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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • A61K31/47—Quinolines; Isoquinolines
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• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

Definitions

• the invention relates to substituted 2-mercaptoquinoline-3-carboxamides, methods for the preparation thereof, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.
• a pathophysiological feature of chronic pain is the overexcitability of neurons.
• Neuronal excitability is decisively influenced by the activity of K + channels, since these significantly determine the resting potential of the cell and hence the excitability threshold.
• Heteromeric K + channels of the molecular subtype KCNQ2/3 (Kv7.2/7.3) are expressed in neurons of various regions of the central (hippocampus, amygdala) and peripheral (dorsal root ganglia) nervous system and regulate the excitability thereof.
• Activation of KCNQ2/3 K + channels leads to a hyperpolarisation of the cell membrane and, accompanying this, to a decrease in the electrical excitability of these neurons.
• KCNQ2/3-expressing neurons of the dorsal root ganglia are involved in the transmission of nociceptive stimuli from the periphery into the spinal cord (Passmore et al., J. Neurosci. 2003; 23(18):7227-36).
• the KCNQ2/3 K + channel thus represents a suitable starting point for the treatment of pain; in particular pain chosen from the group consisting of chronic pain, neuropathic pain, inflammatory pain and muscular pain (Nielsen et al., Eur J. Pharmacol. 2004; 487(1-3): 93-103), in particular neuropathic and inflammatory pain.
• the KCNQ2/3 K + channel is a suitable target for therapy of a large number of further diseases, such as, for example, migraine (US2002/0128277), cognitive diseases (Gribkoff, Expert Opin Ther Targets 2003; 7(6): 737-748), anxiety states (Korsgaard et al., J Pharmacol Exp Ther.
• a weak or non-existent interaction with transporter molecules, which are involved in the uptake and excretion of medicaments, can also be taken as an indication of improved bioavailability and at most low medicament interaction.
• interactions with the enzymes involved in the breakdown and excretion of medicaments should also be as low as possible, since such test results likewise indicate that at most low or even no medicament interactions whatsoever are to be anticipated.
• the compounds exhibit a high selectivity towards other receptors of the KCNQ family (specificity), for example towards KCNQ1, KCNQ3/5 or KCNQ4.
• a high selectivity can have a favourable effect on the side-effects profile. It is known, for example, that compounds which (also) bind to KCNQ1 are associated with a high risk of cardiac side effects, for which reason a high selectivity towards KCNQ1 can be desirable.
• a high selectivity towards other receptors can also be advantageous, however.
• a low affinity for the hERG ion channel or for the L-type calcium ion channel can be advantageous, as these receptors are associated with the occurrence of cardiac side effects.
• Overall an improved selectivity with regard to binding to other endogenous proteins i.e. receptors or enzymes for example) can lead to an improvement in the side-effects profile and hence to an improved compatibility.
• An object of the invention was therefore to provide novel compounds having advantages over the prior art compounds.
• the compounds should in particular be suitable as pharmacological active ingredients in medicaments, preferably in medicaments for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 K + channels.
• Substituted quinolinyl compounds are known from the prior art which are suitable as inhibitors of hYAK1 and hYAK3 kinases (WO 02/081728 A2). Furthermore 4-hydroxyquinoline-3-carboxylic acid derivatives are known as light stabilisers (EP 0 900 824 A1).
• substituted 2-mercaptoquinoline-3-carboxamides having the general formula (1) given below are suitable for the treatment of pain. It has further surprisingly been found that substituted 2-mercaptoquinoline-3-carboxamides having the general formula (1) given below also have an excellent affinity for the KCNQ2/3 K + channel and are therefore suitable for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 K + channels.
• substituted 2-mercaptoquinoline-3-carboxamides act here as modulators, i.e. agonists or antagonists, of the KCNQ2/3 K + channel.
• the invention provides substituted 2-mercaptoquinoline-3-carboxamides having the general formula (1)
• R 0 stands for C 1-10 alkyl or C 2-10 heteroalkyl, each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted; C 3-10 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; C 1-8 alkyl- or C 2-8 heteroalkyl-bridged C 3-10 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted, wherein the alkyl or heteroalkyl chain can in each case be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or C 1-8 alkyl- or C 2-8 heteroalkyl-bridged aryl or heteroaryl, each unsubstit
• alkyl or “C 1-10 alkyl”, “C 1-8 alkyl” and “C 1-4 alkyl” include acyclic saturated or unsaturated aliphatic hydrocarbon radicals, which can be branched or unbranched and unsubstituted or mono- or polysubstituted, having respectively 1 to 10 or 1 to 8 or 1 to 4 C atoms, i.e.
• Alkenyls have at least one C—C double bond and alkynyls have at least one C—C triple bond.
• Alkyl is preferably selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, ethenyl (vinyl), ethynyl, propenyl (—CH 2 CH ⁇ CH 2 , —CH ⁇ CH—CH 3 , —C( ⁇ CH 2 )—CH 3 ), propynyl (—CH—C ⁇ CH, —C ⁇ C—CH 3 ), butenyl, butynyl, pentenyl, pentynyl, hexenyl and hexynyl, heptenyl, heptyny
• heteroalkyl or “C 2-10 heteroalkyl” and “C 2-8 heteroalkyl” include acyclic aliphatic saturated or unsaturated hydrocarbon radicals having 2 to 10 C atoms, i.e. C 2-10 heteroalkanyls, C 2-10 heteroalkenyls and C 2-10 heteroalkynyls, or having 2 to 8 C atoms, i.e.
• C 2-8 heteroalkanyls, C 2-8 heteroalkenyls and C 2-8 heteroalkynyls which can each be branched or unbranched and unsubstituted or mono- or polysubstituted and in which at least one, optionally also two or three carbon atoms are replaced by a heteroatom or a heteroatom group selected independently of one another from the group consisting of O, S, S( ⁇ O), S( ⁇ O) 2 , N, NH, and N(C 1-8 alkyl), preferably N(CH 3 ), wherein the initial carbon atom of a C 2-10 heteroalkyl or a C 2-8 heteroalkyl via which the C 2-10 heteroalkyl or the C 2-8 heteroalkyl is bound to the higher-order general structure cannot be replaced by a heteroatom or a heteroatom group and adjacent carbon atoms cannot simultaneously be replaced by a heteroatom or a heteroatom group.
