US 2005O137194A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0137194A1 Cristoph (43) Pub. Date: Jun. 23, 2005

(54) COMBINATION OF SELECTED OPIOIDS (30) Foreign Application Priority Data WITH OTHER ACTIVE COMPOUNDS FOR TREATMENT OF URINARY INCONTINENCE May 29, 2002 (DE)...... 102 24 107.4 (75) Inventor: Thomas Cristoph, Aachen (DE) Publication Classification Correspondence Address: CROWELL & MORING LLP (51) Int. Cl." ...... A61K 31/5377; A61K 31/485 INTELLECTUAL PROPERTY GROUP (52) U.S. Cl...... 514/235.2; 514/282 P.O. BOX 14300 WASHINGTON, DC 20044-4300 (US) (73) Assignee: Gruenenthal GmbH, Aachen (DE) (57) ABSTRACT (21) Appl. No.: 10/998,164 The invention relates to the combination of compounds of (22) Filed: Nov. 29, 2004 group A, especially opioids, with compounds of group B for for the treatment of urinary urgency or urinary incontinence. Related U.S. Application Data The invention also relates to corresponding pharmaceutical formulations and to methods for treating urinary urgency or (63) Continuation of application No. PCT/EP03/05529, urinary incontinence with a compound of group A and a filed on May 27, 2003. compound of group B. US 2005/0137194A1 Jun. 23, 2005

COMBINATION OF SELECTED OPODS WITH urinary tract (Wein, A. J., 1998, Urology 51 (Suppl. 21): OTHER ACTIVE COMPOUNDS FOR TREATMENT 43-47). These are usually medicaments which have an OF URINARY INCONTINENCE inhibiting action on the detrusor muscle, which is respon sible for the internal bladder pressure. These medicaments CROSS REFERENCE TO RELATED are e.g. parasympatholytics, Such as Oxybutynin, propiverine APPLICATIONS or tolterodine, tricyclic antidepressants, Such as imipramine, or muscle relaxants, Such as flavoxate. Other medicaments 0001. This application is a continuation of International which in particular increase the resistance of the urethra or Patent Application No. PCT/EP03/05529, filed May 27, of the neck of the bladder show affinities for O-adrenore 2003, designating the United States of America, and pub ceptors, Such as ephedrine, to B-adrenoreceptors, Such as lished in German as WO 03/099268 A1, the entire disclosure clenbuterol, or are hormones, Such as oestradiol. of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany Patent 0007 An accurate insight into the therapeutics and treat Application No. 102 24 107.4, filed May 29, 2002. ment methods used, in particular in respect of the antimus carinics and other peripherally acting Substances, is given in FIELD OF THE INVENTION this context by the review article by K. E. Andersson et al. “The pharmacological treatment of urinary incontinence', 0002 The invention relates to the use of a combination of BJU International (1999), 84,923-947. compounds of group A, in particular opioids, and com pounds of group B, for the preparation of a medicament for 0008 Certain diarylmethylpiperazines and -piperidines treatment of an increased urge to urinate and urinary incon are also described for this indication in WO 93/15062. A tinence, and corresponding medicaments and methods for positive effect on bladder function has also been demon treatment of an increased urge to urinate and urinary incon strated for tramadol in a rat model of rhythmic bladder tinence. contractions (Nippon-Shinyaku, WO 98/46216). Further more, there are investigations in the literature for character ization of the opioid Side effect of urine retention, from BACKGROUND OF THE INVENTION which emerge Some indications of influencing of bladder 0.003 Urinary incontinence is the involuntary discharge functions by weak opioids, Such as diphenoxylate (Fowler et of urine. This occurs in an uncontrolled manner when the al., 1987, J. Urol 138: 735-738) and meperidine (Doyle and pressure within the urinary bladder exceeds that needed to Briscoe, 1976, Br J Urol 48: 329-335), by mixed opioid close the ureter. Causes can be on the one hand an increased agonists/antagonists, such as buprenorphine (Malinovsky et internal bladder pressure (e.g. due to detrusor instability) al., 1998 Anesth Analg87: 456-461; Drenger and Magora, with the consequence of urgency incontinence and on the 1989 Anesth Analg 69: 348-353), pentazocine (Shimizu et other hand a reduced sphincter pressure (e.g. following al. (2000) Br. J. Pharmacol. 131 (3): 610-616 and nalbuphine giving birth or Surgical interventions) with the consequence (Malinovsky et al., 1998, loc. cit.), and by potent opioids, of StreSS incontinence. The detrusor is a coarsely bundled such as morphine (Malinovsky et al., 1998 loc. cit.; Kontani multilayered bladder wall musculature, contraction of which and Kawabata, (1988); Jpn J. Pharmacol. Sep.; 48(1):31) leads to voiding of urine, and the Sphincter is the muscle and fentanyl (Malinovsky et al., 1998 loc. cit.). However, which closes the urethra. Mixed forms of these types of these investigations were usually carried out in analgesically incontinence as well as So-called overflow incontinence (e.g. active concentrations. in cases of benign prostate hyperplasia) or reflex inconti 0009. With the indications in question here, it should be nence (e.g. following damage to the spinal marrow) occur. remembered that it is a matter in general of very long-term Further details in this context are to be found in Chutka, D. uses of medicaments and, in contrast to many situations in S. and Takahashi, P. Y., 1998, Drugs 560: 587-595. which analgesics are employed, those affected are faced with 0004. The urge to urinate is the state of increased bladder a situation which is very unpleasant but not unendurable. It muscle tension as the bladder capacity is approached (or should therefore be ensured here-even more so than with when this is exceeded), the aim of which is voiding of urine analgesics-that Side effects are avoided if the perSon (micturition). This tensioning acts as a stimulus to micturi affected does not want to replace one evil by the other. tion. An increased urge to urinate is understood in this Furthermore, analgesic actions are also largely undesirable context in particular as meaning the occurrence of a prema during long-term urinary incontinence treatment. ture or more frequent and Sometimes even painful urge to urinate. This leads as a consequence to Significantly more SUMMARY OF THE INVENTION frequent micturition. Causes can be, inter alia, inflammation 0010. One object of the present invention was therefore of the urinary bladder and neurogenic bladder disorders and to discover Substances or Substance combinations which are also bladder tuberculosis. However, all the causes have not helpful for treatment of an increased urge to urinate and yet been clarified. urinary incontinence, and in the active doses preferably at 0005. An increased urge to urinate and also urinary the same time show a lower degree of Side effects and/or incontinence are found to be extremely unpleasant, and there analgesic actions than known from the prior art. Preferably, is a clear need to achieve an improvement in perSons the combinations show a Synergistic effect for treatment of affected by these indications which is as long-term as urinary incontinence. possible. 0011 Surprisingly, it has now been found that a combi 0006 An increased urge to urinate and in particular nation of compounds from group A, which comprises opio urinary incontinence are conventionally treated with Sub ids and other centrally acting Substances which interact with stances which are involved in the reflexes of the lower opioid receptors, the effects of which can be antagonized by US 2005/0137194A1 Jun. 23, 2005

naloxone, or in particular Substances which act via an opiate 0037 morphine receptor, in particular the u receptor, and compounds of group B, which comprises muscarine antagonists and other 0038 nalorphine predominantly peripherally acting Substances which are 0039) oxycodone known to be active in urinary incontinence, have an out Standing action on bladder function. Furthermore, these 0040 pentazocine combinations are highly and Significantly, unexpectedly, 0041 piritramide active at very low doses So that it is possible to employ the combined active compounds in a low dose. As a result, it is 0042 alfentanil to be expected that side effects which otherwise occur at the 0043 buprenorphine higher necessary dosages will decrease significantly, while the therapeutic action is fully retained by this combination of 0044) etorphine peripheral antimuscarinic effect acting predominantly 0045 fentanyl directly on the bladder or bladder musculature and central opioid effect or u receptor effect. 0046 remifentanil 0012. The invention accordingly provides the use of an 0047 sufentanil active compound combination, or pharmaceutical formula 0048 as the free base or acid and/or in the form of tion of at least one of the compounds A and at least one of physiologically acceptable Salts, in particular in the the compounds B, where compound A is chosen from: form of their physiologically acceptable acidic and basic Salts or Salts with cations and bases or with 0013 Group a) comprising: anions and acids, optionally in the form of the 0014 tramadol, O-demethyltramadol or O-dem enantiomers, diastereomers, in particular mixtures of ethyl-N-monodemethyl-tramadol as the free base or their enantiomers or diastereomers, or an individual acid and/or in the form of physiologically acceptable enantiomer or diastereomer; Salts, in particular in the form of their physiologi cally acceptable acidic and basic Salts or Salts with 0049 Group c) comprising: cations and bases or with anions and acids, in the 0050 1-phenyl-3-dimethylamino-propane CO form of the enantiomers, diastereomers, in particular pounds according to the general formula I mixtures of their enantiomers or diastereomers, or an individual enantiomer or diastereomer; 0015 Group b) comprising: 0016 codeine 0017 dextropropoxyphene 0018 dihydrocodeine 0019 diphenoxylate 0020 ethylmorphine 0021 meptazinol 0022 nalbuphine 0023 pethidine (meperidine) 0051 wherein 0024 tilidine 0.052 X is chosen from OH, F, Cl, H or OC(O)R7, where R is chosen from C-alkyl, branched or 0025) tramadol unbranched, Saturated or unsaturated, unsubstituted 0026 viminol or mono- or poly Substituted, 0027) butorphanol 0053) R' is chosen from C-alkyl, branched or unbranched, Saturated or unsaturated, unsubstituted 0028) dextromoramide or mono- or poly Substituted, 0029 dezocine 0054 R and R in each case independently of one 0030) diacetylmorphine (heroin) another are chosen from H or C-alkyl, branched or 0031 hydrocodone unbranched, Saturated or unsaturated, unsubstituted or mono- or poly Substituted, or 0032 hydromorphone 0055 R and R together form a saturated C-7- 0033 ketobemidone cycloalkyl radical, unsubstituted or mono- or 0034) levomethadone poly Substituted, 0035) levomethadyl acetate (1-O-acetylmethadol 0056 R to R' in each case independently of one another are chosen from H, F, Cl, Br, I, CHF, CHF, (LAAM)) CF, OH, SH, OR'', OCF, SR'', NR7R', SOCH, 0036 levorphanol SOCF; SOCH, SOCF, CN, COOR, NO, US 2005/0137194A1 Jun. 23, 2005

CONR'R'; Co-alkyl, branched or unbranched, 0.066 R to R' in each case independently of one Saturated or unsaturated, unsubstituted or mono- or another are chosen from H, F, Cl, Br, I, CHF, CHF, poly Substituted; phenyl, unsubstituted or mono- or CF, OH, SH, OR'', OCF, SR'', NR7R', SOCH, poly Substituted; SOCF; SOCH, SOCF, CN, COOR, NO, 0057 where R' is chosen from Cle-alkyl; pyridyl, CONR'R'; Co-alkyl, branched or unbranched, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in Saturated or unsaturated, unsubstituted or mono- or each case unsubstituted or mono- or poly Substituted; poly Substituted; phenyl, unsubstituted or mono- or PO(O-C-alkyl), CO(OC-alkyl), CONH poly Substituted; CH-(C3-alkyl), CO(C-s-alkyl), CO CHR''- 0067 where R'' is chosen from C-alkyl; pyridyl, NHR, CO-CH-R", where R' is ortho thienyl, thiazolyl, phenyl, benzyl or phenethyl, in OCOC-alkyl or meta- or para-CHN(R'), where each case unsubstituted or mono- or poly Substituted; R' is C-alkyl or 4-morpholino, wherein in the PO(O-C-alkyl), CO(OCs-alkyl), CONH radicals R', R' and R' the alkyl groups can be CH-(C-alkyl), CO(C-s-alkyl), branched or unbranched, Saturated or unsaturated, CO-CHR7 NHR'. Co-CH-R', where R is unsubstituted or mono- or polySubstituted; ortho-OCOC-alkyl or meta- or para-CH-N(R'), 0.058 where R7 and R' in each case independently where R is C-alkyl or 4-morpholino, wherein in of one another are chosen from H, C-alkyl, the radicals R', R' and R' the alkyl groups can be branched or unbranched, Saturated or unsaturated, branched or unbranched, Saturated or unsaturated, unsubstituted or mono- or polySubstituted; phenyl, unsubstituted or mono- or poly Substituted; benzyl or phenethyl, in each case unsubstituted or 0068 where R7 and R' in each case independently mono- or poly Substituted, or of one another are chosen from H, C-alkyl, 0059 R and R' or R and R'' together form an branched or unbranched, Saturated or unsaturated, OCHO, OCHCHO, OCH=CH, CH=CHO, unsubstituted or mono- or poly Substituted; phenyl, CH=C(CH)O, OC(CH)=CH, (CH) or benzyl or phenethyl, in each case unsubstituted or OCH=CHO ring, mono- or polySubstituted, or 0060 as the free base or acid and/or in the form of 0069 R and R' or R'' and R'' together form an physiologically acceptable Salts, in particular in the OCHO, OCHCHO, OCH=CH, CH=CHO, form of their physiologically acceptable acidic and CH=C(CH)O, OC(CH.)=CH, (CH), or basic Salts or Salts with cations and bases or with OCH=CHO ring, anions and acids, in the form of the enantiomers, 0070 as the free base or acid and/or in the form of diastereomers, in particular mixtures of their enan physiologically acceptable Salts, in particular in the tiomers or diastereomers, or an individual enanti form of their physiologically acceptable acidic and omer or diastereomer; basic Salts or Salts with cations and bases or with 0061 Group d) comprising: anions and acids, in the form of the enantiomers, diastereomers, in particular mixtures of their enan 0062 substituted 6-dimethylaminomethyl-1-phe tiomers or diastereomers, or an individual enanti nylcyclohexane compounds according to the general omer or diastereomer, and/or formula II 0071 Group e) comprising:

II 0072 6-dimethylaminomethyl-1-phenyl-cyclohex R11 ane compounds according to the general formula III RIQ R12 III

R9 R13

N-CH

1. CH

H N-CH CH 0063 wherein 0.064 X is chosen from OH, F, Cl, H or OC(O)R’, where R7 is chosen from C-alkyl, branched or 0.073 wherein unbranched, Saturated or unsaturated, unsubstituted 0.074 X is chosen from OH, F, Cl, H or OC(O)R’, or mono- or polySubstituted, where R is chosen from C-alkyl, branched or 0065) R' is chosen from C-alkyl, benzyl, CFs, unbranched, Saturated or unsaturated, unsubstituted OH, OCH-CH, O-C-alkyl, C1 or F and or mono- or poly Substituted, and US 2005/0137194A1 Jun. 23, 2005

