EP1507520A1 - Combinaison d'opioides selectionnes et d'autres principes actifs pour le traitement de l'incontinence urinaire - Google Patents

Combinaison d'opioides selectionnes et d'autres principes actifs pour le traitement de l'incontinence urinaire

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Publication number
EP1507520A1
EP1507520A1 EP03730120A EP03730120A EP1507520A1 EP 1507520 A1 EP1507520 A1 EP 1507520A1 EP 03730120 A EP03730120 A EP 03730120A EP 03730120 A EP03730120 A EP 03730120A EP 1507520 A1 EP1507520 A1 EP 1507520A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
unsubstituted
mono
och
saturated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03730120A
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German (de)
English (en)
Inventor
Thomas Christoph
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
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Gruenenthal GmbH
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Filing date
Publication date
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Publication of EP1507520A1 publication Critical patent/EP1507520A1/fr
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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
    • 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

Definitions

  • Urinary incontinence is the involuntary loss of urine. This occurs in an uncontrolled manner when the pressure inside the bladder exceeds the pressure necessary to close the ureter.
  • the causes can be, on the one hand, an increased internal bladder pressure (e.g. due to detrusor instability) with the consequence of urge incontinence and, on the other hand, a reduced sphincter pressure (e.g. after birth or surgery) with the
  • the detrusor is the roughly bundled, multi-layered bladder wall muscles, the contraction of which leads to emptying of the urine, the sphincter the sphincter of the urethra.
  • Mixed forms of these types of incontinence as well as so-called abundance incontinence (eg with benign prostatic hyperplasia) or reflex incontinence (eg after spinal cord damage) occur. More on this can be found in Chutka, D.S. and Takahashi, P. Y., 1998, Drugs 560: 587-595.
  • Urge to urinate is the state of increased bladder muscle tension aimed at emptying urine (micturition) when the bladder capacity is approached
  • the subject of the invention is the use of a combination of active ingredients comprising at least one of the compounds A and at least one of the compounds B, with compound A selected from:
  • X is selected from OH, F, Cl, H or OC (O) R 7 with R 7 selected from C 1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
  • R ⁇ is selected from C ⁇ alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
  • R ⁇ and R ⁇ are each independently selected from
  • R ⁇ and R together form a saturated C 4 - cycloalkyl radical, unsubstituted or mono- or polysubstituted,
  • R9 to R " 1 ⁇ are each independently selected from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR14 0CF3,
  • R "14 selected from C ⁇ _6-alkyl; pyridyl, thienyl,
  • Alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
  • R1 7 and R18 each independently selected from H; G ⁇ ß-Alky !, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,
  • X is selected from OH, F, Cl, H or OC (O) R 7 with R 7 selected from C j _3-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
  • R 1 is selected from C
  • R9 to R13 are each independently selected from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 4, OCF3, SR 14 ,
  • R1 4 selected from C- ⁇ _6-alkyl; Pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, each unsubstituted or substituted one or more times; PO (O-C ⁇ -4-alkyl) 2 , CO (OC ⁇
  • R ⁇ 7 and R18 each independently selected from H; C-ß-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,
  • X is selected from OH, F, Cl, H or OC (O) R 7 with R 7 selected from C 1 -C 3 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, and
  • R 9 to R ⁇ 8 are each independently selected from H, F, Cl, Br, I, CH 2 F, CHF 2> CF 3 , OH, SH, OR 14 , OCF 3 ,
  • R1 4 selected from Ci.ß-alkyl; Pyridyl, thienyl,
  • R ⁇ 7 and R18 each independently selected from H; C ⁇ _6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted, or
  • the antimuscarinics atropine, oxybutinin, propiverine, propantheline, emepronium, trospium, tolterodine, darifenacin and ⁇ , ⁇ -diphenylacetic acid 4- (N-methylpiperidyl) ester, as well as duloxetine, imipramine and desmopressin,
  • Venlafaxine is a selective norepinephrine reuptake inhibitor with efficacy in stress incontinence (Bae J.H. et al., BJU
  • Fesoterodine is a mACh antagonist developed by Schwarz Pharma.
  • Solifenacin (YM905) is a mACh antagonist developed by Yamanouchi.
  • Resiniferatoxin is a VR1 agonist developed by Afferon, Mundipharma and ICOS (but especially for local use).
