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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
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  • 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
  • C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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  • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
  • C07D295/28—Nitrogen atoms
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  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to sulfonylguanidines, processes for their preparation, medicaments containing these compounds and the use of sulfonylguamdines for the production of medicaments for the treatment of pain and in other indications.
• Cyclic GABA analog gabapentin is a clinically proven antiepileptic.
• Gabapentin also shows other interesting, medically relevant properties, especially as an analgesic.
• interesting are therefore new structural classes that have affinity for the gabapentin binding site.
• Classic opioids such as morphine are effective in treating severe to severe pain. However, their use is limited by the known side effects such as respiratory depression, vomiting, sedation, constipation and tolerance development. They are also neuropathic or incidental pain, in particular from which tumor patients suffer, is less effective.
• the object of the invention was therefore to find structures, preferably new structures, which have affinity for the gabapentin binding site and / or corresponding physiological activity, for example with regard to analgesia, but also have other GBP indications.
• the invention therefore relates to the use of a sulfonylguanidine according to the general tautomeric formulas I and Ia,
• R 1 is selected from C 10 alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl or bicyclic alkylene, each saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each unsubstituted or single or multiple substituted; or aryl, C .g-cycloalkyl or heteroaryl bonded via saturated or unsaturated Ci-3-alkyl, in each case unsubstituted or mono- or polysubstituted;
• R 2 is selected from C 10 alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or via saturated or unsaturated Ci-3-alkyl. S (O) 2 or NH bound
• Aryl, C3_g-cycloalkyl or heteroaryl in each case unsubstituted or mono- or polysubstituted; or
• R 4 , R 5 independently selected from H; C ⁇ - 8 alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl, C .g-cycloalkyl bonded via saturated or unsaturated Ci-3-alkyl or
• Heteroaryl each unsubstituted or mono- or polysubstituted; or
• R 6 selected from C ⁇ - 18 alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl bonded via saturated or unsaturated Ci-3-alkyl, C. 9-Cycloalky! or heteroaryl, each unsubstituted or mono- or polysubstituted;
• R 4 and R 5 together: -CH2CH2OCH2CH2-; -CH 2 CH2N (R 7 ) CH 2 CH2- form with R 7 selected from C ⁇ -alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl, C3- bonded via saturated or unsaturated C 3 alkyl. g-cycloalkyl or heteroaryl, each unsubstituted or mono- or polysubstituted;
• R 3 is selected from H, Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl bonded via saturated or unsaturated C 3 alkyl, 03.9-
• R 8 selected from Cr 18 alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalky! or bicyclic alkylene, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl, C3_g-cycloalkyl or heteroaryl bonded via saturated or unsaturated Ci-3-alkyl, in each case unsubstituted or mono- or polysubstituted;
• a medicament for the treatment of pain in particular neuropathic, chronic or acute pain, epilepsy and / or migraine
• hyperalgesia and allodynia for the manufacture of a medicament for the treatment of hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold allodynia, or of inflammatory or postoperative pain
• ALS amyotropic lateral sclerosis
• RSD reflex sympasthetic dystrophy
• spastic paralysis restless leg syndrome
• psychiatric or neuropathological disorders such as bi
• R 1 is selected from Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl or bicyclic alkylene, each saturated or unsaturated, mono- or polysubstituted or unsubstituted; Phenyl, unsubstituted or mono- or polysubstituted.
• R 2 is selected from Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl bonded via saturated or unsaturated C 3 alkyl, C _Q-
• Cycloalkyl or heteroaryl each unsubstituted or mono- or polysubstituted.
• sulfonylguanidines used according to the general tautomeric formulas I and la that
• R 3 is selected from H or CH 3 .
• R 1 is selected from C 3 -C 8 cycloalkyl or bicyclic alkylene, in each case saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or via saturated or unsaturated C1-4-
• R 2 is selected from Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl bound via saturated or unsaturated C 3 alkyl, 03.9-
• R 3 is selected from H, Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted.
• alkyl or cycloalkyl radicals are taken to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
• 5 -Alkyi for C1-, C2-, C3-, C4- or C5-alkyl, de-alkyl for C1-, C2-, C3-, C4-, C5- or C6-alkyl, C ⁇ .