0075) R' to R' in each case independently of one their enantiomers or diastereomers, or an individual another are chosen from H, F, Cl, Br, I, CHF, CHF, enantiomer or diastereomer; CF, OH, SH, OR'', OCF, SR'', NR7R', SOCH, SOCF; SOCH, SOCF, CN, COOR, NO, 0085 for the preparation of a medicament for treat CONR'R'; Co-alkyl, branched or unbranched, ment of an increased urge to urinate and urinary Saturated or unsaturated, unsubstituted or mono- or incontinence. poly Substituted; phenyl, unsubstituted or mono- or 0086) Surprisingly, it had been found that the combina poly Substituted; tion of the Substances mentioned Significantly positively 0076 where R' is chosen from Cle-alkyl; pyridyl, influence certain physiological parameters which are of thienyl, thiazolyl, phenyl, benzyl or phenethyl, in importance in cases of an increased urge to urinate and each case unsubstituted or mono- or poly Substituted; urinary incontinence. Each of these individual changes can PO(O-C-alkyl), CO(OCs-alkyl), CONH mean a significant alleviation of the Symptomatic picture of CH-(C-alkyl), CO(C-s-alkyl), patients affected. CO-CHR7 NHR, CO-CH-R, where R 0087. The compounds of group B predominantly have a is ortho-OCOC-alkyl or meta- or para peripheral action on urinary incontinence. In this context, CHN(R'), where R' is C-alkyl or 4-mor Venlafaxine is a Selective noradrenalin reuptake inhibitor pholino, wherein in the radicals R', R' and R the having an activity in Stress incontinence (Bae J. H. et al., alkyl groups can be branched or unbranched, Satu BJU International 2001, 88, 771, 775). Fesoterodine is an rated or unsaturated, unsubstituted or mono- or mACh antagonist developed by Schwarz Pharma. Solifena poly Substituted; cin (YM905) is an mACh antagonist developed by Yaman 0.077 where R7 and R' in each case independently ouchi. Resiniferatoxin is a VR1 agonist developed by Aff of one another are chosen from H, C-alkyl, eron, Mundipharma and ICOS (although in particular for branched or unbranched, Saturated or unsaturated, local use). Cizolirtine is a compound described in European unsubstituted or mono- or polySubstituted; phenyl, Patent EP 289 380 B1 (2-phenyl(1-methyl-1H-pyrazol-5- benzyl or phenethyl, in each case unsubstituted or yl)methoxy-N,N-dimethylethanamine, which can also be mono- or poly Substituted, or called 5-alpha-(2-dimethylaminoethoxy)benzyl-1-methyl 1H-pyrazole or 5-N,N-(dimethylaminoethoxy)phenylme 0078 R and R' or R'' and R'' together form an thyl-1-methyl-1H-pyrazole) with a hitherto unknown action OCHO, OCHCHO, OCH=CH, CH=CHO, mechanism, which is being investigated clinically in urinary CH=C(CH)O, OC(CH.)=CH, (CH), or incontinence by Esteve (ES). Nitro-flurbiprofen and HCT OCH=CHO ring, 1026 are two Substances which act on NO+COX and have 0079 with the proviso that if R, R'' and R' been developed by NicOx. Talnetant is an NK antagonist correspond to H and one of R' or R' corresponds developed by Glaxo Smith Kline. TAK-637 is an NK to H and the other corresponds to OCH, X may not antagonist developed by Takeda. SL 251039 is an aAR be OH, agonist developed by Sanofi. R450 is an aAR agonist 0080 as the free base or acid and/or in the form of developed by Roche. Rec 15/3079 is a 5HT antagonist physiologically acceptable Salts, in particular in the developed by Recordati. (-)-DDMS is a substance devel form of their physiologically acceptable acidic and oped by Sepracor which acts on NA+D. NS-8 is a substance basic Salts or Salts with cations and bases or with developed by Nippon Shinyaku which acts on PCA. DRP anions and acids, in the form of the enantiomers, 001 is a Substance of unknown action mechanism developed diastereomers, in particular mixtures of their enan by Sosei for urgency incontinence. tiomers or diastereomers, or an individual enanti 0088. In the context of this invention, alkyl and omer or diastereomer; cycloalkyl radicals are understood as meaning Saturated and 0081 and with at least one of the compounds B unsaturated (but not aromatic), branched, unbranched and chosen from cyclic hydrocarbon radicals, which can be unsubstituted or mono- or poly Substituted. In this context, C2-alkyl repre 0082 the antimuscarinics: atropine, oxybutynin, Sents C1- or C2-alkyl, C-alkyl represents C1-, C2- or propiverine, propantheline, emepronium, troSpium, C3-alkyl, C-alkyl represents C1-, C2-, C3- or C4-alkyl, tolterodine, darifenacin and C.C.-diphenylacetic acid Cs-alkyl represents C1-, C2-, C3-, C4- or C5-alkyl, C 4-(N-methylpiperidyl) ester, as well as dulloxetine, alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl, C.- imipramine and desmopressin, and alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl, Cis-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or 0.083 venlafaxine, feSoterodine, Solifenacin C8-alkyl, Co-alkyl represents C1-, C2-, C3-, C4-, C5-, (YM905), resiniferatoxin, cizolirtine, nitro-flurbi C6-, C7-, C8-, C9- or C10-alkyl and C-alkyl represents profen, HCT1026, talnetant, TAK-637, SL 251039, C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, R 450, Rec 15/3079, (-)-DDMS, NS-8 and/or DRP C12-, C13-, C14-, C15-, C16-, C17- or Cs-alkyl. Further OO1 more, C-cycloalkyl represents C3- or C4-cycloalkyl, 0084 as the free base or acid and/or in the form of Cs-cycloalkyl represents C3-, C4- or C5-cycloalkyl, C physiologically acceptable Salts, in particular in the cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl, C-7- form of their physiologically acceptable acidic and cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl, basic Salts or Salts with cations and bases or with Cs-cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cy anions and acids, optionally in the form of the cloalkyl, Cs-cycloalkyl represents C4- or C5-cycloalkyl, enantiomers, diastereomers, in particular mixtures of Co-cycloalkyl represents C4-, C5- or C6-cycloalkyl, C-7- US 2005/0137194A1 Jun. 23, 2005 cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, Cse the aryl or heteroaryl by R, OR, a halogen, preferably F cycloalkyl represents C5- or C6-cycloalkyl and C-7-cy and/or Cl, a CF, a CN, an NO, an NR'R'', a C-alkyl cloalkyl represents C5-, C6- or C7-cycloalkyl. In respect of (Saturated), a C6-alkoxy, a C-s-cycloalkoxy a C-8-cy cycloalkyl, the term also includes Saturated cycloalkyls in cloalkyl or a C-alkylene. which one or 2 carbon atoms are replaced by a heteroatom S, N or O. However, the term cycloalkyl also includes in 0.095. In this context, the radical R represents H, a particular mono- or poly-, preferably monounsaturated Co-alkyl, preferably a C-alkyl, or an aryl or heteroaryl cycloalkyls without a heteroatom in the ring as long as the radical or an aryl or heteroaryl radical bonded via a C cycloalkyl is not an aromatic System. Preferably, the alkyl alkylene group, where these aryland heteroaryl radicals may and cycloalkyl radicals are methyl, ethyl, vinyl (ethenyl), not themselves be substituted by aryl or heteroaryl radicals propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 0.096 the radicals R and R’ are identical or dif 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, ferent and denote H, a Co-alkyl, preferably a 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpro Co-alkyl, or an aryl or a heteroaryl radical or an aryl pyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopro or heteroaryl radical bonded via a C-alkylene pyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopen group, where these aryl and heteroaryl radicals may tylmethyl, cyclohexyl, cycloheptyl, cyclooctyl and also not themselves be substituted by aryl or heteroaryl adamantyl, CHF, CF or CH-OH, as well as pyrazolinone, radicals Oxopyrazolinone, 1,4dioxane or dioxolane. 0097) or the radicals R and R together denote 0089. In this context, in connection with alkyl and CHCHOCHCH, CHCHNR CHCH or cycloalkyl-as long as this is not expressly defined other (CH), and wise-the term Substituted in the context of this invention is understood as meaning Substitution of at least one (option 0098) the radical R represents H, a C-to-alkyl, ally also several) hydrogen radical(s) by F, Cl, Br, I, NH, preferably a C-alkyl, or an aryl or heteroaryl SH or OH, where “polysubstituted” or “substituted” in the radical, or represents an aryl or heteroaryl radical case of multiple Substitution is to be understood as meaning bonded via a C-alkylene group, where these aryl that the Substitution is both on different and on the same and heteroaryl radicals may not themselves be Sub atoms Several times with the same or different Substituents, Stituted by aryl or heteroaryl radicals. for example three times on the same C atom as in the case 0099. The term salt is to be understood as meaning any of CF or in various places as in the case of -CH(OH)— form of the active compound according to the invention in CH=CH-CHCl2. Particularly preferred substituents here which this assumes an ionic form or is charged and is are F, Cl and OH. In respect of cycloalkyl, the hydrogen coupled with a counter-ion (a cation or anion) or is in radical can also be replaced by OC-alkyl or C-alkyl (in Solution. This is also to be understood as meaning com each case mono- or polySubstituted or unsubstituted), in plexes of the active compound with other molecules and particular methyl, ethyl, n-propyl, i-propyl, CF, methoxy or ions, in particular complexes which are complexed via ionic ethoxy. interactions. 0090 Pharmaceutical formulation means that that ingre 0100. The term of the physiologically acceptable salt dients are prepared for coadministration. with cations or bases in the context of this invention is 0.091 The term (CH) is to be understood as meaning understood as meaning Salts of at least one of the compounds CH-CH-CH-, CH-CH-CH-CH-, according to the invention-usually a (deprotonated) acid CH-CH-CH-CH-CH- and -CH-CH as the anion with at least one, preferably inorganic cation, CH-CH-CH-CH-, (CH) is to be understood as which are physiologically acceptable-in particular when meaning CH-, CH-CH , CH-CH used in humans and/or mammals. Particularly preferred Salts CH-and-CH-CH-CH-CH-, (CH) is is to be are the Salts of the alkali metals and alkaline earth metals, understood as meaning -CH-CH-CH-CH- and but also with NH, but in particular (mono)- or (di)-sodium, CH-CH-CH-CH-CH - etc. (mono)- or (di)-potassium, magnesium or calcium salts. 0092 An aryl radical is understood as meaning ring 0101 The term of the physiologically acceptable salt Systems having at least one aromatic ring but without with anions or acids is understood in the context of this heteroatoms in even only one of the rings. Examples are invention as meaning Salts of at least one of the compounds phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or inda according to the invention-usually protonated, for example nyl, in particular 9H-fluorenyl or anthracenyl radicals, which on the nitrogen-as the cation with at least one anion which can be unsubstituted or mono- or poly Substituted. are physiologically acceptable-in particular when used in 0093. A heteroaryl radical is understood as meaning humans and mammals. In particular, in the context of this heterocyclic ring Systems having at least one unsaturated invention this is understood as meaning the Salt formed with ring, which contain one or more heteroatoms from the group a physiologically acceptable acid, namely Salts of the par consisting of nitrogen, oxygen and/or Sulfur and can also be ticular active compound with inorganic or organic acids mono- or poly Substituted. Examples which may be men which are physiologically acceptable-in particular when tioned from the group of heteroaryls are furan, benzofuran, used in humans and/or mammals. Examples of physiologi thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, cally acceptable Salts of particular acids are Salts of hydro pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5- chloric acid, hydrobromic acid, Sulfuric acid, methane thiadiazole, benzothiazole, indole, benzotriazole, benzo Sulfonic acid, formic acid, acetic acid, oxalic acid, Succinic dioxolane, benzodioxane, carbazole, indole and quinazoline. acid, malic acid, tartaric acid, mandelic acid, fumaric acid, 0094. In this context, in connection with aryl and het lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihy eroaryl, Substituted is understood as meaning Substitution of drow-benzodisothiazol-3-one (Saccharic acid), monom US 2005/0137194A1 Jun. 23, 2005 ethylsebacic acid, 5-OXO-proline, hexane-1-Sulfonic acid, 0131 X is chosen from nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimeth ylbenzoic acid, C-liponic acid, acetylglycine, acetylsalicylic 0132) OH, F, Cl, OC(O)CH, or H, preferably OH, F, acid, hippuric acid and/or aspartic acid. The hydrochloride OC(O)CH or H, and/or Salt is particularly preferred. 0133) R' is chosen from 0102 Suitable salts in the context of this invention and in 0.134 C-alkyl, Saturated and unsubstituted, each use described and each of the medicaments described branched or unbranched; preferably CH, CH5, are Salts of the particular active compound with inorganic or CH or t-butyl, in particular CH, or C.Hs, and/or organic acids and/or a Sugar Substitute, Such as Saccharin, cyclamate or aceSulfame. However, the hydrochloride is 0135 R and R independently of one another are particularly preferred. chosen from 0103) Compounds of group c) and their preparation are 0136 H or C-alkyl, saturated and unsubstituted, known from DE 4426 245 A1 and U.S. Pat. No. 6,248,737. branched or unbranched; preferably H, CH, CH5, Compounds of group d) and e) and their preparation are i-propyl or t-butyl, in particular H or CH, preferably known from DE 19525 137 A1 and U.S. Pat. No. 5,733,936 R=H, or and US RE37355E. 0137 R and R together form a C-cycloalkyl radical, Saturated or unsaturated, unsubstituted or 0104. In a preferred embodiment, for the use according to mono- or poly Substituted, preferably Saturated and the invention the compound A in group a) is chosen from: unsubstituted, in particular cyclohexyl, and/or 0105 tramadol, (+)-tramadol, (+)-O-demethyltra madol or (+)-O-demethyl-N-mono-demethyl-tra (0138) R” to R', where 3 or 4 of the radicals R to madol, preferably tramadol or (+)-tramadol, in par R must correspond to H, independently of one ticular (+)-tramadol. another are chosen from 0139 H., Cl, F, OH, CFH, CF, or C-alkyl, satu 0106. In a preferred embodiment, for the use according to rated and unsubstituted, branched or unbranched; the invention the compound A in group b) is chosen from: OR or SR'', where R' is chosen from C-alkyl, 01.07 codeine Saturated and unsubstituted, branched or 0.108 dextropropoxyphene unbranched; 0140 preferably H, C, F, OH, CFH, CF, OCH or 0109) dihydrocodeine SCH, 0110 diphenoxylate 0141 or R'' and R' form a 3,4-OCH=CH ring 0111) ethylmorphine 0.142 in particular 0112 meptazinol 0143) if R, R'' and R' correspond to H, one of R' 0113 nalbuphine or R'' also corresponds to H, while the other is chosen from: 0114 pethidine (meperidine) 0144) C1, F, OH, CFH, CF, OR' or SR'', prefer 0115 tilidine ably OH, CFH, OCH or SCH or 0116 viminol 0145) if R and R' correspond to H and R' corre sponds to OH, OCH, C1 or F, preferably Cl, one of 0117 butorphanol R" or R'' also corresponds to H, while the other 0118 dezocine corresponds to OH, OCH, Clor F, preferably Cl, or 0119) nalorphine 0146) if R, R', R'' and R' correspond to H, R' 0120 pentazocine is chosen from CF, CFH, C1 or F, preferably F, or 0147 if R', R'' and R' correspond to H, one of R 0121 buprenorphine or R' also corresponds to H, while the other is 0122) preferably chosen from OH, OCH or OCH7. 0123 codeine 0148. In this context, for compounds of group c) it is particularly preferable if compounds of the formula I where 0.124 dextropropoxyphene R=H are present in the form of the diastereomers having 0125 dihydrocodeine the relative configuration Ia 0.126 meptazinol Ia 0127 nalbuphine Ro R1 X 0128 tilidine 0129 buprenorphine 0130. In a preferred embodiment, for the use according to the invention the compound A in group c) is chosen from compounds according to formula I for which: US 2005/0137194A1 Jun. 23, 2005

