EP2776400A1 - Dérivés de carboxamide et d'urée à base de pyrazolyle substitué portant un fragment phényle remplacé par un groupe contenant co comme ligands des récepteurs vanilloïdes - Google Patents

Dérivés de carboxamide et d'urée à base de pyrazolyle substitué portant un fragment phényle remplacé par un groupe contenant co comme ligands des récepteurs vanilloïdes

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Publication number
EP2776400A1
EP2776400A1 EP12781344.2A EP12781344A EP2776400A1 EP 2776400 A1 EP2776400 A1 EP 2776400A1 EP 12781344 A EP12781344 A EP 12781344A EP 2776400 A1 EP2776400 A1 EP 2776400A1
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EP
European Patent Office
Prior art keywords
methyl
group
chlorophenyl
pyrazol
carbamoyl
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Withdrawn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
EP12781344.2A
Other languages
German (de)
English (en)
Inventor
Robert Frank-Foltyn
Thomas Christoph
Nils Damann
Bernhard Lesch
Gregor Bahrenberg
Derek John Saunders
Hannelore Stockhausen
Yong-Soo Kim
Myeong-Seop Kim
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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Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to EP12781344.2A priority Critical patent/EP2776400A1/fr
Publication of EP2776400A1 publication Critical patent/EP2776400A1/fr
Withdrawn legal-status Critical Current

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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • the invention relates to substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with a CO-containing group as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
  • the subtype 1 vanilloid receptor (VR1/TRPV1 ), which is often also referred to as the capsaicin receptor, is a suitable starting point for the treatment of pain, in particular of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain.
  • This receptor is stimulated inter alia by vanilloids such as capsaicin, heat and protons and plays a central role in the formation of pain.
  • a weak or non-existent interaction with transporter molecules, which are involved in the ingestion and the excretion of pharmaceutical compositions, is also to be regarded as an indication of improved bioavailability and at most low interactions of pharmaceutical compositions.
  • the interactions with the enzymes involved in the decomposition and the excretion of pharmaceutical compositions should also be as low as possible, as such test results also suggest that at most low interactions or no interactions at all, of pharmaceutical compositions are to be expected.
  • the compounds should be suitable in particular as pharmacological active ingredients in pharmaceutical compositions, preferably in pharmaceutical compositions for the treatment and/or prophylaxis of disorders or diseases which are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1 receptors).
  • VR1/TRPV1 receptors vanilloid receptors 1
  • substituted compounds of general formula (U), as given below display outstanding affinity to the subtype 1 vanilloid receptor (VR1 /TRPV1 receptor) and are therefore particularly suitable for the prophylaxis and/or treatment of disorders or diseases which are at least partially mediated by vanilloid receptors 1 (VR1/TRPV1 ).
  • substituted compounds of general formula (U), as given below that in addition to their activity with regard to the VR1 -receptor show one or more additional advantageous properties, for example, suitable potency, suitable efficacy, no increase in body temperature and/or heat pain threshold; appropriate solubility in biologically relevant media such as aqueous media, in particular in aqueous media at a physiologically acceptable pH value, such as in buffer systems, for instance in phosphate buffer systems; suitable metabolic stability and diversity (e.g. sufficient stability towards the oxidative capabilities of hepatic enzymes such as cytochrome P450 (CYP) enzymes and sufficient diversity with regard to the metabolic elimination via these enzymes); and the like.
  • suitable potency, suitable efficacy, no increase in body temperature and/or heat pain threshold such as in buffer systems, for instance in phosphate buffer systems
  • suitable metabolic stability and diversity e.g. sufficient stability towards the oxidative capabilities of hepatic enzymes such as cytochrome P450 (CYP) enzymes and sufficient diversity with regard to the metabolic elimination via
  • the present invention therefore relates to a substituted compound of general formula (U),
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 CH 2 -OH, CH 2 -OCH 3 , CH 2 CH 2 - OCH 3 , OCFH 2 , OCF 2 H, OCF 3 , OH, NH 2 , a d- 4 alkyl, an O-C1-4 alkyl, a NH-C1-4 alkyl, and a N(Ci- 4 alkyl) 2 , wherein the Ci -4 alkyl is in each case unsubstituted,
  • R 2 represents CF 3 , an unsubstituted Ci -4 alkyl or an unsubstituted C 3 - 6 cycloalkyl,
  • R 7 and R 9 are independently of one another selected from the group consisting of H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, OH, OCF 3 , a d- 4 alkyl, and an O-C1-4 alkyl, wherein the d- 4 alkyl is in each case unsubstituted,
  • A denotes N, CH or C(CH 3 ),
  • R 04 represents
  • R 07 is selected from the group consisting of
  • single stereoisomer preferably means in the sense of the present invention an individual enantiomer or diastereomer.
  • mixture of stereoisomers means in the sense of this invention the racemate and mixtures of enantiomers and/or diastereomers in any mixing ratio.
  • physiologically acceptable salt preferably comprises in the sense of this invention a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base.
  • a physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid which is physiologically acceptable - in particular when used in human beings and/or other mammals.
  • physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, p- toluenesulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1 -sulphonic acid, nicotinic acid, 2, 3 or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, oc-lipoic acid, acetyl glycine, hippuric acid, phosphoric acid, aspartic acid.
  • Citric acid and hydrochloric acid are particularly preferred.
  • Hydrochloride salts and citrate salts are therefore particularly preferred salts.
  • a physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention as an anion with at least one preferably inorganic cation, which is physiologically acceptable - in particular when used in human beings and/or other mammals.
  • Particularly preferred are the salts of the alkali and alkaline earth metals but also ammonium salts [NH X R 4 .
  • alkyl and Ci -4 alkyl preferably comprise in the sense of this invention acyclic saturated aliphatic hydrocarbon residues, which can be respectively branched or unbranched and can be unsubstituted or can be mono- or polysubstituted, e.g. mono-, di- or trisubstituted, and which contain 1 to 4, i.e.
  • Ci -4 alkanyl residues are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, and tert.-butyl.
  • alkyl and "Ci -4 alkyl”
  • the term “monosubstituted” or “polysubstituted” such as di- or tri-substituted refers in the sense of this invention, with respect to the corresponding residues or groups, to the single substitution or multiple substitution, e.g. disubstitution or trisubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent.
  • polysubstituted such as di- or tri-substituted with respect to polysubstituted residues and groups such as di- or tri-substituted residues and groups includes the polysubstitution of these residues and groups either on different or on the same atoms, for example trisubstituted on the same carbon atom, as in the case of CF 3 or CH 2 CF 3 or at various points, as in the case of CH(OH)-CH 2 CH 2 -CHCI 2 .
  • the multiple substitution can be carried out using the same or using different substituents.
  • cycloalkyl and “C 3 - 6 cycloalkyl” preferably mean for the purposes of this invention cyclic aliphatic (cycloaliphatic) hydrocarbons containing 3, 4, 5, or 6 carbon atoms, i.e. C 3 - 6 - cycloaliphatic residues, wherein the hydrocarbons are saturated and which can be unsubstituted or can be mono- or polysubstituted, e.g. mono-, di- or trisubstituted.
  • the cycloalkyl can be bound to the respective superordinate general structure via any desired and possible ring member of the cycloalkyl residue.
  • cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, more preferably from the group consisting of cyclopropyl and cyclobutyl.
  • a particularly preferred cycloalkyl is cyclopropyl.
  • heterocyclyls are thus heterocycloaliphatic residues.
  • a heterocyclyl may e.g. be formed from radical R 07 .
  • Preferred heterocyclys according to the present invention are selected from the group consisting of azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, imidazolidinyl, isoxazolidinyl, morpholinyl, oxiranyl, oxetanyl, pyrrolidinyl, piperazinyl, 4- methylpiperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, t
  • a heterocyclyl according of the present invention formed from radicals R 06 and R 07 together with the nitrogen atom connecting them contains at least one N as a ring member and may contain further heteroatom(s) or heteroatom group(s).
