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US20030225084A1 - Sulfonylguanidine compounds and pharmaceutical uses thereof - Google Patents

Sulfonylguanidine compounds and pharmaceutical uses thereof Download PDF

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Publication number
US20030225084A1
US20030225084A1 US10/402,382 US40238203A US2003225084A1 US 20030225084 A1 US20030225084 A1 US 20030225084A1 US 40238203 A US40238203 A US 40238203A US 2003225084 A1 US2003225084 A1 US 2003225084A1
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Prior art keywords
amino
methylene
methyl
pyridin
singly
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US10/402,382
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English (en)
Inventor
Matthias Gerlach
Heinz Uragg
Michael Haurand
Claudia Puetz
Corinna Maul
Boris Chizh
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority claimed from DE10048716A external-priority patent/DE10048716A1/de
Priority claimed from DE10112068A external-priority patent/DE10112068A1/de
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Assigned to GRUENENTHAL GMBH reassignment GRUENENTHAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: URAGG, HEINZ, GERLACH, MATTHIAS, PUETZ, CLAUDIA KATHARINA, HAURAND, MICHAEL, MAUL, CORINNA, CHIZH, BORIS
Publication of US20030225084A1 publication Critical patent/US20030225084A1/en
Priority to US11/742,946 priority Critical patent/US7671074B2/en
Abandoned legal-status Critical Current

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    • C07D213/02—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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
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    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/64—X and Y being nitrogen atoms, e.g. N-sulfonylguanidine
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    • C07D213/02—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
    • 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
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D213/02—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
    • 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
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
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    • 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
    • C07D231/14—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
    • C07D231/38—Nitrogen 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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    • C07D295/00—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
    • C07D295/22—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
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • 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
    • C07D333/06—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 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to sulfonylguanidine compounds, processes for their production, pharmaceutical compositions containing these compounds, and the use of sulfonylguanidines for the production of medicaments and for treating pain and other medical conditions.
  • the cyclic GABA analogue gabapentin is a clinically proven antiepileptic. Gabapentin additionally exhibits further interesting, medically relevant properties, in particular as an analgesic. New classes of structures that have an affinity for the gabapentin binding site are therefore of interest. In connection with the aforementioned medical indications there is a further need of substances that are similar in their properties to gabapentin, for example as regards analgesic effect.
  • Conventional opioids such as morphine are highly effective in treating severe to extremely severe pain. Their use is however limited by the known side effects such as for example respiratory depression, vomiting, sedation, constipation and development of tolerance. Also, they are less effective in treating neuropathic or incidental pain afflicting in particular tumor patients.
  • An object of the invention was accordingly to provide new methods of treating pain and other medical conditions.
  • Another object of the invention was to provide new compounds that have an affinity for the gabapentin binding site and/or corresponding physiological activities, for example with regard to analgesia, but also other GBP indications.
  • the present invention accordingly provides for the use of a sulfonylguanidine according to the general tautomeric formulas I and Ia,
  • R 1 is selected from C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl or bicyclic alkylene, in each case saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 2 is selected from C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, S(O) 2 or NH, in each case unsubstituted or singly or multiply substituted; or NR 4 R 5 ,
  • R 4 , R 5 independently of one another are selected from H; C 1-8 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted; or SO 2 R 6 ,
  • R 6 is selected from C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 4 and R 5 together form: —CH 2 CH 2 OCH 2 CH 2 —;
  • R 7 is selected from C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 3 is selected from H, C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted; or
  • R 8 is selected from C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl or bicyclic alkylene that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • hyperalgesia and allodynia for the production of a medicament and for the treatment of hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold-induced allodynia, or inflammatory or post-operative pain, or
  • ALS amyotropic lateral sclerosis
  • RSD reflex sympathetic dystrophy
  • spastic paralysis restless leg syndrome
  • acquired nystagmus psychiatric or neuropathological disorders such as bipolar disorders, anxiety, panic attacks, mood fluctuations, 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; gastrointestinal lesions; erythromelalgic or post-poliomyelitic pain, trigeminal or post-herpetic neuralgia; or as an anticonvulsant, analgesic or anxiolytic.
