WO2013156154A1 - Substituted 6-amino-nicotinamides bearing an oh-containing group as kcnq2/3 modulators - Google Patents

Substituted 6-amino-nicotinamides bearing an oh-containing group as kcnq2/3 modulators Download PDF

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Publication number
WO2013156154A1
WO2013156154A1 PCT/EP2013/001134 EP2013001134W WO2013156154A1 WO 2013156154 A1 WO2013156154 A1 WO 2013156154A1 EP 2013001134 W EP2013001134 W EP 2013001134W WO 2013156154 A1 WO2013156154 A1 WO 2013156154A1
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Prior art keywords
aliphatic residue
residue
unsubstituted
polysubstituted
mono
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PCT/EP2013/001134
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French (fr)
Inventor
Simon Lucas
Sven KÜHNERT
Gregor Bahrenberg
Wolfgang Schröder
Achim Kless
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Grünenthal GmbH
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Priority to BR112014025840A priority Critical patent/BR112014025840A2/en
Priority to CA2870573A priority patent/CA2870573A1/en
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Priority to ES13719386.8T priority patent/ES2605947T3/en
Priority to LTEP13719386.8T priority patent/LT2888233T/en
Priority to EP13719386.8A priority patent/EP2888233B1/en
Priority to RS20161120A priority patent/RS55466B1/en
Priority to DK13719386.8T priority patent/DK2888233T3/en
Priority to CN201380019282.3A priority patent/CN104428287A/en
Priority to MX2014012494A priority patent/MX2014012494A/en
Priority to AU2013248637A priority patent/AU2013248637A1/en
Priority to JP2015506121A priority patent/JP6033403B2/en
Priority to EA201401142A priority patent/EA201401142A1/en
Priority to SI201330394A priority patent/SI2888233T1/en
Publication of WO2013156154A1 publication Critical patent/WO2013156154A1/en
Priority to IL235030A priority patent/IL235030A0/en
Priority to HK15111080.1A priority patent/HK1210173A1/en
Priority to HRP20161424TT priority patent/HRP20161424T1/en
Priority to CY20161101222T priority patent/CY1118255T1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to substituted 6-amino-nicotinamides bearing an OH-containing group, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
  • a pathophysiological feature of chronic pain is the overexcitability of neurons.
  • Neuronal excitability is influenced decisively by the activity of K + channels, since these determine decisively the resting membrane potential of the cell and therefore 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 hyperpolarization 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 marrow (Passmore et a/., 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 of pain selected from the group consisting of chronic pain, acute pain, neuropathic pain, inflammatory pain, visceral pain and muscular pain (Nielsen et a/., Eur J Pharmacol. 2004; 487(1 -3): 93-103), in particular of 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 (Korsgaard et al., J Pharmacol Exp Ther.
  • Substituted compounds that have an affinity for the KCNQ2/3 K + channel are e.g. known from the prior art (WO 2008/046582, WO 2010/046108, WO 2010/102809 and WO 2002/066036).
  • the compounds show a high selectivity towards other receptors of the KCNQ family ⁇ specificity), e.g. towards KCNQ1 , KCNQ3/5 or KCNQ4.
  • a high selectivity may have a positive effect on the side effects profile: for example it is known that compounds which (also) have an affinity to KCNQ1 are likely to have a potential for cardial side effects. Therefore, a high selectivity towards KCNQ1 may be desirable.
  • the compounds may show a low affinity for the hERG ion channel or the L-type calcium ion channel (phenylalkylamine-, benzothiazepin-, dihydropyridine-binding site) since these receptors are known to possibly have a potential for cardial side effects.
  • an improved selectivity towards binding to other endogenic proteins i.e. receptors or enzymes may result in a better side effects profile and, consequently to an improved tolerance.
  • substituted compounds of the general formula (I) given below are suitable for the treatment of pain. It has also been found, surprisingly, that substituted compounds of the general formula (I) given below also have an excellent affinity for the KCNQ2/3 K + channel and are therefore suitable for the prophylaxis and/or treatment of disorders and/or diseases that are mediated at least in part by KCNQ2/3 K + channels. The substituted compounds thereby act as modulators, i.e. agonists or antagonists, of the KCNQ2/3 K + channel.
  • the present invention therefore relates to a substituted compound of general formula (I),
  • R 1 represents a C 2 - 6 -aliphatic residue, unsubstituted or mono- or polysubstituted; or a C 3 _ 6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and in each case optionally bridged via a C 1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or represents OR 6 , wherein
  • R 6 represents a C -6 -aliphatic residue, unsubstituted or mono- or polysubstituted; or a C 3 . 6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted;
  • R 2 and R 3 independently of one another represent H; F; CI; Br; I; CN; CH 2 F; CHF 2 ; CF 3 ; OH; OCH 2 F; OCHF 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, or an 0-C 1-4 aliphatic residue, wherein the Ci -4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C 3 .
  • R 4 and R 5 independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; a C -4 -aliphatic residue, wherein the C -4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C 3 .
  • R 4 and R 5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C 3 .i 0 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and the respective remaining substituents of R 2 and R 3 each independently of one another represent H; F; CI; Br; I; CN; CH 2 F; CHF 2 ; CF 3 ; OH; OCH 2 F; OCHF 2 ; OCF 3 ; SCF 3 ; a C 1-4 - aliphatic residue, or an 0-C 1-4 aliphatic residue, wherein the C -4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C 3 .
  • R 2 and R 3 denotes H or is linked via a carbon atom
  • R 4 and R 5 each independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; a C 1-4 -aliphatic residue, wherein the C 1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C 3 .
  • R 2 and R 4 together with the carbon atoms connecting them, form a C 3 . 10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and R 3 represents H; F; CI; Br; I; CN; CH 2 F; CHF 2 ; CF 3 ; OH; OCH 2 F; OCHF 2 ; OCF 3 ; SCF 3 ; a C -4 -aliphatic residue, or an O-C ⁇ aliphatic residue, wherein the C 1- aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C 3 .
  • R 5 represents H; CH 2 F; CHF 2 ; CF 3 ; a C ⁇ -aliphatic residue, wherein the C 1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C 3 .
  • single stereoisomer preferably means in the sense of the present invention an individual enantiomer or diastereomer.
  • mixture of stereoisomers preferably means in the sense of this invention the racemate and mixtures of enantiomers and/or diastereomers in any mixing ratio.
  • physiologically acceptable salt preferably comprises in the sense of this invention a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base.
  • a physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid which is physiologically acceptable - in particular when used in human beings and/or other mammals.
  • physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, p- toluenesulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1 -sulphonic acid, nicotinic acid, 2, 3 or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, a-lipoic acid, acetyl glycine, hippuric acid, phosphoric acid, aspartic acid.
  • Citric acid and hydrochloric acid are particularly preferred.
  • Hydrochloride salts and citrate salts are therefore particularly preferred salts.
  • a physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention as an anion with at least one preferably inorganic cation, which is physiologically acceptable - in particular when used in human beings and/or other mammals.
  • Ci. 6 -aliphatic residue preferably comprise in the sense of this invention acyclic saturated or unsaturated aliphatic hydrocarbon residues, which can be branched or unbranched and also unsubstituted or mono- or polysubstituted, containing 1 to 6, or 2 to 6, or 1 to 4 carbon atoms, respectively, i.e. Ci-6 alkanyls, C 2 -6 alkanyls, C 2 .6 alkenyls and C 2 . 6 alkynyls as well as C 1-4 alkanyls, C 2 -4 alkenyls and C 2 .
  • aliphatic residues are selected from the group consisting of alkanyl (alkyl) and alkenyl residues, more preferably are alkanyl residues.
  • Preferred Ci_ 6 alkanyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.
  • C -4 alkanyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl and tert. -butyl. Preferred C 2 .
  • Preferred C 2 Preferred C 2 .
  • alkynyl residues are selected from the group consisting of ethynyl, propynyl (-CH 2 -C ⁇ CH, -C ⁇ C-CH 3 ), butynyl, pentynyl and hexynyl Preferred C 2 .
  • 4 alkynyl residues are selected from the group consisting of ethynyl, propynyl (-CH 2 -C ⁇ CH, -C ⁇ C-CH 3 ) and butynyl.
  • C 3 . 6 .cycloaliphatic residue and “C 3 . 10 .cycloaliphatic residue” preferably mean for the purposes of this invention cyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbon atoms and 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively, wherein the hydrocarbons in each case can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted.
  • the cycloaliphatic residues can be bound to the respective superordinate general structure via any desired and possible ring member of the cycloaliphatic residue.
  • the cycloaliphatic residues can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. with cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residues which can in turn be unsubstituted or mono- or polysubstituted.
  • C 3-10 cycloaliphatic residue can furthermore be singly or multiply bridged such as, for example, in the case of adamantyl, bicyclo[1.1.1 Jpentyl, bicyclo[2.2.1 ]heptyl or bicyclo[2.2.2]octyl.
  • Preferred C 3 . 10 cycloaliphatic residues are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
  • C 3 . 6 cycloaliphatic residues are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.
  • 3-6-membered heterocycloaliphatic residue preferably mean for the purposes of this invention heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3-6, i.e. 3, 4, 5 or 6 ring members, and 4-7, i.e. 4, 5, 6 or 7 ring members, and 3-10, i.e.
  • the heterocycloaliphatic residue can be bound to the superordinate general structure via any desired and possible ring member of the heterocycloaliphatic residue if not indicated otherwise.
  • heterocycloaliphatic residues can also be condensed with further saturated, (partially) unsaturated (hetero)cycloaliphatic or aromatic or heteroaromatic ring systems, i.e. with cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residues, which can in turn be unsubstituted or mono- or polysubstituted.
  • condensed also optionally includes spirocycles, i.e. an at least bicyclic ring system, wherein the heterocycloaliphatic residue is connected through just one (spiro)atom with a further saturated, (partially) unsaturated system.
  • spirocycles i.e. an at least bicyclic ring system
  • heterocycloaliphatic residues can furthermore optionally be singly or multiply bridged with a d- or C 2 -aliphatic group such as, for example, in the case of Preferred heterocycloaliphatic residues are selected from the group consisting of azetidinyl, aziridinyl, azepanyl, azocanyl, diazepanyl, dithiolanyl, dihydroquinolinyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dioxepanyl, dihydroindenyl, dihydropyridinyl, dihydrofuranyl, dihydroisoquinolinyl, dihydroindolinyl, dihydroisoindolyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, oxetanyl, oxazepanyl, pyrrolidinyl, pipe
  • heterocycloaliphatic residues are pyrrolidinyl, piperidinyl, oxazepanyl, azetidinyl, morpholinyl, piperazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolinyl, and dihydroisoindolyl.
  • Most preferred heterocycloaliphatic residues are pyrrolidinyl, piperidinyl, oxazepanyl, azetidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolinyl, and dihydroisoindolyl.
  • aryl preferably means for the purpose of this invention aromatic hydrocarbons having 6 to 14 ring members, i.e. 6, 7, 8, 9, 10, 11 , 12, 13 or 14 ring members, including phenyls and naphthyls.
  • Each aryl residue can be unsubstituted or mono- or polysubstituted, wherein the aryl substituents can be the same or different and in any desired and possible position of the aryl.
  • the aryl can be bound to the superordinate general structure via any desired and possible ring member of the aryl residue.
  • aryl residues can also be condensed with further saturated, (partially) unsaturated, (hetero)cycloaliphatic, aromatic or heteroaromatic ring systems, i.e. with a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residue, which can in turn be unsubstituted or mono- or polysubstituted.
  • condensed aryl residues are benzodioxolanyl and benzodioxanyl.
  • aryl is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, fluorenyl and anthracenyl, each of which can be respectively unsubstituted or mono- or polysubstituted.
  • a particularly preferred aryl is phenyl, unsubstituted or mono- or polysubstituted.
  • heteroaryl for the purpose of this invention preferably represents a 5 or 6- membered cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted; in the case of substitution on the heteroaryl, the substituents can be the same or different and be in any desired and possible position of the heteroaryl.
  • the binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue.
  • the heteroaryl can also be part of a bi- or polycyclic system having up to 14 ring members, wherein the ring system can be formed with further saturated, (partially) unsaturated, (hetero)cycloaliphatic or aromatic or heteroaromatic rings, i.e. with a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residue, which can in turn be unsubstituted or mono- or polysubstituted.
  • heteroaryl residue is selected from the group consisting of benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl,
  • cycloaliphatic residue bridged via a C 1-4 -aliphatic group preferably means for the purpose of the invention that the expression "cycloaliphatic residue” has the above-defined meaning and that said residue is bound to the respective superordinate general structure via a C 1- -aliphatic group.
  • the Ci. aliphatic group can in all cases be branched or unbranched, unsubstituted or mono- or polysubstituted.
  • the C 1-4 aliphatic group can in all cases be furthermore saturated or unsaturated, i.e. can be a Ci. 4 alkylene group, a C 2 . 4 alkenylene group or a C 2-4 alkynylene group.
  • the C 1-4 -aliphatic group is a Ci_ alkylene group or a C 2 - 4 alkenylene group, more preferably a C 1- alkylene group.
  • Preferred C -4 alkylene groups are selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 - CH 2 -, -CH(CH 3 )-CH 2 -, -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 -, -CH(CH 3 )-CH(CH 3 )-, -CH(CH 2 CH 3 )-CH 2 -, -C(CH 3 ) 2 -
  • Preferred C 2 . 4 alkynylene groups are selected from the group consisting of -C ⁇ C-, -C ⁇ C-CH 2 -, -C ⁇ C-CH 2 -CH 2 -, -C ⁇ C-CH(CH 3 )-, -CH 2 -C ⁇ C- CH 2 - and -C ⁇ C-C ⁇ C-.
  • a substituent can if appropriate for its part in turn be mono- or polysubstituted. The multiple substitution can be carried out using the same or using different substituents.
  • polysubstituted with respect to polysubstituted residues and groups includes the polysubstitution of these residues and groups either on different or on the same atoms, for example disubstituted on the same carbon atom, as in the case of 1 ,1- difluorocyclohexyl, or at various points, as in the case of 1-chloro-3-fluorocyclohexyl.
  • a substituent can if appropriate for its part in turn be mono- or polysubstituted.
  • the multiple substitution can be carried out using the same or using different substituents.
  • the 3 rd generation substituents may not be resubstituted, i.e. there are then no 4 th generation substituents.
  • the 2 nd generation substituents may not be resubstituted, i.e. there are then not even any 3 rd generation substituents.
  • the functional groups for R 1 to R 5 can each if appropriate be substituted; however, the respective substituents may then for their part not be resubstituted.
  • the compounds according to the invention are defined by substituents which are or carry an aryl or heteroaryl residue, respectively unsubstituted or mono- or polysubstituted, or which form together with the carbon atom(s) or heteroatom(s) connecting them, as the ring member or as the ring members, a ring, for example an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted.
  • substituents which are or carry an aryl or heteroaryl residue, respectively unsubstituted or mono- or polysubstituted, or which form together with the carbon atom(s) or heteroatom(s) connecting them, as the ring member or as the ring members, a ring, for example an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted.
  • Both these aryl or heteroaryl residues and the (hetero)aromatic ring systems formed in this way can if appropriate be
  • cycloaliphatic residue, or heterocycloaliphatic residue preferably a 3 to 6 membered heterocycloaliphatic residue, or with aryl or heteroaryl, e.g. with a C 3 . 6 cycloaliphatic residue such as cyclopentyl, or a 3 to 6 membered heterocycloaliphatic residue such as morpholinyl, or an aryl such as phenyl, or a heteroaryl such as pyridyl, wherein the cycloaliphatic or heterocycloaliphatic residues, aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted.
  • the compounds according to the invention are defined by substituents which are or carry a cycloaliphatic residue or a heterocycloaliphatic residue, respectively, in each case unsubstituted or mono- or polysubstituted, or which form together with the carbon atom(s) or heteroatom(s) connecting them, as the ring member or as the ring members, a ring, for example a cycloaliphatic or a heterocycloaliphatic ring system.
  • Both these cycloaliphatic or heterocycloaliphatic ring systems and the (hetero)cycloaliphatic ring systems formed in this manner can if appropriate be condensed with aryl or heteroaryl, preferably selected from the group consisting of phenyl, pyridyl and thienyl, or with a cycloaliphatic residue, preferably a C 3 . 6 cycloaliphatic residue, or a heterocycloaliphatic residue, preferably a 3 to 6 membered heterocycloaliphatic residue, e.g.
  • aryl such as phenyl, or a heteroaryl such as pyridyl, or a cycloaliphatic residue such as cyclohexyl, or a heterocycloaliphatic residue such as morpholinyl, wherein the aryl or heteroaryl residues or cycloaliphatic or heterocycloaliphatic residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted.
  • this residue can have respectively different meanings for various substituents: if, for example, both R 2 and R 3 denote a C 1- - aliphatic residue, then the C 1- -aliphatic residue residue can e.g. represent methyl for R 2 and can represent ethyl for R 3 .
  • R 2 -R 5 have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof and R 1 represents a C 2 - 6 -aliphatic residue, unsubstituted or mono- or polysubstituted; or a C 3 . 6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted, optionally bridged via a C 1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted.
  • R 1 represents OR 6 , wherein R 6 represents a Ci -6 -aliphatic residue, unsubstituted or mono- or polysubstituted.
  • Preferred embodiments of the compound according to general formula (I) are compounds which have the general formulae (l-a) and/or (l-b):
  • Another preferred embodiment of the compound according to general formula (I) is a compound which has the general formula (l-c),
  • Yet another preferred embodiment of present invention is a compound according to general formula (I), wherein
  • Ci -4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted 0-C 1-4 -aliphatic residue, or represents a C 3 . 6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N0 2 , NH 2 , an NH(d.
  • C 1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted O-C ⁇ -aliphatic residue, and wherein the C 3 .
  • 6 -cycloaliphatic residue may optionally be bridged via a C 1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted 0-C 1-4 -aliphatic residue, or represents OR 6 , wherein
  • C -4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , 0CF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted 0-C - -aliphatic residue, R 2 and R 3 independently of one another represent H; F; CI; Br; I; CN; CH 2 F; CHF 2 ; CF 3 ; OH; OCH 2 F; OCHF 2 ; OCF 3 ; SCF 3 ; a C 1-4 -aliphatic residue, or an O-C1.4 aliphatic residue, wherein the C ⁇ -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF
  • R 4 and R 5 independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; a C ⁇ -aliphatic residue, wherein the C 1-4 -aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted O-C ⁇ -aliphatic residue, or represent a C 3 .
