EP2150531A2 - Nouveaux ligands de récepteur vanilloïde et leur utilisation pour la fabrication de médicaments - Google Patents

Nouveaux ligands de récepteur vanilloïde et leur utilisation pour la fabrication de médicaments

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Publication number
EP2150531A2
EP2150531A2 EP08748889A EP08748889A EP2150531A2 EP 2150531 A2 EP2150531 A2 EP 2150531A2 EP 08748889 A EP08748889 A EP 08748889A EP 08748889 A EP08748889 A EP 08748889A EP 2150531 A2 EP2150531 A2 EP 2150531A2
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EP
European Patent Office
Prior art keywords
phenyl
methyl
trifluoromethyl
fluoro
methylsulfonamido
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08748889A
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German (de)
English (en)
Inventor
Robert Frank
Gregor Bahrenberg
Thomas Christoph
Klaus Schiene
Jean De Vry
Derek John Saunders
Bernd Sundermann
Jeewoo Lee
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Gruenenthal GmbH
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Gruenenthal GmbH
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Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP2150531A2 publication Critical patent/EP2150531A2/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel vanilloid receptor ligands, processes for their preparation, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.
  • a suitable starting point for the treatment of pain in particular pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, most preferably neuropathic pain; represents the vanilloid receptor subtype 1 (VR1 / TRPV1), which is often referred to as the capsaicin receptor.
  • This receptor is u.a. by vanilloids such as e.g. Capsaicin, heat and protons stimulates and plays a central role in the onset of pain.
  • An object of the present invention was therefore to provide novel compounds which are particularly suitable as pharmacological agents in medicaments, preferably in medicaments for the treatment of disorders or diseases mediated, at least in part, by vanilloid receptors 1 (VR1 / TRPV1 receptors).
  • VR1 / TRPV1 receptors vanilloid receptors 1
  • the substituted compounds of general formula I given below have an excellent affinity for the vanilloid receptor of subtype 1 (VR1 / TRPV1 receptor) and are therefore particularly suitable for the prophylaxis and / or treatment of disorders or diseases which at least partially mediated by vanilloid receptors 1 (VR1 / TRPV1). Also, the substituted compounds of general formula I given below have anti-inflammatory activity.
  • D is N or CH
  • R 1 is -SF 5 ; -0-CF 3 ; -O-CFH 2 ; -0-CF 2 H; -CFH 2 ; -CF 2 H; -CF 3 ; or is an unsubstituted or at least monosubstituted tert-butyl radical;
  • R 2 for -NHR 7 ; -NR 8 R 9 ; -OR 10 ; -SR 11 ;
  • a ring member having 3-, 4-, 5-, 6-, 7-, 8- or ⁇ -membered cycloaliphatic radical, each having a carbon atom in the Ring of the cycloaliphatic radical is bonded to the skeleton and may be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system;
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of one another, respectively
  • a ring member having 3-, 4-, 5-, 6-, 7-, 8- or 9-membered cycloaliphatic radical having a saturated or unsaturated , unsubstituted or at least monosubstituted mono- or polycyclic ring system condensed and / or can be bonded via a linear or branched, unsubstituted or at least monosubstituted d ⁇ -Alkylen group or 2- to 6-membered heteroalkylene group;
  • R 8 and R 9 in each case together with the nitrogen atom connecting them as a ring member a saturated or unsaturated, unsubstituted or at least monosubstituted 4-, 5-, 6-, 7-, 8- or 9-membered, optionally at least one other Heteroatom form a ring member having heterocycloaliphatic radical which may be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system;
  • R 12 , R 13 , R 14 , R 15 and R 16 are each independently H; F; Cl;
  • R 17 is a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1-10 radical;
  • hetero cycloaliphatic radicals may each optionally have 1, 2 or 3 (further) heteroatom (s) independently selected from the group consisting of oxygen, nitrogen and sulfur;
  • heteroaryl radicals in each case optionally have 1, 2, 3, 4 or 5 heteroatom (s) independently of one another selected from the group consisting of oxygen, nitrogen and sulfur as ring member (s).
  • heteroalkylene denotes an alkylene chain in which one or more C atoms have each been replaced by a heteroatom selected independently of one another from the group consisting of oxygen, sulfur and nitrogen (NH)
  • Heteroalkylene groups may preferably be 1, 2 or 3 heteroatom (s), particularly preferably a heteroatom, independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as chain member (s)
  • Heteroalkylen groups may preferably 2-6-membered, more preferably 2- or 3-membered.
  • Examples include heteroalkylene groups such as -CH 2 -CH 2 -O-CH 2 -, -CH 2 -CH (CH 3) -O-CH 2 -, - (CHz) -O-, - (CHz) 2 -O -, - (CH 2 ) S -O-, - (CH 2 ) 4 -O-, -O- (CH 2 ) -, -O- (CH 2 ) 2 -, -O- (CH 2 ) 3 - , -O- (CHz) 4 -, -C (C 2 H 5 ) (H) -O-, -O-C (C 2 H 5 ) (H) -, -CH 2 -O-CH 2 -, -CH 2 -S-CH 2 -, -CH 2 -NH-CH 2 -, -CH 2 -NH- and -CH 2 -CH 2 -NH-CH 2 -CH 2 called.
  • substituents have a linear or branched C 6 alkylene group, this may preferably be selected from the group consisting of - (CH 2) -, - (CHz) 2 -, -C (H) (CH 3 ) -, - (CH 2 ) 3 -, - (CH 2 ) 4 -, - (CH 2 ) S-, -C (H) (C (H) (CH 3 ) Z) - and -C ( C 2 H 5 ) (H) -.
  • C 1- I 0 aliphatic radicals can stand for a Ci-io alkyl, C 2- io-alkenyl or C 2- io alkynyl radical.
  • C 2- I 0 alkenyl radicals have at least one, preferably 1, 2, 3 or 4 carbon-carbon double bonds, and C i 0 2- alkynyl radicals at least one, preferably 1, 2, 3 or 4 carbon-carbon triple bonds.