  • Cizolirtine is one in the European
  • Patent EP 289 380 B1 described compound (2- [phenyl (1-methyl-1H-pyrazole-5-yl) methoxy] -N, N-dimethylethanamine, which is also known as 5- [alpha - (2- dimethylaminoethoxy) benzyl] -1-methyl-1H-pyrazole or 5 - ⁇ [N, N-dimethylaminoethoxy) phenyl] methyl ⁇ -1-methyl-1H-pyrazole) can be called)) with a mechanism of action previously unknown by the company Esteve (ES) is being clinically examined in urinary incontinence.
  • Nitro-Flurbiprofen and HCT-1026 are two substances developed by NicOx that act on NO + COX.
  • Talnetant is an NK antagonist developed by Glaxo Smith Kline.
  • TAK-637 is an NK antagonist developed by Takeda.
  • SL 251039 is an a-iAR agonist developed by Sanofi.
  • R 450 is an a-iAR agonist developed by Röche. Rec 15/3079 is a 5HT ⁇ A antagonist developed by Recordati.
  • (-) - DDMS is a substance developed by Sepracor that acts on NA + D.
  • NS-8 is a substance developed by Nippon Shinyaku that acts on PCA.
  • DRP-001 is a substance developed by Sosei for urge incontinence with an unknown mechanism of action.
  • alkyl or cycloalkyl radicals are taken to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
  • C 2 alkyl is C1 or C2 alkyl
  • C 1-3 alkyl is C1, C2 or C3 alkyl
  • C 4 alkyl is C1, C2, C3 or C4 alkyl C 1-5 alkyl for C1, C2, C3, C4 or C5 alkyl
  • C 1-6 alkyl for C1, C2, C3, C4, C5 or C6 alkyl
  • C 1-7 alkyl for C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • C 1-8 -alkyl for C1-, C2-, C3-, C4-, C5- , C6-, C7- or C8-alkyl
  • d-io-alkyl for C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and C 1 -18 -alkyl for C1-, C2-, C
  • C 3-4 -cycloalkyl stands for C3- or C4-cycloalkyl, C 3-5 -cycloalkyl for C3-, C4- or C5-cycloalkyl, C 3-6 -cycloalkyl for C3-, C4-, C5- or C6 -Cycloalkyl, C 3-7 -cycloalkyl for C3-, C4-, C5-, C6- or C7-cycloalkyl, C 3-8 -cycloalkyl for C3-, C4-, C5-, C6-, C7- or C8- Cycloalkyl, C 4-5 cycloalkyl for C4 or C5 cycloalkyl, C 4-6 cycloalkyl for C4, C5 or C6 cycloalkyl, C 4-7 cycloalkyl for C4, C5, C6 or C7 -Cycloalkyl, C 5-6 -cycloalkyl for C5- or C5
  • cycloalkyl also includes saturated cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O.
  • cycloalkyl in particular also includes one or more, preferably single, unsaturated cycloalkyls without
  • the alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, Pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-
  • Particularly preferred substituents here are F, Cl and OH.
  • the hydrogen radical can also be substituted by OC ⁇ -3-alkyl or C ⁇ -Alky! (j ⁇ e '' se ' n_ or multiply substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
  • (CH 2 ) 3 -6 is -CH2-CH2-CH 2 -, -CH2-CH 2 -CH 2 -CH 2 -, -CH 2 -CH2-CH2-CH2- and CH 2 -CH2 -CH 2 -CH2-CH 2 -CH2- to understand (CH 2 ) ⁇ -4 means -CH 2 -, -CH2-CH2-, -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -, under (CH 2 ) 4-5 is -CH2-CH2-CH2- and -CH2-CH2-CH2-CH2-CH 2 - to understand etc.
  • An aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even 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 to mean 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.
  • Examples include from the group of heteroaryls furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1, 2.5 thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, Indole and quinazoline listed.
  • aryl and heteroaryl this is understood to mean the substitution of aryl or heteroaryl with R 23 , OR 23, a halogen, preferably F and / or Cl, a CF3, a CN, a NO2,
  • the radical R 28 stands for H, a C 1-10 alkyl- > preferably a C 1-6 alkyl, an aryl or heteroaryl or for an aryl or heteroaryl bonded via a C-1.3 alkylene group -Rest, this aryl and heteroaryl radicals themselves may not be substituted by aryl or heteroaryl radicals,
  • the radicals R 2 and R 2 ⁇ 4 identical or different, represent H, a C j.-io-alkyl, preferably a Cj.g-alkyl, an aryl, a heteroaryl or a C ⁇ -Alkylene group-bound aryl or heteroaryl radical, these aryl and heteroaryl radicals themselves not being allowed to be substituted with aryl or heteroaryl radicals,
  • radicals R 24 and R 25 together represent CH2CH 2 OCH2CH2,
  • R 28 for H a C ⁇
  • salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution.