  • C -4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted 0-C 1-4 - aliphatic residue, on the condition that if R 4 and/or R 5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
  • R 2 and R 3 each independently of one another represent H; F; CI; Br; I; CN; CH 2 F; CHF 2 ; CF 3 ; OH; OCH 2 F; OCHF 2 ; OCF 3 ; SCF 3 ; a C 1-4 - aliphatic residue, or an 0-C 1- aliphatic residue, wherein the C 1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , 0CF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted 0-C 1-4 - aliphatic residue, or represent a C 3 .
  • C 1-4 -aliphatic residue wherein the C 1-4 -aliphatic residue in each case may be unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstltuted 0-d. 4 - aliphatic residue, or represents a C 3 .
  • C 1- -aliphatic residue wherein the C 1- -aliphatic residue in each case may be unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstltuted 0-C 1-4 - aliphatic residue, and the remaining substituent R 5 represents H; CH 2 F; CHF 2 ; CF 3 ; a d.
  • C 1- -aliphatic residue may be unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted 0-C 1-4 -aliphatic residue, or represents a C 3 .
  • R 1 represents a C 2 . 6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N0 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(d.
  • 4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted 0-C 1-4 -aliphatic residue, or represents a C 3 . 6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N0 2 , NH 2 , an NH(C 1-4 aliphatic residue), an N(d.
  • C 1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, 0CH 2 F, OCHF 2 , OCF 3 , CH 2 F, CHF 2 , CF 3 and an unsubstituted 0-C 1-4 -aliphatic residue.
  • R represents a C 2 . 6 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-d. 4 -aliphatic residue, or represents a C 3 . 6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C 1-4 -aliphatic residue, or represents OR 6 , wherein
  • R 6 represents a C -4 -aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C 1-4 -aliphatic residue.
  • R 6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, CH 2 OH, CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , and CH(OH)CH 2 OH.
  • R represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OR 6 , wherein R 6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 1 represents ethyl, n-propyl, 2-propyl, tert.-butyl, or cyclopropyl.
  • R 2 and R 3 independently of one another represent H; F; CI; Br; I; CH 2 F; CHF 2 ; CF 3 ; OH; OCH 2 F; OCHF 2 ; OCF 3 ; a C -4 -aliphatic residue, or an 0-Ci. 4 aliphatic residue, wherein the C -4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C 1-4 -aliphatic residue, or represent a C 3 .
  • R 4 and R 5 independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; a Ci. 4 -aliphatic residue, wherein the Ci. 4 -aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C 1- -aliphatic residue, or represent a C 3 . 6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C 3 .
  • R 4 and R 5 preferably R 2 and R 3 or R 4 and R 5 , in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C 3 . 0 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, preferably a C 3 .
  • -aliphatic residue or represent a C 3 . 6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C 3 . 6 -cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C 1-4 -aliphatic residue, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , and a C 1-4 - aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci.
  • R 4 and/or R 5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
  • R 2 and R 4 together with the carbon atoms connecting them, form a C 3 . 10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, preferably a C 3 . 10 -cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an O-C ⁇ -aliphatic residue, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , and a C ⁇ -aliphatic residue, wherein the C 1-4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci.
  • R 3 represents H; F; CI; Br; I; CH 2 F; CHF 2 ; CF 3 ; OH; OCH 2 F; OCHF 2 ; OCF 3 ; a C ⁇ -aliphatic residue, or an 0-C 1-4 aliphatic residue, wherein the C ⁇ -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted O-C ⁇ -aliphatic residue, or represents a C 3 .
  • 6 -cycloaliphatic residue in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C 1-4 -aliphatic residue, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , and a C-,.
  • C 1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci. -aliphatic residue, and the remaining substituent R 5 represents H; FCH 2 F; CHF 2 ; CF 3 ; a C ⁇ -aliphatic residue, wherein the C-
  • 4 -aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C 1- -aliphatic residue, or represents a C 3 . 6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C 3 .
  • 6 -cycloaliphatic residue in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C 1-4 -aliphatic residue, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , and a C 1-4 - aliphatic residue, wherein the Ci_ 4 -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C 1- -aliphatic residue, on the condition that if R 5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom.
  • R 2 and R 3 independently of one another represent H; F; CI; Br; I; CH 2 F; CHF 2 ; CF 3 ; OH; a Ci. 4-aliphatic residue, or an O-C ⁇ aliphatic residue, wherein the C 1- -aliphatic residue is in each case unsubstituted, or represent a C 3 . 6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C 3 . 6 -cycloaliphatic residue, in each case unsubstituted, with the proviso that at least one of R 2 and R 3 denotes H or is linked via a carbon atom,
  • R 4 and R 5 independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; a Ci. 4 -aliphatic residue,. wherein the C -4 -aliphatic residue is unsubstituted, or represent a C 3 . 6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C 3 . 6 -cycloaliphatic residue, in each case unsubstituted, on the condition that if R 4 and/or R 5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
  • R 4 and R 5 preferably R 2 and R 3 or R 4 and R 5 , in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C 3 . 10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, preferably a C 3 .io-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C 1 . 4 -aliphatic residue, CH 2 F, CHF 2 , CF 3 , and a Ci.
  • 6 -cycloaliphatic residue in each case unsubstituted, with the proviso that at least one of R 2 and R 3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R 4 and R 5 each independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; a C 1- -aliphatic residue, wherein the C 1- -aliphatic residue is in each unsubstituted, or represent a C 3 . 6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C 3 .
  • R 4 and/or R 5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
  • R 2 and R 4 together with the carbon atoms connecting them, form a C 3 . 10 -cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, preferably a C 3-10 -cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an O-C ⁇ -aliphatic residue, CH 2 F, CHF 2 , CF 3 , and a Ci.
  • R 3 represents H; F; CI; Br; I; CH 2 F; CHF 2 ; CF 3 ; OH; a C 1- - aliphatic residue, or an 0-Ci. aliphatic residue, wherein the C -4 -aliphatic residue is in each case unsubstituted, or represents a C 3 . 6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C 3 .
  • R 5 represents H; CH 2 F; CHF 2 ; CF 3 ; a Ci -4 -aliphatic residue, wherein the C 1-4 -aliphatic residue is in each case unsubstituted, or represents a C 3-6 -cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C 3 . 6 -cycloaliphatic residue, in each case unsubstituted, on the condition that if R 5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom.
  • R 2 and R 3 independently of one another represent H; OH; an unsubstituted C 1-4 -aliphatic residue, or an unsubstituted 0-C 1-4 aliphatic residue, with the proviso that at least one of R 2 and R 3 denotes H or is linked via a carbon atom,
  • R 4 and R 5 independently of one another represent H; CH 2 F; CHF 2 ; CF 3 ; an unsubstituted d. 4-aliphatic residue, or
  • R 4 and R 5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C 3 .i 0 -cycloaliphatic residue, preferably a C 3 - 6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, CH 2 F, CHF 2 , CF 3 , an unsubstituted 0-C - -aliphatic residue, and an unsubstituted C 1-4 -aliphatic residue, and the respective remaining substituents of R 2 and R 3 each independently of one another represent H; OH; an unsubstituted C 1-4 -aliphatic residue, or an unsubstituted 0-C 1-4 aliphatic residue, with the proviso that at least one of R 2 and R 3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R 4 and
  • R 2 and R 4 together with the carbon atoms connecting them, form a C 3 . 0 -cycloaliphatic residue, preferably a C 3 . 6 -cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an unsubstituted O-C ⁇ -aliphatic residue, CH 2 F, CHF 2 , CF 3 , and a an unsubstituted C 1-4 -aliphatic residue, and the remaining substituent R 3 represents H; F; CI; Br; I; OH; an unsubstituted C 1-4 - aliphatic residue, or an unsubstituted 0-C 1-4 aliphatic residue, and the remaining substituent R 5 represents H; CH 2 F; CHF 2 ; CF 3 ; an unsubstituted Ci- 4 - aliphatic residue.
  • R 2 and R 3 independently of one another represent H; OH; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH 2 - CH(CH 3 )(C 2 H 5 ), C(CH 3 ) 2 (C 2 H 5 ), OCH 3 or OCH 2 CH 3 ,with the proviso that at least one of R 2 and R 3 denotes H or is linked via a carbon atom,; preferably represent H; methyl; ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, CH2-CH
  • R 4 and R 5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH 2 - CH(CH 3 )(C 2 H 5 ), C(CH 3 ) 2 (C 2 H 5 ), CH 2 F; CHF 2 ; CF 3 ;, or
  • R 4 and R 5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C 3 . 6 -cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH 2 F, CHF 2 , CF 3 , OCH 3 and OCH 2 CH 3 , and the respective remaining substituents of R 2 and R 3 each independently of one another represents H; OH; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-buty
  • R 2 and R 4 together with the carbon atoms connecting them, form a C 3 . 6 -cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, CH 2 F, CHF 2 , CF 3 , OCH 3 and OCH 2 CH 3 , and R 3 represents H; OH; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.- butyl, n-pentyl, isopentyl,
  • R 2 and R 3 independently of one another represent H; OH; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH 2 - CH(CH 3 )(C 2 H 5 ), C(CH 3 ) 2 (C 2 H 5 ), OCH 3 or OCH 2 CH 3 , with the proviso that at least one of R 2 and R 3 denotes H or is linked via a carbon atom, preferably represent H; methyl; ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, CH 2 -
  • R 4 and R 5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH 2 - CH(CH 3 )(C 2 H 5 ), C(CH 3 ) 2 (C 2 H 5 ), CH 2 F; CHF 2 ; CF 3 ;, or
  • R 2 and R 4 together with the carbon atoms connecting them, form a C 3-6 -cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, CH 2 F, CHF 2 , CF 3 , OCH 3 and OCH 2 CH 3 , and the respective remaining substituent R 3 represents H; OH; methyl; ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopent
  • At least one of R 2 , R 3 , R 4 and R 5 denotes H, preferably at least two of R 2 , R 3 , R 4 and R 5 denote H.
  • At least one of R 3 and R 5 denotes H, preferably both R 3 and R 5 denote H.
  • R 1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OR 6 , wherein
  • R 6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,
  • R 2 and R 3 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, or tert.-butyl, preferably R 2 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, or tert.-butyl, and R 3 denotes H,
  • R 4 and R 5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH 2 F, CHF 2 , or CF 3 ; preferably R 4 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH 2 F, CHF 2 , and CF 3 ; and R 5 denotes H, or
  • R 2 and R 3 or R 4 and R 5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C 3-6 -cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, CH 2 F, CHF 2 , CF 3 , OCH 3 and OCH 2 CH 3 , and the respective remaining substituents of R 2 and R 3 in dependently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably R 2
  • R 2 and R 4 together with the carbon atoms connecting them, form a C 3-6 -cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.- butyl, CH 2 F, CHF 2 , CF 3 , OCH 3 and OCH 2 CH 3 , and R 3 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.- butyl, preferably R 3 denotes H, and R 5 represents H; methyl; ethyl, n-
  • R 1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OR 6 , wherein
  • R 6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,
  • R 2 and R 3 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, or tert.-butyl, preferably R 2 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec. -butyl, or tert.-butyl, and R 3 denotes H,
  • R 4 and R 5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH 2 F, CHF 2 , or CF 3 ; preferably R 4 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH 2 F, CHF 2 , and CF 3 , and R 5 denotes H. or
  • R 2 and R 4 together with the carbon atoms connecting them, form a C 3 . 6 -cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.- butyl, CH 2 F, CHF 2 , CF 3 , OCH 3 and OCH 2 CH 3 , and the respective remaining substituent R 3 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably R 3 denotes H, and the respective remaining substituent R 5 represents H;
  • substituted compounds according to the invention of the aforementioned general formula (I) and corresponding stereoisomers and also the respective corresponding salts and solvates are toxicologically safe and are therefore suitable as pharmaceutical active ingredients in pharmaceutical compositions.
  • the present invention therefore further relates to a pharmaceutical composition containing at least one compound according to general formula (I), in each case optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally one or more pharmaceutically acceptable auxiliaries.
  • a pharmaceutical composition containing at least one compound according to general formula (I), in each case optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally one or more pharmaceutically acceptable auxiliaries.
  • compositions according to the invention are suitable in particular for the modulation of KCNQ2/3 K + channels, preferably for KCNQ2/3 K + channel inhibition and/or KCNQ2/3 K + channel stimulation, i.e. they exert an agonistic or antagonistic effect.
  • compositions according to the invention are preferably suitable for the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K + channels.
  • the pharmaceutical composition according to the invention is suitable for administration to adults and children, including toddlers and babies.
  • the pharmaceutical composition according to the invention may be prepared as a liquid, semisolid or solid pharmaceutical form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and also be administered as much.
  • the pharmaceutical composition according to the invention conventionally may contain further physiologically acceptable pharmaceutical auxiliaries which, for example, can be selected from the group consisting of excipients, fillers, solvents, diluents, surface-active substances, dyes, preservatives, blasting agents, slip additives, lubricants, aromas and binders.
  • the physiologically acceptable auxiliaries and also the amounts thereof to be used depend on whether the pharmaceutical composition is to be applied orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermal ⁇ , intramuscularly, intranasally, buccally, rectally or locally, for example to infections of the skin, the mucous membranes and of the eyes.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral application; solutions, suspensions, easily reconstitutable dry preparations and also sprays are preferably suitable for parenteral, topical and inhalative application.
  • substituted compounds according to the invention used in the pharmaceutical composition according to the invention in a repository, in a dissolved form or in a plaster, and further agents promoting skin penetration being added if appropriate, are suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the respective substituted compound according to the invention also in a delayed manner.
  • compositions according to the invention can be prepared with the aid of conventional means, devices, methods and process known in the art, such as are described for example in ..Remington's Pharmaceutical Sciences", A.R. Gennaro (Editor), 17 th edition, Mack Publishing Company, Easton, Pa, 1985, in particular in Part 8, Chapters 76 to 93.
  • the corresponding description is introduced herewith by way of reference and forms part of the disclosure.
  • the amount to be administered to the patient of the respective substituted compounds according to the invention of the above-indicated general formula (I) may vary and is for example dependent on the patient's weight or age and also on the type of application, the indication and the severity of the disorder. Conventionally, 0.001 to 100 mg/kg, preferably 0.05 to 75 mg/kg, particularly preferably 0.05 to 50 mg of at least one compound according to the invention are applied per kg of the patient's body weight.
  • the pharmaceutical composition according to the invention is preferably suitable for the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K + channels.
  • the pharmaceutical composition according to the invention is more preferably suitable for the treatment and/or prophylaxis of one or more diseases and/or disorders selected from the group consisting of pain, in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias.
  • the pharmaceutical composition according to the invention is suitable particularly preferably for the treatment of pain, more particularly preferably of acute pain, chronic pain, neuropathic pain, visceral pain, inflammatory pain and muscular pain, and most particularly for the treatment of neuropathic pain.
  • the pharmaceutical composition according to the invention is also preferably suitable for the treatment and/or prophylaxis of epilepsy.
  • the present invention further relates to at least one compound according to general formula (I), optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally of one or more pharmaceutically acceptable auxiliaries for use in the modulation of KCNQ2/3 K + channels, preferably for use in KCNQ2/3 K + channel inhibition and/or stimulation.
  • general formula (I) optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally of one or more pharmaceutically acceptable auxiliaries for use in the modulation of KCNQ2/3 K + channels, preferably for use in KCNQ2/3 K + channel inhibition and/or stimulation.
  • the present invention therefore further relates to at least one compound according to general formula (I), optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally of one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K + channels.
  • general formula (I) optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally of one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K + channels.
  • pain in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain
  • epilepsy urinary incontinence
  • anxiety, dependency, mania, bipolar disorders migraine, cognitive diseases and dystonia-associated dysk
  • At least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of epilepsy are also given.
  • the present invention further relates to at least one compound according to general formula (I) and also optionally one or more pharmaceutically acceptable auxiliaries for the modulation of KCNQ2/3 K + channels, preferably for KCNQ2/3 K + channel inhibition and/or stimulation.
  • the present invention therefore further relates to at least one compound according to general formula (I) and also optionally of one or more pharmaceutically acceptable auxiliaries for the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K + channels.
  • pain especially pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias.
  • At least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for the prophylaxis and/or treatment of epilepsy are also given.
  • the present invention further relates to at least one compound according to general formula (I) and also optionally one or more pharmaceutically acceptable auxiliaries for use in the preparation of a medicament for prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K + channels.
  • pain in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias.
  • At least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for use in the preparation of a medicament for the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, most particularly neuropathic pain.
  • At least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for use in the preparation of a medicament for the prophylaxis and/or treatment of epilepsy.
  • Another aspect of the present invention is a method of treatment and/or prophylaxis of disorders and/or diseases, which are mediated, at least in part, by KCNQ2/3 K + channels, in a mammal, preferably of disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic
  • the effectiveness against pain can be shown, 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), by tail flick experiments (e.g. according to D'Amour und Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941 )) or by the formalin test (e.g. according to D.
  • the compounds according to the invention preferably have a EC 5 o value of not more than 10000 nM or not more than 8000 nM, more preferably not more than 7000 nM or not more than 6000 nM, yet more preferably not more than 5000 nM or not more than 3000 nM, even more preferably not more than 2000 nM or not more than 1000 nM, yet even more preferably not more than 800 nM or not more than 700 nM, still more preferably not more than 600 nM or not more than 500 nM, yet still more preferably not more than 400 nM or not more than 300 nM, most preferably not more than 200 nM or not more than 150 nM and especially not more than 120 nM or not more than 100 nM.
  • 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 as described below under "pharmacological experiments”.
  • the invention further provides processes for the preparation of the substituted compounds according to the invention.
  • the reactions described can each be carried out under the conventional conditions with which the person skilled in the art is familiar, for example with regard to pressure or the order in which the components are added. If appropriate, the person skilled in the art can determine the optimum procedure under the respective conditions by carrying out simple preliminary tests.
  • the intermediate and end products obtained using the reactions described hereinbefore can each be purified and/or isolated, if desired and/or required, using conventional methods known to the person skilled in the art. Suitable purifying processes are for example extraction processes and chromatographic processes such as column chromatography or preparative chromatography. All of the process steps described below, as well as the respective purification and/or isolation of intermediate or end products, can be carried out partly or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.
  • substituted compounds according to the invention of the aforementioned general formula (I) are obtained, after preparation thereof, in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and/or diastereomers, they can be separated and if appropriate isolated using conventional processes known to the person skilled in the art. Examples include chromatographic separating processes, in particular liquid chromatography processes under normal pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallisation processes.