• the heteroatom groups NH and N(C 1-8 alkyl) of the heteroalkyl can optionally be mono- or polysubstituted.
• C 2-10 heteroalkenyls and C 2-8 heteroalkenyls have at least one C—C or one C—N double bond and C 2-10 heteroalkynyls and C 2-8 heteroalkynyls have at least one C—C triple bond.
• Heteroalkyl is preferably selected from the group comprising —CH 2 —O—CH 3 , —CH 2 —CH 2 —O—CH 3 , —CH 2 —CH 2 —O—CH 2 —CH 3 , —CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 3 , —CH ⁇ CH—O—CH 3 , —CH ⁇ CH—O—CH 2 —CH 3 , ⁇ CH—O—CH 3 , ⁇ CH—O—CH 2 —CH 3 , ⁇ CH—CH 2 —O—CH 2 —CH 3 , ⁇ CH—CH 2 —O—CH 3 , —CH 2 —NH—CH 3 , —CH 2 —CH 2 —NH—CH 3 , —CH 2 —CH 2 —NH—CH 2 —CH 3 , —CH 2 —CH 2 —NH—CH 2 —CH 3 , —CH 2 —CH 2 —NH—CH
• cycloalkyl or “C 3-10 cycloalkyl” denotes cyclic aliphatic hydrocarbons having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, wherein the hydrocarbons can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted.
• the binding of the cycloalkyl to the higher-order general structure can be made via any desired and possible ring member of the cycloalkyl radical.
• the cycloalkyl radicals can also be fused to further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e.
• Cycloalkyl is preferably selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,
• cyclodecyl adamantyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
• heterocyclyl or “heterocycloalkyl” includes aliphatic saturated or unsaturated (but not aromatic) cycloalkyls having three to ten, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 ring members, in which at least one, optionally also two or three, carbon atoms are replaced by a heteroatom or a heteroatom group selected independently of one another from the group consisting of O, S, N, NH and N(C 1-8 alkyl), preferably N(CH 3 ), wherein the ring members can be unsubstituted or mono- or polysubstituted.
• the binding of the heterocyclyl to the higher-order general structure can be made via any desired and possible ring member of the heterocyclyl radical.
• the heterocyclyl radicals can also be fused to further saturated, (partially) unsaturated, (hetero)cyclic or aromatic or heteroaromatic ring systems, i.e. to cycloalkyl, heterocyclyl, aryl or heteroaryl, which can in turn be unsubstituted or mono- or polysubstituted.
• heterocyclyl radicals from the group comprising azetidinyl, aziridinyl, azepanyl, azocanyl, diazepanyl, dithiolanyl, dihydroquinolinyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydroindenyl, dihydropyridinyl, dihydrofuranyl, dihydroisoquinolinyl, dihydroindolinyl, dihydroisoindolyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, oxetanyl, pyrrolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinol
• aryl denotes aromatic hydrocarbons having up to 14 ring members, inter alia phenyls and naphthyls.
• Each aryl radical can be present in unsubstituted or mono- or polysubstituted form, wherein the aryl substituents can be identical or different and can be at any desired and possible position of the aryl.
• the binding of the aryl to the higher-order general structure can be made via any desired and possible ring member of the aryl radical.
• the aryl radicals can also be fused to further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e.
• Aryl is preferably selected from the group including phenyl, 1-naphthyl and 2-naphthyl, each of which can be unsubstituted or mono- or polysubstituted.
• a particularly preferred aryl is phenyl, unsubstituted or mono- or polysubstituted.
• heteroaryl stands for a 5- or 6-membered cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms can each be selected independently of one another from the group S, N and O and the heteroaryl radical can be unsubstituted or mono- or polysubstituted; if the heteroaryl is substituted, the substituents can be identical or different and can be at any desired and possible position of the heteroaryl.
• the binding to the higher-order general structure can be made via any desired and possible ring member of the heteroaryl radical.
• the heteroaryl can also be part of a bicyclic or polycyclic system having up to 14 ring members, wherein the ring system can be formed with further saturated, (partially) unsaturated, (hetero)cyclic or aromatic or heteroaromatic rings, i.e. with cycloalkyl, heterocyclyl, aryl or heteroaryl, which can in turn be unsubstituted or mono- or polysubstituted.
• the heteroaryl radical is preferably selected from the group comprising benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazolyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyrid
• C 1-4 alkyl- or C 1-8 alkyl-bridged aryl, heteroaryl, heterocyclyl or cycloalkyl mean that C 1-4 alkyl or C 1-8 alkyl and aryl or heteroaryl or heterocyclyl or cycloalkyl have the meanings defined above and the aryl or heteroaryl or heterocyclyl or cycloalkyl radical is bound by a C 1-4 alkyl or a C 1-8 alkyl group to the higher-order general structure.
• the alkyl chain can in all cases be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.
• C 1-4 alkyl or C 1-8 alkyl are preferably selected from the group comprising —CH 2 —, —CH 2 —CH 2 —, —CH(CH 3 )—, —CH 2 —CH 2 —CH 2 —, —CH(CH 3 )—CH 2-3 —CH(CH 2 CH 3 )—, —CH 2 —(CH 2 ) 2 —CH 2 —, —CH(CH 3 )—CH 2 —CH 2 —, —CH 2 —CH(CH 3 )—CH 2-3 —CH(CH 3 )—CH(CH 3 )—, —CH(CH 2 CH 3 )—CH 2 —, —C(CH 3 ) 2 —CH 2 —, —CH(CH 2 CH 2 CH 3 )—, —C(CH 3 )(CH 2 CH 3 )—, —CH 2 —(CH 2 ) 3 —CH 2 —, —CH(CH 3 )—CH 2 —CH 2
• C 2-8 heteroalkyl-bridged aryl, heteroaryl, heterocyclyl or cycloalkyl mean that C 2-8 heteroalkyl and aryl or heteroaryl or heterocyclyl or cycloalkyl have the meanings defined above and the aryl or heteroaryl or heterocyclyl or cycloalkyl radical is bound by a C 2-8 heteroalkyl group to the higher-order general structure.
• the heteroalkyl chain can in all cases be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted.