• Cycloalkyl for C3 or C4 cycloalkyl C 3-5 cycloalkyl for C3, C4 or C5-cycloalkyl, C 3 - 6 cycloalkyl for C3, C4, C5 or C6-cycloalkyl, C. 3 7 cycloalkyl for C3, C4, C5, C6 or C7 cycloalkyl, C 3-8 cycloalkyl for C3, C4, C5, C6, C7 or C8 cycloalkyl, C 4 _ 5 - Cycloalkyl for C4 or C5 cycloalkyl, C 4 .
• cycloalkyl For 6 -cycloalkyl C4-, C5- or C6- cycloalkyl, C 4 - 7 cycloalkyl for C4, C5, C6 or C7 -cycloalkyl, C 5 - 6 cycloalkyl of C5 or C6 cycloalkyl, and C 5 , 7- Cycloalkyl for C5-, C6- or C7-cycloalkyl.
• cycloalkyl the term also includes saturated cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O.
• cycloalkyl also includes, in particular, one or more, preferably mono-, unsaturated cycloalkyls without a hetero atom in the ring, as long as the cycloalkyl is not an aromatic system.
• the alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, Pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl,
• Particularly preferred substituents here are F, Cl and OH.
• the hydrogen radical can also be derived from OC-
• (CH 2 ) 3 -6 is -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-. -CH 2 -CH 2 -CH 2 - CH2-CH 2 - and CH2-CH2-CH2-CH2-CH2-CH2- to understand, under (CH 2 ) ⁇ -4 is -CH 2 -, - CH2-CH 2 -, -CH2-CH2-CH2- and -CH2-CH2-CH2- to understand, under (CH 2 ) 4 -5 is - CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH2-CH2- to understand, etc.
• An aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or mono- or polysubstituted.
• a heteroaryl radical is understood to mean heterocyclic ring systems with at least one unsaturated ring which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and can also be mono- or polysubstituted.
• heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo [1,2,5] thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane and benzodioxane , Carbazole, indole and quinazoline.
• aryl and heteroaryl this is understood to mean the substitution of aryl or heteroaryl with R 23 , OR 23, a halogen, preferably F and / or Cl, a CF3, a CN, a NO2, an NR 24 R 25 , a C. ⁇ _ - alkyl (saturated), a C ⁇ j _g alkoxy, a C3_8 cycloalkoxy, a C3_3 cycloalkyl or a C2_g alkylene.
• the rest is there preferably a C j .g alkyl, an aryl or heteroaryl or for about C - ⁇ - alkyl, saturated or unsaturated, or a C "
• the radicals R 24 and R 25, identical or different, represent H, a C- .- j j o alkyl, preferably a C ⁇ _g alkyl, an aryl, a heteroaryl or a via C ⁇ - alkyl , saturated or unsaturated, or an aryl or heteroaryl radical bonded to a C 1-4 alkylene group, these aryl and heteroaryl radicals themselves not being allowed to be substituted by aryl or heteroaryl radicals,
• radicals R 24 and R 25 together mean CH2CH2OCH2CH2, CH 2 CH2NR 26 CH 2 CH2 or (CH 2 ) 3_g, and
• R 26 for H, a C-
• salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution.
• a counterion a cation or anion
• This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.
• physiologically compatible salt with cations or bases means salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation, which is physiologically - in particular when used in humans and / or mammal - are compatible.
• the salts of the alkali and alkaline earth metals are also particularly preferred, but also with NH 4 + , but in particular (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.
• physiologically compatible salt with anions or acids is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which is physiologically - in particular when used in humans and / or Mammal - are compatible.
• this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
• physiologically acceptable salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1 ⁇ 6 - benzo [d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid , ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid.
• the hydrochloride salt is particularly preferred.
• the substances listed above and defined for use displace gabapentin from its binding site, which is still unknown in science. However, this implies that the substances according to the invention bind at the same binding site and act physiologically through them are likely to have the same activity profile as gabapentin. The analgesic effect proves that this assumption of the same effect also applies to the same binding site. Thus, the compounds according to the invention not only displace gabapentin from its binding site but, like gabapentin, also have a clearly analgesic effect. Accordingly, the subject of the invention is the use of the above-mentioned and defined thioamino acids in the above-mentioned indications in which gabapentin acts, i.e. in particular in pain therapy, for epilepsy or migraines, but especially also in neuropathic pain, i.e. hyperalgesia and allodynia and the other gabapentin indications ,
• Gabapentin is a well-known antiepileptic with an anticonvulsant effect.
• gabapentin is also used in various other indications, including by treating doctors for migraines and bipolar disorders as well as hot flashes (e.g. in postmenopause) (M. Schrope, Modern Drug Discovery, September 2000, p. 11).