  • C M o-alkyl radicals are preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-methyl-but- 1-yl, 2-pentyl, 3-pentyl, sec-pentyl, neo-pentyl, 4-methyl-pent-1-yl, (3,3) -dimethyl-but-1-yl, n-hexyl, n- Heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, n-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl and (2,6) -dimethyl-hept-4 yl optionally with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of
  • C 2- io-alkenyl radicals are selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-propen-1-yl, 3 -Methyl-but-2-en-1-yl, (3,3) -dimethyl-but-1-enyl, 2-methyl-buten-2-yl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4 Pentenyl, 1-hexenyl, 1-heptenyl and 1-octenyl optionally with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH , -NH 2 , -SH, -O-CH 3 , -O-C 2 H 5 , -O- CH (CHs) 2 , -OC (CH 3 ) 3 , -S-CH 3 , -SC
  • alkynyl radicals C 2 i are preferably selected from the group consisting of (3,3) -dimethyl-but-1-ynyl, 4-methyl-pent-1-ynyl, 1-hexynyl, ethynyl, 1- Propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl and 4-pentynyl, optionally with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH, -O-CH 3 , -O-C 2 H 5 , -O-CH (CH 3 ) 2 , -OC (CH 3) 3, -S-CH 3, -SC 2 H 5, -S-CH (CH 3) 2, -S-C (CH
  • Particularly preferred optionally substituted C 1-10 aliphatic radicals are selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, -CF 2 Cl, -CCl 2 F, -CCl 3 , -CBr 3 , -CH 2 -CN, -CH 2 -O-CH 3 , -CH 2 -O-CF 3 , -CH 2 -SF 3 , -CH 2 -NH 2 , -CH 2 -OH, -CH 2 -SH, -CH 2 - NH-CH 3 , -CH 2 -N (CH 3 J 2 , -CH 2 -N (C 2 Hg) 2 , -CH 2 -N (CH 3 ) (C 2 H 5 ), ethyl, -CF 2 -CH 3 , -CHF-CF 2 Cl, -CF 2 -CFCI 2 , -CFCI-CF 2 Cl, -CFCI-
  • substituents are a (hetero) cycloaliphatic radical which may optionally be condensed with a saturated or unsaturated, unsubstituted or at least monosubstituted mono- or polycyclic ring system, this may preferably be selected from the group consisting of Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl, (1, 2,3,6) -tetrahydropyridinyl, azepanyl, Azocanyl, cyclobutyl,
  • Hetero cycloaliphatic radicals can form a spirocyclic radical in the sense of the present invention with a further (hetero) cycloaliphatic radical via a common carbon atom in both rings.
  • Suitable spirocyclic radicals are a 6-aza-spiro [2.5] octyl radical, 8-azaspiro [4.5] decyl radical and a 1-oxa-2,8-diaza-spiro [4.5] dec-2-enyl radical. Called remainder.
  • substituents are an aryl radical, this may preferably be selected from the group consisting of phenyl and naphthyl (1-naphthyl and 2-naphthyl).
  • substituents is a heteroaryl radical
  • this may preferably be selected from the group consisting of tetrazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, benzoxazolyl, benzisoxazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl and isoquinolinyl.
  • Suitable aryl and heteroaryl radicals which may be unsubstituted or monosubstituted or polysubstituted and which have been condensed with a monocyclic or bicyclic ring system are, for example, isoindolyl, indolyl, (1, 2,3,4) -tetrahydroquinolinyl, ( 1, 2, 3, 4) -tetrahydroisoquinolinyl, (2,3) -dihydro-1H-isoindolyl, (1,2,3,4) -tetrahydronaphthyl, (2,3) -dihydrobenzo [1,4] dioxinyl, ( 2,3) - dihydrothieno [3,4-b] [1,4] dioxinyl, benzo [1,3] dioxolyl and (1,4) benzodioxanyl.
  • a polycyclic ring system such as a bicyclic ring system
  • the different rings may have a different degree of saturation, i. be saturated or unsaturated.
  • a polycyclic ring system is a bicyclic ring system.
  • R 2 and A are each as defined above;
  • A is a radical selected from the group consisting of
  • R 1 is -SF 5 ; -0-CF 3 ; -0-CFH 2 ; -O-CF 2 H; -CFH 2 ; -CF 2 H; -CF 3 ; or is a tert-butyl radical, each unsubstituted or having 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of F, Cl, Br, I, - CN, -NO 2 , -OH, -NH 2 , -SH, -O-CH 3 , -O-C 2 H 5 , -O-CH (CH 3 ) 2 , -NH-CH 3 and -NH-C 2 H 5 may be substituted;
  • R 2 for -NHR 7 ; -NR 8 R 9 ; -OR 10 ; -SR 11 ;
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of one another, respectively
  • -CH 2 -O-, -CH 2 -CH 2 -O-, -CH 2 -CH 2 -O- CH 2 -, -CH 2 -CH (CHs) -O-CH 2 -, - ( CH 2 ) -, - (CH 2 ) 2 - or - (CH 2 ) 3 group may be bonded and / or in each case unsubstituted or optionally with 1, 2, 3, 4 or 5 substituents independently selected from the group from
  • R 8 and R 9 together with the nitrogen atom connecting them as ring member a radical selected from the group consisting of 3-azabicyclo [3.1.1] heptyl, 6-aza-spiro [2.5] octyl, 3-azabicyclo [ 3.2.1] octyl, 6-azabicyclo [3.3.1] heptyl, 8-azabicyclo [3.2.1] octyl, 1-oxa-2,8-diaza-spiro [4.5] dec-2-enyl, Azocanyl, isoindolyl, indolyl, (1, 2,3,6) -tetrahydropyridinyl, (4,5,6,7) -tetrahydroisoxazolo [5,4-c] pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and Form thiomorpholinyl, each unsubsti
  • R 12 , R 13 , R 14 , R 15 and R 16 are each independently H; F; Cl; Br; I; -SF 5 ; NO 2 ; -CF 3 ; -CN; -NH 2 ; -OH; SH; Methyl; ethyl; isopropyl; n-propyl; n-butyl; tert-butyl; iso-butyl, sec-butyl; -O-phenyl; -0-CH 3; -0-C 2 H 5 ; -OC (CH 3 ) 3 ; -O- CH (CH 3 J 2 or -O-CH 2 -CH 2 -CH 2 -CH 3 ; and R 17 is hydrogen or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-p
  • D is N or CH
  • R 1 is -SF 5 ; -0-CF 3 ; -O-CFH 2 ; -O-CF 2 H; -CFH 2 ; -CF 2 H; -CF 3 ; or represents a tert-butyl radical;
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br;
