WO2013068462A1 - Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an n-containing group as vanilloid receptor ligands - Google Patents

Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an n-containing group as vanilloid receptor ligands Download PDF

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Publication number
WO2013068462A1
WO2013068462A1 PCT/EP2012/072141 EP2012072141W WO2013068462A1 WO 2013068462 A1 WO2013068462 A1 WO 2013068462A1 EP 2012072141 W EP2012072141 W EP 2012072141W WO 2013068462 A1 WO2013068462 A1 WO 2013068462A1
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Prior art keywords
methyl
phenyl
pyrazol
fluoro
trifluoromethyl
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PCT/EP2012/072141
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English (en)
French (fr)
Inventor
Robert Frank
Thomas Christoph
Nils Damann
Bernhard Lesch
Gregor Bahrenberg
Derek John Saunders
Hannelore Stockhausen
Yong-Soo Kim
Myeong-Seop Kim
Jeewoo Lee
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Grünenthal GmbH
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Priority to CA2854935A priority Critical patent/CA2854935A1/en
Priority to IN847KON2014 priority patent/IN2014KN00847A/en
Priority to JP2014540454A priority patent/JP2014532742A/ja
Priority to KR1020147015425A priority patent/KR20140096351A/ko
Priority to EP12781341.8A priority patent/EP2776399A1/en
Priority to MX2014005611A priority patent/MX2014005611A/es
Priority to AU2012334066A priority patent/AU2012334066A1/en
Priority to CN201280055195.9A priority patent/CN103906736A/zh
Priority to BR112014010957A priority patent/BR112014010957A2/pt
Publication of WO2013068462A1 publication Critical patent/WO2013068462A1/en
Priority to HK15102577.0A priority patent/HK1202116A1/xx

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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 an N-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 (R), 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 (R), 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 (R),
  • 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, OCF3, OH, NH 2 , a d- 4 alkyl, an O-C 1 -4 alkyl, a NH-C 1 -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 0-d_ 4 alkyl, wherein the d_ 4 alkyl is in each case unsubstituted,
  • A denotes N, CH or C(CH 3 ), q denotes 0, 1 or 2,
  • 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. 1 , 2, 3 or 4, carbon atoms, i.e. Ci -4 aliphatic residues, i.e. Ci -4 alkanyls.
  • 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 according of the present invention is formed from radicals R 2 and R 3 together with the nitrogen atom connecting them, i.e. contains at least one N as a ring member.
  • 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 .
  • 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 , 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 ,
  • 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 0 is selected from the group consisting of F, 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, 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, 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, CF 3 , OCF 3 , CH 3 and 0-CH 3
  • R 0 is selected from the group consisting of F, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 - OCH 3 , OCF3, 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, 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, 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, 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, CF 3 , OCF 3 , CH 3 and 0-CH 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,
  • part structure (RS2) is a particularly preferred embodiment according to the present invention.
  • N preferably is selected from the group consisting of in particular when q denotes 0, 1 or 2, and A denotes N.
  • part structure (RS2) is a particularly preferred embodiment according to the present invention.
  • A denotes CH or C(CH 3 ), preferably is selected from the group consisting of in particular when q denotes 1 or 2, and A denotes CH or C(CH 3 ).
  • 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 , O-CH3, 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, 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. In another particularly preferred embodiment of the compound according to the present invention A denotes C(CH 3 ).
  • q denotes 1 or 2, preferably 1 .
  • A denotes CH or C(CH 3 ),
  • q denotes 0, 1 or 2, preferably 1 or 2, more preferably 1
  • A denotes N
  • R 0 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 ; 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 ; 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 ; even more
  • R 02 and R 03 are independently of one another selected from the group consisting of
  • A denotes CH or C(CH 3 ), preferably C(CH 3 ),
  • R 0 is selected from the group consisting of H, F, 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 ; preferably is selected from the group consisting of H, F, 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 ; more preferably is selected from the group consisting of H, F, CFH 2 , CF 2 H, CF 3 , OCF 3 , CH 3 , 0-CH 3 , and 0-CH 2 CH 3 ; even more preferably is selected from the group consisting of
  • R 02 and R 03 are independently of one another selected from the group consisting of
  • R m represents NH 2 or an unsubstituted d -4 alkyl; preferably represents NH 2 , CH 3 or CH 2 CH 3 , more preferably represents NH 2 or CH 3 , in particular represents CH 3 , or represents the part structure (PR2-a) or (PR2-b) "C -4 alkyl
  • the part structure (RS1 ) is a part structure (RS1 )
  • (RS1 ) represents the part structure (PR1 )
  • R m represents NH 2 or an unsubstituted d -4 alkyl; preferably represents NH 2 , CH 3 or CH 2 CH 3 , more preferably represents NH 2 or CH 3 , in particular represents CH 3 .
  • R 0 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 02 and R 03 are independently of one another selected from the group consisting of
  • A denotes CH or C(CH 3 ), preferably C(CH 3 ), and
  • R 0 is selected from the group consisting of H, F, 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 02 and R 03 are independently of one another selected from the group consisting of
  • 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 , preferably, wherein at least one of R 7 and R 9 is ⁇ H, the part structure (RS1 )
  • (RS1 ) represents the part structure (PR1 )
  • R m represents NH 2 , CH 3 or CH 2 CH 3 .