• a terminal carbon atom of the C 2-8 heteroalkyl group is replaced by a heteroatom or a heteroatom group, the binding of a heteroaryl or a heterocyclyl to the heteroatom or the heteroatom group of the C 2-8 heteroalkyl is always made via a carbon atom of the heteroaryl or heterocyclyl.
• the terminal carbon atom is understood to mean the carbon atom within the C 2-8 heteroalkyl which within the chain is the furthest away from the general higher-order structure.
• C 2-8 heteroalkyl is preferably selected from the group comprising —CH 2 —NH—, —CH 2 —N(CH 3 )—, —CH 2 —O—, —CH 2 —CH 2 —NH—, —CH 2 —CH 2 —N(CH 3 )—, —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH 2 —NH—, —CH 2 —CH 2 —CH 2 —N(CH 3 )—, —CH 2 —CH 2 —CH 2 —O—, —CH 2 —O—CH 2 —, —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2
• alkyl In connection with “alkyl”, “heteroalkyl”, “heterocyclyl” and “cycloalkyl” the term “mono- or polysubstituted” within the meaning of this invention is understood to mean the single or multiple, e.g.
• alkyl Preferred “alkyl”, “heteroalkyl”, “heterocyclyl” and “cycloalkyl” substituents are selected from the group comprising F; Cl; Br; I; NO 2 ; CF 3 ; CN; ⁇ O; ⁇ NH; R 0 ; C( ⁇ O)(R 0 or H); C( ⁇ O)O(R 0 or H); C( ⁇ O)N(R 0 or H) 2 ; OH; OR 0 ; O—C( ⁇ O)—R 0 ; O—(C 1-8 alkyl)-OH; O—(C 1-8 alkyl)-O—C 1-8 alkyl; OCF 3 ; N(R 0 or H) 2 ; N(R 0 or H)—C( ⁇ O)—R 0 ; N(R 0 or H)—C( ⁇ O)—N(R 0 or H) 2 ; SH; SCF 3 ; SR 0 ; S( ⁇ O) 2 R
• alkyl Particularly preferred “alkyl”, “heteroalkyl”, “heterocyclyl” and “cycloalkyl” substituents are selected from the group consisting of F; Cl; Br; I; NO 2 ; CF 3 ; CN; ⁇ O; C 1-8 alkyl; C 2-8 heteroalkyl; aryl; heteroaryl; C 3-10 cycloalkyl; heterocyclyl; C 1-8 alkyl- or C 2-8 heteroalkyl-bridged aryl, heteroaryl, C 3-10 cycloalkyl or heterocyclyl; CHO; C( ⁇ O)C 1-8 alkyl; C( ⁇ O) aryl; C( ⁇ O) heteroaryl; CO 2 H; C( ⁇ O)O—C 1-8 alkyl; C( ⁇ O)O— aryl; C( ⁇ O)O-heteroaryl; CONH 2 ; C( ⁇ O)NH—C 1-8 alkyl; C( ⁇ O)N(C 1-8 al
• aryl and “heteroaryl” the expression “mono- or polysubstituted” within the meaning of this invention is understood to mean the single or multiple, e.g. two, three or four times, substitution of one or more hydrogen atoms in the ring system, each independently of one another, with substituents selected from the group comprising F; Cl; Br; I; NO 2 ; CF 3 ; CN; R 0 ; O( ⁇ O)H; C( ⁇ O)R 0 ; CO 2 H; C( ⁇ O)OR 0 ; CONH 2 ; C( ⁇ O)NHR 0 ; C( ⁇ O)N(R 0 ) 2 ; OH; OR 0 ; O—C( ⁇ O)—R 0 ; O—C( ⁇ O)—O—R 0 ; O—(C ⁇ O)—NH—R 0 ; O—C( ⁇ O)—N(R 0 ) 2 ; O—S( ⁇ O) 2 —R
• Preferred “aryl” and “heteroaryl” substituents are F; Cl; Br; I; NO 2 ; CF 3 ; CN; R 0 ; C( ⁇ O)(R 0 or H); C( ⁇ O)O(R 0 or H); C( ⁇ O)N(R 0 or H) 2 ; OH; OR 0 ; O—C( ⁇ O)—R 0 ; O—(C 1-8 alkyl)-O—C 1-8 alkyl; OCF 3 ; N(R 0 or H) 2 ; N(R 0 or H)—C( ⁇ O)—R 0 ; N(R 0 or H)—C( ⁇ O)—N(R 0 or H) 2 ; SH; SCF 3 ; SR 0 ; S( ⁇ O) 2 R 0 ; S( ⁇ O) 2 O(R 0 or H); S( ⁇ O) 2 —N(R 0 or H) 2 .
• aryl and “heteroaryl” substituents are selected from the group consisting of F; Cl; Br; I; NO 2 ; CF 3 ; CN; C 1-8 alkyl; or C 2-8 heteroalkyl; aryl; heteroaryl; C 3-10 cycloalkyl; heterocyclyl; C 1-8 alkyl- or C 2-8 heteroalkyl-bridged aryl, heteroaryl, C 3-10 cycloalkyl or heterocyclyl; CHO; C( ⁇ O)C 1-8 alkyl; C( ⁇ O) aryl; C( ⁇ O) heteroaryl; CO 2 H; C( ⁇ O)—O—C 1-8 alkyl; C( ⁇ O)O-aryl; C( ⁇ O)O-heteroaryl; CONH 2 ; C( ⁇ O)NH—C 1-8 alkyl; C( ⁇ O)N(C 1-8 alkyl) 2 ; C( ⁇ O)NH-aryl; C( ⁇ O)N(aryl; C
• the compounds according to the invention are defined by substituents, for example by R 1 , R 2 and R 3 (1 st generation substituents), which are in turn optionally substituted (2 nd generation substituents).
• substituents of the substituents can themselves be substituted again (3 rd generation substituents).
• C 1-10 alkyl can then itself be substituted again, for example with Cl (3 rd generation substituent). This then gives in total the functional group aryl-NHC 1-10 alkyl-Cl.
• the 3 rd generation substituents cannot, however, be substituted again, i.e. there are then no 4 th generation substituents.
• the 2 nd generation substituents cannot be substituted again, i.e. there are then no 3 rd generation substituents either.