  • R 8 and R 9 together with the nitrogen atom connecting them as ring member, are a radical selected from the group consisting of 3-azabicyclo [3.1.1] heptyl, 6-aza-spiro [2.5] octyl, 3-azabicyclo [3.2.1] octyl, 6-azabicyclo [3.3.1] heptyl, 8-azabicyclo [3.2.1] octyl, 1-oxa-2,8-diaza-spiro [4.5] dec-2-enyl , Azocanyl, isoindolyl, indolyl, (1, 2,3,6) -tetrahydropyridinyl, (4,5,6,7) -tetrahydroisoxazolo [5,4-c] pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and thiomorpholinyl,
  • R 12 , R 13 , R 14 , R 15 and R 16 are each independently H; F; Cl; Br or -CF 3 stand;
  • R 17 is hydrogen or a group selected from the group consisting of methyl, ethyl, n -propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert -butyl;
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br;
  • R 8 and R 9 together with the nitrogen atom connecting them as ring member, are a radical selected from the group consisting of 3-azabicyclo [3.1.1] heptyl, 6-aza-spiro [2.5] octyl, 3-azabicyclo [3.2.1] octyl, 6-azabicyclo [3.3.1] heptyl, 8-azabicyclo [3.2.1] octyl, 1-oxa-2,8-diaza-spiro [4.5] dec-2-enyl , Azocanyl, isoindolyl, indolyl, (1, 2,3,6) -tetrahydropyridinyl, (4,5,6,7) -tetrahydroisoxazolo [5,4-c] pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and thiomorpholinyl,
  • R 12 , R 13 , R 14 , R 15 and R 16 are each independently H; F; Cl; Br or -CF 3 stand;
  • R 17 is hydrogen or a group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl;
  • D is N or CH
  • R 1 is -SF 5 ; -0-CF 3 ; -CF 3 ; or represents a tert-butyl radical;
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br;
  • R 8 and R 9 together with the nitrogen atom connecting them as a ring member form a radical selected from the group consisting of azocanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and thiomorpholinyl, each of which is unsubstituted or optionally with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl may be substituted;
  • R 12 , R 13 , R 14 , R 15 and R 16 are each H;
  • R 17 is hydrogen or a group selected from the group consisting of methyl, ethyl, n -propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert -butyl;
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br;
  • R 8 and R 9 together with the nitrogen atom connecting them as a ring member form a radical selected from the group consisting of azocanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl and thiomorpholinyl, each of which is unsubstituted or optionally with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl may be substituted; R 12 , R 13 , R 14 , R 15 and R 16 are each H;
  • R 17 is hydrogen or a group selected from the group consisting of methyl, ethyl, n -propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert -butyl;
  • D is N or CH
  • R 1 is -SF 5 ; -0-CF 3 ; -O-CFH 2 ; -0-CF 2 H; -CFH 2 ; -CF 2 H; -CF 3 ; or represents a tert-butyl radical;
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br; NO 2 ; -CF 3 ; -CN; -OH; Methyl; ethyl; isopropyl; n-propyl; n-butyl; tert-butyl; sec-butyl; iso-butyl, -O-phenyl; -O-CH 3 or -O-C 2 H 5 ;
  • R 11 is a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl , n-octyl, n-nonyl, 5-nonyl, (2,6) -dimethyl-hept-4-yl,
  • R 12 , R 13 , R 14 , R 15 and R 16 are each independently H; F; Cl; Br or -CF 3 stand;
  • R 17 is hydrogen or a group selected from the group consisting of methyl, ethyl, n -propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert -butyl;
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br;
  • R 11 is a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-heptyl, 4-heptyl , n-octyl, n-nonyl, 5-nonyl, (2,6) -dimethyl-hept-4-yl, 3-methyl-butyl, n-hexyl, (3,3) -dimethylbutyl, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -OC 2 H 5 , -CH 2 -CH 2 -CH 2 -O-CH 3 , ethenyl, propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and 3-pentenyl; is a radical selected from the group consist
  • R 12 , R 13 , R 14 , R 15 and R 16 are each independently H; F; Cl; Br or -CF 3 stand;
  • R 17 is hydrogen or a group selected from the group consisting of methyl, ethyl, n -propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert -butyl;
  • D is N or CH
  • R 1 is -SF 5 ; -0-CF 3 ; -CF 3 ; or represents a tert-butyl radical;
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br;
  • R 11 is a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each unsubstituted or optionally with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and sec-butyl;
  • R 12 , R 13 , R 14 , R 15 and R 16 are each H;
  • R 17 is hydrogen or a group selected from the group consisting of methyl, ethyl, n -propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert -butyl;
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br;
  • R 11 is a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each unsubstituted or optionally with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl, ethyl , n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and tert-butyl;
  • R> 1 1 2 ⁇ 1 D R1 1 3 J , D R1 1 4 4 , R D 1 1 5 0 and R 1 1 6 0 are each H;
  • R 17 is hydrogen or a group selected from the group consisting of methyl, ethyl, n -propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert -butyl; in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
  • Another preferred subject matter of the present invention are also compounds of the general formulas A, B, C and D.
  • R 3 , R 4 , R 5 and R 6 are each H; F; Cl; Br; NO 2 ; -CF 3 ; -CN; -OH; Methyl; ethyl; isopropyl; n-propyl; n-butyl; tert-butyl; iso-butyl, sec-butyl; -O-phenyl; -O-CH 3 or -O-C 2 H 5 ; R 12 , R 13 , R 14 , R 15 and R 16 are each independently H; F; Cl; Br or -CF 3 stand;
  • R 17 is hydrogen or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.
  • the Ca 2+ influx is determined using a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA). quantified as described below.