• Other indications in which gabapentin shows therapeutic potential have been identified during human studies and clinical use (JS Bryans, D. Wustrow; "3-Substituted GABA Analogs with Central Nervous System Activity: A Review" in Med. Res. Rev. (1999), pp.
• Gabapentin is effective in the treatment of chronic pain and behavioral disorders.
• anticonvulsive and antiepileptic effects the use against chronic, neuropathic pain , in particular thermal hyperalgesia, mechanical allodynia, cold allodynia. It is also effective against neuropathy caused by nerve damage, especially neuropathic pain, as well as inflammatory and postoperative pain.
• Gabapentin is also successful in antipsychotic effects, especially as an anxiolytic Include: Amyotropic Lateral Sclerosis (ALS), Reflex Sympasthetic Dystrophy (RSD), Spastic Paralysis, Restless Leg Syndrome, Treatment of Symptoms and Pain due to Multiple Sclerosis, Acquired Nystagmus, Treatment of Symptoms of Parkinson's Disease, Painful Diabetic Neuropathy and Psychiatric Disorders , eg bipolar disorders, mood swings, manic behavior. Further Gabapentin was successfully used in erythromelalgic pain, postpoliomyelitis pain, trigeminal neuralgia and postherpetic neuralgia (Bryans and Wustrow (1999), op. cit.).
• neurodegenerative diseases are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy.
• the effectiveness of gabapentin in gastrointestinal damage is also known.
• R 1 is selected from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted; or aryl or heteroaryl bound via saturated or unsaturated Ci-3-alkyl, in each case unsubstituted or mono- or polysubstituted;
• R 1 is selected from aryl or heteroaryl, unsubstituted or singly or multiply, preferably with NO 2 , NH 2 , F, Cl, Br, I, OH or SH; or -NHC (0) -C 1 . 4 alkyl, -C- alkyl, -OC- M alkyl, -N (C1. 4 alkyl) 2, with the d. 4 - alkyl group in each case branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted;
• R 1 is selected from phenyl or naphthyl, in particular phenyl, unsubstituted or singly or multiply, preferably with F, Cl, Br, I, OH, NO 2 , NH 2 ; C 4 alkyl, Od 4 alkyl, in particular CH 3 , C 2 H 5 , t-butyl, i-propyl, methoxy, OCF 3 or ethoxy, each branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; preferably meta or para, in particular para; substituted.
• R 2 is selected from aryl or heteroaryl bonded via saturated or unsaturated C 3 alkyl, in particular CH 2 , in each case unsubstituted or mono- or polysubstituted;
• R 2 is selected from heteroaryl bonded via saturated or unsaturated Ci-3-alkyl, in particular -CH 2 -, in each case unsubstituted or mono- or polysubstituted;
• R 2 is selected from pyridinyl, thiophenyl, furanyl or pyrimidinyl, preferably pyridinyl, bonded via saturated or unsaturated Ci-3-alkyl, in particular -CH 2 -, in each case unsubstituted or singly or multiply, preferably simply, in particular with F, Cl, Br , I, OH, NO 2 , SH, NH 2 , C 1 -4- alkyl, O-C ⁇ _ 4 alkyl, preferably para, substituted.
• R 3 is selected from H or C 4 alkyl, preferably H or CH 3), in particular H.
