) -3- (3-Dimethylamino-1-ethyl-2-methyl-propyl) -phenol, [190] (-)-(1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, [191] (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, [192] (+)-(1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, [193] (+)-(1R, 2R) -Acetic acid 3-dimethylamino-1-ethyl-1- (3-methoxy-phenyl) -2-methyl-propyl ester, [194] (1RS) -1- (1-dimethylaminomethyl-cyclohexyl) -1- (3-methoxy-phenyl) -propan-1-ol, [195] (2RS, 3RS) -3- (4-Chlorophenyl) -1-dimethylamino-2-methyl-pentan-3-ol, [196] (+)-(2R, 3R) -3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl) -phenol, [197] (2RS, 3RS) -4-Dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol and [198] A compound of group A is selected from (+)-(2R, 3R) -4-dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol, preferably their hydrochlorides Is particularly preferred. [199] In the active compound combinations, the compound of group A is selected from group (d) [200] X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F and H, and / or in particular OH, [201] R 1 is selected from C 1-4 -alkyl, CF 3 , OH, OC 1-4 -alkyl, Cl and F, preferably OH, CF 3 , and CH 3 , [202] R 9 to R 13 should be H, Cl, F, OH, CF 2 H, CF 3 or unsaturated or branched, with each occurrence of 3 or 4 of R 9 to R 13 independently of each other; Or unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably Or selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, [203] In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH, CF 2 H, OR 14 and SCH 3 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 , or [204] When R 9 and R 13 are H and R 11 is OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is also H and the remaining radicals are OH, OCH 3 , Cl or F, preferably Is Cl, [205] When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or [206] When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H, or the remaining radicals are selected from OH, OC 2 H 5 and OC 3 H 7 , [207] Very particularly preferably, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH and OR 14 , in particular OH and OC 1-3 -alkyl, preferably selected from compounds according to formula II, selected from compounds according to formula II, selected from OH and OCH 3 Is particularly preferred. [208] In this category, the compounds of formula (II) are in the form of diastereoisomers having the relative arrangement of formula (IIa), in particular mixtures of which the content of such diastereomers are higher than the contents of other diastereomers, or pure diastereomers , [209] The compound of formula (II) is a mixture of racemic compounds in which the content of (+)-enantiomers, in particular (+)-enantiomers, is higher than that of (-)-enantiomers, or pure (+)-enantithio It is especially preferable when it is a compound of main group (C). [210] Formula IIa [211] [212] In this category, the compounds of group A [213] (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, [214] (+)-(1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, [215] (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxy-phenyl) -cyclohexane-1,3-diol, [216] (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, [217] (+)-(1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl) -phenol and [218] A compound of Group A is selected from (1RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl) -phenol, preferably their hydrochlorides The case is particularly preferred. [219] In the active compound combinations, the compound of group A is selected from group (e) [220] X is selected from OH, F, Cl, OC (O) CH 3 or H, preferably OH, F or H, in particular F or H, [221] If 3 or 4 radicals of R 9 to R 13 must correspond to H, then R 9 to R 13 are each independently of each other H, Cl, F, OH, CF 2 H, CF 3 or not saturated or saturated. , Branched or unbranched C 1-4 -alkyl, OR 14 or SR 14 , wherein R 14 is selected from saturated or unsaturated, branched or unbranched C 1-3 -alkyl, and is preferred. Preferably selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 or SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, [222] In particular, when R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H and the other radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , preferably OH, CF 2 H, OCH 3 or SCH 3 , in particular OH or OC 1-3 -alkyl, preferably OH or OCH 3 , or [223] If R 9 and R 13 correspond to H and R 11 corresponds to OH, CH 3 , Cl or F, preferably Cl, one of R 10 or R 12 also corresponds to H and the other radicals are OH, OCH 3 , Cl or F, preferably corresponds to Cl, [224] 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 [225] When R 10 , R 11 and R 12 correspond to H, one of R 9 or R 13 also corresponds to H, the other radical is selected from OH, OC 2 H 5 or OC 3 H 7 , [226] Very particularly preferably, if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H and the other radicals are Cl, F, OH, SH, CF 2 H, CF Preference is given to being selected from compounds according to formula III, which is selected from 3 , OR 14 or SR 14 , preferably OH or OR 14 , in particular OH or OC 1-3 -alkyl, preferably OH or OCH 3 . [227] In this category, the compound of formula III is in the form of a diastereomer having the relative arrangement of formula IIIa, in particular a mixture of said diastereomers having a higher content than other diastereomers, or a pure diastereomer , [228] The compound of formula III is a mixture of racemic compounds in which the content of (+)-enantiomers, in particular (+)-enantiomers, is higher than the content of (-)-enantiomers, or