  • the compound may be 2- (3-fluoro-4-methanesulfonylamino-phenyl) -N- (4-methyl-6'-trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2'-bipyridinyl] 3'-ylmethyl) - butyramide, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or in each case in the form corresponding salts, or in each case in the form of corresponding solvates, be excluded.
  • a further subject matter of the present invention is a process for the preparation of compounds of the above-indicated general formulas I, Ia, Ia1, Ia2, Ia3, Ia4, Ib1, Ib2, Ib3, Ib4, Ic, Id, Ie, If, Ib 1 A, B, C and D according to the at least one compound of general formula II,
  • R 1 , R 2 and D have the abovementioned meaning and R is hydrogen or a linear or branched C- ⁇ - 6 alkyl radical, in a reaction medium, in the presence of at least one reducing agent, preferably in the presence of at least one reducing agent selected from the group consisting of sodium hydride, sodium, potassium hydride, lithium aluminum hydride, sodium borohydride and di (isobutyl) aluminum hydride to at least one compound of general formula III,
  • R 1 , R 2 and D have the abovementioned meaning, and if necessary this is purified and / or isolated,
  • R 1 , R 2 and D have the abovementioned meaning, and if necessary this is purified and / or isolated,
  • At least one compound of general formula IV in a reaction medium in the presence of at least one reducing agent, preferably in the presence of at least one reducing agent selected from the group consisting of sodium hydride, potassium hydride, lithium aluminum hydride, sodium borohydride and di (isobutyl) aluminum hydride
  • a catalyst preferably in the presence of a catalyst based on platinum or palladium, more preferably in the presence of palladium on carbon, and in the presence of hydrogen or in the presence of hydrazine or in a reaction medium in the presence of triphenylphosphine
  • R 1 , R 2 and D have the abovementioned meaning, and if necessary this is purified and / or isolated,
  • At least one catalyst in the presence of at least one catalyst, preferably in the presence of at least one catalyst based on palladium or platinum, more preferably in the presence of palladium on carbon, under a hydrogen atmosphere, if appropriate in the presence of at least one acid, preferably in the presence of hydrochloric acid,
  • At least one reducing agent selected from the group consisting of BH 3 -S (CHh) 2 , lithium aluminum hydride and sodium borohydride, if appropriate in the presence of NiCb,
  • A has the abovementioned meaning, in a reaction medium, if appropriate in the presence of at least one suitable coupling agent, if appropriate in the presence of at least one base,
  • A has the abovementioned meaning and LG is a leaving group, preferably a chlorine or bromine atom, in a reaction medium, if appropriate in the presence of at least one base, to form at least one compound of the general formula I,
  • R 1 , R 2 , D and A have the abovementioned meaning, and this is optionally purified and / or isolated.
  • the reaction of compounds of the abovementioned general formula V with carboxylic acids of the abovementioned general formula VII to give compounds of the abovementioned general formula I is preferably carried out in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1, 2) -dichloroethane, dimethylformamide, dichloromethane and corresponding mixtures, if appropriate in the presence of at least one coupling reagent, preferably selected from the group consisting of 1-benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N ' - (3-dimethylaminopropyl) -N-ethy
  • reaction of compounds of the above general formulas V with carboxylic acid derivatives of the above-mentioned general formula VIII, wherein LG is a leaving group, preferably a chlorine or bromine atom, is carried out to compounds of the above general formulas Ih or Im preferably in a reaction medium from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, if appropriate in the presence of an organic or inorganic base, preferably selected from the group consisting of triethylamine, dimethylaminopyridine, pyridine and diisopropylamine, at temperatures of -70 0 C to 100 0 C.
  • LG is a leaving group, preferably a chlorine or bromine atom
  • step 1a compounds of general formula S1 in which R 3 and R 4 have the abovementioned meaning, are reacted using phosphorus pentachloride into the corresponding compounds of general formula T1, which can then be reacted to give the corresponding ethyl esters of general formula U.
  • the process is described in US 3,306,909 described. The relevant parts of the reference are hereby incorporated by reference.
  • step 1b compounds of the general formula S1 in which R 3 and R 4 have the abovementioned meaning, are reacted using thionyl chloride in the corresponding compounds of the general formula T2, which can then be converted to the corresponding ethyl esters of the general formula U.
  • the method is described inter alia in DE 1966974. The relevant parts of the reference are hereby incorporated by reference.
  • esterification of the chlorophenylacetic acid of the general formula T2 can be carried out with the aid of standard esterification protocols as described, for example, in J. Prakt. Chem. 99, (1919), page 224; Synthesis 6, (2001), pages 943-946; J. Fluorine Chem. 79, 2, (1996), pages 167-172 and Tetrahedron 52, 44, (1996), pages 13867-13880.
  • the relevant parts of the reference are hereby incorporated by reference.
  • step 1a compounds of the general formula V in which R 5 and R 6 have the abovementioned meaning, can be converted into the corresponding compounds of the general formula W, as described in US 2003/144546.
  • the relevant parts of the reference are hereby incorporated by reference.
  • stage 1 b compounds of the general formula Y in which R 5 and R 6 have the abovementioned meaning, are converted into the corresponding compounds of the general formula W, for example in HeIv. Chim. Acta 66, 4, (1983), pages 1028-1030; J. Am. Chem. Soc. 85, (1963), pages 3394-3396 and Tetrahedron Letters, 28, 17, (1987), pages 1873-1876.
  • esterification of the chlorophenylpropanoic acid of the general formula W can be carried out with the aid of standard esterification protocols, as described, for example, in J. Prakt. Chem. 99, (1919), page 224; Synthesis 6, (2001), pages 943-946; J. Fluorine Chem. 79, 2, (1996), pages 167-172 and Tetrahedron 52, 44, (1996), pages 13867-13880 described described.
  • the relevant parts of the reference are hereby incorporated by reference.
  • the reactions described above may in each case be carried out under the customary conditions known to the person skilled in the art, for example with regard to pressure or sequence of addition of the components. Possibly. can be determined under the respective conditions optimal process control by the skilled person by simple preliminary tests.