  • R 1 is selected from C 11 -oalkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl or bicyclic alkylene, in each case saturated or unsaturated, singly or multiply substituted or unsubstituted; phenyl that is unsubstituted or singly or multiply substituted.
  • R 2 is selected from C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted.
  • R 3 is selected from H or CH 3 .
  • R 1 is selected from C 3-8 -cycloalkyl or bicyclic alkylene, in each case saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-8 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-4 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 2 is selected from C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted; and
  • R 3 is selected from H, C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted.
  • alkyl radicals and cycloalkyl radicals are understood to be saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons that may be unsubstituted or singly or multiply substituted.
  • C 1-2 -alkyl denotes C1- or C2-alkyl
  • C 1-3 -alkyl denotes C1-, C2- or C3-alkyl
  • C 1-4 -alkyl denotes Cl-, C2-, C3- or C4-alkyl
  • C 1-5 -alkyl denotes C1-, C2-, C3-, C4 or C5-alkyl
  • C 1-6 -alkyl denotes C1-, C2-, C3-, C4-, C5- or C6-alkyl
  • C 1-7 -alkyl denotes C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • C 1-8 -alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7 or C8-alkyl
  • C 1-10 -alkyl denotes C1-, C2-, C
  • C 3-4 -cycloalkyl denotes C3- or C4-cycloalkyl
  • C 3-5 -cycloalkyl denotes C3-, C4- or C5-cycloalkyl
  • C 3-6 -cycloalkyl denotes C3-, C4-, C5- or C6-cycloalkyl
  • C 3,7 -cycloalkyl denotes C3-, C4-, C5-, C6- or C7-cycloalkyl
  • C 3-8 -cycloalkyl denotes C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl
  • C 4-5 -cycloalkyl denotes C4- or C5-cycloalkyl
  • cycloalkyl also includes saturated cycloalkyls in which 1 or 2 carbon atoms are replaced by a heteroatom, i.e. S, N or O.
  • cycloalkyl however also includes in particular singly or multiply, preferably singly, unsaturated cycloalkyls without a heteroatom in the ring as long as the cycloalkyl does not form an aromatic system.
  • the alkyl or 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, but also adamantyl, CHF 2 , CF 3 or CH 2 OH as well as pyrazolinone, oxopyrazolinone, [1,4]dioxan
  • substituted within the context of the present invention denotes—unless expressly defined otherwise—the substitution of at least one (optionally also several) hydrogen atom(s) by F, Cl, Br, I, NH 2 , SH or OH, wherein the terms “multiply substituted” and “substituted” in the case of multiple substitution denote that the substitution takes place on different as well as on the same atoms multiply with the same or different substituents, for example triple substitution on the same C atom as in the case of CF 3 , or at different positions as in the case of —CH(OH)—CH ⁇ CH—CHCl 2 .
  • substituents in this connection are F, Cl and OH.
  • the hydrogen atom may also be replaced by OC 1-3 -alkyl or C 1-3 -alkyl (in each case singly or multiply substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
  • (CH 2 ) 3-6 is understood to denote —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 —
  • the term (CH 2 ) 1-4 is understood to denote —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —
  • the term (CH 2 ) 4-5 is understood to denote —CH 2 —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, etc.
  • aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indenyl, in particular 9H-fluorenyl or anthracenyl radicals, which may be unsubstituted or singly or multiply substituted.
  • heteroaryl radical is understood to mean heterocyclic ring systems with at least one unsaturated ring that may contain one or more heteroatoms from the group comprising nitrogen, oxygen and/or sulfur, and which may also be singly or multiply substituted.
  • groups of heteroaryls that may be mentioned include furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.