• the functional groups for R 0 to R 7 can each optionally be substituted, but the various substituents cannot then themselves be substituted again.
• the compounds according to the invention are defined by substituents which are or which carry an aryl or heteroaryl radical, each unsubstituted or mono- or polysubstituted, or which together with the carbon atom(s) or heteroatom(s) binding them as ring member or ring members form a ring, for example an aryl or heteroaryl, each unsubstituted or mono- or polysubstituted.
• aryl or heteroaryl radicals and the aromatic ring systems formed in this way can optionally be fused to C 3-10 cycloalkyl or heterocyclyl, each saturated or unsaturated, i.e.
• C 3-10 cycloalkyl such as cyclopentyl or to a heterocyclyl such as morpholinyl, wherein the C 3-10 cycloalkyl or heterocyclyl radicals fused in this way can themselves be unsubstituted or mono- or polysubstituted.
• the compounds according to the invention are defined by substituents which are or which carry a C 3-10 cycloalkyl or heterocyclyl radical, each unsubstituted or mono- or polysubstituted, or which together with the carbon atom(s) or heteroatom(s) binding them as ring member or ring members form a ring, for example a C 3-10 cycloalkyl or heterocyclyl, each unsubstituted or mono- or polysubstituted.
• substituents which are or which carry a C 3-10 cycloalkyl or heterocyclyl radical, each unsubstituted or mono- or polysubstituted, or which together with the carbon atom(s) or heteroatom(s) binding them as ring member or ring members form a ring, for example a C 3-10 cycloalkyl or heterocyclyl, each unsubstituted or mono- or polysubstituted.
• aryl such as phenyl or to a heteroaryl such as pyridyl, wherein the aryl or heteroaryl radicals fused in this way can themselves be unsubstituted or mono- or polysubstituted.
• the compounds according to the invention are defined by radicals within which two substituents are referred to by the general expression “(“substituent 1” or “substituent 2” or “substituent 3”)”.
• This expression means that “substituent 1” and “substituent 2” and “substituent 3” within such a radical can occur in any possible combination.
• the expression “(R 0 or H)” within a radical means that R 0 and H can occur within this radical in any possible combination.
• the radical “N(R 0 or H) 2 ” can stand for “NH 2 ”, “NHR 0 ” and)“N(R 0 ) 2 ”, for example.
• R 0 occurs more than once within a radical, as in the case of)“N(R 0 ) 2 ”, then R 0 can have the same or different meanings in each case: in the present example of)“N(R 0 ) 2 ”, for example, R 0 can stand twice for aryl, giving the functional group “N(aryl) 2 ”, or R 0 can stand once for aryl and once for C 1-10 alkyl, giving the functional group “N(aryl)(C 1-10 alkyl)”.
• salt formed with a physiologically compatible acid is understood to mean salts of the individual active ingredient with inorganic or organic acids which are physiologically—particularly when used in humans and/or mammals—compatible. Hydrochloride is particularly preferred.
• physiologically compatible acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharinic acid, monomethyl sebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric acid, phosphoric acid and/or aspartic acid.
• Citric acid and hydrochloric acid are particularly preferred.
• Physiologically compatible salts with cations or bases are salts of the individual compound as anion with at least one, preferably inorganic, cation, which are physiologically—particularly when used in humans and/or mammals—compatible.
• Particularly preferred are the salts of the alkali and alkaline-earth metals, but also ammonium salts, but in particular (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
• R 1 , R 2 , R 3 and R 4 are each selected independently of one another from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; R 0 ; C( ⁇ O)(R 0 or H); C( ⁇ O)O(R 0 or H); C( ⁇ O)N(R 0 or H) 2 ; OH; OR 0 ; O—(C 1-8 alkyl)-OH; O—(C 1-8 alkyl)-O—C 1-8 alkyl; OCF 3 ; O—C( ⁇ O)—R 0 ; N(R 0 or H) 2 ; N(R 0 or H)—C( ⁇ O)—R 0 ; N(R 0 or H)—C( ⁇ O)—N(R 0 or H) 2 ; SH; SCF 3 ; SR 0 ; S( ⁇ O) 2 R 0 ; S( ⁇ O)
• R 1 , R 2 , R 3 and R 4 are preferably each selected independently of one another from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; C( ⁇ O)H; C( ⁇ O)—OH; C( ⁇ O)NH 2 ; C 1-8 alkyl, O—C 1-8 alkyl, C( ⁇ O)C 1-8 alkyl, C( ⁇ O)—O—C 1-8 alkyl, O—C( ⁇ O)—C 1-8 alkyl, C( ⁇ O)NH—C 1-8 alkyl, C( ⁇ O)N(C 1-8 alkyl) 2 , NH—C 1-8 alkyl, N(C 1-8 alkyl) 2 , NH—C( ⁇ O)C 1-8 alkyl, N(C 1-8 alkyl)-C( ⁇ O)C 1-8 alkyl, S—C 1-8 alkyl, S( ⁇ O) 2 C 1-8 alkyl, S( ⁇ O) 2 O
• the substituents R 1 , R 2 , R 3 and R 4 are particularly preferably each selected independently of one another from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; CH 2 CF 3 ; C( ⁇ O)—OH; C( ⁇ O)NH 2 ; SH; SCF 3 ; S( ⁇ O) 2 OH; NH 2 ; OCF 3 ; OH; C 1-8 alkyl, O—C 1-8 alkyl, NH—C 1-8 alkyl, N(C 1-8 alkyl) 2 , each saturated, branched or unbranched, unsubstituted or mono-, di- or trisubstituted with one, two or three substituents selected independently of one another from the group consisting of O-methyl and OH; C( ⁇ O)C 1-8 alkyl, C( ⁇ O)O—C 1-8 alkyl, O—C( ⁇ O)—C 1-8 alkyl, C( ⁇ O)NH—C 1-8
• R 1 , R 2 , R 3 and R 4 are most particularly preferably each selected independently of one another from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; methyl; ethyl; n-propyl; isopropyl; cyclopropyl; cyclopropyl; n-butyl; sec-butyl; tert-butyl; CH 2 CF 3 ; C( ⁇ O)-methyl; C( ⁇ O)-ethyl; C( ⁇ O)—OH; C( ⁇ O)—O-methyl; C( ⁇ O)—O-ethyl; C( ⁇ O)—NH 2 ; C( ⁇ O)—N(methyl) 2i C( ⁇ O)—N(ethyl) 2i C( ⁇ O)—NH-methyl; C( ⁇ O)—NH-ethyl; C( ⁇ O)—N(methyl)(ethyl); OH; O-methyl; O-ethy
• substituents R 1 , R 2 , R 3 and R 4 are each selected independently of one another from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; methyl; ethyl; C( ⁇ O)-methyl; O-methyl; O—(CH 2 ) 2 —O—CH 3 ; OCF 3 ; O—C( ⁇ O)-methyl; NH—C( ⁇ O)-methyl; N(methyl) 2 ; morpholinyl; S-methyl; SCF 3 ; benzyl and phenyl, each unsubstituted.