  • the intermediate and end products obtained according to the above-described reactions can each be purified and / or isolated, if desired and / or required, by customary methods known to those skilled in the art. Suitable purification methods are, for example, extraction methods and chromatographic methods, such as column chromatography or preparative chromatography. All of the above-described process steps as well as in each case also the purification and / or isolation of intermediate or end products can be carried out partially or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.
  • the free bases of the respective substituted compounds of the aforementioned general formula I and corresponding stereoisomers can also be converted with the free acid or a salt of a sugar substitute, such as saccharin, cyclamate or acesulfame, into the corresponding physiologically tolerable salts.
  • a sugar substitute such as saccharin, cyclamate or acesulfame
  • the free acids of the substituted compounds of the abovementioned general formula I and corresponding stereoisomers can be converted by reaction with a suitable base into the corresponding physiologically tolerable salts.
  • a suitable base for example, mention may be made of the alkali metal salts, alkaline earth metal salts or ammonium salts [NH x R 4 -J + , where x is 0, 1, 2, 3 or 4 and R is a linear or branched C 1-4 -alkyl radical.
  • substituted compounds of the abovementioned general formula I and corresponding stereoisomers according to the invention can also be prepared in the form of their solvates, preferably in the form of their hydrates, by customary methods known to the person skilled in the art. to be obtained.
  • substituted compounds of the abovementioned general formula I according to the invention are obtained 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, these can be separated by customary methods known to the person skilled in the art and if necessary be isolated. Examples which may be mentioned are chromatographic separation processes, in particular liquid chromatography processes under atmospheric pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallization processes.
  • Another object of the present invention is therefore a medicament containing at least one compound of the invention of the above general formula I, in each case optionally in the form of one of their pure stereoisomers, in particular enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, especially the enantiomers and / or diastereomers, in any mixing ratio, or each in the form of a corresponding salt, or each in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients.
  • medicaments according to the invention are particularly suitable for vanilloid receptor 1 (VR1 / TRPV1) regulation, preferably for vanilloid receptor 1 (VR1 / TRPV1) inhibition and / or for vanilloid receptor 1 (VR1H " RPV1) stimulation ,
  • the medicaments according to the invention are likewise preferably suitable for the prophylaxis and / or treatment of disorders or diseases which are at least partially mediated by vanilloid receptors 1.
  • the medicament according to the invention is preferably suitable for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; Joint pain; hyperalgesia; allodynia; causalgia; Migraine; Depressions; Neuropathy; Nerve injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; Epilepsy; Respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pneumonia; To cough; urinary incontinence; an overactive bladder (OAB); Diseases and / or injuries of the gastrointestinal tract; Duodenal ulcers; Stomach ulcers; Irritable bowel syndrome; Stroke; Eye irritation; Skin irritation; neurotic skin diseases; allergic skin diseases; Psiorasis; vitiligo
  • the medicament according to the invention is particularly preferably suitable for the treatment and / or prophylaxis 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 and visceral pain; Joint pain; Migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiencies, particularly preferred memory disorders; Inflammation, preferably inflammation of the intestine, eyes, bladder, skin or nasal mucosa; urinary incontinence; an overactive bladder (overactive bladder, OAB); Drug addiction; Drug abuse; Withdrawal symptoms in drug dependence; Development of tolerance to drugs, preferably development of tolerance to natural or synthetic opioids; Drug addiction; Drug abuse; Withdrawal symptoms in drug addiction; Alcohol dependency; Alcohol abuse and withdrawal symptoms in alcohol dependence.
  • pain preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain
  • the pharmaceutical composition according to the invention is suitable for the treatment and / or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, and / or urinary incontinence.
  • Another object of the present invention is the use of at least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for the preparation of a medicament for vanilloid receptor 1- (VR1 / TRPV1) regulation, preferably to the vanilloid receptor 1- (VR1 / TRPV1) inhibition and / or for vanilloid receptor 1 (VR1 / TRPV1) stimulation.
  • a medicament for vanilloid receptor 1- (VR1 / TRPV1) regulation preferably to the vanilloid receptor 1- (VR1 / TRPV1) inhibition and / or for vanilloid receptor 1 (VR1 / TRPV1) stimulation.
  • Preferred is the use of at least one substituted compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the prophylaxis and / or treatment of disorders or diseases which are mediated at least partially by vanilloid receptors 1.
  • Particularly preferred is the use of at least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of pain, preferably selected from the group consisting of pain acute Pain, chronic pain, neuropathic pain and visceral pain and joint pain.
  • At least one compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of one or more diseases selected from the group consisting of hyperalgesia; allodynia; causalgia; Migraine; Depressions; Nervous disorders; Nerve injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficits, particularly preferred memory disorders; Epilepsy; Respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pneumonia; To cough; urinary incontinence; an overactive bladder (overactive bladder, OAB); Diseases and / or injuries of the gastrointestinal tract; Duodenal ulcers; Stomach ulcers; Irritable bowel syndrome; Stroke; Eye irritation; Skin irritation; neurotic skin diseases; allergic skin diseases; Psiorasis; vitiligo
  • pain preferably pain selected from the group
  • At least one substituted compound of the invention and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment and / or prophylaxis of pain, preferably selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral Pain, and / or urinary incontinence.
  • the pharmaceutical composition of the invention is suitable for administration to adults and children, including infants and babies.
  • the medicament according to the invention can be used as a liquid, semisolid or solid dosage form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, patches, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed into tablets, filled into capsules or suspended in a liquid, are present and as such also administered.
  • the medicament according to the invention usually contains further physiologically acceptable pharmaceutical excipients which can be selected, for example, from the group consisting of carrier materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants Lubricants, lubricants, flavors and binders.
  • physiologically acceptable excipients depend on whether the drug is administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on infections of the skin, mucous membranes and on the eyes, to be applied.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferred for oral administration, solutions, suspensions, readily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration.
  • substituted compounds according to the invention which are used according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous administration preparations.
  • Oral or Percutaneously applicable preparation forms can also release the respective substituted compound according to the invention with a delay.