  • a counterion a cation or anion
  • This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.
  • physiologically compatible salt with cations or bases means salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation, which is physiologically - in particular when used in humans and or Mammal - are tolerated.
  • Particularly preferred are the salts of the alkali and alkaline earth metals but also with NH 4 + , but especially (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.
  • physiologically compatible salt with anions or acids is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which is physiologically - in particular when used in humans and / or Mammal - are compatible.
  • this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
  • physiologically compatible salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo-1, 2 dihydro1b6-benzo [d] isothiazol-3-one (saccharic acid),
  • Nicotinic acid 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, a-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid.
  • the hydrochloride salt is particularly preferred.
  • Suitable salts in the sense of this invention and in each described use and each of the described medicinal products are salts of the respective active substance with inorganic or organic acids and / or a sugar substitute such as saccharin, cyclamate or acesulfame.
  • the hydrochloride is particularly preferred.
  • Compounds of group c) and their preparation are known from DE 44 26 245 A1 and US 6,248,737.
  • Compounds of groups d) and e) and their preparation are known from DE 195 25 137 A1 or US 5,733,936 or US RE37355E.
  • the compound A in group a) is selected from:
  • Tramadol (+) - tramadol, (+) - O-demethyltramadol or (+) - O- desmethyl-N-mono-desmethyl-tramadol, preferably Tramadol or (+) - Tramadol, in particular (+) - Tramadol.
  • the use according to the invention is that the compound A in group b) is selected from:
  • buprenorphine preferably
  • the compound A in group c) is selected from compounds of the formula I for which:
  • X is selected from
  • R 1 is selected from
  • R 2 and R 3 are independently selected from
  • R 2 and R 8 together form a C 5 - 6 cycloalkyl form, 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, are selected independently of one another from
  • R 14 selected from C «
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from: Cl, F, OH, CF 2 H, CF 3) OR 14 or SR 14 , preferably OH,
  • R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
  • one of R 10 or R 12 also corresponds to H, while the other OH, OCH 3 , Cl or F, preferably Cl corresponds to
  • R 11 is selected from CF 3 , CF 2 H, Cl or F, preferably F,
  • R 10 , R 11 and R 12 correspond to H
  • one of R 9 or R 13 also corresponds to H, while the other is selected from OH, OC 2 H 5 or OC 3 H 7 .
  • the compounds of formula I are used in the form of the (+) ⁇ enantiomer, in particular in mixtures with a higher proportion of the (+) - enantiomer compared to the (-) - enantiomer of a racemic compound or as a pure (+) - enantiomer.
  • the use according to the invention is that the compound A in group d) is selected from compounds of the formula II for which:
  • X is selected from
  • R 1 is selected from
  • C ⁇ _4-alkyl CF3, OH, O-C ⁇ _4-alkyl, Cl or F, preferably OH, CF 3 or CH 3 ,
  • R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, are selected independently of one another from H, Cl, F, OH, CF 2 H, CF 3 or C 1 _ 4 alkyl, saturated and unsubstituted, branched or unbranched; OR 14 or SR 14 , with R 14 selected from C - ⁇ - alkyl, saturated and unsubstituted, branched or unbranched;
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from:
  • Alkyl preferably OH or OCH3,
  • R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3l Cl or F, preferably Cl
  • one of R 10 or R 12 also corresponds to H, while the other OH, OCH 3 , Cl or F, preferably Cl, corresponds,
  • R 11 is selected from CF 3 , CF 2 H, Cl or F, preferably F,
  • R 10 , R 11 and R 12 correspond to H
  • one of R 9 or R 13 also corresponds to H, while the other is selected from OH, OC 2 H 5 or OC 3 H 7 ,
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from:
  • OR 14 or SR 14 preferably OH or OR 14, in particular OH or OC j _3-alkyl, preferably
  • the compounds of formula II are used in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.
  • the compound A in group e) is selected from compounds of the formula III for which:
  • X is selected from
  • OH, F, Cl, OC (O) CH 3 or H preferably OH, F or H, in particular F or H.
