Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

• the invention relates to the use of a combination of compounds of group A, in particular opioids, and compounds of group B, in particular anti-muscarine agents and other substances which have a predominantly peripheral action, for the preparation of a medicament for treatment of an increased urge to urinate or urinary incontinence and to corresponding medicaments and methods for treatment of an increased urge to urinate or urinary incontinence.
• Urinary incontinence is the involuntary discharge of urine. This occurs in an uncontrolled manner when the pressure within the urinary bladder exceeds the pressure needed to close the ureter. Causes can be, on the one hand, an increased internal pressure in the bladder (e.g., due to detrusor instability) with the consequence of urgency incontinence, and, on the other, a reduced sphincter pressure (e.g., following giving birth or surgical interventions) with the consequence of stress incontinence.
• the detrusor is the coarsely bundled multilayered bladder wall musculature, contraction of which leads to voiding of urine, and the sphincter is the closing muscle of the urethra.
• the urge to urinate is the state, aimed at voiding of urine (micturition), of increased bladder muscle tension as the bladder capacity is approached (or exceeded). This tension acts here as a stimulus to micturition.
• An increased urge to urinate is understood here in particular as the occurrence of premature or an increased and sometimes even painful urge to urinate up to so-called strangury. This consequently leads to a significantly more frequent micturition.
• causes can be, inter alia, inflammations of the urinary bladder and neurogenic bladder disorders, and also bladder tuberculosis. However, not all the causes have yet been clarified.
• medicaments which in particular increase the resistance of the urethra or of the neck of the bladder, show affinities for ⁇ -adrenoreceptors, such as ephedrine, for ⁇ -adrenoreceptors, such as clenbutarol, or are hormones, such as oestradiol.
• ⁇ -adrenoreceptors such as ephedrine
• ⁇ -adrenoreceptors such as clenbutarol
• hormones such as oestradiol.
• the object of the present invention was therefore to provide substances or substance combinations which are helpful for treatment of an increased urge to urinate or urinary incontinence and, at the active doses, preferably at the same time show fewer side effects and/or analgesic actions than known from the prior art, in particular show a synergistic effect for treatment of urinary incontinence.
• the invention accordingly provides the use of an active compound combination of at least one of the compounds A and at least one of the compounds B, with compound A chosen from:
• Group a) comprising: tramadol, O-demethyltramadol, or O-demethyl-N-mono-demethyl-tramadol, optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in the form of their solvates, in particular the hydrates;
• Group b) comprising:
• LAAM levomethadyl acetate
• Group c) comprising:
• X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
• R 2 is chosen from C 1-4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
• R 2 and R 3 in each case independently of one another are chosen from H or C 1-4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, or
• R 2 and R 3 together form a saturated C 1-7 -cycloalkyl radical, unsubstituted or mono- or polysubstituted,
• R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
• R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; PO(
• R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
• R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH ⁇ CH, CH ⁇ CHO, CH ⁇ C(CH3)O, OC(CH3) ⁇ CH, (CH 2 ) 4 or OCH ⁇ CHO ring,
• Group d) comprising:
• X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
• R 1 is chosen from C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 —C 6 H 5 , O—C 1-4 -alkyl, Cl or F and
• R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
• R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; PO(
• R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted,
• R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH ⁇ CH, CH ⁇ CHO, CH ⁇ C(CH3)O, OC(CH 3 ) ⁇ CH, (CH 2 ) 4 or OCH ⁇ CHO ring,
• X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and
• R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
• R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; PO(
• R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH ⁇ CH, CH ⁇ CHO, CH ⁇ C(CH3)O, OC(CH 3 ) ⁇ CH, (CH 2 ) 4 or OCH ⁇ CHO ring,
• the anti-muscarine agents atropine, oxybutinin, propiverine, propantheline, emepronium, trospium, tolterodine, darifenacin and ⁇ , ⁇ -diphenylacetic acid 4-(N-methylpiperidyl) ester, as well as duloxetine, imipramine and desmopressin,
• alkyl or cycloalkyl radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
• C 1-2 -alkyl represents C1- or C2-alkyl
• C 1-3 -alkyl represents C1-, C2- or C3-alkyl
• C 1-4 -alkyl represents C1-, C2-, C3- or C4-alkyl
• C 1-5 -alkyl represents C1-, C2-, C3-, C4- or C5-alkyl
• C 1-6 -alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl
• C 1-7 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
• C 1-8 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
• C 1-10 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6
• C 3-4 -cycloalkyl represents C3- or C4-cycloalkyl
• C 3-5 -cycloalkyl represents C3-, C4- or C5-cycloalkyl
• C 3-6 -cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl
• C 3-7 -cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl
• C 3-8 -cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl
• C 4-5 -cycloalkyl represents C4- or C5-cycloalkyl
• C 4-6 -cycloalkyl represents C4-, C5- or C6-cycloalkyl
• C 4-7 -cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C 5-6
• cycloalkyl in respect of cycloalkyl, the term also includes saturated cycloalkyls in which one or 2 carbon atoms are replaced by a heteroatom, S, N or O.