  • the preparation of the pharmaceutical compositions according to the invention is carried out by means of conventional means, devices, methods and processes known from the prior art, as described, for example, in "Remington's Pharmaceutical Sciences", published by AR Gennaro, 17th edition, Mack Publishing Company, Easton, Pa , 1985, in particular in part 8, chapters 76 to 93.
  • the corresponding description is hereby incorporated by reference and is part of the disclosure
  • the amount of the respective substituted compounds according to the invention of the above-indicated general formula I to be administered to the patient may vary and depends, for example, on the weight or age of the patient as well as the mode of administration, the indication and the severity of the disease. Usually 0.001 to 100 mg / kg, preferably 0.05 to 75 mg / kg, particularly preferably 0.05 to 50 mg / kg, body weight of the patient of at least one such compound according to the invention applied.
  • the agonistic or antagonistic action of the substances to be tested on the vanilloid receptor 1 (VR1 / TRPV1) of the rat species can be determined by the following assay.
  • Ca 2+ influx through the receptor channel is monitored using a Ca 2+ -sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, USA ).
  • FCS fetal calf serum, Gibco Invitrogen GmbH, Düsseldorf, Germany, heat-inactivated
  • AA solution antioxidants / antimycotics solution, PAA, Pasching, Austria
  • 25 ng / ml medium NGF 2.5S, Gibco Invitrogen GmbH, Düsseldorf, Germany
  • Cell culture plate Poly-D-lysine-coated black 96-well plates with clear bottom (96 well black / clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Düsseldorf, Germany) by diluting laminin to a concentration of 100 ⁇ g / ml with PBS (Ca-Mg-free PBS, Gibco Invitrogen GmbH, Düsseldorf, Germany). Aliquots are taken at a concentration of 100 ug / mL of laminin and stored at -20 0 C.
  • the aliquots are diluted with PBS in the ratio 1:10 to 10 ⁇ g / ml laminin and pipetted in each case 50 .mu.l of the solution into a well of the cell culture plate.
  • the cell culture plates are incubated for at least two hours at 37 ° C., and the supernatant is washed twice with PBS.
  • the coated cell culture plates are stored with overhanging PBS and this is removed just before the task of the cells.
  • HBSS buffer Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany
  • AA solution antibiotics / Antifungal solution, PAA, Pasching, Austria
  • the spinal column is severed longitudinally and taken together with fascia the vertebral canal. Subsequently, the dorsal root ganglia (DRGs) are removed and again stored in cold HBSS buffer mixed with 1% by volume of an AA solution.
  • DDGs dorsal root ganglia
  • the completely freed from blood residues and spinal nerves DRGs are transferred each in 500 ⁇ l_ cold type 2 collagenase (PAA, Pasching, Austria) and incubated for 35 minutes at 37 0 C. After addition of 2.5% by volume of trypsin (PAA, Pasching, Austria) is incubated at 37 0 C for a further 10 minutes. After the complete incubation, the enzyme solution is carefully pipetted off and the remaining DRGs are each mixed with 500 ⁇ l of complete medium.
  • the DRGs are in each case suspended several times, drawn through cannulae No. 1, No. 12 and No. 16 using a syringe and transferred into 50 ml Falcon tubes and this is filled up to 15 ml with complete medium. The contents of each Falcon tube are each filtered through a 70 ⁇ m Falcon filter cartridge and centrifuged for 10 minutes at 1200 rpm at room temperature. The resulting pellet is taken up in 250 ⁇ l complete medium and the cell count is determined.
  • the number of cells in the suspension is adjusted to 3 times 10 5 per ml and each 150 ul_ of this suspension in a well of the cell culture plates coated as described above. In the incubator, the plates at 37 0 C, 5 vol% CO 2 and 95% relative humidity allowed to stand for two to three days.
  • the cells are incubated with 2 ⁇ M Fluo-4 and 0.01% by volume Pluronic F127 (Molecular Probes Europe BV, Leiden Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) for 30 min 37 0 C, washed 3 times with HBSS buffer and after a further incubation for 15 minutes at room temperature for Ca 2+ measurement in FLIPR assay used.
  • the FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 ⁇ M) are pipetted onto the cells and the Ca 2+ influx is compared with the control (capsaicin 10 ⁇ M). This gives the indication in% activation based on the Ca 2+ signal after addition of 10 ⁇ M capsaicin (CP). After 5 minutes of incubation, 100 nM capsaicin are administered and also the influx of Ca 2+ is determined.
  • IC.sub.50 inhibitory concentrations were calculated which cause a 50% displacement of capsaicin.
  • Kj values were obtained for the test substances (Cheng, Prusoff, Biochem Pharmacol., 22, 3099-3108, 1973).
  • the agonistic or antagonistic effect of the substances to be examined on vanilloid receptor (VR1) can also be determined by the following assay.
  • Ca 2+ influx through the channel is monitored using a Ca 2+ -sensitive dye (Fluo-4, Molecular Probes, Europe BV, Leiden, The Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale , USA).
  • FLIPR Fluorescent Imaging Plate Reader
  • CHO K1 cells Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC) Great Britain) are stably transfected with the VR1 gene. For functional studies, these cells are plated on poly-D-lysine-coated black 96-well clear bottom plates (BD Biosciences, Heidelberg, Germany) at a density of 25,000 cells / well. Overnight, the cells are incubated at 37 ° C. and 5% CO 2 in a culture medium (Nutrient Mixture 's F12, 10% by volume FCS (Fetal calf serum), 18 ⁇ g / mL L-proline).
  • a culture medium Nutrient Mixture 's F12, 10% by volume FCS (Fetal calf serum), 18 ⁇ g / mL L-proline.
  • the FLIPR protocol consists of 2 substance additions. At first, the substances to be tested (10 .mu.M) are pipetted onto the cells and the Ca 2+ influx with the control (capsaicin 10 .mu.M) compared (% activation based on the Ca 2+ signal after addition of 10 uM capsaicin). After 5 minutes of incubation, 100 nM capsaicin are administered and also the influx of Ca 2+ is determined.
  • the first (early) phase (0 to 15 minutes after formalin injection) and the second (late) phase (15 to 60 minutes after formalin injection).