  • R 0 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 02 and R 03 are independently of one another selected from the group consisting of
  • 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 , preferably, wherein at least one of R 7 and R 9 is ⁇ H,
  • A denotes N, and
  • R 2 represents H or a d -4 alkyl, which is unsubstituted, preferably denotes H, CH 3 or CH 2 CH 3 , more preferably denotes H or CH 3 , in particular denotes H,
  • A denotes CH or C(CH 3 ), preferably C(CH 3 ),
  • R 2 represents H or a Ci -4 alkyl, which is unsubstituted, preferably denotes H, CH 3 or CH 2 CH 3 , more preferably denotes H or CH 3 , in particular denotes H,
  • Preferred embodiments of the compound according to the invention of general formula (R) have general formulae (RO-a) and/or (RO-b):
  • preferred embodiments of the compound according to the invention of general formula (R) have general formulae (R1 -c), (R1 -c-1 ) and/or (R1 -c-2):
  • preferred embodiments of the compound according to the invention of general formula (R) have general formulae (R1 -f), (R1 -f-1 ) and/or (R1 -f-2):
  • radical R 0 in the compound of general formula (R), (R1-a), (R1-a-1), (R1-b), (R1-b-1), (R1-c), (R1-C-1), (R1-d) and/or (R1-d-1) 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 in the compound of general formula (R), (R1-a), (R1-a-2), (R1-b), (R1-b-2), (R1-c), (R1-C-2), (R1-d) and/or (R1-d-2), represents F, CF 3 or 0-CH 3 , preferably F or OCH 3 , most preferably F - 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 in the compound of general formula (R1-e), (R1-e-1), (R1-e-2), (R1-f), (R1-f-1) and/or (R1-f-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.
  • B70 1 [[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3- fluoro-4-[(sulfamoylamino)-methyl]-phenyl]-urea; B71 1 -[3-Fluoro-4-[(sulfamoylamino)-methyl]-phenyl]-3-[[2-(3-methoxyphenyl)-5-
  • 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.
  • the pharmaceutical 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.
  • the 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.
  • the pharmaceutical 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 (R-ll),
  • R-lll in which Hal represents a halogen, preferably Br or CI, and R 7 , R 9 , R 2 , R 3 and q each have one of the foregoing meanings and A denotes CH or C(CH 3 ), in a reaction medium, if appropriate in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base, to form a compound of general formula (R),
  • R in which A represents CH or C(CH 3 ) and R 0 , R 02 , R 03 and R 2 as well as R 7 , R 9 , R 2 , R 3 and q have one of the foregoing meanings; or in that at least one compound of general formula (R- II),
  • R-IV in which R 0 , R 02 , R 03 and R 2 have one of the foregoing meanings, in a reaction medium, in the presence of phenyl chloroformiate, if appropriate in the presence of at least one base and/or at least one coupling reagent, and said compound is if appropriate purified and/or isolated, and a compound of general formula (R-IV) is reacted with a compound of general formula (R-V),
  • R-V in which R 7 , R 9 , R 2 , R 3 and q have one of the foregoing meanings, and A denotes N, in a reaction medium, if appropriate in the presence of at least one suitable coupling reagent, if appropriate in the presence of at least one base, to form a compound of general formula (R),
  • R in which A represents N and R 0 , R 02 , R 03 and R 2 as well as R 7 , R 9 , R 2 , R 3 and q have one of the foregoing meanings.
  • 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.
  • the 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 (RS2), i.e. Hal-(RS2), 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 (RS2) 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-(RS2)
  • Hal is preferably CI, Br or I
  • a boronic acid B(OH) 2 (RS2) 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 (R-ll) can in this way be obtained.
  • a suitable catalyst such as palladium/activated carbon or using suitable hydrogenation reagents
  • step j07 the compound (R-ll) can be converted into the compound (R-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 (R-V) can be converted into the compound (R-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 in n-hexane).
  • Step a To a solution of sodium ethoxide (freshly prepared by dissolving sodium (1 g, 8.2 mmol, 1 .2 equivalents) in ethanol (30 mL)), diethyl oxalate (0.92 mL, 6.85 mmol, 1 equivalent) was added at room temperature followed by addition of cyclopropyl methyl ketone (0.74 mL, 7.5 mmol, 1 .1 equivalents) dropwise at 0 ' ⁇ . The reaction mixture was slowly warmed to room temperature and stirred for 3 h. Ice cold water (10 mL) was added and ethanol was evaporated under reduced pressure. The residual aqueous layer was diluted with 2 N aq. HCI (15mL) and extracted with diethyl ether (2 ⁇ 25 mL). The organic layer was washed with brine solution and dried over sodium sulphate, filtered and concentrated to give a pale brown liquid (400 mg, 31 %).
  • diethyl oxalate (0.92
  • Step b To a solution of step-a product (200 mg, 0.543 mmol, 1 equivalent) in ethanol (8 mL), methoxylamine hydrochloride (30 % solution in water, 0.4 mL, 0.651 mmol, 1 .2 equivalents) was added at room temperature and the reaction mixture stirred for 1 h. ethanol was evaporated under reduced pressure and the residual aqueous layer was extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a pale yellow liquid (180 mg, 78 %).
  • Step c A mixture of step-b product (1 .1 g, 5.164 mmol, 1 equivalent) and 3-chlorophenyl hydrazine hydrochloride (1 .84 g, 10.27 mmol, 2 equivalents) was taken in acetic acid (20 mL), 2-methoxy ethanol (10 mL) and the reaction mixture was heated at 105 °C for 3 h. Solvent was evaporated and the residue was extracted with ethyl acetate (60 mL). The organic layer washed with water (10 mL), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography (silica gel: 100-200 mesh; eluent: ethyl acetate-petroleum ether (4:96)) afforded a pale brown semi solid (1 .15g, 77 %).