  • substituted is understood to mean the substitution of the aryl or heteroaryl group by R 23 , OR 23 , a halogen, preferably F and/or Cl, a CF 3 , a CN, an NO 2 , an NR 24 R 25 , a C 1-6 -alkyl (saturated), a C 1-6 -alkoxy, a C 3-8 -cycloalkoxy, a C 3-8 -cycloalkyl or a C 2-6 -alkylene.
  • the radical R 23 denotes H, a C 1-10 -alkyl, preferably a C 1-6 -alkyl, an aryl or heteroaryl radical, or an aryl or heteroaryl radical bonded via C 1-3 -alkyl that is saturated or unsaturated, or a C 1-3 -alkylene group, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals;
  • the radicals R 24 and R 25 which may be identical or different, denote H, a C 1-10 -alkyl, preferably a C 1-6 -alkyl, an aryl, a heteroaryl radical, or an aryl or heteroaryl radical bonded via a C 1-3 -alkyl that is saturated or unsaturated, or a C 1-3 -alkylene group, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals, or the radicals
  • the term salt is understood to mean any form of the active constituent according to the invention in which this adopts an ionic form or is charged and is coupled to a counterion (a cation or anion), and is present in solution.
  • the term is also understood to include complexes of the active constituent with other molecules and ions, in particular complexes that are complexed via ionic interactions.
  • physiologically compatible salts with cations or bases is understood within the context of the present invention to mean salts of at least one of the compounds according to the invention—generally of a (deprotonated) acid—as an anion with at least one, preferably inorganic cation, that are physiological compatible, especially when used in humans and/or mammals.
  • Particularly preferred are the salts of alkali and alkaline earth metals, but also with NH 4 + , and in particular (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
  • physiologically compatible salt with anions or acids is understood within the context of the present invention to mean salts of at least one of the compounds according to the invention—generally protonated, for example on the nitrogen atom—as a cation with at least one anion, that are physiologically compatible, especially when used in humans and/or mammals.
  • the term is particularly understood to denote the salt formed with a physiologically compatible acid, namely salts of the respective active constituent with inorganic or organic acids, that are physiologically compatible, especially when used in humans and/or mammals.
  • physiologically compatible salts of specific 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-dihydro 16-benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxoproline, hexane-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.
  • the hydrochloride salt is particularly preferred.
  • the compounds according to the invention not only displace gabapentin from its binding site but—like gabapentin—also have a marked analgesic effect. Accordingly, the invention provides for the use of the aforementioned and defined sulfonylguanidines in the previously mentioned medical indications in which gabapentin is active, i.e. in particular in the treatment of pain, epilepsy or migraine, but specifically also in neuropathic pain including hyperalgesia and allodynia, and other conditions for which the use of gabapentin is indicated.
  • Gabapentin is a known antiepileptic having an anticonvulsive action.
  • gabapentin is also used in various other medical conditions, and inter alia is prescribed by physicians for the treatment of migraine and bipolar disorders as well as hot flashes (e.g. in the post menopause) (M. Schrope, Modern Drug Discovery, September 2000, p. 11).
  • Other medical conditions in which gabapentin exhibits a therapeutic potential have been identified in human studies and in clinical practice (J. S. Bryans, D. J. Wustrow; “3-Substituted GABA Analogs with Central Nervous System Activity: A Review” in Med. Res. Rev. (1999), pp. 149-177).
  • gabapentin is listed in detail in this review article.
  • gabapentin is effective in the treatment of chronic pain and behavioral disturbances.
  • the following properties of gabapentin are listed: anticonvulsive and antiepileptic actions, the use to treat chronic, neuropathic pain, in particular thermal hyperalgesia, mechanical allodynia, and cold-induced allodynia.
  • gabapentin is effective against neuropathy triggered by nerve damage, and in particular is also successful in treating neuropathic pain as well as inflammatory and post-operative pain.
  • Gabapentin is also useful as an antipsychotic agent, in particular as an anxiolytic.
  • ALS amyotrophic lateral sclerosis
  • RSD reflex sympathetic dystrophy
  • spastic palsy restless leg syndrome
  • treatment of symptoms and pain caused by multiple sclerosis acquired nystagmus
  • treatment of the symptoms of Parkinson's disease painful diabetic neuropathy and psychiatric disorders, for example bipolar disorders, mood fluctuations, manic behavior.
