EP2406265A2 - 3-aminoisoxazolopyridines substituées en tant que modulateurs de kcnq 2/3 - Google Patents

3-aminoisoxazolopyridines substituées en tant que modulateurs de kcnq 2/3

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Publication number
EP2406265A2
EP2406265A2 EP10707838A EP10707838A EP2406265A2 EP 2406265 A2 EP2406265 A2 EP 2406265A2 EP 10707838 A EP10707838 A EP 10707838A EP 10707838 A EP10707838 A EP 10707838A EP 2406265 A2 EP2406265 A2 EP 2406265A2
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EP
European Patent Office
Prior art keywords
alkyl
amine
heteroaryl
isoxazolo
aryl
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EP10707838A
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German (de)
English (en)
Inventor
Sven KÜHNER
Gregor Bahrenberg
Wolfgang Schröder
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority to EP10707838A priority Critical patent/EP2406265A2/fr
Publication of EP2406265A2 publication Critical patent/EP2406265A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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 3-Aminoisoxazolopy ⁇ idine, process for their preparation, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.
  • K + channels of the molecular subtype KCNQ2 / 3 (Kv7.2 / 7.3) are expressed in neurons of different regions of the central (hippocampus, amygdala) and peripheral (dorsal root ganglia) nervous system and regulate their excitability. Activation of KCNQ2 / 3 K + channels leads to hyperpolarization of the cell membrane and concomitant decrease in the electrical excitability of these neurons.
  • KCNQ2 / 3-expressing neurons of the dorsal root ganglia are involved in the transmission of nociceptive excitations from the periphery to the spinal cord (Passmore et al., J Neurosci., 2003; 23 (18) 7227-36).
  • the KCNQ2 / 3 agonist retigabine has demonstrated analgesic efficacy in preclinical neuropathic and inflammatory pain models (Blackbum-Munro and Jensen, Eur J Pharmacol., 2003; 3): 109-16; Dost et al., Naunyn Schmiedeberg's Arch Pharmacol 2004; 369 (4): 382-390).
  • the KCNQ2 / 3 K + channel thus provides a suitable starting point for the treatment of pain; in particular pain selected from the group consisting of chronic pain, neuropathic pain, inflammatory pain and muscular pain (Nielsen et al., Eur J Pharmacol. 2004; 487 (1-3): 93-103), especially neuropathic and inflammatory pain represents.
  • the KCNQ2 / 3 K + channel is a suitable target for the therapy of a variety of other diseases such as migraine (US2002 / 0128277), cognitive disorders (Gribkoff, Expert Opin Ther Targets 2003; 7 (6): 737-748), Anxiety states (Korsgaard et al., J Pharmacol Exp Ther.
  • PK / PD Pharmacokinetic / Pharmacodynamic
  • a weak or non-existent interaction with transporter molecules involved in the uptake and excretion of drugs is to be regarded as an indication of improved bioavailability and possibly low drug interactions.
  • the interactions with the enzymes involved in the degradation and excretion of drugs should also be as low as possible, since such test results also indicate that little or no drug interactions are to be expected.
  • the compounds show a high selectivity towards other receptors of the KCNQ family (specificity), for example against KCNQ1, KCNQ3 / 5 or KCNQ4.
  • High selectivity can have a favorable effect on the side effect profile.
  • compounds which (also) bind to KCNQ1 bring with them a high risk of cardiac side effects, and therefore high selectivity to KCNQ1 may be desirable.
  • high selectivity may also be advantageous over other receptors.
  • Low affinity for the hERG ion channel or the L-type calcium ion channel phenylalkylamine, benzothiazepine, dihydropyridine binding sites
  • improved selectivity for binding to other endogenous proteins i.e., e.g., receptors or enzymes
  • An object of the invention was therefore to provide new compounds which have advantages over the compounds of the prior art.
  • the compounds should be particularly useful as pharmacologically active agents in medicaments, preferably in medicaments for the treatment of disorders or diseases mediated at least in part by KCNQ2 / 3K + channels.
  • Isoxazolopyridines which are suitable as modulators of the C-kit receptor are known from the prior art (WO 2008/011080 and WO 2008/011110).