pure (+)-enantithio It is especially preferable when it is a compound of main group (c). [229] Formula IIIa [230] [231] In this category, the compounds of group A [232] (+)-(1R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) -phenol, [233] (+)-(1S, 2S) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol or [234] (1S, 2S) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol or [235] (-)-(1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol, [236] (1R, 2R) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol, [237] (-)-(1R, 2R)-[2- (3-methoxy-phenyl) -cyclohexylmethyl] -dimethylamine and [238] Particular preference is given to the case where compounds of group A are selected from (1R, 2R)-[2- (3-methoxy-phenyl) -cyclohexylmethyl] -dimethylamine, preferably their hydrochlorides. [239] In a particularly preferred form of the active compound combination according to the invention, group B is selected from darfenacecin, dulocetin, oxybutynin and tolterodine, preferably from dulocetin, oxybutynin and tolterodine And preferably from oxybutynin and tolterodine. [240] The invention also provides a medicament for the treatment of urinary or incontinence, preferably of increased urgency, comprising the active compound combination according to the invention and optionally suitable additive and / or adjuvant materials. [241] Suitable additive and / or adjuvant materials in the scope of the present invention are all materials for obtaining pharmaceutical formulations, known to those skilled in the art. The choice of these adjuvants and the amount of adjuvant administered depend on the mode of administration of the medicament (ie oral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, intraoral or topical). . Formulations in the form of tablets, chewable tablets, coated tablets, capsules, granules, drops, juices or syrups are suitable for oral administration and parenteral administration in liquid, suspension form, dry, easy to reconstitute formulations and sprays. Suitable for topical and aspiration administration. Suppositories may also be used for rectal administration. Use in a carrier film or patch in a dissolving form depot, optionally with the addition of agents that promote skin penetration, is an example of a suitable transdermal dosage form. Examples of auxiliaries and additives for oral administration are disintegrants, lubricants, binders, fillers and mold release agents including solvents, flavoring agents, sugars, in particular carriers, diluents, colorants, antioxidants and the like. In particular, waxes or fatty acid esters may be used for suppositories, and compositions for parenteral administration may include carriers, preservatives and suspension aids. The amount of active compound administered to a patient varies depending on the weight of the patient, the method of administration and the severity of the disease. The compounds according to the invention can be used in the form of sustained release formulations for oral, rectal or parenteral administration. In the instructions according to the invention, particular preference is given to sustained release formulations, in particular in the form of "once daily" formulations which are taken only once daily. [242] In order to prevent side effects or analgesic effects, agents are also preferred which comprise a dosage of the active compound having at least 0.05 to 90.0%, especially low activity. At least one compound of formula (I) is usually administered from 0.1 to 5,000 mg, in particular from 1 to 500 mg, preferably from 2 to 250 mg per kg of body weight. However, it is also preferred and common to administer from 0.01 to 5 mg, preferably from 0.03 to 2 mg, in particular from 0.05 to 1 mg per kg of body weight. [243] Auxiliary materials include, for example, water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified Starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffin, wax, natural rubber, synthetic rubber, gum arabic, know Nates, dextran, saturated fatty acids, unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, cooking oil, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, Polyoxyethylene fatty acid ester, polyoxypropylene fatty acid ester, sorbitan fatty acid ester , 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, caustic potassium, phosphoric acid Calcium, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidone, agar and bentonite. [244] Pharmaceuticals and pharmaceutical compositions according to the present invention are prepared using agents, devices, methods and procedures well known in the art in the pharmaceutical formulation. See, "Remington's Pharmaceutical Sciences", ed. A. R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), part 8, chapters 76-93. [245] Thus, for example, in solid dosage forms such as tablets, the active compound of the medicament may be a pharmaceutical carrier, e.g., a conventional tablet component (e.g., starch, lactose, sucrose, sorbitol, talc, magnesium stearate, phosphoric acid). Granules with dicalcium or a pharmaceutically acceptable gum) and a pharmaceutical diluent (such as water) to form a solid composition comprising the homogeneous distribution of the active compounds. As used herein, "homogeneous distribution" is understood to mean that the active compound can be easily divided into unit dosage forms (e.g. tablets, pills or capsules) with the same action, since the active compounds are uniformly distributed over the entire composition. do. The solid composition is therefore divided into unit dosage forms. Tablets or pills of a medicament