  • 2,6-dichloro-nicotinic acids of the general formula SM01 can be transformed into the corresponding esters of the general formula IM01 according to methods known to the person skilled in the art, for example using a suitable alkylation reagent, for example methyl iodide or ethyl iodide.
  • a suitable alkylation reagent for example methyl iodide or ethyl iodide.
  • 2,6-dichloro-nicotinic acid esters of the general formula IM01 can be transformed into 2-chhloro-6-morpholin-nicotinic acid esters of the general formula IM02 using morpholine according to methods known to the person skilled in the art, for example by conventional or microwave heating, neat or in solution, for example in acetonitrile, dimethylformamide, dioxane, N-methyl-2-pyrrolidone or tetrahydrofuran, optionally in the presence of a suitable base, for example triethylamine, ⁇ , ⁇ -diisopropylethylamine, potassium carbonate, caesium carbonate, sodium tert-butoxide or potassium tert-butoxide, optionally by addition of a suitable coupling reagent, for example tetrakis(triphenylphosphin)-palladium, bis(dibenzylideneacetone)-palladium(0), or tris(dibenzy
  • 2-chhloro-6-morpholin-nicotinic acid esters of the general formulae IM02 can be transformed into the intermediates of the general formula IM03 according to methods known to the person skilled in the art with compounds of the general formula Y-R 1 , where Y denotes hydrogen, a metal or organometallic residue, for example sodium, magnesium bromide, magnesium chloride, tributyltin or boronic acid, or a residue to form an organometallic reagent, according to methods known to the person skilled in the art, for example by conventional or microwave heating, neat or in solution, for example in acetonitrile, dimethylformamide, dioxane, N-methyl-2-pyrrolidone, tetrahydrofuran, methanol or ethanol, optionally in the presence of a suitable base, for example triethylamine, N,N- diisopropylethylamine, potassium carbonate, caesium carbonate, sodium tert-butoxide or potassium
  • nicotinic acid esters of the general formula IM03 can be transformed into the corresponding nicotinic acids of the general formula I 04 according to methods known to the person skilled in the art, for example by employing a base, for example sodium hydroxide.
  • a base for example sodium hydroxide.
  • nicotinic acids of the general formula IM04 can be converted to yield amides of the general formula I with amines of the general formula SM02 according to methods known to the person skilled in the art, for example by using a suitable coupling reagent, for example 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • a suitable coupling reagent for example 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • Amines of the general formula SM02, in which R 2 and R 3 denote hydrogen, herein thereafter referred to as SM02a can be prepared from substituted 2-hydroxyacetic acids of the general formula SM03, according to methods known to the person skilled in the art.
  • Enantiomerically pure amines of the general formula SM02a can be obtained from enantiomerically pure 2- hydroxyacetic acids of the general formula SM03.
  • 2-hydroxyacetic acids of the general formula SM03 can be transformed into the corresponding diols of the general formula IM05 according to methods known to the person skilled in the art, for example by employing a reducing agent, for example lithium aluminium hydride.
  • diols of the general formula IM05 can be transformed into the corresponding p-toluenesulfonic acid esters of the general formula IM06 according to methods known to the person skilled in the art, for example by treating with 4-toluenesulfonyl chloride.
  • p-toluenesulfonic acid esters of the general formula IM06 can be transformed into the corresponding nitrites general formula IM07 according to methods known to the person skilled in the art, for example by treating with sodium cyanide.
  • nitriles general formula IM07 can be transformed into the corresponding tert-butyl carbamates of the general formula IM08 according to methods known to the person skilled in the art, for example by treating with nickel(ll) chloride and sodium borohydride in the presence of di-tert-butyl dicarbonate.
  • tert-butyl carbamates of the general formula IM08 can be transformed into the corresponding amines of the general formula SM02a according to methods known to the person skilled in the art, for example by treating with hydrochloric acid.
  • amines of the general formula SM02 can be prepared from substituted 3- oxopropanenitriles of the general formula SM04, according to methods known to the person skilled in the art.
  • 3-oxopropanenitriles of the general formula SM04 can be transformed into the corresponding 3-hydroxypropanenitriles of the general formula IM09 according to methods known to the person skilled in the art, for example by employing a reducing agent, for example sodium borohydride, borane dimethyl sulfide complex or borane tetrahydrofuran complex (affording compounds in which R 5 denotes a hydrogen), optionally in presence of a suitable ligand, for example CBS-oxazaborolidines, or alternatively by treating with compounds of the general formula Y-R 5 , where Y denotes a metal or organometallic residue, for example sodium, magnesium bromide, magnesium chloride, or a residue to form an organometallic reagent, according to methods
  • 3- hydroxypropanenitriles of the general formula IM09 can be transformed into the corresponding tert-butyl carbamates of the general formula IM10 according to methods known to the person skilled in the art, for example by treating with nickel(ll) chloride and sodium borohydride in the presence of di-tert-butyl dicarbonate.
  • tert-butyl carbamates of the general formula IM10 can be transformed into the corresponding amines of the general formula SM02 according to methods known to the person skilled in the art, for example by treating with hydrochloric acid.
  • a plurality of additional synthesis paths to compounds of the general formulae SM02, SM02a, SM03, SM04 with a very broad substitution pattern for residues R 2 to R 5 are known in the current specialist literature.
  • Previously unknown intermediates of the general formulae SM02, SM02a, SM03, S 04 with similar substitution patterns for residues R 2 to R 5 as outlined above and whose syntheses are not described in greater detail can be produced by the person skilled in the art according to these known methods or by combination of the known methods.
  • the indication mushroomsM are indications of concentration in mol/l, “d” means days, “brine” means saturated aqueous sodium chloride solution, “h” means hour(s), “MS” means mass spectrometry, “RT” means room temperature (23 ⁇ 7 °C), “TLC” means thin layer chromatography, “v/v” means volume to volume.
  • the stationary phase used for the column chromatography was silica gel 60 (0.04 - 0.063 mm) from E. Merck, Darmstadt. All starting materials which are not explicitly described were either commercially available (the details of suppliers such as for example Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc.
  • the mixing ratios of solvents or eluents for chromatography are specified in v/v.
  • the crude product is purified by flash chromatography (silica gel, 25% ethyl acetate/cyclohexane) to yield 2-chloro-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid ethyl ester (10.5 g, 36.9 mmol, 29%).
  • the crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield the first eluting diastereomer of 2-cyclopropyl-N-([2-hydroxy- cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 4a) (0.34 g, 0.95 mmol, [M+H] + 360.2) and the second eluting diastereomer of 2-cyclopropyl- N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 4b) (0.27 g, 0.75 mmol, [M+H] + 360.2) as white solids.
  • the modulation of the KCNQ opening state (and consequently the voltage potential of a cell) by test compounds such as compounds according to the present invention results in an increased or reduced amount of a voltage-sensitive dye in the cytoplasm of the cells tested.
  • These voltage-sensitive dyes are fluorescent dyes and, therefore, are forming the link between cell potential influenced by KCNQ modulation and fluorescence intensity.
  • a KCNQ agonist leads to an opening of the channel, potassium and dye efflux, a following hyperpolarization and a reduction of the inner fluorescence intensity in a kinetic protocol. If applying an ion jump by KCI depolarization, KCNQ agonists increase the AF/F value. An antagonist performs vice versa, respectively.
  • the ' fluorimetry EC 50 ' is the half maximum effective concentration (EC 50 ), where the concentration of a drug/compound induces a response halfway between the baseline and maximum plateau effect.
  • said value represents the concentration of a compound, where 50% of its maximal effect in the fluorimetric assay is observed if the substance concentration is graphed against the corresponding AF/F values (for which the calculation method is described below). Therefore, ' fluorimetry EC 50 ' is a measure for the compound potency.
  • the compound efficacy is mirrored by 'fluorimetry % efficacy ' ('%Efficacy ' ) and refers to the maximum response achievable by the test compound, i.e. the plateau effect.
  • This drug ' s plateau effect is related to the plateau effect, which can be achieved by applying a saturated concentration of a reference compound, e.g. Retigabine (50 ⁇ ), in independent wells of the same experimental plate or series.
  • a reference compound e.g. Retigabine (50 ⁇ )
  • a compound showing 100% efficacy is as efficacious as the reference compound (Retigabine) with a saturated concentration.
  • This calculation ' %Efficacy' method was introduced in order to normalize the AF/F values of different experiments to a common comparator compound, and make the test drug effects comparable.
  • Human CHO-K1 cells expressing KCNQ2/3 channels are cultivated adherently at 37°C, 5% C0 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 (1x, liquid, Invitrogen, #22571), 10% fetal calf serum (FCS) (Invitrogen, #10270-106, heat-inactivated) and the necessary selection antibiotics.
  • FCS fetal calf serum
  • the cells are washed with 1 x DPBS buffer Ca 2+ /Mg 2+ -free (e.g. Invitrogen, #14190-094) and detached from the bottom of the culture vessel by using Accutase (PAA Laboratories, #L1 1-007) (incubation with Accutase for 15 min at 37°C).
  • the cell number is determined using a CASYTM cell counter (TCC, Scharfe System).
  • 20,000-30,000 cells/well/100 ⁇ are seeded onto 96-well CorningTM CellBINDTM assay plates (Flat Clear Bottom Black Polystyrene Microplates, #3340).
  • the voltage-sensitive fluorescent dye from the Membrane Potential Assay Kit (Red Bulk format part R8123 for FLIPR, MDS Analytical TechnologiesTM) is prepared by dissolving the contents of one vessel Membrane Potential Assay Kit Red Component A in 200 ml of extracellular buffer (ES buffer, 120 mM NaCI, 1 mM KCI, 10 mM HEPES, 2 mM CaCI 2 , 2 mM MgCI 2 , 10 mM glucose; pH 7.4). After removal of the nutrient medium, the cells are washed once with 200 ⁇ of ES buffer, then loaded for 45 min at room temperature in 100 ⁇ of dye solution in the dark.
  • ES buffer 120 mM NaCI, 1 mM KCI, 10 mM HEPES, 2 mM CaCI 2 , 2 mM MgCI 2 , 10 mM glucose; pH 7.4
  • Fluorescence measurements are carried out in a BMG Labtech FLUOstarTM, BMG Labtech NOVOstarTM or BMG Labtech POLARstarTM instrument (525 nm excitation, 560 nm emission, Bottom Read mode).
  • 50 ⁇ of the test substances in the desired concentrations, or 50 ⁇ of ES buffer for control purposes are applied to the wells of the assay plate and incubated for 30 min at room temperature while being shielded from light.
  • the fluorescence intensity of the dye is then measured for 5 min and the fluorescence value FT of each well is thus determined at a given, constant time.
  • 15 ⁇ of a KCI solution are then added to each well (final concentration of potassium ions 92 mM).
  • the change in fluorescence intensity is subsequently monitored until all the relevant 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 corrected for the fluorescence intensity F ⁇ and the activity (AF/F) of the target compound on the potassium channel is determined as follows:
  • F In order to determine whether a substance has agonistic activity, F can be related to
  • ⁇ F K of control wells is determined by adding to the well only the buffer solution instead of the test substance, determining the value F 1 K of the fluorescence intensity, adding the potassium ions as described above, and measuring a value F 2K of the fluorescence intensity.
  • F 2K and F 1 K are then calculated as follows:
  • a substance has an agonistic activity on the potassium channel if F is greater than f F ⁇
  • the determination of the antinociceptive effect of the compounds according to the invention towards an acute noxious thermal stimulus is carried out by measuring the withdrawal reflex of the rat tail (tail flick) in response to a radiant heat beam (analgesia meter; model 2011 of the company Rhema Labortechnik, Hofheim, Germany) according to the method described by D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941).
  • a radiant heat beam analgesia meter; model 2011 of the company Rhema Labortechnik, Hofheim, Germany
  • the stimulus intensity was adjusted to result in a mean pre-drug control withdrawal latency of about 7 s, thus also allowing a supraspinal modulation of the spinally mediated acute nociceptive reflex.
  • a cutoff time of 30 s was applied to avoid tissue damage.
  • Male Sprague- Dawley rats (Janvier, Le Genest St. Isle, Finland) with weights of 200-250 g were used. 10 rats were used per group. Before administration of a compound according to the invention, the animals were pre-tested twice in the course of five minutes and the mean of these measurements was calculated as the pre-test mean. The antinociceptive effect was determined at 20, 40 and 60 min after peroral compound administration.
  • T 0 is the control latency time before and T
  • T 2 is the cutoff time
  • MPE is the maximum possible effect.
  • Employing variant analysis (repeated measures ANOVA) allowed testing of statistically significant differences between the compounds according to the invention and the vehicle group. The significance level was set to p ⁇ 0.05.
  • the particular compound according to the invention was administered in 3-5 logarithmically increasing doses, including a threshold dose and a maximum effective dose, and the ED 50 values were determined with the aid of regression analysis. The ED 50 calculation was performed at the time of maximum efficacy (usually 20 min after administration of the compounds).

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Abstract

The invention relates to substituted 6-amino-nicotinamides bearing an OH-containing group, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

Description

Substituted 6-amino-nicotinamides bearing an OH-containing group as KCNQ2/3 modulators
The invention relates to substituted 6-amino-nicotinamides bearing an OH-containing group, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
The treatment of pain, in particular of neuropathic pain, is of great importance in medicine. There is a worldwide need for effective pain therapies. The urgent need for action for a target-orientated treatment of chronic and non-chronic states of pain appropriate for the patient, by which is to be understood the successful and satisfactory treatment of pain for the patient, is also documented in the large number of scientific works which have recently been published in the field of applied analgesics and of fundamental research into nociception.
A pathophysiological feature of chronic pain is the overexcitability of neurons. Neuronal excitability is influenced decisively by the activity of K+ channels, since these determine decisively the resting membrane potential of the cell and therefore 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 hyperpolarization 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 marrow (Passmore et a/., J. Neurosci. 2003; 23(18): 7227-36).
It has accordingly been possible to detect an analgesic activity in preclinical neuropathy and inflammatory pain models for the KCNQ2/3 agonist retigabine (Blackburn-Munro and Jensen, Eur J Pharmacol. 2003; 460(2-3); 109-16; Dost et a/., Naunyn Schmiedebergs Arch Pharmacol 2004; 369(4): 382-390).
The KCNQ2/3 K+ channel thus represents a suitable starting point for the treatment of pain; in particular of pain selected from the group consisting of chronic pain, acute pain, neuropathic pain, inflammatory pain, visceral pain and muscular pain (Nielsen et a/., Eur J Pharmacol. 2004; 487(1 -3): 93-103), in particular of neuropathic and inflammatory pain. Moreover, 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 (Korsgaard et al., J Pharmacol Exp Ther. 2005, 14(1 ): 282-92), epilepsy (Wickenden et a/., Expert Opin Ther Pat 2004; 14(4): 457-469; Gribkoff, Expert Opin Ther Targets 2008, 12(5): 565-81 ; Miceli et al., Curr Opin Pharmacol 2008, 8(1 ): 65-74), urinary incontinence (Streng et al., J Urol 2004; 172: 2054-2058), dependency (Hansen et al., Eur J Pharmacol 2007, 570(1 -3): 77-88), mania/bipolar disorders (Dencker et al., Epilepsy Behav 2008, 12(1 ): 49-53) and dystonia- associated dyskinesias (Richter et al., Br J Pharmacol 2006, 149(6): 747-53).
Substituted compounds that have an affinity for the KCNQ2/3 K+ channel are e.g. known from the prior art (WO 2008/046582, WO 2010/046108, WO 2010/102809 and WO 2002/066036).
DE 25 13 949 and GB 1 420 987 disclose substituted nicotinamides and derivatives thereof as coupling components for the preparation of azo dyes.
There is a demand for further compounds having comparable or better properties, not only with regard to affinity to KCNQ2/3 K+ channels per se (potency, efficacy).
Thus, it may be advantageous to improve the metabolic stability, the solubility in aqueous media or the permeability of the compounds. These factors can have a beneficial effect on oral bioavailability or can alter the PK/PD (pharmacokinetic/pharmacodynamic) profile; this can lead to a more beneficial period of effectiveness, for example. A weak or non-existent interaction with transporter molecules, which are involved in the ingestion and the excretion of pharmaceutical compositions, is also to be regarded as an indication of improved bioavailability and at most low interactions of pharmaceutical compositions. Furthermore, the interactions with the enzymes involved in the decomposition and the excretion of pharmaceutical compositions should also be as low as possible, as such test results also suggest that at most low interactions, or no interactions at all, of pharmaceutical compositions are to be expected.
In addition, it may be advantageous if the compounds show a high selectivity towards other receptors of the KCNQ family {specificity), e.g. towards KCNQ1 , KCNQ3/5 or KCNQ4. A high selectivity may have a positive effect on the side effects profile: for example it is known that compounds which (also) have an affinity to KCNQ1 are likely to have a potential for cardial side effects. Therefore, a high selectivity towards KCNQ1 may be desirable. However, it may also be advantageous for the compounds to show a high selectivity towards other receptors. For instance, it may be advantageous for the compounds to show a low affinity for the hERG ion channel or the L-type calcium ion channel (phenylalkylamine-, benzothiazepin-, dihydropyridine-binding site) since these receptors are known to possibly have a potential for cardial side effects. Further, an improved selectivity towards binding to other endogenic proteins (i.e. receptors or enzymes) may result in a better side effects profile and, consequently to an improved tolerance.
It was therefore an object of the invention to provide new compounds having advantages over the compounds of the prior art. These compounds should be suitable in particular as pharmacological active ingredients in pharmaceutical compositions, preferably in pharmaceutical compositions for the treatment and/or prophylaxis of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K+ channels.
That object is achieved by the subject-matter of the patent claims and by the subject-matter described herein.
It has been found, surprisingly, that substituted compounds of the general formula (I) given below are suitable for the treatment of pain. It has also been found, surprisingly, that substituted compounds of the general formula (I) given below also have an excellent affinity for the KCNQ2/3 K+ channel and are therefore suitable for the prophylaxis and/or treatment of disorders and/or diseases that are mediated at least in part by KCNQ2/3 K+ channels. The substituted compounds thereby act as modulators, i.e. agonists or antagonists, of the KCNQ2/3 K+ channel.