• R 1 , R 2 , R 3 and R 4 are each selected independently of one another from the group consisting of H, F, Cl, CF 3 and OCF 3 .
• the substituent R 5 is selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; R 0 ; C( ⁇ O)(R 0 or H); C( ⁇ O)O(R 0 or H); C( ⁇ O)N(R 0 or H) 2 ; N(R 0 or H) 2 ; N(R 0 or H)—C( ⁇ O)—R 0 ; N(R 0 or H)—C( ⁇ O)—N(R 0 or H) 2 ; SH; SCF 3 ; SR 0 ; S( ⁇ O) 2 R 0 ; S( ⁇ O) 2 O(R 0 or H); S( ⁇ O) 2 —N(R 0 or H) 2 .
• the substituent R 5 is selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; R 0 ; C( ⁇ O)(R 0 or H); C( ⁇ O)O(R 0 or H); C( ⁇ O)N(R 0 or H) 2 ; OR 0 ; —O—(C 1-8 alkyl)-OH; O—(C 1-8 alkyl)-O—C 1-8 alkyl; OCF 3 ; O—C( ⁇ O)—R 0 ; N(R 0 or H) 2 ; N(R 0 or H)—C( ⁇ O)—R 0 ; N(R 0 or H)—C( ⁇ O)—N(R 0 or H) 2 ; SH; SCF 3 ; SR 0 ; S( ⁇ O) 2 R 0 ; S( ⁇ O) 2 O(R 0 or H); S( ⁇ O) 2 —N(R 0 or H); SH; SCF
• the substituent R 5 is preferably selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; C( ⁇ O)H; C( ⁇ O)—OH; C( ⁇ O)—NH 2 ; C 1-8 alkyl, O—C 1-8 alkyl, C( ⁇ O)C 1-8 alkyl, C( ⁇ O)O—C 1-8 alkyl, O—C( ⁇ O)—C 1-8 alkyl, C( ⁇ O)NH—C 1-8 alkyl, C( ⁇ O)N(C 1-8 alkyl) 2 , NH—C 1-8 alkyl, N(C 1-8 alkyl) 2 , NH—C( ⁇ O)C 1-8 alkyl, N(C 1-8 alkyl)-C( ⁇ O)C 1-8 alkyl, S—C 1-8 alkyl, S( ⁇ O) 2 C 1-8 alkyl, S( ⁇ O) 2 O—C 1-8 alkyl, each saturated or unsaturated,
• the substituent R 5 is particularly preferably selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; CH 2 CF 3 ; C( ⁇ O)—OH; C( ⁇ O)—NH 2 ; SH; SCF 3 ; S( ⁇ O) 2 OH; NH 2 ; OCF 3 ; C 1-8 alkyl, O—C 1-8 alkyl, NH—C 1-8 alkyl, N(C 1-8 alkyl) 2 , each saturated, branched or unbranched, unsubstituted or mono-, di- or trisubstituted with one or more substituents selected independently of one another from the group consisting of O-methyl and OH; C( ⁇ O)C 1-8 alkyl, C( ⁇ O)O—C 1-8 alkyl, O—C( ⁇ O)—C 1-8 alkyl, C( ⁇ O)NH—C 1-8 alkyl, C( ⁇ O)N(C 1-8 alkyl) 2 ,
• the substituent R 5 is most particularly preferably selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; methyl; ethyl; n-propyl; isopropyl; cyclopropyl; cyclopropyl; n-butyl; sec-butyl; tert-butyl; CH 2 CF 3 ; C( ⁇ O)-methyl; C( ⁇ O)-ethyl; C( ⁇ O)—OH; C( ⁇ O)—O-methyl; C( ⁇ O)—O-ethyl; C( ⁇ O)—NH 2 ; C( ⁇ O)—N(methyl) 2i C( ⁇ O)—N(ethyl) 2 ; C( ⁇ O)—NH-methyl; C( ⁇ O)—NH-ethyl; C( ⁇ O)—N(methyl)(ethyl); O-methyl; O-ethyl; O—(CH 2 ) 2 —O—CH
• substituent R 5 is selected from the group consisting of H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; methyl; ethyl; —CH 2 —O-methyl, C( ⁇ O)-methyl; O-methyl; O—(CH 2 ) 2 —O—CH 3 ; OCF 3 ; O—C( ⁇ O)-methyl; NH—C( ⁇ O)-methyl; N(methyl) 2i morpholinyl; S-methyl; SCF 3 ; benzyl, unsubstituted.
• R 5 is methyl, OMe or —CH 2 O-methyl.
