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WO2006010627A1 - Aryl (ou heteroaryl) azolylcarbinols - Google Patents

Aryl (ou heteroaryl) azolylcarbinols Download PDF

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Publication number
WO2006010627A1
WO2006010627A1 PCT/EP2005/008239 EP2005008239W WO2006010627A1 WO 2006010627 A1 WO2006010627 A1 WO 2006010627A1 EP 2005008239 W EP2005008239 W EP 2005008239W WO 2006010627 A1 WO2006010627 A1 WO 2006010627A1
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WIPO (PCT)
Prior art keywords
methyl
pyrazol
methoxy
phenyl
ethoxy
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Ceased
Application number
PCT/EP2005/008239
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English (en)
Inventor
Ramon Merce-Vidal
Antonio José FARRE-GOMIS
Jordi Frigola-Constansa
Blas Andaluz-Mataro
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Esteve Pharmaceuticals SA
Original Assignee
Laboratorios del Dr Esteve SA
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Priority to EP05764357A priority Critical patent/EP1784178A1/fr
Publication of WO2006010627A1 publication Critical patent/WO2006010627A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present application provides the use of derivatives of aryl (or heteroaryl) azolylcarbinols of general formulas (I), (II), (III) or (IV) and their physiologically acceptable salts, as medicinal products for human and/or animal therapeutics for the treatment of various diseases including urinary incontinence and pain.
  • Depression is a common problem that affects a large segment of the population in all age groups. Antidepressants account for almost half of worldwide, psychiatric related drug sales.
  • substance P a takchykinin
  • substance P may function as a neurotransmitter.
  • Substance P have synaptic contacts with cholinergic neurons, and the stimulation of the NKl receptors by substance P results in an increase of the release of acetylcholine (J.J. Anderson, J. Pharmacol. Exp. Ther. ., 1995, 274, 928-936) .
  • Substance P has been implicated in the pathophysiology of several neuropsychiatric disorders, including schizophrenia, drug addiction, cognitive disorders, manic depressive psychosis, locomotive disorders, sexual dysfunction, and depression. A clear relation between depressive states and levels of substance P may be assumed, since products which act as inhibitors of substance P have a clear anti-depressive component when studied in several laboratory animal models.
  • the present application provides a method of treating a subject suffering from a form of urinary incontinence which comprises administering to the subject an amount of a compound having the structure:
  • Useful forms of the compound include the racemate, pure stereoisomers, especially enantiomers or diastereomers or mixtures of stereoisomers, enantiomers or diastereomers, in any suitable ratio.
  • the compound may be used in the form shown or in form of an acid, a base, or a salt, especially a physiologically acceptable salt; or in form of a solvate.
  • Figure 1 is a diagrammatic representation of the putative mechanism of action of the N-desraethyl metabolite of cizolirtine showing how the metabolite contributes to the cizolirtine increasing serotonin and noradrenaline uptake level on the mPFC and PAG areas of the brain and thereby- decreasing substance P and cGRP at the spinal level resulting in a decrease in the symptoms of stress urinary incontinence and urge incontinence.
  • Figure 2 shows a comparison of the percentage of change of rat bladder contraction amplitude in anesthetized rats treated with (R) - (+) -2- ( (l-methyl-lH-pyrazol-5- yl) (phenyl)methoxy-N-methylethanamine citrate, (S)-(-)- 2- ( (l-methyl-lH-pyrazol-5-yl) (phenyl)methoxy-N- methylethanamine citrate, compared with the control vehicle.
  • Figure 3 shows a comparison of urodynamic parameters of the isovoumetric rhythmic bladder contractions in the anesthetized rat treated with 2- ( (l-methyl-lH-pyrazol-5- yl) (phenyl)methoxy-N-methylethanamine, cizolirtine, and duloxetine to those treated with a control vehicle.
  • Figure 4 shows the relative effect of treatment of anesthetized rats with 2- ( (l-methyl-lH-pyrazol-5- yl) (phenyl)methoxy-N-methylethanamine, cizolirtine, and duloxetine on acetic acid-induced bladder hyperactivity compared to the control vehicle. Specifically measured is the number of micturitions and volume for first micturition.
  • Figure 5 shows the effect of anesthetized rats with 2- ( (l-methyl-lH-pyrazol-5-yl) (phenyl)methoxy-N- methylethanamine, cizolirtine, and duloxetine, on acetic acid-induced bladder hyperactivity compared to the control vehicle. Specifically measured was the effect on micturition volume, intravesical pressure increase, and AUC of intravesical pressure.
  • This application provides a method of treating a subject suffering from a form of urinary incontinence which comprises administering to the subject an amount of a compound having the structure:
  • the compound according to that structure is in the following text sometimes referred to as N-desmethyl metabolite.
  • an aspect of the application is the use of such a compound in the preparation of a medicament for the treatment of forms of urinary incontinence, including urge incontinence, hyperreflexia; urinary stress incontinence, mixed incontinence and enuresis.
  • Urinary incontinence is a urinary disorder which can be defined as the involuntarily discharge of urine. This effect can be demonstrated objectively.
  • This functional disorder of the bladder is a health problem of increasing social and hygienic relevance for those that suffer from it. Urinary incontinence is estimated to occur in approximately 1.5 to 5% of men, and 10 to 30% of women, between 15 and 64 years old. Moreover, in the non- hospitalized population sector over 60 years old, the prevalence ranges from 15% to 35%. When hospitalized patients over 60 years old are considered, the incidence is even higher.