• cycloalkyl also includes, in particular, mono- or poly-, preferably monounsaturated cycloalkyls without a heteroatom in the ring as long as the cycloalkyl is not an aromatic system.
• alkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl, CHF 2 , CF 3 or CH 2 OH, as well as pyrazolinone, oxopyrazolinone, [1,4]dioxan
• substituted here in the context of this invention is understood as substitution of at least one (optionally also several) hydrogen radical(s) by F, Cl, Br, I, NH 2 , SH or OH, where “polysubstituted” or “substituted” in the case of polysubstitution is to be understood as meaning that the substitution takes place both on different and on the same atoms several times with the same or different substituents, for example three times on the same C atom as in the case of CF 3 , or at different places as in the case of —CH(OH)—CH ⁇ CH—CHCl 2 .
• substituents here are F, Cl and OH.
• the hydrogen radical can also be replaced by OC 1-3 -alkyl or C 1-3 -alkyl (in each case mono- or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
• (CH 2 ) 3-6 is to be understood as meaning —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —
• (CH 2 ) 1-4 is to be understood as meaning —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —and —CH 2 —CH 2 —CH 2 —CH 2 —(CH 2 ) 4-5 is to be understood as meaning —CH 2 —CH 2 —CH 2 —CH 2 —and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 — etc.
• An aryl radical is understood as meaning ring systems with at least one aromatic ring, but without heteroatoms in even only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or mono- or polysubstituted.
• a heteroaryl radical is understood as meaning heterocyclic ring systems with at least one unsaturated ring, which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur and can also be mono- or polysubstituted.
• heteroaryls examples which may be mentioned from the group of heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.
• substituted is understood as meaning substitution of the aryl or heteroaryl by R 23 , OR 23 a halogen, preferably F and/or Cl, a CF 3 , a CN, an NO 2 , an NR 24 R 25 , a C 1-6 -alkyl (saturated), a C 1-6 -alkoxy, a C 3-8 -cycloalkoxy, a C 3-8 -cycloalkyl or a C 2-6 -alkylene.
• the radical R 23 represents H, a C 1-10 -alkyl, preferably a C 1-6 -alkyl, an aryl or heteroaryl or an aryl or heteroaryl radical bonded via a C 1-3 -alkylene group, where these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals
• the radicals R 24 and R 25 are identical or different and denote for H, a C 1-10 -alkyl, preferably a C 1-6 -alkyl, an aryl, a heteroaryl or an aryl or heteroaryl radical bonded via a C 1-3 -alkylene group, where these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals,
• the radical R 26 denotes H, a C 1-10 -alkyl, preferably a C 1-6 -alkyl, an aryl or heteroaryl radical or an aryl or heteroaryl radical bonded via a C 1-3 -alkylene group, where these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals.
• salt in the context of this invention is to be understood as meaning any form of the active compound according to the invention in which this assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
• a counter-ion a cation or anion
• complexes of the active compound with other molecules and ions in particular complexes which are complex via ionic interactions.
• physiologically acceptable salt in particular with cations or bases
• physiologically acceptable salts are understood as meaning salts of at least one of the compounds according to the invention—usually a (deprotonated) acid—as the anion with at least one preferably inorganic cation, which are physiologically acceptable—in particular when used on humans and/or mammals.
• Particularly preferred salts are those of the alkali metals and alkaline earth metals, but also with NH 4 +, but in particular (mono-) or (di-)sodium, (mono-) or (di-)potassium, magnesium or calcium salts.