• the sulfonylguamdines used according to the invention are selected from the following group: ⁇ / - ⁇ Amino- [pyridin-2ylmethyl) amino] methylene ⁇ -4-methylbenzenesulfonamide (1) ⁇ / - [Amino- (benzylamino-methylene)] - 4-methylbenzenesulfonamide (2) ⁇ / - (amino-morpholine -4yl-methylene) -4-methylbenzenesulfonamide (3) ⁇ / - (amino-cyclohexylaminomethylene) -4-methylbenzenesulfonamide (4) ⁇ / - (amino-phenylaminomethylene) -4-methylbenzenesulfonamide (5) ⁇ / - [(amino-4 -methoxybenzylamino) methylene] -4-methylbenzenesulfonamide (6) ⁇ /
• N- ⁇ Amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -4-iodobenzenesulfonamide (35) N- ⁇ Amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -benzenesulfonamide ( 36) Naphthalene-2-sulfonic acid amino - [(pyridin-2-ylmethyl) amino] methylene amide (37) N- [4 - ( ⁇ Amino - [(pyridin-2-ylmethyl) amino] methylene ⁇ sulfamoyl) -phenyl] -acetamide (39)
• N- ⁇ Amino - [(pyridin-2-ylmethyl) amino] -methylene ⁇ -4-butyl-benzenesulfonamide (50) N- ⁇ Amino - [(furan-2-ylmethyl) -amino] -methylene ⁇ -4-butyl-benzenesulfonamide (52) N- ⁇ amino - [(furan-2-ylmethyl) amino] -methylene ⁇ -4-methyl-benzenesulfonamide (53) N- ⁇ amino - [(furan-2-ylmethyl) -amino] -methylene ⁇ -4-isopropyl-benzenesulfonamide (54) N- ⁇ amino - [(furan-2-ylmethyl) -amino] -methylene ⁇ -4-propyl-benzenesulfonamide (55) N- ⁇ amino - [(furan-2-ylmethyl) amino] -methylene
• N- ⁇ Amino - [(thiophene-2-ylmethyl) amino] -methylene ⁇ -4-chloro-benzenesulfonamide (61) N- ⁇ Amino - [(thiophene-2-ylmethyl) -amino] -methylene ⁇ -4- methyl benzenesulfonamide (62) • N- ⁇ amino - [(furan-2-ylmethyl) amino] methylene ⁇ -4-chloro-benzenesulfonamide (63)
• N- ⁇ amino- [pyridin-2ylmethyl) amino] methylene ⁇ -4-chlorobenzenesulfonamide (21) N- ⁇ amino- [pyridin-4ylmethyl) amino] methylene ⁇ -4-methylbenzenesulfonamide (22) N- ⁇ amino - [pyridin-3ylmethyl) amino] methylene ⁇ -4-methylbenzenesulfonamide (23) N- ⁇ amino - [(pyridin-2-ylmethyl) amino] methylene ⁇ -4-bromobenzenesulfonamide (32) N- ⁇ Amino - [(pyridin-2-ylmethyl) amino] methylene ⁇ -3,4-dichlorobenzenesulfonamide (33)
• N- ⁇ Amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -4-iodobenzenesulfonamide (35) N- ⁇ Amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -benzenesulfonamide ( 36) Naphthalene-2-sulfonic acid amino - [(pyridin-2-ylmethyl) amino] methylene amide (37) N- [4 - ( ⁇ Amino - [(pyridin-2-ylmethyl) amino] methylene ⁇ - sulfamoyl) phenyl] acetamide (39)
• N- ⁇ Amino - [(pyridin-2-ylmethyl) amino] -methylene ⁇ -4-butyl-benzenesulfonamide (50) N- ⁇ Amino - [(furan-2-ylmethyl) -amino] -methylene ⁇ -4- butyl-benzenesulfonamide (52) • N- ⁇ amino - [(furan-2-ylmethyl) amino] methylene ⁇ -4-methyl-benzenesulfonamide (53)
• sulfonylguanidine used according to the invention is wholly or predominantly in the tautomeric form according to formula I.
• Another preferred subject matter of this application comprises sulfonylguanidines used according to the invention which are wholly or predominantly in the tautomeric form according to formula Ia.
• Another object of the invention are the sulfonylguanidines according to the general tautomeric formulas I and la,
• R is selected from Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl or bicyclic alkylene, each saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or via saturated or unsaturated Ci-4-alkyl, in particular C ⁇ . 3 alkyl; bound aryl, C3_g-cycloalkyl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
• R 2 is selected from Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or bound via saturated or unsaturated Ci-3-alkyl, S (O) 2 or NH
• Aryl, C3_g-cycloalkyl or heteroaryl in each case unsubstituted or mono- or polysubstituted; or
• R independently selected from H; C ⁇ 8 alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl, C3_9-cycloalkyl or via saturated or unsaturated C 3 alkyl
• Heteroaryl each unsubstituted or mono- or polysubstituted; or
• R 6 with R 6 selected from Cns-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl bonded via saturated or unsaturated Ci-3-alkyl, C3. g-cycloalkyl or heteroaryl, each unsubstituted or mono- or polysubstituted;
• R 4 and R 5 together: -CH2CH2OCH2CH2-; -CH 2 CH2N (R 7 ) CH 2 CH2- form with R 7 selected from C ⁇ -alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl, C3_g-cycloalkyl or heteroaryl bound via saturated or unsaturated C 3 alkyl, in each case unsubstituted or mono- or polysubstituted;
• R 3 is selected from H, Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or about saturated or unsaturated C 1 -C 3 -alkyl-bonded aryl, 03.9-
• R 8 selected from C ⁇ s-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl or bicyclic alkylene, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl bonded via saturated or unsaturated Ci-3-alkyl, C3. g-cycloalkyl or heteroaryl, each unsubstituted or mono- or polysubstituted;
• R 1 is selected from d- 10 alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -Cs cycloalkyl or bicyclic alkylene, each saturated or unsaturated, mono- or polysubstituted or unsubstituted; Phenyl, unsubstituted or mono- or polysubstituted;
• R 2 is selected from Cno-alkyl, branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; C 3 -C 8 cycloalkyl, saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each unsubstituted or mono- or polysubstituted; or aryl bound via saturated or unsaturated Ci-3-alkyl, 03.9-
• R 3 is selected from H or CH 3 .