The present invention therefore relates to a substituted compound of general formula (I),
Figure imgf000004_0001
R1 represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted; or a C3_6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and in each case optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or represents OR6, wherein
R6 represents a C -6-aliphatic residue, unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted;
R2 and R3 independently of one another represent H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-aliphatic residue, or an 0-C1-4 aliphatic residue, wherein the Ci-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom (to the remaining part of the superordinate structure, i.e. of general formula (I)),
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; a C -4-aliphatic residue, wherein the C -4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom (to the remaining part of the superordinate structure, i.e. of general formula (I)), or
R2 and R3
and/or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.i0-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and the respective remaining substituents of R2 and R3 each independently of one another represent H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4- aliphatic residue, or an 0-C1-4 aliphatic residue, wherein the C -4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; a C1-4-aliphatic residue, wherein the C1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R4 together with the carbon atoms connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and R3 represents H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C -4-aliphatic residue, or an O-C^ aliphatic residue, wherein the C1- aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; and R5 represents H; CH2F; CHF2; CF3; a C^-aliphatic residue, wherein the C1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if R5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, in which an "aliphatic group" and an "aliphatic residue" can in each case be branched or unbranched, saturated or unsaturated, in which a "cycloaliphatic residue" and a "heterocycloaliphatic residue" can in each case be saturated or unsaturated, in which "mono- or polysubstituted" with respect to an "aliphatic group" and an "aliphatic residue" relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an (C!.4 aliphatic residue)2, a NH-C(=0)-C1- aliphatic residue, a N(C1-4-aliphatic residue)-
Figure imgf000007_0001
residue)- S(=0)2-C1-4 aliphatic residue, =0, OH, OCH2F, OCHF2, OCF3, a 0-C1-4-aliphatic residue, a O- C(=0)-C1.4-aliphatic residue, SH, SCF3, a S-C|.4-aliphatic residue, S(=0)2OH, a S(=0)-C - - aliphatic residue, a S(=0)2-C1.4-aliphatic residue, a S(=0)2-0-C1- -aliphatic residue, a S(=0)2- NH-C1-4-aliphatic residue, a S(=0)2-N(C1-4-aliphatic residue)2, CN, CH2F, CHF2, CF3, CHO, COOH, a C^-aliphatic residue, CH2OH, CH2-OCH3, C2H4-OH, C2H4-OCH3 CH2-CF3, a
Figure imgf000007_0002
residue, a C3.6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0)-NH2, a C(=0)-NH(d. aliphatic residue), and a C(=0)-N(C1-4 aliphatic residue)2; in which "mono- or polysubstituted" with respect to a "cycloaliphatic residue" and a "heterocycloaliphatic residue" relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a
Figure imgf000007_0003
aliphatic residue, a N(C1- - aliphatic residue)-C(=0)-C1- aliphatic residue, a NH-S(=0)2-C1- aliphatic residue, a N(Ci-4- aliphatic residue)-S(=0)2-C1-4 aliphatic residue, =0, OH, OCH2F, OCHF2, OCF3, a 0-Ci-4- aliphatic residue, a 0-C(=0)-C . -aliphatic residue, SH, SCF3, a S-C^-aliphatic residue, S(=0)2OH, a
Figure imgf000007_0004
aliphatic residue, a S(=0)2-NH-C1- -aliphatic residue, a S(=0)2-N(C1.4-aliphatic residue)2, CN, CH2F, CHF2, CF3, CHO, COOH, a C1-4-aliphatic residue, CH2OH, CH2-OCH3, C2H4-OH, C2H4-OCH3 CH2-CF3, a C(=0)-C1-4-aliphatic residue, a C(=0)-0-C1.4-aliphatic residue, a C3.6- cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0)-NH2, a C(=0)- NH(C1-4 aliphatic residue), and a 0(=0)-Ν(01-4 aliphatic residue)2; optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof and/or a physiologically acceptable solvate, in particular hydrate, thereof.
The term "single stereoisomer" preferably means in the sense of the present invention an individual enantiomer or diastereomer. The term "mixture of stereoisomers" preferably means in the sense of this invention the racemate and mixtures of enantiomers and/or diastereomers in any mixing ratio.
The term "physiologically acceptable salt" preferably comprises in the sense of this invention a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base.
A physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid which is physiologically acceptable - in particular when used in human beings and/or other mammals. Examples of physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, p- toluenesulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1 -sulphonic acid, nicotinic acid, 2, 3 or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, a-lipoic acid, acetyl glycine, hippuric acid, phosphoric acid, aspartic acid. Citric acid and hydrochloric acid are particularly preferred. Hydrochloride salts and citrate salts are therefore particularly preferred salts.
A physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention as an anion with at least one preferably inorganic cation, which is physiologically acceptable - in particular when used in human beings and/or other mammals. Particularly preferred are the salts of the alkali and alkaline earth metals but also ammonium salts [NHXR4-X]+, in which x = 0, 1 , 2, 3 or 4 and R represents a branched or unbranched C1-4 aliphatic residue residue, in particular (mono-) or (di)sodium, (mono-) or (di)potassium, magnesium or calcium salts.
The terms "Ci.6-aliphatic residue", "C2.6-aliphatic residue", and "d^-aliphatic residue", preferably comprise in the sense of this invention acyclic saturated or unsaturated aliphatic hydrocarbon residues, which can be branched or unbranched and also unsubstituted or mono- or polysubstituted, containing 1 to 6, or 2 to 6, or 1 to 4 carbon atoms, respectively, i.e. Ci-6 alkanyls, C2-6 alkanyls, C2.6 alkenyls and C2.6 alkynyls as well as C1-4 alkanyls, C2-4 alkenyls and C2.4 alkynyls, respectively. In this case, alkenyls comprise at least one C-C double bond (a C=C-bond) and alkynyls comprise at least one C-C triple bond (a C≡C-bond). Preferably, aliphatic residues are selected from the group consisting of alkanyl (alkyl) and alkenyl residues, more preferably are alkanyl residues. Preferred Ci_6 alkanyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert. -butyl, n-pentyl, isopentyl, neopentyl and n-hexyl. Preferred C -4 alkanyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl and tert. -butyl. Preferred C2.6 alkenyl residues are selected from the group consisting of ethenyl (vinyl), propenyl (-CH2CH=CH2, -CH=CH-CH3, -C(=CH2)-CH3), butenyl, pentenyl and hexenyl. Preferred C2-4 alkenyl residues are selected from the group consisting of ethenyl (vinyl), propenyl (-CH2CH=CH2, -CH=CH-CH3, -C(=CH2)-CH3) and butenyl. Preferred C2.6 alkynyl residues are selected from the group consisting of ethynyl, propynyl (-CH2-C≡CH, -C≡C-CH3), butynyl, pentynyl and hexynyl Preferred C2.4 alkynyl residues are selected from the group consisting of ethynyl, propynyl (-CH2-C≡CH, -C≡C-CH3) and butynyl.
The terms "C3.6.cycloaliphatic residue" and "C3.10.cycloaliphatic residue" preferably mean for the purposes of this invention cyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbon atoms and 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively, wherein the hydrocarbons in each case can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted. The cycloaliphatic residues can be bound to the respective superordinate general structure via any desired and possible ring member of the cycloaliphatic residue. The cycloaliphatic residues can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. with cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residues which can in turn be unsubstituted or mono- or polysubstituted. C3-10 cycloaliphatic residue can furthermore be singly or multiply bridged such as, for example, in the case of adamantyl, bicyclo[1.1.1 Jpentyl, bicyclo[2.2.1 ]heptyl or bicyclo[2.2.2]octyl. Preferred C3.10 cycloaliphatic residues are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
Figure imgf000009_0001
cyclononyl, cyclodecyl, adamantyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Preferred C3.6 cycloaliphatic residues are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.
The terms "3-6-membered heterocycloaliphatic residue", "4-7-membered heterocycloaliphatic residue" and "3-10-membered heterocycloaliphatic residue" preferably mean for the purposes of this invention heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3-6, i.e. 3, 4, 5 or 6 ring members, and 4-7, i.e. 4, 5, 6 or 7 ring members, and 3-10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 ring members, respectively, in which in each case at least one, if appropriate also two or three carbon atoms are replaced by a heteroatom or a heteroatom group each selected independently of one another from the group consisting of O, S, S(=0)2, N, NH and N(C1-8 alkyl), preferably N(CH3), wherein the ring members can be unsubstituted or mono- or polysubstituted. The heterocycloaliphatic residue can be bound to the superordinate general structure via any desired and possible ring member of the heterocycloaliphatic residue if not indicated otherwise. The heterocycloaliphatic residues can also be condensed with further saturated, (partially) unsaturated (hetero)cycloaliphatic or aromatic or heteroaromatic ring systems, i.e. with cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residues, which can in turn be unsubstituted or mono- or polysubstituted. The term "condensed" also optionally includes spirocycles, i.e. an at least bicyclic ring system, wherein the heterocycloaliphatic residue is connected through just one (spiro)atom with a further saturated, (partially) unsaturated system. Example of such spiro
Figure imgf000010_0001
heterocycloaliphatic residues can furthermore optionally be singly or multiply bridged with a d- or C2-aliphatic group such as, for example, in the case of
Figure imgf000010_0002
Preferred heterocycloaliphatic residues are selected from the group consisting of azetidinyl, aziridinyl, azepanyl, azocanyl, diazepanyl, dithiolanyl, dihydroquinolinyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dioxepanyl, dihydroindenyl, dihydropyridinyl, dihydrofuranyl, dihydroisoquinolinyl, dihydroindolinyl, dihydroisoindolyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, oxetanyl, oxazepanyl, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroindolinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrahydropyridoindolyl, tetrahydronaphthyl, tetrahydrocarbolinyl, tetrahydroisoxazolo- pyridinyl, thiazolidinyl, tetrahydroimidazo[1 ,2-a]pyrazinyl, octahydropyrrolo[1 ,2-a]pyrazinyl and thiomorpholinyl. More preferred heterocycloaliphatic residues are pyrrolidinyl, piperidinyl, oxazepanyl, azetidinyl, morpholinyl, piperazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolinyl, and dihydroisoindolyl. Most preferred heterocycloaliphatic residues are pyrrolidinyl, piperidinyl, oxazepanyl, azetidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolinyl, and dihydroisoindolyl.
The term "aryl" preferably means for the purpose of this invention aromatic hydrocarbons having 6 to 14 ring members, i.e. 6, 7, 8, 9, 10, 11 , 12, 13 or 14 ring members, including phenyls and naphthyls. Each aryl residue can be unsubstituted or mono- or polysubstituted, wherein the aryl substituents can be the same or different and in any desired and possible position of the aryl. The aryl can be bound to the superordinate general structure via any desired and possible ring member of the aryl residue. The aryl residues can also be condensed with further saturated, (partially) unsaturated, (hetero)cycloaliphatic, aromatic or heteroaromatic ring systems, i.e. with a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residue, which can in turn be unsubstituted or mono- or polysubstituted. Examples of condensed aryl residues are benzodioxolanyl and benzodioxanyl. Preferably, aryl is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, fluorenyl and anthracenyl, each of which can be respectively unsubstituted or mono- or polysubstituted. A particularly preferred aryl is phenyl, unsubstituted or mono- or polysubstituted.
The term "heteroaryl" for the purpose of this invention preferably represents a 5 or 6- membered cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted; in the case of substitution on the heteroaryl, the substituents can be the same or different and be in any desired and possible position of the heteroaryl. The binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue. The heteroaryl can also be part of a bi- or polycyclic system having up to 14 ring members, wherein the ring system can be formed with further saturated, (partially) unsaturated, (hetero)cycloaliphatic or aromatic or heteroaromatic rings, i.e. with a cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl residue, which can in turn be unsubstituted or mono- or polysubstituted. It is preferable for the heteroaryl residue to be selected from the group consisting of benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl. Furyl, pyridyl, oxazolyl, thiazolyl and thienyl are particularly preferred.
The term "cycloaliphatic residue bridged via a C1-4-aliphatic group" preferably means for the purpose of the invention that the expression "cycloaliphatic residue" has the above-defined meaning and that said residue is bound to the respective superordinate general structure via a C1- -aliphatic group. The Ci. aliphatic group can in all cases be branched or unbranched, unsubstituted or mono- or polysubstituted. The C1-4 aliphatic group can in all cases be furthermore saturated or unsaturated, i.e. can be a Ci.4 alkylene group, a C2.4 alkenylene group or a C2-4 alkynylene group. Preferably, the C1-4-aliphatic group is a Ci_ alkylene group or a C2-4 alkenylene group, more preferably a C1- alkylene group. Preferred C -4 alkylene groups are selected from the group consisting of -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2- CH2-, -CH(CH3)-CH2-, -CH(CH2CH3)-, -CH2-(CH2)2-CH2-, -CH(CH3)-CH2-CH2-, -CH2- CH(CH3)-CH2-, -CH(CH3)-CH(CH3)-, -CH(CH2CH3)-CH2-, -C(CH3)2-
CH2-, -CH(CH2CH2CH3)- and -C(CH3)(CH2CH3)-. Preferred C2.4 alkenylene groups are selected from the group consisting of -CH=CH-, -CH=CH-CH2-, -C(CH3)=CH2-, -CH=CH-CH2- CH2-, -CH2-CH=CH-CH2-, -CH=CH-CH=CH-, -C(CH3)=CH-CH2-, -CH=C(CH3)- CH2-, -C(CH3)=C(CH3)- and -C(CH2CH3)=CH-. Preferred C2.4 alkynylene groups are selected from the group consisting of -C≡C-, -C≡C-CH2-, -C≡C-CH2-CH2-, -C≡C-CH(CH3)-, -CH2-C≡C- CH2- and -C≡C-C≡C-.
In relation to "aliphatic residue" and "aliphatic group" the term "mono- or polysubstituted" preferably refers in the sense of this invention, with respect to the corresponding residues or groups, to the single substitution or multiple substitution, e.g. disubstitution, trisubstitution and tetrasubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci- aliphatic residue), an N(C -4 aliphatic residue)2, a NH-C(=0)-C . aliphatic residue, a N(C1-4 aliphatic residue)-C(=0)-C1-4 aliphatic residue, a NH-S(=0)2-C1.4 aliphatic residue, N(C1-4 aliphatic residue)-S(=0)2-C1-4 aliphatic residue, =0, OH, OCH2F, OCHF2, OCF3, a O- C1- -aliphatic residue, a 0-C(=0)-C1- -aliphatic residue, SH, SCF3, a S-C1-4-aliphatic residue, S(=0)2OH, a
Figure imgf000012_0001
residue, a S(=0)2-0-C1-4- aliphatic residue, a S(=0)2-NH-C1- -aliphatic residue, a S(=0)2-N(C1- -aliphatic residue)2, CN, CH2F, CHF2, CF3, CHO, COOH, a C1-4-aliphatic residue, CH2OH, CH2-OCH3, C2H4-OH, C2H4-OCH3 CH2-CF3, a
Figure imgf000012_0002
residue, a C3.6- cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0)-NH2, a C(=0)- NH(C1-4 aliphatic residue), and a C(=0)-N(C1. aliphatic residue)2. The term "polysubstituted" with respect to polysubstituted residues and groups includes the polysubstitution of these residues and groups either on different or on the same atoms, for example trisubstituted on the same carbon atom, as in the case of CF3 or CH2CF3, or at various points, as in the case of CH(OH)-CH=CH-CHCI2. A substituent can if appropriate for its part in turn be mono- or polysubstituted. The multiple substitution can be carried out using the same or using different substituents.
In relation to "cycloaliphatic residue" and "heterocycloaliphatic residue" the term "mono- or polysubstituted" preferably refers in the sense of this invention, with respect to the corresponding residues, to the single substitution or multiple substitution, e.g. disubstitution, trisubstitution and tetrasubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH-C(=0)-C1-4 aliphatic residue, a N(d.4 aliphatic residue)-C(=0)-C1.4 aliphatic residue, a NH-S(=0)2-C -4 aliphatic residue, a N(C-|.4 aliphatic residue)-S(=0)2-C1- aliphatic residue, =0, OH, OCH2F, OCHF2, OCF3, a 0-C1-4-aliphatic residue, a 0-C(=0)-d. -aliphatic residue, SH, SCF3, a S-d- 4-aliphatic residue, S(=0)2OH, a S(=0)-d. -aliphatic residue, a S(=0)2-C1.4-aliphatic residue, a S(=0)2-0-d. -aliphatic residue, a S(=0)2-NH-d. -aliphatic residue, a S(=0)2-N(d.4- aliphatic residue)2, CN, CH2F, CHF2, CF3, CHO, COOH, a d.4-aliphatic residue, CH2OH, CH2-OCH3, C2H4-OH, C2H4-OCH3 CH2-CF3, a C(=0)-C1-4-aliphatic residue, a C(=0)-0-C - aliphatic residue, a C3.6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0)-NH2, a C(=0)-NH(d. aliphatic residue), and a C(=0)-N(C1-4 aliphatic residue)2. The term "polysubstituted" with respect to polysubstituted residues and groups includes the polysubstitution of these residues and groups either on different or on the same atoms, for example disubstituted on the same carbon atom, as in the case of 1 ,1- difluorocyclohexyl, or at various points, as in the case of 1-chloro-3-fluorocyclohexyl. A substituent can if appropriate for its part in turn be mono- or polysubstituted. The multiple substitution can be carried out using the same or using different substituents.
Preferred substituents of "aliphatic residue" and "aliphatic group" are selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1- aliphatic residue)2, =0, OH, OCH2F, OCHF2, OCF3, a 0-C1-4-aliphatic residue, SH, SCF3, a S-C1- - aliphatic residue, a S(=0)-d.4-aliphatic residue, a S(=0)2-C .4-aliphatic residue, a S(=0)2- NH-C1-4-aliphatic residue, a S(=0)2-N(C1-4-aliphatic residue)2, CN, CH2F, CHF2, CF3, a C1-4- aliphatic residue, CH2OH, CH2-OCH3, C2H4-0H, C2H4-OCH3 CH2-CF3, a C(=0)-C1-4-aliphatic residue, a C(=0)-0-C1- -aliphatic residue, C0NH2, a C(=0)-NH(C1-4 aliphatic residue), and a C(=0)-N(C1- aliphatic residue)2. Preferred substituents of "cycloaliphatic residue" and "heterocycloaliphatic residue" are selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, =0, OH, OCH2F, OCHF2, OCF3, a 0-C1-4-aliphatic residue, SH, SCF3, a S-C - -aliphatic residue, a S(=0)-C1.4-aliphatic residue, a S(=0)2-C1.4-aliphatic residue, a S(=0)2-NH-C1.4-aliphatic residue, a S(=0)2-N(C . -aliphatic residue)2, CN, CH2F, CHF2, CF3, a d.4-aliphatic residue, CH2OH, CH2-OCH3, C2H4-OH, C2H4-OCH3 CH2-CF3, a
Figure imgf000014_0001
aliphatic residue), and a C(=0)-N(C1.4 aliphatic residue)2.
