EP2146962A2 - Neue vanilloid-rezeptor liganden und ihre verwendung zur herstellung von arzneimitteln - Google Patents

Neue vanilloid-rezeptor liganden und ihre verwendung zur herstellung von arzneimitteln

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Publication number
EP2146962A2
EP2146962A2 EP08735252A EP08735252A EP2146962A2 EP 2146962 A2 EP2146962 A2 EP 2146962A2 EP 08735252 A EP08735252 A EP 08735252A EP 08735252 A EP08735252 A EP 08735252A EP 2146962 A2 EP2146962 A2 EP 2146962A2
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EP
European Patent Office
Prior art keywords
butyl
group
methyl
alkyl
unsubstituted
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Withdrawn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
EP08735252A
Other languages
German (de)
English (en)
French (fr)
Inventor
Robert Frank
Gregor Bahrenberg
Thomas Christoph
Klaus Schiene
Jean De Vry
Derek Saunders
Michael Przewosny
Bernd Sundermann
Jeewoo Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
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Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP2146962A2 publication Critical patent/EP2146962A2/de
Withdrawn legal-status Critical Current

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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.
  • n O, 1, 2, 3 or 4;
  • R 6 is in each case hydrogen or a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C-MO radical;
  • R 7 is hydrogen or -OH
  • R 6 and R 7 together with the carbon atom connecting them as ring member form a saturated or unsaturated, unsubstituted or at least monosubstituted 3-, 4-, 5- or 6-membered cycloaliphatic radical;
  • R 8 is -SF 5 ; -0-CF 3 ; -CF 3 ; -0-CFH 2 ; -0-CF 2 H; -CFH 2 ; -CF 2 H; or is an unsubstituted or at least monosubstituted tert-butyl radical;
  • T is CR 35 and U is CR 36 and V is CR 37 and W is CR 38 ;
  • R 26 and R 27 independently of each other, respectively for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic Ci-io radical;
  • cycloaliphatic radical having a saturated or unsaturated may be fused, unsubstituted or at least mono-substituted mono- or polycyclic ring system and / or bonded via a linear or branched, unsubstituted or at least mono-substituted Ci -6 alkylene group or 2- to 6-membered heteroalkylene group;
  • R 35 , R 36 and R 37 independently of each other, each for H; F; Cl; Br; I; -SF 5 ;
  • Ci -6 alkylene group or C 2-6 alkenylene group or C 2-6 alkynylene group may be bonded group;
  • Ci.io radical for a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic Ci.io radical;
  • 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 C- ⁇ -6-alkylene group or 2- to 6-membered heteroalkylene group;
  • R 40 and R 41 are each taken together with the nitrogen atom connecting them as
  • Ring member a saturated or unsaturated, unsubstituted or substituted by 1, 2, 3, 4 or 5 groups
  • R 57 is -NHR 58 , -NR 59
  • R 60 is a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C 1-10 radical;
  • R 61 is a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic C-MO radical;
  • each of the above-mentioned heteroalkylene groups optionally has 1, 2 or 3 heteroatom (s) independently selected from the group consisting of oxygen, sulfur and nitrogen (NH) as chain member (s);
  • rings of the abovementioned mono- or polycyclic ring systems are each 5-, 6- or 7-membered and may in each case optionally have 1, 2, 3, 4 or 5 heteroatom (s) as ring member (s) which are independent of one another 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 refers to an alkylene chain in which one or more C atoms have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur and nitrogen (NH).
  • Heteroalkylene groups may preferably have 1, 2 or 3 heteroatom (s), more preferably a heteroatom, independently selected from the group consisting of oxygen, sulfur and nitrogen (NH) as a chain member (s).
  • Heteroalkylene groups may preferably be 2- to 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 -, - (CH 2) -O-, - (CHz) 2 - O-, - (CH 2 ) 3 -O-, - (CH 2 J 4 -O-, -O- (CH 2 ) -, -O- (CH 2 ) 2 -, -O- (CH 2 ) 3 -, -O- (CH 2 ) 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.
  • heteroalkylene groups such
  • substituents have a linear or branched C- ⁇ - 6 alkylene group, this may preferably be selected from the group consisting of - (CH 2) -, - (CH 2 J 2 -, -C (H) (CH 3 ) -, - (CH 2 ) 3 -, - (CH 2 ) 4 -, - (CH 2 ) S-, -C (H) (C (H) (CH 3 ) 2 ) - and -C (C 2 H 5 ) (H) -.