• C 1-10 alkyl or C 2-10 heteroalkyl each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents selected independently of one another from the group consisting of F, Cl, Br, I, NO 2 , CF 3 , CN, OH, ⁇ O, C( ⁇ O)—OH, OCF 3 , NH 2 , S( ⁇ O) 2 OH, SH, SCF 3 , C 1-8 alkyl, O—C 1-8 alkyl, S—C 1-8 alkyl, NH—C 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-10 cycloalkyl and heterocyclyl, wherein the aforementioned alkyl radicals can each be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents selected independently of one another from the group consisting of F, Cl, Br,
• R 8a and R 8b stand independently of each other for H; F; Cl; Br; I; NO 2 ; OF 3 ; CN; OH; OCF 3 ; NH 2 ; C 1-4 alkyl, O—C 1-4 alkyl, NH—C 1-4 alkyl, N(C 1-4 alkyl) 2 , each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents selected independently of one another from the group consisting of F, Cl, Br, I, O—C 1-4 alkyl, OH and OCF 3 ; C 3-10 cycloalkyl or heterocyclyl, each saturated or unsaturated, unsubstituted or mono- or polysubstituted with one or more substituents selected independently of one another from the group consisting of F, Cl, Br, I, C 1-4 alkyl, OH, ⁇ O, O—C 1-4 alkyl, OCF 3 , NH
• R 8a and R 8b stand independently of each other for H; F; Cl; Br; I; NO 2 ; CF 3 ; CH 2 CF 3 ; CN; OH; OCF 3 , NH 2 ; C 1-4 alkyl, 0-C 1-4 alkyl, 0-C 1-4 alkyl-OH, O—C 1-4 alkyl-OCH 3 , NH—C 1-4 alkyl, N(C 1-4 alkyl) 2 , each saturated or unsaturated, branched or unbranched, unsubstituted; C 3-10 cycloalkyl, saturated or unsaturated, unsubstituted or mono- or polysubstituted with one or more substituents selected independently of one another from the group consisting of F, Cl, Br, I, C 1-4 alkyl, OH, O—C 1-4 alkyl; m stands for 0, 1, 2, 3 or 4; Y stands for O or NR 9 ;
• R 8a and R 8b stand independently of each other for H; F; Cl; Br; I; NO 2 ; CF 3 ; CN; methyl; ethyl; n-propyl; isopropyl; cyclopropyl; cyclopropyl; n-butyl; sec-butyl; tert-butyl; CH 2 CF 3 ; OH; O-methyl; O-ethyl; O—(CH 2 ) 2 —O—CH 3 ; O—(CH 2 ) 2 —OH; OCF 3 ; NH 2 ; NH-methyl; N(methyl) 2 ; NH-ethyl; N(ethyl) 21 or N(methyl)(ethyl);
• R 8a and R 8b stand independently of each other for H; F; Cl; Br; I; methyl; ethyl; n-propyl; isopropyl; n-butyl; sec-butyl; tert-butyl; OH; O-methyl; O-ethyl; O—(CH 2 ) 2 —O—CH 3 ; or O—(CH 2 ) 2 —OH;
• R 8a and R 8b stand independently of each other for H, m stands for 1, n for 0 and A for phenyl, pyridyl or thienyl, each substituted 0, 1, 2 or 3 times with a substituent selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, O—C 1-4 alkyl, OCF 3 , C 1-4 alkyl, C( ⁇ O)—OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , SH, S—C 1-4 alkyl, SCF 3 and S( ⁇ O) 2 OH.
• a substituent selected from the group consisting of F, Cl, Br, I, NO 2 , CN, OH, O—C 1-4 alkyl, OCF 3 , C 1-4 alkyl, C( ⁇ O)—OH, CF 3 , NH 2 , NH(C 1-4 alkyl), N(C
• C 1-10 alkyl or C 2-10 heteroalkyl each saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents selected independently of one another from the group consisting of F, Cl, Br, I, NO 2 , CF 3 , CN, OH, ⁇ O, C( ⁇ O)—OH, OCF 3 , NH 2 , S( ⁇ O) 2 OH, SH, SCF 3 , C 1-8 alkyl, O—C 1-8 alkyl, S—C 1-8 alkyl, NH—C 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-10 cycloalkyl and heterocyclyl, wherein the aforementioned alkyl radicals can each be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted with one or more substituents selected independently of one another from the group consisting of F, Cl, Br,
• Particularly preferred compounds are those from the group comprising:
• substituted 2-mercaptoquinoline-3-carboxamides according to the invention and the corresponding acids, bases, salts and solvates are suitable as pharmaceutical active ingredients in medicaments.
• the invention therefore also provides a medicament containing at least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention having the general formula (I), wherein the radicals R 1 to R 7 have the meaning given above, and optionally one or more pharmaceutically compatible auxiliary substances.
• the medicaments according to the invention optionally contain, in addition to at least one compound according to the invention, suitable additives and/or auxiliary substances, including carrier materials, fillers, solvents, diluents, dyes and/or binders, and can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray plasters or aerosols.
• suitable additives and/or auxiliary substances including carrier materials, fillers, solvents, diluents, dyes and/or binders
• auxiliary substances, etc., and the amount thereof to use depend on whether the medicament is to be administered by oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or local means, for example on the skin, mucous membranes or in the eyes.
• Preparations in the form of tablets, pastilles, capsules, granules, drops, juices and syrups are suitable for oral administration; solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
• Compounds according to the invention in a depot formulation, in dissolved form or in a plaster, optionally with addition of agents promoting skin penetration, are suitable preparations for percutaneous administration.
• Preparation forms suitable for oral or percutaneous administration can deliver the compounds according to the invention on a delayed release basis.
• the compounds according to the invention can also be used in parenteral long-term depot forms, such as implants or implanted pumps, for example.
• Other additional active ingredients known to the person skilled in the art can be added in principle to the medicaments according to the invention.
• medicaments according to the invention are suitable for influencing KCNQ2/3 channels and exert an agonistic or antagonistic, in particular an agonistic, action.
• the medicaments according to the invention are preferably suitable for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 channels.
• the medicaments according to the invention are preferably suitable for the treatment of one or more diseases chosen from the group consisting of pain, preferably pain chosen from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain; epilepsy, urinary incontinence, anxiety states, dependency, mania, bipolar disorders, migraine, cognitive diseases, dystonia-associated dyskinesias and/or urinary incontinence.
• pain preferably pain chosen from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain
• epilepsy urinary incontinence
• anxiety states dependency, mania, bipolar disorders, migraine, cognitive diseases, dystonia-associated dyskinesias and/or urinary incontinence.
• the medicaments according to the invention are particularly preferably suitable for the treatment of pain, most particularly preferably chronic pain, neuropathic pain, inflammatory pain and muscular pain.
• the medicaments according to the invention are further particularly preferably suitable for the treatment of epilepsy.
• the invention also provides the use of at least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the preparation of a medicament for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 channels.