  • Step d To a solution of step-c product (2.5 g, 8.62 mmol, 1 eq) in tetrahydrofuran (15 mL) - methanol (9 mL) - water (3 mL), lithium hydroxide (1 .08 g, 25.71 mmol, 3 equivalents) was added at 0 °C and the reaction mixture was stirred for 2 h at room temperature. Solvent was evaporated and pH of the residue was adjusted to ⁇ 3 sing 2 N aqueous HCI (1 .2 mL).
  • Step e To a solution of step-d product (1 .4 g, 5.34 mmol, 1 equivalent) in 1 ,4-dioxane (30 mL), pyridine (0.25 mL, 3.2 mmol, 0.6 equivalents) and di-tert-butyl dicarbonate (1 .4 mL, 6.37 mmol, 1 .2 equivalents) were added at 0 'C and the resulting mixture was stirred for 30 minutes at the same temperature. Ammonium bicarbonate (0.84 g, 10.63 mmol, 2 equivalents) was added at 0 'C and the reaction mixture was stirred at room temperature overnight.
  • Step f To a solution of step-e product (2 g, 7.66 mmol, 1 equivalent) in tetrahydrofuran (25 mL), BH 3 .DMS (1 .44 mL, 15.32 mmol, 2 equivalents) was added at 0 °C and the reaction mixture was heated at 70 ⁇ for 3 h. The reaction mixture was cooled to 0 'C and methanol (15 mL) was added and reaction mixture heated at reflux for 1 h. The reaction mixture was brought to room temperature and solvent was evaporated under reduced pressure.
  • the acid of general formula (R-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 (R-lll) is in this way converted into the corresponding acid chloride.
  • a chlorinating agent preferably with thionyl chloride
  • the amine of general formulae (R-ll) (1 .1 equivalents) is dissolved in dichloromethane (1 mmol of acid in 6 ml_) and mixed with triethylamine (3 equivalents) at 0 'C.
  • reaction mixture is stirred for 20 h at room temperature and the crude product is purified by means of column chromatography (Si0 2 , n-hexane/EtOAc in different ratios such as 2:1 ) and (R) is in this way obtained.
  • the exemplary compounds B1 -B10, B13, B15-B23, B26, B29-B30, B37, B42-B43, B47, BBS- Bee, B76, B82, B88, B93-B98 and B102-B104 and B106-B107 were obtained using one of the methods described hereinbefore.
  • Step j07/step v1 The amine of general formula (R-ll) or (R-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 (R-IV) or (R-Va) is in this way obtained.
  • Step j08/step v2 The carbamic acid phenyl ester (R-IV) or (R-Va) obtained (1 equivalent) and the corresponding amine (R-V) or (R-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 (R) is in this way obtained.
  • Step 1 To a stirred solution of (4-bromophenyl)methanamine (500 mg, 2.687 mmol) in pyridine were added methanesulfonyl chloride (0.4 ml_, 5.106 mmol) at O'C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried (MgS0 4 ) and filtered. The solvent removed in vacuo. The crude was purified by CC. N-(4-bromobenzyl)methanesulfonamide (675 mg) was obtained (95 % yield).
  • Step 2 To a stirred solution of N-(4-bromobenzyl)methanesulfonamide (675 mg, 2.555 mmol) in DMF were added ethyl 2-chloropropionate (0.42 ml_), manganese (280 mg) and (2,2'-bipyridine)nickel(ll)-dibromide (NiBr 2 bipy) (67 mg, 0.17885mmol). TFA (1 -2 drops) was added. The reaction mixture was stirred for 36 h at 60 °C. After cooling down to room temperature, the mixture was hydrolyzed by 1 N HCI and extracted with diethyl ether. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by CC. Ethyl 2-(4-(methylsulfonamidomethyl)phenyl)propanoate (325 mg) was obtained.
  • Step 3 To a stirred solution of ethyl 2-(4-(methylsulfonamidomethyl)phenyl)propanoate (325 mg, 1 .139 mmol) in a co-solvent of THF and water (1 :1 ) was added sodium hydroxide (1 14 mg, 2.8475 mmol). The reaction mixture was refluxed for 16 h, then cooled to room temperature, acidified to pH 3-4 with AcOH. The residue dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent removed in vacuo. The crude was purified by CC. 2-(4-(methylsulfonamidomethyl)phenyl)propanoic acid (74 mg) was obtained in 25 % yield.
  • Step 4 To a stirred solution of 2-(4-(methylsulfonamidomethyl)phenyl)propanoic acid (37 mg, 0.144 mmol) and (1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine (44 mg, 0.158 mmol) in acetonitrile were added EDC (41 mg, 0.216 mmol), HOBt (29 mg, 0.216 mmol) and triethylamine (0.05 mL, 0.36 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in EtOAc and washed with water and brine.
  • Example compound B5 (62 mg) was obtained in 84 % yield.
  • H NMR 300 MHz, CDCI 3 ): ⁇ 7.35 (m, 8H), 6.35 (s, 1 H), 5.56 (t, 1 H), 4.5 (m, 3H), 4.32 (d, 2H), 3.53 (q, 1 H), 2.94 (s, 3H), 1 .50 (d, 3H).
  • Step 1 4-Bromo-2-fluorobenzylamine (924 mg, 4.53 mmol) was dissolved in pyridine and ethane sulfonyl chloride (0.82 mL, 8.60 mmol) was added to the solution at O 'C. The mixture was stirred for 1 h at O 'C. Then, the mixture was quenched with 1 N HCI and extracted with ethyl acetate (EtOAc).