  • C 1-10 aliphatic radicals can stand for a Ci.io alkyl, C 2- io-alkenyl or C 2 O -i alkynyl radical.
  • C 2- io-alkenyl radicals have at least one, preferably 1, 2, 3 or 4 C-C-double bonds and C 2- io-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 which optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from
  • C 2 -alkeno radicals selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propylene, 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 1 -CN, -NO 2 , -OH , -NH 2 , -SH, -O-CH 3 , -O-C 2 H 5 , -O-CH (CHa) 2 , -OC (CH 3 ) 3 , -S-CH 3 , -SC 2 H 5 ,
  • C 2-io-alkynyl radicals are selected from the group consisting of (3,3) -dimethyl-but-1-ynyl, 4-methyl-pent-i-ynyl, 1-hexynyl, ethynyl, 1-propynyl , 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl and 4-pentynyl optionally containing 1, 2 or 3 substituents independently selected from the group from F, Cl, Br, I, -CN, -NO 2, -OH, -NH 2, -SH, -0-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, -SC (CH 3) 3, -NH-CH 3, -NH-C 2
  • 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 (CHa) 2 , -CH 2 -N (C 2 Hs) 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,
  • Suitable (hetero) cycloaliphatic radicals which may be unsubstituted or monosubstituted or polysubstituted and which have been condensed with a monocyclic or bicyclic ring system are (4,5,6,7) -tetrahydroisoxazolo [5,4-pyridinyl, (2,3) -dihydro-1H-indenyl, 3-azabicyclo [3.1.1] heptyl, 3-azabicyclo [3.2.1] octyl, 6-azabicyclo [3.3.1] heptyl, 8 -Aza-bicyclo [3.2.1] octyl, isoindolyl, indolyl, (1, 2,3,4) -tetrahydroquinolinyl, (1,2,3,4) -tetrahydroisoquinolinyl, (2,3) -dihydro-1H- isoindolyl, (1, 2,3,4) -tetrahydron
  • 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). If one or more of the abovementioned 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, indazoly
  • 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 can have a different degree of saturation, ie be saturated or unsaturated.
  • a polycyclic ring system is a bicyclic ring system.
  • aryl radicals which are condensed with a monocyclic or polycyclic ring system are (1,3) -benzodioxolyl and (1,4) -benzodioxanyl.
  • radicals R 41 and R 42 with the nitrogen atom connecting them form as ring member a heterocycloaliphatic radical which is substituted by 1, 2, 3, 4 or 5 radicals R 57 , these radicals R 57 can each independently have one of the meanings indicated , Preference is given to compounds of the general formula Ia 1
  • D is N or CH
  • R 8 is -SF 5 ; -0-CF 3 ; -CF 3 ; tert-butyl or -C (CH 3 ) 2 (CH 2 OH);
  • R 13 , R 16 , R 17 , R 22 , R 23 and R 27 are each independently a radical selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, -CF 2 -CH 3 , -CH 2 -CF 3 , -C 2 F 5 , 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 and ethenyl ;
  • R 42 is a radical selected from the group consisting of methyl, -CH 2 -O- CH 3 , ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3) -dimethylbutyl, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -OC 2 H 5 and -CH 2 -CH 2 -CH 2 -O-CH 3 stands;
  • D is N or CH
  • R 8 is -SF 5 ; -O-CF 3 ; -CF 3 ; tert-butyl or -C (CH 3 ) 2 (CH 2 OH);
  • R 13 , R 16 , R 17 , R 22 , R 23 and R 27 are each a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl tert-butyl, n-pentyl and ethenyl;
  • R 42 is a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl and (3,3) Dimethylbutyl;
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each 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, n-pentyl, may be substituted;
  • R 1 for H; F; Cl; Br or I is;
  • R 2 for H; F; Cl; Br; I; Methyl; -OH; -NH 2 or -OR 16 is;
  • R 5 is H; F; Cl; Br or I is;
  • R 8 is -SF 5 ; -0-CF 3 ; -CF 3 ; tert-butyl or -C (CH 3 ) 2 (CH 2 OH);
  • R 13 , R 16 , R 17 , R 22 , R 23 and R 27 are each a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl tert-butyl, n-pentyl and ethenyl;
  • R 42 is a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl and (3,3) Dimethylbutyl;
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each 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, n-pentyl, may be substituted;
  • D is N or CH
  • R 8 is -SF 5 ; -0-CF 3 ; -CF3; tert-butyl or -C (CH 3 ) 2 (CH 2 OH);
  • R 13 , R 16 , R 17 , R 22 , R 23 and R 27 are each independently a radical selected from the group consisting of methyl, -CF 3, -CHF 2 , -CH 2 F, ethyl, -CF 2 - CH 3 , -CH 2 -CF 3 , -C 2 F 5 , 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-he
