HK1075205B - Combination of selected opioids with muscarine antagonists for treating urinary incontinence - Google Patents

Description

Combination of selected opioids with muscarinic antagonists for the treatment of urinary incontinence

The invention relates to the use of compounds of group A (in particular opioids) and of compounds of group B (in particular muscarine-resistant drugs) and other substances with a predominantly peripheral action for producing medicaments for the treatment of severe urinary urgency or incontinence, and to corresponding medicaments and methods for the treatment of severe urinary urgency or incontinence.

Urinary incontinence is involuntary urination. Uncontrolled urinary incontinence can occur when intravesical pressure exceeds the pressure required to seal the urethra. The etiology may be, on the one hand, increased intravesical pressure (e.g., due to detrusor instability) leading to urinary incontinence, and, on the other hand, decreased sphincter pressure (e.g., post-partum or post-surgical intervention) leading to stress incontinence. The detrusor is a multiple layer bladder wall muscle tissue of the thick fascicle that contracts resulting in urination, while the sphincter is the muscle that seals the urethra. There are mixed forms of these types of urinary incontinence as well as so-called overflow or reflex incontinence (e.g. after spinal cord injury). Thus, for example, urinary incontinence, urgency and frequency are all possible symptoms of benign prostatic hyperplasia. Further details on this aspect are found in Chutka, d.s. and Takahashi, p.y., 1998, Drugs 560: 587-595.

Urgency refers to a state in which the muscle tone of the bladder increases as the bladder approaches (or exceeds) its capacity, with the aim of discharging urine (urination). This muscle tension acts to stimulate urination. Severe urgency is herein understood to mean in particular the occurrence of urgency which is premature or more frequent, sometimes even accompanied by painful urgency, so-called painful dribbling. This will cause severe more frequent urination. The etiology may include bladder inflammation and neurological bladder disease, as well as tuberculosis of the bladder. However, all etiologies have not been elucidated.

Both severe urgency and urinary incontinence are considered to be extremely unpleasant conditions, and there is therefore a clear need for the greatest possible long-term improvement in patients suffering from these conditions.

Severe urgency, in particular urinary incontinence, is commonly used as a substance treatment for the lower urinary tract reflexes (Wein, A.J., 1998, Urology 51 (suppl.21): 43-47). In general, these drugs have an inhibitory effect on the detrusor muscle, which produces intravesical pressure. These include, for example, parasympathetic blocking agents, such as oxybutynin, propiverine or tolterodine; tricyclic antidepressants, such as imipramine; or a muscle relaxant, such as flavoxate. Other drugs that specifically increase resistance in the neck of the urethra or bladder have affinity for alpha-adrenoceptors (e.g., ephedrine), beta-adrenoceptors (e.g., clenbutarol), or are hormones such as estradiol.

A review article by K.E. Andersson et al, "pharmacological treatment of urinary incontinence", BJUInterative (1999), 84, 923-947, gave an accurate insight into therapeutics and the treatment methods employed, particularly against muscarine and other substances with peripheral effects.

Certain diarylmethylpiperazines and diarylmethylpiperidines for use in such diseases are also described in WO 93/15062. Tramadol has been shown to have a positive effect on bladder function in a rhythmic bladder contraction model in rats (Nippon-Shinyaku, WO 98/46216). In addition, the characteristics of the side effects of opioid urine retention are also investigated in the literature, which states that weak opioids, such as diphenoxylate (Fowler et al, 1987J. Urol 138: 735-, the diseases discussed in the present invention usually require long-term administration. This is in contrast to many cases where analgesics are used, where patients are exposed to a very unpleasant, but not intolerable situation. Thus, if the patient does not want to replace one by another unfortunate, it should be ensured here that-even more than with analgesics-side effects are avoided. Furthermore, in the long-term treatment of urinary incontinence, analgesic effects are likewise highly undesirable.

It is therefore an object of the present invention to find substances or substance combinations which are useful for the treatment of severe urinary urgency or incontinence and which, at the active dose, preferably simultaneously exhibit lower side effects and/or analgesic effects than the medicaments known from the prior art, in particular a synergistic effect for the treatment of urinary incontinence.

It has now surprisingly been found that a combination of a group a compound and a group B compound has a significant effect on bladder function, wherein the group a compound comprises opioids and other substances which have a central effect and are capable of interacting with opioid receptors and whose effect can be antagonized by naloxone, or in particular substances which act via opioid receptors (in particular μ -receptors); group B compounds include muscarinic antagonists and other substances known to be active against urinary incontinence and which have primarily a peripheral effect. Far beyond expectation, these combinations have also proved to be quite active at very low doses, thus making it possible to use low doses of the active compound combination. Thus, in therapeutic use, side effects at high doses are significantly reduced, while the therapeutic effect is substantially maintained by the combined effect of the peripheral antitoxicaline effect and the central opioid or mu-receptor effect acting primarily directly on the bladder or bladder muscle.

The present invention therefore provides the use of a combination of at least one active compound of compound a and at least one active compound of compound B for the preparation of a medicament for the treatment of urinary urgency or incontinence, wherein compound a is selected from:

a) a group comprising: tramadol, O-nortramadol or O-nor-N-mono-nor-tramadol, optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of a mixture of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

b) a group comprising:

codeine

Dextropropoxyphene

Dihydrocodeine

Diphenoxylate ester

Ethylmorphine

Meptazinol

Nalbuphine

Meperidine

Tilidine

Tramadol. the preparation of tramadol

Vimi alcohol

Butorphanol

Dextro molamine

Dezocine

Diamorphine (heroin)

Hydrocodone

Hydromorphone

Ketomitone

Levomethadone

Levo-acetylmethadol (1-alpha-acetylmethadol (LAAM))

Levorphanol

Morphine (C)

Nalorphine

Oxycodone

Pentazocine

Piperazinoamide

Alfentanil

Buprenorphine

Etorphine

Fentanyl

Remifentanil

Sufentanil

Optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

c) a group comprising:

1-phenyl-3-dimethylamino-propane compounds of the general formula I

Wherein

X is selected from OH, F, Cl, H or OC (O) R⁷Wherein R is⁷Selected from branched or unbranchedSaturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-3-an alkyl group,

R¹selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-4-alkyl, R²And R³Each independently selected from H or branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-4-an alkyl group,

or

R²And R³Together forming an unsubstituted or mono-or polysubstituted saturated C_4-7-a cycloalkyl group,