  • Step 2 To a solution of N-(4-bromo-2-fluorobenzyl)ethanesulfonamide (305 mg, 1 .03 mmol) in DMF, manganese (1 13 mg, 2.06 mmol), NiBr 2 bipy (27 mg, 0.07 mmol), ethyl-2-chloro propionate (0.17 ml, 1 .34 mmol) was added, followed by addition of TFA (0.002 ml, 0.028 mmol). The mixture was stirred for 1 day at 65 ° C. The reaction mixture was quenched by cone. HCI (7-drops) and then extracted with diethyl ether, dried (MgS0 4 ) and the solvent was evaporated in vacuo.
  • Step 3 To a solution of ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate (305 mg, 1 .03 mmol) in DMF, manganese (1 13 mg, 2.06 mmol), NiBr 2 bipy (27 mg, 0.07 mmol), ethyl-2-chloro propionate (0.17 mL, 1 .34 mmol) was added, followed by addition of TFA (0.002 mL, 0.028 mmol). The mixture was stirred for 1 day at 65 ° C. The reaction mixture was quenched by cone.
  • Step 4 2-(4-(ethyl-sulfonamidomethyl)-3-fluorophenyl)propanoic acid (60 mg, 0.207 mmol) and (1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine (63 mg, 0.228 mmol) were dissolved and mixed in 1 ,4-dioxane followed by addition of HOBt (42 mg, 0.310 mmol) and EDC (60 mg, 0.313 mmol) and TEA (0.07 mL, 0.518 mmol). The reaction mixture was stirred for overnight and then quenched by water and extracted with EtOAc.
  • Step 1 To a stirred solution of 1 (3 g, 16.078 mmol) in methanol (35 mL) was added sulfuric acid (0.3 mL). The reaction mixture was refluxed for 15 h and cooled to room temperature. The solvent was evaporated. The residue was dissolved in EtOAc and extracted with a sat. solution of NaHC0 3 . The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by CC. 2 (3.557 g) was obtained in 99 % yield.
  • Step 2 To a stirred solution of 2 (3.557 g, 17.73 mmol) and TEA (2.5 mL, 17.73 mmol) in dichloromethane, triflic anhydride (3 mL, 17.73 mmol) is added dropwise at O 'C. The reaction mixture was stirred for 2 h. The residue was extracted with CH 2 CI 2 and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by CC. 3 (5.15 g) was obtained in 87 % yield.
  • Step 3 To a stirred solution of 3 (4.419 g, 13.283 mmol) in DMF were added zinc(ll) cyanide (1 .6 g, 13.681 mmol) and Pd(PPh 3 ) 4 (1 .5 g, 1 .3283 mmol). The reaction mixture was stirred for 34 hours at 80 °C, then cooled to room temperature and diluted with EtOAc. The mixture was filtered using a celite pad. The filtrate was diluted with EtOAc and extracted with a sat. solution of NaHC0 3 . The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 4 (1 .044 g) was obtained in 37 % yield.
  • Step 4 To a stirred solution of 4 (931 mg, 4.441 mmol) in DMF were added sodium hydride (60 wt.-% in mineral oil, 178 mg, 4.441 mmol) and iodomethane (0.3 ml, 4.441 mmol) at 0 ° C. The reaction mixture was stirred for 1 hour at ⁇ ' ⁇ , then diluted with water. The residue dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 5 (642 mg) was obtained in 65 % yield.
  • Step 5 To a stirred solution of 5 (642 mg, 2.870 mmol) in a co-solvent of THF and water (1 :1 ) was added sodium hydroxide (287 mg, 7.175 mmol). The reaction mixture was stirred for 15 hours at room temperature, then acidified to pH 3-4 with AcOH. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 6 (665 mg) was obtained in 99 % yield.
  • Step 6 To a stirred solution of 6 (224 mg, 1 .069 mmol) and 7 (324 mg, 1 .175 mmol) in acetonitrile were added EDC (307 mg, 1 .064 mmol), HOBt (217 mg, 1 .064 mmol) and triethylamine (0.4 ml_, 2.673 mmol). The reaction mixture was stirred for 15 hours at room temperature. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 8 (366 mg) was obtained in 78 % yield.
  • Step 7 To a stirred solution of 8 (366 mg, 1 .460 mmol) in methanol, cooled to 0°C, were added Boc 2 0 (342 mg, 1 .566 mmol) and NiCI 2 -6H 2 0 (19 mg, 0.0783 mmol). NaBH 4 (207 mg, 5.481 mmol) was then added in small portions. The reaction was exothermic and
  • Step 8 To a stirred solution of 9 (227 mg, 0.397 mmol) in dichloromethane (4 mL), cooled to 0°C, were added trifluoroacetic acid (2 mL). The resulting reaction mixture was stirred for 1 hour at 0°C and 1 hour at room temperature, then basified to pH 8-9 with aq. NaHC0 3 . The mixture was filtered using a celite pad. The filtrate was dissolved in dichloromethane and extracted with a sat. solution of NaHC0 3 . The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 10 (1 16 mg) was obtained in 62 % yield.
  • Step 9 To a stirred solution of 10 (1 16 mg, 0.246 mmol) in pyridine, cooled to ⁇ ' ⁇ , was added methanesulfonyl chloride (1 16 mg). The resulting reaction mixture was stirred for 15 hours at room temperature. The mixture dissolved in dichloromethane and washed with 1 N HCI. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 11 (108 mg) was obtained as 80 % yield.
  • Step 1 To a stirred solution of 1 (299 mg, 1 .952 mmol) in dichloromethane was added triethylamine (0.3 ml, 2.147 mmol). Methanesulfonyl chloride (0.18 ml, 2.343 mmol) is added dropwise at ⁇ ' ⁇ . The reaction mixture was heated to 80 °C and stirred for 4 hours, then cooled to room temperature, and diluted with dichloromethane. The mixture was washed with water. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 2 (333 mg) was obtained in 74 % yield.