  • R 43 is a radical selected from the group consisting of methyl, -CH 2 -O- CH 3 , ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl, (3,3) -dimethylbutyl, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -OC 2 H 5 and -CH 2 -CH 2 -CH 2 -O-CH 3 stands;
  • D is N or CH
  • R 8 is -SF 5 ; -0-CF 3 ; -CF 3 ; tert-butyl or -C (CH 3 ) 2 (CH 2 OH);
  • R 13 , R 16 , R 17 , R 22 , R 23 and R 27 are each a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl tert-butyl, n-pentyl and ethenyl;
  • R 43 is a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl and (3,3) Dimethylbutyl;
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each 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, n-pentyl, may be substituted; 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.
  • R 1 for H; F; Cl; Br or I is;
  • R " is H; F; Cl; Br; I; methyl; -OH; -NH 2 or -OR 1 1 6 0 ;
  • R 8 is -SF 5 ; -0-CF 3 ; -CF 3 ; tert-butyl or -C (CH 3 ) 2 (CH 2 OH);
  • R, 1 1 3 J , D R1 1 6 0 , D R1 1 7 ', D R2 "2, D R2" 3 and R 27 are each independently a radical selected from the group consisting of methyl, ethyl, n Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and ethenyl;
  • R> 43 is a radical selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 3-pentyl, n-hexyl and (3,3 ) - dimethylbutyl;
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each 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, n-pentyl, may be substituted;
  • R 4 for H; F; Cl; Br; I; NO 2 ; -CF 3 ; -CN; -NH 2 ; -OH; -NH-C (O) -R 13 ; -OR 16 ; -SR 17 ; - S (O) 2 -NR 22 R 23 ; -S (O) 2 -R 27 or a radical selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl and tert-butyl;
  • R 5 is H; F; Cl; Br; I; NO 2 ; -CF 3 ; -CN; -NH 2 ; -OH; -NH-C (O) -R 13 ; -OR 16 ; -SR 17 ; - S (O) 2 -NR 22 R 23 ; -S (O) 2 -R 27 or a radical selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl and tert-butyl;
  • R 8 is -SF 5 ; -0-CF 3 ; -CF3; tert-butyl or -C (CH 3 ) 2 (CH 2 OH);
  • R 13 , R 16 , R 17 , R 22 , R 23 and R 27 are each independently a radical selected from the group consisting of methyl, -CF 3 , -CHF 2 , -CH 2 F, ethyl, -CF 2 -CH 3 , -CH 2 -CF 3 , -C 2 F 5 , 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 and ethenyl ; R 40 and R 41 , independently of each other, respectively
  • R 40 and R 41 in each case 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 Thiomorpholinyl form whose hetero
  • R 57 is -NHR 58 , -NR 59 R 60 or an alkyl radical selected from the group consisting of -CF 3 , -CH 2 -CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n Butyl, sec-butyl and isobutyl;
  • R 61 is an alkyl radical selected from the group consisting of -CF 3 , -CH 2 -CF 3 , methyl, ethyl, n -propyl, isopropyl, tert -butyl, n -butyl, sec -butyl and isobutyl;
  • R 8 is -SF 5 ; -0-CF 3 ; -CF 3 ; tert-butyl or -C (CH 3 ) 2 (CH 2 OH);
  • R 13 , R 16 , R 17 , R 22 , R 23 and R 27 are each a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl tert-butyl, n-pentyl and ethenyl;
  • R 40 and R 41 together with the nitrogen atom connecting them as a ring member form a radical selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and azepanyl whose heterocycloaliphatic moiety is unsubstituted or substituted by 1, 2, 3, 4 or 5 radicals R 57 may be substituted;
  • R 57 is an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert -butyl, n -butyl, sec -butyl and isobutyl;
  • R 1 for H; F; Cl; Br or I is;
  • R 2 for H; F; Cl; Br; I; Methyl; -OH; -NH 2 or -OR 16 is;
  • R 4 for H; F; Cl; Br; I; Methyl, -OH; -NH 2 or -OR 1 1 6 b ;
  • R 5 is H; F; Cl; Br or I is;
  • R 8 is -SF 5 ; -0-CF 3 ; -CF 3 ; tert-butyl or -C (CHa) 2 (CH 2 OH);
  • R 13 , R 16 , R 17 , R 22 , R 23 and R 27 are each a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl tert-butyl, n-pentyl and ethenyl;
  • R 40 and R 41 together with the nitrogen atom connecting them as a ring member form a radical selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and azepanyl whose heterocycloaliphatic moiety is unsubstituted or substituted by 1, 2, 3, 4 or 5 radicals R 57 may be substituted; and R 57 is an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert -butyl, n -butyl, sec -butyl and isobutyl;
  • 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.