  • Urinary incontinence can be considered as a symptom or as a pathological condition.
  • the following are possible classifications of this functional disorder.
  • Imperative micturition or urge incontinence This form of urinary incontinence occurs when the involuntary discharge of urine is accompanied by an intense desire to urinate (urgency) . This can be separated into motor urgency incontinence or sensitive urgency incontinence. Motor urgency incontinence is associated with hyperactivity of the detrusor muscle and/or reduced distensibility of the detrusor. Hyperactivity is characterised by involuntary contractions of the detrusor during the filling stage, either spontaneous or provoked, that the patient cannot totally suppress. Hyperactivity of the detrusor muscle can occur when there is obstruction of the exiting urinary flow, inflammation and conditions in which the bladder is irritated, or it can be of unknown etiology (idiopathic) .
  • Hyperreflexia is described as a condition that presents uncontrolled contractions of the detrusor muscle associated with neurological disorders such as multiple sclerosis or plaque sclerosis, sequelae of medular traumatisms, or Parkinson's disease.
  • Urinary stress incontinence is typically due to a defective urethral closure mechanism. There is involuntary discharge of urine in the absence of detrusor contraction that occurs when the intravesical pressure exceeds the pressure in the urethra. Involuntary discharge occurs when some physical exertion is made such as jumping, coughing, going down stairs etc. One additional factor can be due to structural changes in the urethra due to menopausal hypooestrogenia.
  • Mixed incontinence refers to the existence of both urgency incontinence and stress incontinence.
  • Enuresis refers to any involuntary loss of urine and more specifically to incontinence during sleep. It most often applies to children with a higher incidence in boys, particularly those up to 5 years of age.
  • This application provides a method of treating a subject suffering from a form of urinary incontinence which comprises administering to the subject an amount of a compound having the structure:
  • the compound is in the form of a racemic mixture.
  • the compound is in the form of a pure stereoisomer or as a mixture of stereoisomers in a suitable relative ratio.
  • the compound in the form of an enantiomer, a diastereomer, or a mixture of enantiomers and/or diasteromers in a suitable relative ratio.
  • the compound is in the form of an acid, a base, a phisiologically acceptable salt, or a solvate.
  • the compound is in the form of a solvate, and the solvate is a hydrate.
  • the compound is in the form of an enantiomer selected from the group consisting of: • (R)-(+)-2-( (l-methyl-lH-pyrazol-5- yl) (phenyl)methoxy-N-methylethanamine
  • the compound in the form of a pharmaceutically acceptable salt which is a citrate.
  • the subject is a human being.
  • the effective amount is between 0.167 and 13.333 mg/kg body weight of the subject/day.
  • the effective amount is between 0.167 and 3.333 mg/kg body weight of the subject/day
  • the effective amount is between 0.333 and 1.667 mg/kg body weight of the subject/day.
  • the effective amount is between 10 and 800 mg administered daily. Preferably, between 10 and 200 mg administered daily; more preferably between 20 and 100 mg administered daily; In another embodiment, the effective amount is 200 mg administered daily; preferably 100 mg administered daily; more preferably 50 mg administered daily; or 20 mg administered daily.
  • the compound is administered twice per day.
  • the compound is present in a formulation that contains a coating agent and the formulation is administered daily.
  • the coating agent is a controlled release coating agent.
  • the formulation comprises any of the following: sodium croscarmelose; colloidal silica dioxide; a salt with stearic acid; providone; microcrystalline cellulose; lactose monohydrate; or polyethylene glycol.
  • the compound being is administered in the form of a tablet or capsule.
  • the compound is administered in the form of an immediate release formulation.
  • the subject is a woman.
  • the woman is an elderly woman.
  • the subject is a man. In an embodiment the subject is an elderly man.
  • the subject is a child.
  • the form of urinary incontinence is urge urinary incontinence; stress urinary incontinence or urinary stress incontinence; hyperreflexive urinary incontinence; or enuresis.
  • compound is in the form of a racemic mixture.
  • the compound in the form of a pure stereoisomer or as a mixture of stereoisomers in a suitable relative ratio.
  • the compound is in the form of an enantiomer, a diastereomer, or a mixture of enantiomers and/or diasteromers in a suitable relative ratio.
  • the compound is in the form of an acid f a base, a physiologically acceptable salt, or a solvate.
  • the compound is in the form of a solvae, and the solvate is a hydrate.
  • the compound is in the form of an enantimer selected from the the group consisting of:
  • the compound is in the form of a pharmaceutically acceptable salt which is a citrate.
  • the effective amount is between 0.167 and 13.333 mg/kg body weight of the subject/day; preferably, between 0.167 and 3.333 mg/kg body weight of the subject/day; and more preferably, between 0.333 and 1.667 mg/kg body weight of the subject/day.
  • the effective amount is between 10 and 800 mg; preferably, 10 and 200 mg; and more preferably, between 20 and 200 mg; In yet another embodiment, effective amount is 200 mg; preferably, 100 mg; more preferably, 50 mg; or 20 mg.
  • the compound is present in a formulation comprising any of the following: sodium croscarmelose; colloidal silica dioxide; a salt with stearic acid; providone; microcrystalline cellulose; lactose monohydrate; or polyethylene glycol.
  • the compound is in the form of a tablet or capsule.