  • cycloalkyl C 3 . 6 cycloalkyl
  • heterocyclyl heterocyclyl
  • the term “monosubstituted” or “polysubstituted” such as di- or tri-substituted refers in the sense of this invention, with respect to the corresponding residues or groups, to the single substitution or multiple substitution, e.g. disubstitution or trisubstitution, of one or more hydrogen atoms each independently of one another by at least one substituent.
  • polysubstituted such as di- or tri-substituted with respect to polysubstituted residues and groups such as di- or tri-substituted residues and groups includes the polysubstitution of these residues and groups either on different or on the same atoms, for example disubstituted on the same carbon atom, as in the case of 1 ,1 -difluorocyclohexyl, or at various points, as in the case of 1 -chloro-3-fluorocyclohexyl.
  • the multiple substitution can be carried out using the same or using different substituents.
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 -OCH 3 , OCF 3 , OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 .
  • H H
  • F CI, Br
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 -OCH 3 , OCF 3 , OH, CH 3 , O- CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 .
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OCH 3 , OCF 3 , CH 3 , 0-CH 3 , 0-CH 2 CH 3 and N(CH 3 ) 2 .
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, CFH 2 , CF 2 H, CF 3 , OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 .
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, CF 3 , OCF 3 , CH 3 and 0-CH 3 .
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, CF 3 and 0-CH 3 .
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI and 0-CH 3 .
  • At least one of R 101 , R 02 and R 03 is ⁇ H.
  • R 101 , R 02 and R 03 denote(s) H.
  • R 0 , R 02 and R 03 represents H, preferably R 03 represents H.
  • R 0 and R 02 are independently of one another selected from the group consisting of
  • H F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 -OCH 3 , OCF 3 , OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , and R 03 represents H.
  • R 0 and R 02 are independently of one another selected from the group consisting of
  • H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 -OCH 3 , OCF 3 , OH, CH 3 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 more preferably are independently of one another selected from the group consisting of H, F, CI, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OCH 3 , OCF 3 , CH 3 , 0-CH 3 , O- CH 2 CH 3 and N(CH 3 ) 2 , even more preferably are independently of one another selected from the group consisting of H, F, CI, CFH 2 , CF 2 H, CF 3 , OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 , still more preferably are independently of one another selected from the group consisting of H, F,
  • R 0 is selected from the group consisting of F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 - OCH 3 , OCF 3 , OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , and both R 02 and R 03 represents H.
  • R 0 is selected from the group consisting of F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 - OCH 3 , OCF 3 , OH, CH 3 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , more preferably is selected from the group consisting of F, CI, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OCH 3 , OCF 3 , CH 3 , O- CH 3 , O-CH 2 CH 3 and N(CH 3 ) 2 , even more preferably is selected from the group consisting of F, CI, CFH 2 , CF 2 H, CF 3 , OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 , still more preferably is selected from the group consisting of F, CI, CF 3 ,
  • R 02 is selected from the group consisting of F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 - OCH 3 , OCF 3 , OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , and both R 0 and R 03 represents H.
  • R 02 is selected from the group consisting of F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 - OCH 3 , OCF 3 , OH, CH 3 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , more preferably is selected from the group consisting of F, CI, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OCH 3 , OCF 3 , CH 3 , O- CH 3 , 0-CH 2 CH 3 and N(CH 3 ) 2 , even more preferably is selected from the group consisting of F, CI, CFH 2 , CF 2 H, CF 3 , OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 , still more preferably is selected from the group consisting of F, CI, CF 3 , O
  • R 0 is selected from the group consisting of F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 - OCH 3 , OCF 3 , OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 ,
  • R 02 is selected from the group consisting of H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 -OCH 3 , OCF 3 , OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , and R 03 represents H.
  • R 03 represents H.
  • R 0 is selected from the group consisting of F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 - OCH 3 , OCF3, OH, CH 3 , O-CH3, 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , more preferably is selected from the group consisting of F, CI, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OCH 3 , OCF 3 , CH 3 , O- CH 3 , 0-CH 2 CH 3 and N(CH 3 ) 2 , even more preferably is selected from the group consisting of F, CI, CFH 2 , CF 2 H, CF 3 , OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 , still more preferably is selected from the group consisting of F, CI, CF 3 , OCF 3
  • R 02 is selected from the group consisting of H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 -OCH 3 , OCF 3 , OH, CH 3 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , more preferably is selected from the group consisting of H, F, CI, CFH 2 , CF 2 H, CF 3 , CN, CH 2 - OCH 3 , OCF 3 , CH 3 , 0-CH 3 , 0-CH 2 CH 3 and N(CH 3 ) 2 , even more preferably is selected from the group consisting of H, F, CI, CFH 2 , CF 2 H, CF 3 , OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 , still more preferably is selected from the group consisting of H, F,
  • R 2 represents CF 3 , methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec-butyl, tert.- butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 2 represents CF 3 , 2-propyl, n-butyl, iso-butyl, sec-butyl, tert.-butyl, cyclopropyl, or cyclobutyl.
  • R 2 represents CF 3 , tert.-butyl or cyclopropyl.
  • R 2 represents CF 3 .
  • R 2 represents tert.-butyl
  • R 2 represents cyclopropyl
  • R 7 and R 9 are independently of one another selected from the group consisting of H, F, CI, Br, CF 3 , CN, OH, OCF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , and 0-CH 2 CH 3 .
  • R 7 and R 9 are independently of one another selected from the group consisting of H, F, CI, CF 3 , CN, OH, OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 .
  • R 7 and R 9 are independently of one another selected from the group consisting of H, F, CI, CF 3 , 0-CH 3 , and 0-CH 2 CH 3 . Even more preferably,
  • R 7 and R 9 are independently of one another selected from the group consisting of H, F, CI, and 0-CH 3 , still more preferably are independently of one another selected from the group consisting of H, F and CI.
  • At least one of R 7 and R 9 is ⁇ H.
  • R 9 denotes H.
  • R 7 is selected from the group consisting of F, CI, Br, CF 3 , CN, OH, OCF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , and 0-CH 2 CH 3 , preferably is selected from the group consisting of F, CI, CF 3 , CN, OH, OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 , more preferably is selected from the group consisting of F, CI, CF 3 , 0-CH 3 , and 0-CH 2 CH 3 , even more preferably is selected from the group consisting of F, CI, and 0-CH 3 , still more preferably is selected from the group consisting of F and CI, and R 9 represents H.
  • A denotes N or C(CH 3 ).
  • A denotes N.
  • A denotes C(CH 3 ).