The compounds according to the invention are defined by substituents, for example by R1, R2 and R3 (1st generation substituents) which are for their part if appropriate substituted (2nd generation substituents). Depending on the definition, these substituents of the substituents can for their part be re-substituted (3rd generation substituents). If, for example, R1 is = a C2.6 aliphatic residue (1 st generation substituent), then the C2.6 aliphatic residue can for its part be substituted, for example with a NH-C1-4 aliphatic residue (2nd generation substituent). This produces the functional group R1 = (C2.6 aliphatic residue-NH-C1-4 aliphatic residue). The NH- C1- aliphatic residue can then for its part be resubstituted, for example with CI (3rd generation substituent). Overall, this produces the functional group R1 = C2.6 aliphatic residue-NH-C^ aliphatic residue, wherein the Ci.4 aliphatic residue of the NH-C1- aliphatic residue is substituted by CI.
However, in a preferred embodiment, the 3rd generation substituents may not be resubstituted, i.e. there are then no 4th generation substituents.
In another preferred embodiment, the 2nd generation substituents may not be resubstituted, i.e. there are then not even any 3rd generation substituents. In other words, in this embodiment, in the case of general formula (I), for example, the functional groups for R1 to R5 can each if appropriate be substituted; however, the respective substituents may then for their part not be resubstituted.
In some cases, the compounds according to the invention are defined by substituents which are or carry an aryl or heteroaryl residue, respectively unsubstituted or mono- or polysubstituted, or which form together with the carbon atom(s) or heteroatom(s) connecting them, as the ring member or as the ring members, a ring, for example an aryl or heteroaryl, in each case unsubstituted or mono- or polysubstituted. Both these aryl or heteroaryl residues and the (hetero)aromatic ring systems formed in this way can if appropriate be condensed with a cycloaliphatic, preferably a C3.6 cycloaliphatic residue, or heterocycloaliphatic residue, preferably a 3 to 6 membered heterocycloaliphatic residue, or with aryl or heteroaryl, e.g. with a C3.6 cycloaliphatic residue such as cyclopentyl, or a 3 to 6 membered heterocycloaliphatic residue such as morpholinyl, or an aryl such as phenyl, or a heteroaryl such as pyridyl, wherein the cycloaliphatic or heterocycloaliphatic residues, aryl or heteroaryl residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted.
In some cases, the compounds according to the invention are defined by substituents which are or carry a cycloaliphatic residue or a heterocycloaliphatic residue, respectively, in each case unsubstituted or mono- or polysubstituted, or which form together with the carbon atom(s) or heteroatom(s) connecting them, as the ring member or as the ring members, a ring, for example a cycloaliphatic or a heterocycloaliphatic ring system. Both these cycloaliphatic or heterocycloaliphatic ring systems and the (hetero)cycloaliphatic ring systems formed in this manner can if appropriate be condensed with aryl or heteroaryl, preferably selected from the group consisting of phenyl, pyridyl and thienyl, or with a cycloaliphatic residue, preferably a C3.6 cycloaliphatic residue, or a heterocycloaliphatic residue, preferably a 3 to 6 membered heterocycloaliphatic residue, e.g. with an aryl such as phenyl, or a heteroaryl such as pyridyl, or a cycloaliphatic residue such as cyclohexyl, or a heterocycloaliphatic residue such as morpholinyl, wherein the aryl or heteroaryl residues or cycloaliphatic or heterocycloaliphatic residues condensed in this way can for their part be respectively unsubstituted or mono- or polysubstituted. e scope of the present invention, the symbol
Figure imgf000015_0001
used in the formulae denotes a link of a corresponding residue to the respective superordinate general structure.
If a residue occurs multiply within a molecule, then this residue can have respectively different meanings for various substituents: if, for example, both R2 and R3 denote a C1- - aliphatic residue, then the C1- -aliphatic residue residue can e.g. represent methyl for R2 and can represent ethyl for R3.
In a preferred embodiment of the compound according to general formula (I) the particular radicals R2-R5 have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof and R1 represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted, optionally bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted.
In another preferred embodiment of the compound according to general formula (I) the particular radicals R2-R5 have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof and
R1 represents OR6, wherein R6 represents a Ci-6-aliphatic residue, unsubstituted or mono- or polysubstituted.
Preferred embodiments of the compound according to general formula (I) are compounds which have the general formulae (l-a) and/or (l-b):
Figure imgf000016_0001
(l-a), (l-b), wherein the particular radicals R2, R3, R4, and R5, have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.
Another preferred embodiment of the compound according to general formula (I) is a compound which has the general formula (l-c),
Figure imgf000016_0002
(l-c), wherein the particular radicals R1 , R2 and R4 have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof. Further preferred embodiments of the compound according to general formula (I) are compounds which have the general formula (l-d) and/or (l-e),
Figure imgf000017_0001
(l-d) (l-e), wherein the particular radicals R2 and R4 have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.
Further preferred embodiments of the compound according to general formula (I) are compounds which have the general formula (l-f) and/or (l-g),
Figure imgf000017_0002
(l-f) (i-g), wherein the particular radical R1 has the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.
Yet another preferred embodiment of present invention is a compound according to general formula (I), wherein
R1 represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a S(=0)-C1-4- aliphatic residue, a S(=0)2-C1-4-aliphatic residue, CN, and a Ci.4-aliphatic residue, wherein the Ci-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4-aliphatic residue, or represents a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(d.4 aliphatic residue), an Ν(01-4 aliphatic residue)2, OH, =0, an 0-C1- - aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C^-aliphatic residue, a S(=0)-C1- -aliphatic residue, a S(=0)2-C1.4-aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue, and wherein the C3.6-cycloaliphatic residue may optionally be bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4-aliphatic residue, or represents OR6, wherein
R6 represents a C -6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C 4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a
Figure imgf000018_0001
aliphatic residue, CN, and a C^-aliphatic residue; wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, 0CF3, CH2F, CHF2, CF3 and an unsubstituted 0-C - -aliphatic residue, R2 and R3 independently of one another represent H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-aliphatic residue, or an O-C1.4 aliphatic residue, wherein the C^-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4- aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an U{C .4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a S(=0)-C1-4-aliphatic residue, a S(=0)2-C - -aliphatic residue, CN, and a C - -aliphatic residue, wherein the C - -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4- aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; a C^-aliphatic residue, wherein the C1-4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an O-C^-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C -4-aliphatic residue, a S(=0)-Cm-aliphatic residue, a S(=0)2-C1.4-aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4- aliphatic residue, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R3
and/or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci_4 aliphatic residue), an NKC^ aliphatic residue)2, OH, =0, an O-C^-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a
Figure imgf000020_0001
Ci-4-aliphatic residue, CN, and a C1- -aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-Ci.4- aliphatic residue, and the respective remaining substituents of R2 and R3 each independently of one another represent H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4- aliphatic residue, or an 0-C1- aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, 0CF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4- aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C-i-4 aliphatic residue), an N(Ci.4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C -4-aliphatic residue, a S(=0)-C .4-aliphatic residue, a S(=0)2-C1.4-aliphatic residue, CN, and a C -4-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4- aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4- aliphatic residue, or represent a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1- aliphatic residue), an N(Ci-4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-Ci.4-aliphatic residue, a S(=0)-C . -aliphatic residue, a S(=0)2-C1-4-aliphatic residue, CN, and a C1- -aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, 0CH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4- aliphatic residue, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or R2 and R4 together with the carbon atoms connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-d.4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-d.4-aliphatic residue, a
Figure imgf000022_0001
residue, CN, and a C1- -aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstltuted 0-C1-4- aliphatic residue, and the remaining substituent R3 represents H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C - -aliphatic residue, or an 0-Ci. aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstltuted 0-d.4- aliphatic residue, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci- aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-d.4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-d.4-aliphatic residue, a
Figure imgf000022_0002
residue, CN, and a d. -aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstltuted 0-C1-4- aliphatic residue, and the remaining substituent R5 represents H; CH2F; CHF2; CF3; a d.4-aliphatic residue, wherein the C1- -aliphatic residue may be unsubstltuted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4-aliphatic residue, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NHiC^ aliphatic residue), an N(C -4 aliphatic residue)2, OH, =0, an O-C aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a
Figure imgf000023_0001
residue, CN, and a C -4-a!iphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4- aliphatic residue, on the condition that if R5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom.
In another preferred embodiment of the compound according to general formula (I), the residue
R1 represents a C2.6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(d.4 aliphatic residue)2, OH, =0, an O-d^-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C^-aliphatic residue, a S(=0)-C1-4- aliphatic residue, a S(=0)2-C1-4-aliphatic residue, CN, and a Ci- -aliphatic residue, wherein the Ci.4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4-aliphatic residue, or represents a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(d. aliphatic residue)2, OH, =0, an 0-C1-4- aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C^-aliphatic residue, a
Figure imgf000023_0002
residue, a residue, CN, and a C -4-aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-Ci.4-aliphatic residue, or represents OR6, wherein
R6 represents a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a S(=0)-C1. -aliphatic residue, a S(=0)2-C1- - aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, 0CH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4-aliphatic residue.
Preferably,
R1 represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci-4 aliphatic residue), an N(C1- aliphatic residue)2, OH, =0, an 0-Ci. -aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a S(=0)-C1-4- aliphatic residue, a S(=0)2-C1-4-aliphatic residue, CN, and a Ci_4-aliphatic residue, wherein the C1- -aliphatic residue is in each case unsubstituted, or represents a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(Ci-4 aliphatic residue)2, OH, =0, an 0-Ci.4- aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a S^OJ-C^-aliphatic residue, a S(=0)2-C . -aliphatic residue, CN, and a C1- -aliphatic residue, wherein the C -4-aliphatic residue is in each case unsubstituted, or represents OR , wherein
R6 represents a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(d.4 aliphatic residue), an N(d.4 aliphatic residue)2, OH, =0, an 0-d.4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-d.4-aliphatic residue, a S(=0)-C1.4-aliphatic residue, a S(=0)2-C1-4- aliphatic residue, CN, and a C - -aliphatic residue, wherein the C - -aliphatic residue is in each case unsubstituted.
More preferably,
R represents a C2.6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-d.4-aliphatic residue, or represents a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue, or represents OR6, wherein
R6 represents a C -4-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue.
Even more preferably,
R1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), ethenyl or propenyl (-CH2CH=CH2, -CH=CH-CH3, -C(=CH2)-CH3), or represents a C3.6-cycloaliphatic residue, preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted O- C1-4-aliphatic residue, preferably unsubstituted, or represents OR6, wherein
R6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, CH2OH, CH2OCH3, CH2CH2OH, CH2CH2OCH3, and CH(OH)CH2OH.
In particular,
R represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OR6, wherein R6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
Most preferred,
R1 represents ethyl, n-propyl, 2-propyl, tert.-butyl, or cyclopropyl.
In another preferred embodiment of the compound according to general formula (I), the residues
R2 and R3 independently of one another represent H; F; CI; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a C -4-aliphatic residue, or an 0-Ci.4 aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4- aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted O-C^-aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; a Ci.4-aliphatic residue, wherein the Ci.4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1- -aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an O-C^-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1- - aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R3
and/or R4 and R5, preferably R2 and R3 or R4 and R5, in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3. 0-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, preferably a C3.10-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-Ci_ -aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4-aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1- -aliphatic residue,, and the respective remaining substituents of R2 and R3 each independently of one another represent H; F; CI; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a C1-4-aliphatic residue, or an O-C^ aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, 0CHF2, OCF3, and a C1-4- aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; a C1-4-aliphatic residue, wherein the C -4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci. -aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4- aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci.4-aliphatic residue, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R4 together with the carbon atoms connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, preferably a C3.10-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an O-C^-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C^-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci.4-aliphatic residue, and the remaining substituent R3 represents H; F; CI; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a C^-aliphatic residue, or an 0-C1-4 aliphatic residue, wherein the C^-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted O-C^-aliphatic residue, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C-,.4- aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci. -aliphatic residue, and the remaining substituent R5 represents H; FCH2F; CHF2; CF3; a C^-aliphatic residue, wherein the C-|.4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1- -aliphatic residue, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4- aliphatic residue, wherein the Ci_4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1- -aliphatic residue, on the condition that if R5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom.
Preferably,
R2 and R3 independently of one another represent H; F; CI; Br; I; CH2F; CHF2; CF3; OH; a Ci. 4-aliphatic residue, or an O-C^ aliphatic residue, wherein the C1- -aliphatic residue is in each case unsubstituted, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; a Ci.4-aliphatic residue,. wherein the C -4-aliphatic residue is unsubstituted, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R3
and/or R4 and R5, preferably R2 and R3 or R4 and R5, in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, preferably a C3.io-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1.4-aliphatic residue, CH2F, CHF2, CF3, and a Ci.4- aliphatic residue, wherein the C -4-aliphatic residue is in each case unsubstituted, and the respective remaining substituents of R2 and R3 each independently of one another represent H; F; CI; Br; I; CH2F; CHF2; CF3; OH; a C -4-aliphatic residue, or an 0-Ci-4 aliphatic residue, wherein the C1-4-aliphatic residue is in each unsubstituted, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; a C1- -aliphatic residue, wherein the C1- -aliphatic residue is in each unsubstituted, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R4 together with the carbon atoms connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, preferably a C3-10-cycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an O-C^-aliphatic residue, CH2F, CHF2, CF3, and a Ci. -aliphatic residue, wherein the C^-aliphatic residue is in each case unsubstituted, and the remaining substituent R3 represents H; F; CI; Br; I; CH2F; CHF2; CF3; OH; a C1- - aliphatic residue, or an 0-Ci. aliphatic residue, wherein the C -4-aliphatic residue is in each case unsubstituted, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted, and the remaining substituent R5 represents H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the C1-4-aliphatic residue is in each case unsubstituted, or represents a C3-6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, in each case unsubstituted, on the condition that if R5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom.
More preferably,
R2 and R3 independently of one another represent H; OH; an unsubstituted C1-4-aliphatic residue, or an unsubstituted 0-C1-4 aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; an unsubstituted d. 4-aliphatic residue, or
R2 and R3
or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.i0-cycloaliphatic residue, preferably a C3-6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, CH2F, CHF2, CF3, an unsubstituted 0-C - -aliphatic residue, and an unsubstituted C1-4-aliphatic residue, and the respective remaining substituents of R2 and R3 each independently of one another represent H; OH; an unsubstituted C1-4-aliphatic residue, or an unsubstituted 0-C1-4 aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; an unsubstituted C - -aliphatic residue, or
R2 and R4 together with the carbon atoms connecting them, form a C3. 0-cycloaliphatic residue, preferably a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an unsubstituted O-C^-aliphatic residue, CH2F, CHF2, CF3, and a an unsubstituted C1-4-aliphatic residue, and the remaining substituent R3 represents H; F; CI; Br; I; OH; an unsubstituted C1-4- aliphatic residue, or an unsubstituted 0-C1-4 aliphatic residue, and the remaining substituent R5 represents H; CH2F; CHF2; CF3; an unsubstituted Ci-4- aliphatic residue.
Even more preferably,
R2 and R3 independently of one another represent H; OH; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2- CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3,with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,; preferably represent H; methyl; ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2- CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3;, or
R2 and R3
or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituents of R2 and R3 each independently of one another represents H; OH; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, preferably represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3;, or
R2 and R4 together with the carbon atoms connecting them, form a C3.6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and R3 represents H; OH; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, preferably represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, and R5 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3.
Still more preferably,
R2 and R3 independently of one another represent H; OH; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2- CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, preferably represent H; methyl; ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2- CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3;, or
R2 and R4 together with the carbon atoms connecting them, form a C3-6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituent R3 represents H; OH; methyl; ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2- CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, preferably represent H; methyl; ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, and the respective remaining substituents R5 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2- CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3.
In another preferred embodiment of the compound according to general formula (I), at least one of R2, R3, R4 and R5 denotes H, preferably at least two of R2, R3, R4 and R5 denote H.
In yet another preferred embodiment of the compound according to general formula (I), at least one of R3 and R5 denotes H, preferably both R3 and R5 denote H.
In a further preferred embodiment of the compound according to general formula (I),
R1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OR6, wherein
R6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,
R2 and R3 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, or tert.-butyl, preferably R2 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, or tert.-butyl, and R3 denotes H,
R4 and R5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, or CF3; preferably R4 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, and CF3; and R5 denotes H, or
R2 and R3 or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3-6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n- propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituents of R2 and R3 in dependently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably R2 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, or tert.-butyl, and R3 denotes H, and the respective remaining substituents of R4 and R5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, or CF3; preferably R4 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, and CF3; and R5 denotes H, or
R2 and R4 together with the carbon atoms connecting them, form a C3-6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.- butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and R3 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.- butyl, preferably R3 denotes H, and R5 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, or CF3, preferably R5 denotes H.
In a further preferred embodiment of the compound according to general formula (I),
R1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OR6, wherein
R6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,
R2 and R3 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, or tert.-butyl, preferably R2 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec. -butyl, or tert.-butyl, and R3 denotes H,
R4 and R5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, or CF3; preferably R4 is selected from the group consisting of methyl; ethyl, n-propyl, 2-propyl, n- butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, and CF3, and R5 denotes H. or
R2 and R4 together with the carbon atoms connecting them, form a C3.6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.- butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituent R3 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, preferably R3 denotes H, and the respective remaining substituent R5 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, and CF3, preferably R5 denotes H.
Particularly preferred are compounds according to general formula (I) selected from the group comprising:
1 2-Cyclopropyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl-pyridine- 3-carboxylic acid amide;
2 2-Cyclopropyl-N-[[(1 S,2R)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide;
3 2-Cyclopropyl-N-[[(1 R,2S)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide;
4 2-Cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine- 3-carboxylic acid amide;
5 N-(3-Hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid amide;
6 2-lsopropyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-3-hydroxy-butyl)-pyridine-3- carboxylic acid amide;
7 N-[[(1 S,2R)-2-Hydroxy-cyclohexyl]-methyl]-2-isopropyl-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide; and
8 2-Ethoxy-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid amide, optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof.
The substituted compounds according to the invention of the aforementioned general formula (I) and corresponding stereoisomers and also the respective corresponding salts and solvates are toxicologically safe and are therefore suitable as pharmaceutical active ingredients in pharmaceutical compositions.
The present invention therefore further relates to a pharmaceutical composition containing at least one compound according to general formula (I), in each case optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally one or more pharmaceutically acceptable auxiliaries.