  • R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, are selected independently of one another from
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from:
  • R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
  • one of R 10 or R 12 also corresponds to H, while the other OH, OCH 3 , Cl or F, preferably Cl corresponds to
  • R 11 is selected from CF 3 , CF 2 H, Cl or F, preferably F,
  • R 10 , R 11 and R 12 correspond to H
  • one of R 9 or R 13 also corresponds to H, while the other is selected from OH, OC 2 H 5 or OC 3 H 7 ,
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from:
  • OR 14 or SR 14 preferably OH or OR 14 , in particular OH or OC ⁇ alkyl, preferably OH or OCH 3 .
  • the compounds of formula III are used in the form of the (+) enantiomer, especially in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.
  • compound B is selected from:
  • compound B is selected from:
  • Another object of the invention is an active ingredient combination of at least one of the compounds A and at least one of the compounds B, with compound A selected from:
  • physiologically compatible salts in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or
  • LAAM Levomethadyl Acetate
  • sufentanil as free base or acid and / or in the form of physiologically compatible salts, in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or acids, optionally in the form of the enantiomers, diastereomers, in particular mixtures of them Enantiomers or diastereomers or a single enantiomer or diastereomer;
  • X is selected from OH, F, Cl, H or OC (O) R 7 with R 7 selected from C - ⁇ - alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted, R ⁇ is selected from C ⁇ - alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or substituted one or more times,
  • R 2 and R 8 are each independently selected from H or C ⁇
  • R 2 and R 8 together are a saturated C 4 - 7 -cycloalkyl form, unsubstituted or mono- or polysubstituted,
  • R 9 to R ⁇ 8 are each independently selected from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, 0R1, OCF 3 ,
  • R 14 selected from Ci.g-alkyl; Pyridyl, thienyl,
  • R ⁇ 7 and R18 each independently selected from H; C ⁇ _6-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,
  • X is selected from OH, F, Cl, H or OC (O) R 7 with R 7 selected from C 1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted,
  • R 1 is selected from C ⁇
  • R 9 to R ⁇ 8 are each independently selected from H, F, Cl, Br, 1, CH 2 F, CHF 2) CF3, OH, SH, OR 14 , OCF3, SR1 4 ,
  • R ⁇ 4 selected from Cj.ß-alkyl; Pyridyl, thienyl,
  • Alkyl groups can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted;
  • R1 7 and R18 each independently selected from H; C ⁇ _g-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,
  • X is selected from OH, F, Cl, H or OC (O) R 7 with R 7 selected from C ⁇
  • R 9 to R ⁇ 8 are each independently selected from H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 ,
  • NHR 18 CO-C6H4-R 5, with R 5 ortho-OCOC-
  • R1 7 and R18 each independently selected from H; Cj.ö-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Phenyl, benzyl or phenethyl, each unsubstituted or mono- or polysubstituted,
  • the antimuscarinics atropine, oxybutinin, propiverine, propantheline, emepronium, trospium, tolterodine,
  • physiologically compatible salts in particular in the form of their physiologically compatible acidic and basic salts or salts with cations or bases or with anions or
  • Acids optionally in the form of the enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers or a single enantiomer or diastereomer.
  • Suitable salts for the purposes of this invention and in each of the pharmaceuticals described are salts of the respective active ingredient with inorganic or organic acids and / or a sugar substitute such as saccharin, cyclamate or acesulfame.
  • the hydrochloride is particularly preferred.
  • the compound A in group a) is selected from:
  • Tramadol (+) - tramadol, (+) - O-demethyltramadol or (+) - O- desmethyl-N-mono-desmethyl-tramadol, preferably Tramadol or (+) - Tramadol, in particular (+) - Tramadol.
  • the compound A in group b) is selected from:
  • the compound A in group c) is selected from compounds of the formula I for which:
  • X is selected from
  • R is selected from
  • _4-alkyl saturated and unsubstituted, branched or unbranched; preferably CH 3 , C 2 H 5 , C 4 H 9 or t-butyl, in particular CH 3 or C 2 H 5 ,
  • R 2 and R 3 are independently selected from
  • R 2 and R 8 together form a C 5 - 6 cycloalkyl radical, saturated or unsaturated, unsubstituted or mono- or polysubstituted, saturated Preferably, 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, are selected independently of one another from
  • R 14 selected from C ⁇
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from: Cl, F, OH, CF 2 H, CF 3 , OR 14 or SR 14 , preferably OH,
  • R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, preferably Cl
  • one of R 10 or R 12 also corresponds to H, while the other OH, OCH 3 , Cl or F, preferably Cl corresponds to
  • R 11 is selected from CF 3 , CF 2 H, Cl or F, preferably F,
  • R 10 , R 11 and R 12 correspond to H
  • one of R 9 or R 13 also corresponds to H, while the other is selected from OH, OC 2 H 5 or OC 3 H 7 .