  • substituted 3-aminoisoxazolopyridines of general formula (1) given below are suitable for the treatment of pain. It has further been found, surprisingly, that substituted 3-aminoisoxazolopyridines of the general formula (1) given below also have an excellent affinity for the KCNQ2 / 3K + channel and are therefore suitable for the treatment of disorders or diseases which are at least partially due to KCNQ2 / 3K + Channels are taught.
  • the substituted 3-aminoisoxazolopyridines act as modulators, ie agonists or antagonists, of the KCNQ2 / 3K + channel.
  • An object of the invention are substituted 3-Aminoisoxazolopyridine of the general formula (1)
  • a 1 is N or CR 1
  • a 2 is N or CR 2
  • a 3 is N or CR 3
  • a 4 is N or CR 4 ,
  • R 1 can not be NH-R 0 when A 4 is N;
  • R 5 is aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted; with the proviso that when R 5 is heteroaryl, unsubstituted or monosubstituted or polysubstituted; means that the heteroaryl is linked via a carbon atom of the heteroaryl;
  • R 6a, R 6b are each independently hydrogen, F, Cl, Br, CN 1 CF 3, C 1-4 alkyl or O-Ci 4 alkyl, wherein "alkyl" in the definition of R 6a, R 6b can also be branched and / or unsaturated and / or substituted;
  • n is a natural number in the range of 1 to 6, preferably 1 to 3;
  • alkyl or "Ci.io-alkyl", 11 C 1-8 -AIKyI "and” C 1-4 alkyl "for the purposes of this invention include acyclic saturated or unsaturated aliphatic hydrocarbon radicals, branched or unbranched and unsubstituted or may be mono- or polysubstituted, having 1 to 10 or 1 to 8 or 1 to 4 carbon atoms, ie C ⁇ o-alkanyls, C 2- io-alkenyls and C 2- io-alkynyl or C 1-8 alkanyls, C 2-8 - alkenyls and C 2-8 -alkenyls or C 1-4 -alkanyles, C 2-4 -alkenyls and C 2-4 -alkynyls, alkenyls having at least one C-C double bond and alkynyls have at least one C-C triple bond
  • alkyl is selected from the group consisting
  • heteroalkyl and “C 2 -io-heteroalkyl” and “C 2-8 heteroalkyl” include for the purposes of this invention acyclic saturated or unsaturated aliphatic hydrocarbon residues having 2 to 10 carbon atoms, ie C 2- i 0 - Heteroalkanyle, C 2- C io- Heteroalkenyle and 2- io-Heteroalkinyle and having 2 to 8 carbon atoms, ie C 2-8 - Heteroalkanyle, C 2-8 -Heteroalkenyle and C 2-8 -Heteroalkinyle, each branched or unsubstituted or unsubstituted or monosubstituted or polysubstituted and in which at least one, optionally also two or three, carbon atoms are each independently selected from the group consisting of O, N, NH and N (C 1) by a heteroatom or a heteroatom group.
  • the heteroatom groups NH and N (d -8- alkyl) of the heteroalkyl may be monosubstituted or polysubstituted.
  • C 2- io-Heteroalkenyle and C 2-8 -Heteroalkenyle have at least one C-C or CN double bond, and C 2 -io-Heteroalkinyle and C 2-8 -Heteroalkinyle at least one carbon-carbon triple bond.
  • cycloalkyl or "C 1-10 cycloalkyl” for the purposes of this invention means cyclic aliphatic hydrocarbons having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, the hydrocarbons being saturated or unsaturated (but not aromatic ), unsubstituted or mono- or polysubstituted.
  • the bonding of the cycloalkyl to the respective general structure above can take place via any and possible ring member of the cycloalkyl radical.
  • the cycloalkyl radicals can also be condensed with further saturated, (partially) unsaturated, (hetero) cyclic, aromatic or heteroaromatic ring systems, ie with cycloalkyl, heterocyclyl, aryl or heteroaryl, which in turn may be unsubstituted or monosubstituted or polysubstituted.
  • the cycloalkyl radicals can furthermore be mono- or polysubstituted, for example in the case of adamantyl, bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl.