  • Step 2 To a stirred solution of 2 (333 mg, 1 .440 mmol) in DMF was added potassium phthallimide (293 mg, 1 .584 mmol). The reaction mixture was stirred for 16 hours. The mixture was dissolved in EtOAc, washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent removed in vacuo. The crude was purified by column chromatography. 3 (535 mg) was obtained as a crude.
  • Step 3 To a stirred solution of 3 (218 mg, 0.772 mmol) in THF were added hydrazine monohydrate (246 mg, 3.089 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.0772 mmol). The reaction mixture was stirred for 4 hours at ⁇ ' ⁇ , then cooled to room
  • Step 4 To a stirred solution of 4 (46 mg, 0.302 mmol) in pyridine, cooled to 0 ° C, was added methanesulfonyl chloride (46 mg). The resulting reaction mixture was stirred for 1 hour at room temperature. The mixture dissolved in dichloromethane and washed with 1 N HCI. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 5 (43 mg) was obtained in 62 % yield.
  • Step 5 To a stirred solution of 5 (43 mg, 0.188 mmol) in EtOAc was added 10 % palladium on carbon (5 mg). The mixture was charged with a H 2 (gas) balloon. The resulting mixture was stirred for 3 hours, then filtered over celite. The solvent was removed in vacuo. The crude was purified by column chromatography. 6 (41 mg) was obtained in 99 % yield.
  • Step 6 To a stirred solution of 6 (41 mg, 0.204 mmol) in tetrahydrofuran and acetonitrile as co-solvent were added phenylchloroformate (34 mg, 0.2142 mmol) and pyridine (0.02 ml_, 0.2448 mmol). The reaction mixture was stirred for 3 hours at room temperature. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 7 (54 mg) was obtained in 83 % yield.
  • Step 7 To a stirred solution of 7 (28 mg, 0.087 mmol) and 8 (23 mg, 0.087 mmol) in acetonitrile was added DMAP (1 1 mg, 0.087 mmol). The reaction mixture was stirred for 15 hours at 50 °C. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 9 (example compound B28) (32 mg) was obtained in 75 % yield.
  • Step 1 Commercially available (4-bromo-2-fluorophenyl)methanamine is stirred in pyridine and methanesulfonyl chloride (1 .9 eq.) is added drop-wise at 0°C. The reaction mixture is stirred at room-temperature for 1 h. The reaction is quenched with 1 N HCI and extracted with EtOAc. The organic layer is dried over by MgS0 4 and the solvent evaporated. The crude is purified by column chromatography and 1 obtained.
  • Step 2 Compound 1 is dissolved in anhydrous DMF and charged with N 2 .
  • Commercially available rthyl-2-chloro propionate (1 .3 eq.) is added dropwise and manganese (2 eq.), NiBr 2 bipy (0.1 equiv.) are added followed by TFA (0.026 eq.).
  • the reaction mixture is refluxed overnight.
  • the reaction mixture is warmed to ambient temperature.
  • the reaction is quenched with 1 N HCI and the organic layer is extracted with diethyl ether.
  • the extracted organic layer is dried over MgS0 4 , and concentrated into compound 2 that is used in the next step without further purification.
  • Step 3 Crude compound 2 is stirred in acetone at 0°C, and K 2 C0 3 (1 .5 eq.) is added. Methyl iodide (3 eq.) is added drop-wise and the reaction mixture is refluxed. After 15 h, the reaction mixture is quenched with water and extracted with EtOAc. The organic layer is dried over MgS0 4 and concentrated. The crude is purified by column chromatography and obtained as desired product 3.
  • Step 4 To a solution of compound 3 in THF and water (1 :1 ) was added NaOH (2.5 equiv.) and the resulting mixture was stirred at room temperature. After 15 hours, the reaction mixture was acidified with AcOH acid to a pH of 2-3. The mixture is extracted with DCM and water. The organic layer was washed with water, dried (MgS0 4 ) and concentrated in vacuo. The product was purified by column chromatography and the desired product 4 was obtained.
  • Step 5 To a solution of the carboxylic acid (4) in 1 ,4-dioxane was added EDC (1 .5 eq.), HOBt (1 .5 eq.), and (1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine (1 eq.) and dropwise TEA (2.5 eq.). The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extracted organic layer was dried over MgS0 4 . Evaporation of the solvent followed by column chromatographic purification (EtOAc/n-hexane) afforded example compound B29.
  • Step 1 To a stirred solution of 1 (1.993 g, 12.847 mmol) in carbon tetrachloride were added benzoyl peroxide (497 mg, 1 .2847 mmol) and N-bromosuccinimide (2.972 g, 16.701 mmol). The reaction mixture was refluxed for 18 h, then cooled to room temperature. The mixture was diluted with EtOAc, then washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 2 (780 mg) was obtained in 26 % yield.
  • Step 2 To a stirred solution of 2 (780 mg, 3.333 mmol) in DMF was added potassium phthallimide (1 .235 g, 6.666 mmol). The reaction mixture was stirred for 18 h. The mixture was dissolved in EtOAc, washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 3 (1 .034 g) was obtained as crude.
  • Step 3 To a stirred solution of 3 (1.034 g, 3.444 mmol) in THF were added hydrazine monohydrate (1 .104 g, 13.776 mmol) and p-toluenesulfonic acid monohydrate (66 mg, 0.3444 mmol). The reaction mixture was refluxed for 6 hours, then cooled to room
  • Step 4 To a stirred solution of 4 (131 mg, 0.770 mmol) in pyridine, cooled to 0°C, was added methanesulfonyl chloride (131 mg). The resulting reaction mixture was stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane and washed with 1 N HCI. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 5 (173 mg) was obtained in 91 % yield.