  • Gabapentin has also been successfully used to treat erythromelalgic pain, post-poliomyelitic pain, trigeminal neuralgia and post-herpetic neuralgia (Bryans and Wustrow (1999), etc.).
  • neurodegenerative conditions include for example Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy.
  • Such neurodegenerative conditions include for example Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy.
  • the effectiveness of gabapentin in gastrointestinal disorders is also known.
  • R 1 is selected from aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl or heteroaryl bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 1 is selected from aryl or heteroaryl that is unsubstituted or singly or multiply substituted, preferably with NO 2 , NH 2 , F, Cl, Br, I, OH or SH; or —NHC(O)—C 1-4 -alkyl, —C 1-4 -alkyl, —OC 1-4 -alkyl, —N(C 1-4 -alkyl) 2 ,
  • C 1-4 -alkyl group is in each case branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted;
  • R 1 is selected from phenyl or naphthyl, especially phenyl, that is unsubstituted or singly or multiply substituted, preferably by F, Cl, Br, I, OH, NO 2 , NH 2 ; C 1-4 -alkyl, O—C 1-4 -alkyl, in particular CH 3 , C 2 H 5 , tert.-butyl, i-propyl, methoxy, OCF 3 or ethoxy, in each case branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; preferably substituted in the meta or para position and in particular in the para position.
  • R 2 is selected from aryl or heteroaryl bonded via saturated or unsaturated C 1-3 -alkyl, in particular CH 2 , in each case unsubstituted or singly or multiply substituted;
  • R 2 is selected from heteroaryl bonded via saturated or unsaturated C 1-3 -alkyl, in particular —CH 2 —, in each case unsubstituted or singly or multiply substituted;
  • R 2 is selected from pyridinyl, thiophenyl, furanyl or pyrimidinyl, preferably pyridinyl, bonded via saturated or unsaturated C 1-3 -alkyl, in particular —CH 2 —, in each case unsubstituted or singly or multiply, preferably singly substituted, in particular by F, Cl, Br, I, OH, NO 2 , SH, NH 2 , C 1-4 -alkyl, O—C 1-4 -alkyl, preferably substituted in the para position.
  • R 3 is selected from H or C 1-4 -alkyl, preferably H or CH 3 , in particular H.
  • the sulfonylguanidines employed are selected from the group consisting of:
  • Preferred compounds according to the invention are selected from the group consisting of:
  • the present invention preferably also provides sulfonylguanidines used according to the invention that are present entirely or substantially entirely in the tautomeric form according to formula Ia.
  • the invention moreover provides the sulfonylguanidines according to the general tautomeric formulas I and Ia,
  • R 1 is selected from C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl or bicyclic alkylene, in each case saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-4 -alkyl, in particular C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 2 is selected from C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, S(O) 2 or NH, in each case unsubstituted or singly or multiply substituted; or NR 4 R 5 ,
  • R 4 , R 5 independently of one another are selected from H; C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted;
  • aryl or heteroaryl in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted; or SO 2 R 6 ,
  • R 6 is selected from C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 4 and R 5 together form —CH 2 CH 2 OCH 2 CH 2 —;
  • R 7 is selected from C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 3 is selected from H, C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted;
  • R 8 is selected from C 1-18 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl or bicyclic alkylene that is saturated or
  • R 1 is selected from C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl or bicyclic alkylene, in each case saturated or unsaturated, singly or multiply substituted or unsubstituted; phenyl that is unsubstituted or singly or multiply substituted.
  • R 2 is selectd from C 1-10 -alkyl that is branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; C 3-8 -cycloalkyl that is saturated or unsaturated, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; or aryl, C 3-9 -cycloalkyl or heteroaryl, bonded via saturated or unsaturated C 1-3 -alkyl, in each case unsubstituted or singly or multiply substituted,
  • R 3 is selected from H or CH 3 .