  • cycloalkyl is selected from the group comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • heterocyclyl or “heterocycloalkyl” embraces aliphatic saturated or unsaturated (but not aromatic) cycloalkyls having three to ten, ie 3, 4, 5, 6, 7, 8, 9 or 10 ring members in which at least one, if appropriate also two or three carbon atoms are replaced by a heteroatom or a heteroatom group each independently selected from the group consisting of O, S, N, NH and N (C 1-8 alkyl), preferably N (CH 3 ), wherein the ring members unsubstituted or mono- or polysubstituted.
  • the bonding of the heterocyclyl to the general structure above can take place via any and possible ring member of the heterocyclyl radical.
  • heterocyclyl radicals may also be condensed with further saturated, (partially) unsaturated (hetero) cyclic or aromatic or heteroaromatic ring systems, ie with cycloalkyl, heterocyclyl, aryl or heteroaryl, which in turn may be unsubstituted or monosubstituted or polysubstituted.
  • heterocyclyl radicals from the group comprising azetidinyl, aziridinyl, azepanyl, azocanyl, diazepanyl, dithiolanyl, dihydroquinolinyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydroindenyl, dihydropyridinyl, dihydrofuranyl, dihydroisoquinolinyl, dihydroindolinyl, dihydroisoindolyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, oxetanyl, Pyrrolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroiso
  • aryl in the context of this invention means aromatic hydrocarbons having up to 14 ring members, including phenyls and naphthyls.
  • Each aryl radical can be unsubstituted or monosubstituted or polysubstituted, where the aryl substituents can be the same or different and in any desired and possible position of the aryl.
  • the attachment of the aryl to the general structure above can take place via any and possible ring member of the aryl radical.
  • aryl radicals can also be condensed with further saturated, (partially) unsaturated, (hetero) cyclic, aromatic or heteroaromatic ring systems, ie with cycloalkyl, heterocyclyl, aryl or heteroaryl, which in turn may be unsubstituted or monosubstituted or polysubstituted.
  • Preferred fused aryl radicals are benzodioxolanyl and benzodioxanyl.
  • Aryl is preferably selected from the group which contains phenyl, 1-naphthyl and 2-naphthyl, which may each be unsubstituted or monosubstituted or polysubstituted.
  • a particularly preferred aryl is phenyl, unsubstituted or monosubstituted or polysubstituted.
  • heteroaryl represents a 5- or 6-membered cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each independently selected from the group S, N and O and the heteroaryl radical may be unsubstituted or mono- or polysubstituted; in the case of heteroaryl substitution, the substituents may be the same or different and may be in any and possible position of the heteroaryl.
  • the binding to the general structure above can take place via any and possible ring member of the heteroaryl radical.
  • the heteroaryl may also be part of a bi- or polycyclic system having up to 14 ring members, which ring system may be formed with further saturated, (partially) unsaturated, (hetero) cyclic or aromatic or heteroaromatic rings, i. with cycloalkyl, heterocyclyl, aryl or heteroaryl, which in turn may be unsubstituted or monosubstituted or polysubstituted.
  • heteroaryl moiety 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, phthaloyl, pyrazolyl, pyridyl (2-pyridyl, 3-
  • aryl, heteroaryl, heterocyclyl or cycloalkyl bridged by C 1-8 -alkyl in the context of the invention means that C 1-8 -alkyl and aryl or heteroaryl or heterocyclyl or cycloalkyl have the meanings defined above and Aryl or heteroaryl or heterocyclyl or cycloalkyl radical is bonded via a Ci -8 alkyl group to the respective parent general structure.
  • the Alkyl chain can in all cases be saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted.
  • C 1-8 alkyl is selected from the group comprising -CH 2 -, -CH 2 -CH 2 -, -CH (CH 3 ) -, -CH 2 - CH 2 -CH 2 -, -CH (CH 3 ) -CH 2 -, -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 -CH 2 -, -CH ( CH 2 CH 3 ) -, -C (CH 3 ) 2 -CH 2 -, -CH ( CH 2 CH 3 ) -, -C (CH 3 ) (CH 2 CH 3 ) -,
  • aryl, heteroaryl, heterocyclyl or cycloalkyl bridged via C 2-8 -heteroalkyl in the context of the invention mean that C 2-8 -heteroalkyl and aryl or heteroaryl or heterocyclyl or cycloalkyl have the meanings defined above and Aryl or heteroaryl or heterocyclyl or cycloalkyl radical is bonded via a C 2-8 heteroalkyl group to the respective parent general structure.