  • the early phase represents a model of acute pain as a direct response to formalin injection, while the late phase is considered a model of persistent (chronic) pain (T J. Coderre et al., Pain 1993, 52, 259-285).
  • the corresponding literature descriptions are hereby incorporated by reference and are considered part of the disclosure.
  • the compounds according to the invention are investigated in the second phase of the formalin test in order to obtain statements on substance effects on chronic / inflammatory pain.
  • the time of application of the compounds according to the invention prior to the formalin injection is selected.
  • the intravenous administration of 10 mg / kg body weight of the test substances takes place 5 minutes before the formalin injection. This is done by a single subcutaneous formalin injection (20 .mu.l, 1% aqueous solution) in the dorsal side of the right hindpaw, so that in nociceptive animals a nociceptive reaction is induced, resulting in significant licking and biting of the paw manifests.
  • nociceptive behavior is continuously monitored by observation of the animals.
  • the pain behavior is quantified by the summation of the seconds in which the animals show a licking and biting of the affected paw during the examination period.
  • control animals which, instead of the compounds according to the invention, receive vehicle (0.9% strength aqueous sodium chloride solution) prior to formalin administration. Based on the quantification of pain behavior, the substance effect in the formalin test is determined as a change from the corresponding control in percent.
  • mice male NMRI mice weighing 25 to 30 g were used. 10 minutes after intravenous administration of the compounds to be tested, groups of 10 animals per compound dose were given 0.3 ml / mouse of a 0.02% strength aqueous solution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen, Germany, preparation of the solution with the addition of 5 Wt .-% ethanol and storage in a water bath at 45 ° C) intraperitoneally applied. The animals were placed individually in observation cages.
  • phenylquinone phenylbenzoquinone
  • the hypothermia assay is performed in male NMRI mice (weight 25-35 grams, breeder IFFA CREDO, Brussels, Belgium). The animals were kept under standardized conditions: light / dark rhythm (6:00 to 18:00 light, 18:00 to 6:00 dark phase), room temperature 19-22 0 C, relative humidity 35-70%, 15 Room air change per hour, air movement ⁇ 0.2 m / sec. The animals received standard food (ssniff R / M attitude, ssniff special diets GmbH, Soest, Germany) and tap water. Water and food were removed during the experiment. All animals were used only once in the experiment. The animals had a settling-in phase of at least 5 days.
  • capsaicin (VR-1 agonist) leads to a decrease in body core temperature in rats and mice via a stimulation of thermal sensors. Only specific VR-1 receptor antagonists can antagonize capsaicin-induced hypothermia. In contrast, morphine-induced hypothermia is not antagonized by VR-1 antagonists. This model is therefore suitable for identifying substances with VR-1 antagonistic properties via the effect on body temperature.
  • thermometer For the measurement of the body core temperature, a digital thermometer (Thermalert TH-5, physitemp, Clifton NJ, USA) was used. The probe is inserted into the rectum of the animals.
  • one group of animals is treated only with the test substance and one group only with vehicle.
  • the evaluation or representation of the measured values takes place as the mean value +/- SEM of the absolute values as a graph.
  • the antagonistic effect is calculated as the percent reduction in capsaicin-induced hypothermia.
  • NMRI mice weighing 16-18g are treated with three loose ligatures of the right nervus ischiaticus under Ketavet-Rompun anesthesia.
  • the animals develop hypersensitivity to the paw innervated by the damaged nerve, which is quantified after a recovery period of one week for about three weeks using a 4 ° C cold metal plate (cold allodynia).
  • the animals are kept for a period of 2 min. observed on this plate and the number of pull-out reactions of the injured paw is measured.
  • the substance effect over a certain period of time is determined at different times (eg 15, 30, 45, 60 min after application) and the resulting area under the curve (AUC) and / or the inhibition of cold allodynia expressed as a percentage of the individual measuring points, the effect on the vehicle control (AUC) or on the initial value (individual measuring points).
  • the chemicals and solvents used were obtained commercially from conventional suppliers (Acros, Avocado, Aldrich, Bachern, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc.) or synthesized by conventional methods known to those skilled in the art.
  • Step 1
  • nitrile 26 g, 0.091 mol
  • BH 3 -DMS 13.78 g, 0.182 mol
  • the reaction was treated with 100 ml MeOH and stirred for 15 minutes at room temperature.
  • di-tert-butyl dicarbonate 29.7 g, 0.136 mol
  • R2 aryl, heteroaryl, cycloalkenyl VI-A VI-E V-D
  • Step 1
  • Step 1
  • the amine component of the general formula F (1 equivalent) is initially charged in dichloromethane and pyridine and cooled to 0 ° C.
  • Methanesulfonyl chloride (1.5 equivalents) are added dropwise at 0 0 C and the reaction mixture is stirred for 2 h at room temperature. After renewed cooling of the mixture to 0 0 C is acidified with 4 N aq. HCl to pH 3.
  • the organic phase is extracted several times with dichloromethane.
  • the combined organic phases are washed with water and sat. aq. NaCl solution. washed, dried over MgSO 4 and concentrated to dryness.
  • the column-chromatographic purification (eluent: EA in hexane) gives the desired product.
  • Step 1 Synthesis of ethyl 2-chloro-2-cyclohexylacetate
  • Step 2 Synthesis of ethyl 2-cyclohexyl-2- (3-fluoro-4-nitrophenyl) acetate
  • Step 3 Synthesis of ethyl 2- (4-amino-3-fluorophenyl) -2-cyclohexylacetate
  • Step 4 Synthesis of ethyl 2-cyclohexyl-2- (3-fluoro-4- (methylsulfonamido) phenyl) acetate
  • the amine compound ethyl 2- (4-amino-3-fluorophenyl) -2-cyclohexylacetate (5 g, 179 mmol) was dissolved in 15 mL pyridine, cooled to 0 ° C. under a nitrogen atmosphere and treated with 2 mL methanesulfonyl chloride (26.8 mmol) and the reaction mixture was stirred at 0 0 C for 1 h.