  • Step 5 To a stirred solution of 5 (187 mg, 0.753 mmol) in tetrahydrofuran and ethanol as co- solvent were added 10 % palladium on carbon (20 mg). The mixture was charged with H 2 (gas) balloon. The resulting mixture was stirred for 15 hours, then filtered using celite. The solvent was removed in vacuo. The crude was purified by column chromatography. 6 (135 mg) was obtained in 82 % yield.
  • Step 6 To a stirred solution of 6 (135 mg, 0.618 mmol) in tetrahydrofuran and acetonitrile as co-solvent were added phenylchloroformate (0.08 ml_, 0.6489 mmol) and pyridine (0.06 ml_, 0.7416 mmol). The reaction mixture was stirred for 1 hour at room temperature. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 7 (140 mg) was obtained in 67 % yield.
  • Step 7 To a stirred solution of 7 (46 mg, 0.136 mmol) and 8 (36 mg, 0.136 mmol) in acetonitrile was added DMAP (17 mg, 0.136 mmol). The reaction mixture was stirred for 15 hours at 50 ° C. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 9 (72 mg) was obtained in 99 % yield.
  • Step 1 NBS (1 .51 g, 8.509 mmol) was added to a solution of 4-nitro-toluene 1 (1 .2 g, 7.735 mmol) in carbon tetrachloride. 70% Benzoyl peroxide (120 mg) was added to the mixture at room temperature. The mixture was refluxed. After 24 h, the mixture was extracted with ethyl acetate (EtOAc). Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 2 in pure form in 61 % yield.
  • EtOAc ethyl acetate
  • Step 2 To a solution of compound 2 (1 .1 g , 4.69 mmol) in DMF, potassium phthalimide(1 .9 g, 10.314 mmol) was added. The mixture was stirred overnight and then extracted with EtOAc and washed by brine. Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 3 in pure form in 99 % yield.
  • Step 3 To a solution of compound 3 (1 .6 g, 5.33 mmol) in THF, hydrazine monohydrate (4 eq) was added. The mixture was refluxed for 6 hours and cooled to RT. The mixture was treated with potassium bicarbonate to a pH of 12-13. The mixture was extracted with EtOAc and washed by brine. Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 4 in pure form in 65 % yield (592 mg).
  • Step 4 Chlorosulfonyl isocyanate (0.063 ml_) and t-BuOH (0.07 ml_) were mixed in DCM. After 10 minutes, a solution of compound 4 (100 mg, 0.657 mmol) in DCM was added at 50 'C. After stirring for 30 min. the mixture was cooled to room temperature and then TEA (0.1 1 ml_) was added and the mixture was stirred for 3 hours and then extracted with EtOAc and washed by brine.
  • TEA 0.1 1 ml_
  • Step 5 10% Palladium on carbon (7 mg) was added to a solution of compound 5 (65 mg) in ethanol and THF and the mixture was charged with H 2 (g). After stirring the reaction mixture for 6 h, the mixture was filtered using Celite and the solvent evaporated in vacuo to give the compound 6 in pure form in 58 % yield (98 mg).
  • Step 6 Compound 6 (86 mg, 0.285 mmol) was dissolved in THF/acetonitrile. Pyridine (0.03 ml_, 0.342 mmol) was added and then it addition of phenylchloroformate (0.04 ml, 0.300 mmol) at O 'C followed. The mixture was stirred at 0°C for 30 min and heated up to room temperature and then it was stirred for 30 min. After that, it was extracted with EtOAc and washed by brine.
  • Step 7 Compound 7 (58 mg, 0.138 mmol) was dissolved in MeCN. Compound 8 (38 mg, 0.138 mmol) and DMAP (16 mg) were added to the solution. The reaction mixture was stirred overnight at 50 °C. The mixture was extracted with EtOAc and washed by brine. Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 9 in pure form in 50 % yield (60 mg).
  • Step 8 To a solution of compound 9 (80 mg, 0.133 mmol) in DCM (6 ml_), TFA (2 ml_) is added at 0 °C. The mixture was stirred for 30 min and stirred for 2 hr more at room temperature. The mixture was neutralized with sodium bicarbonate to a pH of 7-8 and then extracted with EtOAc and washed by brine. Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 10 in pure form in 75 % yield (50 mg).
  • Step 4 Compound 4 (100 mg, 0.588 mmol) was dissolved in DCM. At 0°C, Boc 2 0 (154 mg, 0.705 mmol) was added to the solution. After stirring for 30 min, the mixture was heated to room temperature and then TEA (0.13 ml) was added and the mixture was stirred overnight. And then it was extracted with EtOAc and washed by brine. Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 5 in pure form in 86 % yield (136 mg).
  • Step 5 10% Palladium on carbon (20 mg) was added to a solution of compound 5 (136 mg) in ethanol and THF and the mixture was charged with H 2 (g). After stirring the reaction mixture for 6 h, the mixture was filtered using Celite and the solvent was evaporated in vacuo. Compound 6 was obtained in 85% (103 mg).
  • Step 6 Compound 6 (103 mg, 0.429 mmol) was dissolved in THF/MeCN. Pyridine (0.04 mL, 0.515 mmol) was added and then addition of phenylchloroformate (0.06 mL, 0.450 mmol) at O 'C was followed. The mixture was stirred at 0°C for 30 min and heated up to room temperature and then it was stirred for another 30 min. After that, it was extracted with EtOAc and washed by brine.