R⁹-R¹³each independently selected from H, F, Cl, Br, I, CH₂F、CHF₂、CF₃、OH、SH、OR¹⁴、OCF₃、SR¹⁴、NR¹⁷R¹⁸、SOCH₃、SOCF₃；SO₂CH₃、SO₂CF₃、CN、COOR¹⁴、NO₂、CONR¹⁷R¹⁸(ii) a Branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6-an alkyl group; unsubstituted or mono-or polysubstituted phenyl;

wherein R is¹⁴Is selected from C_1-6-an alkyl group; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted; PO (O-C)_1-4-alkyl groups)₂、CO(OC_1-5Alkyl), CONH-C₆H₄-(C_1-3Alkyl), CO (C)_1-5Alkyl), CO-CHR¹⁷-NHR¹⁸、CO-C₆H₄-R¹⁵Wherein R is¹⁵Is ortho-OCOC_1-3-alkyl or m-or p-CH₂N(R¹⁶)₂Wherein R is¹⁶Is C_1-4-alkyl or 4-morpholinyl, wherein in the radical R¹⁴、R¹⁵And R¹⁶The alkyl group may be branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstitutedOf (1);

wherein R is¹⁷And R¹⁸Each is independently selected from H; branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6-an alkyl group; phenyl, benzyl or phenethyl, which are each unsubstituted or mono-or polysubstituted,

or

R⁹And R¹⁰Or R¹⁰And R¹¹Together form OCH₂O、OCH₂CH₂O、OCH＝CH、CH＝CHO、CH＝C(CH₃)O、OC(CH₃)＝CH、(CH₂)₄Or an OCH ═ CHO ring,

optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

d) a group comprising:

substituted 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula II

Wherein

X is selected from OH, F, Cl, H or OC (O) R⁷Wherein R is⁷Selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-3-an alkyl group,

R¹is selected from C_1-4-alkyl, benzyl, CF₃、OH、OCH₂-C₆H₅、O-C_1-4-alkyl, Cl or F, and

R⁹-R¹³each independently selected from H, F, Cl, Br, I, CH₂F、CHF₂、CF₃、OH、SH、OR¹⁴、OCF₃、SR¹⁴、NR¹⁷R¹⁸、SOCH₃、SOCF₃；SO₂CH₃、SO₂CF₃、CN、COOR¹⁴、NO₂、CONR¹⁷R¹⁸(ii) a Branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6An alkyl group; unsubstituted or mono-or polysubstituted phenyl;

wherein R is¹⁴Is selected from C_1-6-an alkyl group; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted; PO (O-C)_1-4-alkyl groups)₂、CO(OC_1-5Alkyl), CONH-C₆H⁴-(C_1-3Alkyl), CO (C)_1-5Alkyl), CO-CHR¹⁷-NHR¹⁸、CO-C₆H₄-R¹⁵Wherein R is¹⁵Is ortho-OCOC_1-3-alkyl or m-or p-CH₂N(R¹⁶)₂Wherein R is¹⁶Is C_1-4-alkyl or 4-morpholinyl, wherein in the radical R¹⁴、R¹⁵And R¹⁶The alkyl group may be branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted;

wherein R is¹⁷And R¹⁸Each is independently selected from H; branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6-an alkyl group; phenyl, benzyl or phenethyl, which are each unsubstituted or mono-or polysubstituted,

or

R⁹And R¹⁰Or R¹⁰And R¹¹Together form OCH₂O、OCH₂CH₂O、OCH＝CH、CH＝CHO、CH＝C(CH₃)O、OC(CH₃)＝CH、(CH₂)₄Or an OCH ═ CHO ring,

optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

e) a group comprising:

6-dimethylaminomethyl-1-phenyl-cyclohexane compounds of the general formula III

Wherein

X is selected from OH, F, Cl, H or OC (O) R⁷Wherein R is⁷Selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-3-alkyl, and

R⁹-R¹³each independently selected from H, F, Cl, Br, I, CH₂F、CHF₂、CF₃、OH、SH、OR¹⁴、OCF₃、SR¹⁴、NR¹⁷R¹⁸、SOCH₃、SOCF₃；SO₂CH₃、SO₂CF₃、CN、COOR¹⁴、NO₂、CONR¹⁷R¹⁸(ii) a Branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6-an alkyl group; unsubstituted or mono-or polysubstituted phenyl;

wherein R is¹⁴Is selected from C_1-6-an alkyl group; pyridyl, thienyl, thiazolePhenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted; PO (O-C)_1-4-alkyl groups)₂、CO(OC_1-5Alkyl), CONH-C₆H⁴-(C_1-3Alkyl), CO (C)_1-5Alkyl), CO-CHR¹⁷-NHR¹⁸、CO-C₆H₄-R¹⁵Wherein R is¹⁵Is ortho-OCOC_1-3-alkyl or m-or p-CH₂N(R¹⁶)₂Wherein R is¹⁶Is C_1-4-alkyl or 4-morpholinyl, wherein in the radical R¹⁴、R¹⁵And R¹⁶The alkyl group may be branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted;

wherein R is¹⁷And R¹⁸Each is independently selected from H; branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6-an alkyl group; phenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted;

or

R⁹And R¹⁰Or R¹⁰And R¹¹Together form OCH₂O、OCH₂CH₂O、OCH＝CH、CH＝CHO、CH＝C(CH₃)O、OC(CH₃)＝CH、(CH₂)₄Or an OCH ═ CHO ring,

with the proviso that if R⁹、R¹¹And R¹³Represents H and R¹⁰Or R¹²One represents H and the other represents OCH₃Then, X may not be OH,

optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

and wherein at least one compound B is selected from:

antitoxic muscarine, atropine, oxybutynin, propiverine, propantheline, emetamil, trospium, tolterodine, darifenacin and 4- (N-methylpiperidinyl) alpha, alpha-diphenylacetate, as well as duloxetine, imipramine and desmopressin,

optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates.

It was surprisingly found that the combination of the substances mentioned has a significant positive effect on certain important physiological parameters of severe urgency or urinary incontinence. Each of these compounds may be meant to significantly improve the patient's symptom profile.