  • the compounds of the formula I are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.
  • compound A is selected from the following group:
  • the compound A in group d) is selected from compounds of the formula II for which:
  • X is selected from
  • R 1 is selected from
  • R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, are selected independently of one another from H, Cl, F, OH, CF 2 H, CF 3 or C ⁇ alkyl, saturated and unsubstituted, branched or unbranched; OR 14 or SR 14 , with R 14 selected from C 1-4 alkyl, saturated and unsubstituted, branched or unbranched;
  • R 9 , R 11 and R 13 correspond to H
  • one of R 0 or R 12 also corresponds to H, while the other is selected from:
  • Alkyl preferably OH or OCH 3 ,
  • R 9 and R 13 correspond to H and R 11 OH, OCH 3 , Cl or F,
  • 10 12 preferably corresponds to Cl, one of R or R also corresponds to H, while the other corresponds to OH, OCH 3 , Cl or F, preferably Cl,
  • R 11 is selected from CF3, CF 2 H, Cl or F, preferably F,
  • R 10 , R 11 and R 12 correspond to H
  • one of R 9 or R 13 also corresponds to H, while the other is selected from OH, OC 2 H 5 or OC 3 H 7 ,
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from:
  • the compounds of the formula I are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.
  • compound A is selected from the following group:
  • the compound A in group e) is selected from compounds of the formula III for which:
  • X is selected from
  • OH, F, Cl, OC (O) CH 3 or H preferably OH, F or H, in particular F or H.
  • R 9 to R 13 where 3 or 4 of the radicals R 9 to R 13 must correspond to H, are selected independently of one another from
  • R 14 selected from C ⁇
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from:
  • R 9 and R 13 correspond to H and R 11 corresponds to OH, OCH 3 , Cl or F, 5 preferably Cl
  • one of R 10 or R 12 also corresponds to H, while the other OH, OCH 3 , Cl or F, preferably Cl, corresponds to
  • R 11 is selected from CF 3 , CF 2 H, Cl or F, preferably F,
  • R 10 , R 11 and R 12 correspond to H
  • one of R 9 or R 13 also corresponds to H, while the other is selected from OH, OC 2 H 5 or OC 3 H 7 ,
  • R 9 , R 11 and R 13 correspond to H
  • one of R 10 or R 12 also corresponds to H, while the other is selected from:
  • the compounds of the formula IM are in the form of the (+) enantiomer, in particular in mixtures with a higher proportion of the (+) enantiomer compared to the (-) enantiomer of a racemic compound or as a pure (+) enantiomer.
  • compound A is selected from the following group:
  • compound B is selected from:
  • Oxybutinin or tolterodine is preferably selected from Oxybutinin or tolterodine.
  • compound B is selected from: venlafaxine, fesoterodine, solifenacin (YM905), cizolirtine or
  • Another object of the invention is a medicament, preferably for the treatment of increased urge to urinate or urinary incontinence, containing an active ingredient combination according to the invention and, if appropriate, suitable additives and / or auxiliaries.
  • Suitable additives and / or auxiliary substances in the sense of this invention are all substances known to the person skilled in the art from the prior art for achieving galenic formulations.
  • the selection of these auxiliaries and the amounts to be used depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally.
  • Preparations in the form of tablets, chewable tablets, dragees, capsules, granules, drops, juices or syrups are suitable for oral administration, solutions, suspensions, easily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration. Another possibility is suppositories for use in the rectum.
  • auxiliaries and additives for oral administration forms are disintegrants, lubricants, binders, fillers, mold release agents, if appropriate solvents, flavorings, sugar, in particular carriers, diluents, colorants, antioxidants etc.
  • suppositories waxes or fatty acid esters and for parenteral administration agents can be used, for example Carriers, preservatives, suspension aids etc. are used become.
  • the amounts of active ingredient to be administered to patients vary depending on the weight of the patient, the type of application and the severity of the disease.
  • the compounds according to the invention can be released in a delayed manner from preparation forms which can be used orally, rectally or percutaneously.