• physiologically acceptable salt in particular with anions or acids
• physiologically acceptable salts of at least one of the compounds according to the invention usually protonated, for example on the nitrogen—as the cation with at least one anion, which are physiologically acceptable—in particular when used on humans and/or mammals.
• this is understood as meaning the salt formed with a physiologically acceptable acid, namely salts of the particular active compound with inorganic or organic acids which are physiologically acceptable—in particular when used on humans and/or mammals.
• physiologically acceptable salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1b6-benzo[d]isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, a-liponic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
• the hydrochloride salt is particularly preferred.
• Suitable salts in the context of this invention and in each use described and each of the medicaments described are salts of the particular active compound with inorganic or organic acids and/or a sugar substitute, such as saccharin, cyclamate or acesulfam.
• a sugar substitute such as saccharin, cyclamate or acesulfam.
• the hydrochloride is particularly preferred.
• the compound A in group a) is chosen from:
• the compound A in group b) is chosen from:
• the compound A in group c) is chosen from compounds according to formula I for which:
• X is chosen from
• OH, F, Cl, OC(O)CH 3 or H preferably OH, F,
• R 1 is chosen from
• R 2 and R 3 independently of one another are chosen from
• H C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; preferably H, CH 3 , C 2 H 5 , i-propyl or t-butyl, in particular H or CH 3 , preferably R 3 ⁇ H, or
• R 2 and R 3 together form a C 5-6 -cycloalkyl radical, saturated or unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted, in particular cyclohexyl.
• R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
• one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, preferably Cl, or
• R 11 is chosen from CF 3 , CF 2 H, Cl or F, preferably F, or
• R 10 , R 11 and R 12 correspond to H
• one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 .
• the compounds of the formula I are used in the form of the (+)-enantiomer, in particular in mixtures with a higher content of the (+)-enantiomer compared with the ( ⁇ )-enantiomer of a racemic compound or as the pure (+)-enantiomer.
• (+)-(1R,2R)-acetic acid 3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl-propyl ester
• the compound A in group d) is chosen from compounds according to formula II for which:
• OH, F, Cl, OC(O)CH 3 or H preferably OH, F or H, in particular OH, and/or
• R 1 is chosen from
• R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
• one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, preferably Cl, or
• R 11 is chosen from CF 3 , CF 2 H, Cl or F, preferably F, or
• R 10 , R 11 and R 12 correspond to H
• one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 . very particularly preferably
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• the compounds of the formula II are used in the form of the (+)-enantiomer, in particular in mixtures with a higher content of the (+)-enantiomer compared with the ( ⁇ )-enantiomer of a racemic compound or as the pure (+)-enantiomer.
• the compound A in group e) is chosen from compounds according to formula III for which:
• OH, F, Cl, OC(O)CH 3 or H preferably OH, F or H, in particular F or H, and/or
• R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
• one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, preferably Cl, or
• R 11 is chosen from CF 3 , CF 2 H, Cl or F, preferably F, or
• R 10 , R 11 and R 12 correspond to H
• one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 , very particularly preferably
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• the compounds of the formula III are used in the form of the (+)-enantiomer, in particular in mixtures with a higher content of the (+)-enantiomer compared with the ( ⁇ )-enantiomer of a racemic compound or as the pure (+)-enantiomer.