Alkyl or cycloalkyl is understood herein to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or mono-or polysubstituted. Here, C_1-2Alkyl represents C1-or C2-alkyl, C_1-3Alkyl represents C1-, C2-or C3-alkyl, C_1-4Alkyl represents C1-, C2-, C3-or C4-alkyl, C_1-5Alkyl represents C1-, C2-, C3-, C4-or C5-alkyl, C_1-6Alkyl represents C1-, C2-, C3-, C4-, C5-or C6-alkyl, C_1-7Alkyl represents C1-, C2-, C3-, C4-, C5-, C6-or C7-alkyl, C_1-8Alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-or C8-alkyl, C_1-10Alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-or C10-alkyl and C_1-18Alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17-or C18-alkyl. In addition, C_3-4Cycloalkyl represents C3-or C4-cycloalkyl, C_3-5Cycloalkyl represents C3-, C4-or C5-cycloalkyl, C_3-6Cycloalkyl represents C3-, C4-, C5-or C6-cycloalkyl, C_{3- 7}Cycloalkyl represents C3-, C4-, C5-, C6-or C7-cycloalkyl, C_3-8Cycloalkyl is C3-, C4-, C5-, C6-, C7-or C8-cycloalkyl, C_4-5Cycloalkyl represents C4-or C5-cycloalkyl, C_4-6Cycloalkyl represents C4-, C5-or C6-cycloalkyl, C_4-7Cycloalkyl represents C4-, C5-, C6-or C7-cycloalkyl, C_5-6Cycloalkyl represents C5-or C6-cycloalkyl and C_5-7Cycloalkyl represents C5-, C6-or C7-cycloalkyl. The term cycloalkyl also includes saturated cycloalkyl groups in which 1 or 2 carbon atoms are replaced by a heteroatom S, N or O. However, the term cycloalkyl in particular also includes mono-or poly-unsaturated cycloalkyl groups, preferably mono-unsaturated cycloalkyl groups which contain no heteroatoms in the ring, while cycloalkyl groups are not aromatic systems. Alkyl and cycloalkyl are preferably methyl, ethyl, vinyl, propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl, CHF₂、CF₃Or CH₂OH, and pyrazolone, oxopyrazolinone, [1, 4 ]]Dioxane or dioxolane.

Unless otherwise stated, the term substituted alkyl and cycloalkyl in this context is understood to mean that at least one, optionally also several, hydrogen radical is replaced by F, Cl, Br, I, NH₂SH or OH substitution, wherein "polysubstituted" or "substituted" in the case of polysubstitution is to be understood as meaning substitution several times, for example three times, on the same C atom, by the same or different substituents on different and the same atoms (CF)₃Or in different positions (e.g., -CH (OH) -CH ═ CH-CHCl)₂The case(s). Particularly preferred substituents here are F, Cl and OH. For cycloalkyl radicals, the hydrogen radical may also be replaced by OC_1-3-alkyl or C_1-3Alkyl, especially methyl, ethyl, n-propyl, isopropyl, CF₃Methoxy or ethoxy substitution (both mono-or polysubstituted or unsubstituted).

Term (CH)₂)_3-6Is understood to mean-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-CH₂-and-CH₂-CH₂-CH₂-CH₂-CH₂-CH₂-，(CH₂)_1-4Is understood to mean-CH₂-、-CH₂-CH₂-、-CH₂-CH₂-CH₂-and-CH₂-CH₂-CH₂-CH₂-，(CH₂)_4-5Is understood to mean-CH₂-CH₂-CH₂-CH₂-and-CH₂-CH₂-CH₂-CH₂-CH₂-and the like.

Aryl is understood to mean a ring system which has at least one aromatic ring, but which does not contain heteroatoms even on only one ring. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, 1, 2, 3, 4-tetrahydronaphthyl or 2, 3-dihydroindenyl, in particular 9H-fluorenyl or anthracenyl, which may be unsubstituted or mono-or polysubstituted.

Heteroaryl is understood as meaning a heterocyclic ring system having at least one unsaturated ring, which contains one or more heteroatoms selected from nitrogen, oxygen and/or sulfur and may also be mono-or polysubstituted. Examples of heteroaryl groups which may be mentioned are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, 2, 3-naphthyridine, benzo [1, 2, 5] thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.

Herein, substitution in combination with aryl and heteroaryl is understood to mean that aryl or heteroaryl is substituted by R²³、OR²³Halogen, preferably by F and/or Cl, CF₃、CN、NO₂、NR²⁴R²⁵、C_1-6Alkyl (saturated), C_1-6-alkoxy, C_3-8Cycloalkoxy, C_3-8-cycloalkyl or C_2-6-alkylene substitution.

Here, the radical R²³Representation H, C_1-10-alkyl, preferably C_1-6Alkyl, aryl or heteroaryl or by C_1-3Alkylene-bonded aryl or heteroaryl, where these aryl and heteroaryl are not themselves substituted by aryl or heteroaryl,

radical R²⁴And R²⁵Are identical or different and are denoted H, C_1-10-alkyl, preferably C_1-6Alkyl, aryl, heteroaryl or through C_1-3Alkylene-bonded aryl or heteroaryl, where these aryl and heteroaryl are not themselves substituted by aryl or heteroaryl,

or a radical R²⁴And R²⁵Together represent CH₂CH₂OCH₂CH₂、CH₂CH₂NR²⁶CH₂CH₂Or (CH)₂)_3-6And are and

radical R²⁶Representative H, C_1-10-alkyl, preferably C_1-6Alkyl, aryl or heteroaryl or by C_1-3Alkylene-bonded aryl or heteroaryl, where these aryl and heteroaryl are not themselves substituted by aryl or heteroaryl.

The term salt is understood herein to mean any form of the active compound of the invention in which it is in ionic form or is charged and coupled to a counter-ion (cation or anion) or in solution. This is also understood to mean complexes of the active compounds with other molecules or ions, in particular complexes which complex by ionic interactions.

The term physiologically acceptable salt, especially salts containing cations or bases, is understood herein to mean at least one compound of the invention-usually a (deprotonated) acid-as anion in salt with at least one preferably inorganic cation, which is a physiologically acceptable salt, especially when used in humans and/or mammals. Particularly preferred salts are the salts of alkali metals and alkaline earth metals, but also NH is possible₄ ⁺Salts, particularly preferably (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.

The term physiologically acceptable salt (especially salts containing anions or acids) is also to be understood herein as meaning at least one compound of the invention-usually protonated, e.g. at the nitrogen-as a cation with at least one anion forming a salt which is a physiologically acceptable salt, especially when used in humans and/or mammals. In particular, it is to be understood herein as meaning salts with physiologically acceptable acids, i.e. salts of the particular active compounds with inorganic or organic acids, which are physiologically acceptable salts, especially when used in humans and/or mammals. Examples of physiologically acceptable salts of specific acids are the salts of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1-dioxo-1, 2-dihydro-1 b 6-benzo [ d ] isothiazol-3-one (glucaric acid), monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3-or 4-aminobenzoic acid, 2, 4, 6-trimethyl-benzoic acid, a-liponic acid, acetyl glycine, acetyl salicylic acid, hippuric acid and/or aspartic acid. Among them, hydrochloride is particularly preferable.

Suitable salts in each of the uses described here and in each of the medicaments described are the salts of the particular active compounds with inorganic or organic acids and/or sugar substitutes, for example saccharin, cyclamate or acesulfame. However, the hydrochloride is particularly preferred.

Compounds of group c) and processes for their preparation are known from DE 4426245a1 and US 6,248,737. Compounds of groups d) and e) and processes for their preparation are known from DE 19525137a1 and US 5,733,936 and US RE 37355E.