  • the compound is in the form of an immediate release formulation.
  • the form of urinary incontinence is urge urinary incontinence; stress urinary incontinence or urinary stress incontinence; hyperreflexive urinary incontinence; or enuresis.
  • the compound is present in a formulation that contains a coating agent.
  • the coating agent is a controlled release coating agent.
  • An additional object of this application is to provide an aryl or heteroaryl azolylcarbinole derivative of general formula (I), (II), (III) or (IV)
  • R 1 represents a hydrogen atom or a lower alkyl group from C x to C 4 ;
  • R 2 represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxy, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy, or -0- (glucuronic acid);
  • R 3 represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci- 4 -Alkyl
  • R 5 represents H or Ci- 4 -Alkyl
  • R is glucuronic acid
  • R 10 represents Ci- 4 -Alkyl
  • n 1 to 4 or p is 1 to 3
  • R 1 , R 2 and R 3 have the meanings already mentioned and Z represents one of the following groups:
  • R 4 represents H or Ci-4-Alkyl
  • R 5 represents H or Ci-4-Alkyl
  • R 9 is glucuronic acid
  • R ,10 represents Ci- 4 -Alkyl
  • n 1 to 4 or p is 1 to 3
  • the new derivatives of aryl or heteroaryl azolylcarbinoles described herein are surprisingly useful in the treatment of disorders related to substance P, especially in the treatment of depression but also in other indications.
  • alkyl radicals are understood as meaning saturated and unsaturated, branched or unbranched hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
  • Cl-2-alkyl represents Cl- or C2-alkyl
  • Cl-3-alkyl represents Cl-, C2- or C3-alkyl
  • Cl-4-alkyl represents Cl-, C2-, C3- or C4-alkyl
  • Cl-5-alkyl represents Cl-, C2-, C3-, C4-, o.r C5-alkyl
  • Cl-6-alkyl represents Cl-, C2-, C3-, C4-, C5- or C6-alkyl
  • Cl-7-alkyl represents Cl-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • Cl-8-alkyl represents Cl-, C2-, C3- , C4-, C5-, C6-, Cl- or C8-al
  • the alkyl 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, CHF 2 , CF 3 or CH2OH.
  • Particularly preferred substituents here are F, Cl and OH.
  • the hydrogen radical can also be replaced by O-Cl-3-alkyl or Cl-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 ) 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 -, (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 -, etc.
  • aryl heterocycle is understood as meaning a heterocyclic ring system which have at least one unsaturated ring and can 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, 5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole and quinazoline.
  • substituted is understood as meaning substitution of the aryl or heteroaryl by R, OR, a halogen, preferably F and/or Cl, a CF 3 , a CN, an NO 2 , an NRR, a Cl- ⁇ -alkyl (saturated), a Cl- ⁇ -alkoxy, a C3-8-cycloalkoxy, a C3-8-cycloalkyl or a C2- 6-alkylene.
  • glucoronic acid means a radical of this structure:
  • coating agent is to be understood to be a chemical substance added to a coating or as a coating to produce an effect on the surface of the pharmaceutical composition or one of its subunits.
  • the effects desired include release control, chemical stability enhancement (e.g. gastrointestinal coating, light exclusion) , physical stability enhancement (hardening, confining/conserving the surface), or e.g. coloring.
  • coating agent is understood as "release control coating agent,” which is used herein synonymously with “controlled release coating agent,” a chemical substance added to or as a coating to control the release of the active compound/principle from the pharmaceutical composition or from one of its subunits.
  • a preferred coating agent for this application is ethylcellulose.
  • the ethylcellulose is used as a pseudo-latex containing plasticizer already incorporated into dispersed particles in water or "in situ" with ethylcellulose plus organic solvents or solvent mixture.
  • Other coating agents, especially for release control, commonly used and also suitable for the application are (as examples and not limiting) :
  • Fats and waxes e.g., glyeril monostearate, beeswax, carnauba wax
  • These coatings normally function by erosion and not by diffusion as ethylcellulose.
  • Acrylic polymers (polymethacrilates) : Eudragit series
  • solvate is understood in particular, in the context of this application as a compound formed by salvation (the combination of solvent molecules with molecules or ions of the solute) .
  • salt means any form of the active substance according to the application, in which this assumes an ionic form and is loaded/charged, and coupled with a counterion (a cation or anion) found in solution.
  • physiologically acceptable salt with anions or acids means salts of at least one of the combinations according to the application - mostly, e.g. those protonated at the nitrogen atom, - as a cation with at least one anion, which are physiologically acceptable - in particular while using in humans and/or mammals.
  • the salt made from a physiologically acceptable acid, namely salts of the respective active substances with inorganic or organic acids, which are physiologically acceptable - in particular while using in humans and/or mammals.
  • physiologically acceptable salts of certain acids are the 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-dihydrolb 6 - benzo[d] isothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxo-proline, hexan-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6- trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid, and/or aspartic acid.
  • hydrochloride salt Included are also salts of alkali metals and
  • a "salt made from a physiologically acceptable acid” means the salts of the respective active substance with inorganic or organic acids, which are physiologically acceptable - in particular while using in humans and/or mammals. Especially preferred is the hydrochloride.