according to the invention or tablets or pills of a composition according to the invention may also be coated or adjuvted in another way to provide a sustained release dosage form. Suitable coating compositions are in particular mixtures of polymeric acids and polymeric acids comprising substances such as shellac, cetyl alcohol and / or cellulose acetate. [246] Although the agents according to the invention show only low levels of side effects, for example, in addition to the combination of the compounds of group A and the compounds of group B, morphine antagonists, in particular naloxone, naltrexone and / or levallo It may also be advantageous to prevent certain forms of addiction to the use of the plates. [247] The present invention also relates to a method for treating urinary incontinence or urinary incontinence, in which an active compound combination of a compound of group A and a compound of group B is used in a therapeutically active dosage, in particular (in each case). It is about. [248] The following examples are intended to illustrate the invention without limiting the invention. [249] Example 1 Bladder Endometry Test System for Undosed Anesthesia Rats [250] Bladder pressure studies on female rats that were not tested in animals were performed by literature methods. Kimura et al., (1996), Int. J. Urol. 3: 218-227. The anesthetized and oxygenated rat is opened and the ureter is ligated. Urine is excreted from the kidneys. Insert the catheter into the bladder and fix it. Until the bladder exhibits regular spontaneous activity, a brine is injected into the bladder in a concentration form that can be recorded through a conduit by a infusion pump and through a pressure transducer in contact. After reaching a stable starting value, the test substance is administered intravenously. The effect on bladder function has been demonstrated through the suppression of spontaneous contractions. [251] In this example, compounds of Group A [(+)-(2R, 3R) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol; Hydrochloric acid] 0.1 mg / kg (intravenous) is combined with 0.03 mg / kg (intravenous) of a compound of group B (oxybutynin) and the action of the combination is compared with the action of each of the substances. Each material and combination thereof inhibited the rate of contraction (urination / min). The data is summarized in the following table. [252] matterCompounds of group A 0.1 mg / kg intravenously0.3 mg / kg intravenous compound of group BCompounds in Group A 0.1 mg / kg Intravenous + Group B Compounds in 0.3 mg / kg IntravenousVehicle control vein Suppression of shrinkage rate compared to preliminary test [% MPE]21.7%10.7%42.5%40.% [253] Inhibition of spontaneous contraction on rats could be observed in all materials and combinations reported herein. [254] The combination of substances studied showed a positive effect on the bladder and is therefore suitable for the treatment of urinary incontinence. [255] Example 2: Parenteral Dosage Forms [256] 20 g of tramadol and 1 g of tolterodine are dissolved in 1 l of water for injection at room temperature, and then the solution is adjusted to isotonic state by adding NaCl.
权利要求:
Claims (27) [1" claim-type="Currently amended] As an active compound combination of at least one compound of Group A with at least one compound of Group B, The compound of group A is selected from groups (a) to (e), Group (a) may comprise tramadol, O-demethyltramadol or O-demethyl-N-mono-demethyl-tramadol, optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers). ) Or in the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) and any of their acid or base forms or salts thereof (particularly physiologically acceptable salts) in any desired mixing ratio, Or in the form of solvates (particularly hydrates) thereof, Group (b) is codeine, dextrosepropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphine, pentidine (meperidine), tilidine, tramadol, biminol, butorpanol, Dextromoramide, dezosin, diacetylmorphine (heroin), hydrocodone, hydromorphone, ketobemidone, levometadon, levomethadyl acetate [1-α-acetylmethol (LAAM)], levorpanol, Morphine, nalopine, oxycodone, pentazosin, pyritramide, alfentanil, buprenopine, etopin, fentanyl, remifentanil or serfentanil, optionally in their racemic form, their pure stereoisomers (especially enan Thiomers or diastereomers) or mixtures of stereoisomers (especially enantiomers or diastereomers) in any desired mixing ratio and acids or bases thereof or salts thereof (especially physiologically) Allowed Salt) or solvates (particularly hydrates) thereof, Group (c) may optionally contain the 1-phenyl-3-dimethylamino-propane compounds of formula I in their racemic form, their pure stereoisomers (in particular enantiomers or diastereomers) or any desired mixtures. In the form of mixtures of ratio stereoisomers (especially enantiomers or diastereomers) and their acid or base forms or salts thereof (especially physiologically acceptable salts), or solvates thereof In the form of (carb), Group (d) may be selected from the 6-dimethylaminomethyl-1-phenylcyclohexane compounds of formula (II), optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers) or any desired In the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) in mixed ratios and in the form of their acids or bases or salts thereof (particularly physiologically acceptable salts), or solvates thereof ( Particularly, in the form of hydrates), (e) the group may contain the 6-dimethylaminomethyl-1-phenyl-cyclohexane compound of formula III, optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers) or any desired In the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) and acids or bases thereof or salts thereof (particularly physiologically acceptable salts), or solvates thereof (Especially in the form of hydrates), The at least one group B compound is an antimuscarinic agent such as atropine, oxybutynin, propiberine, propanetellin, emepronium, trophypichet, tolterodine, darfenacin and α, α-diphenylacetic acid As well as 4- (N-methylpiperidyl) esters, as well as dulocetin, imipramine and desmopressin, which are optionally in their racemic form, their pure stereoisomers (especially enantiomers or Diastereomers) or mixtures of stereoisomers (especially enantiomers or diastereomers) in any desired mixing ratio, and their acid or base forms or salts thereof (especially physiologically acceptable) Use of active compound combinations, including salts), or in the form of solvates (particularly hydrates) thereof, to prepare drugs for the treatment of an increased urge to urinate or urinary incontinence The purpose. Formula I In Formula I above, X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), R 1 is selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-4 -alkyl, R 2 and R 3 , at each occurrence, are independently selected from H, or branched or unbranched, saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted C 1-4 -alkyl, R 2 and R 3 together form an unsubstituted, mono- or polysubstituted saturated C 4-7 -cycloalkyl radical, R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring. Formula II In Formula II above, X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), R 1 is selected from C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 -C 6 H 5 , OC 1-4 -alkyl, Cl and F, R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring. Formula III In Formula III above, X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) forms a 4 or OCH = CHO ring, provided that R 9 , R 11 and R 13 correspond to H, one of R 10 and R 12 corresponds to H and the remaining groups correspond to OCH 3 , X cannot be OH. [2" claim-type="Currently amended] The compound of claim 1 wherein the compound of Group A is in the group (a) a tramadol, (+)-tramadol, (+)-O-demethyltramadol and (+)-O-demethyl-N-mono-demethyl- Use from tramadol, preferably from tramadol and (+)-tramadol, particularly preferably from tramadol. [3" claim-type="Currently amended] The compound of claim 1, wherein the compound of Group A is selected from group (b) for codeine, dextrosepropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphine, pentidine (meperidine), tilly From Dean, Biminol, Butropanol, Dezosin, Nalopin, Pentazosin and Buprenopine, preferably Codeine, Dextrosepropoxyphene, Dihydrocodeine, Cetazinol, Nalbuphine, Tilidine and Buprenopine Use, characterized in that selected from. [4" claim-type="Currently amended] The compound of claim 1, wherein the compound of group A is in group (c), X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F, OC (O) CH 3 and H, and / or R 1 is saturated or unsaturated, branched or unbranched C 1-4 -alkyl, preferably CH 3 , C 2 H 5 , C 4 H 9 and tert-butyl, in particular CH 3 and C 2 H 5 Selected from R 2 and R 3 , in each case, independently of each other H or saturated or unsaturated, branched or unbranched C 1-4 -alkyl, preferably H, CH 3 , C 2 H 5 , i-propyl And tert-butyl, in particular H and CH 3 , preferably R 3 is H, R 2 and R 3 together form a saturated, unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted C 5-6 -cycloalkyl radical, in particular cyclohexyl, R 9 to R 13 should be H, Cl, F, OH, CF 2 H, CF 3 or unsaturated or branched, with each occurrence of 3 or 4 of R 9 to R 13 independently of each other; Or unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably Or selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H while the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably Is selected from OH, CF 2 H, OCH 3 and SCH 3 , or If R 9 and R 13 are H and R 11 corresponds to OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is also H and the remaining radicals are OH, OCH 3 , Cl or F , Preferably Cl, When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H and the remaining radicals are selected from compounds according to formula I, selected from OH, OC 2 H 5 and OC 3 H 7 . Use. [5" claim-type="Currently amended] The compound of formula (I) according to claim 4, wherein the compound of formula (I) in which R 3 is H is in the form of diastereoisomers having a relative arrangement of formula (Ia), in particular used as a mixture wherein the content of such diastereomers is higher than the content of other diastereomers Used as pure diastereomers, and / or Compounds of formula (I) are used in the form of (+)-enantiomers, in particular as mixtures of racemic compounds with a higher content of (+)-enantiomers than (-)-enantiomers, or pure (+)-enan Use as a thiomer. Formula Ia [6" claim-type="Currently amended] The method according to claim 4 or 5, (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, (+)-(2R, 3R) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, (2RS, 3RS) -3- (3,4-Dichlorophenyl) -l-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-methylsulfanyl-phenyl) -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) -phenol, (-)-(1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (+)-(1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (+)-(1R, 2R) -Acetic acid 3-dimethylamino-1-ethyl-1- (3-methoxy-phenyl) -2-methyl-propyl ester, (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 