In a preferred embodiment, the compound a of group a) for use in the present invention is selected from:

tramadol, (+) -O-nortramadol or (+) -O-nor-N-mono-nor-tramadol, preferably tramadol or (+) -tramadol, especially (+) -tramadol.

In a preferred embodiment, for the use according to the invention, the compound a of group b) is selected from:

codeine

Dextropropoxyphene

Dihydrocodeine

Diphenoxylate ester

Ethylmorphine

Meptazinol

Nalbuphine

Meperidine

Tilidine

Vimi alcohol

Butorphanol

Dezocine

Nalorphine

Pentazocine

Buprenorphine

Preferably, it is

Codeine

Dextropropoxyphene

Dihydrocodeine

Meptazinol

Nalbuphine

Tilidine

Buprenorphine

In a preferred embodiment, the compounds a of group c) for use in the present invention are selected from compounds of formula I, wherein:

x is selected from

OH、F、Cl、OC(O)CH₃Or H, preferably OH, F, OC (O) CH₃Or a combination of H and a nitrogen atom,

and/or

R¹Is selected from

Saturated and unsubstituted, branched or unbranched C_1-4-an alkyl group; preferably CH₃、C₂H₅、C₄H₉Or tert-butyl, especially CH₃Or C₂H₅，

And/or

R²And R³Each independently selected from

H. Saturated and unsubstituted, branched or unbranched C_1-4-alkyl, preferably H, CH₃、C₂H₅Isopropyl or tert-butyl, especially H or CH₃Preferably R³＝H，

Or

R²And R³Together form a saturated or unsaturated, unsubstituted or mono-or polysubstituted, preferably saturated and unsubstituted C_5-6Cycloalkyl, especially cyclohexyl.

And/or

R⁹-R¹³3 or 4 of the radicals must represent H, the remainder being each independently selected from

H、Cl、F、OH、CF₂H、CF₃Or saturated and unsubstituted, branched or unbranched C_1-4-an alkyl group; OR (OR)¹⁴Or SR¹⁴Wherein R is¹⁴Selected from saturated and unsubstituted, branched or unbranched C_1-3-an alkyl group;

preferably H, Cl, F, OH, CF₂H、CF₃、OCH₃Or SCH₃

Or R¹²And R¹¹Formation of 3, 4-OCH ═ CH ring

In particular

If R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents H, then the other is selected from:

Cl、F、OH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH and CF₂H、OCH₃Or SCH₃

Or

If R is⁹And R¹³Represents H and R¹¹Represents OH, OCH₃Cl or F, preferably Cl, R¹⁰Or R¹²One of them also represents H, then the other represents OH, OCH₃Cl or F, preferably Cl,

or

If R is⁹、R¹⁰、R¹²And R¹³Represents H, R¹¹Selected from CF₃、CF₂H. Cl or F, preferably F,

or

If R is¹⁰、R¹¹And R¹²Represents H, R⁹Or R¹³One of which also represents H, then the other is selected from OH, OC₂H₅Or OC₃H₇。

In this context, particular preference is given toIn which R is present in the diastereoisomeric form having the relative configuration Ia³A compound of formula I ═ H:

especially in mixtures in which such diastereomer content is higher than another diastereomer or as pure diastereomer,

and/or

The compounds of formula I are present as the (+) -enantiomer, especially as a mixture of racemic compounds with a higher content of the (+) -enantiomer than the (-) -enantiomer, or as the pure (+) -enantiomer.

Here, particular preference is given to using compounds a selected from the following:

■ (2RS, 3RS) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol

■ (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol,

■ (+) - (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol,

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

■ (2RS, 3RS) -3- (3-difluoromethyl-phenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

■ (2RS, 3RS) -1-dimethylamino-2-methyl-3- (3-methylsulfanyl-phenyl) -pentan-3-ol,

■ (3RS) -1-dimethylamino-3- (3-methoxy-phenyl) -4, 4-dimethyl-pentan-3-ol,

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

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

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

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

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

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

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

■ (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol,

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

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

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

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

■ (2RS, 3RS) -4-dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol, and

■ (+) - (2R, 3R) -4-dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol,

their hydrochloride salts are preferred.

In a preferred embodiment, the compounds a of group d) for use in the present invention are selected from compounds of formula II, wherein:

x is selected from

OH、F、Cl、OC(O)CH₃Or H, preferably OH, F or H, especially OH,

and/or

R¹Is selected from

C_1-4-alkyl, CF₃、OH、O-C_1-4Alkyl, Cl or F, preferably OH, CF₃Or CH₃，

And/or

R⁹-R¹³3 or 4 of the radicals must represent H, the remainder being each independently selected from

H、Cl、F、OH、CF₂H、CF₃Or saturated and unsubstituted, branched or unbranched C_1-4-an alkyl group; OR (OR)¹⁴Or SR¹⁴Wherein R is¹⁴Selected from saturated and unsubstituted, branched or unbranched C_1-3-an alkyl group;

preferably H, Cl, F, OH, CF₂H、CF₃、OCH₃Or SCH₃

Or R¹²And R¹¹Formation of 3, 4-OCH ═ CH ring

In particular

If R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents H, then the other is selected from:

Cl、F、OH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH and CF₂H、OR¹⁴Or SCH₃Especially OH or OC_1-3-alkyl, preferably OH or OCH₃，

Or

If R is⁹And R¹³Represents H and R¹¹Represents OH, OCH₃Cl or F, preferably Cl, R¹⁰Or R¹²One of them also represents H, then the other represents OH, OCH₃Cl or F, preferably Cl,

or

If R is⁹、R¹⁰、R¹²And R¹³Represents H, R¹¹Selected from CF₃、CF₂H. Cl or F, preferably F,

or

If R is¹⁰、R¹¹And R¹²Represents H, R⁹Or R¹³One of which also represents H, then the other is selected from OH, OC₂H₅Or OC₃H₇。

The following are particularly preferred:

if R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents H, then the other is selected from:

Cl、F、OH、SH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH OR OR¹⁴Especially OH or OC_1-3-alkyl, preferably OH or OCH₃。

In this context, particularly preferred compounds of group d) are compounds of the formula II in the form of diastereomers having the relative configuration IIa:

especially in mixtures in which such diastereomer content is higher than another diastereomer or as pure diastereomer,

and/or

The compounds of formula II are present as the (+) -enantiomer, especially as a mixture of the racemic compound having a higher content of the (+) -enantiomer than the (-) -enantiomer, or as the pure (+) -enantiomer.

Here, particular preference is given to using compounds a selected from the following:

■ (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1, 3-diol,

■ (+) - (1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1, 3-diol,

■ (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxy-phenyl) -cyclohexane-1, 3-diol,

■ (1RS, 3SR, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1, 3-diol,

■ (+) - (1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl) -phenol, or

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

their hydrochloride salts are preferred.