  • R 06 represents
  • R 07 is selected from the group consisting of
  • R 04 represents
  • R 05 represents H or a C 1 -4 alkyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of NH 2 , OH and OCH 3 , or NR 06 R 1 07 , wherein
  • R 06 represents
  • R 04 represents
  • R 05 represents H or a d -4 alkyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , or NR 06 R 107 , wherein
  • R 06 represents
  • H or a d-4 alkyl which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , and
  • R 07 is selected from the group consisting of
  • H a C-1-4 alkyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , a C 3 -6 cycloalkyl or a 3 to 6 membered heterocyclyl, which is in each case unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OH,
  • a phenyl which is mono-, di- or trisubstituted with 1 , 2 or 3 substituents, preferably R 20 , R 202 and/or R 203 , independently of one another selected from the group consisting of F, CI, Br, CN, CF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , OH, OCF 3 and OCH 3 , or a heteroaryl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of F, CI, Br, CN, CF 3 , CH 3 , CH 2 CH 3 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , OH, OCF 3 and OCH 3 , with the proviso that R 07 cannot denote H when A represents CH or C(CH 3
  • R 04 represents
  • Ci-4 alkyl which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 ,
  • R 05 represents H or a d -4 alkyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , or NR 06 R 107 , wherein
  • R 06 represents
  • Ci-4 alkyl which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , and
  • R 07 is selected from the group consisting of
  • Ci-4 alkyl which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , a C 3 -6 cycloalkyl or a 3 to 6 membered heterocyclyl, which is in each case unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of CH 3 , OH, and OCH 3 , a phenyl, which is mono-, di- or trisubstituted with 1 , 2 or 3 substituents, preferably R 20 , R 202 and/or R 203 , independently of one another selected from the group consisting of F, CI, CF 3 , CH 3 , OH, OCF 3 and OCH 3 , or an unsubstituted heteroaryl, or wherein R 06 and R 07 together with the nitrogen atom connecting them form
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, Br, CF 3 , CN, CH 2 -OH, CH 2 -OCH 3 , OCF 3 , OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , 0-CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 , preferably wherein at least one of R 0 , R 02 and R 03 is ⁇ H,
  • R 2 represents CF 3 , tert.-butyl or cyclopropyl
  • R 7 and R 9 are independently of one another selected from the group consisting of H, F, CI, Br, CF 3 , CN, OH, OCF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , 0-CH 3 , and 0-CH 2 CH 3 , wherein at least one of R 7 and R 9 is ⁇ H,
  • A denotes N, CH or C(CH 3 ), preferably N or C(CH 3 ),
  • R 04 represents
  • H a C1 -4 alkyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 ,
  • R 05 represents H or a d -4 alkyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , or NR 06 R 107 , wherein
  • R 06 represents H or a Ci -4 alkyl, which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , and
  • R 07 is selected from the group consisting of
  • Ci-4 alkyl which is unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of OH and OCH 3 , a C-3-6 cycloalkyl or a 3 to 6 membered heterocyclyl, which is in each case unsubstituted or mono-, di- or trisubstituted with 1 , 2 or 3 substituents independently of one another selected from the group consisting of CH 3 , OH, and OCH 3 , a phenyl, which is mono-, di- or trisubstituted with 1 , 2 or 3 substituents, preferably R 20 , R 202 and/or R 203 , independently of one another selected from the group consisting of F, CI, CF 3 , CH 3 , OH, OCF 3 and OCH 3 , or an unsubstituted heteroaryl, or wherein R 06 and R 07 together with the nitrogen atom connecting them form
  • Preferred embodiments of the compound according to the invention of general formula (U) have general formulae (UO-a) and/or (UO-b):
  • preferred embodiments of the compound according to the invention of general formula (U) have general formulae (U1 -c), (U1 -c-1 ) and/or (U1 -c-2):
  • radical R 0 in the compound of general formula (U), (UO-a), (UO-b), (U1-a), (U1-a-1), (U1-a-2), (U1-b), (U1-b-1), (U1-b-2), (U1-c), (U1-C-1), (U1-C-2), (U1-d), (U1-d-1) and/or (U1-d-2) represents F, CI, CF 3 or 0-CH 3 , preferably F or CI, most preferably CI - preferably when R 03 is H and R 02 represents H, F, CI, CF 3 or OCH 3 , more preferably when R 03 is H and R 02 represents H, F or CI, even more preferably when both R 02 and R 03 denote H -, and the remaining particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.
  • radical R 0 represents F, CI, CF 3 or 0-CH 3 , preferably F or CI, most preferably CI - preferably when R 03 is H and R 02 represents H, F, CI, CF 3 or OCH 3 , more preferably when R 03 is H and R 02 represents H, F or CI, even more preferably when both R 02 and R 03 denote H -, at least one of radicals R 7 and R 9 is ⁇ H, and R 7 and R 9 as well as the remaining particular radicals
  • E10 4-[1 -[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl-carbamoyl]-ethyl]-2- fluoro-N-methyl-benzamide; E11 4-[1 -[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl-carbamoyl]- ethyl]-2-fluoro-N-methyl-benzamide;
  • E20 4-[1 -[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl-carbamoyl]- ethyl]-2-fluoro-N-(1 -methyl-piperidin-4-yl)-benzamide;
  • E29 4-[1 -[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl-carbamoyl]-ethyl]-2- fluoro-N-phenyl-benzamide; 4-[[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl-carbamoyl]-methyl]-N-(4- chlorophenyl)-benzamide;
  • E53 4-[1 -[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl-carbamoyl]-ethyl]-2- fluoro-N-thiazol-2-yl-benzamide;
  • E61 1 [[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-(3-fluoro-4- formyl-phenyl)-urea; optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt thereof.
  • capsaicin which is present at a concentration of 100 nM
  • a FLIPR assay with CHO K1 cells which were transfected with the human VR1 gene at a concentration of less than 2 000 nM, preferably less than 1 000 nM, particularly preferably less than 300 nM, most particularly preferably less than 100 nM, even more preferably less than 75 nM, additionally preferably less than 50 nM, most preferably less than 10 nM.
  • the Ca 2+ influx is quantified in the FLIPR assay with the aid of a Ca 2+ - sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA), as described hereinafter.
  • a Ca 2+ - sensitive dye type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands
  • FLIPR fluorescent imaging plate reader
  • substituted compounds according to the invention and corresponding stereoisomers and also the respective corresponding acids, bases, salts and solvates are toxicologically safe and are therefore suitable as pharmaceutical active ingredients in pharmaceutical compositions.
  • the present invention therefore further relates to a pharmaceutical composition containing at least one compound according to the invention, in each case if appropriate in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or respectively in the form of a corresponding salt, or respectively in the form of a corresponding solvate, and also if appropriate one or more pharmaceutically compatible auxiliaries.
  • compositions according to the invention are suitable in particular for vanilloid receptor 1 -(VR1/TRPV1 ) regulation, preferably for vanilloid receptor 1 -(VR1/TRPV1 ) inhibition and/or for vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation, i.e. they exert an agonistic or antagonistic effect.
  • compositions according to the invention are preferably suitable for the prophylaxis and/or treatment of disorders or diseases which are mediated, at least in part, by vanilloid receptors 1 .
  • the pharmaceutical composition according to the invention is suitable for administration to adults and children, including toddlers and babies.
  • the pharmaceutical composition according to the invention may be found as a liquid, semisolid or solid pharmaceutical form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and also be administered as much.
  • the pharmaceutical composition according to the invention conventionally contains further physiologically compatible pharmaceutical auxiliaries which can for example be selected from the group consisting of excipients, fillers, solvents, diluents, surface-active substances, dyes, preservatives, blasting agents, slip additives, lubricants, aromas and binders.
  • physiologically compatible auxiliaries and also the amounts thereof to be used depend on whether the pharmaceutical composition is to be applied orally, subcutaneously, parenterally, intravenously, intraperitoneal ⁇ , intradermal ⁇ , intramuscularly, intranasally, buccally, rectally or locally, for example to infections of the skin, the mucous membranes and of the eyes.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral application; solutions, suspensions, easily reconstitutable dry preparations and also sprays are preferably suitable for parenteral, topical and inhalative application.
  • substituted compounds according to the invention used in the pharmaceutical composition according to the invention in a repository in dissolved form or in a plaster, agents promoting skin penetration being added if appropriate, are suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the respective substituted compound according to the invention also in a delayed manner.
  • compositions according to the invention are prepared with the aid of conventional means, devices, methods and process known in the art, such as are described for example in exceedingRemington's Pharmaceutical Sciences", A.R. Gennaro (Editor), 17 th edition, Mack Publishing Company, Easton, Pa, 1985, in particular in Part 8, Chapters 76 to 93.
  • the corresponding description is introduced herewith by way of reference and forms part of the disclosure.
  • the amount to be administered to the patient of the respective substituted compounds according to the invention of the above-indicated general formula I may vary and is for example dependent on the patient's weight or age and also on the type of application, the indication and the severity of the disorder. Conventionally 0.001 to 100 mg/kg, preferably 0.05 to 75 mg/kg, particularly preferably 0.05 to 50 mg of at least one such compound according to the invention are applied per kg of the patient's body weight.