  • Step 7 Compound 7 (70 mg, 0.194 mmol) was dissolved in MeCN.
  • Compound 8 52 mg, 0.137 mmol
  • DMAP 24 mg
  • the reaction mixture was stirred overnight at 50 °C.
  • the mixture was extracted with EtOAc and washed by brine. Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 9 in pure form in 97 % yield (100 mg).
  • Step 8 To a solution of compound 9 (100 mg, 0.189 mmol) in DCM (6 mL), TFA (2 mL) is added at O 'C and the mixture was stirred for 30 min and stirred for 2 h more at room temperature. The mixture was neutralized with sodium bicarbonate to a pH of 7-8 and then extracted with EtOAc and washed by brine. Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 10 in pure form in 74 % yield (60 mg).
  • Step 4 Chlorosulfonyl isocyanate (0.1 mL) and t-BuOH (0.12 mL) were mixed in DCM. After 10 minutes, a solution of compound 4 (200 mg, 1 .176 mmol) in DCM was added at 50 'C. After stirring for 30 min. the mixture was cooled to room temperature and then TEA (0.1 1 mL) was added and the mixture was stirred for 3 hours and then extracted with EtOAc and washed by brine.
  • TEA 0.1 1 mL
  • Step 5 10% Palladium on carbon (42 mg) was added to a solution of compound 5 (135 mg) in ethanol and THF and the mixture was charged with H 2 (g). After stirring the reaction mixture for 6 h, the mixture was filtered using Celite and the solvent evaporated in vacuo to give the compound 6 in pure form in 99 % yield (127 mg).
  • Step 6 Compound 6 (127 mg, 0.398 mmol) was dissolved in THF/acetonitrile. Pyridine (0.04 ml, 0.478 mmol) was added and then addition of phenylchloroformate (0.05 mL, 0.418 mmol) at O 'C followed. The mixture was stirred at O'C for 30 min and heated up to room
  • Step 7 Compound 7 (50 mg, 0.1 14 mmol) was dissolved in MeCN.
  • Compound 8 (30 mg, 0.1 14 mmol) and DMAP (14 mg) were added to the solution.
  • the reaction mixture was stirred overnight at 50 °C.
  • the mixture was extracted with EtOAc and washed by brine. Drying (MgS0 4 ) and evaporation of the ethyl acetate followed and the residue was purified by column chromatography (EtOAc/n-hexane) to give the compound 9 in pure form in 65 % yield (45 mg).
  • Step 8 To a solution of compound 9 (45 mg, 0.074 mmol) in DCM (6 mL), TFA (2 mL) is added at 0 °C. The mixture was stirred for 30 min and stirred for 2 h more at room
  • Step 1 To a stirred solution of 2-(3-Fluoro-4-nitro-phenyl)-propionic acid in methanol was added sulfuric acid (0.3 mL). The reaction mixture was refluxed for 15 h and cooled to room temperature. The solvent was evaporated. The residue was dissolved in EtOAc and extracted with a sat. solution of NaHC0 3 . The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by CC. 1 was obtained.
  • Step 2 10% Palladium on carbon was added to a solution of ethyl ester (1 ) in ethanol and THF and the mixture was charged with H 2 (g). After stirring the reaction mixture for 6 h, the mixture was filtered using Celite and purified by column chromatography to obtain 2.
  • Step 3 A solution of p-TsOH.H 2 0 (3 equiv.) in CH 3 CN was added to a solution of 2 (1 eq.) in CH 3 CN. The resulting suspension was cooled to 10-15 °C and to this was added, gradually, a solution of NaN0 2 (2 eq.) and Kl (2.5 eq.) in H 2 0.
  • Step 4 Compound 3, Pd 2 (dba) 3 , dppf, Zn powder, Zn(CN) 2 were placed in round flask charged with N 2 and DMA (0.02 equiv.) was added dropwise by syringe. The reaction mixture was stirred at 120 ⁇ for 15 hours and cooled to room temperature followed by extraction with EtOAc and washing with a 2N NH 4 OH solution. The organic layer was washed with water, dried (Na 2 S0 4 ) and concentrated in vacuo. The residue was purified on CC to give the desired product 4.
  • Step 6 EDC (1 .5 equiv), HOBt (1 .5 equiv), and (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5- yl)methanamine (1 eq.) are added to a solution of (5) and then added drop-wise is TEA (2.5 ml_). The reaction mixture is stirred overnight at room temperature. The reaction is quenched with water and extracted with ethyl acetate. The extracted organic layer is dried over MgS0 4 . After evaporation of the solvent, the residue is purified by column chromatographic purification (eluent EtOAc:n-hexane) and 6 is obtained.
  • EtOAc eluent EtOAc:n-hexane
  • Step 7 Nickel(ll) chloride hexahydrate (1 eq.) and compound 6 are stirred in anhydrous ethanol during 15 minute for activation. Sodium borohydride (7 eq.) is added the mixture stirred for 2 h. Celite was added to the reaction and it was filtered by using a celite packed filter, and washing with ethanol was performe. The residue is purified after concentration to obtain 7.
  • DCM:MeOH 4:1
  • Steps 1-7 are performed as described for the synthesis of example B63
  • Step 8 Sodium cyanoborohydrid is added to a solution of compound 7 and
  • Step 1 To a stirred solution of 1 (300 mg, 1 .683 mmol) in THF were added borane methyl sulfide complex (2M in THF) (1 .4 mL, 2.83 mmol) at room temperature. The reaction mixture was stirred for 16 h at 66 °C, then cooled to room temperature. The residue was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 2 (270 mg) was obtained as 68 % yield.