In a preferred embodiment, the compounds a of group e) for use in the present invention are selected from compounds of formula III, wherein:

x is selected from

OH、F、Cl、OC(O)CH₃Or H, preferably OH, F or H, especially F or H,

and/or

R⁹-R¹³3 or 4 of the radicals must represent H, the remainder being each independently selected from

H、Cl、F、OH、CF₂H、CF₃Or saturated and unsubstituted, branched or unbranched C_1-4-an alkyl group; OR (OR)¹⁴Or SR¹⁴Wherein R is¹⁴Selected from saturated and unsubstituted, branched or unbranched C_1-3-an alkyl group;

preferably H, Cl、F、OH、CF₂H、CF₃、OCH₃Or SCH₃

Or R¹²And R¹¹Formation of 3, 4-OCH ═ CH ring

In particular

If R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents hydrogen, then the other is selected from:

Cl、F、OH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH and CF₂H、OR¹⁴Or SCH₃Especially OH or OC_1-3-alkyl, preferably OH or OCH₃，

Or

If R is⁹And R¹³Represents H and R¹¹Represents OH, OCH₃Cl or F, preferably Cl, R¹⁰Or R¹²One of them also represents hydrogen, the other then represents OH, OCH₃Cl or F, preferably Cl,

or

If R is⁹、R¹⁰、R¹²And R¹³Represents H, R¹¹Selected from CF₃、CF₂H. Cl or F, preferably F,

or

If R is¹⁰、R¹¹And R¹²Represents H, R⁹Or R¹³One of which also represents H, then the other is selected from OH, OC₂H₅Or OC₃H₇，

The following are particularly preferred:

if R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents H, then the other is selected from:

Cl、F、OH、SH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH OR OR¹⁴Especially OH or OC_1-3-alkyl, preferably OH or OCH₃。

In this context, particularly preferred compounds of group e) are compounds of the formula III in the form of diastereomers having the relative configuration IIIa:

especially in mixtures in which such diastereomer content is higher than another diastereomer or as pure diastereomer,

and/or

The compounds of formula III are present as the (+) -enantiomer, especially as a mixture of the racemic compound having a higher content of the (+) -enantiomer than the (-) -enantiomer, or as the pure (+) -enantiomer.

Here, particular preference is given to using compounds a selected from the following:

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

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

■ (1S, 2S) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol, or

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

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

■ (-) - (1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl ] -dimethylamine,

■ (1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl ] -dimethylamine,

their hydrochloride salts are preferred.

For particularly preferred uses, compound B is selected from:

darifenacin, duloxetine, oxybutynin or tolterodine,

preferably selected from

Duloxetine, oxybutynin or tolterodine,

preferably selected from

Oxybutynin or tolterodine.

Although only minor side effects are shown in the use of the present invention, it may be advantageous to use morphine antagonists, in particular naloxone, naltrexone and/or levorphanol, in addition to the combination of compounds a and B, for example in order to avoid certain types of dependence.

The present invention also provides a combination of at least one active compound of compound a and at least one active compound of compound B, compound a being selected from:

a) a group comprising:

tramadol, O-nortramadol or O-nor-N-mono-nor-tramadol, optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of a mixture of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

b) a group comprising:

codeine

Dextropropoxyphene

Dihydrocodeine

Diphenoxylate ester

Ethylmorphine

Meptazinol

Nalbuphine

Meperidine

Tilidine

Tramadol. the preparation of tramadol

Vimi alcohol

Butorphanol

Dextro molamine

Dezocine

Diamorphine (heroin)

Hydrocodone

Hydromorphone

Ketomitone

Levomethadone

Levo-acetylmethadol (1-alpha-acetylmethadol (LAAM))

Levorphanol

Morphine (C)

Nalorphine

Oxycodone

Pentazocine

Piperazinoamide

Alfentanil

Buprenorphine

Etorphine

Fentanyl

Remifentanil

Sufentanil

Optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

c) a group comprising:

1-phenyl-3-dimethylamino-propane compounds of the general formula I

Wherein

X is selected from OH, F, Cl, H or OC (O) R⁷Wherein R is⁷Selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-3-an alkyl group,

R¹selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-4-an alkyl group,

R²and R³Each independently selected from H or branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-4An alkyl group, a carboxyl group,

or

R²And R³Together forming an unsubstituted or mono-or polysubstituted saturated C_4-7-a cycloalkyl group,

R⁹-R¹³each independently selected from H, F, Cl, Br, I, CH₂F、CHF₂、CF₃、OH、SH、OR¹⁴、OCF₃、SR¹⁴、NR¹⁷R¹⁸、SOCH₃、SOCF₃；SO₂CH₃、SO₂CF₃、CN、COOR¹⁴、NO₂、CONR¹⁷R¹⁸(ii) a Branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6An alkyl group; unsubstituted or mono-or polysubstituted phenyl;

wherein R is¹⁴Is selected from C_1-6-an alkyl group; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted; PO (O-C)_1-4-alkyl groups)₂、CO(OC_1-5Alkyl), CONH-C₆H₄-(C_1-3Alkyl), CO (C)_1-5Alkyl), CO-CHR¹⁷-NHR¹⁸、CO-C₆H₄-R¹⁵Wherein R is¹⁵Is ortho-OCOC_1-3-alkyl or m-or p-CH₂N(R¹⁶)₂Wherein R is¹⁶Is C_1-4-alkyl or 4-morpholinyl, wherein in the radical R¹⁴、R¹⁵And R¹⁶The alkyl group may be branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted; wherein R is¹⁷And R¹⁸Each is independently selected from H; branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6-an alkyl group; phenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted;

or

R⁹And R¹⁰Or R¹⁰And R¹¹Together form OCH₂O、OCH₂CH₂O、OCH＝CH、CH＝CHO、CH＝C(CH₃)O、OC(CH₃)＝CH、(CH₂)₄Or an OCH ═ CHO ring,

optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

d) a group comprising:

substituted 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula II

Wherein

X is selected from OH, F, Cl, H or OC (O) R⁷Wherein R is⁷Selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-3-an alkyl group,

R¹is selected from C_1-4-alkyl, benzyl, CF₃、OH、OCH₂-C₆H₅、O-C_1-4-alkyl, Cl or F, and