  • the pharmaceutical composition according to the invention is preferably suitable for the treatment and/or prophylaxis of one or more disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal 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 deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoria
  • the pharmaceutical composition according to the invention is suitable for the treatment and/or prophylaxis of one or more disorders and/or diseases selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; migraine; depression; 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 deficiency states, particularly preferably memory disorders; inflammations, preferably inflammations of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; urinary incontinence; overactive bladder (OAB); medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication, preferably development of tolerance to natural or synthetic opioids; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency.
  • pain preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, vis
  • 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.
  • the present invention further relates to a substituted compound according to the present invention and also if appropriate to a substituted compound according to the present invention and one or more pharmaceutically acceptable auxiliaries for use in vanilloid receptor 1 -(VR1 /TRPV1 ) regulation, preferably for use in vanilloid receptor 1 -(VR1/TRPV1 ) inhibition and/or vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation.
  • the present invention therefore further relates to a substituted compound according to the present invention and also if appropriate to a substituted compound according to the present invention and one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by vanilloid receptors 1 .
  • the present invention therefore further relates to a substituted compound according to the present invention and also if appropriate to a substituted compound according to the present invention and one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal 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 deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcer
  • a substituted compound according to the present invention and also if appropriate to a substituted compound according to the present invention and one or more pharmaceutically acceptable auxiliaries for use in the prophylaxis and/or treatment of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain.
  • the present invention further relates to the use of at least one substituted compound according to the present invention and also if appropriate to the use of at least one substituted compound according to the present invention of one or more pharmaceutically acceptable auxiliaries for the preparation of a pharmaceutical composition for vanilloid receptor 1 -(VR1 /TRPV1 ) regulation, preferably for vanilloid receptor 1 -(VR1/TRPV1 ) inhibition and/or for vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation, and, further for the prophylaxis and/or treatment of disorders and/or diseases which are mediated, at least in part, by vanilloid receptors 1 , such as e.g.
  • disorders and/or diseases selected from the group consisting of pain preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal 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 deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammations, preferably inflammations of the intestine
  • Another aspect of the present invention is a method for vanilloid receptor 1 -(VR1/TRPV1 ) regulation, preferably for vanilloid receptor 1 -(VR1 /TRPV1 ) inhibition and/or for vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation, and, further, a method of treatment and/or prophylaxis of disorders and/or diseases, which are mediated, at least in part, by vanilloid receptors 1 , in a mammal, preferably of disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal 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 deficiency states, particularly preferably memory
  • the effectiveness against pain can be shown, for example, in the Bennett or Chung model (Bennett, G.J. and Xie, Y.K., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain 1988, 33(1 ), 87-107; Kim, S.H. and Chung, J.M., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain 1992, 50(3), 355-363), by tail flick experiments (e.g. according to D'Amour und Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941 )) or by the formalin test (e.g. according to D. Dubuisson et al., Pain 1977, 4, 161 -174).
  • the present invention further relates to processes for preparing substituted compounds according to the invention.
  • the compounds according to the present invention of can be prepared by a process according to which at least one compound of general formula (U-ll),
  • a reaction medium preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol
  • All reactions which can be applied for synthesizing the compounds according to the present invention can each be carried out under the conventional conditions with which the person skilled in the art is familiar, for example with regard to pressure or the order in which the components are added. If appropriate, the person skilled in the art can determine the optimum procedure under the respective conditions by carrying out simple preliminary tests.
  • the intermediate and end products obtained using the reactions described hereinbefore can each be purified and/or isolated, if desired and/or required, using conventional methods known to the person skilled in the art. Suitable purifying processes are for example extraction processes and chromatographic processes such as column chromatography or preparative chromatography.
  • All of the process steps of the reaction sequences which can be applied for synthesizing the compounds according to the present invention as well as the respective purification and/or isolation of intermediate or end products, can be carried out partly or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.
  • substituted compounds according to the invention can be isolated both in the form of their free bases, and also in the form of corresponding salts, in particular physiologically acceptable salts, and further in the form of a solvate such as hydrate.
  • the free bases of the respective substituted compounds according to the invention can be converted into the corresponding salts, preferably physiologically acceptable salts, for example by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1 -sulphonic acid, nicotinic acid, 2, 3 or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, oc-lipoic acid, acetyl glycine, hippuric acid, phosphoric acid and/or aspartic acid.
  • an inorganic or organic acid preferably
  • the free bases of the respective inventive substituted compounds and of corresponding stereoisomers can likewise be converted into the corresponding physiologically acceptable salts using the free acid or a salt of a sugar additive, such as for example saccharin, cyclamate or acesulphame.
  • a sugar additive such as for example saccharin, cyclamate or acesulphame.
  • the substituted compounds according to the invention such as the free acids of the substituted compounds according to the invention can be converted into the corresponding physiologically acceptable salts by reaction with a suitable base.
  • substituted compounds according to the invention and of corresponding stereoisomers can if appropriate, like the corresponding acids, the corresponding bases or salts of these compounds, also be obtained in the form of their solvates, preferably in the form of their hydrates, using conventional methods known to the person skilled in the art.
  • substituted compounds according to the invention are obtained, after preparation thereof, in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and/or diastereomers, they can be separated and if appropriate isolated using conventional processes known to the person skilled in the art. Examples include chromatographic separating processes, in particular liquid chromatography processes under normal pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallisation processes.
  • step j01 an acid halide J-0, in which Hal preferably represents CI or Br, can be esterified using methanol to form the compound J-l by means of methods with which the person skilled in the art is familiar.
  • step j02 the methyl pivalate J-l can be converted into an oxoalkylnitrile J-l I by means of methods known to the person skilled in the art, such as for example using acetonitrile CH 3 - CN, if appropriate in the presence of a base.
  • step j03 the compound J-ll can be converted into an amino-substituted pyrazolyl derivative J-lll by means of methods known to the person skilled in the art, such as for example using hydrazine hydrate, with cyclization.
  • step j04 the amino compound J-lll can first be converted into a diazonium salt by means of methods known to the person skilled in the art, such as for example using nitrite, and the diazonium salt can be converted into a cyano-substituted pyrazolyl derivative J-IV with elimination of nitrogen using a cyanide, if appropriate in the presence of a coupling reagent.
  • step j05 the compound J-IV can be substituted in the N position by means of methods known to the person skilled in the art, for example using a halide of part structure (US2), i.e. Hal-(US2), if appropriate in the presence of a base and/or a coupling reagent, wherein Hal is preferably CI, Br or I, or using a boronic acid B(OH) 2 (US2) or a corresponding boronic acid ester, if appropriate in the presence of a coupling reagent and/or a base and the compound J-V can in this way be obtained.
  • a halide of part structure i.e. Hal-(US2)
  • Hal is preferably CI, Br or I
  • a boronic acid B(OH) 2 (US2) or a corresponding boronic acid ester if appropriate in the presence of a coupling reagent and/or a base and the compound J-V can in this way be obtained.
  • a second synthesis pathway in which in step k01 an ester K-0 is first reduced to form the aldehyde K-l by means of methods known to the person skilled in the art, for example using suitable hydrogenation reagents such as metal hydrides, is suitable for preparing the compound J-V.
  • step k02 the aldehyde K-l can then be reacted with a hydrazine K-V, which can be obtained in step k05, starting from the primary amine K-IV, by means of methods known to the person skilled in the art, to form the hydrazine K-ll by means of methods known to the person skilled in the art with elimination of water.
  • the hydrazine K-ll can be halogenated, preferably chlorinated, by means of methods known to the person skilled in the art with the double bond intact, such as for example using a chlorination reagent such as NCS, and the compound K-lll can in this way be obtained.
  • step k04 the hydrazonoyl halide K-lll can be converted into a cyano-substituted compound J-V by means of methods known to the person skilled in the art, such as for example using a halogen-substituted nitrile, with cyclisation.