• R 1 is selected from aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted;
• R 2 is selected from aryl or heteroaryl bonded via saturated or unsaturated Ci-3-alkyl, each unsubstituted or mono- or polysubstituted
• R 3 corresponds to hydrogen
• R2 is phenyl bonded via CH2 and R1 is phenyl substituted or unsubstituted with methyl or NH 2 - phenyl also with a condensed ring system.
• R 1 is selected from aryl or heteroaryl, unsubstituted or singly or repeatedly with NO 2 , NH 2 , F, Cl, Br, I, OH or SH; or-NHC (O) -C ⁇ _ 4 - alkyl, -C- alkyl, -OC ⁇ alkyl, -N (C ⁇ _ 4 alkyl), each with the C ⁇ - 4 alkyl group branched or unbranched, saturated or unsaturated , mono- or polysubstituted or unsubstituted;
• R 1 is selected from phenyl or naphthyl, in particular phenyl, unsubstituted or singly or repeatedly with F, Cl, Br, I, OH, NO 2) NH 2 ; 4 - alkyl, O-C ⁇ - 4 alkyl, in particular CH 3 , C 2 H 5 , i-propyl, t-butyl, methoxy, OCF 3 or ethoxy, each branched or unbranched, saturated or unsaturated, mono- or polysubstituted or unsubstituted; preferably meta or para, in particular para; substituted.
• R 2 is selected from heteroaryl bonded via saturated or unsaturated Ci-3-alkyl, in particular -CH 2 -, in each case unsubstituted or mono- or polysubstituted;
• R 2 is selected from pyridinyl, thiophenyl, furanyl or pyrimidinyl, preferably pyridinyl, bonded via saturated or unsaturated Ci-3-alkyl, in particular -CH 2 -, in each case unsubstituted or singly or multiply, preferably simply, in particular with F, Cl, Br , I, OH, N02, SH, NH2, C 4 alkyl, O 4 alkyl, preferably para, substituted.
• the sulfonylguanidines according to the invention are selected from the following group:
• N- ⁇ Amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -4-iodobenzenesulfonamide (35) N- ⁇ Amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -benzenesulfonamide ( 36) Naphthalen-2-sulfonic acid amino - [(pyridin-2-ylmethyl) amino] methylene amide (37) 1-methyl-1H-imidazole-4-sulfonic acid amino - [(pyridin-2-ylmethyl) amino ] - methylenamide (38)
• N- ⁇ amino - [(pyridin-2-ylmethyl) amino] -methylene ⁇ -4-fluoro-benzenesulfonamide (40) N- ⁇ amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -2, 4,6-trimethyl-benzenesulfonamide (41) N- ⁇ amino - [(pyridin-2-ylmethyl) amino] methylene ⁇ -4-propyl-benzenesulfonamide (42)
• the sulfonylguanidines according to the invention are selected from the following group:
• N- ⁇ Amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -4-iodobenzenesulfonamide (35) N- ⁇ Amino - [(pyridin-2-ylmethyl) -amino] -methylene ⁇ -benzenesulfonamide ( 36) Naphthalin-2-sulfonic acid amino - [(pyridin-2-ylmethyl) amino] methylenamide (37) 1-methyl-1 H-imidazole-4-sulfonic acid amino - [(pyridin-2-ylmethyl) - amino] - methylene amide (38)
• N- ⁇ Amino - [(furan-2-ylmethyl) amino] methylene ⁇ -4-chloro-benzenesulfonamide (63) optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; in the form shown or in the form of their acids or their bases; or in the form of their salts, in particular the physiologically tolerable salts, preferably the hydrochloride or sodium salt; or in the form of their solvates, in particular the hydrates; in both tautomeric forms according to formulas I and la, exclusively in one of the tautomeric forms according to formulas I or la or also in mixtures of both forms according to formulas I and la, the preferred tautomeric form of compound to compound depending, for example, on the state of matter or on the chosen one Solvent can vary.