R⁹-R¹³each independently selected from H, F, Cl, Br, I, CH₂F、CHF₂、CF₃、OH、SH、OR¹⁴、OCF₃、SR¹⁴、NR¹⁷R¹⁸、SOCH₃、SOCF₃；SO₂CH₃、SO₂CF₃、CN、COOR¹⁴、NO₂、CONR¹⁷R¹⁸(ii) a Branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6An alkyl group; unsubstituted or mono-or polysubstituted phenyl;

wherein R is¹⁴Is selected from C_1-6-an alkyl group; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted; PO (O-C)_1-4-alkyl groups)₂、CO(OC_1-5Alkyl), CONH-C₆H₄-(C_1-3Alkyl), CO (C)_1-5Alkyl), CO-CHR¹⁷-NHR¹⁸、CO-C₆H₄-R¹⁵Wherein R is¹⁵Is ortho-OCOC_1-3-alkyl or m-or p-CH₂N(R¹⁶)₂Wherein R is¹⁶Is C_1-4-alkyl or 4-morpholinyl, wherein in the radical R¹⁴、R¹⁵And R¹⁶The alkyl group may be branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted;

wherein R is¹⁷And R¹⁸Each is independently selected from H; branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6-an alkyl group; phenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted;

or

R⁹And R¹⁰Or R¹⁰And R¹¹Together form OCH₂O、OCH₂CH₂O、OCH＝CH、CH＝CHO、CH＝C(CH₃)O、OC(CH₃)＝CH、(CH₂)₄Or an OCH ═ CHO ring,

optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

and/or

e) A group comprising:

6-dimethylaminomethyl-1-phenyl-cyclohexane compounds of the general formula III

Wherein

X is selected from OH, F, Cl, H or OC (O) R⁷Wherein R is⁷Selected from branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-3-alkyl, and

R⁹-R¹³each independently selected from H, F, Cl, Br, I, CH₂F、CHF₂、CF₃、OH、SH、OR¹⁴、OCF₃、SR¹⁴、NR¹⁷R¹⁸、SOCH₃、SOCF₃；SO₂CH₃、SO₂CF₃、CN、COOR¹⁴、NO₂、CONR¹⁷R¹⁸(ii) a Branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6An alkyl group; unsubstituted or mono-or polysubstituted phenyl;

wherein R is¹⁴Is selected from C_1-6-an alkyl group; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each of which is unsubstituted or mono-or polysubstituted; PO (O-C)_1-4-alkyl groups)₂、CO(OC_1-5Alkyl), CONH-C₆H₄-(C_1-3Alkyl), CO (C)_1-5Alkyl), CO-CHR¹⁷-NHR¹⁸、CO-C₆H₄-R¹⁵Wherein R is¹⁵Is ortho-OCOC_1-3-alkyl or m-or p-CH₂N(R¹⁶)₂Wherein R is¹⁶Is C_1-4-alkyl or 4-morpholinyl, wherein in the radical R¹⁴、R¹⁵And R¹⁶The alkyl group may be branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted;

wherein R is¹⁷And R¹⁸Each is independently selected from H; branched or unbranched, saturated or unsaturated, unsubstituted or mono-or polysubstituted C_1-6-an alkyl group; phenyl, benzylOr phenylethyl, each of which is unsubstituted or mono-or polysubstituted;

or

R⁹And R¹⁰Or R¹⁰And R¹¹Together form OCH₂O、OCH₂CH₂O、OCH＝CH、CH＝CHO、CH＝C(CH₃)O、OC(CH₃)＝CH、(CH₂)₄Or an OCH ═ CHO ring,

with the proviso that if R⁹、R¹¹And R¹³Represents H and R¹⁰Or R¹²One represents H and the other represents OCH₃Then, X may not be OH,

optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form shown or in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

and wherein at least one compound B is selected from:

antitoxic muscarine, atropine, oxybutynin, propiverine, propantheline, emetamil, trospium, tolterodine, darifenacin, and 4- (N-methylpiperidinyl) alpha, alpha-diphenylacetate, as well as duloxetine, imipramine and desmopressin,

optionally in the form of their racemates, their pure stereoisomers, especially enantiomers or diastereomers, or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any desired mixing ratio; in the form of their acids or their bases or in the form of their salts, especially physiologically acceptable salts, or in the form of their solvates, especially hydrates;

for the active compound combinations, it is particularly preferred that the compounds a of group a) are selected from:

tramadol, (+) -O-nortramadol or (+) -O-nor-N-mono-nor-tramadol, preferably tramadol or (+) -tramadol, especially (+) -tramadol.

For the active compound combinations, it is particularly preferred that the compounds a of group b) are selected from:

codeine

Dextropropoxyphene

Dihydrocodeine

Diphenoxylate ester

Ethylmorphine

Meptazinol

Nalbuphine

Meperidine

Tilidine

Vimi alcohol

Butorphanol

Dezocine

Nalorphine

Pentazocine

Buprenorphine

Preferably, it is

Codeine

Dextropropoxyphene

Dihydrocodeine

Meptazinol

Nalbuphine

Tilidine

Buprenorphine

For the active compound combinations, particular preference is given to the compounds a of group c) being selected from compounds of the formula I in which:

x is selected from OH, F, Cl, OC (O) CH₃Or H, preferably OH, F, OC (O) CH₃Or a combination of H and a nitrogen atom,

and/or

R¹Is selected from

Saturated and unsubstituted, branched or unbranched C_1-4-an alkyl group; preferably CH₃、C₂H₅、C₄H₉Or tert-butyl, especially CH₃Or C₂H₅，

And/or

R²And R³Each independently selected from

H. Saturated and unsubstituted, branched or unbranched C_1-4-alkyl, preferably H, CH₃、C₂H₅Isopropyl or tert-butyl, especially H or CH₃Preferably R³＝H，

Or

R²And R³Together form a saturated or unsaturated, unsubstituted or mono-or polysubstituted, preferably saturated and unsubstituted C_5-6Cycloalkyl, especially cyclohexyl.

And/or

R⁹-R¹³3 or 4 of the radicals must represent H, the remainder being each independently selected from

H、Cl、F、OH、CF₂H、CF₃Or saturated and unsubstituted, branched or unbranched C_1-4-an alkyl group; OR (OR)¹⁴Or SR¹⁴Wherein R is¹⁴Selected from saturated and unsubstituted, branched or unbranched C_1-3-an alkyl group;

preferably H, Cl, F, OH, CF₂H、CF₃、OCH₃Or SCH₃

Or R¹²And R¹¹Formation of 3, 4-OCH ═ CH ring

In particular

If R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents hydrogen, then the other is selected from:

Cl、F、OH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH and CF₂H、OCH₃Or SCH₃

Or

If R is⁹And R¹³Represents H and R¹¹Represents OH, OCH₃Cl or F, preferably Cl, R¹⁰Or R¹²One of them also represents H, then the other represents OH, OCH₃Cl or F, preferably Cl,

or if R is⁹、R¹⁰、R¹²And R¹³Represents H, R¹¹Selected from CF₃、CF₂H. Cl or F, preferably F,

or

If R is¹⁰、R¹¹And R¹²Represents H, R⁹Or R¹³One of which also represents H, then the other is selected from OH, OC₂H₅Or OC₃H₇。

In this context, particularly preferred compounds of group c) are those in which R is present in the diastereomeric form with the relative configuration Ia³A compound of formula I ═ H:

especially in mixtures in which such diastereomer content is higher than another diastereomer or as pure diastereomer;

and/or

The compounds of formula I are present as the (+) -enantiomer, especially as a mixture of racemic compounds with a higher content of the (+) -enantiomer than the (-) -enantiomer, or as the pure (+) -enantiomer.