• At least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the preparation of a medicament for the treatment of pain, most particularly preferably chronic pain, neuropathic pain, inflammatory pain and muscular pain.
• At least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the preparation of a medicament for the treatment of epilepsy.
• the invention also provides at least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the treatment of disorders or diseases which are at least partly mediated by KCNQ2/3 channels.
• the invention also provides at least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the treatment of pain, preferably pain chosen from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain; epilepsy, urinary incontinence, anxiety states, dependency, mania, bipolar disorders, migraine, cognitive diseases, dystonia-associated dyskinesias and/or urinary incontinence.
• pain preferably pain chosen from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain; epilepsy, urinary incontinence, anxiety states, dependency, mania, bipolar disorders, migraine, cognitive diseases, dystonia-associated dyskinesias and/or urinary incontinence.
• At least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention is at least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the treatment of pain, most particularly preferably chronic pain, neuropathic pain, inflammatory pain and muscular pain.
• Particularly preferred is also at least one substituted 2-mercaptoquinoline-3-carboxamide according to the invention and optionally one or more pharmaceutically compatible auxiliary substances for the treatment of epilepsy.
• the effectiveness against pain can be demonstrated for example in the Bennett or Chung model (Bennett, G. J. and Xie, Y. K., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain 1988, 33(1), 87-107; Kim, S. H. and Chung, J. M., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain 1992, 50(3), 355-363).
• the effectiveness against epilepsy can be demonstrated for example in the DBA/2 mouse model (De Sarro et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 2001, 363, 330-336).
• the substituted 2-mercaptoquinoline-3-carboxamides according to the invention preferably have an EC 50 value of at most 10 ⁇ M or at most 5 ⁇ M, more preferably at most 3 ⁇ M or at most 2 ⁇ M, even more preferably at most 1.5 ⁇ M or at most 1 ⁇ M, most preferably at most 0.8 ⁇ M or at most 0.5 ⁇ M and in particular at most 0.4 ⁇ M or at most 0.2 ⁇ M.
• Methods for determining the EC 50 value are known to the person skilled in the art.
• the EC 50 value is preferably determined by fluorimetry, particularly preferably by the method described in “Pharmacological experiments”.
• the invention also provides methods for preparing the substituted 2-mercaptoquinoline-3-carboxamides according to the invention.
• the protective group PG 2 of the protected ester S-I or S-VI or S-VIII or S-X which is a tert-butyl or a benzyl group for example, is cleaved by ester cleavage methods known to the person skilled in the art, optionally in the presence of an acid or a base, and S—I, S-VI, S-VIII or S-X are thus converted into the carboxylic acid S-II or S-VII or S-IX or S-XI.
• the carboxylic acid S-II or S-VII or S-IX can be converted into the corresponding amide S-III or S-IV or S-V by methods familiar to the person skilled in the art.
• SA or S-VII or S-IX can first be reacted with a suitable chlorinating agent such as thionyl chloride to form the acid chloride, which is then reacted with the primary amine R 6 —NH 2 , optionally in the presence of a base, to form the amide S-III or S-IV or S-V.
• S-II or S-VII or S-IX can be reacted with the primary amine R 6 —NH 2 in the presence of a suitable coupling reagent, such as for example HATU or CDI, optionally with addition of a base.
• a suitable coupling reagent such as for example HATU or CDI, optionally with addition of a base.
• the thiols S-IV and S-VI protected by the protective group PG 1 can be formed starting from the 2-chloroquinolines S-III and S—I by methods familiar to the person skilled in the art, for example by alkylation with the corresponding thiol PG 1 -SH in an ipso-substitution to form the thio ether S-IV and S-VI, optionally in the presence of a base.
• the thiol S-IV or S-VI or S-VII which is protected as a thio ether for example can be converted into the thiol S-V or S-VIII or S-IX by cleaving off the protective group PG 1 , optionally in the presence of an acid or a base.
• step ax11 the thiol S-IX can be converted into S-VII, which has a thiol function protected by the protective group PG 1 , by methods familiar to the person skilled in the art.
• the thiol S-IX can be alkylated for example by the use of an alkyl halide PG 1 -Hal, optionally in the presence of a base.
• step ax13 the thiol S-VIII can be converted into the corresponding thio ether S-X by methods familiar to the person skilled in the art.
• the thiol S-VIII can be alkylated for example by the use of the alkyl halide R 7 -Hal, optionally in the presence of a base.
• step ax14 the 2-chloroquinoline S-I can first be converted into the corresponding thio ether by methods known to the person skilled in the art, such as for example by substitution with a thiol, for example 3-mercaptopropanoic acid ethyl ester, and then cleaved, optionally in the presence of an acid or a base, to form the thiol S-VIII.
• a thiol for example 3-mercaptopropanoic acid ethyl ester
• the thio ether S-X can be formed starting from the 2-chloroquinoline S-I by methods familiar to the person skilled in the art, e.g. by alkylation with the corresponding thiol R 7 —SH in an ipso-substitution, optionally in the presence of a base.
• step aL1 the thiol S-V can be converted into the corresponding thio ether S-XII by methods familiar to the person skilled in the art.
• the thiol S-V can be alkylated for example by the use of the alkyl halide R 7 -Hal, optionally in the presence of a base.
• step bL1 the carboxylic acid S-XI can be converted into the corresponding amide S-XII by methods familiar to the person skilled in the art.
• S-XI can first be reacted with a suitable chlorinating agent such as thionyl chloride to form the acid chloride, which is then reacted with the primary amine R 6 —NH 2 , optionally in the presence of a base, to form the amide S-XII.
• S-XI can be reacted with the primary amine R 6 —NH 2 in the presence of a suitable coupling reagent, such as for example HATU or CDI, optionally with addition of a base.
• a suitable coupling reagent such as for example HATU or CDI
• step cL1 the thio ether S-XII can be formed starting from 2-chloroquinoline S-III by methods familiar to the person skilled in the art, e.g. by alkylation with the corresponding thiol R 7 —SH in an ipso-substitution, optionally in the presence of a base.
• 6,7-Difluoro-2-hydroxy-4-methyl-quinoline-3-carboxylic acid ethyl ester was prepared from 1-(2-amino-4,5-difluorophenyl)ethanone by the method described for precursor VVV22 sections a) and b).