  • preparation forms which can be used orally, rectally or percutaneously.
  • corresponding slow-release formulations in particular in the form of a “once-daily” preparation, which only has to be taken once a day, are particularly preferred.
  • drugs that contain at least 0.05 to 90.0% of the active ingredient, in particular low effective doses, in order to avoid side effects or analgesic effects.
  • 0.1 to 5000 mg / kg, in particular 1 to 500 mg / kg, preferably 2 to 250 mg / kg body weight of at least one compound of the formula I are applied.
  • 0.01 to 5 mg / kg, preferably 0.03 to 2 mg / kg, in particular 0.05 to 1 mg / kg of body weight is also preferred and usual.
  • Auxiliaries can be, for example: water, ethanol, 2-propanol, glycerin, ethylene glycol, propylene glycol, polyethylene glycol,
  • Polypropylene glycol glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinyl pyrrolidone, natural and synthetic waxes , 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, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and -propylene fatty acid ester, sorbitan, sorbic acid, benzoic acid, citric acid,
  • Ascorbic acid Ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, magnesium oxide, zinc oxide, Silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidone, agar and bentonite.
  • compositions according to the invention are produced with the aid of means, devices, methods and processes well known in the art of pharmaceutical formulation, as described, for example, in "Remington 's Pharmaceutical Sciences", ed. AR Gennaro, 17th ed., Mack Publishing Company, Easton, Pa. (1985), in particular in Part 8, Chapters 76 to 93.
  • a solid formulation such as a tablet
  • the active ingredient of the drug with a pharmaceutical carrier, e.g. conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents such as e.g. Water, granulated to form a solid composition containing active ingredient in homogeneous distribution. Under a homogeneous
  • Distribution is understood here to mean that the active ingredient is uniformly distributed over the entire composition, so that it can be easily divided into equally effective unit dose forms, such as tablets, pills or capsules.
  • 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 some other way in order to provide a dosage form with delayed release.
  • Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as e.g. Shellac,
  • Cetyl alcohol and / or cellulose acetate Even if the medicaments according to the invention show only minor side effects, it may be advantageous, for example to avoid certain forms of dependency, to use morphine antagonists, in particular naioxon, naitrexone and / or levallorphan, in addition to the combination of the compounds A and B.
  • the invention further relates to a method for the treatment of increased urge to urinate or urinary incontinence, in which the combination of active ingredients of compound A and compound B is used
  • Example 2 Test system cystometry on the awake naive rat
  • threshold pressure threshold pressure TP, bladder pressure immediately before micturition
  • Bladder capacity BC residual volume after previous micturition plus volume of the infused solution during the filling phase
  • ICI Inter-contraction interval
  • TP threshold pressure
  • ICI inter-contraction interval
  • BC bladder capacity
  • test substances 1 1.0 mg / kg
  • 2 0.1, 0.3 and 0.5 mg / kg
  • 21 0.5 mg / kg
  • 7 0.3 mg / kg
  • 8 1.0 mg / kg
  • 9 0.5 mg / kg
  • 11 0.5 mg / kg
  • in vehicle 0.9% NaCI applied iv
  • the mean of 3 micturition cycles was determined and presented as a percentage change compared to the previous value (Table 1).
  • Table 1 Influence of the cystometric parameters by the test substances (change from previous value [%]); n corresponds to the number of test animals. Significance (Student T-Test): * p ⁇ 0.05; ** p ⁇ 0.01; *** p ⁇ 0.001.
  • the investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence.
  • the mean of 3 micturition cycles was determined at the effective maximum and presented as a percentage change compared to the previous value (Table 2).
  • the investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence.
  • Example 3 Test system cystometry on the anesthetized naive rat
  • the cystometric examination in naive female rats was carried out according to the method of Kimura et al. (Kimura et al., 1996, Int. J. Urol. 3: 218-227).
  • Kimura et al. 1996, Int. J. Urol. 3: 218-227).
  • ventilated rats the abdomen is opened and the ureters are tied off.
  • the urine is drained from the kidneys.
  • a catheter is inserted into the bladder and fixed. Saline is infused into the bladder by means of an infusion pump until this shows rhythmic spontaneous activity in the form of contractions, which can be recorded via a connected pressure sensor.
  • the test substance is added in a cumulative manner. applied. Influencing the bladder function manifests itself by suppressing the spontaneous contractions. The absence of contractions over a period of 10 minutes is considered a parameter for the suppression.