  • R 1 is selected from aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted;
  • R 2 is selected from aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted and bonded via saturated or unsaturated C 1-3 -alkyl, and
  • R 3 is hydrogen, with the exception of compounds in which R 2 denotes phenyl bonded via CH 2 and R 1 denotes phenyl substituted or
  • R 1 is selected from aryl or heteroaryl that is unsubstituted or singly or multiply substituted with NO 2 , NH 2 , F, Cl, Br, I, OH or SH; or —NHC(O)—C 1-4 -alkyl, —C 1-4 -alkyl, —OC 1-4 -alkyl, —N(C 1-4 -alkyl) 2 , where the C 1-4 -alkyl group is in each case branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted;
  • R 1 is selected from phenyl or naphthyl, in particular phenyl, that is unsubstituted or singly or multiply substituted by F, Cl, Br, I, OH, NO 2 , NH 2 ; C 1-4 -alkyl, O-C 1-4 -alkyl, in particular CH 3 , C 2 H 5 , i-propyl, tert.-butyl, methoxy, OCF 3 or ethoxy, in each case branched or unbranched, saturated or unsaturated, singly or multiply substituted or unsubstituted; preferably substituted in the meta or para position and in particular in the para position.
  • R 2 is selected from heteroaryl bonded via saturated or unsaturated C 1-3 -alkyl, in particular —CH 2 —, in each case unsubstituted or singly or multiply substituted;
  • R 2 is selected from pyridinyl, thiophenyl, furanyl or pyrimidinyl, preferably pyridinyl, bonded via saturated or unsaturated C 1-3 -alkyl, in particular —CH 2 —, in each case unsubstituted or singly or multiply, preferably singly substituted, in particular by F, Cl, Br, I, OH, NO 2 , SH, NH 2 , C 1-4 -alkyl, O—C 1-4 -alkyl, preferably substituted in the para position.
  • the sulfonylguanidines according to the invention are selected from the following group:
  • sulfonylguanidines according to the invention are selected from the following group:
  • the present invention similarly preferably provides sulfonylguanidines according to the invention that are present invention entirely or substantially entirely in the tautomeric form according to formula Ia.
  • the sulfonylguanidines according to the invention are toxicologically harmless, with the result that they are suitable as a pharmaceutically active constituent in medicaments.
  • the invention furthermore also provides medicaments containing at least one of the sulfonylguanidines used according to the invention, as well as optionally suitable additives and/or auxiliary substances and/or optionally further active constituents.
  • compositions according to the invention contain in addition to at least one sulfonylguanidine according to the invention or used according to the invention, optionally suitable additives and/or auxiliary substances, i.e. also carrier materials, fillers, solvents, diluents, colourants and/or binders, and may be administered as liquid medicament forms in the form of injection solutions, droplets or juices, or as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • suitable additives and/or auxiliary substances i.e. also carrier materials, fillers, solvents, diluents, colourants and/or binders
  • auxiliary substances etc., as well as the amounts thereof to be used depend on whether the medicament is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes.
  • preparations in the form of tablets, sugar-coated pills, capsules, granules, drops, juices and syrups are suitable, while for parenteral, topical and inhalative application, solutions, suspensions, readily reconstitutable dry preparations as well as sprays are suitable.
  • Sulfonylguanidines according to the invention in a depôt form, in dissolved form or in a plaster, optionally with the addition of agents promoting skin penetration are suitable percutaneous application preparations.
  • Orally or percutaneously usable preparation forms may provide for a delayed release of the sulfonylguanidines according to the invention used according to the invention.
  • further active constituents known to the person skilled in the art may be added to the medicaments according to the invention.
  • the amount of active constituent to be administered to the patient varies depending on the patient's weight, type of application, medical indication and the severity of the condition. Normally 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg of at least one sulfonylguanidine according to the invention used according to the invention are applied.
  • a contained sulfonylguanidine according to the invention used according to the invention is present 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 Ia or also in mixtures of both forms according to formulas I and Ia.