  • step j06 the compound J-V can be hydrogenated by means of methods known to the person skilled in the art, for example using a suitable catalyst such as palladium/activated carbon or using suitable hydrogenation reagents, and the compound (U-ll) can in this way be obtained.
  • a suitable catalyst such as palladium/activated carbon or using suitable hydrogenation reagents
  • step j07 the compound (U-ll) can be converted into the compound (U-IV) by means of methods known to the person skilled in the art, such as for example using phenyl chloroformate, if appropriate in the presence of a coupling reagent and/or a base.
  • phenyl chloroformate if appropriate in the presence of a coupling reagent and/or a base.
  • a suitable coupling reagent for example HATU or CDI
  • step v1 the compound (U-V) can be converted into the compound (U-Va) by means of methods known to the person skilled in the art, such as for example using phenyl chloroformate, if appropriate in the presence of a coupling reagent and/or a base.
  • phenyl chloroformate if appropriate in the presence of a coupling reagent and/or a base.
  • the stationary phase used for the column chromatography was silica gel 60 (0.04 - 0.063 mm) from E. Merck, Darmstadt.
  • the mixing ratios of solvents or eluents for chromatography are specified in v/v.
  • Step j01 Pivaloyl chloride (J-0) (1 eq., 60 g) was added dropwise to a solution of methanol (120 mL) within 30 min at 0 ' ⁇ and the mixture was stirred for 1 h at room temperature. After the addition of water (120 mL), the separated organic phase was washed with water (120 mL), dried over sodium sulphate and codistilled with dichloromethane (150 mL). The liquid product J-l was able to be obtained at 99 % purity (57 g).
  • Step j02 NaH (50 % in paraffin oil) (1 .2 equivalents, 4.6 g) was dissolved in 1 ,4-dioxane (120 mL) and the mixture was stirred for a few minutes. Acetonitrile (1 .2 equivalents, 4.2 g) was added dropwise within 15 min and the mixture was stirred for a further 30 min. The methyl pivalate (J-l) (1 equivalents, 10 g) was added dropwise within 15 min and the reaction mixture was refluxed for 3 h. After complete reaction, the reaction mixture was placed in iced water (200 g), acidified to pH 4.5 and extracted with dichloromethane (12 x 250 mL).
  • Step j03 At room temperature 4,4-dimethyl-3-oxopentanenitrile (J-ll) (1 equivalents, 5 g) was taken up in ethanol (100 mL), mixed with hydrazine hydrate (2 equivalents, 4.42 g) and refluxed for 3 h. The residue obtained after removal of the ethanol by distillation was taken up in water (100 mL) and extracted with ethyl acetate (300 mL). The combined organic phases were dried over sodium sulphate, the solvent was removed under vacuum and the product (J-ll I ) (5 g, 89 % yield) was obtained as a light red solid after recrystallisation from n- hexane (200 mL).
  • Step j04 3-Tert-butyl-1 H-pyrazol-5-amine (J-lll) (1 equivalents, 40 g) was dissolved in diluted HCI (120 mL of HCI in 120 mL of water) and mixed dropwise with NaN0 2 (1 .03 equivalents, 25 g in 100 mL) at 0 - 5 °C over a period of 30 min. After stirring for 30 minutes, the reaction mixture was neutralised with Na 2 C0 3 .
  • a diazonium salt obtained by reaction of KCN (2.4 equivalents, 48 g), water (120 mL) and CuCN (1 .12 equivalents, 31 g) was added dropwise to the reaction mixture within 30 min and the mixture was stirred for a further 30 min at 75 °C. After complete reaction, the reaction mixture was extracted with ethyl acetate (3 x 500 mL), the combined organic phases were dried over sodium sulphate and the solvent was removed under vacuum. The purification (silica gel: 100-200 mesh, eluent: 20 % ethyl acetate/n-hexane) of the residue by column chromatography produced a white solid (J-IV) (6.5 g, 15 %).
  • Step j05 (method 1):
  • Step j05 [method 2):
  • Step j06 (method 1):
  • Step j06 (method 2):
  • Step k01 LAIH (lithium aluminium hydride) (0.25 equivalents, 0.7g) was dissolved in dry diethyl ether (30 mL) under a protective gas atmosphere and stirred for 2 h at room temperature. The suspension obtained was taken up in diethyl ether (20 mL). Ethyl-2,2,2- trifluoroacetate (K-0) (1 equivalent, 10 g) was taken up in dry diethyl ether (20 mL) and added dropwise to the suspension at -78 ' ⁇ over a period of 1 h. The mixture was then the stirred for a further 2 h at -78 ' ⁇ .
  • K-0 Ethyl-2,2,2- trifluoroacetate
  • Step k05 3-chloroaniline (K-IV) (1 equivalent, 50 g) was dissolved at -5 to 0 °C in concentrated HCI (300 mL) and stirred for 10 min. A mixture of NaN0 2 (1 .2 equivalents, 32.4 g), water (30 mL), SnCI 2 -2H 2 0 (2.2 equivalents, 70.6 g) and concentrated HCI (100 mL) was added dropwise over a period of 3 h while maintaining the temperature. After stirring for a further 2 h at -5 to 0 ' ⁇ , the reaction mixture was set to pH 9 using NaOH solution and extracted with ethyl acetate (250 mL). The combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum.
  • K-IV 3-chloroaniline
  • Step k02 The aldehyde (K-l) (2 equivalents, 300 mL) obtained from k01 and (3- chlorophenyl)hydrazine (K-IV) (1 equivalent, 20 g) were placed in ethanol (200 mL) and refluxed for 5 h. The solvent was removed under vacuum, the residue was purified by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane) and the product (25 g, 72 %) K-ll was obtained as a brown oil.
  • Step k03 The hydrazine K-ll (1 equivalent, 25 g) was dissolved in dimethylformamide (125 mL). N-chlorosuccinimide (1 .3 equivalents, 19.5 g) was added portionwise at room temperature within 15 min and the mixture was stirred for 3 h. The dimethylformamide was removed by distillation and the residue was taken up in ethyl acetate. The ethyl acetate was removed under vacuum, the residue obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane) and the product K-lll (26.5 g, 92 %) was obtained as a pink-coloured oil.
  • Step k04 At room temperature the hydrazonoyl chloride K-lll (1 equivalent, 10 g) was taken up in toluene (150 mL) and mixed with 2-chloroacrylonitrile (2 equivalents, 6.1 mL) and triethylamine (2 equivalents, 10.7 mL). This reaction mixture was stirred for 20 h at 80 ' ⁇ . The mixture was then diluted with water (200 mL) and the phases were separated. The organic phase was dried over magnesium sulphate and the solvent was removed under vacuum.
  • Step j06 ⁇ method 3
  • Step a To a solution of (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5-yl)methanamine (5 g, 18 mmol) in dimethylformamide (25 mL), potassium carbonate (9.16 g, 66 mmol, 3.5 eq) was added and cooled the contents to O'C. Then phenyl chloroformate (3.28 g (2.65 mL), 20 mmol, 1 .1 equivalents) was added dropwise for 15 minutes and the overall reaction mixture was stirred for another 15 minutes at 0 °C. Progress of the reaction was monitored by TLC (20 % ethyl acetate-n-hexane).
  • reaction contents were filtered, filtrate was diluted with cold water (100 mL) and the product extracted with ethyl acetate (3 ⁇ 25 mL). Combined organic layer was washed with brine solution (100 mL), dried over sodium sulphate and concentrated under reduced pressure. Crude obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: 10% ethyl acetate in n-hexane) to yield the required product as a white solid (3.2 g, 45 %).
  • the acid of general formula (U-lll) (1 equivalent) is first mixed with a chlorinating agent, preferably with thionyl chloride and the mixture obtained in this way is boiled under reflux and the acid (U-lll) is in this way converted into the corresponding acid chloride.