  • the heteroalkyl chain may in all cases be saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted.
  • a terminal carbon atom of the C 2 ⁇ -heteroalkyl group is replaced by a heteroatom or a heteroatom group, the bonding of a heteroaryl or a heterocyclyl to the heteroatom or the heteroatom group of the C 2-8 heteroalkyl always takes place via a carbon atom of the heteroaryl or heterocyclyl.
  • the terminal carbon atom is meant the carbon atom within the C 2-8 heteroalkyl which is furthest within the chain from the respective general parent structure.
  • C 2-8 heteroalkyl is selected from the group comprising -CH 2 -NH-, -CH 2 -N (CH 3 ) -, -CH 2 -O-, -CH 2 - CH 2 -NH-, -CH 2 -CH 2 -N (CH 3 ) -, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -CH 2 -NH-, -CH 2 -CH 2 -CH 2 - N (CH 3 ) , -CH 2 -CH 2 -CH 2 -O-, -CH 2 -O-CH 2 -, -CH 2 -CH 2 -O-CH 2 -, -CH 2 -CH 2 -O-CH 2 -, -CH 2 -CH 2 -O-CH 2 -, -CH 2 -CH 2 -O-CH 2 -, -CH 2 -CH 2 -O-CH 2 - CH 2 -, -CH 2
  • R 0 or H within a residue means that R 0 and H within this residue can occur in any possible combination.
  • the rest 11 may N (R 0 or H) 2 "for 11 NH 2," “NHR 0" and 11 N (R 0 J are 2.
  • R 0 as in the case of "N (R °) 2 "occurs multiple times within a residue, then R 0 can each have the same or different meanings: in the present example of 'N (R 0 V', R 0 can for example be twice for aryl, whereby the functional group 'N (aryl) 2 "or R 0 may be once aryl and once Ci -10- alkyl, resulting in the functional group” N (aryl) (C 1-10 alkyl) "results.
  • the 3rd generation substituents may not be substituted again, i. then there are no 4th generation substituents.
  • the substituents of the second generation can not be substituted again, ie there are already no substituents of the 3rd generation.
  • the functional groups for R 0 to R 5 may each be optionally substituted, but the respective substituents may in turn not be substituted again.
  • the compounds of the invention are defined by substituents which represent or carry an aryl or heteroaryl radical, each unsubstituted or monosubstituted or polysubstituted or which together with the carbon or heteroatom (s) connecting them as ring member or as Ring members form a ring, for example an aryl or heteroaryl, in each case unsubstituted or monosubstituted or polysubstituted.
  • Both these aryl or heteroaryl radicals as well as aromatic ring systems thus formed may optionally be fused with C 3- io-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, ie one with a C 3 i 0 cycloalkyl such as cyclopentyl or Heterocyclyl such as morpholinyl, wherein the thus condensed C3-io-cycloalkyl or heterocyclyl radicals in turn each be unsubstituted or mono- or polysubstituted.
  • the compounds of the invention are defined by substituents which represent or carry a C 3 to C 10 cycloalkyl or heterocyclyl radical, each unsubstituted or mono- or polysubstituted or which together with the carbon or heteroatom (s) linking them ) form a ring as a ring member or as ring members, for example a C 3-10 -cycloalkyl or heterocyclyl, in each case unsubstituted or monosubstituted or polysubstituted.
  • Both these C 3 i 0 cycloalkyl or heterocyclyl radicals as well as the aliphatic ring systems formed may be condensed with aryl or heteroaryl optionally, ie with an aryl such as phenyl or a heteroaryl such as pyridyl, wherein the aryl or heteroaryl fused so
  • radicals can each be unsubstituted or monosubstituted or polysubstituted.
  • salt formed with a physiologically acceptable acid means salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals. Particularly preferred is the hydrochloride.