  • the invention moreover provides for the use of a sulfonylguanidine according to the invention of the general tautomeric formulas I and Ia for the production of a medicament for treating pain, in particular neuropathic, chronic or acute pain, epilepsy and/or migraine, or for the production of a medicament for the treatment of hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold-induced allodynia, or inflammatory or post-operative pain, or
  • a medicament for the treatment of hot flashes post-menopausal symptoms, amyotropic lateral sclerosis (ALS), reflex sympathetic dystrophy (RSD), spastic paralysis, restless leg syndrome, acquired nystagmus; psychiatric or neuropathological disorders such as bipolar disorders, anxiety, panic attacks, mood fluctuations, 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; gastrointestinal lesions; erythromelalgic or post-poliomyelitic pain, trigeminal or post-herpetic neuralgia; or
  • the sulfonylguanidine that is used is present 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 Ia or also in mixtures of both forms according to formulas I and Ia.
  • the invention additionally provides a process for treating a person or non-human mammal that requires treatment of medically relevant symptoms by administration of a therapeutically effective dose of a sulfonylguanidine according to the invention or used according to the invention, or of a medicament according to the invention.
  • the invention relates in particular to suitable processes for treating pain, in particular neuropathic, chronic or acute pain, including migraine, hyperalgesia and allodynia, especially thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold-induced allodynia, or for treating inflammatory or post-operative pain, epilepsy, hot flashes, post-menopausal symptoms, amyotropic lateral sclerosis (ALS), reflex sympathetic dystrophy (RSD), spastic paralysis, restless leg syndrome, acquired nystagmus; psychiatric or neuropathological disorders such as bipolar disorders, anxiety, panic attacks, mood fluctuations, 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; erythromelalgic or post-poliomyelitic pain, trigeminal or post-herpetic neuralgi
  • the present invention moreover provides a process for the preparation of a sulfonylguanidine according to the invention as illustrated in the following description and examples.
  • 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 the formula I may also be converted in a manner known per se into their salts with physiologically compatible acids, preferably 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 and/or aspartic acid and in particular hydrochloric acid.
  • the salt formation is preferably carried out in a solvent, preferably diethyl ether, diisopropyl ether, acetic acid alkyl esters, acetone or 2-butanone, or a mixture of these solvents.
  • a solvent preferably diethyl ether, diisopropyl ether, acetic acid alkyl esters, acetone or 2-butanone, or a mixture of these solvents.
  • trimethylsilane in aqueous solution is also suitable for the production of the hydrochlorides.
  • the compounds of the formula I can be converted into their salts in a known manner with physiologically compatible 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[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, a-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
  • physiologically compatible acids for example hydrochloric acid, hydro
  • the salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl esters of acetic acid, acetone and/or 2-butanone or also water.
  • a solvent for example diethyl ether, diisopropyl ether, alkyl esters of acetic acid, acetone and/or 2-butanone or also water.
  • trimethylchlorosilane in aqueous solution is moreover suitable.
  • FIGS. 1 - 40 show further compounds produced according to the following processes, in particular according to the basic process 1, Example 0, which are shown as structural formulas in the figures.
  • the compounds are compounds according to the invention and/or compounds that can be used according to the invention on account of their action structure.
  • a small round-bottomed threaded glass tube (diameter 16 mm, length 125 mm) was provided manually with a stirrer and sealed on the Capper station (see block diagram) with a screw cap with septum. The tube was placed by the robot 1 in the stirrer block kept at 110° C. The robot 2 pipetted in the following reagents in succession:
  • reaction mixture was stirred for 45 hours at 110° C. in one of the stirrer blocks.
  • the reaction solution was then filtered out at the filtration station.
  • the test tube was then rinsed twice, once with 1.5 ml of dichloromethane and once with 1.5 ml of water.