and The compound of Group A selected from (+)-(2R, 3R) -4-dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol, preferably their hydrochlorides Use characterized by being used. [7" claim-type="Currently amended] The compound of claim 1, wherein the compound of group A is in group (d), X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F and H, and / or in particular OH, R 1 is selected from C 1-4 -alkyl, CF 3 , OH, OC 1-4 -alkyl, Cl and F, preferably OH, CF 3 , and CH 3 , R 9 to R 13 should be H, Cl, F, OH, CF 2 H, CF 3 or unsaturated or branched, with each occurrence of 3 or 4 of R 9 to R 13 independently of each other; Or unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably Or selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH, CF 2 H, OR 14 and SCH 3 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 , or When R 9 and R 13 are H and R 11 is OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is also H and the remaining radicals are OH, OCH 3 , Cl or F, preferably Is Cl, When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H, or the remaining radicals are selected from OH, OC 2 H 5 and OC 3 H 7 , Very particularly preferably, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH and OR 14 , in particular OH and OC 1-3 -alkyl, preferably selected from compounds according to formula II, selected from OH and OCH 3 . [8" claim-type="Currently amended] 8. The compound according to claim 7, wherein the compound of formula (II) is in the form of diastereoisomers having the relative arrangement of formula (IIa), in particular used as a mixture in which the content of the diastereomer is higher than the content of other diastereomers, or the pure diastereomer Used as and / or as Compounds of formula (II) are used in the form of (+)-enantiomers, in particular as mixtures of racemic compounds in which the content of (+)-enantiomers is higher than the content of (-)-enantiomers, or pure (+) Use as an enantiomer. Formula IIa [9" claim-type="Currently amended] The method according to claim 7 or 8, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, (+)-(1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxy-phenyl) -cyclohexane-1,3-diol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, (+)-(1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl) -phenol and Compounds of group A selected from (1RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl) -phenol, preferably their hydrochlorides are used Use characterized by. [10" claim-type="Currently amended] The compound of claim 1, wherein the compound of Group A is X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F and H, in particular F and H, R 9 to R 13 are independently branched from each other, in each case H, Cl, F, OH, CF 2 H, CF 3 or saturated or unbranched, while three or four of R 9 to R 13 must be H; Unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably H , Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH, CF 2 H, OR 14 and SCH 3 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 , or When R 9 and R 13 are H and R 11 is OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is H and the other radicals are OH, OCH 3 , Cl or F, Preferably Cl, When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H, and the remaining radicals are selected from OH, OC 2 H 5 and OC 3 H 7 , Very particularly preferably when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH and OR 14 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 . [11" claim-type="Currently amended] A compound according to claim 10, wherein the compound of formula III is in the form of a diastereomer having a relative arrangement of formula IIIa, wherein the content of the diastereomer is used as a mixture higher than the content of the other diastereomers, or as a pure diastereomer. Used and / or Compounds of formula III are used in the form of (+)-enantiomers, in particular as mixtures of racemic compounds in which the content of (+)-enantiomers is higher than the content of (-)-enantiomers, or pure (+) Use as an enantiomer. Formula IIIa [12" claim-type="Currently amended] The method according to claim 10 or 11, wherein (+)-(1R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) -phenol, (+)-(1S, 2S) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol or (1S, 2S) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol or (-)-(1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol, (1R, 2R) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol, (-)-(1R, 2R)-[2- (3-methoxy-phenyl) -cyclohexylmethyl] -dimethylamine and Use of a compound of group A selected from (1R, 2R)-[2- (3-methoxy-phenyl) -cyclohexylmethyl] -dimethylamine, preferably their hydrochlorides. [13" claim-type="Currently amended] The method according to any one of claims 1 to 12, wherein group B is selected from daripenacin, dulocetin, oxybutynin and tolterodine, preferably from dulocetin, oxybutynin and tolterodine, Preferably selected from oxybutynin and tolterodine. [14" claim-type="Currently amended] As an active compound combination of at least one compound of Group A with at least one compound of Group B, The compound of group A is selected from groups (a) to (e), Group (a) may comprise tramadol, O-demethyltramadol or O-demethyl-N-mono-demethyl-tramadol, optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers). ) Or in the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) and any of their acid or base forms or salts thereof (particularly physiologically acceptable salts) in any desired mixing ratio, Or in the form of solvates (particularly