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
  • A61K31/41—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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• the present invention refers to the use of derivatives of aryl (or heteroaryl) azolylcarbinols of general formula (I) 1 and their physiologically acceptable salts, as medicinal products for human and/or animal therapeutics for the treatment of the symptoms of central neuropathic pain, especially certain subtypes of central neuropathic pain, as well as treatment of the disease causing the symptoms, the prevention or the prophylaxis of the symptoms of central neuropathic pain, especially certain subtypes of central neuropathic pain, as well as the prevention or the prophylaxis of the disease causing the symptoms.
• PAIN is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP 1 Classification of chronic pain, 2 nd Edition, IASP Press (2002), 210). Even though pain is always subjective its causes or syndromes can be classified.
• Neuroopathic pain as a subtype is defined by the IASP as “pain initiated or caused by a primary lesion or dysfunction in the nervous system” (IASP, Classification of chronic pain, 2 nd Edition,
• Neuroneurogenic Pain which is defined by the IASP as "pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral or central nervous system".
• central pain is defined as "a pain initiated or caused by a primary lesion or dysfunction in the central nervous system” (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 211 ).
• central neuropathic pain can thus be defined as "pain initiated or caused by a primary lesion or dysfunction in the central nervous system.”
• neuropathic pain which in the past years has developed into a major health problem in broad areas of the population needs a very specific treatment, especially considering that any treatment of neuropathic pain is extremely sensitive to the causes behind the pain, be it the disease ultimately causing it or the mechanistic pathway over which it develops. Since central neuropathic pain is a real tragedy for the patients struck by this dreadful condition and on the other hand a convincing medication is still missing the medical need in this field is extremely high.
• the present invention refers to the use of a carbinol compounds of general formula
• R 31 represents a hydrogen atom, a linear or branched alkyl radical, a linear or branched alkenyl radical, an optionally at least mono- substituted cycloaliphatic radical, which may contain at least one nitrogen atom as ring member, or a phenyl radical,
• R 32 represents a hydrogen atom, an optionally at least one nitrogen atom as ring member containing cycloaliphatic radical, which may be at least mono-substituted by a linear or branched alkyl radical and/or which may be bound via a linear or branched alkylene group, an NR 33 R 34 - moiety, which is bound via a linear or branched alkylene group, or an NR 35 R 36 -moiety, which is bound via a linear or branched alkylene group,
• R 33 and R 34 identical or different, represent hydrogen, a linear or branched alkyl radical or an unsubstituted benzyl radical,
• R 35 and R 36 together with the bridging nitrogen atom represent a saturated, unsubstituted, optionally at least one further heteroatom as ring member containing heterocyclic radical,
• X represents an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted thienyl radical, wherein in each case the substituents may be independently selected from the group consisting of a linear or branched alkyl radical, a linear or branched alkoxy group, a linear or branched alkyl radical, which is at least partially halogenated and a halogen atom,
• Y represents a heteroaryl radical, which contains one or more nitrogen atoms as ring members and which is not substituted or at least mono- substituted by one or more substitutents independently from one another selected from the group consisting of a halogen atom, a linear or branched alkyl radical, a benzyl radical, a ciano group bound via a linear or branched C ⁇ -alkylene group, a carboxy group bound via a linear or branched C 1-4 -alkylene group, a methoxy carbonyl group bound via a linear or branched Ci- 4 -alkylene group, a hydroxy group bound via a linear or branched C ⁇ -alkylene group, an amino group bound via a linear or branched C ⁇ -alkylene group, a (C 1-4 ) dialkylamino group bound via a linear or branched C 1-4 -alkylene group, and a cycloaliphatic radical, which contains at least one nitrogen atom as
• Treating or “treatment” as used in this application are defined as covering treatment in a therapeutical sense including efforts to ameliorate and also to prevent and to deliver a prophylaxis.
• treatment of central neuropathic pain is defined as including the treatment/amelioration of central neuropathic pain - including certain subtypes of neuropathic pain -, treatment/amelioration of the symptoms of central neuropathic pain - including certain subtypes of neuropathic pain -, as well as treatment/amelioration of the disease or disease consequences causing the symptoms; further the prevention or the prophylaxis of central neuropathic pain - including certain subtypes of neuropathic pain -, the prevention or the prophylaxis of the symptoms of central neuropathic pain - including certain subtypes of central neuropathic pain -, as well as the prevention or the prophylaxis of the disease or disease consequences causing the symptoms.
