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
  • A61K31/13—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
• • 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
  • A61P13/06—Anti-spasmodics
• • 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

Definitions

• the present invention relates to the use of substituted 6-dimethylaminomethyl-1-phenylcyclohexane compounds as free bases and/or in the form of physiologically compatible salts for the production of a medicament for treating increased urinary urgency or urinary incontinence, as well as corresponding medicaments and methods for treating increased urinary urgency or urinary incontinence.
• Urinary incontinence is the involuntary passing of urine. This occurs in an uncontrolled manner if the pressure within the bladder exceeds the pressure required to close the ureter. Causes may include on the one hand an increased internal bladder pressure (e.g. due to detrusor instability) resulting in urgency incontinence, and on the other hand a reduced sphincter pressure (e.g. after childbirth or surgical intervention) resulting in stress incontinence.
• the detrusor is the collection of coarse bundles forming the multilayered muscular wall of the bladder, whose contraction leads to the discharge of urine, and the sphincter is the constrictor muscle of the urethra.
• Urinary urgency is the state of increased bladder muscle tension ending in urine discharge (micturition) when the bladder is almost full (or when its capacity is exceeded). This muscle tension acts as a stimulus to urination.
• Increased urinary urgency is understood in this connection to mean in particular the occurrence of premature or more frequent and sometimes even painful urinary urgency up to so-called dysuria. This consequently leads to a significantly increased frequency of micturition.
• the causes may include, inter alia, inflammation of the bladder and neurogenic bladder disorders, as well as bladder tuberculosis. However, all causes have not yet been elucidated.
• medicaments that in particular increase the resistance of the urethra or cervix of the bladder have affinities to ⁇ -adrenoreceptors such as ephedrine, to ⁇ -adrenoreceptors such as clenbutarol, or are hormones such as estradiol.
• ⁇ -adrenoreceptors such as ephedrine
• ⁇ -adrenoreceptors such as clenbutarol
• hormones such as estradiol.
• certain opioids, diarylmethylpiperazines and diarylmethylpiperidines have been described for this medical condition in WO 93/15062.
• the object of the present invention is accordingly to find substances that are helpful in the treatment of increased urinary urgency or urinary incontinence and that at effective doses preferably at the same time exhibit fewer side effects and/or analgesic effects than are known from the prior art.
• the present invention provides for the use of a substituted 6-dimethylaminomethyl-1-phenylcyclohexane compound according to the general formula I
• X is selected from OH, F, Cl, H or OC(O)R 7 where R 7 is selected from C 1-3 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted,
• R 1 is selected 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 are in each case selected independently of one another 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 that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; phenyl that is unsubstituted or singly or multiply substituted;
• R 14 is selected from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or singly or multiply substituted; 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 may be branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted;
• R 17 and R 18 are in each case selected independently of one another from H; C 1-6 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; phenyl, benzyl or phenethyl that is in each case unsubstituted or singly or multiply substituted, 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(CH 3 )0, OC(CH 3 ) ⁇ CH, (CH 2 ) 4 or OCH ⁇ CHO ring,
• alkyl radicals are understood to be saturated or unsaturated, branched or unbranched hydrocarbons that may also be unsubstituted or at least singly substituted.
• Preferred alkyl radicals are methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, n-butyl, sec.-butyl, tert.-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, CHF 2 , CF 3 or CH 2 OH.
• cycloalkyl radicals within the context of this invention are understood to be saturated cyclic hydrocarbons that may also be at least singly substituted.
• Preferred cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• substituted within the context of this invention is understood to mean the replacement of an hydrogen atom by F, Cl, Br, I, NH 2 , SH or OH
• multiply substituted is understood to mean that the substitution takes place on different as well as on the same atoms with the same or different substituents, for example triply on the same C atom as in the case of CF 3 , or at different positions as in the case of —CH(OH)—CH ⁇ CH ⁇ CHCl 2 .
• substituted is preferably understood to mean substitution of H with F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 19 , OCF 3 , SR 9 , NH 2 , CONH 2 , SOCH 3 , SOCF 3 , SO 2 CH 3 , SO 2 CF 3 , CN, COOR 19 , NO 2 ; C 1-6 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; or phenyl that is unsubstituted;
• R 19 is selected from C 1-6 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; or C 3-7 -cycloalkyl.
• Suitable salts within the meaning of the present invention and in each of the claimed uses are salts of the respective active ingredient with inorganic or organic acids and/or a sugar substitute such as saccharine, cyclamate or acesulfam.
• a sugar substitute such as saccharine, cyclamate or acesulfam.
• the hydrochloride is particularly preferred.
• OH, F, Cl, OC(O)CH 3 or H preferably OH, F or H, in particular OH.
• R 12 and R 11 form a 3,4-OCH ⁇ CH ring
• 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, 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, then 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 selected 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 selected from OH, OC 2 H 5 or OC 3 H 7 .
• R 9 , R 11 and R 13 correspond to H
• R 10 or R 12 also corresponds to H
• the other is selected from:
• the compounds of the 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 pure (+) enantiomer.
• (+) enantiomer a smaller proportion of ( ⁇ ) enantiomer compared to the (+) enantiomer is also acceptable and may—but need not be—involved in the use according to the invention.
• the invention also comprises medicaments for treating increased urinary urgency or urinary incontinence, which medicaments contain as active ingredient at least one substituted 6-dimethylaminomethyl-1-phenylcyclohexane compound according to the general formula I
• X is selected from OH, F, Cl, H or OC(O)R 7 where R 7 is selected from C 1-3 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted,
• R 1 is selected 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 are in each case selected independently of one another 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 that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; phenyl that is unsubstituted or singly or multiply substituted;