  • Another object of the present invention is a process for the preparation of compounds of the above general formula I according to the at least one compound of general formula II,
  • R 8 U, T, V and W have the meaning given above, m is 0, 1, 2 or 3 and R is hydrogen or a linear or branched d-6-alkyl residue, 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
  • R 8 , U, T, V and W have the abovementioned meaning and m is 0, 1, 2 or 3, and this is optionally purified and / or isolated, and at least one compound of general formula III in a reaction medium in the presence of diphenylphosphoryl azide or in the presence of HN 3 to at least one compound of general formula IV,
  • R 8 , U, T, V and W have the abovementioned meaning and m is 0, 1, 2 or 3, and this is optionally 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
  • R 8 , U, T, V and W have the abovementioned meaning and m is 0, 1, 2 or 3, and this is optionally purified and / or isolated, or at least one compound of general formula Vl 1
  • R 8 , U, T, V and W have the abovementioned meaning and m is 0, 1, 2 or 3, in a reaction medium
  • 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,
  • reducing agent selected from the group consisting of BH 3 "S (CH 3) 2, lithium aluminum hydride and sodium borohydride, optionally in the presence of NiCl,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the abovementioned meaning, in a reaction medium, optionally in the presence of at least one suitable coupling agent, optionally in the presence of at least one base, or with at least one compound of general formula VIII,
  • R 1, R 2, R 3, R 4, R 5, R 6 and R 7 have the meaning given above and LG is a leaving group, preferably a chlorine or bromine atom, in a reaction medium, optionally in the presence of at least a base, to at least one compound of general formula I,
  • T, U, V, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the abovementioned meaning and n is 1, 2, 3 or 4, is implemented and this is possibly cleaned and / or isolated.
  • Another object of the present invention is a process for the preparation of compounds of the general formula given above according to the at least one compound of general formula X 1
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have 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,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 have the abovementioned meaning and LG is a leaving group, preferably a chlorine or bromine atom, in a reaction medium, optionally in the presence at least a base, to at least one compound of the general formula Im,
  • reaction of compounds of the abovementioned general formulas V or X with carboxylic acids of the abovementioned general formula VII to give compounds of the abovementioned general formulas I or Im 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 i-benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDCI), diisoproylcarbodiimide, 1, 1'-
  • reaction of compounds of the above general formulas V and X with carboxylic acid derivatives of the above-mentioned general formula VIII, wherein LG is a leaving group, preferably a chlorine or bromine atom, takes place to compounds of the above general formulas Im in a reaction medium preferably selected 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 from -70 0 C to 100 ° C.
  • the compounds of the formulas II, III, IV, V, VI, VII, X and VIII given above are in each case commercially available and can also be prepared by customary processes known to the person skilled in the art.
  • 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.
  • substituted compounds according to the invention of the aforementioned general formulas I, Ia, Ib and Ic - hereinafter referred to as compounds of the general formula I - and corresponding stereoisomers can be used both in the form of their free bases, their free acids and in the form of corresponding salts, especially physiologically acceptable salts.
  • 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.