  • physiologically acceptable acids are: 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-l.2-dihydrolb 6 - benzo[d]isothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxo-proline, hexan-1-sulfonic acid, nicotinic acid, 2-, 3-, or 4-aminobenzoic acid, 2,4,6- trimethylbenzoic acid, ⁇ -Lipon acid, acetylglycine., acetylsalicylic acid, hippuric acid, and/or aspartic acid.
  • physiologically acceptable salts with cations or bases means salts having at least one of the combinations according to the application - mostly a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation, which are physiologically acceptable - in particular while using in humans and/or mammals.
  • the salts of the alkali metals and alkaline earth metals but also those with NH 4 + , but particularly (mono) or (di) sodium, (mono) or (di) potassium, magnesium, or calcium salts.
  • salts made from a physiologically acceptable cation means salts of at least one of the respective combinations of an anion with at least one inorganic cation, which are physiologically acceptable - in particular while using in humans and/or mammals.
  • the salts of the alkali metals and alkaline earth metals but also those with NH 4 + , but particularly (mono) or (di) sodium, (mono) or (di) potassium, magnesium, or calcium salts.
  • the citrate is particularly preferred.
  • the compound described above may be used in human and animal subjects to cure, or at least relieve urinary incontinence.
  • the dose of the compounds to be administere.d depends on the severity of the condition to be treated. It is typically between 10 and 800 mg/day; preferably between 10 and 200 mg/day; and most preferably between 20 and 100 mg/day.
  • the compound may be administered in many standard dosage forms known in the art, for example, in the form of a capsule or a tablet.
  • Formulations i.e. pharmaceutical compositions, containing the compound as active ingredient may optionally include at least one auxiliary material and/or additive.
  • a pressure transducer is used to measure intravesical pressure (recording rate and amplitude of bladder contractions) .
  • An infusion pump is used to fill bladder by 0.1 ml increments of saline until rhythmic contractions. After 15 minutes of constant interval bladder contractions, (R) - (+) -2- ( (l-methyl-lH-pyrazol-5-yl) (phenyl)methoxy-N- methylethanamine citrate in 6.83, 13.7, and 27.3 mg/kg dosages; (S) - (-) -2- ( (l-methyl-lH-pyrazol-5- yl) (phenyl)methoxy-N-methylethanamine citrate in 6.83, 13.7 and 27.3 mg/kg dosages; and oxybutinyn in a 1 mg/kg dose were administered by iv. Measurements were made before and then during 15 minute intervals after each administration.
  • Rat bladder was catheterized.
  • a pressure transducer was used to measure intavesical pressure in anesthetized rats treated with 1 mg/kg duloxetine, 10 mg/kg cizolirtine citrate, 10 mg/kg N-desmethyl metabolite citrate or a control vehicle. Recordings were made of the infusion volume, pressure needed for micturition, number of micturitions during the infusion.
  • An infusion pump was used to fill bladder with saline until micturition. After stabilization, treatment compounds or control vehicle were administered by iv.
  • the number of micturitions, volume for first micturition, mean volume for micturition, and AUC of intravesical pressure were measured for each of the treatment groups and compared to the control.
  • the N-desmethyl metabolite like cizolirtine or duloxetine, decreased the number of micturitions and increased the volume for the first micturition and the mean volume of micturition. (See FIG. 3)
  • the N-desmethyl metabolite citrate at 10 mg/kg, like cizolirtine citrate at 5 and 10 mg/kg and duloxetine at 1 mg/kg reduced the number of micturitions and increased the volume for the first micturition compared to the control (See FIG. 4) . Similarly, it increased the number of micturitions (See FIG 5) .
  • N-desmethyl metabolite citrate (10 mg/kg) , like cizolirtine citrate (5, 10 mg/kg, i.v.) and duloxetine (1 mg/kg) , protected the rat bladder against the acetic acid-induced hyperactivity.
  • patients are randomized. Patients are from both genders with ages between 18 and 80 years (inclusive) . They have urinary incontinence secondary to overactive bladder (detrusor hyperreflexia or instability) or idiopathic urge incontinence confirmed by the medical history and urodynamic study.
  • One group of patients is treated with 2- ( (1-methyl-lH- pyrazol-5-yl) (phenyl)methoxy-N-methylethanamine, 50 mg, twice a day, formulated as a tablet for oral administration.
  • Another group is treated with placebo in matching tablets, twice a day, with administration by oral route. The patients are treated for 84 days.
  • Efficacy is measured by the difference from baseline in the mean number of leakages, micturitions, urgencies and voidings/24 hours as provided by a 7-day frequency-volume chart in the end of the study visit.
  • the primary efficacy analysis is based on the PP population.
  • the treatment groups are compared with respect to the treatment effect, defined as the difference between treatment groups for changes from baseline in the number of voidings per 24 hours.
  • the percentage of responders is compared based on an analysis of the number of patients having ⁇ 8 voidings/day or experiencing complete dryness or both, and statistical significance determined.
  • One group of patients is treated with 2- ( (1-methyl-lH- pyrazol-5-yl) (phenyl)methoxy-N-methylethanamine 100 mg formulated as an oral administration (twice daily) .
  • Another group is treated with placebo matching capsules, three per day (morning, afternoon and evening) , . with administration by oral route. The patients are treated for 84 days.
  • Efficacy is measured by the difference from baseline in the mean number of voidings/24 hours as provided by a 7- day frequency-volume chart in the end of study visit.
  • the primary efficacy analysis is based on the PP population.