• sulfonylguanidine according to the invention is wholly or predominantly in the tautomeric form according to formula I.
• Another preferred subject of this application comprises sulfonylguanidines according to the invention which are wholly or predominantly in the tautomeric form according to formula Ia.
• the sulfonylguanidines according to the invention are toxicologically harmless, so that they are suitable as active pharmaceutical ingredients in pharmaceuticals.
• the invention therefore furthermore relates to medicaments comprising at least one sulfonylguanidine according to the invention, and, if appropriate, suitable additives and / or auxiliaries and / or optionally further active compounds.
• the invention therefore furthermore relates to medicaments comprising at least one of the sulfonylguanidines used according to the invention, and, if appropriate, suitable additives and / or auxiliaries and / or if appropriate further active compounds.
• the medicaments according to the invention optionally contain suitable additives and / or auxiliaries, including also carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be in the form of liquid dosage forms in the form of injection solutions, drops or juices , can be administered as semi-solid pharmaceutical forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of excipients etc.
• the amounts to be used depend on whether the medicinal product is orally, orally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on the skin, mucous membranes or in the eyes to be applied.
• Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
• Sulfonylguanidines according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of skin penetration-promoting agents Appropriate percutaneous application preparations.
• Formulations which can be used orally or percutaneously can release the sulfonylguanidines used according to the invention with a delay.
• other active substances known to the person skilled in the art can be added to the medicaments according to the invention.
• the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease. Usually 0.005 to 1000 mg / kg, preferably 0.05 to 5 mg / kg, of at least one sulfonylguanidine according to the invention used.
• a sulfonylguanidine according to the invention contained as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers and / or exclusively in one of the tautomeric forms according to formulas I or la or in mixtures of both forms according to formulas I and la.
• Another object of the invention is the use of a sulfonylguanidine according to the invention according to general tautomeric formulas I and Ia for the manufacture of a medicament for the treatment of pain, in particular neuropathic, chronic or acute pain, epilepsy and / or migraine
• hyperalgesia and allodynia for the manufacture of a medicament for the treatment of hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold allodynia, or of inflammatory or postoperative pain
• ALS amyotropic lateral sclerosis
• RSD reflex sympasthetic dystrophy
• spastic paralysis restless leg syndrome
• acquired nystagmus acquired nystagmus
• a sulfonylguanidine used as a pure diastereomer and / or enantiomer as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers and / or exclusively in one of the tautomeric forms according to formulas I or la or in mixtures of both forms according to formulas I and la.
• Another object of the invention is a method for the treatment of a non-human mammal or human being which needs treatment of medically relevant symptoms by administration of a therapeutically viable dose of a sulfonylguanidine or a medicament according to the invention or a medicament according to the invention.
• the invention relates in particular to corresponding methods for the treatment of pain, in particular neuropathic, chronic or acute pain; Migraines, hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold allodynia, or of inflammatory or postoperative pain; Epilepsy, hot flashes, postmenopausal complaints, amyotropic lateral sclerosis (ALS), reflex sympasthetic dystrophy (RSD), spastic paralysis, restless leg syndrome, acquired nystagmus; psychiatric or neuropathological disorders, such as bipolar disorders, Anxiety, panic attacks, mood swings, manic behavior, depression, manic-depressive behavior; painful diabetic neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's disease, neurodegenerative diseases such as Alzheimer's disease, Huntington 's disease, Parkinson's disease and epilepsy; of erythromelalgic or post-poliomyelitic pain, trigeminal or
• Another object of the invention is a method for producing a sulfonylguanidine according to the invention as set out in the following description and examples.
• the compounds of the invention are synthesized by reacting pyrrazolesulfonamides of the general formula II, which are synthesized by processes known from the literature (Larock 2nd edition), with a wide variety of primary or secondary amines in the presence of methanesulfonic acid.
• R 1 to R 3 have the meaning given above for compounds of the formula I.
• the reactions are preferably carried out in acetonitrile at a bath temperature of preferably 0 ° C. to 110 ° C., in particular at a bath temperature of 100 ° C. to 110 ° C.