• treatment of central neuropathic pain is defined as including the treatment/amelioration of central neuropathic pain - including certain subtypes of neuropathic pain - and treatment/amelioration of the symptoms of central neuropathic pain - including certain subtypes of neuropathic pain -; further the prevention or the prophylaxis of central neuropathic pain - including certain subtypes of neuropathic pain -, and the prevention or the prophylaxis of the symptoms of central neuropathic pain - including certain subtypes of central neuropathic pain.
• treatment of central neuropathic pain is defined as including the treatment/amelioration of central neuropathic pain - including certain subtypes of neuropathic pain - and treatment/amelioration of the symptoms of central neuropathic pain - including certain subtypes of neuropathic pain; further the prevention or the prophylaxis of the symptoms of central neuropathic pain - including certain subtypes of central neuropathic pain.
• alkyl and cycloalkyl radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
• C 1-2 -alkyl represents C1- or C2-alkyl
• C 1-3 -alkyl represents C1-, C2- or C3-alkyl
• d- 4 -alkyl represents C1-, C2-, C3- or C4-alkyl
• C 1-5 -alkyl represents C1- , C2-, C3-, C4-, or C5-alkyl
• d-e-alkyl represents C1-, C2-, C3-, C4-, C5- or C6- alkyl
• C 1-7 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
• C 1-8 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
• C 1-10 -alkyl represents C1-, C2-, C3-, C4-, C5-
• C 3 ⁇ -cycloalkyl represents C3- or C4-cycloalkyl
• C 3- 5 -cycloalkyl represents C3-, C4- or C5-cycloalkyl
• C 3-6 -cycloalkyl represents C3-, C4- , C5- or C6-cycloalkyl
• C 3-7 -cycloalkyl represents C3-, C4-, C5-, C6- or C7- cycloalkyl
• C 3-8 -cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl
• C 4-5 - cycloalkyl represents C4- or C5-cycloalkyl
• C 4-6 -cycloalkyl represents C4-, C5- or
• C6-cycloalkyl C 4 - 7 -cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl
• C 5-6 - cycloalkyl represents C5- or C6-cycloalkyl
• C 5-7 -cycloalkyl represents C5-, C6- or C7-cycloalkyl.
• cycloalkyl the term also includes saturated cycloalkyls in which one or 2 carbon atoms are replaced by a heteroatom, S, N or O.
• mono- or polyunsaturated, preferably monounsaturated, cycloalkyls without a heteroatom in the ring also in particular fall under the term cycloalkyl as long as the cycloalkyl is not an aromatic system.
• alkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1 ,1-dimethylethyl, pentyl, 1 ,1-dimethylpropyl, 1 ,2- dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2- methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl, (if substituted also CHF 2 , CF 3 or CH 2 OH) as well as pyrazolinone, oxopyrazolin
• Particularly preferred substituents here are F, Cl and OH.
• the hydrogen radical can also be replaced by OC 1-3 -alkyl or Ci-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 -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 J 4-5 is to be understood as meaning -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 - CH 2 -CH 2 -, etc.
• aryl radical is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or monosubstituted or polysubstituted.
• a heteroaryl radical is understood as meaning heterocyclic ring systems 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 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 C 1-6 -alkyl (saturated), a C 1-6- alkoxy, a C 3-8 - cycloalkoxy, a C 3- ⁇ -cycloalkyl or a C 2 ⁇ -alkylene.
• salt is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
• a counter-ion a cation or anion
• complexes of the active compound with other molecules and ions in particular complexes which are complexed via ionic interactions.
• physiologically acceptable salt means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
• physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals.
• the salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH4, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
• physiologically acceptable salts can also be formed with anions or acids in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually protonated, for example on the nitrogen - as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals.
• the salt formed with a physiologically tolerated acid that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals.
• physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
• solvate is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
• a polar solvent especially including hydrates and alcoholates, e.g. methanolate.
• Ib and Ic have a stereogenic centre and the invention refers both to the use of a pure enantiomer and to the use of a mixture of enantiomers.
• the enantiomers can be prepared by any of the procedures described in our patents WO 97/20817 (US 5,849,931 ), WO 99/02500 (US 6,187,930), WO 99/07684 (US 6,118,009) and WO
• R 31 represents a hydrogen atom, a linear or branched C 1-4 alkyl radical, a linear or branched C 2-4 alkenyl radical, a 5- or 6-membered cycloaliphatic radical, which may contain at least one nitrogen atom as ring member and/or which may be at least mono-substituted by a linear or branched C 1-4 alkyl radical, or a phenyl radical, preferably a hydrogen atom, a linear or branched C 1-4 alkyl radical, a vinyl group, a cyclohexyl radical, an N-Methyl-piperidyl radical or a phenyl radical.