Here, it is particularly preferred that compound a is selected from:

■ (2RS, 3RS) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol

■ (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol,

■ (+) - (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol,

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

■ (2RS, 3RS) -3- (3-difluoromethyl-phenyl) -1-dimethylamino-2-methyl-pentan-3-ol,

■ (2RS, 3RS) -1-dimethylamino-2-methyl-3- (3-methylsulfanyl-phenyl) -pentan-3-ol,

■ (3RS) -1-dimethylamino-3- (3-methoxy-phenyl) -4, 4-dimethyl-pentan-3-ol,

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

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

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

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

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

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

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

■ (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol,

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

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

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

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

■ (2RS, 3RS) -4-dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol and

■ (+) - (2R, 3R) -4-dimethylamino-2- (3-methoxy-phenyl) -3-methyl-butan-2-ol,

their hydrochloride salts are preferred.

For the active compound combinations, particular preference is given to the compounds a of group d) being selected from compounds of the formula II in which:

x is selected from

OH、F、Cl、OC(O)CH₃Or H, preferably OH, F or H, especially OH,

and/or

R¹Is selected from

C_1-4-alkyl, CF₃、OH、O-C_1-4Alkyl, Cl or F, preferably OH, CF₃Or CH₃，

And/or

R⁹-R¹³3 or 4 of the radicals must represent H, the remainder being each independently selected from

H、Cl、F、OH、CF₂H、CF₃Or saturated and unsubstituted, branched or unbranched C_1-4-an alkyl group; OR (OR)¹⁴Or SR¹⁴Wherein R is¹⁴Selected from saturated and unsubstituted, branched or unbranched C_1-3-an alkyl group;

preferably H, Cl, F, OH, CF₂H、CF₃、OCH₃Or SCH₃

Or R¹²And R¹¹Forming a 3, 4-OCH ═ CH ring;

in particular

If R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents hydrogen, then the other is selected from:

Cl、F、OH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH and CF₂H、OR¹⁴Or SCH₃Especially OH or OC_1-3-alkyl, preferably OH or OCH₃，

Or

If R is⁹And R¹³Represents H and R¹¹Represents OH, OCH₃Cl or F, preferably Cl, R¹⁰Or R¹²One of them also represents H, then the other represents OH, OCH₃Cl or F, preferably Cl,

or

If R is⁹、R¹⁰、R¹²And R¹³Represents H, R¹¹Selected from CF₃、CF₂H. Cl or F, preferably F,

or

If R is¹⁰、R¹¹And R¹²Represents H, R⁹Or R¹³One of which also represents H, then the other is selected from OH, OC₂H₅Or OC₃H₇。

Very particular preference is given to the following cases:

if R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents H, then the other is selected from:

Cl、F、OH、SH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH OR OR¹⁴Especially OH or OC_1-3-alkyl, preferably OH or OCH₃。

In this context, particularly preferred compounds of group d) are compounds of the formula II in the form of diastereomers having the relative configuration IIa:

especially in mixtures in which such diastereomer content is higher than another diastereomer or as pure diastereomer,

and/or

The compounds of formula II are present as the (+) -enantiomer, especially as a mixture of the racemic compound having a higher content of the (+) -enantiomer than the (-) -enantiomer, or as the pure (+) -enantiomer.

Here, it is particularly preferred that compound a is selected from:

■ (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1, 3-diol,

■ (+) - (1R, 3R, 6R) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1, 3-diol,

■ (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-hydroxy-phenyl) -cyclohexane-1, 3-diol,

■ (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1, 3-diol,

■ (+) - (1R, 2R, 5S) -3- (2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl) -phenol, or

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

their hydrochloride salts are preferred.

For the active compound combinations, particular preference is given to the compounds a of group e) being selected from compounds of the formula III, in which:

x is selected from

OH、F、Cl、OC(O)CH₃Or H, preferably OH, F or H, especially F or H,

and/or

R⁹-R¹³3 or 4 of the radicals must represent H, the remainder being each independently selected from

H、Cl、F、OH、CF₂H、CF₃Or saturated and unsubstituted, branched or unbranched C_1-4-an alkyl group; OR (OR)¹⁴Or SR¹⁴Wherein R is¹⁴Selected from saturated and unsubstituted, branched or unbranched C_1-3-an alkyl group;

preferably H, Cl, F, OH, CF₂H、CF₃、OCH₃Or SCH₃，

Or R¹²And R¹¹Forming a 3, 4-OCH ═ CH ring;

in particular

If R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents H, then the other is selected from:

Cl、F、OH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH and CF₂H、OR¹⁴Or SCH₃Especially OH or OC_1-3-alkyl, preferably OH or OCH₃，

Or

If R is⁹And R¹³Represents H and R¹¹Is OH, OCH₃Cl or F, preferably Cl, R¹⁰Or R¹²One of them also represents H, then the other represents OH, OCH₃Cl or F, preferably Cl,

or

If R is⁹、R¹⁰、R¹²And R¹³Represents H, R¹¹Selected from CF₃、CF₂H. Cl or F, preferably F,

or

If R is¹⁰、R¹¹And R¹²Represents H, R⁹Or R¹³One of which also represents H, then the other is selected from OH, OC₂H₅Or OC₃H₇。

Very particular preference is given to the following cases:

if R is⁹、R¹¹And R¹³Represents H, R¹⁰Or R¹²One of which also represents H, then the other is selected from:

Cl、F、OH、SH、CF₂H、CF₃、OR¹⁴or SR¹⁴Preferably OH OR OR¹⁴Especially OH or OC_1-3-alkyl, preferably OH or OCH₃。

In this context, particularly preferred compounds of group e) are compounds of the formula III in the form of diastereomers having the relative configuration IIIa:

especially in mixtures in which such diastereomer content is higher than another diastereomer or as pure diastereomer,

and/or

The compounds of formula III are present as the (+) -enantiomer, especially as a mixture of the racemic compound having a higher content of the (+) -enantiomer than the (-) -enantiomer, or as the pure (+) -enantiomer.