  • the investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence.
  • the investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence. Further attempts have been made with other compounds.
  • the investigated substances have a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence and also appear to be superior to tramadol.
  • the investigated substances show a positive effect on bladder regulation and are therefore suitable for the treatment of urinary incontinence.
  • Example 4 Test system cystometry on the awake naive rat
  • threshold pressure threshold pressure TP, bladder pressure immediately before micturition
  • Inter-contraction interval the time interval between micturition.
  • An increase in the threshold pressure (TP) indicates an important therapeutic effect in one of the indications according to the invention.
  • the inter-contraction interval (ICI) is also an important parameter for measuring the physiological effectiveness of a substance in the treatment of urinary incontinence, as is the bladder capacity (BC).
  • BC bladder capacity
  • the concentration used corresponds to the ED 50 in a known analgesia model for rats, the tail flick.
  • Table 7 Influence of cystometric parameters by buprenorphine (change from previous value [%]); n corresponds to the number of animals used in the experiment. Significance (Student T-Test): * p ⁇ 0.05; p ⁇ 0.01; *** p ⁇ 0.001.
  • Example 5 Test system cystometry on the awake damaged rat
  • This model simulates urge incontinence in the animal model; the oxyhemoglobin (OxyHb) used induces bladder overactivity.
  • threshold pressure threshold pressure TP, bladder pressure immediately before micturition
  • TP threshold pressure
  • ICI inter-contraction interval
  • BC bladder capacity
  • Table 8 Influence of the cystometric parameters by oxyhemoglobin (OxyHb) with and without previous administration of buprenorphine. Average values with standard deviations before (v) and after (h) application of the substances as well as the change (diff.) Compared to the previous value [%] are given; n corresponds to the number of animals used in the experiment. Significance (Student T-Test): * p ⁇ 0.05; ** p ⁇ 0.01; *** p ⁇ 0.001.
  • OxyHb significantly influences the bladder parameters in the sense of urge incontinence. This negative influence is eliminated and even improved by buprenorphine.
  • the micturition pressure drops significantly compared to the urge incontinence caused by OxyHb and also compared to the untreated control.
  • buprenorphine completely normalizes the inter-contraction interval and the bladder capacity and causes a significant and significant increase in the threshold pressure.

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Abstract

L'invention concerne l'utilisation d'une combinaison de composés du groupe A, en particulier d'opioides, et de composés du groupe B pour la production d'un médicament servant au traitement de besoins impérieux accrus d'uriner, en particulier de l'incontinence urinaire, ainsi que des composants correspondants et des procédés pour le traitement de besoins impérieux accrus d'uriner ou de l'incontinence urinaire.
EP03730120A 2002-05-29 2003-05-27 Combinaison d'opioides selectionnes et d'autres principes actifs pour le traitement de l'incontinence urinaire Withdrawn EP1507520A1 (fr)

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DE10224107 2002-05-29
DE2002124107 DE10224107A1 (de) 2002-05-29 2002-05-29 Kombination ausgewählter Opioide mit anderen Wirkstoffen zur Therapie der Harninkontinenz
PCT/EP2003/005529 WO2003099268A1 (fr) 2002-05-29 2003-05-27 Combinaison d'opioides selectionnes et d'autres principes actifs pour le traitement de l'incontinence urinaire

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DE10315917A1 (de) * 2003-04-08 2004-11-18 Schwarz Pharma Ag Hochreine Basen von 3,3-Diphenylpropylaminmonoestern
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ES2244326B1 (es) * 2004-04-05 2007-02-16 Laboratorios Del Dr. Esteve, S.A. Combinacion de substancias activas.
EP1584335A3 (fr) * 2004-04-05 2006-02-22 Laboratorios Del Dr. Esteve, S.A. Combinaison de substances actives comprenant un composé carbinol et un opioïde
EP1632227A1 (fr) * 2004-09-07 2006-03-08 Laboratorios del Dr. Esteve S.A. Dérivés des aryl (ou des heteroaryl) azolylcarbinols (en particulier cizolirtin citrate) pour le traitement de la dépendance des opioides
US7815939B2 (en) 2005-07-20 2010-10-19 Astellas Pharma Inc. Coated fine particles containing drug for intrabuccally fast disintegrating dosage forms
DE102005061428A1 (de) * 2005-12-22 2007-08-16 Grünenthal GmbH Substituierte Cyclohexylmethyl-Derivate
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