• the compounds of formula I can be combined with physiologically compatible acids, preferably hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, Convert fumaric acid, lactic acid, citric acid, glutamic acid and / or aspartic acid and especially hydrochloric acid into their salts in a manner known per se.
• Salt formation is preferably carried out in a solvent, preferably diethyl ether, diisopropyl ether, alkyl acetate, acetone or 2-butanone or a mixture of these solvents.
• trimethylsilane in aqueous solution is also suitable for the production of the hydrochloride.
• the compounds of formula I can be combined with physiologically acceptable acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2 -dihydro1 ⁇ 6 -benzo [ ⁇ ] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl -benzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid, convert into their salts in a known manner.
• physiologically acceptable acids for example
• Salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetate, acetone and / or 2-butanone or else water.
• a solvent for example diethyl ether, diisopropyl ether, alkyl acetate, acetone and / or 2-butanone or else water.
• Trimethylchlorosilane in aqueous solution is also suitable for the preparation of the hydrochlorides.
• Fig. 1- Fig. 40 show further connections produced according to the following processes, in particular according to the basic process 1 Example 0, which are shown in the figures as structural formulas. These examples are compounds according to the invention and / or compounds which can be used according to the invention due to their structure of action. Examples
• the analysis was carried out using ESI mass spectrometry or HPLC.
• a round-bottom tube made of glass (diameter 16 mm, length 125 mm) with thread was manually provided with a stirrer and closed with a screw cap with a septum on the capper station (see block diagram).
• Robot 1 placed the tube in the stirring block, which was heated to 110 ° C.
• Robot 2 pipetted the following reagents one after the other:
• the reaction mixture was stirred at 110 ° C in one of the stirring blocks for 45 hours.
• the reaction solution was then filtered off at the filtration station.
• the tube was rinsed twice with 1.5 ml dichloromethane and 1.5 ml water.
• the rack with the samples was placed manually on the processing plant.
• the reaction mixture was shaken for 30 minutes.
• the centrifuge was briefly centrifuged to form the phase boundary.
• the phase boundary was detected optically and the organic phase was pipetted off.
• the aqueous phase was again mixed with 1.5 ml of dichloromethane, shaken, centrifuged and the organic phase was pipetted off.
• the combined organic phases were dried over 2.4 g of MgSO4 (granulated).
• the solvent was removed in a vacuum centrifuge.
• Each sample was analyzed with ESI-MS and / or NMR.
• Example 1 The automated synthesis ensures that all samples are treated equally and that the reaction is carried out extremely consistently.
• Example 1 The automated synthesis ensures that all samples are treated equally and that the reaction is carried out extremely consistently.
• Example 1 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml 2-picolylamine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 2 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml of benzylamine solution (1.0 M, acetonitrile) is shown in a substance library.
• Example 3 was according to the attached synthesis instructions from 0.5 ml of N - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml Morpholine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 4 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml cyclohexylamine solution (1.0 M, acetonitrile) is shown in a substance library.
• Example 5 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml aniline solution (1.0 M, acetonitrile) presented in a substance library.
• Example 6 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml of 4-methoxybenzylamine solution (1.0 M, acetonitrile) is shown in a substance library.
• Example 7 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml 2-naphthylamine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 8 was according to the attached synthesis instructions from 0.5 ml of N - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml N-Amino-4-methylpiperazine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 9 was according to the attached synthesis instructions from 0.5 ml of A / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-hydrazinopyridine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 10 was according to the attached synthesis instructions from 0.5 ml of A - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml nPropylamine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 11 was made according to the attached synthesis instructions from 0.5 ml of A / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml t? butylamine solution (1.0 M, acetonitrile) is shown in a substance library.
• Example 12 was made according to the attached synthesis instructions from 0.5 ml of A - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml Piperidine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 13 was prepared from 0.5 ml of ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, Acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml N-methylaniline solution (1.0 M, acetonitrile) in a substance library.
• Example 14 was according to the attached synthesis instructions from 0.5 ml ⁇ - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml Phenethylamine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 15 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml sButylamine solution (1.0 M, acetonitrile) is shown in a substance library.
• Example 16 was according to the attached synthesis instructions from 0.5 ml ml / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml of tosylhydrazide solution (1.0 M, acetonitrile) is shown in a substance library.
• Example 17 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml 2-aminopyrazole solution (1.0 M, acetonitrile) presented in a substance library.