  • physiologically tolerated acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane 1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric acid, phosphoric acid and / or aspartic acid.
  • Particularly preferred are citric acid and hydrochloric acid.
  • Physiologically acceptable salts with cations or bases are salts of the respective compound - as an anion with at least one, preferably inorganic, cation, which are physiologically compatible - especially when used in humans and / or mammals.
  • Particularly preferred are the salts of alkali and alkaline earth metals but also ammonium salts, but especially (mono-) or (di) sodium, (mono-) or (di) potassium, magnesium or calcium salts.
  • Preferred embodiments of the compounds of the general formula (1) according to the invention have the general formula (1a), (1b), (1c) or (1d):
  • n 1, 2 or 3, more preferably 1.
  • R 1 , R 2 , R 3 and R 4 are each independently H; F; Cl; Br; I; CN; O-C 1-8 alkyl; OCF 3 ; Ci -8- alkyl; CF 3 ; NH 2 ; S-Ci -8- alkyl; SCF 3 ;
  • R 1 and R 2 are each independently H; F; Cl; Br; I; O-C 1-8 alkyl; C 1-8 alkyl; OCF 3 ; CF 3 ;
  • R 3 and R 4 are each independently H; F; Cl; Br; I; SC 1-8 alkyl; SCF 3 ; or R 2 and R 3 , together with the carbon atoms connecting them, form an unsubstituted phenyl.
  • R 1 and R 2 are each independently H; C 1-8 alkyl; CF 3 ;
  • R 3 is H
  • R 4 is H; F; Cl; Br; I; S-Ci -8- alkyl;
  • R 7a , R 7b and R 7c are each independently H; F; Cl; Br; I; CN; OH; O-Ci -8- alkyl; OCF 3 ; C 1-8 alkyl; CF 3 ; SCF 3 stand;
  • each m is O, 1 or 2;
  • each is 1, 2 or 3;
  • each p is 1, 2 or 3;
  • each q is 0, 1 or 2;
  • X 1 and X 2 are each independently CH 2 , O, NH or N (C 1-8 alkyl);
  • R 8a and R 8b each independently represent F 1 Cl, Br, I, NO 2 , CN, OH, OC 1-8 alkyl, OCF 3 , C 1-8 alkyl, CF 3 , NH 2 , NH (Ci -8- alkyl) and N (C 1-8 -alkyl) 2 ;
  • R 6a and R 6b are each independently of one another H, F, Cl, Br, I, Ci -8 -AlkVl 1 saturated, unsaturated, branched or unbranched, unsubstituted;
  • R 7a, R 7b, and R 7c each independently of one another represent H; F; Cl; Br; I; Ods alkyl; OCF 3 ; C 1-8 alkyl; CF 3 ; SCF 3 stand;
  • R öc each represents H or ds-alkyl.
  • R 1 , R 2 , R 3 and R 4 are each independently H; F; Cl; Br; I; CN; O-Ci -8- alkyl; OCF 3 ; C 1-8 alkyl; CF 3 ; NH 2 ; SC 1-8 alkyl; SCF 3 ; mean;
  • substituted 3-aminoisoxazolopyridines according to the invention and in each case the corresponding acids, bases, salts and solvates are suitable as pharmaceutical active ingredients in medicaments.
  • Another object of the invention is therefore a medicament containing at least one inventive substituted 3-Aminoisoxazolopyridin the general formula (1) wherein the radicals R 1 -R 5 have the meaning given above and optionally one or more pharmaceutically acceptable excipients.
  • the medicaments according to the invention optionally contain suitable additives and / or adjuvants, such as carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of injection solutions, drops or juices, as semisolid Dosage forms in the form of granules, tablets, pellets, patches, capsules, patches / spray patches or aerosols. The choice of excipients etc.
  • the amounts to be used depend on whether the drug is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or topical, for example on the skin, mucous membranes or in the eyes, to be applied.
  • preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays.
  • Compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration, are suitable percutaneous administration preparations.
  • Orally or percutaneously applicable preparation forms can release the compounds according to the invention with a delay.
  • the compounds of the invention may also be administered in parenteral long-term depot forms such as e.g. Implants or implanted pumps.