  • 2M in THF borane methyl sulfide complex
  • Step 2 To a stirred solution of 2 (190 mg, 1 .04 mmol) in pyridine was added
  • Step 3 To a stirred solution of 3 (205 mg, 0.79 mmol) in tetrahydrofuran and ethanol as co- solvent was added 10 % palladium on carbon (21 mg). The mixture was charged with H 2 (gas) balloon. The resulting mixture was stirred for 16 h, then filtered using celite. The filtrate removed in vacuo. The filtrate removed in vacuo. The crude was purified by column chromatography. 4 (190 mg) was obtained as 99 % yield.
  • Step 4 To a stirred solution of 4 (190 mg, 0.83 mmol) in THF (6 ml_) and CH 3 CN (8 ml_) as co-solvent were added phenyl chloroformate (0.1 1 ml_, 0.866 mmol) and pyridine (0.08 ml_, 0.99 mmol). The reaction mixture was stirred for 3 h at room temperature. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 5 (238 mg) was obtained as 82 % yield.
  • Step 5 To a stirred solution of 5 (79 mg, 0.225 mmol) in MeCN and 6 (57 mg, 0.225 mmol) were added DMAP (28 mg, 0.225 mmol). The reaction mixture was stirred for 16 hours at 50 ' ⁇ . The residue dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgS0 4 ) and filtered. The solvent was removed in vacuo. The crude was purified by column chromatography. 7 (104 mg) was obtained as 90 % yield.
  • Steps 1-5 are performed as described for the synthesis of example B63
  • Step 6 EDC (1 .5 equiv), HOBt (1 .5 equiv), and (1 -(3-chlorophenyl)-3-cyclopropyl-1 H- pyrazol-5-yl)methanamine (1 eq.) are added to a solution of (5) and then added drop-wise is TEA (2.5 mL). The reaction mixture is stirred overnight at room temperature. The reaction is quenched with water and extracted with ethyl acetate. The extracted organic layer is dried over MgS0 4 . After evaporation of the solvent, the residue is purified by column
  • Step 7 Nickel(ll) chloride hexahydrate (1 eq.) and compound 6 are stirred in anhydrous ethanol during 15 minute for activation. Sodium borohydride (7 eq.) is added the mixture stirred for 2 hours. Celite was added to the reaction and it was filtered by using a celite packed filter, and washing with ethanol was performed. The residue is purified after concentration to obtain 7.
  • Step 8 Compound 7 and compound 8 are dissolved in DCM. TEA (0.1 eq.) is added dropwise. The reaction mixture is stirred for 15 h at room temperature and quenched with water. The organic layer is extracted with DCM and concentrated. After purification by CC, compound 9 is obtained.
  • Step 9 TFA (12 ml_) is added to a solution of compound 9 in a solution of DCM and the reaction mixture is stirred for 4 h at room temperature. Water is added to the mixture and the separated mixture is extracted with DCM. The residue is purified after concentration by CC and compound 10 (example B95) is obtained.
  • Step 10 1 eq. of CSI (Chlorosulfonyl isocyanate) is added dropwise to a cold solution of tert- butyl alcohol (1 eq.) in anhydrous DCM. Then DMAP (2 eq.) is added. The mixture is stirred for 3 h at room temperature. The organic layer is extracted with DCM and washed with water. After column chromatography, a colorless powder (compound 8) is obtained.
  • CSI Chlorosulfonyl isocyanate
  • Step 6 EDC (1 .5 equiv), HOBt (1 .5 equiv), and (1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H- pyrazol-5-yl)methanamine (1 eq.) are added to a solution of (5) and then added drop-wise is TEA (2.5 mL). The reaction mixture is stirred overnight at room temperature. The reaction is quenched with water and extracted with ethyl acetate. The extracted organic layer is dried over MgS0 4 . After evaporation of the solvent, the residue is purified by column
  • 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.
PCT/EP2012/072141 2011-11-09 2012-11-08 Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an n-containing group as vanilloid receptor ligands WO2013068462A1 (en)

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JP2014540454A JP2014532742A (ja) 2011-11-09 2012-11-08 バニロイド受容体リガンドとしての、ｎ含有基で置換されたフェニル部分を担持する置換ピラゾリルをベースとするカルボキサミドおよび尿素誘導体
KR1020147015425A KR20140096351A (ko) 2011-11-09 2012-11-08 바닐로이드 수용체 리간드로서의 ｎ­함유 그룹으로 치환된 페닐 모이어티를 갖는 치환된 피라졸릴계 카복스아미드 및 우레아 유도체들
EP12781341.8A EP2776399A1 (en) 2011-11-09 2012-11-08 Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an n-containing group as vanilloid receptor ligands
MX2014005611A MX2014005611A (es) 2011-11-09 2012-11-08 Derivados de carboxamida y urea basados en pirazolilo, sustituidos, que contienen una porcion fenilo sustituida con un grupo que contiene n como ligandos del receptor de vanilloide.
AU2012334066A AU2012334066A1 (en) 2011-11-09 2012-11-08 Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an N-containing group as vanilloid receptor ligands
CN201280055195.9A CN103906736A (zh) 2011-11-09 2012-11-08 作为类香草素受体配体的具有被含n-基团取代的苯基基团的被取代的基于吡唑基的羧酰胺和脲衍生物
BR112014010957A BR112014010957A2 (pt) 2011-11-09 2012-11-08 derivados de ureia e carboxamida com base em pirazolila substituída transportando uma porção de fenila substituída por um grupo contendo n como ligantes de receptor de vaniloide
HK15102577.0A HK1202116A1 (en) 2011-11-09 2015-03-13 Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an -containing group as vanilloid receptor ligands

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