  • the treatment groups are compared with respect to the treatment effect, defined as the difference between treatment groups for changes from baseline in the number of voidings per 24 hours. Additionally, the percentage of responders is compared based on analysis of the number of patients having ⁇ 8 voidings per day or experienced complete dryness or both., and statistical significance determined.
  • Microcrystalline cellulose (Avicel 14.6 mg PH-102)
  • Microcrystalline cellulose (Avicel 123 mg PH-102)
  • Lactose monohydrate (Farmatose 200 129 mg __
  • Microcrystalline cellulose (Avicel 37.5 mg PH-102)
  • Microcrystalline cellulose (Avicel 3.75 mg PH-102)
  • IR (film) 2940, 2866, 1451, 1088, 1071, 783, 747, 725, 703 cm "1 .
  • CytP450 3A4 and CytP450 2D6 at 37° C. Following that, the solution is separated using HPLC and the metabolites are isolated.
  • the antidepressant activity of compound 1 has been studied in different test. First, of all it has been shown that compound 1 has affinity for serotonin transporter receptor like other antidepressants.
  • the antidepressant activity of compound 1 has also been shown in 3 experimental tests in vivo: test of inhibition of reserpine-induced ptosis in mice, test of inhibition of aversive situation-induced immobility in mice and water despair test in rats.
  • mice were administered by ip route, and 30 minutes later mice were submitted to an aversive situation: they were tail suspended in the itematic-TST for 6 minutes. Mobility time and movements power were automatically measured and registered in the above mentioned device. The potential antidepressant reduce the mice immobility time.
  • Compound 1 had a similar activity to that of imipramine and sertraline. Its ED-50 wasl7 mg/Kg, i.p. (Table 1) .
  • mice In mice In rats ED50 (mg/Kg,p.o.) ED50 (mg/Kg,Lp.) ED50 (mg/Kg,i.p.)
  • Desipramine I 32% (30 mg/Kg) Sertraline 17 28
  • Cizolirtine 26 17 inactive (40 mg/Kg)
  • acetic acid-induced bladder hyperactivity is tested.
  • the infusion of acetic acid (0.3% v/v) caused a significant increase of micturition frequency and a significant reduction of micturition volume.
  • These alterations are significantly reduced by acute administration of cizolirtine (10 mg/kg; i.v.) .
  • Acetic acid infusion also increased bladder pressure, an effect that was reversed by cizolirtine.
  • acetic acid nor cizolirtine significantly affected contractile capacity of the bladder.
  • R 1 represents a hydrogen atom or a lower alkyl group from Ci to C 4 ;
  • R 2 represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxy, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy, or -0- (glucoronic acid);
  • R 3 represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci- 4 -Alkyl
  • R represents H or Ci_ 4 -Alkyl
  • R 9 is glucoronic acid
  • R 10 represents Ci_ 4 -Alkyl
  • n 1 to 4 or p is 1 to 3 ;
  • R 2 is a phenyl group unsubstituted or substituted with 1, 2 or 3 equal or different substitutents selected from fluoride, chloride , bromide, trifluoromethyl or methoxy, R 4 is not H or Cl alkyl within formula I and R 4 or R 5 are not Cl alkyl within formula II.
  • R 1 represents a hydrogen atom or a lower alkyl group from Ci to C 4 ;
  • R 2 represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxy, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy, or -0- (glucoronic acid);
  • R 3 represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci_ 4 -Alkyl
  • R 5 represents H or Ci- 4 -Alkyl
  • R 9 is glucuronic acid
  • R 10 represents Ci- 4 -Alkyl
  • n 1 to 4 or p is 1 to 3;
  • R 2 is a phenyl group unsubstituted or substituted with 1, 2 or 3 equal or different substitutents selected from, fluoride, chloride, bromide, trifluoromethyl or methoxy and Z represents:
  • R 4 is not H or Cl alkyl
  • R 2 is a phenyl group unsubstituted or substituted with 1, 2 or 3 equal or different substitutents selected from, fluoride, chloride, bromide, trifluoromethyl or methoxy and Z represents:
  • R 4 or R 5 are not Cl alkyl.
  • Ri is selected from hydrogen or from a group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert- butyl.
  • this application provides and currently preferred is an aryl or heteroaryl azolylcarbinole derivative of general formula (I), (II), (III) or (IV), in which R 3 is selected from
  • R 6 being selected from hydrogen, fluoride, chloride, bromide and methyl. There it is preferred if R 6 is hydrogen or methyl.
  • R 2 is selected from:
  • R 7 being selected from the group consisting of hydroxyl, hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy, or -0- (glucuronic acid) .
  • R 7 is hydrogen or hydroxyl, or -O- (glucoronic acid) .
  • R 2 represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxyl, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
  • R 4 represents H or Ci- 4 -Alkyl
  • R 5 represents H or Ci- 4 -Alkyl
  • R 6 is selected from hydrogen, fluoride, chloride, bromide and methyl.
  • R 2 is selected from:
  • R 7 being selected from the group consisting of hydroxyl, hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy.
  • R 7 is hydrogen or hydroxyl.
  • aryl or heteroaryl azolylcarbinole derivative of general formula (Ha) in which R 5 is hydrogen, methyl or ethyl, preferably hydrogen or methyl.