Here, it is particularly preferred that compound a is selected from:

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

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

■ (1S, 2S) -3- (2-dimethylaminomethyl-cyclohexyl) -phenol, or

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

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

■ (-) - (1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl ] -dimethylamine,

■ (1R, 2R) - [2- (3-methoxy-phenyl) -cyclohexylmethyl ] -dimethylamine,

their hydrochloride salts are preferred.

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

darifenacin, duloxetine, oxybutynin or tolterodine,

preferably selected from

Duloxetine, oxybutynin or tolterodine,

preferably selected from

Oxybutynin or tolterodine.

The invention also provides a medicament, preferably for the treatment of severe urinary urgency or incontinence, comprising as active compound combination according to the invention, optionally together with suitable additives and/or adjuvants.

Suitable additives and/or adjuvants in the context of the present invention are substances which are known to the expert in the art from the prior art and which can be formulated into pharmaceutical preparations. The choice of these auxiliary substances and the amounts used depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically. Formulations in the form of tablets, chewable tablets, coated tablets, capsules, granules, drops, mists or syrups are suitable for oral administration; solutions, suspensions, reconstitutable dry formulations and sprays are suitable for parenteral, topical and inhalation administration. The use of suppositories in the rectum is also possible. The use of depot agents (depot) in dissolved form, carrier films or patches, optionally with the addition of additives which facilitate penetration through the skin, is an example of a suitable transdermal administration. Examples of adjuvants and additives for oral administration are: disintegrants, lubricants, binders, fillers, mold release agents, suitable solvents, flavorings, sugars, especially carriers, diluents, colorants, antioxidants, and the like. Waxes, fatty acid esters, and the like may be particularly useful for suppositories, while carriers, preservatives, suspension aids, and the like may be useful in compositions for parenteral administration. The amount of active compound administered to a patient will vary with the weight of the patient, the mode of administration and the severity of the disease. The compounds of the present invention may be delivered in a sustained release manner from oral, rectal or transdermal formulations. Suitable sustained release formulations, particularly "once daily" formulations provided that the formulation is consumed once a day, are particularly preferred for the symptoms of the present invention.

Furthermore, to avoid side effects or analgesic effects, drugs containing at least 0.05% to 90.0% of active compound, especially low active doses, are preferred. At least one compound of the formula I in an amount of from 0.1 to 5,000mg/kg of body weight, in particular from 1 to 500mg/kg of body weight, preferably from 2 to 250mg/kg of body weight, is customarily administered. However, it is also preferred and conventional to administer 0.01-5mg/kg body weight, preferably 0.03-2mg/kg body weight, especially 0.05-1mg/kg body weight.

Adjuvants may be, for example, water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffin oil, wax, natural and synthetic gums, acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glycerol stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and-propylene fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic acid, citric acid, sodium lactate, polyoxyethylene and-propylene fatty acid esters, sorbitan fatty acid esters, sorbitol fatty acid esters, and the like, Ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potassium carbonate, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidone, agar and bentonite.

The medicaments and pharmaceutical compositions according to the invention are prepared by means, equipment, methods and procedures for pharmaceutical preparations well known in the art, which are described, for example, in the following documents: "Remington's Pharmaceutical Sciences", eds A.R. Gennaro, 17 th edition, Mack Publishing Company, Easton, Pa. (1985), especially section 8, chapters 76-93.

Thus, for example, for solid formulations such as tablets, the pharmaceutically active compound may be granulated with a pharmaceutical carrier such as conventional tablet ingredients, e.g., corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and a pharmaceutical diluent, e.g., water, to form a solid composition containing a homogeneous distribution of the active compound. Homogeneous distribution is understood here to mean that the active compound is distributed homogeneously throughout the composition, so that it can be easily divided into unit dosage forms having the same effect, such as tablets, pills or capsules. The solid composition is then divided into unit dosage forms. To provide a sustained release dosage form, tablets or pellets of the medicament according to the invention, or of the pharmaceutical composition according to the invention, may also be coated or otherwise admixed. Suitable coating compositions are, inter alia, polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and/or cellulose acetate, and the like.

Although the medicaments according to the invention exhibit only mild side effects, it may be advantageous to use morphine antagonists, in particular naloxone, naltrexone and/or levorphanol, in addition to the combination of compounds a and B, for example in order to avoid certain forms of dependence.

The invention also relates to a method for the treatment of severe urinary urgency or incontinence, in which active compound combinations of compound a and compound B are used, in particular in therapeutically active (in each case) doses.

The following examples are intended to illustrate the invention without limiting it.

Example 1: detection system for intravesical pressure measurement method of anesthetized young mouse

Cystometrography studies were performed in neonatal female rats according to the method of Kimura et al (Kimura et al, (1996), int.J.Urol.3: 218-227). The abdomen of the rat was opened under anesthesia and ventilation (ventilated) and the ureters were ligated. Urine is drained from the kidneys. The catheter is inserted into the bladder and fixed in place. Saline is infused into the bladder with an infusion pump through a catheter until it undergoes rhythmic autoregulatory contractile activity, and the contractions can be recorded by a connected pressure recorder. After a stable initial value is obtained, the test compound is injected intravenously. The effects on bladder function are manifested as an inhibition of spontaneous contractions. In the examples of the invention, a dose of 0.1mg/kg i.v. of compound a ((+) - (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol) was combined with a dose of 0.03mg/kg i.v. of compound B (oxybutynin) and the effect of this combination was compared with the effect of each individual substance. Each individual substance and the combination showed an inhibitory effect on the frequency of contractions (urination/min). The data are summarized in the following table.

Substance(s)	Compound A0.1mg/kg i.v.	Compound B0.03 mg/kg i.v.	Compound a0.1mg/kg i.v. + compound b0.3mg/kg i.v.	Vehicle control group i.v.
					Inhibition of contraction frequency [% MPE ] compared to before test]	21.7％	10.7％	42.5％	4.0％

All the substances listed here have a measurable inhibitory effect on spontaneous contractions in rats.

The combination of substances studied showed a positive effect on bladder regulation and is therefore suitable for the treatment of urinary incontinence.

Example 2: parenteral administration mode

At room temperature, 20g tramadol and 1g tolterodine were dissolved in 11 parts of water for injection, and the solution was made isotonic by addition of NaCl.

Claims (2)

1. Use of the active compound combinations of (+) - (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pent-3-ol in the form of a physiologically acceptable salt and oxybutynin in the form of a physiologically acceptable salt for the preparation of a medicament for the treatment of urinary urgency or incontinence.

2. Active compound combinations of (+) - (2R, 3R) -1-dimethylamino-3- (3-methoxy-phenyl) -2-methyl-pentan-3-ol in the form of a physiologically acceptable salt and oxybutynin in the form of a physiologically acceptable salt.