• R 32 represents a hydrogen atom, an optionally at least one nitrogen atom as ring member containing, 5- or 6-membered cycloaliphatic radical, which may be at least mono-substituted by a linear or branched C ⁇ -alkyl radical and/or which may be bound via a linear or branched C 1-4 -alkylene group, a NR 33 R 34 - moiety, which is bound via a linear or branched C 1-4 alkylene group, or a NR 35 R 36 - moiety, which is bound via a linear or branched Ci -4 alkylene group, preferably a hydrogen atom, an optionally at least one nitrogen atom as ring member containing, 5- or 6-membered cycloaliphatic radical, which may be at least mono-substituted by a linear or branched C 1-4 -alkyl radical and/or which may be bound via a linear or branched
• the compound according to formula Il used is characterized in that R 33 and R 34 , identical or different, independently from one another represent hydrogen; a linear or branched Ci -4 alkyl radical or an unsubstituted benzyl radical, preferably hydrogen or a linear or branched Ci -4 alkyl radical.
• the compound according to formula Il used is characterized in that R 35 and R 36 together with the bridging nitrogen atom represent a saturated, unsubstituted, optionally at least one oxygen atom as ring member containing, 5- or 6-membered heterocyclic radical.
• the compound according to formula Il used is characterized in that X represents an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted thienyl radical, wherein in each case the substituents may be independently selected from the group consisting of a linear or branched Ci -4 alkyl radical, a linear or branched alkoxy radical, a linear or branched Ci -4 alkyl radical, which is at least partially fluorinated, a fluorine atom, a chlorine atom and a bromine atom, preferably represents an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted thienyl radical, wherein in each case the substituents may be independently selected from the group consisting of a methyl radical, a methoxy radical, a trifluoromethyl radical, a fluorine atom, a chlorine atom and a bromine atom.
• X represents an optionally
• R 37 represents a linear or branched C 1 - 12 alkyl radical, a benzyl radical or a radical of the type:
• n 1 or 2
• R 38 represents a hydrogen atom, a methyl radical or a halogen atom, preferably a hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,
• R 39 represents a hydrogen atom, a C 1 - 12 alkyl radical, a benzyl radical, or a radical of the general formula (b1 ):
• At least one compound used according to the invention is a carbinol compound of general formula Il R 31
• R 31 represents a hydrogen atom, a methyl radical, an ethyl radical, an n-propyl radical, an iso-propyl radical, a sec-butyl radical, a tert-butyl radical, an n-butyl radical, a vinyl radical, a cyclohexyl radical, an N-methyl-piperidinyl group, or a phenyl group,
• R 32 represents a hydrogen atom, a monomethylaminoethyl group, a dimethylaminoethyl group, an aminoethyl group, a pyrrolidinylethyl group, a piperidinylethyl group, a methyl-benzyl-aminoethyl group, a morpholinylethyl group, a diisopropylaminoethyl group, a dimethylaminopropyl group, a piperidinylpropyl group, a pyrrolidinylpropyl group, a morpholinylpropyl group, an N-methyl-2-piperidyl group, an N-ethyl-2-piperidyl group, an N-propyl- 2-piperidyl group, an N-methyl-2-pyrrolidinyl group, an N-ethyl-2-pyrrolidinyl group, an N-propyl-2-pyrrolidinyl group, or
• X represents a phenyl radical, a 2-methyl-phenyl radical, a 3-methyl-phenyl radical, a 4-methyl phenyl radical, a 2-chloro-phenyl radical, a 3-chloro-phenyl radical, a 4-chloro-phenyl radical, a 2-fluoro-phenyl radical, a 3-fluoro-phenyl radical, a 4-fluoro-phenyl radical, a 2-trifluoromethyl-phenyl radical, a 3- trifluoromethyl-phenyl radical, a 4-trifluoromethyl-phenyl radical, a 2-methoxy- phenyl radical, a 3-methoxy-phenyl radical, a 4-methoxy-phenyl radical, a 3,4,5- tris-methoxy phenyl radical, a 3,4-dichloro-phenyl radical, a 2,4-dichloro- phenylradical, a thien-2-yl radical, a
• Y represents an azole radical selected from the group consisting of
• R 37 represents a methyl radical, an ethyl radical, an n-propyl radical, an iso- propyl radical, an n-butyl radical, a sec-butyl radical or a tert-butyl radical,
• R 38 represents a hydrogen atom, a methyl radical, a bromine atom or a chlorine atom,
• R 39 represents a hydrogen atom, a methyl radical, an ethyl radical, an n-propyl radical, an iso-butyl radical, an n-butyl radical, a sec-butyl radical a tert-butyl radical, an n-pentyl radical, an n-hexyl radical, an n- heptyl radical, an n-octyl radical, an n-nonyl radical, an n-decyl radical, an n-undecyl radical an n-dodecyl radical, a benzyl radical, or a radical of the general formula (b1 ):