• Lawesson's reagent were added at RT to a solution of 550 mg (2.1 mmol) 6,7-difluoro-2-hydroxy-4-methyl-quinoline-3-carboxylic acid ethyl ester in a pyridine/toluene blend (1:10 vv, 6 ml) and then the mixture was heated for 3 h at 80° C. Then it was quenched with a saturated aqueous NaHCO 3 solution (20 ml) and extracted with EE (3 ⁇ 60 ml). The combined organic phases were washed with water, dried over Na 2 SO 4 , filtered and concentrated to small volume under vacuum.
• 2-Ethylsulfanyl-7-fluoro-4-methyl-quinoline-3-carboxylic acid ethyl ester was prepared from 1-(2-amino-4-fluorophenyl)ethanone by the method described for precursor VVV30 sections a) and b).
• Human CHO-K1 cells expressing KCNQ2/3 channels are cultivated adherently at 37° C., 5% CO 2 and 95% humidity in cell culture bottles (e.g. 80 cm 2 TC flasks, Nunc) with DMEM-high glucose (Sigma Aldrich, D7777) including 10% FCS (PAN Biotech, e.g. 3302-P270521) or alternatively MEM Alpha Medium (1 ⁇ , liquid, Invitrogen, #22571), 10% foetal calf serum (FCS) (Invitrogen, #10270-106, heat-inactivated) and the necessary selection antibiotics.
• FCS PAN Biotech, e.g. 3302-P270521
• MEM Alpha Medium 1 ⁇ , liquid, Invitrogen, #22571
• FCS foetal calf serum
• the cells are washed with a 1 ⁇ DPBS buffer without Ca 2+ /Mg 2+ (e.g. Invitrogen, #14190-094) and detached from the bottom of the culture vessel by means of Accutase (PAA Laboratories, #L11-007) (incubation with Accutase for 15 min at 37° C.).
• a 1 ⁇ DPBS buffer without Ca 2+ /Mg 2+ e.g. Invitrogen, #14190-094
• Accutase PAA Laboratories, #L11-007
• the cell count then present is determined using a CASYTM cell counter (TCC model, Scharfe System) in order subsequently to apply 20,000 to 30,000 cells/well/100 ⁇ l of the described nutrient medium, depending on density optimisation for the individual cell line, to 96-well measuring plates of the CorningTM CeIIBINDTM type (flat clear-bottom black polystyrene microplates, #3340). Incubation is then carried out for one hour at room temperature, without gassing or adjusting the humidity, followed by incubation for 24 hours at 37° C., 5% CO 2 and 95% humidity.
• the voltage-sensitive fluorescent dye from the Membrane Potential Assay Kit (RedTM bulk format part R8123 for FLIPR, MDS Analytical TechnologiesTM) is prepared by dissolving the contents of a vessel of Membrane Potential Assay Kit Red Component A in 200 ml of extracellular buffer (ES buffer, 120 mM NaCl, 1 mM KCl, 10 mM HEPES, 2 mM CaCl 2 , 2 mM MgCl 2 , 10 mM glucose; pH 7.4). After removal of the nutrient medium, the cells are washed with 200 ⁇ l of ES buffer, then covered with a layer of 100 ⁇ l of the dye solution prepared above and incubated for 45 min at room temperature with exclusion of light.
• ES buffer 120 mM NaCl, 1 mM KCl, 10 mM HEPES, 2 mM CaCl 2 , 2 mM MgCl 2 , 10 mM glucose; pH 7.4
• the fluorescence measurements are carried out with a BMG Labtech FLUOstarTM, BMG Labtech NOVOstarTM or BMG Labtech POLARstarTM instrument (525 nm excitation, 560 nm emission, bottom-read mode).
• 50 ⁇ l of the substances to be tested in the desired concentrations, or 50 ⁇ l of ES buffer for control purposes are introduced into separate cavities of the measuring plate and incubated for 30 min at room temperature whilst being shielded from light.
• the fluorescence intensity of the dye is then measured for 5 min and the fluorescence value F 1 of each well is thus determined at a given, constant time.
• 15 ⁇ l of a 100 mM KCl solution (final concentration 92 mM) are then added to each well.
• the change in fluorescence is subsequently measured until all relevant measured values have been obtained (mainly 5-30 min).
• a fluorescence value F 2 is determined, in this case at the time of the fluorescence peak.
• the fluorescence intensity F 2 is compared with the fluorescence intensity F 1 , and the agonistic activity of the target compound on the potassium channel is determined therefrom.
• F 2 and F 1 are calculated as follows:
• F 1K of the fluorescence intensity is determined by adding to the reaction batch only the buffer solution instead of the substance to be tested, determining the value F 1K of the fluorescence intensity, adding the potassium ions as described above and measuring a value F 2K of the fluorescence intensity. Then F 2K and F 1K are calculated as follows:
• a substance has an agonistic activity on the potassium channel if
• a target compound has an agonistic activity if an increase in
• the antinociceptive activity of the test substance against an acute noxic thermal stimulant was examined in the tail-flick test in rats using the method described by D′Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941)).
• Male Sprague-Dawley rats weighing between 200 and 250 g were used (breeder: Janvier, Le Genest St. Isle, France).
• the animals were placed in special test compartments and the base of the tail was exposed to a focused light beam from an analgesia meter (model 2011, Rhema Labortechnik, Hofheim, Germany). 10 animals were used per group.
• the tail-flick latency time from switching on the light beam to the flick of the tail
• the intensity of the light beam was chosen so that the control latency time was 7 to 9 seconds.
• the measurement of the tail-flick latency was then repeated 10, 20, 30 and 60 minutes after peroral administration of the substance.
• the antinociceptive action of the test substance was determined as the increase in the tail-flick latency time using the following formula:
• MPE[%] [( T 1 ⁇ T 0 )/( T 2 ⁇ T 0 )] ⁇ 100
• T 0 control latency time before administration of the substance
• T 1 latency time after administration of the substance
• T 2 maximum exposure time to the light beam (30 seconds)
• MPE maximum possible effect.
• 4-OH-2-Mercapto-quinoline-3-carboxamides are known from FR2532939 for which a pharmacological action in a pain model and in an inflammatory model are described, without specifying a mechanism of action.

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