  • Example II The compound of Example I was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-picolylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 304.37; found mol. wt. (M+H) 305.2; 609.0 (Dimer)
  • Example 2 The compound of Example 2 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-benzylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 303.38; found mol. wt. (M+H) 304.4; 607.9 (Dimer)
  • Example 3 The compound of Example 3 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of morpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 283.35; found mol. wt. (M+H) 284.1
  • Example 4 The compound of Example 4 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of cyclohexylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 295.40; found mol. wt. (M+H) 296.1; 591.5 (Dimer)
  • Example 5 The compound of Example 5 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of aniline solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 289.35; found mol. wt. (M+H) 290.2; 579.0 (Dimer)
  • Example 6 The compound of Example 6 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 4-methoxybenzylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 333.41; found mol. wt. (M+H) 334.2; 667.0 (Dimer)
  • Example 7 The compound of Example 7 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-naphthylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 339.41; found mol. wt. (M+H) 340.3; 679.1 (Dimer)
  • Example 8 The compound of Example 8 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-amino-4-methylpiperazine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 311.40; found mol. wt. (M+H) 312.2; 623.0 (Dimer)
  • Example 10 The compound of Example 10 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of n-propylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 255.34; found mol. wt. (M+H) 256.2; 511.0 (Dimer)
  • Example 11 The compound of Example 11 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of n-butylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 269.36; found mol. wt. (M+H) 270.3; 539.1 (Dimer)
  • Example 12 The compound of Example 12 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of piperidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 281.37; found mol. wt. (M+H) 282.2; 562.9 (Dimer)
  • Example 13 The compound of Example 13 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-methylaniline solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 303.38; found mol. wt. (M+H) 304.2
  • Example 14 The compound of Example 14 was prepared according to the accompanying synthesis procedure from 0 . 5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of phenethylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 317.41; found mol. wt. (M+H) 318.3; 635.1 (Dimer)
  • Example 15 The compound of Example 15 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]- 4 -methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of s-butylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 269.36; found mol. wt. (M+H) 270.2; 539.1 (Dimer)
  • Example 16 The compound of Example 16 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of tosylhydrazide solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 382.46; found mol. wt. (M+H) 383.2; 764.9 (Dimer)
  • Example 17 The compound of Example 17 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-aminopyrazole solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 279.32; found mol. wt. (M+H) 280.3; 559.0 (Dimer)
  • Example 18 The compound of Example 18 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 267.35; found mol. wt. (M+H) 268.2; 534.9 (Dimer)
  • Example 19 The compound of Example 19 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 1-naphthylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 339.41; found mol. wt. (M+H) 340.3; 679.1 (Dimer)
  • Example 20 The compound of Example 20 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 298.11; found mol. wt. (M+H) 299.3; 597.1 (Dimer)
  • Example 21 The compound of Example 21 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 2-picolylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 327.79; found mol. wt. (M+H) 328.3; 655.6 (Dimer)
  • Example 22 The compound of Example 22 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 4-picolylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 304.37; found mol. wt. (M+H) 305.2; 609.1 (Dimer)
  • Example 23 The compound of Example 23 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 3-picolylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 304.37; found mol. wt. (M+H) 305.3; 609.2 (Dimer)
  • Example 24 The compound of Example 24 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 3-aminopyridine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 290.34; found mol. wt. (M+H) 291.1; 580.9 (Dimer)
  • Example 25 The compound of Example 25 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 287.77; found mol. wt. (M+H) 288.3; 574.8 (Dimer)
  • Example 26 The compound of Example 26 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-benzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 253.32; found mol. wt. (M+H) 254.3; 506.9 (Dimer)
  • Example 27 The compound of Example 27 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-2-nitrobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of pyrrolidine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 298.32; found mol. wt. (M+H) 299.3; 596.8 (Dimer)
  • Example 28 The compound of Example 28 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 318.78; found mol. wt. (M+H) 319.3; 637.0 (Dimer)
  • Example 29 The compound of Example 29 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-benzenesulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 284.34; found mol. wt. (M+H) 285.3; 569.1 (Dimer)
  • Example 30 The compound of Example 30 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-naphthol-1-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of N-aminomorpholine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 334.39; found mol. wt. (M+H) 335.3; 669.1 (Dimer)
  • Gabapentin was used in a binding assay in order to check the binding and affinities of the selected compounds.