0149 in particular are used in mixtures having a 0173 R' is chosen from higher content of this diastereomer compared with the other diastereomer or as the pure diastereomer 0.174 C-alkyl, CF, OH, O-C-alkyl, Cl or F, and/or preferably OH, CF or CH, and/or

0150 if the compounds of the formula I are used in 017513 R to R', where 3 or 4 of the radicals R to the form of the (+)-enantiomer, in particular in R must correspond to H, independently of one mixtures having a higher content of the (+)-enanti another are chosen from omer compared with the (-)-enantiomer of a racemic 0176) H, C, F, OH, CFH, CF or C-alkyl, satu compound or as the pure (+)-enantiomer. rated and unsubstituted, branched or unbranched; 0151. In this context, it is particularly preferable if com OR or SR'', where R' is chosen from C-alkyl, pound A chosen from the following group is used: Saturated and unsubstituted, branched or unbranched; 0152 (2RS,3RS)-1-dimethylamino-3-(3-methoxy phenyl)-2-methyl-pentan-3-ol, 0177) preferably H, C, F, OH, CFH, CF, OCH or 0153 (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy SCH, phenyl)-2-methyl-pentan-3-ol, 0178 or R'' and R' form a 3,4-OCH=CH ring 0154) (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethy 0179 in particular lamino-2-methyl-pentan-3-ol, 0180 if R, R'' and R' correspond to H, one of R' O155 (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dim or R'' also corresponds to H, while the other is ethylamino-2-methyl-pentan-3-ol, chosen from: 0156 (2RS,3RS)-1-dimethylamino-2-methyl-3-(3- 0181 C1, F, OH, CFH, CF, OR' or SR'', prefer methylsulfanyl-phenyl)-pentan-3-ol, ably OH, CFH, OR' or SCH, in particular OH or 0157 (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)- OC-alkyl, preferably OH or OCH, or 4,4-dimethyl-pentan-3-ol, 0182) if R and R' correspond to H and R' corre 0158 (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hy sponds to OH, OCH, C1 or F, preferably Cl, one of droxy-2-methyl-propyl)-phenol, R' or R'' also corresponds to H, while the other corresponds to OH, OCH, Clor F, preferably Cl, or 0159 (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2- dimethyl-propyl)-phenol, 0183) if R, R', R'' and R' correspond to H, R' 0160 (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1, is chosen from CF, CFH, C1 or F, preferably F, or 2-dimethyl-propyl)-phenol, 0184) if R', R'' and R' correspond to H, one of R 0161 (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1, or R' also corresponds to H, while the other is 2-dimethyl-propyl)-phenol, chosen from OH, OCH or OCH7. 0162 (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-me 0185 very particularly preferably thyl-propyl)-phenol, 0186 if R, R'' and R' correspond to H, one of R' 0163 (+)-(1R,2R)-acetic acid 3-dimethylamino-1- or R'' also corresponds to H, while the other is ethyl-1-(3-methoxy-phenyl)-2-methyl-propyl ester, chosen from: 0164 (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)- 0187 C1, F, OH, SH, CFH, CF, OR' or SR'', 1-(3-methoxy-phenyl)-propan-1-ol, preferably OH or OR", in particular OH or OCs alkyl, preferably OH or OCH. 0.165 (2RS,3RS)-3-(4-chlorophenyl)-1-dimethy lamino-2-methyl-pentan-3-ol, 0188 In this context, for compounds of group d) it is particularly preferable if compounds of the formula II are 0166 (+)-(2R,3R)-3-(3-dimethylamino-1-ethyl-1-hy present in the form of the diastereomers having the relative droxy-2-methyl-propyl-phenol, configuration IIa 0167 (2RS,3RS)-4-dimethylamino-2-(3-methoxy phenyl)-3-methyl-butan-2-ol and IIa 0168 (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy phenyl)-3-methyl-butan-2-ol, 0169 preferably as the hydrochloride. 0170 In a preferred embodiment, for the use according to the invention the compound A in group d) is chosen from compounds according to formula II for which: 0171 X is chosen from 0172 OH, F, C1, OC(O)CH, or H, preferably OH, F or H, in particular OH, and/or US 2005/0137194A1 Jun. 23, 2005

0189 in particular, where they are used in mixtures 0211 if R', R'' and R' correspond to H, one of R having a higher content of this diastereomer com or R' also corresponds to H, while the other is pared with the other diastereomer or as the pure chosen from OH, OCH or OCH7. diastereomer and/or 0212 very particularly preferably 0.190 if the compounds of the formula II are used in the form of the (+)-enantiomer, in particular in mixtures having 0213) if R, R'' and R' correspond to H, one of R' a higher content of the (+)-enantiomer compared with the or R'' also corresponds to H, while the other is (-)-enantiomer of a racemic compound or as the pure chosen from: (+)-enantiomer. 0214) C1, F, OH, SH, CFH, CF, OR' or SR'', 0191 In this context, it is particularly preferable if com preferably OH or OR'', in particular OH or OC pound A chosen from the following group is used: alkyl, preferably OH or OCH. 0.192 (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3- 0215. In this context, for compounds of group e) it is methoxy-phenyl)-cyclohexane-1,3-diol, particularly preferable if compounds of the formula III are 0193 (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3- present in the form of their diastereomers having the relative methoxy-phenyl)-cyclohexane-1,3-diol, configuration IIIa 0194 (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3- IIIa hydroxy-phenyl)-cyclohexane-1,3-diol, 0.195 (1RS,3 SR,6RS)-6-dimethylaminomethyl-1-(3- methoxy-phenyl)-cyclohexane-1,3-diol, 0196 (+)-(1R,2R,5 S)-3-(2-dimethylaminomethyl-1- hydroxy-5-methyl-cyclohexyl)-phenol or 0197) (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1- hydroxy-5-trifluoromethyl-cyclohexyl)-phenol, 0198 preferably as the hydrochloride. 0199. In a preferred embodiment, for the use according to the invention the compound A in group e) is chosen from 0216) in particular are used in mixtures having a compounds according to formula III for which: higher content of this diastereomer compared with 0200 X is chosen from the other diastereomer or as the pure diastereomer 0201 OH, F, C1, OC(O)CH, or H, preferably OH, F and/or or H, in particular For H, and/or 0217 if the compounds of the formula III are used in the (0202) R” to R', where 3 or 4 of the radicals R to form of the (+)-enantiomer, in particular in mixtures having R must correspond to H, independently of one a higher content of the (+)-enantiomer compared with the another are chosen from (-)-enantiomer of a racemic compound or as the pure (+)-enantiomer. 0203 H, C, F, OH, CFH, CF or C-alkyl, satu rated and unsubstituted, branched or unbranched; 0218. In this context, it is particularly preferable if com OR or SR'', where R' is chosen from C3-alkyl, pound A chosen from the following group is used: Saturated and unsubstituted, branched or 0219 (+)-(1R,2R)-3-(2-dimethylaminomethyl-1- unbranched; fluoro-cyclohexyl)-phenol, 0204 preferably H, Cl, F, OH, CFH, CF, OCH or 0220 (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclo SCH hexyl)-phenol or 0205 or R'' and R' form a 3,4-OCH=CH ring 0221 (-)-(1R,2R)-3-(2-dimethylaminomethyl-cyclo 0206 in particular characterized in that hexyl)-phenol, 0207 if R, R'' and R' correspond to H, one of R' or R'' also corresponds to H, while the other is 0222 preferably as the hydrochloride chosen from: 0223 For a particularly preferred use, the compound B is 0208 C1, F, OH, CFH, CF, OR' or SR'', prefer chosen from: ably OH, CFH, OR' or SCH, in particular OH or 0224 darifenacin, dulloxetine, oxybutynin or OC-alkyl, preferably OH or OCH, or tolterodine, 0209 if R and R' correspond to H and R' corre sponds to OH, OCH, C1 or F, preferably Cl, one of 0225 is preferably chosen from R' or R'' also corresponds to H, while the other 0226 duloxetine, oxybutynin or tolterodine, corresponds to OH, OCH, C1 or F, preferably Cl, or 0227 is preferably chosen from 0210 if R, R, R and R' correspond to H, R'' is chosen from CF, CFH, C1 or F, preferably F, or 0228 oxybutynin or tolterodine. US 2005/0137194A1 Jun. 23, 2005

0229. For another particularly preferred use, the com 0260 pentazocine pound B is chosen from: 0261 piritramide 0230 venlafaxine, feSoterodine, Solifenacin (YM905), cizolirtine or resiniferatoxin. 0262 alfentanil 0231. Even if the uses according to the invention show 0263 buprenorphine only a low degree of Side effects, it may also be advanta 0264 etorphine geous, for example to avoid certain forms of dependency, also to use morphine antagonists, in particular naloxone, 0265 fentanyl naltrexone and/or levallorphan, in addition to the combina 0266 remifentanil tion of the compounds A and B. 0267 sufentanil 0232 The invention also provides an active compound combination of at least one of the compounds A and at least 0268 as the free base or acid and/or in the form of one of the compounds B, where compound A is chosen from: physiologically acceptable Salts, in particular in the form of their physiologically acceptable acidic and 0233 Group a) comprising: basic Salts or Salts with cations and bases or with 0234 tramadol, O-demethyltramadol or O-dem anions and acids, optionally in the form of the ethyl-N-mono-demethyl-tramadol as the free base or enantiomers, diastereomers, in particular mixtures of acid and/or in the form of physiologically acceptable their enantiomers or diastereomers, or an individual Salts, in particular in the form of their physiologi enantiomer or diastereomer; cally acceptable acidic and basic Salts or Salts with 0269 Group c) comprising: cations and bases or with anions and acids, in the form of the enantiomers, diastereomers, in particular 0270 1-phenyl-3-dimethylamino-propane CO mixtures of their enantiomers or diastereomers, or an pounds according to the general formula I individual enantiomer or diastereomer;

0235 Group b) comprising: 0236 codeine 0237 dextropropoxyphene 0238 dihydrocodeine 0239) diphenoxylate 0240 ethylmorphine 0241 meptazinol 0242 nalbuphine 0243 pethidine (meperidine) 0271 wherein 0244 tilidine 0272 X is chosen from OH, F, Cl, H or OC(O)R’, 0245 tramadol where R is chosen from C-alkyl, branched or 0246 viminol unbranched, Saturated or unsaturated, unsubstituted 0247 butorphanol or mono- or poly Substituted, 0273) R' is chosen from C-alkyl, branched or 0248 dextromoramide unbranched, Saturated or unsaturated, unsubstituted 0249 dezocine or mono- or poly Substituted, 0250) diacetylmorphine (heroin) 0274 R and R in each case independently of one another are chosen from H or C-alkyl, branched or 0251 hydrocodone unbranched, Saturated or unsaturated, unsubstituted 0252 hydromorphone or mono- or poly Substituted, or 0253 ketobemidone 0275 R and R together form a saturated C cycloalkyl radical, unsubstituted or mono- or 0254 levomethadone poly Substituted, 0255 levomethadyl acetate (1-O-acetylmethadol 0276 R to R' in each case independently of one (LAAM)) another are chosen from H, F, Cl, Br, I, CHF, CHF, 0256 levorphanol CF, OH, SH, OR'', OCF, SR'', NR7R', SOCH, SOCF; SOCH, SOCF, CN, COOR, NO, 0257 morphine CONR'R'; Co-alkyl, branched or unbranched, Saturated or unsaturated, unsubstituted or mono- or 0258 nalorphine poly Substituted; phenyl, unsubstituted or mono- or 0259 oxycodone poly Substituted; US 2005/0137194A1 Jun. 23, 2005

0277 where R' is chosen from Cle-alkyl; pyridyl, Saturated or unsaturated, unsubstituted or mono- or thienyl, thiazolyl, phenyl, benzyl or phenethyl, in poly Substituted; phenyl, unsubstituted or mono- or each case unsubstituted or mono- or poly Substituted; poly Substituted; PO(O-C-alkyl), CO(OC-alkyl), CONH 0286 where R'' is chosen from C-alkyl; pyridyl, CH-(C-alkyl), CO(C-s-alkyl), CO CHR''- thienyl, thiazolyl, phenyl, benzyl or phenethyl, in NHR'. Co-CH-R', where R is ortho-OCOC each case unsubstituted or mono- or poly Substituted; 3-alkyl or meta- or para-CH-N(R'), where R' is PO(O-C-alkyl), CO(OCs-alkyl), CONH C-alkyl or 4-morpholino, wherein in the radicals CH-(C-alkyl), CO(C5 S-alkyl), R", Rand R the alkyl groups can be branched or CO-CHR7 NHR, CO-CH-R, where R unbranched, Saturated or unsaturated, unsubstituted is ortho-OCOC-alkyl or meta- or para or mono- or polySubstituted; CHN(R'), where R' is C-alkyl or 4-mor 0278 where R7 and R' in each case independently pholino, wherein in the radicals R', R' and R' the of one another are chosen from H, C-alkyl, alkyl groups can be branched or unbranched, Satu branched or unbranched, Saturated or unsaturated, rated or unsaturated, unsubstituted or mono- or unsubstituted or mono- or polySubstituted; phenyl, poly Substituted; benzyl or phenethyl, in each case unsubstituted or 0287 where R7 and R' in each case independently mono- or poly Substituted, or of one another are chosen from H, C-alkyl, 0279 R and R' or R'' and R'' together form an branched or unbranched, Saturated or unsaturated, OCHO, OCHCHO, OCH=CH, CH=CHO, unsubstituted or mono- or poly Substituted; phenyl, CH=C(CH)O, OC(CH.)=CH, (CH), or benzyl or phenethyl, in each case unsubstituted or OCH=CHO ring, mono- or polySubstituted, or 0280 as the free base or acid and/or in the form of 0288 R and R' or R and R'' together form an physiologically acceptable Salts, in particular in the OCHO, OCHCHO, OCH=CH, CH=CHO, form of their physiologically acceptable acidic and CH=C(CH)O, OC(CH)=CH, (CH) or basic Salts or Salts with cations and bases or with OCH=CHO ring, as the free base or acid and/or in anions and acids, in the form of the enantiomers, the form of physiologically acceptable Salts, in par diastereomers, in particular mixtures of their enan ticular in the form of their physiologically acceptable tiomers or diastereomers, or an individual enanti acidic and basic Salts or salts with cations and bases omer or diastereomer; or with anions and acids, in the form of the enanti 0281 Group d) comprising: omers, diastereomers, in particular mixtures of their enantiomers or diastereomers, or an individual enan 0282 substituted 6-dimethylaminomethyl-1-phe tiomer or diastereomer; nylcyclohexane compounds according to the general formula II 0289 and/or 0290 Group e) comprising: II 0291 6-dimethylaminomethyl-1-phenyl-cyclohex R11 ane compounds according to the general formula III R1 R12 III R11 R9 R13