  • substituted compounds of the abovementioned general formula I and corresponding stereoisomers according to the invention may optionally, as well as the corresponding acids, the corresponding bases or salts of these compounds, 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.
  • Enantiomers for example by means of HPLC on a chiral stationary phase or by crystallization with chiral acids, such as (+) - tartaric acid, (-) - tartaric acid or (+) - 10 camphorsulfonic acid, formed diastereomeric salts are separated.
  • chiral acids such as (+) - tartaric acid, (-) - tartaric acid or (+) - 10 camphorsulfonic acid
  • Another object of the present invention is therefore a medicament containing at least one inventive compound of the above general formula I 1 each 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, 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.
  • inventive compound of the above general formula I 1 each 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, 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- (VR1TRTRVV1) 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 deficits, 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
  • 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.
  • 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; 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 (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.
  • oral administration are preferably preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups, for parenteral, topical and inhalative administration solutions, suspensions, easily reconstitutable dry preparations and Sprays.
  • 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. Orally or percutaneously applicable preparation forms can release the particular substituted compound according to the invention also delayed.
  • 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, more preferably 0.05 to 50 mg / kg, body weight the patient of at least one such connector 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 1 Leiden Netherlands) in the Fluorescent Imaging Plate Reader (FLIPR 1 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 1 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 each resuspended several times, drawn through cannulae No. 1, No. 12 and No. 16 using a syringe and transferred to 50 mL Falcon tubes and this is made 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 and RT. 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 ⁇ 10 5 per mL and in each case 150 ⁇ L of this suspension are added to a well of the cell culture plates coated as described above. In the incubator, the plates are allowed to stand at 37 ° C, 5 vol% CO2 and 95% relative humidity 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 (Hanks buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) for 30 min at 37 0 C, washed 3 times with HBSS buffer and used after a further incubation of 15 minutes at RT for Ca 2+ measurement in FLIPR assay.
  • 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.
  • 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.
  • Fluo-4 Fluo-42 ⁇ M, Pluronic F127 0.01% by volume, Molecular Probes in HBSS (Hanks buffered saline solution), Gibco Invitrogen GmbH, Düsseldorf, Germany) for 30 minutes at 37
  • 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.
  • IC 50 inhibitory concentrations were calculated which were a 50% displacement of Effect capsaicin.
  • values were obtained for the test substances (Cheng, Prusoff, Biochem Pharmacol., 22, 3099-3108, 1973).
  • 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% by weight. -% ethanol and storage in a water bath at 45 ° C) intraperitoneally. 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), RT 19-22 ° 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.
  • reaction mixture is filtered through Celite and extracted several times with EA.
  • the combined organic phases are washed with sat. aq. NaCl solution. washed, dried over MgSO 4 and the solvent was removed in vacuo.
  • the residue is purified by column chromatography respectively (SiO 2, various mixtures of hexane / EA).
  • R 38 aryl, heteroaryl, cycloalkenyl
  • reaction mixture is then slowly stirred into ice-water (700 mL) and the resulting yellow mixture is stirred for 15 minutes and filtered to remove the aluminum salts.
  • the filtrate is extracted with dichloromethane (3 x 50 mL) and the combined organic phases are washed with sat. aq. sodium bicarbonate solution (1 x 50 mL).
  • the methyl (3-chloro-4-methylsulfanyl-phenyl) oxoacetate is obtained as an oil (36.4 g, 60%) (a).
  • a solution of this ester (61, 7 g, 252 mmol) in toluene (120 mL) is heated to 50 0 C.
  • the reaction mixture After addition of the fourth portion of KOH, the reaction mixture is boiled at 100 ° C. for 16 h. After cooling the homogeneous reaction mixture to room temperature is diluted with water (12 ml_) and after transfer to a separating funnel more water (12 ml_) and diethyl ether (40 ml_) was added. After phase separation, the organic phase is extracted with water (2 ⁇ 15 ml). Heptane (20 ml) is added to the combined aqueous phases and the mixture is stirred vigorously. While maintaining the temperature below 50 ° C by means of ice bath is conc. Over a period of 30 min conc. HCl (26 ml) was added and the resulting suspension was stirred at room temperature for 3 h.
  • methylthiophenylpropanoic acids are converted to the corresponding methylsulfonylphenylpropanoic acids.