These pharmaceutical compositions according to the invention are suitable in particular for the modulation of KCNQ2/3 K+ channels, preferably for KCNQ2/3 K+ channel inhibition and/or KCNQ2/3 K+ channel stimulation, i.e. they exert an agonistic or antagonistic effect.
Likewise, the pharmaceutical compositions according to the invention are preferably suitable for the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K+ channels.
The pharmaceutical composition according to the invention is suitable for administration to adults and children, including toddlers and babies.
The pharmaceutical composition according to the invention may be prepared as a liquid, semisolid or solid pharmaceutical form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and also be administered as much.
In addition to at least one substituted compound of general formula (I), optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, the pharmaceutical composition according to the invention conventionally may contain further physiologically acceptable pharmaceutical auxiliaries which, for example, can be selected from the group consisting of excipients, fillers, solvents, diluents, surface-active substances, dyes, preservatives, blasting agents, slip additives, lubricants, aromas and binders.
The selection of the physiologically acceptable auxiliaries and also the amounts thereof to be used depend on whether the pharmaceutical composition is to be applied orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermal^, intramuscularly, intranasally, buccally, rectally or locally, for example to infections of the skin, the mucous membranes and of the eyes. Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral application; solutions, suspensions, easily reconstitutable dry preparations and also sprays are preferably suitable for parenteral, topical and inhalative application. The substituted compounds according to the invention used in the pharmaceutical composition according to the invention in a repository, in a dissolved form or in a plaster, and further agents promoting skin penetration being added if appropriate, are suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the respective substituted compound according to the invention also in a delayed manner.
The pharmaceutical compositions according to the invention can be prepared with the aid of conventional means, devices, methods and process known in the art, such as are described for example in ..Remington's Pharmaceutical Sciences", A.R. Gennaro (Editor), 17th edition, Mack Publishing Company, Easton, Pa, 1985, in particular in Part 8, Chapters 76 to 93. The corresponding description is introduced herewith by way of reference and forms part of the disclosure. The amount to be administered to the patient of the respective substituted compounds according to the invention of the above-indicated general formula (I) may vary and is for example dependent on the patient's weight or age and also on the type of application, the indication and the severity of the disorder. Conventionally, 0.001 to 100 mg/kg, preferably 0.05 to 75 mg/kg, particularly preferably 0.05 to 50 mg of at least one compound according to the invention are applied per kg of the patient's body weight.
The pharmaceutical composition according to the invention is preferably suitable for the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K+ channels. The pharmaceutical composition according to the invention is more preferably suitable for the treatment and/or prophylaxis of one or more diseases and/or disorders selected from the group consisting of pain, in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias.
The pharmaceutical composition according to the invention is suitable particularly preferably for the treatment of pain, more particularly preferably of acute pain, chronic pain, neuropathic pain, visceral pain, inflammatory pain and muscular pain, and most particularly for the treatment of neuropathic pain.
The pharmaceutical composition according to the invention is also preferably suitable for the treatment and/or prophylaxis of epilepsy.
The present invention further relates to at least one compound according to general formula (I), optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally of one or more pharmaceutically acceptable auxiliaries for use in the modulation of KCNQ2/3 K+ channels, preferably for use in KCNQ2/3 K+ channel inhibition and/or stimulation.
The present invention therefore further relates to at least one compound according to general formula (I), optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and also optionally of one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K+ channels.
Preference is given to at least one compound according to general formula (I), optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a solvate, in particular hydrate, thereof, and optionally one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias.
Particular preference is given to at least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, most particularly neuropathic pain.
Particular preference is also given to at least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of epilepsy.
The present invention further relates to at least one compound according to general formula (I) and also optionally one or more pharmaceutically acceptable auxiliaries for the modulation of KCNQ2/3 K+ channels, preferably for KCNQ2/3 K+ channel inhibition and/or stimulation. The present invention therefore further relates to at least one compound according to general formula (I) and also optionally of one or more pharmaceutically acceptable auxiliaries for the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K+ channels.
Preference is given to at least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, especially pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias.
Particular preference is given to at least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, most particularly neuropathic pain.
Particular preference is also given to at least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for the prophylaxis and/or treatment of epilepsy.
The present invention further relates to at least one compound according to general formula (I) and also optionally one or more pharmaceutically acceptable auxiliaries for use in the preparation of a medicament for prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K+ channels.
Preference is given to at least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for use in the preparation of a medicament for the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias. Particular preference is given to at least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for use in the preparation of a medicament for the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, most particularly neuropathic pain.
Particular preference is also given to at least one compound according to general formula (I) and optionally one or more pharmaceutically acceptable auxiliaries for use in the preparation of a medicament for the prophylaxis and/or treatment of epilepsy.
Another aspect of the present invention is a method of treatment and/or prophylaxis of disorders and/or diseases, which are mediated, at least in part, by KCNQ2/3 K+ channels, in a mammal, preferably of disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic
pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias, which comprises administering an effective amount of at least one compound of general formula (I) to the mammal.
The effectiveness against pain can be shown, 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), by tail flick experiments (e.g. according to D'Amour und Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941 )) or by the formalin test (e.g. according to D. Dubuisson et al., Pain 1977, 4, 161 -174). 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 compounds according to the invention preferably have a EC5o value of not more than 10000 nM or not more than 8000 nM, more preferably not more than 7000 nM or not more than 6000 nM, yet more preferably not more than 5000 nM or not more than 3000 nM, even more preferably not more than 2000 nM or not more than 1000 nM, yet even more preferably not more than 800 nM or not more than 700 nM, still more preferably not more than 600 nM or not more than 500 nM, yet still more preferably not more than 400 nM or not more than 300 nM, most preferably not more than 200 nM or not more than 150 nM and especially not more than 120 nM or not more than 100 nM. Methods for determining the EC50 value are known to the person skilled in the art. The EC50 value is preferably determined by fluorimetry, particularly preferably as described below under "pharmacological experiments".
The invention further provides processes for the preparation of the substituted compounds according to the invention.
The chemicals and reaction components used in the reactions and schemes described below are available commercially or in each case can be prepared by conventional methods known to the person skilled in the art.
The reactions described can each be carried out under the conventional conditions with which the person skilled in the art is familiar, for example with regard to pressure or the order in which the components are added. If appropriate, the person skilled in the art can determine the optimum procedure under the respective conditions by carrying out simple preliminary tests. The intermediate and end products obtained using the reactions described hereinbefore can each be purified and/or isolated, if desired and/or required, using conventional methods known to the person skilled in the art. Suitable purifying processes are for example extraction processes and chromatographic processes such as column chromatography or preparative chromatography. All of the process steps described below, as well as the respective purification and/or isolation of intermediate or end products, can be carried out partly or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.
If the substituted compounds according to the invention of the aforementioned general formula (I) are obtained, after preparation thereof, in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and/or diastereomers, they can be separated and if appropriate isolated using conventional processes known to the person skilled in the art. Examples include chromatographic separating processes, in particular liquid chromatography processes under normal pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallisation processes. These processes allow individual enantiomers, for example diastereomeric salts formed by means of chiral stationary phase HPLC or by means of crystallisation with chiral acids, for example (+)-tartaric acid, (-)-tartaric acid or (+)-10- camphorsulphonic acid, to be separated from one another. General reaction scheme I:
Figure imgf000046_0001
In staged , 2,6-dichloro-nicotinic acids of the general formula SM01 can be transformed into the corresponding esters of the general formula IM01 according to methods known to the person skilled in the art, for example using a suitable alkylation reagent, for example methyl iodide or ethyl iodide.
In stage02, 2,6-dichloro-nicotinic acid esters of the general formula IM01 can be transformed into 2-chhloro-6-morpholin-nicotinic acid esters of the general formula IM02 using morpholine according to methods known to the person skilled in the art, for example by conventional or microwave heating, neat or in solution, for example in acetonitrile, dimethylformamide, dioxane, N-methyl-2-pyrrolidone or tetrahydrofuran, optionally in the presence of a suitable base, for example triethylamine, Ν,Ν-diisopropylethylamine, potassium carbonate, caesium carbonate, sodium tert-butoxide or potassium tert-butoxide, optionally by addition of a suitable coupling reagent, for example tetrakis(triphenylphosphin)-palladium, bis(dibenzylideneacetone)-palladium(0), or tris(dibenzylideneacetone)-dipalladium(0), optionally in presence of an additional ligand, for example (2-biphenyl)di-tert-butylphosphine or 2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl.
In stage03 2-chhloro-6-morpholin-nicotinic acid esters of the general formulae IM02 can be transformed into the intermediates of the general formula IM03 according to methods known to the person skilled in the art with compounds of the general formula Y-R1, where Y denotes hydrogen, a metal or organometallic residue, for example sodium, magnesium bromide, magnesium chloride, tributyltin or boronic acid, or a residue to form an organometallic reagent, according to methods known to the person skilled in the art, for example by conventional or microwave heating, neat or in solution, for example in acetonitrile, dimethylformamide, dioxane, N-methyl-2-pyrrolidone, tetrahydrofuran, methanol or ethanol, optionally in the presence of a suitable base, for example triethylamine, N,N- diisopropylethylamine, potassium carbonate, caesium carbonate, sodium tert-butoxide or potassium tert-butoxide, optionally by addition of a suitable coupling reagent, for example tetrakis(triphenylphosphin)-palladium, bis(dibenzylideneacetone)-palladium(0), tris(di- benzylideneacetone)-dipalladium(O), [1 ,3-bis(diphenylphosphino)propane]-dichloronickel(ll) or iron(lll) acetylacetonate, optionally in presence of an additional ligand, for example (2- biphenyl)di-tert-butylphosphine or 2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl.
In stage04 nicotinic acid esters of the general formula IM03 can be transformed into the corresponding nicotinic acids of the general formula I 04 according to methods known to the person skilled in the art, for example by employing a base, for example sodium hydroxide.
In stage05 nicotinic acids of the general formula IM04 can be converted to yield amides of the general formula I with amines of the general formula SM02 according to methods known to the person skilled in the art, for example by using a suitable coupling reagent, for example 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
General reaction scheme II:
Figure imgf000047_0001
S 03 IM05 IM06
Figure imgf000047_0002
IM07 IM08 SM02a
Amines of the general formula SM02, in which R2 and R3 denote hydrogen, herein thereafter referred to as SM02a can be prepared from substituted 2-hydroxyacetic acids of the general formula SM03, according to methods known to the person skilled in the art. Enantiomerically pure amines of the general formula SM02a can be obtained from enantiomerically pure 2- hydroxyacetic acids of the general formula SM03. In stage06, 2-hydroxyacetic acids of the general formula SM03 can be transformed into the corresponding diols of the general formula IM05 according to methods known to the person skilled in the art, for example by employing a reducing agent, for example lithium aluminium hydride. In stage07, diols of the general formula IM05 can be transformed into the corresponding p-toluenesulfonic acid esters of the general formula IM06 according to methods known to the person skilled in the art, for example by treating with 4-toluenesulfonyl chloride. In stage08, p-toluenesulfonic acid esters of the general formula IM06 can be transformed into the corresponding nitrites general formula IM07 according to methods known to the person skilled in the art, for example by treating with sodium cyanide. In stage09, nitriles general formula IM07 can be transformed into the corresponding tert-butyl carbamates of the general formula IM08 according to methods known to the person skilled in the art, for example by treating with nickel(ll) chloride and sodium borohydride in the presence of di-tert-butyl dicarbonate. In stagel 0, tert-butyl carbamates of the general formula IM08 can be transformed into the corresponding amines of the general formula SM02a according to methods known to the person skilled in the art, for example by treating with hydrochloric acid.
General reaction scheme III: s stagel 2
Figure imgf000048_0001
IM09
Figure imgf000048_0002
IM10 S 02
Alternatively, amines of the general formula SM02 can be prepared from substituted 3- oxopropanenitriles of the general formula SM04, according to methods known to the person skilled in the art. In stagel 1 , 3-oxopropanenitriles of the general formula SM04 can be transformed into the corresponding 3-hydroxypropanenitriles of the general formula IM09 according to methods known to the person skilled in the art, for example by employing a reducing agent, for example sodium borohydride, borane dimethyl sulfide complex or borane tetrahydrofuran complex (affording compounds in which R5 denotes a hydrogen), optionally in presence of a suitable ligand, for example CBS-oxazaborolidines, or alternatively by treating with compounds of the general formula Y-R5, where Y denotes a metal or organometallic residue, for example sodium, magnesium bromide, magnesium chloride, or a residue to form an organometallic reagent, according to methods known to the person skilled in the art (affording compounds in which R5 denotes a substituted carbon). In stage12, 3- hydroxypropanenitriles of the general formula IM09 can be transformed into the corresponding tert-butyl carbamates of the general formula IM10 according to methods known to the person skilled in the art, for example by treating with nickel(ll) chloride and sodium borohydride in the presence of di-tert-butyl dicarbonate. In stage13, tert-butyl carbamates of the general formula IM10 can be transformed into the corresponding amines of the general formula SM02 according to methods known to the person skilled in the art, for example by treating with hydrochloric acid.
A plurality of additional synthesis paths to compounds of the general formulae SM02, SM02a, SM03, SM04 with a very broad substitution pattern for residues R2 to R5 are known in the current specialist literature. Previously unknown intermediates of the general formulae SM02, SM02a, SM03, S 04 with similar substitution patterns for residues R2 to R5 as outlined above and whose syntheses are not described in greater detail can be produced by the person skilled in the art according to these known methods or by combination of the known methods.
The invention will be described hereinafter with the aid of a number of examples. This description is intended merely by way of example and does not limit the general idea of the invention.
Examples
The indication„M" are indications of concentration in mol/l, "d" means days, "brine" means saturated aqueous sodium chloride solution, "h" means hour(s), "MS" means mass spectrometry, "RT" means room temperature (23 ± 7 °C), "TLC" means thin layer chromatography, "v/v" means volume to volume.
The yields of the compounds prepared were not optimized. All temperatures are uncorrected.
The stationary phase used for the column chromatography was silica gel 60 (0.04 - 0.063 mm) from E. Merck, Darmstadt. All starting materials which are not explicitly described were either commercially available (the details of suppliers such as for example Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available Chemicals Database of MDL, San Ramon, US or the SciFinder® Database of the ACS, Washington DC, US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS, Washington DC, US, respectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.
The mixing ratios of solvents or eluents for chromatography are specified in v/v.
All the intermediate products and exemplary compounds were analytically characterised by means of 1H-NMR spectroscopy. In addition, mass spectrometry tests (MS, m/z for [M+H]+) were carried out for all the exemplary compounds and selected intermediate products.
Synthesis of exemplary compounds
Synthesis of example 1 : 2-Cyclopropyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide
Figure imgf000050_0001
a) Synthesis of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid ethyl ester
A mixture of 2,6-dichlor-4-methylpyridin-3-carboxylic acid (100 g, 485 mmol) and potassium carbonate (100 g, 728 mmol) in dimethylformamide (1.25 I) is stirred for 30 h at RT before ethyl iodide (59.5 ml, 728 mmol) is added and stirring is continued for 18 h. After completion of the reaction, water is added and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water (2x) and brine (1x), dried over magnesium sulphate and evaporated to dryness to yield 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid ethyl ester (112 g), which was used without further purification. b) Synthesis of 2-chloro-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester
A mixture of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid ethyl ester (29.7 g, 127 mmol), potassium carbonate (26.3 g, 190 mmol), and morpholine (13.3 g, 152 mmol) in dimethylformamide (350 ml) is stirred for 18 h at 95 °C. After completion of the reaction, water is added and the mixture is extracted with diethyl ether (3x). The combined organic layers are washed with water (2x) and brine (1x), dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 25% ethyl acetate/cyclohexane) to yield 2-chloro-4-methyl-6-morpholin-4-yl-pyridine-3- carboxylic acid ethyl ester (10.5 g, 36.9 mmol, 29%). c) Synthesis of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester To a solution 2-chloro-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (7.0 g, 24.6 mmol) in tetrahydrofuran-N-methyl-2-pyrrolidone (2:3) (250 ml) is added iron(lll) acetylacetonate (1.74 g, 4.92 mmol) and the mixture is cooled to -20 °C. At this temperature, a solution of cyclopropylmagnesium bromide (0.7 M in tetrahydrofuran) (105 ml, 73.8 mmol) is slowly added and the mixture is warmed to 0 °C within 30 min. After completion of the reaction, 10% aqueous ammonium chloride is added and the mixture is extracted with ethyl acetate (2x). The combined organic layers are washed with water and brine, dried over magnesium sulphate and evaporated to dryness. The reaction is repeated once and the combined crude products are purified by flash chromatography (silica gel, 75% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (15.1 g). d) Synthesis of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid
A solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (16.8 g, 57.8 mmol) in methanol-tetrahydrofuran (1 :1 ) (90 ml) is treated for 3 days with a 2M aqueous solution of sodium hydroxide at reflux. The organic solvent is distilled off and the aqueous layer treated with 2M hydrochloric acid, and extracted with ethyl acetate. The combined organic layers are dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 75% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (10.4 g, 39.6 mmol, 69%). e) Synthesis of 2-cyclopropyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide
To a solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (1.90 g, 7.24 mmol) in tetrahydrofuran (60 ml) are added triethylamine (3.0 ml, 21.7 mol) and 0-(7- azabenzotriazol-1 -yl)N,N,N',N'-tetramethyluronium hexafluorophosphate (2.75 g, 7.24 mmol). The mixture is stirred for 15 min at RT, before 1-amino-4,4-dimethylpentan-3-ol (1.05 g, 7.97 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-N-(3- hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 1) (1.74 g, 4.63 mmol, 64%). [M+H]+ 376.4.
Examples 1a and 1 b: 2-Cyclopropyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide (1.64 g) was resolved into its corresponding enantiomers using chiral HPLC with the following conditions. Column, Chiralpak AD-H, 5 μ, 250 x 20 mm; mobile phase, n-heptane/iso-propanol = 90: 10 (v/v); flow rate, 19 ml/min; detection, UV (254 nm), 180 separations with 10 mg racemic material each. Analytical HPLC conditions. Column, Chiralpak AD-H, 250 x 4.6 mm; mobile phase, n-heptane/iso-propanol = 90:10 (v/v); flow rate, 1 ml/min; detection, UV (254 nm). Retention time (min): first eluting enantiomer, 8.59 (>99% ee); second eluting enantiomer, 10.45 (94% ee). Separation by chiral HPLC affords the first eluting enantiomer of 2-cyclopropyl-N-(3-hydroxy-4,4-dimethyl- pentyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 1a) (0.49 g; [M+H]+ 376.4) and the second eluting enantiomer of 2-cyclopropyl-N-(3-hydroxy-4,4- dimethyl-pentyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 1 b) (0.49 g; [M+H]+ 376.4) as white solids.