• R 40 represents a piperidinyl radical, a phenyl radical, a cyano group, a hydroxy I radical, a carboxy radical, an amino group, a dimethylamino group, or a methyl ester group,
• At least one compound according to formula Il used is selected from the group consisting of
• the compound used for the manifacture of a medicament for the treatment of neuropathic pain
• 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 a group consisting of fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
• R 1 represents hydrogen or a lower alkyl group from Ci to C 4 ;
• R 2 represents a dialkyl(C 1 -C 4 )aminoalkyl (C 2 -Ca), a monoalkyl(Ci-C 4 )aminoalkyl (C 2 -C 3 ), an aminoalkyl (C 2 -C 3 ), or azaheterocyclylalkyl (C 2 -C 3 ) radical; and 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 consisting of fluoride, chloride, bromide and methyl;
• the compound according to formula I used is characterized in that R 1 is selected from hydrogen or from a group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
• the compound according to formula I used is characterized in that R 2 is selected from among a group consisting of dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylaminopropyl, methylaminoethyl, methylaminopropyl, aminoethyl, aminopropyl, piperidinylethyl, piperidinylpropyl, morpholinylpropyl, morpholinylethyl, pirrolidinylpropyl and pirrolidinylethyl;
• dimethylaminoethyl preferably dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidinylethyl, morpholinylpropyl, and pirrolidinylethyl.
• the compound according to formula I used is a compound of general formula (Ia)
• n 1 or 2;
• R 3 is selected from:
• R 4 is selected from hydrogen, fluoride, chloride, bromide and methyl
• R 5 and R 6 are independently selected from hydrogen, lower C (1-4) -Alkyl or together with the Nitrogen form an azaheterocyclic ring
• R 7 is selected from the group consisting of hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
• the compound according to formula Ia used is characterized in that R 7 is hydrogen.
• the compound according to formula Ia used is characterized in that R 4 is Methyl.
• the compound according to formula Ia used is characterized in that R 5 and R 6 are either hydrogen, CH 3 or C 2 H 5 or together with the Nitrogen form a piperidinyl, morpholinyl or pirrolidinyl ring.
• the compound according to formula Ia used is selected from among a group consisting of:
• the compound according to formula I and Ia used is a compound of general formula (Ib)
• R is selected from hydrogen, fluoride, chloride, bromide and methyl
• R 9 and R 10 are independently selected from hydrogen, lower C (1-4) -Alkyl or together with the Nitrogen form an azaheterocyclic ring;
• R 11 is selected from the group consisting of hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy;
• the compound according to formula Ib used is characterized in that R 11 is hydrogen.
• the compound according to formula Ib used is characterized in that R 8 is Methyl.
• the compound according to formula Ib used is characterized in that R 9 and R 10 are either hydrogen, CH 3 or C 2 H 5 or together with the Nitrogen form a piperidinyl, morpholinyl or pirrolidinyl ring;
• R 9 and R 10 are either hydrogen, CH 3 or C 2 H 5 ;
• R 9 and R 10 are equal and either CH 3 or C 2 H 5 ;
• R 9 and R 10 are both CH 3 .
• the compound according to formula Ib used is characterized in that m is 1.
• the compound according to formula Ib used is selected from among a group consisting of:
• the compound according to formula Ia used is a compound of general formula (Ic)
• R 12 is selected from hydrogen, fluoride, chloride, bromide and methyl
• R 13 and R 14 are independently selected from hydrogen, lower or together with the Nitrogen form an azaheterocyclic ring;
• R 15 is selected from the group consisting of hydrogen, fluoride, chloride, bromide, methyl, trifluoromethyl and methoxy.
• the compound according to formula Ic used is characterized in that R 15 is hydrogen. In a preferred aspect of the invention the compound according to formula Ic used is characterized in that R 12 is Methyl.
• the compound according to formula Ic used is characterized in that R 13 and Ru are either hydrogen, CH 3 or C 2 H 5 or together with the Nitrogen form a piperidinyl, morpholinyl or pirrolidinyl ring;
• Ri 3 and R 14 are either CH 3 or C 2 H 5 ;
• R 13 and R 14 are equal and either CH 3 or C 2 H 5 ;
• R 13 and R 14 are both CH 3 .