  • this application further provides and currently highly preferred is an aryl or heteroaryl azolylcarbinole derivative of general formula (I) or (II) in which the compound is a compound according to one of the general formulas (Ib), (Ic), (lib) or (lie)
  • n 1 or 2;
  • R 3 represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci- 4 -Alkyl
  • R 5 represents H or Ci- 4 -Alkyl
  • R 7 is selected from the group consisting of hydroxyl, hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy.
  • R 6 being selected from hydrogen, fluoride, chloride, bromide and methyl. There it is preferred if R 6 is hydrogen or methyl.
  • this application provides and currently highly preferred is an aryl or heteroaryl azolylcarbinole derivative of general formula (I) or (II) in which the compound is a compound according to one of the general formulas (Id), (Ie), (Hd) or (He)
  • n 1 or 2;
  • R 4 is selected from H or lower C( 1 - 4 )-Alky1;
  • R 5 is selected from H or lower C(i- 4 )-Alkyl
  • R 6 is selected from hydrogen, fluoride, chloride, bromide and methyl; and R 7 is selected from the group consisting of hydroxyl, hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy.
  • aryl or heteroaryl azolylcarbinole derivative of general formula (Id), (Ie), (Hd) or (He), in which R 7 is hydrogen or hydroxyl.
  • aryl or heteroaryl azolylcarbinole derivative of general formula (Hd) or (He) , in which R 5 is hydrogen, methyl or ethyl, preferably hydrogen or methyl.
  • a " represents an anion
  • R 1 represents a hydrogen atom or a lower alkyl group from Ci to C 4 ;
  • R 2 represents a phenyl radical or a thienyl radical,, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxyl, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
  • R represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci_ 4 -Alkyl
  • R 5 represents H or Ci- 4 -Alkyl. It is also highly preferred if the new aryl or heteroaryl azolylcarbinole derivatives according to the application are selected from:
  • Also highly preferred compounds are the enantiomers of the compounds described only as metabolites of the racemate in L. Martinez et al., "Absorption, distribution, metabolism and excretion of cizolirtine, a new analgesic compound, in rat and dog," Xenobiotica, 1999 (29) 8, 859-871 or in Puig S., et al. J. Pharm. Biomed. Anal. "Validation of a chromatographic method to determine E-6006 and its metabolite E-6332 in rat and dog plasma by solid-phase extraction and capillary gas chromatography.” Application in pharmacokinetics, 24 (2001) 887-896 which are also highly active selected from:
  • a salt especially a physiologically acceptable salt, most preferably the citrate or oxalate or in form of a solvate, especially a hydrate.
  • Another aspect of the application is a combination of at least one aryl or heteroaryl azolylcarbinole derivative according to the application or one compound selected from
  • Ar represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
  • Rn represents a hydrogen atom or a lower alkyl group from Ci to C 4 ;
  • Ri 2 represents a dialkyl (Ci- C 4 ) aminoalkyl (C 2 -C 3 ), or azaheterocyclylalkyl (C 2 -C 3 ) radical;
  • Het represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • a combination according to the application including a compound of general formula (VII) , in which Rn is selected from a hydrogen atom or from the group comprised by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • a combination according to the application including a compound of general formula (VII) , in which R 12 is selected from among a group comprised of dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidinylethyl, morpholinylpropyl and pirrolidinylethyl.
  • R 12 is selected from among a group comprised of dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidinylethyl, morpholinylpropyl and pirrolidinylethyl.
  • a combination according to the application including a compound of general formula (VII) , in which the compound of general formula (VII) is selected from among a group comprised by:
  • This application also discloses a process for the production of an aryl or heteroaryl azolylcarbinole derivative according to formula (I) according to the application in which a compound according to formula (VI)
  • R 1 represents a hydrogen atom or a lower alkyl group from Ci to C 4 ;
  • R represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxyl, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy or -0-(glucuronic acid) ;
  • R 3 represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci- 4 -Alkyl;
  • R 5 represents H or Ci-4-Alkyl;
  • n represents 1 to 4 is injected into a mammal (excluding humans) , blood of the mammal is collected and the products chromatographically separated and isolated.
  • the compounds are of high interest as pharmaceutical compounds.
  • the derivatives according to the application are nontoxic and are surprisingly effective in the treatment of depression and in other indications. Therefore, a further object of the application is a pharmaceutical composition comprising at least one derivative or combination according to the application or one compound selected from
  • the auxiliary material and/or additive can be selected from carrier, excipient, support materials, glidants, fillers, solvents, diluents, colorants, taste conditioners like sugars, antioxidants and/or binders. In the case of a suppository this might involve waxes or fatty acid esters or conserving agents, emulsifiers and/or carriers for parenteral application.
  • carrier excipient
  • support materials gli
  • composition according to the application can be adapted for topical or systemical application, especially dermal, subcutaneous, intramuscular, intra-articular and/or intraperitoneal, pulmonal, buccal, sublingual, nasal, percutaneous, vaginal, oral or parenteral, pulmonal, nasal, rectal and/or intravenous application.
  • the pharmaceutical composition according to the application might preferably be in the form of a plaster and/or gauze providing an occlusion of the burned or wounded skin.
  • the pharmaceutical composition according to the application is in the form of an ointment, a gel, a cream, a lotion, a suspension, an emulsion, a suppository, a solution, a tablet, a chewable tablet, a dragee, a capsule, a granules, drops, a juice and/or a syrup.