Synthesis of example 2: 2-Cyclopropyl-N-[[(1 S,2R)-2-hydroxy-cyclohexyl]-methyl]-4-methyl- 6-morpholin-4-yl-pyridine-3-carboxylic acid amide
Figure imgf000052_0001
To a solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized according to the methods described in sections a) to d) of example 1) (0.15 g, 0.57 mmol) in dichloromethane (10 ml) are added N-ethyl-diisopropylamine (0.24 ml, 1.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.13 g, 0.69 mmol), and 1- hydroxybenzotriazole hydrate (0.015 g, 0.1 1 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0 °C, before (1 R,2S)-2-(aminomethyl)cyclohexanol (0.07 g, 0.57 mmol) is added and stirring is continued for 3 days. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-N- [[(1 S,2R)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 2) (0.21 g, 0.56 mmol, 98%). [M+H]+ 374.2.
Synthesis of example 3: 2-Cyclopropyl-N-[[(1 R,2S)-2-hydroxy-cyclohexyl]-methyl]-4-methyl- 6-morpholin-4-yl-pyridine-3-carboxylic acid amide
Figure imgf000053_0001
To a solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized according to the methods described in sections a) to d) of example 1) (0.15 g, 0.57 mmol) in dichloromethane (10 ml) are added N-ethyl-diisopropylamine (0.24 ml, 1.43 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.13 g, 0.69 mmol), and 1- hydroxybenzotriazole hydrate (0.015 g, 0.11 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0 °C, before (1 S,2R)-2-(aminomethyl)cyclohexanol (0.07 g, 0.57 mmol) is added and stirring is continued for 3 days. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 60% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-N- [[(1 R,2S)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 3) (0.17 g, 0.45 mmol, 80%). [M+Hf 374.3.
Synthesis of example 4: 2-Cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide
Figure imgf000054_0001
To a solution of 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized according to the methods described in sections a) to d) of example 1 ) (0.50 g, 1.91 mmol) in dichloromethane (20 ml) are added N-ethyl-diisopropylamine (0.81 ml, 4.77 mmol), 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.42 g, 2.29 mmol), and 1-hydroxybenzotriazole hydrate (0.05 g, 0.38 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0 °C, before 2-(aminomethyl)cyclopentanol (0.22 g, 1.91 mmol) is added and stirring is continued for 3 days. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness affording example 4 as crude product. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield the first eluting diastereomer of 2-cyclopropyl-N-([2-hydroxy- cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 4a) (0.34 g, 0.95 mmol, [M+H]+ 360.2) and the second eluting diastereomer of 2-cyclopropyl- N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 4b) (0.27 g, 0.75 mmol, [M+H]+ 360.2) as white solids.
Synthesis of example 5: N-(3-Hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide
Figure imgf000054_0002
To a solution of 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized similar to the methods described in sections a) to d) of example 1) (1.86 g, 7.05 mmol) in tetrahydrofuran (60 ml) are added triethylamine (2.9 ml, 21.1 mol) and 0-(7- azabenzotriazol-1 -yl)N,N,N',N'-tetramethyluronium hexafluorophosphate (2.69 g, 7.05 mmol). The mixture is stirred for 15 min at RT, before 1 -amino-4,4-dimethylpentan-3-ol (1.02 g, 7.76 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate/cyclohexane) to yield N-(3-hydroxy-4,4- dimethyl-pentyl)-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 5) (1.30 g, 3.44 mmol, 49%). [M+H]+ 378.3.
Examples 5a and 5b: N-(3-Hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl-6-morpholin- 4-yl-pyridine-3-carboxylic acid amide (1.1 g) was resolved into its corresponding enantiomers using chiral HPLC with the following conditions. Column, Chiralpak AD-H, 5 μ, 250 x 20 mm; mobile phase, n-heptane/iso-propanol = 90: 10 (v/v); flow rate, 19 ml/min; detection, UV (254 nm), 80 separations with 15 mg racemic material each. Analytical HPLC conditions. Column, Chiralpak AD-H, 250 x 4.6 mm; mobile phase, n-heptane/iso-propanol = 90:10 (v/v); flow rate, 1 ml/min; detection, UV (254 nm). Retention time (min): first eluting enantiomer, 6.07 (94% ee); second eluting enantiomer, 8.40 (99% ee). Separation by chiral HPLC affords the first eluting enantiomer of N-(3-hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide (example 5a) (0.44 g; [M+H]+ 378.3) and the second eluting enantiomer of N-(3-hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide (example 5b) (0.42 g; [M+H]+ 378.3) as white solids.
Synthesis of example 6: 2-lsopropyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-3-hydroxy- butyl)-pyridine-3-carboxylic acid amide
Figure imgf000055_0001
To a solution of 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized similar to the methods described in sections a) to d) of example 1 ) (1.40 g, 5.30 mmol) in tetrahydrofuran (40 ml) are added triethylamine (2.9 ml, 21.2 mol) and 0-(7- azabenzotriazol-1 -yl)N,N,N',N'-tetramethyluronium hexafluorophosphate (2.9 g, 5.3 mmol). The mixture is stirred for 15 min at RT, before 4-amino-1 , 1 ,1-trifluorobutan-2-ol hydrochloride (1.05 g, 5.8 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield 2- lsopropyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-3-hydroxy-butyl)-pyridine-3-carboxylic acid amide (example 6) (1.24 g, 3.18 mmol, 60%). [M+H]+ 390.2.
Examples 6a and 6b: 2-lsopropyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-3-hydroxy- butyl)-pyridine-3-carboxylic acid amide was resolved into its corresponding enantiomers using chiral HPLC with the following conditions. Column, Chiralpak AD-H, 5 μ, 250 x 20 mm; mobile phase, n-heptane/iso-propanol = 90: 10 (v/v); flow rate, 19 ml/min; detection, UV (254 nm). Analytical HPLC conditions. Column, Chiralpak AD-H, 250 x 4.6 mm; mobile phase, n- heptane/ethanol = 95:5 (v/v); flow rate, 1 ml/min; detection, UV (254 nm). Retention time (min): first eluting enantiomer, 9.60 (example 6a); second eluting enantiomer, 12.21 (example 6b).
Synthesis of example 7: N-[[(1 S,2R)-2-Hydroxy-cyclohexyl]-methyl]-2-isopropyl-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide
Figure imgf000056_0001
To a solution of 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized similar to the methods described in sections a) to d) of example 1) (0.20 g, 0.76 mmol) in dichloromethane (15 ml) are added N-ethyl-diisopropylamine (0.32 ml, 0.89 mmol), 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.17 g, 0.91 mmol), and 1- hydroxybenzotriazole hydrate (0.02 g, 0.15 mmol). The mixture is stirred for 15 min at RT, and then cooled to 0 °C, before (1 R,2S)-2-(aminomethyl)cyclohexanol (0.09 g, 0.76 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield N-[[(1 S,2R)-2-hydroxy- cyclohexyl]-methyl]-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 7) (0.18 g, 0.48 mmol, 63%). [M+H]+ 376.3.
Synthesis of example 8: 2-Ethoxy-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin- 4-yl-pyridine-3-carboxylic acid amide
Figure imgf000057_0001
a) Synthesis of 6-chloro-2-ethoxy-4-methyl-pyridine-3-carboxylic acid
To a suspension of sodium hydride (60% dispersion in mineral oil) (4.2 g, 175 mmol) in tetrahydrofuran (200 ml) is added ethanol (4.08 ml, 70 mmol) at 10 °C. The mixture is allowed to warm to RT and stirring is continued for 1 h before 2,6-dichloro-4-methyl-pyridine- 3-carboxylic acid (15.1 g, 73.5 mmol) in tetrahydrofuran (300 ml) is added and the mixture is stirred for additional 18 h at RT. Upon completion, the mixture is acidified with 2M hydrochloric acid and extracted with ethyl acetate (2 x 200 ml). The combined organic layers are washed with water (2 x 100 ml) and brine (2 x 100 ml), dried over magnesium sulfate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 5% methanol/ ethyl acetate) to yield 6-chloro-2-ethoxy-4-methyl-pyridine-3-carboxylic acid (13.8 g, 64.0 mmol, 87%). b) Synthesis of 6-chloro-2-ethoxy-4-methyl-pyridine-3-carboxylic acid ethyl ester
A mixture of 6-chloro-2-ethoxy-4-methyl-pyridine-3-carboxylic acid (11.6 g, 53.8 mmol) in dimethylformamide (140 ml) is treated with potassium carbonate (11.1 g, 80.7 mmol) for 30 min, before ethyl iodide (6.6 ml, 80.7 mmol) is added and stirring is continued for 18 h. Upon completion, water is added and the mixture is extracted with ethyl acetate (2 x 50 ml). The combined organic layers are washed with brine, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield 6-chloro-2-ethoxy-4-methyl-pyridine-3-carboxylic acid ethyl ester (11.2 g, 45.9 mmol, 85%). c) Synthesis of 2-ethoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester
A mixture of 6-chloro-2-ethoxy-4-methyl-pyridine-3-carboxylic acid ethyl ester (1 1.2 g, 45.9 mmol), morpholine (4.36 ml, 50.5 mmol) and triethylamine (12.7 ml, 91.9 mmol) in 1-methyl- 2-pyrrolidon (45 ml) is heated at 90 °C for 2d. After completion of the reaction, the solvent is distilled off and the residue is taken up in 1 M aqueous sodium hydrogen carbonate and extracted with ethyl acetate (3 x 50 ml). The combined organic layers are dried over magnesium sulfate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 25% ethyl acetate/cyclohexane) to yield 2-ethoxy-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (7.36 g, 25.0 mmol, 55%). d) Synthesis of 2-ethoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid
A solution of 2-ethoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (7.34 g, 24.9 mmol) in tetrahydrofuran/methanol (1 : 1) (120 ml) is treated with a solution of lithium chloride (3.56 h, 149.7 mmol) in water (75 ml) and stirred at 75°C for 18 h. After completion of the reaction, the mixture is concentrated in vacuo, acidified with 2M hydrochloric acid, and extracted with ethyl acetate (3 x 50 ml). The combined organic layers are dried over magnesium sulfate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate/cyclohexane) to yield 2-ethoxy-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid (2.47 g, 9.28 mmol, 37%). e) Synthesis of 2-ethoxy-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide
To a solution of 2-ethoxy-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (0.23 g, 0.86 mmol) in dichloromethane (15 ml) are added diisopropylethylamine (0.37 ml, 2.16 mmol), 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.2 g, 1.04 mmol) and 1-hydroxybenzotriazol hydrate (23 mg, 0.17 mmol). The mixture is stirred for 15 min at RT, before 1-amino-4,4- dimethylpentan-3-ol (0.11 g, 0.86 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate/cyclohexane) to yield 2-ethoxy-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide (example 8) (0.22 g, 0.58 mmol, 67%). [M+H]+ 380.3.
Pharmacological experiments
Method I. Fluorescence assay using a voltage sensitive dye (fluorimetry)
The modulation of the KCNQ opening state (and consequently the voltage potential of a cell) by test compounds such as compounds according to the present invention results in an increased or reduced amount of a voltage-sensitive dye in the cytoplasm of the cells tested. These voltage-sensitive dyes are fluorescent dyes and, therefore, are forming the link between cell potential influenced by KCNQ modulation and fluorescence intensity. A KCNQ agonist leads to an opening of the channel, potassium and dye efflux, a following hyperpolarization and a reduction of the inner fluorescence intensity in a kinetic protocol. If applying an ion jump by KCI depolarization, KCNQ agonists increase the AF/F value. An antagonist performs vice versa, respectively.
The 'fluorimetry EC50 ' is the half maximum effective concentration (EC50), where the concentration of a drug/compound induces a response halfway between the baseline and maximum plateau effect. In other words, said value represents the concentration of a compound, where 50% of its maximal effect in the fluorimetric assay is observed if the substance concentration is graphed against the corresponding AF/F values (for which the calculation method is described below). Therefore, 'fluorimetry EC50' is a measure for the compound potency. The compound efficacy is mirrored by 'fluorimetry % efficacy' ('%Efficacy') and refers to the maximum response achievable by the test compound, i.e. the plateau effect. This drug's plateau effect is related to the plateau effect, which can be achieved by applying a saturated concentration of a reference compound, e.g. Retigabine (50 μΜ), in independent wells of the same experimental plate or series. A compound showing 100% efficacy is as efficacious as the reference compound (Retigabine) with a saturated concentration. This calculation '%Efficacy' method was introduced in order to normalize the AF/F values of different experiments to a common comparator compound, and make the test drug effects comparable.
Human CHO-K1 cells expressing KCNQ2/3 channels are cultivated adherently at 37°C, 5% C02 and 95% humidity in cell culture bottles (e.g. 80 cm2 TC flasks, Nunc) with DMEM-high glucose (Sigma Aldrich, D7777) including 10% FCS (PAN Biotech, e.g. 3302-P270521) or alternatively MEM Alpha Medium (1x, liquid, Invitrogen, #22571), 10% fetal calf serum (FCS) (Invitrogen, #10270-106, heat-inactivated) and the necessary selection antibiotics.
Before being sown out for the measurements, the cells are washed with 1 x DPBS buffer Ca2+/Mg2+-free (e.g. Invitrogen, #14190-094) and detached from the bottom of the culture vessel by using Accutase (PAA Laboratories, #L1 1-007) (incubation with Accutase for 15 min at 37°C). The cell number is determined using a CASY™ cell counter (TCC, Scharfe System). Depending on the optimal density for each individual cell line, 20,000-30,000 cells/well/100 μΙ are seeded onto 96-well Corning™ CellBIND™ assay plates (Flat Clear Bottom Black Polystyrene Microplates, #3340). Freshly seeded cells are then left to settle for one hour at room temperature, followed by incubation for 24 hours at 37°C, 5% C02 and 95% humidity. The voltage-sensitive fluorescent dye from the Membrane Potential Assay Kit (Red Bulk format part R8123 for FLIPR, MDS Analytical Technologies™) is prepared by dissolving the contents of one vessel Membrane Potential Assay Kit Red Component A in 200 ml of extracellular buffer (ES buffer, 120 mM NaCI, 1 mM KCI, 10 mM HEPES, 2 mM CaCI2, 2 mM MgCI2, 10 mM glucose; pH 7.4). After removal of the nutrient medium, the cells are washed once with 200 μΙ of ES buffer, then loaded for 45 min at room temperature in 100 μΙ of dye solution in the dark.
Fluorescence measurements are carried out in a BMG Labtech FLUOstar™, BMG Labtech NOVOstar™ or BMG Labtech POLARstar™ instrument (525 nm excitation, 560 nm emission, Bottom Read mode). After incubation with the dye, 50 μΙ of the test substances in the desired concentrations, or 50 μΙ of ES buffer for control purposes, are applied to the wells of the assay plate and incubated for 30 min at room temperature while being shielded from light. The fluorescence intensity of the dye is then measured for 5 min and the fluorescence value FT of each well is thus determined at a given, constant time. 15 μΙ of a KCI solution are then added to each well (final concentration of potassium ions 92 mM). The change in fluorescence intensity is subsequently monitored until all the relevant values have been obtained (mainly 5-30 min). At a given time post KCI application, a fluorescence value F2 is determined, in this case at the time of the fluorescence peak.
For calculation, the fluorescence intensity F2 is corrected for the fluorescence intensity F^ and the activity (AF/F) of the target compound on the potassium channel is determined as follows:
Figure imgf000060_0001
AF
In order to determine whether a substance has agonistic activity, F can be related to
' AF ] f F ^
^ F K of control wells. ^ F K is determined by adding to the well only the buffer solution instead of the test substance, determining the value F1 K of the fluorescence intensity, adding the potassium ions as described above, and measuring a value F2K of the fluorescence intensity. F2K and F1 K are then calculated as follows:
Figure imgf000061_0001
AF
A substance has an agonistic activity on the potassium channel if F is greater than f F\
F )K■
AF ( AF^
F V r JK
Independently of the comparison of
Figure imgf000061_0002
is possible to conclude that a target
AF
compound has agonistic activity if F increases dose dependency.
Calculations of EC50 and IC50 values are carried out with the aid of 'Prism v4.0' software (GraphPad Software™).
Method II. Low-intensity tail flick test (rat)
In the low-intensity tail flick test, the determination of the antinociceptive effect of the compounds according to the invention towards an acute noxious thermal stimulus is carried out by measuring the withdrawal reflex of the rat tail (tail flick) in response to a radiant heat beam (analgesia meter; model 2011 of the company Rhema Labortechnik, Hofheim, Germany) according to the method described by D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941). To this end, the rats were placed in a plexiglas restrainer, and a low- intensity radiant heat beam (48°C) was focused onto the dorsal surface of the tail root. The stimulus intensity was adjusted to result in a mean pre-drug control withdrawal latency of about 7 s, thus also allowing a supraspinal modulation of the spinally mediated acute nociceptive reflex. A cutoff time of 30 s was applied to avoid tissue damage. Male Sprague- Dawley rats (Janvier, Le Genest St. Isle, Frankreich) with weights of 200-250 g were used. 10 rats were used per group. Before administration of a compound according to the invention, the animals were pre-tested twice in the course of five minutes and the mean of these measurements was calculated as the pre-test mean. The antinociceptive effect was determined at 20, 40 and 60 min after peroral compound administration. The antinociceptive effect was calculated based on the increase in the tail withdrawal latency according to the following formula and is expressed as percentage of the maximum possible effect (MPE [%]): MPE = [(T1-T0)/(T2-To)]*100
In this, T0 is the control latency time before and T, the latency time after administration of the compound, T2 is the cutoff time and MPE is the maximum possible effect. Employing variant analysis (repeated measures ANOVA) allowed testing of statistically significant differences between the compounds according to the invention and the vehicle group. The significance level was set to p≤ 0.05. To determine the dose dependency, the particular compound according to the invention was administered in 3-5 logarithmically increasing doses, including a threshold dose and a maximum effective dose, and the ED50 values were determined with the aid of regression analysis. The ED50 calculation was performed at the time of maximum efficacy (usually 20 min after administration of the compounds).
Pharmacological data
The pharmacological effects of the compounds according to the invention were determined as described hereinbefore (pharmacological experiments, methods I and II respectively).
The corresponding pharmacological data are summarized in Table 1.