hydrates) thereof, Group (b) is codeine, dextrosepropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphine, pentidine (meperidine), tilidine, tramadol, biminol, butorpanol, Dextromoramide, dezosin, diacetylmorphine (heroin), hydrocodone, hydromorphone, ketobemidone, levometadon, levomethadyl acetate [1-α-acetylmethol (LAAM)], levorpanol, Morphine, nalopine, oxycodone, pentazosin, pyritramide, alfentanil, buprenopine, etopin, fentanyl, remifentanil or serfentanil, optionally in their racemic form, their pure stereoisomers (especially enan Thiomers or diastereomers) or mixtures of stereoisomers (especially enantiomers or diastereomers) in any desired mixing ratio and in the form of their acids or bases or salts thereof (especially physiological to Salts for), or comprises a form thereof, Group (c) may optionally contain the 1-phenyl-3-dimethylamino-propane compounds of formula I in their racemic form, their pure stereoisomers (in particular enantiomers or diastereomers) or any desired mixtures. In the form of mixtures of ratio stereoisomers (especially enantiomers or diastereomers) and their acid or base forms or salts thereof (especially physiologically acceptable salts), or solvates thereof In the form of (carb), Group (d) may be selected from the 6-dimethylaminomethyl-1-phenylcyclohexane compounds of formula (II), optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers) or any desired In the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) in mixed ratios and in the form of their acids or bases or salts thereof (particularly physiologically acceptable salts), or solvates thereof ( Particularly, in the form of hydrates), (e) the group may contain the 6-dimethylaminomethyl-1-phenyl-cyclohexane compound of formula III, optionally in their racemic form, their pure stereoisomers (especially enantiomers or diastereomers) or any desired In the form of a mixture of stereoisomers (particularly enantiomers or diastereomers) and acids or bases thereof or salts thereof (particularly physiologically acceptable salts), or solvates thereof (Especially in the form of hydrates), The at least one group B compound is an antimuscarinic agent such as atropine, oxybutynin, propiberine, propanetellin, emepronium, trophypichet, tolterodine, darfenacin and α, α-diphenylacetic acid As well as 4- (N-methylpiperidyl) esters, as well as dulocetin, imipramine and desmopressin, which are optionally in their racemic form, their pure stereoisomers (especially enantiomers or Diastereomers) or mixtures of stereoisomers (especially enantiomers or diastereomers) in any desired mixing ratio, and their acid or base forms or salts thereof (especially physiologically acceptable) Salt) or solvates (particularly hydrates) thereof. Formula I In Formula I above, X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), R 1 is selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-4 -alkyl, R 2 and R 3 , at each occurrence, are independently selected from H, or branched or unbranched, saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted C 1-4 -alkyl, R 2 and R 3 together form an unsubstituted, mono- or polysubstituted saturated C 4-7 -cycloalkyl radical, R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring. Formula II In Formula II above, X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), R 1 is selected from C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 -C 6 H 5 , OC 1-4 -alkyl, Cl and F, R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) form a 4 or OCH = CHO ring. Formula III In Formula III above, X is from OH, F, Cl, H and OC (O) R 7 , wherein R 7 is not branched or branched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-3 -alkyl Is selected), R 9 to R 13 are each independently of each other 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 ; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And unsubstituted, mono- or polysubstituted phenyl, wherein R 14 is C 1-6 -alkyl; In each case, unsubstituted or mono- or polysubstituted pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl; 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 and CO-C 6 H 4 -R 15 , wherein R 15 is ortho-OCOC 1-3 -alkyl, or meta-CH 2 N (R 16 ) 2 or para-CH 2 N (R 16 ) 2 , wherein R 16 is C 1-4 -alkyl or 4-morpholino; and in the radicals R 14 , R 15 and R 16 the alkyl group is not branched or branched, saturated or saturated And unsubstituted or single or polysubstituted, R 17 and R 18 are, at each occurrence, independently of one another; Branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted C 1-6 -alkyl; And, in each case, unsubstituted, mono- or polysubstituted phenyl, benzyl or phenethyl}, R 9 and R 10 or R 10 and R 11 together are OCH 2 O, OCH 2 CH 2 O, OCH = CH, CH = CHO, CH = C (CH 3 ) O, OC (CH 3 ) = CH, (CH 2 ) forms a 4 or OCH = CHO ring, provided that R 9 , R 11 and R 13 correspond to H, one of R 10 and R 12 corresponds to H and the remaining groups correspond to OCH 3 , X cannot be OH. [15" claim-type="Currently amended] The compound of claim 14, wherein the compound of group A is selected from the group consisting of tramadol, (+)-tramadol, (+)-O-demethyltramadol and (+)-O-demethyl-N-mono-demethyl- Active compound combinations, characterized in that they are selected from tramadol, preferably from tramadol and (+)-tramadol, particularly preferably from tramadol. [16" claim-type="Currently amended] The compound of claim 14, wherein the compound of Group A is selected from group (b) for codeine, dextrosepropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphine, pentidine (metheridine), tilly Dean, Biminol, Butropanol, Dezosin, Nalopin, Pentazosin and Buprenopine, preferably Codeine, Dextrosepropoxyphene, Dihydrocodeine, Cetazinol, Nalbuphine, Tilidine and Buprenopine The active compound combination, characterized in that the selected from. [17" claim-type="Currently amended] The compound of claim 14, wherein the compound of Group A is in group (c), X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F, OC (O) CH 3 and H, and / or R 1 is saturated or unsaturated, branched or unbranched C 1-4 -alkyl, preferably CH 3 , C 2 H 5 , C 4 H 9 and tert-butyl, in particular CH 3 and C 2 H 5 Selected from R 2 and R 3 , in each case, independently of each other H or saturated or unsaturated, branched or unbranched C 1-4 -alkyl, preferably H, CH 3 , C 2 H 5 , i-propyl And tert-butyl, in particular H and CH 3 , preferably R 3 = H, R 2 and R 3 together form a saturated, unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted C 5-6 -cycloalkyl radical, in particular cyclohexyl, R 9 to R 13 should be H, Cl, F, OH, CF 2 H, CF 3 or unsaturated or branched, with each occurrence of 3 or 4 of R 9 to R 13 independently of each other; Or unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably Or selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H while the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , preferably Is selected from OH, CF 2 H, OCH 3 and SCH 3 , or If R 9 and R 13 are H and R 11 corresponds to OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is also H and the remaining radicals are OH, OCH 3 , Cl or F , Preferably Cl, When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H and the remaining radicals are selected from compounds according to formula I, selected from OH, OC 2 H 5 and OC 3 H 7 . Active compound formulation. [18" claim-type="Currently amended] 18. The compound of formula (I) according to claim 17, wherein the compound of formula (I) in which R 3 is H is in the form of diastereomers having a relative arrangement of formula (Ia), in particular mixtures of which the content of said diastereomers is higher than the content of other diastereomers, or Diastereoisomers and / or Is a mixture of racemic compounds having a higher content of (+)-enantiomer than (-)-enantiomer, or a pure (+)-enantiomer Characterized in that the active compound combination. Formula Ia [19" claim-type="Currently amended] The compound of claim 17 or 18, wherein the compound of Group A is (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, (+)-(2R, 3R) -1-Dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol, (2RS, 3RS) -3- (3,4-Dichlorophenyl) -l-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-methylsulfanyl-phenyl) -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) -phenol, (-)-(1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (+)-(1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (+)-(1R, 2R) -Acetic acid 3-dimethylamino-1-ethyl-1- (3-methoxy-phenyl) -2-methyl-propyl ester, (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 and (+)-(2R, 3R) -4-dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol, preferably their hydrochloride salts, Active compound combinations. [20" claim-type="Currently amended] The compound of claim 14, wherein the compound of Group A is in group (d), X is selected from OH, F, Cl, OC (O) CH 3 and H, preferably OH, F and H, and / or in particular OH, R 1 is selected from C 1-4 -alkyl, CF 3 , OH, OC 1-4 -alkyl, Cl and F, preferably OH, CF 3 , and CH 3 , R 9 to R 13 are each branched independently of H, Cl, F, OH, CF 2 H, CF 3, or saturated or unbranched, with 3 or 4 of R 9 to R 13 being H Or unbranched C 1-4 -alkyl, OR 14 and SR 14 , wherein R 14 is selected from saturated or unsaturated and unbranched or unbranched C 1-3 -alkyl, preferably Or selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 and SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, In particular, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 and SR 14 , preferably OH, CF 2 H, OR 14 and SCH 3 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 , or When R 9 and R 13 are H and R 11 is OH, CH 3 , Cl or F, preferably Cl, one of R 10 and R 12 is also H and the remaining radicals are OH, OCH 3 , Cl or F, preferably Is Cl, When R 9 , R 10 , R 12 and R 13 are H, R 11 is selected from CF 3 , CF 2 H, Cl and F, preferably F or When R 10 , R 11 and R 12 are H, one of R 9 and R 13 is also H or the remaining radicals are selected from OH, OC 2 H 5 and OC 3 H 7 , Very particularly preferably, when R 9 , R 11 and R 13 are H, one of R 10 and R 12 is also H and the remaining radicals are Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 and Active compound combination, characterized in that it is selected from compounds according to formula (II), preferably selected from SR 14 , preferably OH and OR 14 , in particular OH and OC 1-3 -alkyl, preferably OH and OCH 3 . [21" claim-type="Currently amended] The compound according to claim 20, wherein the compound of formula II is in the form of a diastereomer having a relative arrangement of formula IIa, in particular a mixture of which the content of the diastereomer is higher than the content of the other diastereomers, or a pure diastereomer. Or The compound of formula (II) is a mixture of racemic compounds in which the content of (+)-enantiomers, in particular (+)-enantiomers, is higher than that of (-)-enantiomers, or pure (+)-enantithio An active compound combination, characterized by a mud. Formula IIa [22" claim-type="Currently amended] The compound of claim 20 or 21, wherein the compound