• compound B is chosen from:
• the invention also provides an active compound combination of at least one of the compounds A and at least one of the compounds B, with compound A chosen from:
• Group a) comprising:
• tramadol, O-demethyltramadol or O-demethyl-N-mono-demethyl-tramadol optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any desired mixing ratio; in the form of their acids or their bases or in the form of their salts, in particular the physiologically acceptable salts, or in the form of their solvates, in particular the hydrates;
• Group b) comprising:
• LAAM levomethadyl-acetate
• Group c) comprising:
• X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
• R 2 is chosen from C 1-4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
• R 2 and R 3 in each case independently of one another are chosen from H or C 1-4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, or
• R 2 and R 3 together form a saturated C 4-7 -cycloalkyl radical, unsubstituted or mono- or polysubstituted,
• R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
• R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; PO(
• R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
• R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH ⁇ CH, CH ⁇ CHO, CH ⁇ C(CH3)O, OC(CH 3 ) ⁇ CH, (CH 2 ) 4 or OCH ⁇ CHO ring,
• X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
• R 1 is chosen from C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 —C 6 H 5 , O—C 1-4 -alkyl, Cl or F and
• R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
• R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; PO(
• R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
• R 9 and R 10 or R 10 and R 11 together form an OCH 2 O, OCH 2 CH 2 O, OCH ⁇ CH, CH ⁇ CHO, CH ⁇ C(CH3)O, OC(CH 3 ) ⁇ CH, (CH 2 ) 4 or OCH ⁇ CHO ring,
• X is chosen from OH, F, Cl, H or OC(O)R 7 , where R 7 is chosen from C 1-3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and
• R 9 to R 13 in each case independently of one another are chosen from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 ; SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, unsubstituted or mono- or polysubstituted;
• R 14 is chosen from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO-CHR 17 -NHR 18 , CO—C 6 H 4 —R 15 , where R 15 is ortho-OCOC 1-3 -alkyl or meta- or para-CH 2 N(R 16 ) 2 where R 16 is C 1-4 -alkyl or 4-morpholino, wherein in the radicals R 14 , R 15 and R 16 the alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; PO(
• R 17 and R 18 in each case independently of one another are chosen from H; C 1-6 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; phenyl, benzyl or phenethyl, in each case unsubstituted or mono- or polysubstituted, or
• the anti-muscarine agents atropine, oxybutinin, propiverine, propantheline, emepronium, trospium, tolterodine, darifenacin and ⁇ , ⁇ -diphenylacetic acid 4-(N-methylpiperidyl) ester, as well as duloxetine, imipramine and desmopressin,
• the compound A in group a) is chosen from:
• the compound A in group b) is chosen from:
• buprenorphine preferably
• the compound A in group c) is chosen from compounds according to formula I for which:
• R 1 is chosen from
• R 2 and R 3 independently of one another are chosen from
• H C 1-4 -alkyl, saturated and unsubstituted, branched or unbranched; preferably H, CH 3 , C 2 H 5 , i-propyl or t-butyl, in particular H or CH 3 , preferably R 3 ⁇ H, or
• R 2 and R 3 together form a C 5-6 -cycloalkyl radical, saturated or unsaturated, unsubstituted or mono- or polysubstituted, preferably saturated and unsubstituted, in particular cyclohexyl. and/or
• R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 preferably OH, CF 2 H, OCH 3 or SCH 3 or
• R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
• one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, preferably Cl, or
• R 11 is chosen from CF 3 , CF 2 H, Cl or F, preferably F, or
• R 10 , R 11 and R 12 correspond to H
• one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 .
• the compounds of the formula I are in the form of the (+)-enantiomer, in particular in mixtures with a higher content of the (+)-enantiomer compared with the ( ⁇ )-enantiomer of a racemic compound or as the pure (+)-enantiomer.
• compound A is chosen from the following group:
• the compound A in group d) is chosen from compounds according to formula II for which:
• X is chosen from
• OH, F, Cl, OC(O)CH 3 or H preferably OH, F or H, in particular OH, and/or
• R 1 is chosen from
• R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
• one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, preferably Cl, or
• R 11 is chosen from CF 3 , CF 2 H, Cl or F, preferably F, or
• R 10 , R 11 and R 12 correspond to H
• one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 . very particularly preferably
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• the compounds of the formula II are in the form of the (+)-enantiomer, in particular in mixtures with a higher content of the (+)-enantiomer compared with the ( ⁇ )-enantiomer of a racemic compound or as the pure (+)-enantiomer.
• compound A is chosen from the following group:
• the compound A in group e) is chosen from compounds according to formula III for which:
• OH, F, Cl, OC(O)CH 3 or H preferably OH, F or H, in particular F or H, and/or
• R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, independently of one another are chosen from
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
• one of R 10 or R 12 also corresponds to H while the other corresponds to OH, OCH 3 , Cl or F, preferably Cl, or
• R 11 is chosen from CF 3 , CF 2 H, Cl or F, preferably F, or
• R 10 , R 11 and R 12 correspond to H
• one of R 9 or R 13 also corresponds to H while the other is chosen from OH, OC 2 H 5 or OC 3 H 7 , very particularly preferably
• R 9 , R 11 and R 13 correspond to H
• one of R 10 or R 12 also corresponds to H while the other is chosen from:
• the compounds of the formula III are in the form of the (+)-enantiomer, in particular in mixtures with a higher content of the (+)-enantiomer compared with the ( ⁇ )-enantiomer of a racemic compound or as the pure (+)-enantiomer.