Table 1:
Figure imgf000062_0001

Claims

Patent claims:
1. A substituted compound of general formula (I)
Figure imgf000063_0001
wherein
R1 represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and in each case optionally bridged via a Ci_4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted; or represents OR6, wherein
R6 represents a C e-aliphatic residue, unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted;
R2 and R3 independently of one another represent H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a Ci-4-aliphatic residue, or an 0-Ci_4 aliphatic residue, wherein the C1-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; a C1-4- aliphatic residue, wherein the Ci.4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R3
and/or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and the respective remaining substituents of R2 and R3 each independently of one another represent H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C^-aliphatic residue, or an 0-C1- aliphatic residue, wherein the Ci-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C3.6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; a C -4-aliphatic residue, wherein the C1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3-6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or R2 and R4 together with the carbon atoms connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted, and R3 represents H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-aliphatic residue, or an 0-C1- aliphatic residue, wherein the Ci-4 aliphatic residue may in each case be unsubstituted or mono- or polysubstituted; or a C3.6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; and R5 represents H; CH2F; CHF2; CF3; a C1- -aliphatic residue, , wherein the C1-4 aliphatic residue may be unsubstituted or mono- or polysubstituted; or a C3.6- cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted; on the condition that if R5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, in which an "aliphatic group" and an "aliphatic residue" can in each case be branched or unbranched, saturated or unsaturated, in which a "cycloaliphatic residue" and a "heterocycloaliphatic residue" can in each case be saturated or unsaturated, in which "mono- or polysubstituted" with respect to an "aliphatic group" and an "aliphatic residue" relates, with respect to the corresponding residues or groups, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1- aliphatic residue), an N(C1-4 aliphatic residue)2, a NH-C(=0)-C1-4 aliphatic residue, a N(Ci_4-aliphatic residue)-C(=0)-C1- aliphatic residue, a NH-S(=0)2-C1. aliphatic residue, a N(Ci_4-aliphatic residue)-S(=0)2-C1- aliphatic residue, =0, OH, OCH2F, OCHF2, OCF3, a 0-C1- -aliphatic residue, a
Figure imgf000065_0001
residue, SH, SCF3, a S-C^-aliphatic residue, S(=0)2OH, a S(=0)-C -4-aliphatic residue, a S(=0)2-C1- -aliphatic residue, a S(=0)2-0-C1.4-aliphatic residue, a S(=0)2-NH-d. - aliphatic residue, a S(=0)2-N(C1-4-aliphatic residue)2, CN, CH2F, CHF2, CF3, CHO, COOH, a C1-4-aliphatic residue, CH2OH, CH2-OCH3, C2H4-OH, C2H4-OCH3 CH2-CF3, a C(=0)-C1- -aliphatic residue, a C(=0)-0-C1-4-aliphatic residue, a C3.6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0)-NH2, a
Figure imgf000066_0001
4 aliphatic residue), and a C(=0)-N(C -4 aliphatic residue)2; in which "mono- or polysubstituted" with respect to a "cycloaliphatic residue" and a "heterocycloaliphatic residue" relates, with respect to the corresponding residues, to the substitution of one or more hydrogen atoms each independently of one another by at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, a NH-C(=0)-C .4 aliphatic residue, a N(d.4-aliphatic residue)-C(=0)-C1.4 aliphatic residue, a NH-S(=0)2-C1-4 aliphatic residue, a N(C1-4-aliphatic residue)-S(=0)2-C - aliphatic residue, =0, OH, OCH2F, OCHF2, OCF3, a 0-d.4-aliphatic residue, a 0-C(=0)-C1-4-aliphatic residue, SH, SCF3, a S-Ci.4-aliphatic residue, S(=0)2OH, a S(=0)-C1-4-aliphatic residue, a S(=0)2-d.4-aliphatic residue, a S(=0)2-0-C1-4-aliphatic residue, a S(=0)2-NH-C1. - aliphatic residue, a S(=0)2-N(C1-4-aliphatic residue)2, CN, CH2F, CHF2, CF3, CHO, COOH, a C1-4-aliphatic residue, CH2OH, CH2-OCH3, C2H4-OH, C2H4-OCH3 CH2-CF3, a
Figure imgf000066_0002
residue, a C3.6-cycloaliphatic residue, a 3 to 6 membered heterocycloaliphatic residue, C(=0)-NH2, a C(=0)- NH(C1-4 aliphatic residue), and a C(=0)-N(C1-4 aliphatic residue)2; optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof.
2. The compound according to claim 1 , characterized in that
R1 represents a C2.6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci_ aliphatic residue), an N(Ci_ aliphatic residue)2, OH, =0, an 0-d.4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4- aliphatic residue, a
Figure imgf000066_0003
residue, CN, and a Ci.4-aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, 0CH2F, OCHF2, 0CF3, CH2F, CHF2, CF3 and an unsubstituted 0-Ci. -aliphatic residue, or represents a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci_4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-Ci. -aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1- -aliphatic residue, a
Figure imgf000067_0001
aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C^-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1- -aliphatic residue, and wherein the C3.6-cycloaliphatic residue may optionally be bridged via a C1-4 aliphatic group, which in turn may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, 0CH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-Ci_ -aliphatic residue, or represents OR6, wherein
R6 represents a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1- aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a S(=0)-C1- - aliphatic residue, a S(=0)2-C1. -aliphatic residue, CN, and a C1- - aliphatic residue; wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue,
R2 and R3 independently of one another represent H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a C1-4-aliphatic residue, or an 0-C1-4 aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(d.4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-Ci.4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-Ci- -aliphatic residue, a
Figure imgf000068_0001
residue, a
aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the Ci_4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; or a C1- -aliphatic residue, wherein the C1-4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1- aliphatic residue)2, OH, =0, an 0-Ci.4-aliphatic residue, OCH2F, 0CHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a S(=0)-C1-4-aliphatic residue, a S(=0)2-C1-4- aliphatic residue, CN, and a Ci_4-aliphatic residue, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-Ci-4-aliphatic residue, or
R2 and R3
and/or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02l NH2, an NH(C1-4 aliphatic residue), an N(Ci.4 aliphatic residue)2, OH, =0, an O-C^-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C -4-aliphatic residue, a S(=0)-C . -aliphatic residue, a S(=0)2-C1.4-aliphatic residue, CN, and a C -4-aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, 0CF3, CH2F, CHF2, CF3 and an unsubstituted 0-Ci_ -aliphatic residue, and the respective remaining substituents of R2 and R3 each independently of one another represent H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a Ci- -aliphatic residue, or an 0-C-|.4 aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1- aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-d.4-aliphatic residue, a S(=0)-C1^-aliphatic residue, a S(=0)2-C1-4- aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4-aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the C1- -aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1- -aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(d.4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-Ci. -aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-d.4-aliphatic residue, a
Figure imgf000070_0001
aliphatic residue, CN, and a Ci-4-aliphatic residue, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-Ci.4-aliphatic residue, or
R2 and R4 together with the carbon atoms connecting them, form a C3.10- cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1- aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-Ci- - aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4-aliphatic residue, a
Figure imgf000071_0001
residue, CN, and a C -4- aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, 0CH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4-aliphatic residue, and the remaining substituent R3 represents H; F; CI; Br; I; CN; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; SCF3; a d.4-aliphatic residue, or an 0-C1- aliphatic residue, wherein the Ci_4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-Ci-4-aliphatic residue, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C!.4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-Ci.4-aliphatic residue, OCH2F, 0CHF2, OCF3, SH, SCF3, a S-C^-aliphatic residue, a S(=0)-C1-4-aliphatic residue, a S(=0)2-C1- - aliphatic residue, CN, and a Ci. -aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue, and the remaining substituent R5 represents H; CH2F; CHF2; CF3; OCH2F; OCHF2; OCF3; SCF3; a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1- -aliphatic residue, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci_4 aliphatic residue), an N(Ci_ aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1- -aliphatic residue, a S(=0)-C1- -aliphatic residue, a S(=0)2-C1-4- aliphatic residue, CN, and a C -4-aliphatic residue, on the condition that if R5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the C^-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted O-C^-aliphatic residue.
3. The compound according to claim 1 or 2, characterized in that
R represents a C2.6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci- aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4- aliphatic residue, a S(=0)-C1.4-aliphatic residue, a S(=0)2-C1. -aliphatic residue, CN, and a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1- -aliphatic residue, or represents a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(Ci_ aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-Ci- -aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1- -aliphatic residue, a
Figure imgf000073_0001
aliphatic residue, CN, and a C^-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, 0CH2F, 0CHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1- -aliphatic residue, or represents OR6, wherein
R6 represents a d-e-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1-4 aliphatic residue)2, OH, =0, an 0-C-|. -aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C - -aliphatic residue, a S(=0)-C1-4- aliphatic residue, a S(=0)2-C1-4-aliphatic residue, CN, and a C1-4- aliphatic residue, wherein the Ci. -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, OCH2F, OCHF2, OCF3, CH2F, CHF2, CF3 and an unsubstituted 0-C1-4-aliphatic residue. The compound according to any of the preceding claims, characterized in that
R1 represents a C2-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(C1- aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C1-4- aliphatic residue, a
Figure imgf000074_0001
residue, CN, and a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue is in each case unsubstituted, or represents a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(Ci_4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-Ci- -aliphatic residue, a S(=0)-C1-4-aliphatic residue, a S(=0)2-C1- - aliphatic residue, CN, and a C1-4-alip atic residue, wherein the ^^-aliphatic residue is in each case unsubstituted, or represents OR6, wherein
R6 represents a C1-6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, N02, NH2, an NH(C1-4 aliphatic residue), an N(CL4 aliphatic residue)2, OH, =0, an 0-C1-4-aliphatic residue, OCH2F, OCHF2, OCF3, SH, SCF3, a S-C^-aliphatic residue, a S(=0)-C1-4- aliphatic residue, a S(=0)2-C1. -aliphatic residue, CN, and a Ci. - aliphatic residue, wherein the C - -aliphatic residue is in each case unsubstituted.
The compound according to any of the preceding claims, characterized in that
R1 represents a C2.6-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue, or represents a C3.6-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1- -aliphatic residue, or represents OR6, wherein
R6 represents a d^-aliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci.4-aliphatic residue.
The compound-according to any of the preceding claims, characterized in that
R1 represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), ethenyl or propenyl (-CH2CH=CH2, -CH=CH-CH3, -C(=CH2)-CH3), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OR6, wherein
R6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, CH2OH, CH2OCH3, CH2CH2OH, CH2CH2OCH3, and CH(OH)CH2OH.
The compound according to any of the preceding claims, characterized in that
R2 and R3 independently of one another represent H; F; CI; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a Ci. -aliphatic residue, or an 0-C1- aliphatic residue, wherein the Ci_4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C^-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1- -aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; a Ci- - aliphatic residue, wherein the C1- -aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C -4-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-Ci.4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4-aliphatic residue, wherein the Ci_ -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R3
and/or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.i0-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-Ci.4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4-aliphatic residue, wherein the Ci.4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-d.4-aliphatic residue,, and the respective remaining substituents of R2 and R3 each independently of one another represent H; F; CI; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a d- 4-aliphatic residue, or an 0-d_ aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci.4-aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a d.4-aliphatic residue, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-d.4-aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the C1-4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-d. -aliphatic residue, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1- -aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C^-aliphatic residue, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the C^-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1-4-aliphatic residue, or
R2 and R4 together with the carbon atoms connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4-aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C -4-aliphatic residue, and the remaining substituent R3 represents H; F; CI; Br; I; CH2F; CHF2; CF3; OH; OCH2F; OCHF2; OCF3; a C1-4-aliphatic residue, or an 0-d.4 aliphatic residue, wherein the C1- -aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1- -aliphatic residue, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a C1-4-aliphatic residue, wherein the C -4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted O-C^-aliphatic residue, and the remaining substituent R5 represents H; CH2F; CHF2; CF3; a Ci-4-aliphatic residue, wherein the C -4-aliphatic residue may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-C1- -aliphatic residue, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-Ci.4-aliphatic residue, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, and a d.4-aliphatic residue, on the condition that if R5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, wherein the C1-4-aliphatic residue in each case may be unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, and an unsubstituted 0-Ci. -aliphatic residue.
8. The compound according to any of the preceding claims, characterized in that
R2 and R3 independently of one another represent H; F; CI; Br; I; CH2F; CHF2; CF3; OH; a C -4-aliphatic residue, or an O-C^ aliphatic residue, wherein the Ci-4-aliphatic residue is in each case unsubstituted, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; a Ci_4- aliphatic residue, wherein the C1- -aliphatic residue is unsubstituted, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R3
and/or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.i0-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2> CF3) and a C1-4-aliphatic residue, wherein the C - -aliphatic residue is in each case unsubstituted, and the respective remaining substituents of R2 and R3 each independently of one another represent H; F; CI; Br; I; CH2F; CHF2; CF3; OH; a C1-4-aliphatic residue, or an 0-Ci_4 aliphatic residue, wherein the C1- -aliphatic residue is in each unsubstituted, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; a C1-4-aliphatic residue, wherein the C1-4-aliphatic residue is unsubstituted, or represent a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, on the condition that if R4 and/or R5 denote(s) a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom, or
R2 and R4 together with the carbon atoms connecting them, form a C3.10-cycloaliphatic residue or a 3 to 10 membered heterocycloaliphatic residue, in each case unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an 0-C1-4-aliphatic residue, CH2F, CHF2, CF3, and a C1- -aliphatic residue, wherein the d.4-aliphatic residue is in each case unsubstituted, and the remaining substituent R3 represents H; F; CI; Br; I; CH2F; CHF2; CF3; OH; a C1-4-aliphatic residue, or an 0-C1-4 aliphatic residue, wherein the Ci_4-aliphatic residue is in each case unsubstituted, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, and the remaining substituent R5 represents H; CH2F; CHF2; CF3; a C1-4-aliphatic residue, wherein the Ci_4-aliphatic residue is unsubstituted, or represents a C3.6-cycloaliphatic residue or a 3 to 6 membered heterocycloaliphatic residue, in each case unsubstituted, on the condition that if R5 denotes a 3 to 6 membered heterocycloaliphatic residue, the 3 to 6 membered heterocycloaliphatic residue is linked via a carbon atom.
9. The compound according to any of the preceding claims, characterized in that
R2 and R3 independently of one another represent H; OH; an unsubstituted Ci- - aliphatic residue, or an unsubstituted 0-C1-4 aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; CH2F; CHF2; CF3; an unsubstituted C1- -aliphatic residue, or
R2 and R3
or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.io-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, CH2F, CHF2, CF3, an unsubstituted O-C^-aliphatic residue, and an unsubstituted C1- -aliphatic residue, and the respective remaining substituents of R2 and R3 each independently of one another represent H; OH; an unsubstituted C1-4-aliphatic residue, or an unsubstituted 0-C1-4 aliphatic residue, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represent H; CH2F; CHF2; CF3; an unsubstituted C1-4-aliphatic residue, or
R2 and R4 together with the carbon atoms connecting them, form a C3.i0-cycloaliphatic residue, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, an unsubstituted O-C ,,- aliphatic residue, CH2F, CHF2, CF3, and a an unsubstituted C1-4-aliphatic residue, and the remaining substituent R3 represents H; F; CI; Br; I; OH; an unsubstituted C1-4- aliphatic residue, or an unsubstituted 0-C1-4 aliphatic residue, and the remaining substituent R5 represents H; CH2F; CHF2; CF3; an unsubstituted Ci-4-aliphatic residue.
10. The compound according to any of the preceding claims, characterized in that
R2 and R3 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2- CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom,
R4 and R5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2- CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3; or
R2 and R3
or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituents of R2 and R3 each independently of one another represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, with the proviso that at least one of R2 and R3 denotes H or is linked via a carbon atom, and the respective remaining substituents of R4 and R5 each independently of one another represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3; or
R2 and R4 together with the carbon atoms connecting them, form a C3.6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of F, CI, Br, I, OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and the respective remaining substituent of R3 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), OCH3 or OCH2CH3, and the respective remaining substituent R5 represents H; methyl; ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, CH2-CH(CH3)(C2H5), C(CH3)2(C2H5), CH2F; CHF2; CF3.
11. The compound according to any of the preceding claims, characterized in that
R represents ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, tert.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or represents OR6, wherein
R6 represents methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, or tert.-butyl,
R2 and R3 in dependently of one another represent H; methyl; ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl,
R4 and R5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, or CF3; or
R2 and R3
or R4 and R5 in pairs, in each case independently of one another, together with the carbon atom connecting them, form a C3.6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, CH2F, CHF2, CF3, OCH3
Figure imgf000085_0001
and the respective remaining substituents of R2 and R3 in dependently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec. -butyl, or tert.- butyl, and the respective remaining substituents of R4 and R5 independently of one another represent H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, or CF3; or
R2 and R4 together with the carbon atoms connecting them, form a C3.6-cycloaliphatic residue selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, unsubstituted or mono- or polysubstituted with at least one substituent selected from the group consisting of OH, methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, CF3, OCH3 and OCH2CH3, and R3 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, or tert.-butyl, and R5 represents H; methyl; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, CH2F, CHF2, or CF3.
12. The compound according to any of the preceding claims, characterized in that the compound is selected from the group comprising 1 2-Cyclopropyl-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide;
2 2-Cyclopropyl-N-[[(1 S,2R)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide;
3 2-Cyclopropyl-N-[[(1 R,2S)-2-hydroxy-cyclohexyl]-methyl]-4-methyl-6- morpholin-4-yl-pyridine-3-carboxylic acid amide;
4 2-Cyclopropyl-N-([2-hydroxy-cyclopentyl]-methyl)-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide;
5 N-(3-Hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide;
6 2-lsopropyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-3-hydroxy-butyl)- pyridine-3-carboxylic acid amide;
7 N-[[(1 S,2R)-2-Hydroxy-cyclohexyl]-methyl]-2-isopropyi-4-methyl-6-morpholin- 4-yl-pyridine-3-carboxylic acid amide; and
8 2-Ethoxy-N-(3-hydroxy-4,4-dimethyl-pentyl)-4-methyl-6-morpholin-4-yl- pyridine-3-carboxylic acid amide, optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof.
13. A pharmaceutical composition comprising at least one compound according to any of the preceding claims, optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof, and optionally at least one pharmaceutically acceptable auxiliary.
14. The compound according to any of claims 1 to 12 for use in the treatment and/or prophylaxis of disorders and/or diseases which are mediated, at least in part, by KCNQ2/3 K+ channels.
15. The compound according to claim 13 for use in the treatment and/or prophylaxis of disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain, visceral pain and inflammatory pain, epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases and dystonia-associated dyskinesias.
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