• the compound according to formula Ic used is characterized in that p is 1.
• the compound according to formula Ic used is selected from among a group consisting of:
• the compound of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon or 15 N-enriched nitrogen are within the scope of this invention.
• a preferred use according to the invention is characterized in that the active compound is used in the medicament at a dose between 50 and 400 mg/day or between 200 and 600 mg/day.
• the complete salt - dose means the dose of the active compound without the salt (which means without the counter ion, for example the citrate ion).
• an effective administered amount of a compound used according to the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer.
• active compounds will typically be administered once or more times a day for example 1 , 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000/mg/kg/day.
• Any formulation or pharmaceutical composition according to the invention contains the active ingredient as well as optionally at least one auxiliary material and/or additive.
• 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 glidants
• fillers solvents, diluents, colorants
• taste conditioners like sugars, antioxidants and/or binders.
• a suppository this might involve waxes or fatty acid esters or conserving agents, emulsifiers and/or carriers for parenteral application.
• the selection of these auxiliary materials and/or additives and of the amounts to be used depends upon how the pharmaceutical composition is to be applied.
• compositions according to the invention 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.
• Solid oral compositions (which are preferred as are liquid ones) may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
• the tablets may for example be prepared by wet or dry granulation and optionally coated according to the methods well known in normal pharmaceutical practice., in particular with an enteric coating.
• a preferred use according to the invention is characterized in that the medicament is for oral administration, especially in form of a tablet or capsule.
• immediate release formulation means any formulation with a release profile from which measured according to a standard measurement (e.g. using the paddle method according to the Pharmacopeia) (e.g. in 0.1% NaCI solution) within 30 minutes more than 50 %, more preferably 60 %, or even more preferably 70 % of the active compound is released.
• a preferred use according to the invention is characterized in that the central neuropathic pain is allodynia; respectively that the symptom to be treated is allodynia.
• IASP allodynia
• the central neuropathic pain is causalgia.
• causalgia is defined as "a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes" (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 210).
• the central neuropathic pain is hyperesthesia.
• hypoesthesia is defined as "increased sensitivity to stimulation, excluding the senses” (IASP, Classification of chronic pain, 2 nd Edition,
• the central neuropathic pain is neuralgia.
• nervegia is defined as "Pain in the distribution of a nerve or nerves” (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 212).
• the central neuropathic pain is neuritis.
• nerves are defined as "Inflammation of a nerve or nerves"
• the central neuropathic pain is neuropathy.
• neuroneuropathy is defined as "a disturbance of function or pathological change in a nerve: in one nerve mononeuropathy, in several nerves mononeuropthy multiplex, if diffuse and bilateral, polyneuropathy" (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 212).
• the central neuropathic pain is hyperalgesia.
• hyperalgesia is defined as "an increased response to a stimulus which is normally painful(IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 211 ).
• the central neuropathic pain is hyperpathia.
• hypopathia is defined as "a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold" (IASP 1 Classification of chronic pain, 2 nd Edition, IASP Press (2002), 212).
• IASP draws the following difference between “allodynia”, “hyperalgesia” and “hyperpathia” (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 212):
• the stimulus evoking the central neuropathic pain is mechanical.
• the stimulus evoking the central neuropathic pain is thermal.
• Figures 1 and 2 Refering to example 7 they show the high efficacy of Cizolirtine in a model for the central neuropathic pain, the ligature of the infraorbital nerve.
• Example 2 Example of formulation for an injectable (im/iv) solution:
• Lactose monohydrate (Farmatose 200M) 158 mg
• Example 4 Example of a formulation (B) for a tablet
• Colloidal silica dioxide (Aerosyl 200) 8 mg Magnesium stearate, NF 16 mg
• Microcrystalline cellulose (Avicel PH-102) 246 mg
• Lactose monohydrate (Farmatose 200M) 258 mg
• Example 7 Rats operated on infraorbital nerve
• Rats were operated placing a ligature around the infraorbital nerve on one side. Following this operation the response threshold in (g) is reduced considerably if comparing the ipsilateral and contralateral side to the response pre ligature (Fig. 2) measured as aversive reactions.
• Cizolirtine (example 1 ) was give i.p. in a dose of 80 mg/kg and effecting the ipsilateral side results in a strong inducement of the nociceptive threshold (%) (Fig. 1). Saline produced no modification of the nociceptive threshold.

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