  • parenteral long-term depot forms such as e.g. Implants or implanted pumps.
  • other active compounds known to the person skilled in the art may be added to the medicaments according to the invention.
  • medicaments according to the invention are suitable for influencing KCNQ2 / 3 channels and exert an agonistic or antagonistic, in particular an agonistic action.
  • the medicaments according to the invention are preferably suitable for the treatment of disorders or diseases which are at least partially mediated by KCNQ2 / 3 channels.
  • the medicaments according to the invention are preferably suitable for the treatment of one or more diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain; Epilepsy, urinary incontinence, anxiety, dependence, mania, bipolar disorder, migraine, cognitive disorders, dystonia-associated dyskinesias and / or urinary incontinence.
  • the medicaments according to the invention are particularly preferably suitable for the treatment of pain, very particularly preferably of chronic pain, neuropathic pain, inflammatory pain and muscular pain.
  • the medicaments according to the invention are particularly preferably suitable for the treatment of epilepsy.
  • Another object of the invention is the use of at least one substituted 3-Aminoisoxazolopyridins invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of disorders or diseases that are mediated at least partially by KCNQ2 / 3 channels.
  • Particularly preferred is the use of at least one substituted 3-Aminoisoxazolopyridins invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for Treatment of pain, most preferably chronic pain, neuropathic pain, inflammatory pain and muscular pain.
  • At least one substituted 3-Aminoisoxazolopyridins invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of epilepsy.
  • Another object of the invention is at least one inventive substituted 3-Aminoisoxazolopyridin and optionally one or more pharmaceutically acceptable excipients for the treatment of disorders or diseases that are mediated at least partially by KCNQ2 / 3 channels.
  • the invention further provides at least one substituted 3-aminoisoxazolopyridine according to the invention and optionally one or more pharmaceutically acceptable excipients for the treatment of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain ; Epilepsy, urinary incontinence, anxiety, dependence, mania, bipolar disorder, migraine, cognitive disorders, dystonia-associated dyskinesias and / or urinary incontinence.
  • pain preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain ; Epilepsy, urinary incontinence, anxiety, dependence, mania, bipolar disorder, migraine, cognitive disorders, dystonia-associated dyskinesias and / or urinary incontinence.
  • At least one substituted 3-aminoisoxazolopyridine according to the invention is at least one substituted 3-aminoisoxazolopyridine according to the invention and optionally one or more pharmaceutically acceptable excipients for the treatment of pain, most preferably of chronic pain, neuropathic pain, inflammatory pain and muscular pain.
  • At least one substituted 3-aminoisoxazolopyridine according to the invention is also particularly preferred.
  • Efficacy against pain can be demonstrated, for example, in the Bennett or Chung model (Bennett, GJ and Xie, YK, A peripheral mononeuropathy in sensation like those seen in man, Pain 1988, 33 (1), 87-107; Kim, SH and Chung, JM, An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain 1992, 50 (3), 355-363).
  • Efficacy 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 invention have an EC 5 o value of at most 10 microns or at most 5 microns, more preferably at most 3 microns or at most 2 microns, more preferably at most 1, 7 uM or up to 1 uM, Rushzugtesten at most 0, 9 ⁇ M or at most 0.6 ⁇ M and in particular at most 0.5 ⁇ M or at most 0.3 ⁇ M.
  • Methods for determining the EC 5 o value are known to the person skilled in the art.
  • the determination of the EC 5 o value preferably takes place by fluorimetry, particularly preferably as described under "Pharmacological Experiments".
  • Another object of the invention are methods for preparing the substituted 3-Aminoisoxazolopyridine invention.
  • the primary amine S-II can be used in stages 1-2 by methods known to those skilled in the art such as, for example, alkylation using the alkyl halide R 5 - (CR 6a R 6b ) n -Hal or a reductive amination using the corresponding carbonyl compound S-III will be transferred.
  • step 2-1 the carboxylic acid S-IV can be converted to the corresponding amide SV by methods known to those skilled in the art.
  • S-IV for example, first with a suitable chlorinating agent such as thionyl chloride for Acid chloride are reacted, which is subsequently reacted, if appropriate in the presence of a base with the primary amine R 5 - (CR 6a R 6b ) n -NH 2 to the amide SV.