  • the compounds according to the application can be released in a delayed manner from forms of preparations which can be applied as mentioned above, especially orally, rectally or percutaneously.
  • Retard formulations are preferred objects of the application.
  • the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, on the type of application, on the indication and on the severity of the illness. 1 to 500 mg of the active ingredient are usually applied per kg.
  • a further object of the application are pharmaceutical compositions containing at least 0.05 to 90.0 % of active ingredient.
  • Another important aspect of the application is the use of an aryl or heteroaryl azolylcarbinole derivative or combination according to the application or one compound selected from
  • Urinary Incontinence Urge Incontinence, Hyperreflexia; Urinary Stress Incontinence, Mixed Incontinence and Enuresis.
  • Urinary incontinence a urinary disorder
  • This functional disorder of bladder is a health problem of increasing social and hygienic relevance for the population that suffers from it.
  • urinary incontinence occurs in approximately 1.5 to 5% of men and 10 to 30% of women in the population between 15 and 64 years old.
  • the non-hospitalised population sector over 60 years old, the prevalence ranges from 15% to 35% of this population.
  • the incidence is higher.
  • Urinary incontinence affects approximately 2 million of the Spanish population.
  • This application also discloses the use of an aryl or heteroaryl azolylcarbinole derivative or combination according to the application or one compound selected from
  • a medicament for the treatment of neuropathic inflammation diabetes, asthma, cystitis, gingivitis, migraine, dermatitis, rhinitis, psoriasis, inflammation of sciatic and lumbar nerves, gastrointestinal processes, ocular inflammation; the treatment of relative respiratory diseases, : cough, bronchitis, chronic obstructive pulmonary diseases, allergic rhinitis, asthma.
  • composition comprising as active ingredient at least one aryl or heteroaryl azolylcarbinole derivative of general formula (I), (II), (III) or (IV)
  • R 1 represents a hydrogen atom or a lower alkyl group from Ci to C 4 ;
  • R 2 represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxy, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy, or -0- (glucuronic acid) ;
  • R 3 represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci_ 4 -Alkyl;
  • R 5 represents H or Ci- 4 -Alkyl;
  • R 9 is glucuronic acid;
  • R 10 represents Ci- 4 -Alkyl; and n is 1 to 4 or p is 1 to 3
  • a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (I), (II), (III) or (IV) in which Ri is selected from hydrogen or from a group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (I), (II), (III) or (IV) in which R 4 is selected from hydrogen, methyl or ethyl, especially methyl or hydrogen.
  • a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (II) in which R 5 is selected from hydrogen, methyl or ethyl, especially methyl or hydrogen.
  • a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (I), (II), (III) or (IV), in which R 3 is selected from
  • R 6 being selected from hydrogen, fluoride, chloride, bromide and methyl. There it is preferred if R 6 is hydrogen or methyl.
  • a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (I), (II), (III) or (IV) in which R 2 is selected from:
  • R 7 being selected from the group consisting of hydroxyl, hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy, or -O- (glucoronic acid) .
  • R 7 is hydrogen or hydroxyl, or -0- (glucoronic acid) .
  • composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (I) or (II) in which the compound is a compound according to one of the general formulas (Ia) or (Ha)
  • m is 1 or 2;
  • R 2 represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxyl, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
  • R 4 represents H or Ci- 4 -Alkyl;
  • R 5 represents H or Ci_ 4 -Alkyl;
  • R 6 is selected from hydrogen, fluoride, chloride, bromide and methyl.
  • a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Ia) or (Ha) in which
  • R 2 is selected from:
  • R 7 being selected from the group consisting of hydroxyl, hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy.
  • R 7 is hydrogen or hydroxyl.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Ia) or (Ha) in which R 4 is methyl or ethyl, preferably methyl.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Ha) , in which R 5 is hydrogen, methyl or ethyl, preferably hydrogen or methyl.
  • a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Ia) or (Ha) in which R 6 is hydrogen or methyl.
  • a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (I) or (II) in which the compound is a compound according to one of the general formulas (Ib), (Ic), (lib) or (lie)
  • n 1 or 2;
  • R represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci- 4 -Alkyl
  • R 5 represents H or Ci- 4 -Alkyl
  • R 7 is selected from the group consisting of hydroxyl, hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Ib), (Ic), (lib) or (lie), in which R 7 is hydrogen or hydroxyl.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Ib), (Ic), (lib) or (lie), in which R 3 is selected from
  • R 6 being selected from hydrogen, fluoride, chloride, bromide and methyl. There it is preferred if R 6 is hydrogen or methyl.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Ib) , (Ic) , (lib) or (lie) , in which R 4 is methyl or ethyl, preferably methyl.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (lib) or (lie) , in which R 5 is hydrogen, methyl or ethyl, preferably hydrogen or methyl.
  • composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (I) or (II) in which the compound is a compound according to one of the general formulas (Id), (Ie), (Hd) or (He)
  • n 1 or 2;
  • R 4 is selected from H or lower C (1 - 4 )-Alky1;
  • R 5 is selected from H or lower C(i_ 4) -Alkyl
  • R 6 is selected from hydrogen, fluoride, chloride, bromide and methyl
  • R 7 is selected from the group consisting of hydroxyl, hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Id), (Ie), (Hd) or (He), in which R 7 is hydrogen or hydroxyl.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Id), (Ie), (Hd) or (He), in which R 6 is hydrogen or methyl.