  • a solution of methylthiophenylpropanoic acid (0.16 mmol) is dissolved in formic acid (0.19 mL, 4.8 mmol) and cooled to 0 ° C. After addition of 30% aq hydrogen peroxide solution (0.10 mL, 0.8 mmol) is stirred at 0 ° C for 30 min and then the reaction was quenched with 10% aq sodium bisulfite solution.
  • the reaction mixture is diluted with water (5 mL) and extracted with ethyl acetate (2 ⁇ 5 mL). The combined organic phases are dried over Mg 2 SO 4 and the solvent removed in vacuo. The resulting residue is dissolved in methanol (1 mL) and a solution of KMNO 4 (0.028 g, 0.176 mmol) in water (0.5 mL) is added dropwise. The dark brown solution is then stirred for 30 min at room temperature and then diluted with methanol (10 mL). After filtration of the solution, the filtrate is concentrated in vacuo and purified by column chromatography (hexane / ethyl acetate 1 A) (a).
  • the sulfamoyl-arylbromide is reacted with ethylchloropropionate to produce the sulfamoyl-arylpropanoic acid ester.
  • ethylchloropropionate 1.6 ml, 13 mmol
  • sulphamoyl-arylbromide 10 mmol is stirred under argon atmosphere at room temperature in 15 ml of DMF.
  • phenylpropanoic acids can be obtained by reaction with diethyl malonate.
  • a solution of aryl bromide (16.5 mmol), CuBr (4.72 g, 32.9 mmol) and diethyl malonate (5 mL, 32.9 mmol) in 1, 4-dioxane (20 mL) is added Room temperature with slow stirring NaH (60%, 1, 45 g, 36.2 mmol) was added and stirred at 100 0 C for 16 h. After filtration, the filtrate is concentrated in vacuo and purified by column chromatography (hexane / ethyl acetate 4: 1) (a).
  • the methoxy ether is cleaved by means of HBr in glacial acetic acid and the corresponding phenylhydroxypropanoic acid is obtained (d).
  • the difluoromethropropanoate (2.59 g, 10 mmol) was dissolved in EtOH / acetic acid ester (200 mL, 1: 1) and in the H-cube (1 bar, 25 0 C 1 1 mL / min, 0.25 mol / L) hydrogenated.
  • Exemplary compound 23 2- (3,5-dibromo-4-hydroxy-phenyl) -N- (4-methyl-6'-trifluoromethyl-3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl -3'-ylmethyl) -acetamide
  • Exemplary compound 25 2- (3,5-dibromo-phenyl) -N- (4-methyl-6'-trifluoromethyl-3,4,5,6-tetrahydro-2H-
  • Example compounds 28-32 and 35-38 can also be obtained by the methods described above.
  • the affinity of the compounds according to the invention for the vanilloid receptor 1 was determined as described above (pharmacological methods I or II).
  • the compounds of the formula I indicated above have an excellent affinity for the VR1 / TRPV1 receptor (Table 1).
  • ne means no effect, ie no reaction was observed.
  • the value after the "@" sign indicates the concentration at which the inhibition (in percent) was determined.

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KR20100016594A (ko) 2010-02-12
AU2008238245A1 (en) 2008-10-23
IL201506A0 (en) 2010-05-31
CN101687799A (zh) 2010-03-31
US8791268B2 (en) 2014-07-29
US20080262039A1 (en) 2008-10-23
BRPI0810031A2 (pt) 2014-10-14
JP2010523726A (ja) 2010-07-15
JP5557734B2 (ja) 2014-07-23
ECSP099693A (es) 2009-11-30
NZ580381A (en) 2012-05-25
CN101687799B (zh) 2014-07-23
RU2487120C2 (ru) 2013-07-10
US8642775B2 (en) 2014-02-04
WO2008125337A3 (de) 2009-02-26
WO2008125337A2 (de) 2008-10-23
CO6220938A2 (es) 2010-11-19
DE102007018151A1 (de) 2008-10-23
MX2009011139A (es) 2009-10-30
KR101497357B1 (ko) 2015-03-02
NZ599254A (en) 2013-07-26
RU2009142024A (ru) 2011-05-27
ZA200907096B (en) 2013-03-27
CA2683910A1 (en) 2008-04-16
US20110184020A1 (en) 2011-07-28

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