N-CH

1. CH H N-CH 0283 wherein CH 0284 X is chosen from OH, F, Cl, H or OC(O)R’, where R7 is chosen from C-alkyl, branched or 0292 wherein unbranched, Saturated or unsaturated, unsubstituted or mono- or polySubstituted, 0293 X is chosen from OH, F, Cl, H or OC(O)R’, 0285) R' is chosen from C-alkyl, benzyl, CFs, where R7 is chosen from C-alkyl, branched or OH, OCH-CHs, O-C-alkyl, Clor F and R to unbranched, Saturated or unsaturated, unsubstituted R" in each case independently of one another are or mono- or poly Substituted, and chosen from H, F, Cl, Br, I, CHF, CHF, CF, OH, 0294) R' to R' in each case independently of one SH, OR'', OCF, SR'', NR7R, SOCH, SOCF; another are chosen from H, F, Cl, Br, I, CHF, CHF, SOCH, SOCF, CN, COOR, NO, CF, OH, SH, OR'', OCF, SR'', NR7R', SOCH, CONR'R'; C-alkyl, branched or unbranched, SOCF; SOCH, SOCF, CN, COOR, NO, US 2005/0137194A1 Jun. 23, 2005 11

CONR'R'; Co-alkyl, branched or unbranched, active compound with inorganic or organic acids and/or a Saturated or unsaturated, unsubstituted or mono- or Sugar Substitute, Such as Saccharin, cyclamate or aceSulfame. poly Substituted; phenyl, unsubstituted or mono- or However, the hydrochloride is particularly preferred. poly Substituted; 0305 For the active compound combination, it is par 0295) where R' is chosen from Cle-alkyl; pyridyl, ticularly preferable if the compound A in group a) is chosen thienyl, thiazolyl, phenyl, benzyl or phenethyl, in from: each case unsubstituted or mono- or poly Substituted; PO(O-C-alkyl), CO(OC-alkyl), CONH 0306 tramadol, (+)-tramadol, (+)-O-demethyltra CH-(C-alkyl), CO(C-s-alkyl), madol or (+)-O-demethyl-N-mono-demethyl-tra CO-CHR'7-NHR, CO CH-R', where R' madol, preferably tramadol or (+)-tramadol, in par is ortho-OCOC-alkyl or meta- or para ticular (+)-tramadol. CHN(R'), where R' is C-alkyl or 4-mor 0307 For the active compound combination, it is par pholino, wherein in the radicals R', R' and R the ticularly preferable if compound A in group b) is chosen alkyl groups can be branched or unbranched, Satu from: rated or unsaturated, unsubstituted or mono- or poly Substituted; 0308) codeine 0296 where R7 and R' in each case independently 0309 dextropropoxyphene of one another are chosen from H, C-alkyl, 0310 dihydrocodeine branched or unbranched, Saturated or unsaturated, unsubstituted or mono- or polySubstituted; phenyl, 0311 diphenoxylate benzyl or phenethyl, in each case unsubstituted or 0312) ethylmorphine mono- or poly Substituted, or 0313 meptazinol 0297 R and R' or R'' and R'' together form an OCHO, OCHCHO, OCH=CH, CH=CHO, 0314 nalbuphine CH=C(CH)O, OC(CH.)=CH, (CH), or 0315 pethidine (meperidine) OCH=CHO ring, 0316 tilidine 0298 with the proviso that if R, R'' and R' correspond to H and one of R' or R' corresponds 0317 viminol to H and the other corresponds to OCH, X may not 0318 butorphanol be OH, 0319 dezocine 0299 as the free base or acid and/or in the form of physiologically acceptable Salts, in particular in the 0320 nalorphine form of their physiologically acceptable acidic and 0321 pentazocine basic Salts or Salts with cations and bases or with anions and acids, in the form of the enantiomers, 0322 buprenorphine diastereomers, in particular mixtures of their enan 0323 preferably tiomers or diastereomers, or an individual enanti omer or diastereomer; 0324 codeine 0300 and with at least one of the compounds B 0325 dextropropoxyphene chosen from 0326) dihydrocodeine 0301 the antimuscarinics: atropine, oxybutynin, propiverine, propantheline, emepronium, troSpium, 0327 meptazinol tolterodine, darifenacin and C.C.-diphenylacetic acid 0328 nalbuphine 4-(N-methylpiperidyl) ester, as well as dulloxetine, imipramine and desmopressin, and 0329 tilidine 0302) venlafaxine, feSoterodine, Solifenacin 0330 buprenorphine (YM905), cizolirtine, resiniferatoxin, nitro-flurbi 0331 For the active compound combination, it is par profen, HCT1026, talnetant, TAK-637, SL 251039, ticularly preferable if the compound A in group c) is chosen R 450, Rec 15/3079, (-)-DDMS, NS-8 and/or DRP from compounds according to formula I for which: OO1 0332 X is chosen from 0303 as the free base or acid and/or in the form of physiologically acceptable Salts, in particular in the 0333 OH, F, Cl, OC(O)CH, or H, preferably OH, F, form of their physiologically acceptable acidic and OC(O)CH or H, and/or basic Salts or Salts with cations and bases or with anions and acids, optionally in the form of the 0334) R' is chosen from enantiomers, diastereomers, in particular mixtures of 0335 C-alkyl, Saturated and unsubstituted, their enantiomers or diastereomers, or an individual branched or unbranched; preferably CH, CH5, enantiomer or diastereomer. CH or t-butyl, in particular CHs or C-Hs, and/or 0304 Suitable salts in the context of this invention and in 0336 R and R independently of one another are each of the medicaments described are Salts of the particular chosen from US 2005/0137194A1 Jun. 23, 2005

0337 H or C-alkyl, Saturated and unsubstituted, 0351. In this context, it is particularly preferable if com branched or unbranched; preferably H, CH, CH5, pound A is chosen from the following group: i-propyl or t-butyl, in particular H or CH, preferably 0352 (2RS,3RS)-1-dimethylamino-3-(3-methoxy R=H, or phenyl)-2-methyl-pentan-3-ol, 0338 R and R together form a Cse-cycloalkyl 0353 (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy radical, Saturated or unsaturated, unsubstituted or mono- or polySubstituted, preferably Saturated and phenyl)-2-methyl-pentan-3-ol, unsubstituted, in particular cyclohexyl, and/or 0354) (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethy 0339) R to R', where 3 or 4 of the radicals R to lamino-2-methyl-pentan-3-ol, R13 must correspond to H, independently of one 0355 (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dim another are chosen from ethylamino-2-methyl-pentan-3-ol, 0340 H, Cl, F, OH, CFH, CF, or C-alkyl, satu 0356 (2RS,3RS)-1-dimethylamino-2-methyl-3-(3- rated and unsubstituted, branched or unbranched; methylsulfanyl-phenyl)-pentan-3-ol, OR or SR'', where R' is chosen from C3-alkyl, Saturated and unsubstituted, branched or 0357 (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)- unbranched; 4,4-dimethyl-pentan-3-ol, 0341 preferably H, Cl, F, OH, CFH, CF, OCH or 0358 (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hy SCH droxy-2-methyl-propyl)-phenol, 0342 or R'' and R' form a 3,4-OCH=CH ring in 0359 (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2- particular dimethyl-propyl)-phenol, 0343) if R, R'' and R' correspond to H, one of R' 0360 (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1, or R'' also corresponds to H, while the other is 2-dimethyl-propyl)-phenol, chosen from: 0361 (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1, 0344) C1, F, OH, CFH, CF, OR' or SR'', prefer 2-dimethyl-propyl)-phenol, ably OH, CFH, OCH or SCH or 0362 (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-me 0345) if R and R' correspond to H and R' corre thyl-propyl)-phenol, sponds to OH, OCH, C1 or F, preferably Cl, one of 0363 (+)-(1R,2R)-acetic acid 3-dimethylamino-1- R" or R'' also corresponds to H, while the other ethyl-1-(3-methoxy-phenyl)-2-methyl-propyl ester, corresponds to OH, OCH, Clor F, preferably Cl, or 0364 (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)- 0346) if R, R', R'' and R' correspond to H, R' 1-(3-methoxy-phenyl)-propan-1-ol, is chosen from CF, CFH, C1 or F, preferably F, or 0365 (2RS,3RS)-3-(4-chlorophenyl)-1-dimethy 0347) if R', R'' and R' correspond to H, one of R lamino-2-methyl-pentan-3-ol, or R' also corresponds to H, while the other is 0366 (+)-(2R,3R)-3-(3-dimethylamino-1-ethyl-1-hy chosen from OH, OCH or OCH7. droxy-2-methyl-propyl-phenol, 0348. In this context, for compounds of group c) it is particularly preferable if the compounds of the formula I 0367 (2RS,3RS)-4-dimethylamino-2-(3-methoxy where R=H are present in the form of the diastereomers phenyl)-3-methyl-butan-2-ol and having the relative configuration Ia 0368 (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy phenyl)-3-methyl-butan-2-ol,

Ia 0369 preferably as the hydrochloride. 0370 For the active compound combination, it is par ticularly preferable if the compound A in group d) is chosen from compounds according to formula II for which: 0371 X is chosen from 0372 OH, F, C1, OC(O)CH, or H, preferably OH, F or H, in particular OH, and/or 0373) R' is chosen from 0349) in particular in mixtures having a higher con tent of this diastereomer compared with the other 0374 C-alkyl, CF, OH, O-C-alkyl, Cl or F, diastereomer or as the pure diastereomer and/or preferably OH, CF or CH, and/or 0350 if the compounds of the formula I are present 037513 R to R', where 3 or 4 of the radicals R to in the form of the (+)-enantiomer, in particular in R must correspond to H, independently of one mixtures having a higher content of the (+)-enanti another are chosen from omer compared with the (-)-enantiomer of a racemic 0376 H, C, F, OH, CFH, CF or C-alkyl, satu compound or as the pure (+)-enantiomer. rated and unsubstituted, branched or unbranched; US 2005/0137194A1 Jun. 23, 2005

OR' or SR'', where R'' is chosen from C-alkyl, 0393 (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3- Saturated and unsubstituted, branched or methoxy-phenyl)-cyclohexane-1,3-diol, unbranched; 0394 (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3- 0377 preferably H, Cl, F, OH, CFH, CF, OCH or hydroxy-phenyl)-cyclohexane-1,3-diol, SCH 0395 (1RS,3 SR,6RS)-6-dimethylaminomethyl-1-(3- 0378 or R'' and R' form a 3,4-OCH=CH ring methoxy-phenyl)-cyclohexane-1,3-diol, 0379 in particular 0396 (+)-(1R,2R,5S)-3-(2-dimethylaminomethyl-1- 0380) if R, R'' and R' correspond to H, one of R' hydroxy-5-methyl-cyclohexyl)-phenol or or R'' also corresponds to H, while the other is 0397) (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1- chosen from: hydroxy-5-trifluoromethyl-cyclohexyl)-phenol, 0381) Cl, F, OH, CFH, CF, OR' or SR'', prefer 0398 preferably as the hydrochloride. ably OH, CFH, OR' or SCH, in particular OH or 0399. For the active compound combination, it is par OC-alkyl, preferably OH or OCH, or ticularly preferable if the compound A in group e) is chosen 0382) if R and R' correspond to H and R' corre from compounds according to formula III for which: sponds to OH, OCH, C1 or F, preferably Cl, one of R" or R'' also corresponds to H, while the other 0400 X is chosen from corresponds to OH, OCH, C1 or F, preferably Cl, or 0401) OH, F, C1, OC(O)CH, or H, preferably OH, F 0383) if R, R', R'' and R' correspond to H, R' or H, in particular For H, and/or

is chosen from CF, CFH, C1 or F, preferably F, or 040213 R to R', where 3 or 4 of the radicals R to 0384) if R', R'' and R' correspond to H, one of R R must correspond to H, independently of one or R' also corresponds to H, while the other is another are chosen from chosen from OH, OCH or OCH7. 0403 H, C, F, OH, CFH, CF or C-alkyl, satu rated and unsubstituted, branched or unbranched; 0385 very particularly preferably OR or SR'', where R'' is chosen from C-alkyl, 0386 if R, R'' and R' correspond to H, one of R' Saturated and unsubstituted, branched or or R'' also corresponds to H, while the other is unbranched; chosen from: 0404 preferably H, Cl, F, OH, CFH, CF, OCH or 0387 C1, F, OH, SH, CFH, CF OR' or SR'', SCH, preferably OH or OR", in particular OH or OCs alkyl, preferably OH or OCH. 04.05) or R'' and R' form a 3,4-OCH=CH ring 0388. In this context, for compounds of group d) it is 04.06 in particular characterized in that particularly preferable if the compounds of the formula II 0407 if R, R'' and R' correspond to H, one of R' are present in the form of the diastereomers having the or R'' also corresponds to H, while the other is relative configuration IIa chosen from:

IIa 0408 C1, F, OH, CFH, CF, OR' or SR'', prefer ably OH, CFH, OR' or SCH, in particular OH or OC-alkyl, preferably OH or OCH, or 04.09 if R and R' correspond to H and R' corre sponds to OH, OCH, C1 or F, preferably Cl, one of R" or R'' also corresponds to H, while the other corresponds to OH, OCH, C1 or F, preferably Cl, or 0410 if R, R', R'' and R' correspond to H, R' is chosen from CF, CFH, C1 or F, preferably F, or 0411 if R', R'' and R' correspond to H, one of R 0389) in particular in mixtures having a higher con or R' also corresponds to H, while the other is tent of this diastereomer compared with the other chosen from OH, OCH or OCH7; diastereomer or as the pure diastereomer and/or 0412 very particularly preferably 0390 if the compounds of the formula II are present in the form of the (+)-enantiomer, in particular in 0413) if R, R'' and R' correspond to H, one of R' mixtures having a higher content of the (+)-enanti or R'' also corresponds to H, while the other is omer compared with the (-)-enantiomer of a racemic chosen from: compound or as the pure (+)-enantiomer. 0414) C1, F, OH, SH, CFH, CF, OR' or SR'', 0391) In this context, it is particularly preferable if com preferably OH or OR'', in particular OH or OC pound A is chosen from the following group: alkyl, preferably OH or OCH. 0392 (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3- 0415. In this context, for compounds of group e) it is methoxy-phenyl)-cyclohexane-1,3-diol, particularly preferable if the compounds of the formula III US 2005/0137194A1 Jun. 23, 2005 14 are present in the form of their diastereomers having the medicament is to be administered orally, intravenously, relative configuration IIIa intraperitoneally, intradermally, intramuscularly, intrana Sally, buccally or locally. Formulations in the form of tablets, chewable tablets, coated tablets, capsules, granules, drops, IIIa juices or Syrups are Suitable for oral administration, and Solutions, Suspensions, easily reconstitutable dry formula tions and Sprays are Suitable for parenteral, topical and inhalatory administration. Suppositories for use in the rec tum are a further possibility. The use in a depot in dissolved form, a carrier film or a patch, optionally with the addition of agents which promote penetration through the skin, are examples of Suitable forms for percutaneous administration. Examples of auxiliary Substances and additives for the oral administration forms are disintegrating agents, lubricants, binders, fillers, mould release agents, optionally Solvents, flavourings, Sugars, in particular carrier agents, diluents, 0416) in particular in mixtures having a higher con dyestuffs, antioxidants etc. For Suppositories, inter alia, tent of this diastereomer compared with the other waxes and fatty acid esters can be used, and for parental diastereomer or as the pure diastereomer and/or administration compositions carrier Substances, preserva 0417 if the compounds of the formula III are tives, Suspension auxiliaries etc. can be used. The amounts present in the form of the (+)-enantiomer, in particu of active compound to be administered to patients vary as a lar in mixtures having a higher content of the (+)- function of the weight of the patient, the mode of adminis enantiomer compared with the (-)-enantiomer of a tration and the Severity of the disease. The compounds racemic compound or as the pure (+)-enantiomer. according to the invention can be released in a delayed manner from formulation forms which can be used orally, 0418. In this context, it is particularly preferable if com rectally or percutaneously. Corresponding Sustained-release pound A is chosen from the following group: formulations, in particular in the form of a “once daily 0419 (+)-(1R,2R)-3-(2-dimethylaminomethyl-1- preparation which has to be taken only once a day, are fluoro-cyclohexyl)-phenol, particularly preferred for the indication according to the 0420 (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclo invention. hexyl)-phenol or 0432 Medicaments which comprise at least 0.05 to 90.0% of the active compound, in particular low active 0421 (-)-(1R,2R)-3-(2-dimethylaminomethyl-cyclo dosages, in order to avoid Side effects or analgesic actions, hexyl)-phenol, are furthermore preferred. 0.1 to 5,000 mg/kg, in particular 0422 preferably as the hydrochloride 1 to 500 mg/kg, preferably 2 to 250 mg/kg of body weight of at least one compound of the formula I are conventionally 0423 In a generally particularly preferred form of the administered. However, the administration of 0.01-5 mg/kg, active compound combination according to the invention, preferably 0.03 to 2 mg/kg, in particular 0.05 to 1 mg/kg, is the compound B is chosen from: also preferred and conventional. 0424 darifenacin, dulloxetine, oxybutynin or 0433 Auxiliary substances can be, for example: water, tolterodine, ethanol, 2-propanol, glycerol, ethylene glycol, propylene 0425 is preferably chosen from glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, Sucrose, dextrose, molasses, Starch, modi 0426 duloxetine, oxybutynin or tolterodine, fied Starch, gelatine, Sorbitol, inositol, mannitol, microcrys 0427 is preferably chosen from oxybutynin or talline cellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrroli tolterodine. done, paraffins, waxes, naturally occurring and Synthetic 0428 For a particularly preferred form of the active gums, gum acacia, alginates, dextran, Saturated and unsat compound combination according to the invention, the urated fatty acids, Stearic acid, magnesium Stearate, Zinc compound B is chosen from: Stearate, glyceryl Stearate, Sodium lauryl Sulfate, edible oils, Sesame oil, coconut oil, groundnut oil, Soya bean oil, leci 0429 venlafaxine, feSoterodine, Solifenacin thin, Sodium lactate, polyoxyethylene and -propylene fatty (YM905), cizolirtine or resiniferatoxin. acid esters, Sorbitan fatty acid esters, Sorbic acid, benzoic 0430. The invention also provides a medicament, prefer acid, citric acid, ascorbic acid, tannic acid, Sodium chloride, ably for treatment of an increased urge to urinate and urinary potassium chloride, magnesium chloride, calcium chloride, incontinence, comprising an active compound combination magnesium oxide, Zinc oxide, Silicon dioxide, titanium according to the invention and optionally Suitable additives oxide, titanium dioxide, magnesium Sulfate, Zinc Sulfate, and/or auxiliary Substances. calcium Sulfate, potash, calcium phosphate, dicalcium phos 0431 Suitable additives and/or auxiliary substances in phate, potassium bromide, potassium iodide, talc, kaolin, the context of this invention are all the Substances known to pectin, crospoVidone, agar and bentonite. the expert from the prior art for achieving galenical formu 0434. The medicaments and pharmaceutical composi lations. The choice of these auxiliary Substances and the tions according to the invention are prepared with the aid of amounts thereof to be employed depend on whether the means, devices, methods and processes which are well US 2005/0137194A1 Jun. 23, 2005 15 known in the prior art of pharmaceutical formulation, Such 0436) Even if the medicaments according to the invention as are described, for example, in "Remington's Pharmaceu show only a low degree of Side effects, it may be advanta tical Sciences’, ed. A. R. Gennaro, 17th ed., Mack Publish geous, for example to avoid certain forms of dependency, to ing Company, Easton, Pa. (1985), in particular in part 8, use morphine antagonists, in particular naloxone, naltrexone chapter 76 to 93. and/or levallorphan, in addition to the combination of the 0435 Thus e.g. for a solid formulation, such as a tablet, compounds A and B. the active compound of the medicament can be granulated 0437. The invention also relates to a method for treatment with a pharmaceutical carrier, e.g. conventional tablet con Stituents, Such as maize Starch, lactose, Sucrose, Sorbitol, of an increased urge to urinate and urinary incontinence, in talc, magnesium Stearate, dicalcium phosphate or pharma which the active compound combination of compound A and ceutically acceptable gums, and pharmaceutical diluents, compound B is used. Such as e.g. water, in order to form a Solid composition which comprises the active compound in homogeneous 0438 Certain embodiments of the present invention may distribution. Homogeneous distribution is understood here be further understood by reference to the following specific as meaning that the active compound is uniformly distrib examples. These examples and the terminology used herein uted over the entire composition, So that this can easily be is for the purpose of describing particular embodiments only divided into unit dose forms, Such as tablets, pills or cap and is not intended to be limiting. Sules, having the same activity. The Solid composition is then divided into unit dose forms. The tablets or pills of the EXAMPLES medicament according to the invention or of the composi tions according to the invention can also be coated or Example 1 compounded in another manner in order to provide a dose form with delayed release. Suitable coating compositions List of the Substances Tested are, inter alia, polymeric acids and mixtures of polymeric acids with materials. Such as e.g. Shellac, cetyl alcohol and/or 0439 A list of the compounds tested for their activity cellulose acetate. follows:

Name Cpd. no. (2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, 1. hydrochloride (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, 2 hydrochloride (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol, 3 hydrochloride (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dimethylamino-2-methyl-pentan- 4 3-ol, hydrochloride (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfanyl-phenyl)-pentan- 5 3-ol, hydrochloride (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-4,4-dimethyl-pentan-3-ol, 6 hydrochloride (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)- 7 phenol, hydrochloride (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol, 8 hydrochloride (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol, 9 hydrochloride (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol, 1O hydrochloride (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, 11 hydrochloride (+)-(1R,2R)-acetic acid 3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2- 12 methyl-propyl ester, hydrochloride (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxy-phenyl)- 13 propan-1-ol, hydrochloride (2RS,3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol, 14 hydrochloride (+)-(1R,2R)-3-(2-dimethylaminomethyl-1-fluoro-cyclohexyl)-phenol, 18 hydrochloride (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, hydrochloride 19 (-)-(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol, hydrochloride 2O rac-tramado 23 (-)-(2S,3S)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol, 21 hydrochloride (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)- 24 cyclohexane-1,3-diol, hydrochloride (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)- 25 cyclohexane-1,3-diol, hydrochloride US 2005/0137194A1 Jun. 23, 2005 16

-continued

Name Cpd. no. (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxy-phenyl)- 26 cyclohexane-1,3-diol, hydrochloride (1RS,3SR,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)- 27 cyclohexane-1,3-diol, hydrochloride (+)-(1R,2R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methyl 28 cyclohexyl)-phenol, hydrochloride (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl 29 cyclohexyl)-phenol, hydrochloride

Example 2 TABLE 1. Cystometry Test System on Conscious Naive Rats Influencing of cystometric parameters by the test 0440 Cystometric studies were carried out on naive, substances (change relative to the pre-value 76); female Sprague-Dawley rats in accordance with the method n corresponds to the number of test animals. of Ishizuka et al. (1997), Naunyn-Schmiedeberga Arch. TP BC ICI Pharmacol. 355: 787-793). Three days after implantation of Compound: threshold bladder intercontraction bladder and Venous catheters, the animals were investigated (concentration) pressure capacity interval in the freely mobile, conscious state. The bladder catheter 1. 94% ** 31% * * * +42% was connected to a preSSure transducer and an injection 1.0 mg/kg iv (n = 9) pump. The animals were placed in metabolism cages which 2 28.5% ** +7.8% +15.6% allowed measurement of the volume of urine. Physiological 0.1 mg/kg iv 122% ** +33% * +28% * saline solution was infused into the emptied bladder (10 (n = 5) 77.5% * * +20.6% * +28.6% * 0.3 mg/kg iv ml/h) and the bladder pressure and micturition volume were (n = 8) recorded continuously. After a stabilization phase, a 20 0.5 mg/kg iv minute phase, which was characterized by normal, repro (n = 9 ducible micturition cycles, was recorded. The following 21 -1.1% +3% +10% parameters, inter alia, were determined: 0.5 mg/kg iv (n = 8) 7 95% ** +32% * +28% * 0441 threshold pressure (TP, bladder pressure 0.3 mg/kg iv immediately before micturition), (n = 7) 8 60% ** +7% +14.4% 0442 bladder capacity (BC, residual volume after 1.0 mg/kg i. preceding micturition plus Volume of the infused (n = 8) Solution during the filling phase), 9 56% ** 50% ** +21% * 0.5 mg/kg iv (n = 7) 0443) intercontraction interval (ICI, the interval of 11 +9% +11% +22.6% time between micturitions). 0.5 mg/kg iv 0444 An increase in the threshold pressure (TP) indicates (n = 8) an important therapeutic action on one of the indications Significance (Student T test): according to the invention. The intercontraction interval (ICI) is also an important parameter for measuring the ** p < 0.01; physiological activity of a Substance in the treatment of *** p < 0.001. urinary incontinence, as is the bladder capacity (BC). In this context, because of the very heterogeneous causes of the 0446. The Substances investigated show a positive action Symptoms of this clinical picture, for an activity it is not on bladder regulation and are therefore Suitable for treatment necessary to influence all three parameters positively. It is of urinary incontinence. therefore entirely Sufficient if a positive action can be 0447. It is found, interalia, that of the enantiomers of the detected in only one of these parameters in order for it to be racemic compound 1, only the (+)-enantiomer (compound 2) possible to employ a Substance on urinary incontinence or an is effectively active (and is therefore a particularly preferred increased urge to urinate. compound of this invention), while the (-)-enantiomer 0445. After three reproducible micturition cycles had (compound 21) does not contribute to the action. been recorded as the pre-value, test Substances 1 (1.0 0448. Further experiments were undertaken with other mg/kg), 2 (0.1; 0.3 and 0.5 mg/kg), 21 (0.5 mg/kg), 7 (0.3 compounds. mg/kg), 8 (1.0 mg/kg), 9 (0.5 mg/kg) and 11 (0.5 mg/kg) were administered i.v. in the vehicle=0.9% NaCl and the 0449 After three reproducible micturition cycles had action on the cystometric parameters was recorded for 90 to been recorded as the pre-value, test Substances 24 (1.0, 3.0; 120 minutes. At the action maximum the mean of 3 mictu 5.0 mg/kg), 25 (1.5 mg/kg) and 26 (3.0 mg/kg) were rition cycles was determined and shown as a percentage administered i.v. in the vehicle=0.9% NaCl and the action on change compared with the pre-value (table 1). the cystometric parameters was recorded for 90 to 120 US 2005/0137194A1 Jun. 23, 2005 17 minutes. At the action maximum the mean of 3 micturition cycles was determined and shown as a percentage change TABLE 3-continued compared with the pre-value (table 2). Table 3: (n corresponds to the number of experiments included in the value TABLE 2 Cpd. no. Lowest dose (mg/kg) Table 2: Influencing of cystometric parameters by the test substances (change relative to the pre-value %); 5 2.3 (n = 3) n corresponds to the number of test animals. 6 16.7 (n = 3) 1O 0.2 (n = 3) TP BC ICI 12 30.0 (n = 3) Compound: threshold bladder interconnection 13 20.0 (n = 2) (concentration) pressure capacity interval 14 20.0 (n = 2) 24 +44.0% *** -8.0% -15% * * 1.0 mg/kg iv 94.0% ** -16.0% * -16% * (n = 7) +69.0% * -26.0% * -21.2% 0453 The Substances investigated show a positive action 3.0 mg/kg iv on bladder regulation and are therefore Suitable for treatment 5.0 mg/kg iv of urinary incontinence. (n = 8) 25 +62.0% * -14.0% * -90 * 0454. Further experiments were undertaken with other 1.5 mg/kg iv compounds. (n = 8) 26 -86.0% *** +29.0% * 27.0% * 3.0 mg/kg iv 0455 With all the substances listed here, a suppression of (n = 7) the Spontaneous contractions was measurable in the rats, table 4 showing the mean of the lowest dose of at least 2 Significance (Student T test): * p < 0.05; experiments at which for the first time contractions were ** p < 0.01; absent over a period of 10 minutes. *** p < 0.001. TABLE 4 0450. The Substances investigated show a positive action on bladder regulation and are therefore suitable for treatment Table 4: (n corresponds to the number of urinary incontinence. of experiments included in the value Cpd. no. Lowest dose (mg/kg) Example 3 27 115 (n = 2) 28 16.7 (n = 3) Cystometry Test System on Narcotized Naive Rats 29 23.3 (n = 3) 0451. The cystometric investigation on naive female rats was carried out in accordance with the method of Kimura et 0456. The Substances investigated show a positive action al. (Kimura et al., 1996, Int. J. Urol. 3: 218-227). The abdomen of narcotized, ventilated rats is opened up and the on bladder regulation and are therefore Suitable for treatment ureter is ligated. The urine is drained from the kidneys. A of urinary incontinence. catheter is inserted into the bladder and fixed. Saline is infused into the bladder via this by means of an infusion 0457. Further experiments were undertaken with other pump, until the bladder shows rhythmic Spontaneous activ compounds. ity in the form of contractions, which can be recorded via a 0458 With all the substances listed here, a suppression of connected pressure transducer. After Stable starting values the Spontaneous contractions was measurable in the rats, have been reached, the test Substance is administered i.v. in a cumulative manner. Influencing of the bladder function table 5 showing the mean of the lowest dose of at least 2 manifests itself via Suppression of the Spontaneous contrac experiments at which for the first time contractions were tions. In this context, the absence of contractions over a absent over a period of 10 minutes. period of 10 min is a parameter for the Suppression. TABLE 5 0452. With all the substances listed here, a suppression of the Spontaneous contractions was measurable in the rats, Table 5: (in corresponds to the number table 3 showing the mean of the lowest dose of at least 2 of experiments included in the value experiments at which for the first time contractions were Cpd. no. Lowest dose (mg/kg) absent over a period of 10 minutes. 18 0.2 (n = 3) TABLE 3 19 0.1 (n = 3) 2O 0.5 (n = 3) Table 3: (n corresponds to the number 23 (tramadol) 5.3 (n = 3) of experiments included in the value Cpd. no. Lowest dose (mg/kg) 0459. The Substances investigated show a positive action 3 23.3 (n = 3) on bladder regulation and are therefore Suitable for treatment 4 1.7 (n = 3) of urinary incontinence and also appear to be Superior to tramadol in this. US 2005/0137194A1 Jun. 23, 2005