  • the affinity of the compounds according to the invention was measured via the displacement of gabapentin from its binding site. If the selected compounds replace gabapentin from its binding site, then it may be expected that they will exhibit pharmacological properties comparable to those of gabapentin, for example as an agent to control pain or epilepsy.
  • the compounds according to the invention exhibit a good inhibition/displacement of gabapentin in this assay.
  • the investigated compounds exhibited in this biochemical assay an affinity for the hitherto unknown gabapentin binding site.
  • the tactile withdrawal thresholds were measured 30 minutes after administration. The results are expressed as ED 50 and % maximal possible effect (% MPE; % of the maximal possible effect) on the ipsilateral side, in which the baseline is taken as 0% and the withdrawal threshold of a control group is taken as 100% MPE.
  • Example 1 The substance according to Example 1 showed a 50% effect at a dose of 25 mg/kg, roughly corresponding to the ED 50 , and gabapentin exhibited an ED 50 of 92.6 mg/kg. Both substances acted for at least 30 hours. Accordingly, the substance according to Example 1 is superior to gabapentin in this model by a factor of 4.
  • the compounds according to the invention were investigated in the second phase of the formalin test in order to obtain information on the effects of substances in chronic/inflammatory pain.
  • a nociceptive reaction was induced in unconstrained experimental animals, manifested in a noticeable licking and biting of the affected paw.
  • Example 21 The compound of Example 21 according to the invention exhibited an inhibition of the formalin-induced nociception.
  • the corresponding results in the formalin test on mice are shown in the following Table 2.
  • Gabapentin has an ED 50 value of 79 mg/kg (i.v.).
  • TABLE 2 Analgesia investigation in the formalin test on mice Example No. Formalin Test on Mice - ED 50 21 97 mg/kg

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US20060160900A1 (en) * 2003-10-23 2006-07-20 Medtronic, Inc. Intrathecal Gabapentin for Treatment of Pain

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KR20070091049A (ko) 2002-12-13 2007-09-06 워너-램버트 캄파니 엘엘씨 하부요로증상을 치료하기 위한 알파-2-델타 리간드
CA2451267A1 (en) 2002-12-13 2004-06-13 Warner-Lambert Company Llc Pharmaceutical uses for alpha2delta ligands
RU2320369C2 (ru) 2003-09-12 2008-03-27 Пфайзер Инк. Комбинации, содержащие альфа-2-дельта лиганды и ингибиторы обратного захвата серотонина/норадреналина
DE102004008141A1 (de) 2004-02-19 2005-09-01 Abbott Gmbh & Co. Kg Guanidinverbindungen und ihre Verwendung als Bindungspartner für 5-HT5-Rezeptoren
WO2007022964A2 (de) 2005-08-24 2007-03-01 Abbott Gmbh & Co. Kg Hetaryl substituierte guanidinverbindungen und ihre verwendung als bindungspartner für 5-ht5-rezeptoren
US8937096B2 (en) 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder
US8691867B2 (en) 2005-12-19 2014-04-08 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction
US20070191461A1 (en) * 2006-02-15 2007-08-16 Smith-Swintosky Virginia L Use of benzo-heteroaryl sulfamide derivatives for the treatment of migraine
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EA017171B1 (ru) 2006-12-22 2012-10-30 Рекордати Айерленд Лимитед КОМБИНИРОВАННАЯ ТЕРАПИЯ ЗАБОЛЕВАНИЙ НИЖНИХ МОЧЕВЫВОДЯЩИХ ПУТЕЙ С ИСПОЛЬЗОВАНИЕМ ЛИГАНДОВ αδ И НЕСТЕРОИДНЫХ ПРОТИВОВОСПАЛИТЕЛЬНЫХ ПРЕПАРАТОВ (НПВП)

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