• Example 18 was according to the attached synthesis instructions from 0.5 ml ⁇ - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml Pyrrolidine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 19 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml 1-naphthylamine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 20 was according to the attached synthesis instructions from 0.5 ml of A - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml ⁇ / -Aminomorpholine solution (1.0 M, acetonitrile) shown in a substance library. Calculated mass 298.11; mass found (M + H) 299.3; 597.1 (dimer)
• Example 21 was according to the attached synthesis instructions from 0.5 ml of N - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-chlorobenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml 2-picolylamine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 22 was prepared from 0.5 ml of N - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-chlorobenzoisulfonamide solution (0.2 M, Acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml 4-picolylamine solution (1.0 M, acetonitrile) in a substance library.
• Example 23 was according to the attached synthesis instructions from 0.5 ml of N - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-chlorobenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml 3-Picolylamine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 24 was made according to the attached synthesis instructions from 0.5 ml of N - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-methylbenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml 3-aminopyridine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 25 was made according to the attached synthesis instructions from 0.5 ml of A / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-chlorobenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml pyrrolidine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 26 was made according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -benzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml pyrrolidine Solution (1.0 M, acetonitrile) is shown in a substance library.
• Example 27 was made according to the attached synthesis instructions from 0.5 ml of N - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -2-nitrobenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml Pyrrolidine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 28 was according to the attached synthesis instructions from 0.5 ml ⁇ / - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -4-chlorobenzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml ⁇ / aminomorpholine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 29 was according to the attached synthesis instructions from 0.5 ml / V - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -benzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml ⁇ -Aminomorpholine solution (1.0 M, acetonitrile) presented in a substance library. Calculated mass 284.34; mass found (M + H) 285.3; 569.1 (dimer)
• Example 30 was according to the attached synthesis instructions from 0.5 ml ⁇ - [(3,5-dimethyl-pyrazol-1-yl) -imino-methyl] -naphthol-1-sulfonamide solution (0.2 M, acetonitrile) with 19 mg methanesulfonic acid and 0.5 ml / V-aminomorpholine solution (1.0 M, acetonitrile) presented in a substance library.
• Example 36 Example 36
• the binding assay uses gabapentin to test the binding and affinities of the selected compounds.
• the affinity of the compounds according to the invention is measured by the displacement of gabapentin from its binding site. If the selected compounds can displace gabapentin from its binding site, it can be expected that they will have pharmacological properties comparable to gabapentin e.g. as an agent against pain or epilepsy.
• the compounds of the invention show good inhibition of gabapentin in this assay. In this biochemical assay, the investigated compounds therefore have an affinity for the previously unknown gabapentin binding site.
• na means insufficient measurement signal.
• ED50 or% maximum possible effect (% MPE;% of the maximum possible effect) on the ipsilateral side, assuming the baseline as 0% and the withdrawal threshold of a control group as 100% MPE.
• the substance according to Example 1 showed a 50% effect at 25 mg / kg, which corresponds approximately to the ED50 and gabapentin showed an ED50 of 92.6 mg / kg. Both substances worked for at least 30 hours.
• the substance according to example 1 gabapentin is thus superior in this model by a factor of 4.
• Example 1 and Example 21 also show an effect in the chung. Both substances work for at least 30 h and are superior to gabapentin (ED 50 92.6 mg / kg).
• the early phase is a model for acute pain in direct response to formalin injection, while the late phase is considered a model for persistent (chronic) pain (TJ. Coderre et al, Pain, Vol. 52, pp. 259-285 (1993)).
• the compounds according to the invention were examined in the second phase of the formalin test in order to obtain information about the effects of substances in chronic / inflammatory pain.
• a single subcutaneous formalin injection (20 ⁇ l, 1% aqueous solution) into the dorsal side of the right hind paw induced a nociceptive reaction in free-moving test animals, which manifests itself in marked licking and biting of the affected paw.
• the substance effect in the formalin test was determined as a change in the control in percent.
• the ED5g calculations were carried out using regression analysis.
• the time of application before the formalin injection was chosen (intraperitoneal: 15 min, intravenous: 5 min).
• Example 21 showed an inhibition of formalin-induced nociception.
• the corresponding results in the formalin test on the mouse are shown in Table 2 below.
• Gabapentin shows an ED50 value of 79 mg / kg (IV).
• Table 3 Analgesia test in the formalin test mouse

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