  • Preferred is a pharmaceutical composition comprising an aryl or heteroaryl azolylcarbinole derivative of general formula (Id), (Ie), (Hd) or (He), in which R 4 is methyl or ethyl, preferably methyl.
  • a pharmaceutical composition comprising the salts, the physiologically acceptable salts of the new compounds.
  • the compounds according to general formula (II) are in a form according to general formula (V)
  • R 1 represents a hydrogen atom or a lower alkyl group from Ci to C 4 ;
  • R 2 represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of hydroxyl, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
  • R 3 represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl;
  • R 4 represents H or Ci- 4 -Alkyl
  • R 5 represents H or Ci-4-Alkyl.
  • the new aryl or heteroaryl azolylcarbinole derivatives comprised in the pharmaceutical composition according to this application are selected from:
  • compositions comprising a combination of an aryl or heteroaryl azolylcarbinole derivative according to the application and a compound of general formula VII R11
  • Ar represents a phenyl radical or a thienyl radical, with no substitutions or optionally with 1, 2 or 3 equal or different substituents, selected from the group comprised of fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
  • Rn represents a hydrogen atom or a lower alkyl group from C 1 to C 4 ;
  • Ri 2 represents a dialkyl (C 1 -C4) aminoalkyl (C 2 -C 3 ) , or azaheterocyclylalkyl (C 2 -C 3 ) radical;
  • Het represents a five-armed nitrogenated aromatic heterocycle that contains one to three nitrogen atoms, without substitutions or optionally substituted by 1 or 2 equal or different substituents selected from a group comprised by fluoride, chloride, bromide and methyl.
  • the compounds of formula VII are known from EP 0 289 380 or US 5,017,596 (describing i.a. cizolirtine) as well as EP 1 072 266 or US 6,410,582 included here by referrence.
  • Preferred is a pharmaceutical composition comprising a combination according to the application including a compound of general formula (VII), in which Rn is selected from a hydrogen atom or from the group comprised by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • a pharmaceutical composition comprising a combination according to the application including a compound of general formula (VII) , in which R12 is selected from among a group comprised of dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidinylethyl, morpholinylpropyl and pirrolidinylethyl.
  • VII general formula
  • a pharmaceutical composition comprising a combination according to the application including a compound of general formula (VII) , in which the compound of general formula (VII) is selected from among a group comprised by:
  • medicaments are also useful in the preparation of a medicament for the treatment of disorders mediated by excess of substance P; especially anxiety, depression, schizophrenia, manic depressive psychosis, sexual dysfunction, drug addiction, cognitive disorders, locomotive disorders.
  • pain including acute pain, chronic pain, neuropathic pain and visceral pain especially pain of moderate to high intensity; sciatica, lumbago, dorsalgia, sprains, fractures, dislocations, postoperative pain, and pain of dental origin.
  • Urge Incontinence Urge Incontinence, Hyperreflexia; Urinary Stress Incontinence, Mixed Incontinence and Enuresis.
  • neuropathic inflammation diabetes, asthma, cystitis, gingivitis, migraine, dermatitis, rhinitis, psoriasis, inflammation of sciatic and lumbar nerves, gastrointestinal processes, ocular inflammation; the treatment of relative respiratory diseases, : cough, bronchitis, chronic obstructive pulmonary diseases, allergic rhinitis, asthma.

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Abstract

L'invention concerne un procédé de traitement d'un sujet souffrant d'une forme d'incontinence urinaire, procédé consistant à administrer au sujet, une quantité d'un composé ayant la formule développée (I), efficace pour traiter ledit sujet, le composé étant administré sous une forme appropriée.
PCT/EP2005/008239 2004-07-30 2005-07-29 Aryl (ou heteroaryl) azolylcarbinols Ceased WO2006010627A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007017127A3 (fr) * 2005-07-29 2007-04-19 Esteve Labor Dr Forme dosifiee a liberation controlee de composes pyrazole
AU2017202849B2 (en) * 2013-03-08 2019-04-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Potent and Selective Inhibitors of Monoamine Transporters; Method of Making; and Use Thereof
US11365195B2 (en) 2017-11-13 2022-06-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Atypical inhibitors of monoamine transporters; method of making; and use thereof

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EP1086682A2 (fr) * 1998-05-18 2001-03-28 Laboratorios Del Dr. Esteve, S.A. Utilisation de derives d'aryl(ou heteroaryl)azolylcarbinols dans l'elaboration d'un medicament pour le traitement de l'inflammation neurogene
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ES2334548A1 (es) * 2005-07-29 2010-03-11 Laboratorios Del Dr. Esteve, S.A Forma de dosificacion de liberacion controlada de compuestos de pirazol para el tratamiento de la incontinencia urinaria.
ES2334548B1 (es) * 2005-07-29 2010-10-27 Laboratorios Del Dr. Esteve, S.A Forma de dosificacion de liberacion controlada de compuestos de pirazol para el tratamiento de la incontinencia urinaria.
AU2017202849B2 (en) * 2013-03-08 2019-04-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Potent and Selective Inhibitors of Monoamine Transporters; Method of Making; and Use Thereof
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US10590074B2 (en) 2013-03-08 2020-03-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Potent and selective inhibitors of monoamine transporters; method of making; and use thereof
US10913711B2 (en) 2013-03-08 2021-02-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Potent and selective inhibitors of monoamine transporters; method of making; and use thereof
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