of Group A is (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, (+)-(1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxy-phenyl) -cyclohexane-1,3-diol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol, (+)-(1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl) -phenol and (1RS, 2RS, 5RS) -3- (2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl) -phenol, preferably selected from hydrochlorides thereof Compound blends. [23" claim-type="Currently amended] The compound of claim 14, wherein the compound of Group A is X is selected from OH, F, Cl, OC (O) CH 3 or H, preferably OH, F or H, in particular F or H, If 3 or 4 radicals of R 9 to R 13 must correspond to H, then R 9 to R 13 are each independently of each other H, Cl, F, OH, CF 2 H, CF 3 or not saturated or saturated. , Branched or unbranched C 1-4 -alkyl, OR 14 or SR 14 , wherein R 14 is selected from saturated or unsaturated, branched or unbranched C 1-3 -alkyl, and is preferred. Preferably selected from H, Cl, F, OH, CF 2 H, CF 3 , OCH 3 or SCH 3 F, or R 12 and R 11 form a 3,4-OCH = CH ring, In particular, when R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H and the other radicals are Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , preferably OH, CF 2 H, OCH 3 or SCH 3 , in particular OH or OC 1-3 -alkyl, preferably OH or OCH 3 , or If R 9 and R 13 correspond to H and R 11 corresponds to OH, CH 3 , Cl or F, preferably Cl, one of R 10 or R 12 also corresponds to H and the other radicals are OH, OCH 3 , Cl or F, preferably corresponds to Cl, 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, the other radical is selected from OH, OC 2 H 5 or OC 3 H 7 , Very particularly preferably, if R 9 , R 11 and R 13 correspond to H, one of R 10 or R 12 also corresponds to H and the other radicals are Cl, F, OH, SH, CF 2 H, CF 3 , OR 14 or SR 14 , preferably OH or OR 14 , in particular selected from compounds according to formula III, selected from OH or OC 1-3 -alkyl, preferably OH or OCH 3 Compound blends. [24" claim-type="Currently amended] The compound according to claim 23, wherein the compound of formula III is in the form of a diastereomer having a relative arrangement of formula IIIa, in particular a mixture of which the content of the diastereomer is higher than the content of the other diastereomers or is a pure diastereomer / Or The compound of formula III is a mixture of racemic compounds in which the content of (+)-enantiomers, in particular (+)-enantiomers, is higher than the content of (-)-enantiomers, or pure (+)-enantithio An active compound combination, characterized by a mud. Formula IIIa [25" claim-type="Currently amended] The compound of claim 23 or 24, wherein the compound of Group A is (+)-(1R, 2R) -3- (2-dimethylaminomethyl-1-fluoro-cyclohexyl) -phenol, (+)-(1S, 2S) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol or (1S, 2S) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol or (-)-(1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol, (1R, 2R) -3- (2-Dimethylaminomethyl-cyclohexyl) -phenol, (-)-(1R, 2R)-[2- (3-methoxy-phenyl) -cyclohexylmethyl] -dimethylamine and Active compound combination, characterized in that it is selected from (1R, 2R)-[2- (3-methoxy-phenyl) -cyclohexylmethyl] -dimethylamine, preferably their hydrochlorides. [26" claim-type="Currently amended] The method according to any one of claims 14 to 25, wherein group B is selected from darfenacecin, dulocetin, oxybutynin and tolterodine, preferably from dulocetin, oxybutynin and tolterodine, Active compound combination, characterized in that it is preferably selected from oxybutynin and tolterodine. [27" claim-type="Currently amended] A medicament for the treatment of urinary or incontinence, preferably of increased urgency, comprising the active compound combination according to any one of claims 14 to 26 and optionally suitable additives and / or adjuvant materials.
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同族专利:
公开号 | 公开日 NZ531777A|2006-11-30| DE10146275A1|2003-04-24| CN1589140A|2005-03-02| AT383854T|2008-02-15| HK1075205A1|2009-04-24| ES2299608T3|2008-06-01| CA2460655A1|2003-03-27| NO20041059L|2004-05-12| JP2005507387A|2005-03-17| NO333016B1|2013-02-18| IL160894A|2010-04-29| HU0401485A3|2008-04-28| CN100384413C|2008-04-30| US20040242617A1|2004-12-02| IL160894D0|2004-08-31| US20120016023A1|2012-01-19| MXPA04002510A|2004-05-31| JP4511176B2|2010-07-28| US8946290B2|2015-02-03| EP1429754B1|2008-01-16| PL369235A1|2005-04-18| CA2460655C|2012-02-07| KR100891438B1|2009-04-03| WO2003024444A1|2003-03-27| HU0401485A2|2004-11-29| RU2004111788A|2005-06-10| AU2002342707B2|2006-10-12| RU2305562C2|2007-09-10| PL209272B1|2011-08-31| BR0212714A|2004-08-03| ECSP045025A|2004-04-28| EP1429754A1|2004-06-23| DE50211566D1|2008-03-06| ZA200402853B|2005-02-23|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
2001-09-18|Priority to DE10146275.1 2001-09-18|Priority to DE10146275A 2002-09-18|Application filed by 그뤼넨탈 게엠베하 2002-09-18|Priority to PCT/EP2002/010460 2004-05-31|Publication of KR20040044953A 2009-04-03|Application granted 2009-04-03|Publication of KR100891438B1
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申请号 | 申请日 | 专利标题 DE10146275.1|2001-09-18| DE10146275A|DE10146275A1|2001-09-18|2001-09-18|Combination of selected opioids with muscarinic antagonists for the treatment of urinary incontinence| PCT/EP2002/010460|WO2003024444A1|2001-09-18|2002-09-18|Combination of selected opioids with muscarine antagonists for treating urinary incontinence| 相关专利
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