• compound A is chosen from the following group:
• the compound B is chosen from:
• the invention also provides a medicament, preferably for treatment of an increased urge to urinate or urinary incontinence, comprising an active compound combination according to the invention and optionally suitable additives and/or auxiliary substances.
• Suitable additives and/or auxiliary substances in the context of this invention are all the substances known to the expert from the prior art for achieving pharmaceutical formulations.
• the choice of these auxiliary substances and the amounts thereof to be employed depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally.
• Formulations in the form of tablets, chewable tablets, coated tablets, capsules, granules, drops, juices or syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry formulations and sprays are suitable for parenteral, topical and inhalatory administration. Suppositories for use in the rectum are a further possibility.
• auxiliary substances and additives for the oral administration forms are disintegrating agents, lubricants, binders, fillers, mold release agents, with appropriate solvents, flavorings, sugar, in particular carrier agents, diluents, dyestuffs, antioxidants, etc.
• Waxes and fatty acid esters can be used for suppositories and carrier substances, preservatives, suspension auxiliaries etc. can be used for compositions for parenteral administration.
• the amounts of active compound to be administered to patients vary as a function of the weight of the patient, the mode of administration and the severity of the disease.
• the compounds according to the invention can be released in a delayed manner from formulation forms for oral, rectal or percutaneous use.
• appropriate sustained release formulations in particular in the form of a “once-daily” preparation which has to be taken only once a day, are particularly preferred.
• Medicaments which comprise at least 0.05 to 90.0% of the active compound, in particular dosages with a low action, in order to avoid side effects or analgesic actions, are furthermore preferred.
• 0.1 to 5,000 mg/kg, in particular 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 administered.
• administration of 0.01-5 mg/kg, preferably 0.03 to 2 mg/kg, in particular 0.05 to 1 mg/kg of body weight is also likewise preferred and conventional.
• Auxiliary substances can 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, gelatins, sorbitol, inositol, mannitol, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, naturally occurring and synthetic rubbers, gum acacia, alginates, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearate, sodium lauryl sulfate, edible oils, sesame oil, coconut oil, groundnut oil, soya bean oil, lecithin, sodium lactate,
• the medicaments and pharmaceutical compositions according to the invention are prepared with the aid of agents, devices, methods and processes which are well-known in the prior art of pharmaceutical formulation, such as are described, for example, in “Remington's Pharmaceutical Sciences”, ed. A. R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapter 76 to 93.
• the active compound of the medicament can be granulated with a pharmaceutical carrier, e.g., conventional tablet constituents, such as maize starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, such as, e.g., water, in order to form a solid composition which comprises the active compound in homogeneous distribution.
• a pharmaceutical carrier e.g., conventional tablet constituents, such as maize starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums
• pharmaceutical diluents such as, e.g., water
• the solid composition is then divided into unit dose forms.
• the tablets or pills of the medicament according to the invention or of the compositions according to the invention can also be coated, or compounded in another manner, in order to provide a dose form with delayed release.
• Suitable coating compositions are, inter alia, polymeric acids and mixtures of polymeric acids with materials such as, e.g., shellac, cetyl alcohol and/or cellulose acetate.
• the medicaments according to the invention show only a low degree of side effects, it may be of advantage, for example to avoid certain forms of dependency, also to use morphine antagonists, in particular naloxone, naltrexone and/or levallorphan, in addition to the combination of compounds A and B.
• morphine antagonists in particular naloxone, naltrexone and/or levallorphan
• the invention also relates to a method for treatment of an increased urge to urinate or urinary incontinence, in which the active compound combination of compound A and compound B, in particular in a therapeutically active (in each case) dosage, is used.
• compound A ((+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol; hydrochloride) in the dosage of 0.1 mg/kg intravenously was combined with compound B (oxybutynin) in the dosage of 0.03 mg/kg intravenously and the action of this combination was compared with that of the individual substances.
• the individual substances and combination showed an inhibition of the rate of contractions (micturition events/min).
• the data are summarized in the following table.
• Compound Compound Compound Compound A A B 0.1 mg/kg i.v. + Vehicle 0.1 mg/ 0.03 mg/ compound B control

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