  • the amide S-V can be converted to the corresponding thioamide S-Vl by methods known to those skilled in the art. This can be done, for example, by reaction with a thionating agent such as the Lawesson reagent.
  • stage 2-3 the thioamide S-Vl with hydroxylamine by a method known to those skilled in the art, if appropriate in the presence of a catalyst, to the compound S-VII are reacted, which in step 2-4 also familiar to a person skilled in the method Presence of an acid with ring closure to the bicyclic compound S-VIII can be implemented.
  • Kieselgei 60 (0. ⁇ 4 ⁇ - 0.063 mm) was used as the stationary phase for the column chromatography (SC).
  • Human CHO-K1 cells expressing KCNQ2 / 3 channels are expressed in cell culture floc / c Mi inM with rM ⁇ ⁇ ET ⁇ _h i ⁇ h nli I ⁇ CQ ⁇ IHrioh
  • FCS Fetal CaIf Serum
  • the cells are washed with a 1 ⁇ DPBS buffer without Ca 2+ / Mg 2+ (eg Invitrogen, # 14190-094) and detached from the bottom of the culture vessel by means of Accutase (PAA Laboratories, # L11-007) (Incubation with Accutase for 15 min at 37 ° C).
  • a 1 ⁇ DPBS buffer without Ca 2+ / Mg 2+ eg Invitrogen, # 14190-094
  • Accutase PAA Laboratories, # L11-007
  • the number of cells then determined is determined using a CASY TM cell counter (model TCC, sharpness system), and then, depending on the density optimization for the individual cell line 20,000-30,000 cells / well / 100 .mu.l of the described culture medium on the 96 well plates of Type Corning TM CellBIND TM (Fiat Clear Bottom Black Polystyrene Microplates, # 3340). This is followed by a one-hour incubation at room temperature without fumigation or humidity control, followed by a 24 hour incubation at 37 ° C, 5% CO 2 and 95% humidity.
  • the voltage-sensitive fluorescent dye from the Membrane Potential Assay Kit (Red TM Bulk format part R8123 for FLIPR, MDS Analytical Technologies TM) is prepared by diluting the contents of a jar Membrane Potential Assay Kit Red Component A into 200 ml Extracellular Buffer (ES buffer, 120 mM NaCl, 1mM KCl, 10mM HEPES, 2mM CaCl 2 , 2mM MgCl 2 , 10mM glucose, pH 7.4). After removal of the nutrient medium, the cells are washed with 200 ⁇ l of ES buffer, then overlaid with 100 ⁇ l of the above-prepared dye solution and incubated for 45 min at room temperature under light.
  • ES buffer 120 mM NaCl, 1mM KCl, 10mM HEPES, 2mM CaCl 2 , 2mM MgCl 2 , 10mM glucose, pH 7.4
  • Fluorescence measurements are performed with a BMG Labtech FLUOstar TM, BMG Labtech NOVOstar TM or BMG Labtech POLARstar TM instrument (525 nm Exation, 560 nm emission, bottom read mode).
  • a BMG Labtech FLUOstar TM, BMG Labtech NOVOstar TM or BMG Labtech POLARstar TM instrument 525 nm Exation, 560 nm emission, bottom read mode.
  • the fluorescence intensity of the dye is then measured for 5 minutes and the fluorescence value F 1 of each well is determined at a fixed and constant point in time.
  • 15 ⁇ l of a 100 mM KCl solution final concentration 92 mM
  • the change in fluorescence is then measured until all relevant measured values have been obtained (primarily 5-30 min).
  • a fluorescence value F2 is determined, in this case at the time of the fluorescence peak.
  • the fluorescence intensity F 2 is compared with the fluorescence intensity F 1 and the agonistic activity of the target compound on the potassium channel is determined therefrom.
  • F 2 and Fi are charged as follows:
  • F is determined by Instead of the substance to be tested, only the buffer solution is added to the reaction mixture, the value F 1K of the fluorescence intensity is determined, the potassium ions are added as described above and a value F 2K of the fluorescence intensity is measured. Then F 2K and F 1 K are calculated as follows:
  • a substance has an agonistic activity on the potassium channel, if:
  • Table 3 summarizes the results from the previously described pharmacological models.