0460 The following substances were furthermore tested, 0468. After three reproducible micturition cycles had with the result shown in table 6: been recorded as the pre-value, 10 ug/kg buprenorphine 0461) With all the substances listed here, a suppression of were administered i.v. in the vehicle=0.9% NaCl and the the Spontaneous contractions was measurable in the rats, action on the cystometric parameters was recorded for 90 to table 6 showing the mean of the lowest dose of at least 3 120 minutes. At the action maximum the mean of 3 mictu independent experiments at which for the first time contrac rition cycles was determined and shown as a percentage tions were absent over a period of 10 minutes. change compared with the pre-value (table 7). 0469 The concentration employed corresponds to the TABLE 6 ED. in a known analgesia model for rats, the tail flick. Table 6: (n corresponds to the number of experiments included in the value TABLE 7 Compound Lowest dose (mg/kg) Table 7: Influencing of cystometric parameters by buprenorphine(change relative to the pre-value 76); n corresponds to the number tilidine 0.5 (n = 3) of test animals employed in the study. meptazinol 1.0 (n = 3) codeine (phosphate) 4.7 (n = 3) TP BC ICI threshold bladder intercontraction Buprenorphine pressure capacity interval 0462. The Substances investigated show a positive action 0.01 mg/kg iv +69.9% +3.6% +10.9% on bladder regulation and are therefore Suitable for treatment of urinary incontinence. Significance (Student T test): * p < 0.05; Example 4 ** p < 0.01; *** p < 0.001. Cystometry Test System on Conscious Naive Rats 0463 Cystometric studies were carried out on naive, 0470 Buprenorphine shows a positive action on bladder female Sprague-Dawley rats in accordance with the method regulation precisely on the TP and is therefore suitable in of Ishizuka et al. (1997), Naunyn-Schmiedeberg's Arch. principle for treatment of urinary incontinence. Neverthe Pharmacol. 355: 787-793). Three days after implantation of less, the concentration employed, which has an analgesic bladder and Venous catheters, the animals were investigated action, was evidently too high, Since drip incontinence in the freely mobile, conscious state. The bladder catheter occurred in 2 of the 6 animals. At two lower concentrations, was connected to a preSSure transducer and an injection 0.001 mg/kg i.v. and 0.005 mg/kg i.v., an increase in the TP pump. The animals were placed in metabolism cages which of +27.6% and +37.5% respectively occurred in n=6. allowed measurement of the volume of urine. Physiological saline solution was infused into the emptied bladder (10 Example 5 ml/h) and the bladder pressure and micturition volume were recorded continuously. After a Stabilization phase, a 20 Cystometry Test System on Conscious Damaged minute phase, which was characterized by normal, repro Rats ducible micturition cycles, was recorded. The following 0471. This model simulates the urgency incontinence in parameters, inter alia, were determined: an animal model; the oxyhaemoglobin (OxyHb) employed 0464) threshold pressure (TP, bladder pressure induces a bladder hyperactivity. immediately before micturition), 0472. Cystometric studies were carried out on naive, 0465 bladder capacity (BC, residual volume after female Sprague-Dawley rats in accordance with the method preceding micturition plus Volume of the infused of Pandita et al. (J. Urol. 2000, 164: 545-550)). Three days Solution during the filling phase), after implantation of bladder and Venous catheters, the animals were investigated in the freely mobile, conscious 0466 intercontraction interval (ICI, the interval of State. The bladder catheter was connected to a preSSure time between micturitions). transducer and an injection pump. The animals were placed 0467. An increase in the threshold pressure (TP) indicates in metabolism cages which allowed measurement of the an important therapeutic action on one of the indications Volume of urine. Physiological Saline Solution was infused according to the invention. The intercontraction interval into the emptied bladder (10 ml/h) and the bladder pressure (ICI) is also an important parameter for measuring the and micturition volume were recorded continuously. After a physiological activity of a Substance in the treatment of Stabilization phase, a 20 minute phase, which was charac urinary incontinence, as is the bladder capacity (BC). In this terized by normal, reproducible micturition cycles, was context, because of the very heterogeneous causes of the recorded. The following parameters, inter alia, were deter Symptoms of this clinical picture, for an activity it is not mined: necessary to influence all three parameters positively. It is 0473 threshold pressure (TP, bladder pressure therefore entirely Sufficient if a positive action can be immediately before micturition), detected in only one of these parameters in order for it to be possible to employ a Substance on urinary incontinence, 0474 bladder capacity (BC, residual volume after increased frequency of micturition or an increased urge to preceding micturition plus Volume of the infused urinate. Solution during the filling phase), US 2005/0137194A1 Jun. 23, 2005 19

0475 intercontraction interval (ICI, the interval of 0479. The administration of 5 ug/kg buprenorphine i.v. in time between micturitions) the vehicle=0.9% NaCl before the administration of oxyhe moglobin is capable of Suppressing the changes induced by 0476) micturition pressure (MP, maximum bladder Oxyhemoglobin and moreover also of inducing an increase pressure during a micturition). in the threshold pressure (table 8).

TABLE 8 Table 8: Influencing of the cystometric parameters by oxyhaemoglobin (OxyHb) with and without prior administration of buprenorphine. Average values with standard deviations before (b) and after (a) use of the substances and the change (diff.) in comparison with the pre-value % are stated; in corresponds to the number of animals employed in the study.

MP TP BC ICI micturition threshold bladder intercontraction pressure pressure capacity interval cm H2O cm H2O ml min OxyHb

2.5 x 10 M iv b: S9 8 b: 8.72 + 1.31 b: 0.92 + 0.10 b: 4.96 - 0.33 (n = 5) a: 975 a: 9.84 - 1.56 a: 0.65 + 0.06 a: 3.33 - 0.18 diff.: +64.4% diff.: +12.8% diff: -29.3% diff: -32.9% :::::: :::::: ::::::

buprenorphine

OxyHb: b: 54 - 9 b: 9.07 - 1.29 b:1.19 + 0.12 b: 6.72 - 0.73 2.5 x 10 M a: 378 a: 14.28 2.53 a: 1.17 - 0.13 a: 6.70- 0.88 buprenorphine: diff.:-31.5% diff.: +57.4% diff: -1.7% diff -0.3% 0.005 mg/kg iv : : (n = 6) Significance (Student T test): ** p < 0.01; *** p < 0.001.

0477 An increase in the threshold pressure (TP) indicates 0480. It can be seen that OxyHb clearly adversely influ an important therapeutic action on one of the indications ences the bladder parameters in the Sense of urgency incon according to the invention. The intercontraction interval tinence. This adverse influencing is eliminated by buprenor (ICI) is also an important parameter for measuring the phine, and even improved. Thus, the micturition preSSure physiological activity of a Substance in the treatment of falls significantly compared with the urgency incontinence urinary incontinence, as is the bladder capacity (BC). In this induced by OxyHb and also compare with the untreated context, because of the very heterogeneous causes of the control. In this urgency incontinence model buprenorphine Symptoms of this clinical picture, for an activity it is not furthermore normalizes the intercontraction interval and the necessary to influence all the parameters positively. It is bladder capacity completely and moreover has the effect of therefore entirely Sufficient if a positive action can be a significant and clear increase in the threshold preSSure. detected in only one of these parameters in order for it to be 0481 Evidence is thus provided that buprenorphine, in possible to employ a Substance on urinary incontinence, particular in the area of urgency incontinence, for which the increased frequency of micturition or an increased urge to OxyHb model is the standard model, shows an outstanding urinate. action, and in particular also in the event of damage, that is to Say in the case of disease. 0478 After three reproducible micturition cycles had been recorded as the pre-value, 2.5x10" M oxyhemoglobin Example 6 in the vehicle=0.9% NaCl were infused into the bladder. The action on the cystometric parameters was recorded for about Parenteral Administration Form 20 minutes. At the action maximum the mean of 3 mictu rition cycles was determined and shown as a percentage 0482 20 g tramadol and 1 g venlafaxine are dissolved in change compared with the pre-value (table 8). The treatment 11 water for injection purposes at room temperature and the with oxyhaemoglobin induces a characteristic change in the Solution is then adjusted to isotonic conditions by addition of cystometric parameters with an increase in the micturition NaCl. preSSure, a reduction in the bladder capacity and a reduction 0483 The foregoing description and examples have been in the intercontraction interval. These changes mirror the set forth merely to illustrate the invention and are not changes found in patients with urgency incontinence. intended to be limiting. Since modifications of the described US 2005/0137194A1 Jun. 23, 2005 2O embodiments incorporating the Spirit and Substance of the Group c) consisting of: invention may occur to perSons skilled in the art, the 1-phenyl-3-dimethylamino-propane compounds corre invention should be construed broadly to include all varia tions falling within the Scope of the appended claims and sponding to formula I equivalents thereof.

What is claimed is: 1. A pharmaceutical formulation comprising a combina tion of at least one compound Selected from group A and at least one compound Selected from group B, wherein group A consists of: Group a) consisting of: tramadol, O-demethyltramadol and O-demethyl-N- monodemethyl-tramadol; Group b) consisting of: codeine dextropropoxyphene wherein dihydrocodeine X is chosen from OH, F, Cl, H or OC(O)R’, where R7 is chosen from C-alkyl, branched or unbranched, diphenoxylate Saturated or unsaturated, unsubstituted or mono- or ethylmorphine poly Substituted, meptazinol R" is chosen from C-alkyl, branched or unbranched, Saturated or unsaturated, unsubstituted or mono- or nalbuphine poly Substituted, pethidine (meperidine) RandR in each case independently of one another are tilidine chosen from H or C-alkyl, branched or unbranched, Saturated or unsaturated, unsubstituted tramadol or mono- or poly Substituted, or Viminol R° and R together form a saturated C-cycloalkyl butorphanol radical, unsubstituted or mono- or poly Substituted, dextromoramide R’-R' in each case independently of one another are chosen from H, F, Cl, Br, I, CHF, CHF, CF, OH, dezocine SH, OR'', OCF, SR'', NR7R, SOCH, SOCF; SOCH, SOCF, CN, COOR, NO, diacetylmorphine (heroin) CONR'R'; Co-alkyl, branched or unbranched, hydrocodone Saturated or unsaturated, unsubstituted or mono- or hydromorphone poly Substituted; phenyl, unsubstituted or mono- or poly Substituted; ketobemidone where R'' is chosen from Cle-alkyl; pyridyl, thienyl, levomethadone thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O- levomethadyl acetate (1-O-acetylmethadol (LAAM)) C-alkyl), CO(OC-alkyl), CONH-CH levorphanol (C3-alkyl), CO(C-s-alkyl), CO-CHR''- NHR, CO CH-R', where R' is ortho morphine OCOC-alkyl or meta- or para-CHN(R'), where nalorphine R' is C-alkyl or 4-morpholino, wherein in the Oxycodone radicals R', R' and R' the alkyl groups can be branched or unbranched, Saturated or unsaturated, pentazocine unsubstituted or mono- or poly Substituted; piritramide where R'' and R' in each case independently of one another are chosen from H, C-alkyl, branched or alfentanil unbranched, Saturated or unsaturated, unsubstituted buprenorphine or mono- or polySubstituted; phenyl, benzyl or phen ethyl, in each case unsubstituted or mono- or etorphine poly Substituted, or fentanyl R and R' or R'' and R'' together form an OCHO, remifentanil and OCHCHO, OCH=CH, CH=CHO, CH=C(CH)O, OC(CH.)=CH, (CH), or Sufentanil; OCH=CHO ring: US 2005/0137194A1 Jun. 23, 2005 21

Group d) consisting of:

substituted 6-dimethylaminomethyl-1-phenylcyclo III hexane compounds corresponding to formula II R11 R12 II R11 R19 R12