  • a chlorinating agent preferably with thionyl chloride
  • the amine of general formulae (U-ll) (1 .1 equivalents) is dissolved in dichloromethane (1 mmol of acid in 6 ml_) and mixed with triethylamine (3 equivalents) at 0 'C.
  • Step j07/step v1 The amine of general formula (U-ll) or (U-V) (1 equivalent) is placed in dichloromethane (10 mmol of amine in 70 mL) and phenyl chloroformate (1 .1 equivalents) is added thereto at room temperature and the mixture is stirred for 30 min. After removal of the solvent under vacuum, the residue is purified by means of flash chromatography (Si0 2 , diethyl ether/hexane in different ratios such as 1 :2) and (U-IV) or (U-Va) is in this way obtained.
  • Step j08/step v2 The carbamic acid phenyl ester (U-IV) or (U-Va) obtained (1 equivalent) and the corresponding amine (U-V) or (U-ll) (1 .1 equivalents) are dissolved in THF (10 mmol of the reaction mixture in 120 mL) and stirred for 16 h at room temperature after addition of DBU (1 .5 equivalents). After removal of the solvent under vacuum, the residue obtained is purified by means of flash chromatography (Si0 2 , EtOAc/hexane in different ratios such as 1 :1 ) and (U) is in this way obtained.
  • Step 1 To a solution of 2-(4-Amino-3-fluorophenyl)propionic acid (1 ) (1 g, 5.459 mmol) in EtOH was added SOCI 2 (0.6 ml, 8.189 mmol) at 0 ° C. The mixture was stirred for 2 hours at room temperature and then SOCI 2 was removed under reduced pressure. The residue was diluted with EtOAc and washed with a saturated NaHC0 3 solution. The resulting mixture was dried over MgS0 4 and concentrated. The residue was purified by column chromatography to afford the pure compound 2 (1 g, 87 %).
  • Step 2 To a solution of compound 2 (1 g, 4.734 mmol) in water and H 2 S0 4 (0.5 ml) was added NaN0 2 (490 mg, 7.101 mmol), Kl (2358 mg, 14.202 mmol) at 0 ° C. The reaction mixture was stirred overnight at room temperature and then treated with saturated NaHS0 3 solution and eluted with EtOAc. The organic layer was washed with water, dried over MgS0 4 and concentrated.
  • Step 3 To a solution of starting material 3 (1 .15 g, 3.570 mmol) in DMF was added Zn(CN) 2 (629 mg, 5.355 mmol) and Pd(PPh 3 ) 4 (825 mg, 0.714 mmol). The reaction mixture was refluxed for 8 hours and then cooled to room temperature. The mixture was filtered through a plug of Celite and concentrated. The residue was diluted with EtOAc and washed with 10% HCI solution. The organic layer was dried over MgS0 4 and concentrated. The residue was purified by column chromatography to afford the pure compound 4 (520 mg, 66 %).
  • Step 4 To a solution compound 4 (520 mg, 2.351 mmol) in THF and water was added LiOH monohydrate (148 mg, 3.526 mmol). The reaction mixture was stirred for 2 hours at 40 ° C and then acidified with 10% HCI solution. The mixture was extracted with EtOAc. The organic layer dried over MgS0 4 and concentrated under reduced pressure to afford desired compound 5 (440 mg, 97 %).
  • Step 5 To a solution of compound 5 (440 mg, 2.278 mmol) in acetonitrile was added HOBt (462 mg, 3.417 mmol), EDC (655 mg, 3.417 mmol) and (1 -(3-chlorophenyl)-3- (trifluoromethyl)-l H-pyrazol-5-yl)methanamine (659 mg, 2.392 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound 6 (870 mg, 85 %).
  • Step 6 To a solution compound 6 (870 mg, 1 .930 mmol) in EtOH was added 2N NaOH (9.7 ml, 19.300 mmol). The reaction mixture was stirred overnight at 100 ° C and then was cooled to room temperature. The mixture was acidified with 10% HCI solution and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound 7 (550 mg, 61 %).
  • Step 7 To 7 (150 mg, 0.319 mmol) in DCM was added SOCI 2 (0.12 ml, 1 .597 mmol). The reaction mixture was refluxed for 2 hours and then SOCI 2 was removed under reduced pressure. The residue was dissolved in 1 ,4-dioxane and a solution of NH 3 (0.5 M) in 1 ,4- dioxane (3.2 ml, 1 .595 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then diluted with EtOAc and washed with water. The organic layer was dried over MgS0 4 , filtered and concentrated. The crude was purified by column chromatography to give pure compound 8 (70 mg, 47 %).
  • Step 1 To a solution of 2-fluoro-4-nitrobenzoic acid (1 g, 5.402 mmol) in MeOH was added H 2 S0 4 (2.9 ml). The reaction mixture was refluxed overnight, and then cooled to room temperature and concentrated. The residue was diluted with EtOAc and washed with a saturated NaHC0 3 solution. The organic layer was dried over MgS0 4 and concentrated. The crude was purified by column chromatography to afford the pure compound methyl 2-fluoro- 4-nitrobenzoate (1 .05 g, 98 %).
  • Step 2 Methyl 2-fluoro-4-nitrobenzoate (1 .05 g, 5.273 mmol) was dissolved in MeOH. Pd/C (105 mg) was added to the resulting mixture. The reaction mixture was stirred at room temperature for 2 hours under H 2 . The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound methyl 4-amino-2-fluorobenzoate (870 mg, 98 %).
  • Step 3 To a solution of methyl 4-amino-2-fluorobenzoate (870 mg, 5.143 mmol) in acetonitrile was added DMAP (691 mg, 5.657 mmol) and phenyl (1 -(3-chlorophenyl)-3- (trifluoromethyl)-1 H-pyrazol-5-yl)methylcarbamate (2036 mg, 5.143 mmol) at room temperature. The reaction mixture was refluxed overnight and then cooled to room temperature. The mixture was added water and extracted with EtOAC. The organic layer was dried over MgS0 4 and concentrated.
  • Step 4 To a solution of methyl 4-(3-((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methyl)ureido)-2-fluorobenzoate (1 .3 g, 2.761 mmol) in THF and water was added LiOH monohydrate (174 mg, 4.142 mmol). The reaction mixture was stirred for 2 hours at 40 ° C and then acidified with a 10% HCI solution. The mixture was extracted with EtOAc.
  • Step 5 To a solution of compound 4-(3-((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methyl)ureido)-2-fluorobenzoic acid (100 mg, 0.219 mmol) in DMF was added HBTU (125 mg, 0.329 mmol), DIPEA (0.1 1 ml, 0.657 mmol) and NH 3 (0.5M solution in 1 ,4-dioxane; 1 .3 ml, 0.657 mmol). The reaction mixture was stirred for 2 hours at room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column
  • Step 5 To a solution of compound 4-(3-((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methyl)ureido)-2-fluorobenzoic acid (150 mg, 0.328 mmol) in DMF was added HBTU (187 mg, 0.492 mmol), DIPEA (0.1 1 ml, 0.657 mmol) and methylamine (2M solution in THF; 0.33 ml, 0.657 mmol). The reaction mixture was stirred for 2 hours at room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column
  • Step 5 To a solution of compound 4-(3-((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methyl)ureido)-2-fluorobenzoic acid (150 mg, 0.328 mmol) in DMF was added HBTU (187 mg, 0.492 mmol), DIPEA (0.1 1 ml, 0.657 mmol) and dimethylamine (2M solution in THF; 0.33 ml, 0.657 mmol). The reaction mixture was stirred for 2 hours at room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column
  • Step 5 To a solution of 4-(3-((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methyl)ureido)-2-fluorobenzoic acid (150 mg, 0.328 mmol) in DMF was added HBTU (187 mg, 0.492 mmol), DIPEA (0.1 1 ml, 0.657 mmol) and ethanol amine (0.021 ml, 0.344 mmol). The reaction mixture was stirred for 2 hours at room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound example compound E18 (1 15 mg, 70 %)
  • Step 1 To a solution of 2-(4-Amino-3-fluorophenyl)propionic acid (1 g, 5.459 mmol) in EtOH was added SOCI 2 (0.6 ml, 8.189 mmol) at 0 ° C. The mixture was stirred for 2 hours at room temperature and then SOCI 2 was removed under reduced pressure. The residue was diluted with EtOAc and washed with a saturated NaHC0 3 solution. The resulting mixture was dried over MgS0 4 and concentrated. The residue was purified by column chromatography to afford ethyl 2-(4-amino-3-fluorophenyl)propanoate (1 g, 87 %).