• R 14 is selected from C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or singly or multiply substituted; 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 5 , 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 may be branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted;
• R 17 and R 18 are in each case selected independently of one another from H; C 1-6 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; phenyl, benzyl or phenethyl that is in each case unsubstituted or singly or multiply substituted, 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(CH 3 )O, OC(CH 3 ) ⁇ CH, (CH 2 ) 4 or OCH ⁇ CHO ring,
• Suitable salts within the context of the present invention and in each of the claimed uses are salts of the respective active ingredient with inorganic or organic acids and/or a sugar substitute such as saccharine, cyclamate or acesulfam.
• a sugar substitute such as saccharine, cyclamate or acesulfam.
• the hydrochloride is particularly preferred.
• Suitable additives and/or auxiliary substances within the context of the present invention are all substances known to the person skilled in the art from the prior art for achieving the preparation of galenical formulations.
• the choice of these auxiliary substances as well as the amounts thereof to be used depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically.
• oral application preparations in the form of tablets chewable tablets, sugar-coated pills, capsules, granules, drops, juices or syrups are suitable, while for parenteral, topical and inhalative application solutions, suspensions, readily reconstitutable dry preparations as well as sprays are suitable.
• a further possible form of application are suppositories for rectal use.
• the use in a depot form, in dissolved form, in a carrier film or a plaster, optionally with the addition of agents promoting penetration of the skin are examples of suitable percutaneous application forms.
• suitable percutaneous application forms are examples of auxiliary substances and additives for oral application forms.
• auxiliary substances and additives for oral application forms are disintegrants, lubricants, binders, fillers, mould release agents, optionally solvents, taste enhancers, sugars, in particular excipients, diluents, colorants, antioxidants, etc.
• the amounts of active ingredient to be administered to the patient vary depending on the patient's weight, on the type of application and the severity of the medical condition.
• the compounds according to the invention may be employed in delayed release form in preparations for oral, rectal or percutaneous use.
• Corresponding retard formulations or delayed-release formulations, in particular in the form of a “once daily” preparation that has to be taken only once a day, are particularly preferred for use in the medical condition covered by the invention.
• medicaments that contain at least 0.05 to 90.0% of the active ingredient, in particular low effective dosages in order to avoid side effects or analgesic effects.
• the administration of 0.01 to 5 mg/kg, preferably 0.03 to 2 mg/kg and in particular 0.05 to 1 mg/kg body weight is also preferred and customary.
• Auxiliary substances may for example include the following: 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, natural and synthetic gums, gum arabic, 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, soy bean oil, lecithin, sodium lactate, polyoxyethylene
• the medicaments and pharmaceutical compositions according to the invention are produced with the aid of agents, equipment, methods and processes well known in the prior art for pharmaceutical formulations, such as are described in “Remington's Pharmaceutical Sciences”, Editor A. R. Gennaro, 17 th Edition, 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 medicament i.e. a compound of the general structure I or one of its pharmaceutically acceptable salts
• a pharmaceutical carrier for example conventional tablet constituents such as maize starch, lactose, sucrose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, such as water, in order to form a solid composition that contains a compound according to the invention or a pharmaceutically acceptable salt thereof in homogeneous distribution.
• a homogeneous distribution is understood here to mean that the active ingredient is uniformly distributed over the whole composition so that the latter can be subdivided without any difficulty into equally effective unit dose forms such as tablets, pills or capsules.
• the solid composition is then subdivided into unit dose forms.
• the tablets or pills of the medicament according to the invention or of the compositions according to the invention may also be coated or compounded in another way in order to prepare a dose form with a delayed-release action.
• Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and/or cellulose acetate.
• the medicaments according to the invention exhibit slight side effects it may be advantageous in order to avoid specific forms of dependence to use in addition to the compounds according to the general formula I also morphine antagonists, in particular naloxone, naltrexone and/or levallorphan.
• OH, F, Cl, OC(O)CH 3 or H preferably OH, F or H, in particular OH.
• R 12 and R 11 form a 3,4-OCH ⁇ CH ring
• 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, then 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 selected 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 selected from OH, OC 2 H 5 or OC 3 H 7 .
• medicaments in which compounds according to the general formula I are used, wherein 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:
• (+) enantiomer a smaller proportion of ( ⁇ ) enantiomer compared to the (+) enantiomer is also acceptable and may—but need not—be contained in the medicaments according to the invention.
• medicaments according to the invention that contain at least one compound selected from the following group:
• the invention also provides a process for treating increased urinary urgency or urinary incontinence, in which the substituted 6-dimethylaminomethyl-1-phenylcyclohexane compounds according to the invention of the general formula I are used in the form of their racemates; enantiomers, diastereomers, in particular mixtures of their enantiomers or diastereomers, or in the form of an individual enantiomer or diastereomer; as free base and/or in the form of physiologically compatible salts.
• threshold pressure TP
• bladder pressure immediately before micturition
• bladder capacity (BC), residual volume after prior micturition plus volume of infused solution during the filling phase
• ICI intercontraction interval
• TP threshold pressure
• ICI intercontraction interval
• BC bladder capacity
• test substances 24 1.0; 3.0; 5.0 mg/kg
• 25 1.5 mg/kg
• 26 3.0 mg/kg
• the test substances 24 1.0; 3.0; 5.0 mg/kg
• 25 1.5 mg/kg
• 26 3.0 mg/kg
• the effect on the cystometric parameters was recorded at 90 to 120 minutes.
• the mean value of 3 micturition cycles was determined and recorded as a percentage change compared to the baseline value (Table 1).
• the investigated substances exhibit a positive effect on the bladder regulation and are therefore suitable for treating urinary incontinence.
• the investigated substances exhibit a positive effect on bladder regulation and are thus suitable for treating urinary incontinence.