N-CH R9 R13 CH X N-CH wherein 1. CH R X is chosen from OH, F, Cl, H or OC(O)R’, where R7 H is chosen from C-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or wherein polysubstituted, and R’-R' in each case independently of one another are X is chosen from OH, F, Cl, H or OC(O)R’, where R' chosen from H, F, Cl, Br, I, CHF, CHF, CF, OH, is chosen from C-alkyl, branched or unbranched, SH, OR'', OCF, SR', NR7R', SOCH, SOCF; saturated or unsaturated, unsubstituted or mono- or SOCH, SOCF, CN, COOR, NO, polysubstituted, CONR'R'; Co-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or R" is chosen from C-alkyl, benzyl, CFs, OH, polysubstituted; phenyl, unsubstituted or mono- or OCH-CH, O-C-alkyl, Cl or F and polysubstituted; R’-R' in each case independently of one another are where R' is chosen from Ce-alkyl; pyridyl, thienyl, chosen from H, F, Cl, Br, I, CHF, CHF, CF, OH, thiazolyl, phenyl, benzyl or phenethyl, in each case SH, OR1, OCF, SR'', NR7R, SOCH, SOCF; unsubstituted or mono- or polysubstituted; PO(O- SOCH, SOCF, CN, COOR, NO, C-alkyl), CO(OCs-alkyl), CONH-CH CONR'R'; C-alkyl, branched or unbranched, (C-alkyl), CO(C-s-alkyl), CO-CHR'- saturated or unsaturated, unsubstituted or mono- or NHR, CO-CH-R', where R is ortho polysubstituted; phenyl, unsubstituted or mono- or OCOC-alkyl or meta- or para-CHN(R'), where polysubstituted; R' is C-alkyl or 4-morpholino, wherein in the where R' is chosen from C6-alkyl; pyridyl, thienyl, radicals R', R' and R' the alkyl groups can be thiazolyl, phenyl, benzyl or phenethyl, in each case branched or unbranched, Saturated or unsaturated, unsubstituted or mono- or polysubstituted; PO(O-C unsubstituted or mono- or polysubstituted; 14-alkyl), CO(OCs-alkyl), CONH-CH-(C- where R'' and R' in each case independently of one 3-alkyl), CO(C-alkyl), CO-CHR'7-NHR'. another are chosen from H., Calkyl, branched or Co-CH-R', where R' is ortho-OCOC-3-alkyl unbranched, saturated or unsaturated, unsubstituted or meta- or para-CHN(R'), where R' is C.- or mono- or polysubstituted; phenyl, benzyl or phen alkyl or 4-morpholino, wherein in the radicals R', ethyl, in each case unsubstituted or mono- or R and R' the alkyl groups can be branched or polysubstituted, or unbranched, saturated or unsaturated, unsubstituted R and R' or R'' and R'' together form an OCHO, or mono- or polysubstituted; OCHCHO, OCH=CH, CH=CHO, where R7 and R' in each case independently of one CH=C(CH)O, OC(CH)=CH, (CH), or another are chosen from H, C6-alkyl, branched or OCH=CHO ring, unbranched, saturated or unsaturated, unsubstituted with the proviso that if R, R'' and R' correspond to or mono- or polysubstituted; phenyl, benzyl or phen H and one of R' or R' corresponds to H and the ethyl, in each case unsubstituted or mono- or polysubstituted, or other corresponds to OCH, X may not be OH, and wherein group B consists of: R and R' or R'' and R' together form an OCHO, venlafaxine, fesoterodine, solifenacin (YM905), cizo OCHCHO, OCH=CH, CH=CHO, lirtine, resiniferatoxin, nitro-flurbiprofen, HCT1026, CH=C(CH)O, OC(CH)=CH, (CH), or talnetant, TAK-637, SL 251039, R 450, Rec OCH=CHO ring and 15/3079, (-)-DDMS, NS-8 and DRP-001. Group e) consisting of: 2. The pharmaceutical formulation of claim 1, wherein either or both of the compounds of Group A and Group B are 6-dimethylaminomethyl-1-phenyl-cyclohexane CO present in the form of a salt with a physiologically tolerated pounds corresponding to formula III acid. US 2005/0137194A1 Jun. 23, 2005 22

3. The pharmaceutical formulation of claim 1, wherein X is chosen from OH, F, Cl, OC(O)CH or H; either or both of the compounds of Group A and Group B are present in the form of an acid. R" is chosen from C-alkyl, Saturated and unsubstituted, 4. The pharmaceutical formulation of claim 1, wherein branched or unbranched; either or both of the compounds of Group A and Group B are R° and Rindependently of one another are chosen from present in the form of a free base. H or C-alkyl, Saturated and unsubstituted, branched 5. The pharmaceutical formulation of claim 1, wherein or unbranched; or either or both of the compounds of Group A and Group B are present in the form of a Salt with a physiologically tolerated R and R together form a C5-6-cycloalkyl radical, Satu base. rated or unsaturated, unsubstituted or mono- or 6. The pharmaceutical formulation of claim 1, wherein polySubstituted; either or both of the compounds of Group A and Group B are R-R', where 3 or 4 of the radicals R-R' must corre present in the form of an individual enantiomer or diaste spond to H, independently of one another are chosen reoisomer. from H., Cl, F, OH, CFH, CF or C-alkyl, saturated 7. The pharmaceutical formulation of claim 1, wherein and unsubstituted, branched or unbranched; OR' or either or both of the compounds of Group A and Group B are SR", where R'' is chosen from C-alkyl, saturated present in the form of a mixture of Stereoisomers. and unsubstituted, branched or unbranched; 8. The pharmaceutical formulation of claim 1, wherein the compound A in group a) is selected from: or R'' and R' form a 3,4-OCH=CH ring; tramadol, (+)-tramadol, (+)-O-demethyltramadol and or if R, R'' and R' correspond to H, one of R' or R' (+)-O-demethyl-N-mono-demethyl-tramadol. also corresponds to H, while the other is chosen from: 9. The pharmaceutical formulation of claim 1, wherein the C1, F, OH, CFH, CF, OR' or SR'; compound A in group a) is (+)-tramadol. or if R and R' correspond to Hand R' corresponds to 10. The pharmaceutical formulation of claim 1, wherein OH, OCH, Clor F, one of R' or R'' also corresponds the compound A in group b) is chosen from: to H, while the other corresponds to OH, OCH, Clor codeine F; dextropropoxyphene or if R, R', R'' and R' correspond to H, R' is chosen dihydrocodeine from CF, CFH, C or F; or if R', R'' and R' correspond to H, one of R or R' diphenoxylate also corresponds to H, while the other is chosen from: ethylmorphine OH, OCH or OCH7. 13. The pharmaceutical formulation of claim 12, wherein meptaZinol compounds corresponding to formula I where R=H are nalbuphine present in the form of the diastereomers having the relative pethidine (meperidine) configuration Ia tilidine Ia Viminol butorphanol deZocine nalorphine pentazocine and buprenorphine. 11. The pharmaceutical formulation of claim 1, wherein the compound A in group b) is chosen from: O codeine compounds corresponding to formula I are present in the form of the (+)-enantiomer. dextropropoxyphene 14. The pharmaceutical formulation of claim 13, wherein dihydrocodeine compounds corresponding to formula I where R=H are present in the form of the diastereomers having the relative meptaZinol configuration Ia in a greater amount than the other diaste nalbuphine reomer or the pure diasteromer having the relative configu ration Ia is provided or tilidine and compounds corresponding to formula I are present in the buprenorphine. form of the (+)-enantiomer, said formulation having a 12. The pharmaceutical formulation of claim 1, wherein higher content of the (+)-enantiomer compared with the the compound A in group c) is chosen from compounds (-)-enantiomer or said formulation having the pure according to formula I for which: (+)-enantiomer. US 2005/0137194A1 Jun. 23, 2005 23

15. The pharmaceutical formulation of claim 12, wherein or if R, R'' and R' correspond to H, one of R' or R' compound A is Selected from the group consisting of: also corresponds to H, while the other is chosen from (2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2- C1, F, OH, CFH, CF, OR' or SR'; methyl-pentan-3-ol, or if R and R' correspond to H and R' corresponds to OH, OCH, C1 or F, preferably Cl, one of R' or R' (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2- also corresponds to H, while the other corresponds to methyl-pentan-3-ol, OH, OCH, C1 or F; (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2- or if R, R', R'' and R' correspond to H, R' is chosen methyl-pentan-3-ol, from CF, CFH, C or F; (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dimethy or if R', R'' and R' correspond to H, one of R or R' lamino-2-methyl-pentan-3-ol, also corresponds to H, while the other is chosen from (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfa OH, OCH or OCH7; nyl-phenyl)-pentan-3-ol, or if R, R'' and R' correspond to H, one of R' or R' (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-4,4-dim also corresponds to H, while the other is chosen from ethyl-pentan-3-ol, Cl, F, OH, SH, CFH, CF, OR' or SR''. 18. A pharmaceutical formulation according to claim 17, (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2- wherein compounds corresponding to formula II are present methyl-propyl)-phenol, in the form of the diastereomers having the relative con (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dim figuration IIa ethyl-propyl)-phenol, IIa (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dim ethyl-propyl)-phenol, (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dim ethyl-propyl)-phenol, (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-pro pyl)-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, O (2RS,3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-me thyl-pentan-3-ol, compounds corresponding to formula II are present in the form of the (+)-enantiomer. (+)-(2R,3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2- 19. A pharmaceutical formulation according to claim 18, methyl-propyl-phenol, wherein compounds corresponding to formula II are present in the form of the diastereomers having the relative con (2RS,3RS)-4-dimethylamino-2-(3-methoxy-phenyl)-3- figuration IIa in a greater amount than the other diastereomer methyl-butan-2-ol and or the pure diastereomer having the relative configuration IIa (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy-phenyl)-3- is provided or methyl-butan-2-ol. compounds corresponding to formula II are present in the 16. The pharmaceutical formulation of claim 15, wherein form of the (+)-enantiomer, said formulation having a compound A is in the form of a hydrochloride. higher content of the (+)-enantiomer compared with the 17. The pharmaceutical formulation of claim 1, wherein (-)-enantiomer or said formulation having the pure the compound A in group d) is chosen from compounds (+)-enantiomer. corresponding to formula II for which: 20. A pharmaceutical formulation according to claim 17, wherein compound A is Selected from the group consisting X is chosen from OH, F, Cl, OC(O)CH or H; of: R" is chosen from C-alkyl, CF, OH, O-C-alkyl, Cl (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy or F; phenyl)-cyclohexane-1,3-diol, R-R', where 3 or 4 of the radicals R to R' must (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxy correspond to H, independently of one another are phenyl)-cyclohexane-1,3-diol, chosen from H, Cl, F, OH, CFH, CF or C-alkyl, Saturated and unsubstituted, branched or unbranched; (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxy OR or SR'', where R'' is chosen from C-alkyl, phenyl)-cyclohexane-1,3-diol, Saturated and unsubstituted, branched or unbranched; (1RS,3 SR,6RS)-6-dimethylaminomethyl-1-(3-methoxy or R'' and R' form a 3.4-OCH=CH ring phenyl)-cyclohexane-1,3-diol, US 2005/0137194A1 Jun. 23, 2005 24

(+)-(1R,2R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5- O methyl-cyclohexyl)-phenol and compounds corresponding to formula III are present in the (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1-hydroxy form of the (+)-enantiomer, said formulation having a 5-trifluoromethyl-cyclohexyl)-phenol. higher content of the (+)-enantiomer compared with the 21. A pharmaceutical formulation according to claim 20, (-)-enantiomer or said formulation having the pure wherein compound A is in the form of a hydrochloride. (+)-enantiomer. 22. A pharmaceutical formulation according to claim 1, 25. A composition of matter according to claim 22, wherein compound A in groupe) is chosen from compounds wherein compound A is Selected from the group consisting corresponding to formula III for which: of: (+)-(1R,2R)-3-(2-dimethylaminomethyl-1-fluoro-cyclo X is chosen from OH, F, Cl, OC(O)CH or H; hexyl)-phenol, R-R', where 3 or 4 of the radicals R to R' must correspond to H, independently of one another are (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phe chosen from H, Cl, F, OH, CFH, CF or C-alkyl, nol and Saturated and unsubstituted, branched or unbranched; (-)-(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)- OR or SR'', where R'' is chosen from C-alkyl, phenol. Saturated and unsubstituted, branched or unbranched; 26. A composition of matter according to claim 25, or R'' and R' form a 3,4-OCH=CH ring; wherein compound A is present in the form of a hydrochlo ride. or if R, R'' and R' correspond to H, one of R' or R' 27. A composition of matter according to claim 1, wherein also corresponds to H, while the other is chosen from compound B is Selected from the group consisting of: C1, F, OH, CFH, CF, OR' or SR'; fesoterodine, Solifenacin (YM905), cizolirtine, resinifera or if R and R' correspond to H and R' corresponds to toxin and Venlaxafine. OH, OCH, C1 or F, preferably Cl, one of R' or R' 28. A pharmaceutical formulation comprising: also corresponds to H, while the other corresponds to OH, OCH, C1 or F; a composition of matter according to claim 1 and a pharmaceutically acceptable auxiliary Substance. or if R, R', R'' and R' correspond to H, R' is chosen 29. A method of treating increased urge to urinate or from CF, CFH, C or F; urinary incontinence in a mammal comprising administering or if R', R'' and R' correspond to H, one of R or R' to Said mammal an effective amount of at least one com also corresponds to H, while the other is chosen from pound Selected from group A and at least one compound OH, OCH or OCH7; Selected from group B, wherein group A consists of: or if R, R'' and R' correspond to H, one of R' or R' Group a) consisting of: also corresponds to H, while the other is chosen from tramadol, O-demethyltramadol and O-demethyl-N- Cl, F, OH, SH, CFH, CF, OR' or SR''. monodemethyl-tramadol; 23. A pharmaceutical formulation according to claim 22, wherein compounds corresponding to formula III are present Group b) consisting of: in the form of their diastereomers having the relative con figuration IIa codeine dextropropoxyphene

IIIa dihydrocodeine diphenoxylate ethylmorphine meptazinol nalbuphine pethidine (meperidine) tilidine tramadol Viminol O compounds corresponding to formula III are present in the butorphanol form of the (+)-enantiomer. dextromoramide 24. A pharmaceutical formulation according to claim 23, wherein compounds corresponding to formula 1 ml are deZocine present in the form of the diastereomers having the relative diacetylmorphine (heroin) configuration IIIa in a greater amount than the other dias hydrocodone tereomer or the pure diastereomer having the relative con figuration IIa is provided hydromorphone US 2005/0137194A1 Jun. 23, 2005 25

ketobemidone Saturated or unsaturated, unsubstituted or mono- or poly Substituted; phenyl, unsubstituted or mono- or levomethadone poly Substituted; levomethadyl acetate (1-O-acetylmethadol (LAAM)) where R'' is chosen from C-alkyl; pyridyl, thienyl, levorphanol thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O- morphine C-alkyl), CO(OCs-alkyl), CONH-CH (C-alkyl), CO(C-alkyl), CO-CHR'7- nalorphine NHR, CO-CH-R", where R is ortho Oxycodone OCOC-alkyl or meta- or para-CHN(R'), where R" is C-alkyl or 4-morpholino, wherein in the pentazocine radicals R', R' and R' the alkyl groups can be piritramide branched or unbranched, Saturated or unsaturated, unsubstituted or mono- or poly Substituted; alfentanil where R7 and R' in each case independently of one buprenorphine another are chosen from H, C-alkyl, branched or unbranched, Saturated or unsaturated, unsubstituted etorphine or mono- or polySubstituted; phenyl, benzyl or phen fentanyl ethyl, in each case unsubstituted or mono- or poly Substituted, or remifentanil and R and R' or R'' and R'' together form an OCHO, Sufentanil; OCHCHO, OCH=CH, CH=CHO, CH=C(CH)O, OC(CH.)=CH, (CH), or Group c) consisting of: OCH=CHO ring: 1-phenyl-3-dimethylamino-propane compounds corre Group d) consisting of: sponding to formula I Substituted 6-dimethylaminomethyl-1-phenylcyclo hexane compounds corresponding to formula II