  • Step 2 To a solution of ethyl 2-(4-amino-3-fluorophenyl)propanoate (1 g, 4.734 mmol) in water and H 2 S0 4 (0.5 ml) was added NaN0 2 (490 mg, 7.101 mmol), Kl (2358 mg, 14.202 mmol) at 0 ° C. The reaction mixture was stirred overnight at room temperature and then treated with saturated NaHS0 3 solution and eluted with EtOAc. The organic layer was washed with water, dried over MgS0 4 and concentrated. The residue was purified by column chromatography to afford ethyl 2-(3-fluoro-4-iodophenyl)propanoate (1 .15 g, 75 %).
  • Step 3 To a solution of ethyl 2-(3-fluoro-4-iodophenyl)propanoate (1 .15 g, 3.570 mmol) in DMF was added Zn(CN) 2 (629 mg, 5.355 mmol) and Pd(PPh 3 ) 4 (825 mg, 0.714 mmol). The reaction mixture was refluxed for 8 hours and then cooled to room temperature. The mixture was filtered through a plug of Celite and concentrated. The residue was diluted with EtOAc and washed with 10% HCI solution. The organic layer was dried over MgS0 4 and
  • Step 4 To a solution of ethyl 2-(4-cyano-3-fluorophenyl)propanoate (520 mg, 2.351 mmol) in THF and water was added LiOH monohydrate (148 mg, 3.526 mmmol). The reaction mixture was stirred for 2 hours at 40 ° C and then acidified with 10% HCI solution. The mixture was extracted with EtOAc. The organic layer dried over MgS0 4 and concentrated under reduced pressure to afford desired compound 2-(4-cyano-3-fluorophenyl)propanoic acid (440 mg, 97 %).
  • Step 5 To a solution of 2-(4-cyano-3-fluorophenyl)propanoic acid (440 mg, 2.278 mmol) in acetonitrile was added HOBt (462 mg, 3.417 mmol), EDC (655 mg, 3.417 mmol) and (1 -(3- chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine (659 mg, 2.392 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure.
  • Step 6 To a solution compound N-((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methyl)-2-(4-cyano-3-fluorophenyl)propanamide (870 mg, 1 .930 mmol) in EtOH was added 2N NaOH (9.7 ml, 19.300 mmol). The reaction mixture was stirred overnight at 100 ° C and then was cooled to room temperature. The mixture was acidified with 10% HCI solution and extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated under reduced pressure.
  • Step 7 To 4-(1 -((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methylamino)-1 - oxopropan-2-yl)-2-fluorobenzoic acid (150 mg, 0.319 mmol) in acetonitrile was added SOCI 2 (0.12 ml, 1 .597 mmol). The reaction mixture was refluxed for 2 hours and then SOCI 2 was removed under reduced pressure.
  • Step 1 To a stirred solution of 2-Chloro-4-nitrobenzoic acid (500 mg, 2.48 mmol) in methanol was added sulfuric acid in catalytic amounts. The mixture was heated to reflux overnight. TLC showed complete consumption of starting material. The reaction mixture was slowly cooled room temperature and neutralized with sodium bicarbonate. The mixture was extracted with EtOAc and washed with water and brine. The extract was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column
  • Step 2 To a stirred solution of methyl 2-chloro-4-nitrobenzoate (468 mg, 2.17 mmol) in ethanol was added Sn(ll) chloride and heated to reflux for 1 .5 h. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo and extracted with EtOAc. The organic layer was washed with water and brine. The extract was dried over MgS0 4 and concentrated under reduced pressure to give desired product methyl 4-amino-2-chlorobenzoate (407 mg).
  • Step 3 Methyl 4-amino-2-chlorobenzoate (407 mg, 2.2 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.3 ml, 2.4 mmol) and phenyl chloroformate (0.21 ml, 2.6 mmol) and the mixture was stirred at room temperature for 1 h under N 2 . TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound methyl 2-chloro-4- (phenoxycarbonylamino)benzoate (713 mg).
  • Step 4 To a solution of methyl 2-chloro-4-(phenoxycarbonylamino)benzoate (80 mg, 0.26 mmol) in DMF was added DMAP (32 mg, 0.26 mmol) and (1 -(3-chlorophenyl)-3- (trifluoromethyl)-l H-pyrazol-5-yl)methanamine (74 mg, 0.27 mmol) at room temperature. The reaction mixture was heated to 50°C overnight. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over MgS0 4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure compound example compound E59 (77 mg).
  • Step 1 To a stirred solution of methyl 2-fluoro-4-nitrobenzoate (10.0 g, 49.7 mmol, 1 eq.) in methanol (100 mL) was added sodium borohydride (9.40 g, 248.7 mmol, 5 eq.) at RT and stirred for 4h. The methanol was evaporated and the residue was diluted with ethyl acetate (50 mL x 2) washed with water (50 mL) and brine (50 mL).
  • Step 2 To a stirred solution of (2-fluoro-4-nitrophenyl)methanol (3.0 g, 1 .0 eq.) in EtOAc (30 mL) was added 10% Pd-C and the reaction mixture was stirred under H 2 gas balloon at RT for 6 h. The reaction mixture was passed through a celite pad and the solvent evaporated. The residue was purified by neutral alumina column using PE/EtOAc (3:2) as eluent to get (4-amino-2-fluorophenyl)methanol (1 .1 g, 48%) as a solid; TLC system: EtOAc/PE (1 :1 ), R f : 0.3).
  • Step 3 To a stirred solution of (4-amino-2-fluorophenyl)methanol (100 mg, 0.709 mmol, 1 eq.) in acetone (1 .0 mL) was added pyridine (0.17 mL, 2.12 mmol, 3 eq.) followed by phenyl chloroformate (0.092 mL, 0.709 mmol, 1 eq.) at 0°C and stirred at RT for 1 h.
  • Step 4 To a stirred solution of (1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methanamine (100 mg, 0.316 mmol, 1 .0 eq.) in DCM (2.0 mL) was added Et 3 N (0.07 mL, 0.632 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenylcarbamate (82.4 mg, 0.316 mmol, 1 .0 eq.) at RT and stirred for 16 h.
  • Step 5 To a stirred solution of 1 -((1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (240 mg, 0.54 mmol, 1 .0 eq) in DCM (10 mL) and cooled to 0°C was added Dess-Martin periodinane (345 mg, 0.813 mmol, 1 .5 eq) slowly portion wise at O 'C and stirred for 1 h at 0°C, and then stirred for 30 min. at RT. DCM was evaporated and EtOAC (50 mL) was added.
  • the agonistic or antagonistic effect of the substances to be tested on the rat-species vanilloid receptor 1 can be determined using the following assay.