  • the substituted 3-aminoisoxazolopyridines according to the invention are distinguished by improved solubility in aqueous media, which could, inter alia, lead to improved oral bioavailability.
  • the inventive compounds example 2, 6, 9 and 12 found, the activity against the KCNQ2 / 3 receptor is surprisingly still present.
  • the example compounds 2, 6, 9 and 12 also have an increased solubility by a factor of about 10.

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Abstract

L'invention concerne des 3-aminoisoxazolopyridines substituées, des procédés pour leur fabrication, des médicaments contenant ces composés ainsi que l'utilisation de ces composés pour la fabrication de médicaments.
EP10707838A 2009-03-10 2010-03-09 3-aminoisoxazolopyridines substituées en tant que modulateurs de kcnq 2/3 Withdrawn EP2406265A2 (fr)

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EP10707838A EP2406265A2 (fr) 2009-03-10 2010-03-09 3-aminoisoxazolopyridines substituées en tant que modulateurs de kcnq 2/3
PCT/EP2010/001448 WO2010102778A2 (fr) 2009-03-10 2010-03-09 3-aminoisoxazolopyridines substituées en tant que modulateurs de kcnq 2/3

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TWI504395B (zh) * 2009-03-10 2015-10-21 Substituted 3-amino-2-mercaptoquinoline as a KCNQ2 / 3 modifier
TW201038565A (en) 2009-03-12 2010-11-01 Gruenenthal Gmbh Substituted 2-mercapto-3-aminopyridines as KCNQ2/3 modulators
TWI461197B (zh) 2009-03-12 2014-11-21 2-mercaptoquinoline-3-carboxamide as a KCNQ2 / 3 modifier
TWI475020B (zh) 2009-03-12 2015-03-01 The substituted nicotine amide as a KCNQ2 / 3 modifier
NZ604745A (en) 2010-08-27 2015-01-30 Gruenenthal Chemie Substituted 2-oxy-quinoline-3-carboxamides as kcnq2/3 modulators
EP2609086B1 (fr) 2010-08-27 2015-02-25 Grünenthal GmbH 2-oxo- et 2-thioxo-dihydroquinoléine-3-carboxamides substitués comme modulateurs de kcnq2/3
US8470852B2 (en) 2010-08-27 2013-06-25 Gruenenthal Gmbh Substituted 2-amino-quinoline-3-carboxamides as KCNQ2/3 modulators
MX2013002295A (es) 2010-09-01 2013-05-09 Gruenenthal Gmbh 1-oxo-dihidroisoquinolin-3-carboxamidas sustituidas como moduladores de kcnq2/3.
WO2016024233A1 (fr) * 2014-08-13 2016-02-18 Auckland Uniservices Limited Inhibiteurs de tryptophane dioxygénases (ido1 et tdo) et leur utilisation en thérapie
WO2016047678A1 (fr) * 2014-09-25 2016-03-31 武田薬品工業株式会社 Composé hétérocyclique
AU2016312848A1 (en) 2015-08-27 2018-03-29 Auckland Uniservices Limited Inhibitors of tryptophan dioxygenases (IDO1 and TDO) and their use in therapy
CN110627714A (zh) * 2019-10-16 2019-12-31 安庆博曼生物技术有限公司 3-氟-2-三氟甲基异烟酸的合成方法

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TW201038565A (en) * 2009-03-12 2010-11-01 Gruenenthal Gmbh Substituted 2-mercapto-3-aminopyridines as KCNQ2/3 modulators
TWI461197B (zh) * 2009-03-12 2014-11-21 2-mercaptoquinoline-3-carboxamide as a KCNQ2 / 3 modifier
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US20100234419A1 (en) 2010-09-16
AU2010223555A1 (en) 2011-11-03
CA2754934A1 (fr) 2010-09-16
WO2010102778A2 (fr) 2010-09-16
MX2011008825A (es) 2011-09-21
JP2012520246A (ja) 2012-09-06
WO2010102778A3 (fr) 2010-12-16

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