Landscapes

• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Urology & Nephrology (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (1)

Applications Claiming Priority (3)

Related Parent Applications (1)

Related Child Applications (1)

Publications (1)

Family

ID=7665211

Family Applications (2)

Family Applications After (1)

Country Status (26)

Cited By (3)

Families Citing this family (4)

Citations (3)

Family Cites Families (5)

• 2000
  • 2000-11-30 DE DE10059413A patent/DE10059413A1/de not_active Withdrawn
• 2001
  • 2001-11-28 EP EP01998336A patent/EP1353660B1/de not_active Expired - Lifetime
  • 2001-11-28 DE DE50108711T patent/DE50108711D1/de not_active Expired - Lifetime
  • 2001-11-28 SK SK595-2003A patent/SK287536B6/sk not_active IP Right Cessation
  • 2001-11-28 CZ CZ20031390A patent/CZ299343B6/cs not_active IP Right Cessation
  • 2001-11-28 AT AT01998336T patent/ATE315387T1/de active
  • 2001-11-28 RU RU2003117705/15A patent/RU2279875C2/ru not_active IP Right Cessation
  • 2001-11-28 ES ES01998336T patent/ES2256338T3/es not_active Expired - Lifetime
  • 2001-11-28 BR BR0115881-3A patent/BR0115881A/pt not_active Application Discontinuation
  • 2001-11-28 JP JP2002545685A patent/JP4284065B2/ja not_active Expired - Fee Related
  • 2001-11-28 HU HU0303268A patent/HU227927B1/hu not_active IP Right Cessation
  • 2001-11-28 AU AU2002223688A patent/AU2002223688B2/en not_active Ceased
  • 2001-11-28 KR KR1020037007316A patent/KR100835874B1/ko not_active IP Right Cessation
  • 2001-11-28 DK DK01998336T patent/DK1353660T3/da active
  • 2001-11-28 WO PCT/EP2001/013917 patent/WO2002043714A2/de active IP Right Grant
  • 2001-11-28 MX MXPA03004801A patent/MXPA03004801A/es active IP Right Grant
  • 2001-11-28 PL PL365517A patent/PL203093B1/pl unknown
  • 2001-11-28 AU AU2368802A patent/AU2368802A/xx active Pending
  • 2001-11-28 IL IL15614001A patent/IL156140A0/xx active IP Right Grant
  • 2001-11-28 NZ NZ538924A patent/NZ538924A/en not_active IP Right Cessation
  • 2001-11-28 CA CA2430282A patent/CA2430282C/en not_active Expired - Fee Related
  • 2001-11-28 CN CN018197205A patent/CN1518444B/zh not_active Expired - Fee Related
• 2003
  • 2003-05-27 IL IL156140A patent/IL156140A/en not_active IP Right Cessation
  • 2003-05-27 NO NO20032411A patent/NO333963B1/no not_active IP Right Cessation
  • 2003-05-29 EC EC2003004632A patent/ECSP034632A/es unknown
  • 2003-05-30 US US10/448,443 patent/US20040029878A1/en not_active Abandoned
  • 2003-06-26 ZA ZA200304999A patent/ZA200304999B/en unknown
• 2004
  • 2004-04-21 HK HK04102809A patent/HK1061355A1/xx not_active IP Right Cessation
  • 2004-11-02 US US10/978,565 patent/US7361690B2/en not_active Expired - Fee Related
• 2006
  • 2006-03-10 CY CY20061100341T patent/CY1105142T1/el unknown

Patent Citations (3)

Also Published As

Similar Documents

Legal Events