  • the influx of Ca 2+ through the receptor channel is quantified with the aid of a Ca 2+ -sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
  • a Ca 2+ -sensitive dye type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands
  • FLIPR fluorescent imaging plate reader
  • Complete medium 50 ml_ HAMS F12 nutrient mixture (Gibco Invitrogen GmbH, Düsseldorf, Germany) with 10 % by volume of FCS (foetal calf serum, Gibco Invitrogen GmbH, Düsseldorf, Germany, heat-inactivated); 2mM L-glutamine (Sigma, Kunststoff, Germany); 1 % by weight of AA solution (antibiotic/antimyotic solution, PAA, Pasching, Austria) and 25 ng/mL NGF medium (2.5 S, Gibco Invitrogen GmbH, Düsseldorf, Germany)
  • Cell culture plate Poly-D-lysine-coated, black 96-well plates having a clear base (96-well black/clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Düsseldorf, Germany), the laminin being diluted with PBS (Ca-Mg- free PBS, Gibco Invitrogen GmbH, Düsseldorf, Germany) to a concentration of 100 ⁇ g/mL. Aliquots having a laminin concentration of 100 ⁇ g mL are removed and stored at -20 'C.
  • the aliquots are diluted with PBS in a ratio of 1 : 10 to 10 ⁇ g mL of laminin and respectively 50 ⁇ - of the solution are pipetted into a recess in the cell culture plate.
  • the cell culture plates are incubated for at least two hours at 37 °C, the excess solution is removed by suction and the recesses are each washed twice with PBS.
  • the coated cell culture plates are stored with excess PBS which is not removed until just before the feeding of the cells.
  • the vertebral column is removed from decapitated rats and placed immediately into cold HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany), i.e. buffer located in an ice bath, mixed with 1 % by volume (per cent by volume) of an AA solution (antibiotic/antimyotic solution, PAA, Pasching, Austria).
  • HBSS buffer Horco Invitrogen GmbH, Düsseldorf, Germany
  • AA solution antibiotic/antimyotic solution
  • PAA antibiotic/antimyotic solution
  • PAA dorsal root ganglia
  • the DRG from which all blood remnants and spinal nerves have been removed, are transferred in each case to 500 ⁇ _ of cold type 2 collagenase (PAA, Pasching, Austria) and incubated for 35 minutes at 37 ⁇ . After the addition of 2.5 % by volume of trypsin (PAA, Pasching, Austria), incubation is continued for 10 minutes at 37 ⁇ . After complete incubation, the enzyme solution is carefully pipetted off and 500 ⁇ _ of complete medium are added to each of the remaining DRG.
  • the DRG are respectively suspended several times, drawn through cannulae No. 1 , No. 12 and No. 1 6 using a syringe and transferred to a 50 ml_ Falcon tube which is filled up to 15 ml_ with complete medium.
  • each Falcon tube is respectively filtered through a 70 ⁇ Falcon filter element and centrifuged for 1 0 minutes at 1 ,200 rpm and room temperature. The resulting pellet is respectively taken up in 250 ⁇ _ of complete medium and the cell count is determined.
  • the number of cells in the suspension is set to 3 x 1 0 5 per ml_ and 1 50 ⁇ _ of this suspension are in each case introduced into a recess in the cell culture plates coated as described hereinbefore. In the incubator the plates are left for two to three days at 37 °C, 5 % by volume of C0 2 and 95 % relative humidity.
  • the cells are loaded with 2 ⁇ of Fluo-4 and 0.01 % by volume of Pluronic F1 27 (Molecular Probes Europe BV, Leiden, the Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) for 30 min at 37 °C, washed 3 times with HBSS buffer and after further incubation for 1 5 minutes at room temperature used for Ca 2+ measurement in a FLIPR assay.
  • the FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 ⁇ ) are pipetted onto the cells and the Ca 2+ influx is compared with the control (capsaicin 1 0 ⁇ ). This provides the result in % activation based on the Ca 2+ signal after the addition of 1 0 ⁇ of capsaicin (CP). After 5 minutes' incubation, 100 nM of capsaicin are applied and the Ca 2+ influx is also determined.
  • the agonistic or antagonistic effect of the substances to be tested on the vanilloid receptor 1 can also be determined using the following assay.
  • the influx of Ca 2+ through the channel is quantified with the aid of a Ca 2+ -sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
  • a Ca 2+ -sensitive dye type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands
  • FLIPR fluorescent imaging plate reader
  • CHO K1 cells Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC) United Kingdom) are stably transfected with the VR1 gene. For functional testing, these cells are plated out on poly-D-lysine-coated black 96-well plates having a clear base (BD Biosciences, Heidelberg, Germany) at a density of 25,000 cells/well. The cells are incubated overnight at 37 °C and 5 % C0 2 in a culture medium (Ham's F12 nutrient mixture, 1 0 % by volume of FCS (foetal calf serum), 1 8 ⁇ g ml of L-proline).
  • FCS calcium calf serum
  • the FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 ⁇ ) are pipetted onto the cells and the Ca 2+ influx is compared with the control (capsaicin 10 ⁇ ) (% activation based on the Ca 2+ signal after the addition of 10 ⁇ of capsaicin). After 5 minutes' incubation, 100 nM of capsaicin are applied and the Ca 2+ influx is also determined.
  • the compounds according to the invention display outstanding affinity to the VR1 /TRPV1 receptor (Table 2).
  • the value after thetician@"symbol indicates the concentration at which the inhibition (as a percentage) was respectively determined.

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Abstract

La présente invention concerne des dérivés de carboxamide et d'urée à base de pyrazolyle substitué portant un fragment phényle remplacé par un groupe contenant CO comme ligands des récepteurs vanilloïdes, des compositions pharmaceutiques contenant ces composés ainsi que ces composés pour utilisation dans le traitement et/ou la prophylaxie de la douleur et autres maladies et/ou troubles.
EP12781344.2A 2011-11-09 2012-11-08 Dérivés de carboxamide et d'urée à base de pyrazolyle substitué portant un fragment phényle remplacé par un groupe contenant co comme ligands des récepteurs vanilloïdes Withdrawn EP2776400A1 (fr)

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EP12781344.2A EP2776400A1 (fr) 2011-11-09 2012-11-08 Dérivés de carboxamide et d'urée à base de pyrazolyle substitué portant un fragment phényle remplacé par un groupe contenant co comme ligands des récepteurs vanilloïdes

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EP11008926 2011-11-09
PCT/EP2012/072146 WO2013068467A1 (fr) 2011-11-09 2012-11-08 Dérivés de carboxamide et d'urée à base de pyrazolyle substitué portant un fragment phényle remplacé par un groupe contenant co comme ligands des récepteurs vanilloïdes
EP12781344.2A EP2776400A1 (fr) 2011-11-09 2012-11-08 Dérivés de carboxamide et d'urée à base de pyrazolyle substitué portant un fragment phényle remplacé par un groupe contenant co comme ligands des récepteurs vanilloïdes

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ES2713700T3 (es) 2014-11-24 2019-05-23 Medifron Dbt Inc Derivados de carboxamida y urea a base de oxazol y tiazol sustituidos como ligandos del receptor de vainilloide II
EP3319444B1 (fr) * 2015-07-09 2022-03-09 The Regents of the University of California Modulateurs du récepteur opioïde de type mu
CN105330604A (zh) * 2015-10-14 2016-02-17 湖南华腾制药有限公司 一种替格列汀关键中间体的制备方法
CN113912586B (zh) 2016-08-31 2023-04-07 江苏恒瑞医药股份有限公司 氧代吡啶酰胺类衍生物、其制备方法及其在医药上的应用
AU2018298193A1 (en) 2017-07-06 2020-01-02 Jiangsu Hengrui Medicine Co., Ltd. Indole-formamide derivative, preparation method therefor and use thereof in medicine
WO2019195634A1 (fr) 2018-04-04 2019-10-10 Epiodyne, Inc. Modulateurs du récepteur opioïde, produits et procédés associés
TW202304869A (zh) 2021-04-05 2023-02-01 美商艾碧奧戴股份有限公司 類鴉片受體調節劑

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NZ595759A (en) 2009-05-07 2014-03-28 Gruenenthal Chemie Substituted phenylureas and phenylamides as vanilloid receptor ligands
CA2758289A1 (fr) 2009-05-07 2010-11-11 Gruenenthal Gmbh Derives de carboxamide aromatique et d'uree substitues en tant que ligands du recepteur vanilloide

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