II R11 R1 R12

R9 R13

X N-CH

1. CH R wherein H X is chosen from OH, F, Cl, H or OC(O)R’, where R7 is chosen from C-alkyl, branched or unbranched, wherein Saturated or unsaturated, unsubstituted or mono- or poly Substituted, X is chosen from OH, F, Cl, H or OC(O)R’, where R7 is chosen from C-alkyl, branched or unbranched, R" is chosen from C-alkyl, branched or unbranched, Saturated or unsaturated, unsubstituted or mono- or Saturated or unsaturated, unsubstituted or mono- or poly Substituted, poly Substituted, R" is chosen from C-alkyl, benzyl, CF, OH, RandR in each case independently of one another are OCH-CHs, O-C-alkyl, Cl or F and chosen from H or C-alkyl, branched or unbranched, Saturated or unsaturated, unsubstituted R’-R' in each case independently of one another are or mono- or polySubstituted, or chosen from H, F, Cl, Br, I, CHF, CHF, CF, OH, SH, OR'', OCF, SR'', N'R', SOCH, SOCF; R° and R together form a saturated C-7-cycloalkyl SOCH, SOCF, CN, COOR, NO, radical, unsubstituted or mono- or poly Substituted, CONR'R'; Co-alkyl, branched or unbranched, R’-R' in each case independently of one another are Saturated or unsaturated, unsubstituted or mono- or chosen from H, F, Cl, Br, I, CHF, CHF, CF, OH, poly Substituted; phenyl, unsubstituted or mono- or SH, OR'', OCF, SR'', NR7R, SOCH, SOCF; poly Substituted; SOCH, SOCF, CN, COOR, NO, where R'' is chosen from Cle-alkyl; pyridyl, thienyl, CONR'R'; C-alkyl, branched or unbranched, thiazolyl, phenyl, benzyl or phenethyl, in each case US 2005/0137194A1 Jun. 23, 2005 26

unsubstituted or mono- or polysubstituted; PO(O- where R'' and R' in each case independently of one C-alkyl), CO(OCs-alkyl), CONH-CH another are chosen from H, C-alkyl, branched or (C3-alkyl), CO(C-s-alkyl), CO-CHR''- unbranched, Saturated or unsaturated, unsubstituted NHR, CO-CH-R', where R is ortho or mono- or polySubstituted; phenyl, benzyl or phen OCOC-alkyl or meta- or para-CHN(R'), where ethyl, in each case unsubstituted or mono- or R" is C-alkyl or 4-morpholino, wherein in the poly Substituted, or radicals R', R' and R' the alkyl groups can be R and R' or R'' and R'' together form an OCHO, branched or unbranched, Saturated or unsaturated, OCHCHO, OCH=CH, CH=CHO, unsubstituted or mono- or polySubstituted; CH=C(CH)O, OC(CH.)=CH, (CH), or where R'' and R' in each case independently of one OCH=CHO ring, another are chosen from H, C-alkyl, branched or unbranched, Saturated or unsaturated, unsubstituted with the proviso that if R. R'' and R' correspond to or mono- or polySubstituted; phenyl, benzyl or phen H and one of R' or R' corresponds to H and the ethyl, in each case unsubstituted or mono- or other corresponds to OCH, X may not be OH, and poly Substituted, or wherein group B consists of: R and R' or R'' and R'' together form an OCHO, venlafaxine, fesoterodine, Solifenacin (YM905), cizo OCHCHO, OCH=CH, CH=CHO, lirtine, resiniferatoxin, nitro-flurbiprofen, HCT1026, CH=C(CH)O, OC(CH.)=CH, (CH), or talnetant, TAK-637, SL 251039, R 450, Rec OCH=CHO ring and 15/3079, (-)-DDMS, NS-8 and DRP-001. 30. The method of claim 29, wherein either or both of the Group e) consisting of: compounds of Group A and Group B are present in the form 6-dimethylaminomethyl-1-phenyl-cyclohexane CO of a Salt with a physiologically tolerated acid. pounds corresponding to formula III 31. The method of claim 29, wherein either or both of the compounds of Group A and Group B are present in the form of an acid. III 32. The method of claim 29, wherein either or both of the compounds of Group A and Group B are present in the form of a free base. 33. The method of claim 29, wherein either or both of the compounds of Group A and Group B are present in the form of a Salt with a physiologically tolerated base. 34. The method of claim 29, wherein either or both of the compounds of Group A and Group B are present in the form N-CH of an individual enantiomer or diastereoisomer. 35. The method of claim 29, wherein either or both of the CH compounds of Group A and Group B are present in the form of a mixture of Stereoisomers. 36. The method of claim 29, wherein the compound A in wherein group a) is selected from: X is chosen from OH, F, Cl, H or OC(O)R7, where R7 tramadol, (+)-tramadol, (+)-O-demethyltramadol and is chosen from C-alkyl, branched or unbranched, (+)-O-demethyl-N-mono-demethyl-tramadol. Saturated or unsaturated, unsubstituted or mono- or 37. The method of claim 29, wherein the compound A in poly Substituted, and group a) is (+)-tramadol. R’-R' in each case independently of one another are 38. The method of claim 29, wherein the compound A in chosen from H, F, Cl, Br, I, CHF, CHF, CF, OH, group b) is chosen from: SH, OR'', OCF, SR'', NR7R', SOCH, SOCF; codeine SOCH, SOCF, CN, COOR, NO, CONR'R'; Co-alkyl, branched or unbranched, dextropropoxyphene Saturated or unsaturated, unsubstituted or mono- or dihydrocodeine poly Substituted; phenyl, unsubstituted or mono- or diphenoxylate poly Substituted; where R'' is chosen from Cle-alkyl; pyridyl, thienyl, ethylmorphine thiazolyl, phenyl, benzyl or phenethyl, in each case meptazinol unsubstituted or mono- or polysubstituted; PO(O- C-alkyl), CO(OCs-alkyl), CONH-CH nalbuphine (C-alkyl), CO(C-alkyl), CO-CHR'7- pethidine (meperidine) NHR', CO-CH-R', where R is ortho OCOC-alkyl or meta- or para-CHN(R'), where tilidine R' is C-alkyl or 4-morpholino, wherein in the Viminol radicals R', R' and R' the alkyl groups can be butorphanol branched or unbranched, Saturated or unsaturated, unsubstituted or mono- or polySubstituted; deZocine US 2005/0137194A1 Jun. 23, 2005 27

nalorphine

pentazocine and Ia

buprenorphine. 39. The method of claim 29, wherein the compound A in group b) is chosen from: codeine dextropropoxyphene dihydrocodeine O meptaZinol compounds corresponding to formula I are present in the nalbuphine form of the (+)-enantiomer. 42. The method of claim 41, wherein compounds corre tilidine and sponding to formula I where R=H are present in the form of the diastereomers having the relative configuration Ia in buprenorphine. a greater amount than the other diastereomer or the pure 40. The method of claim 29, wherein the compound A in diasteromer having the relative configuration Ia is provided group c) is chosen from compounds according to formula I O for which: compounds corresponding to formula I are present in the form of the (+)-enantiomer, said formulation having a X is chosen from OH, F, Cl, OC(O)CH or H; higher content of the (+)-enantiomer compared with the (-)-enantiomer or said formulation having the pure R" is chosen from C-alkyl, Saturated and unsubstituted, (+)-enantiomer. branched or unbranched; 43. The method of claim 40, wherein compound A is R and R independently of one another are chosen from Selected from the group consisting of: H or C-alkyl, Saturated and unsubstituted, branched (2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2- or unbranched; or methyl-pentan-3-ol, (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2- R and R together form a C5-6-cycloalkyl radical, Satu methyl-pentan-3-ol, rated or unsaturated, unsubstituted or mono- or polySubstituted; (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2- methyl-pentan-3-ol, R-R', where 3 or 4 of the radicals R-R' must corre (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dimethy spond to H, independently of one another are chosen lamino-2-methyl-pentan-3-ol, from H, Cl, F, OH, CFH, CF or C-alkyl, saturated (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulfa and unsubstituted, branched or unbranched; OR' or nyl-phenyl)-pentan-3-ol, SR", where R'' is chosen from C-alkyl, saturated (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-4,4-dim and unsubstituted, branched or unbranched; ethyl-pentan-3-ol, or R'' and R' form a 34-OCH=CH ring; (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2- or if R, R'' and R' correspond to H, one of R' or R' methyl-propyl)-phenol, also corresponds to H, while the other is chosen from: (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dim C1, F, OH, CFH, CF, OR' or SR'; ethyl-propyl)-phenol, or if R and R' correspond to H and R' corresponds to (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dim OH, OCH, Clor F, one of R' or R'' also corresponds ethyl-propyl)-phenol, to H, while the other corresponds to OH, OCH, C1 or (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dim F; ethyl-propyl)-phenol, (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-pro or if R, R', R'' and R' correspond to H, R' is chosen pyl)-phenol, from CF, CFH, C or F; (+)-(1R,2R)-acetic acid 3-dimethylamino-1-ethyl-1-(3- or if R', R'' and R' correspond to H, one of R or R' methoxy-phenyl)-2-methyl-propyl ester, also corresponds to H, while the other is chosen from: OH, OCH or OCH. (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3- 41. The method of claim 40, wherein compounds corre methoxy-phenyl)-propan-1-ol, sponding to formula I where R=H are present in the form (2RS,3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-me of the diastereomers having the relative configuration Ia thyl-pentan-3-ol, US 2005/0137194A1 Jun. 23, 2005 28

(+)-(2R,3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2- diastereomers having the relative configuration Ia in a methyl-propyl-phenol, greater amount than the other diastereomer or the pure (2RS,3RS)-4-dimethylamino-2-(3-methoxy-phenyl)-3- diastereomer having the relative configuration IIa is pro methyl-butan-2-ol and vided or (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy-phenyl)-3- compounds corresponding to formula II are present in the methyl-butan-2-ol. form of the (+)-enantiomer, said formulation having a 44. The method of claim 43, wherein compound A is in higher content of the (+)-enantiomer compared with the the form of a hydrochloride. (-)-enantiomer or said formulation having the pure 45. The method of claim 29, wherein the compound A in (+)-enantiomer. group d) is chosen from compounds corresponding to for 48. A method according to claim 45, wherein compound mula II for which: A is Selected from the group consisting of X is chosen from OH, F, Cl, OC(O)CH or H; (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy R" is chosen from C-alkyl, CFs, OH, O-C-alkyl, Cl phenyl)-cyclohexane-1,3-diol, or F; R’-R', where 3 or 4 of the radicals R to R' must (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxy correspond to H, independently of one another are phenyl)-cyclohexane-1,3-diol, chosen from H, Cl, F, OH, CFH, CF or C-alkyl, 1RS,3RS,6RS)-6-dimethvlamis s -6-dimethylaminomethyl-1-(3-hydroxy hvl-1-(3-hvd Saturated and unsubstituted, branched or unbranched; phenyl)-cyclohexane-1,3-diol, OR or SR'', where R'' is chosen from C-alkyl, Saturated and unsubstituted, branched or unbranched; (1RS,3SR,6RS)-6-dimethylaminomethyl-1-(3-methoxy or R'' and R' form a 3.4-OCH=CH ring phenyl)-cyclohexane-1,3-diol, or if R, R'' and R' correspond to H, one of R' or R' (+)-(1R,2R,5 S)-3-(2-dimethylaminomethyl-1-hydroxy also corresponds to H, while the other is chosen from 5-methyl-cyclohexyl)-phenol and CI, F, OH, CFH, CF OR' or SR'; (1RS,2RS.5RS)-3-(2-dimethylaminomethyl-1-hydroxy or if R and R' correspond to H and R' corresponds to 5-trifluoromethyl-cyclohexyl)-phenol. OH, OCH, C1 or F, preferably Cl, one of R' or R' 49. A method according to claim 48, wherein compound also corresponds to H, while the other corresponds to A is in the form of a hydrochloride. OH, OCH, C1 or F; 50. A method according to claim 29, wherein compound or if R, R', R'' and R' correspond to H, R' is chosen A in group e) is chosen from compounds corresponding to from CF, CFH, C or F; formula III for which: or if R', R'' and R' correspond to H, one of R or R' also corresponds to H, while the other is chosen from X is chosen from OH, F, Cl, OC(O)CH or H; OH, OCH or OCH7; R-R', where 3 or 4 of the radicals R to R' must or if R, R'' and R' correspond to H, one of R' or R' correspond to H, independently of one another are also corresponds to H, while the other is chosen from chosen from H, Cl, F, OH, CFH, CF or C-alkyl, Cl, F, OH, SH, CFH, CF, OR' or SR''. Saturated and unsubstituted, branched or unbranched; 46. A method according to claim 45, wherein compounds OR or SR", where R'' is chosen from C-alkyl, corresponding to formula II are present in the form of the Saturated and unsubstituted, branched or unbranched; diastereomers having the relative configuration IIa or R'' and R' form a 3,4-OCH=CH ring;

IIa or if R, R'' and R' correspond to H, one of R' or R' also corresponds to H, while the other is chosen from CI, F, OH, CFH, CF OR' or SR'; or if R and R' correspond to H and R' corresponds to OH, OCH, C1 or F, preferably Cl, one of R' or R' also corresponds to H, while the other corresponds to OH, OCH, C1 or F; or if R, R', R'' and R' correspond to H, R' is chosen from CF, CFH, C or F; or if R', R'' and R' correspond to H, one of R or R' O also corresponds to H, while the other is chosen from OH, OCH or OCH7; compounds corresponding to formula II are present in the form of the (+) enantiomer. or if R, R'' and R' correspond to H, one of R' or R' 47. A method according to claim 46, wherein compounds also corresponds to H, while the other is chosen from corresponding to formula II are present in the form of the Cl, F, OH, SH, CFH, CF, OR' or SR''. US 2005/0137194A1 Jun. 23, 2005 29

51. A method according to claim 50, wherein compounds O corresponding to formula III are present in the form of their diastereomers having the relative configuration IIIa compounds corresponding to formula III are present in the form of the (+)-enantiomer, said formulation having a higher content of the (+)-enantiomer compared with the IIIa (-)-enantiomer or said formulation having the pure (+)-enantiomer. 53. A method according to claim 50, wherein compound A is Selected from the group consisting of (+)-(1R,2R)-3-(2-dimethylaminomethyl-1-fluoro-cyclo hexyl)-phenol, (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phe nol and (-)-(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)- phenol. O 54. A method according to claim 53, wherein compound compounds corresponding to formula III are present in the A is present in the form of a hydrochloride. form of the (+)-enantiomer. 55. A method according to claim 29, wherein compound 52. A method according to claim 51, wherein compounds B is Selected from the group consisting of corresponding to formula III are present in the form of the diastereomers having the relative configuration IIIa in a fesoterodine, Solifenacin (YM905), cizolirtine, resinifera greater amount than the other diastereomer or the pure toxin and Venlaxafine. diastereomer having the relative configuration IIa is pro vided