  • the reaction mixture was added under ice-cooling with 15 mL of water and adjusted to pH 1 with 16% HCl. After extraction of the mixture with dichloromethane (3 ⁇ 50 ml), the organic phases were combined, dried over MgSO 4 and concentrated in vacuo. Purification of the crude product was carried out by column chromatography (silica gel: 100-200 mesh, eluent: 50% EA in cyclohexane) to yield 5.4 g (85.4%) of product.
  • Step 5 Synthesis of 2-cyclohexyl-2- (3-fluoro-4- (methylsulfonamido) phenyl) acetic acid
  • Step 2a Synthesis of ethyl 2-chloro-2-phenylacetate
  • Step 3 Synthesis of ethyl 2- (3-fluoro-4-nitrophenyl) -2-phenylacetate
  • Step 4 Synthesis of ethyl 2- (4-amino-3-fluorophenyl) -2-phenylacetate
  • Step 5 Synthesis of ethyl 2-phenyl-2- (3-fluoro-4- (methylsulfonamido) phenyl) acetate
  • the amine compound ethyl 2- (4-amino-3-fluorophenyl) -2-phenylacetate (5.2 g, 19 mmol) was dissolved in 15 mL pyridine, cooled to 0 ° C. under a nitrogen atmosphere and treated with 2.2 mL methanesulfonyl chloride (28.5 mmol ) and the reaction mixture was stirred at 0 0 C for 1 h.
  • the reaction mixture was admixed with 15 ml of water with ice cooling and adjusted to pH 1 with 16% aq. HCl. To Extraction of the mixture with dichloromethane (3 ⁇ 50 ml), the organic phases were combined, dried over MgSO 4 and concentrated in vacuo. Purification of the crude product was carried out by column chromatography (silica gel: 100-200 mesh, eluent: 50% EA in cyclohexane) to afford 5.8 g (87%) of the desired product.
  • Step 6 Synthesis of 2-phenyl-2- (3-fluoro-4- (methylsulfonamido) phenyl) acetic acid
  • Step 1 Sodium cyanide (6.12 g, 124.8 mmol) was dissolved in water (25 mL) and to this was added ammonium chloride (7.35 g, 137.3 mmol).
  • Compound 1 (15 g, 124.8 mmol) in methanol (25 mL) was added to the reaction mixture and stirred at room temperature for two days.
  • Water (100 mL) and benzene (100 mL) were added to the reaction mixture and stirred for ten minutes. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • Compound 2 was thus obtained as a yellow liquid. Yield: 17 g (crude product).
  • Step 2 Compound 2 (17 g, crude product) was dissolved in hydrochloric acid (6N, 110 mL) and heated at reflux for 20 hours. The hydrochloric acid was removed under reduced pressure. The residue was diluted with ethanol (2 x 200 mL) and concentrated under reduced pressure. Then, ethyl acetate (250 ml) was added and stirred at 70 ° C. for one hour. Upon cooling, a solid precipitated, which was filtered through a sintered glass funnel to give a yellow crystalline solid (Compound 3). Yield: 13 g (crude product).
  • reaction mixture was diluted with water (700 ml) and extracted with a mixture of ethyl acetate (20%) in hexane (3 ⁇ 250 ml). Subsequently, the organic phase was dried over anhydrous magnesium sulfate. Removal of the organic solvents under reduced pressure gave a yellowish compound, which was purified by column chromatography (silica gel: particle size 100-200, eluent: 2% ethyl acetate in hexane). Compound 6 was thus obtained as a yellow liquid.
  • Step 2 Compound 2 (17 g, crude product) was dissolved in hydrochloric acid (6N, 250 mL) and heated at reflux for 20 hours. The hydrochloric acid was removed under reduced pressure. The residue was diluted with ethanol (2 x 200 mL) and concentrated under reduced pressure. Then, ethyl acetate (250 ml) was added and stirred at 70 ° C for one hour. Upon cooling, a solid precipitated, which was filtered by means of a glass suction filter to give a yellow crystalline solid (Compound 3). Yield: 13 g (crude product).
  • Step 1 Compound 1 (12 g, 70.5 mmol) was dissolved in tetrahydrofuran (120 mL). Thionyl chloride (10 g, 84.6 mmol) was added to this solution. A catalytic amount of dimethylformamide (1 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure and the residue was diluted with water (200 mL) and extracted with dichloromethane (2 x 200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain Compound 2. Yield: 12 g (crude product).
  • Step 5 Compound 5 (2.3 g, 7.8 mmol) was dissolved in dichloromethane (35 mL). Pyridine (1, 9 mL, 23.4 mmol) was added. Methanesulfonyl chloride (1.1 g, 9.4 mmol) was added dropwise to the reaction mixture at 0 C and stirred at room temperature for 16 hours.
  • the value after the "@" sign indicates the concentration at which the inhibition (in percent) was determined.

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Abstract

La présente invention concerne de nouveaux ligands de récepteur vanilloïde, un procédé pour leur fabrication, des médicaments contenant ces composés et l'utilisation de ces composés pour la fabrication de médicaments.
EP08748889A 2007-04-13 2008-04-11 Nouveaux ligands de récepteur vanilloïde et leur utilisation pour la fabrication de médicaments Withdrawn EP2150531A2 (fr)

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RU2755206C1 (ru) 2020-05-20 2021-09-14 Федеральное государственное бюджетное учреждение науки Тихоокеанский институт биоорганической химии им. Г.Б. Елякова Дальневосточного отделения Российской академии наук (ТИБОХ ДВО РАН) Средство пролонгированного анальгетического действия и лекарственный препарат на его основе

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US3306909A (en) * 1964-05-05 1967-02-28 Mead Johnson & Co 3-carbamoyl-1,5-diphenyl-2,4-pyrrolidinediones
FR2060460A5 (fr) 1968-12-21 1971-06-18 Coll Antonio
KR100707123B1 (ko) 2003-07-02 2007-04-16 그뤼넨탈 게엠베하 바닐로이드 수용체의 길항제로서 강력한 진통효과를나타내는 4-(메틸설포닐아미노)페닐 동족체 및 이를함유하는 약학적 조성물
AR056875A1 (es) * 2005-10-19 2007-10-31 Gruenenthal Gmbh Ligandos del receptor vaniloide y su aplicacion para la fabricacion de medicamentos

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