WO2013068464A1 - Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an so2-containing group as vanilloid receptor ligands - Google Patents

Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an so2-containing group as vanilloid receptor ligands Download PDF

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WO2013068464A1
WO2013068464A1 PCT/EP2012/072143 EP2012072143W WO2013068464A1 WO 2013068464 A1 WO2013068464 A1 WO 2013068464A1 EP 2012072143 W EP2012072143 W EP 2012072143W WO 2013068464 A1 WO2013068464 A1 WO 2013068464A1
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Prior art keywords
methyl
phenyl
fluoro
pyrazol
methylsulfonyl
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PCT/EP2012/072143
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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 HK15102581.4A priority Critical patent/HK1202117A1/xx
Priority to BR112014011108A priority patent/BR112014011108A2/pt
Priority to EP12783220.2A priority patent/EP2776401A1/en
Priority to MX2014005233A priority patent/MX2014005233A/es
Priority to AU2012334068A priority patent/AU2012334068A1/en
Priority to JP2014540456A priority patent/JP2014532744A/ja
Priority to CA2854424A priority patent/CA2854424A1/en
Priority to IN865KON2014 priority patent/IN2014KN00865A/en
Priority to CN201280055221.8A priority patent/CN104066720A/zh
Priority to KR1020147015421A priority patent/KR20140091041A/ko
Publication of WO2013068464A1 publication Critical patent/WO2013068464A1/en

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Definitions

  • the invention relates to substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with a S0 2 -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 (T), 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 (T), 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 (T),
  • R 101 , R 02 and R 03 are independently of one another selected from the group consisting of H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 -OH, CH 2 CH 2 -OH, CH 2 -OCH 3 , CH 2 CH 2 - OCH 3 , OCFH 2 , OCF 2 H, OCF 3 , OH, NH 2 , a d- 4 alkyl, an O-C1-4 alkyl, a NH-C1-4 alkyl, and a N(Ci- 4 alkyl) 2 , wherein the Ci -4 alkyl is in each case unsubstituted,
  • R 2 represents CF 3 , an unsubstituted Ci -4 alkyl or an unsubstituted C 3 - 6 cycloalkyl,
  • R 7 and R 9 are independently of one another selected from the group consisting of H, F, CI, Br, CFH 2 , CF 2 H, CF 3 , CN, OH, OCF 3 , a d- 4 alkyl, and an O-C1-4 alkyl, wherein the d- 4 alkyl is in each case unsubstituted,
  • A denotes N, CH or C(CH 3 ), t 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. d -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 are unsubstituted.
  • 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 cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, more preferably from the group consisting of cyclopropyl and cyclobutyl.
  • a particularly preferred cycloalkyl is cyclopropyl.
  • 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 (TS2) is selected from the group consisting of
  • t denotes 0, 1 or 2, preferably denotes 1 or 2, and A denotes N.
  • part structure (TS2) is selected from the group consisting of
  • N preferably is selected from the group consisting of in particular when t denotes 0, 1 or 2, preferably denotes 1 or 2, and A denotes N.
  • part structure (TS2) in another particularly preferred embodiment according to the present invention the part structure (TS2)
  • TS2 is selected from the group consisting of
  • t denotes 1 or 2, preferably denotes 1 or 2, and A denotes CH or C(CH 3 ).
  • t denotes 1 or 2, preferably denotes 1 or 2, and A denotes CH or C(CH 3 ), preferably is selected from the group consisting of in particular when t denotes 1 or 2, preferably 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 ).
  • t denotes 1 or 2.
  • t denotes 1 .
  • t denotes 2.
  • t denotes 1 or 2, 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
  • 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
  • TS1 represents the part structure (PT1 ), (PT2) or (PT3),
  • R 08 represents an unsubstituted Ci_ 4 alkyl, preferably CH 3 or CH 2 CH 3 , more preferably CH 3 .
  • the part structure (TS1 ) is a part structure (TS1 )
  • TS1 represents the part structure (PT2) or (PT3)
  • 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
  • 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 , preferably, wherein at least
  • 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 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
  • 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 (TS1 )
  • TS1 represents the part structure (PT2) or (PT3)
  • Preferred embodiments of the compound according to the invention of general formula (T) have general formulae (TO-a) and/or (TO-b):
  • preferred embodiments of the compound according to the invention of general formula (T) have general formulae (T1 -b), (T1 -b-1 ) and/or (T1 -b-2):
  • T3-a-2 wherein the particular radicals, variables and indices have the meanings described herein in connection with the compounds according to the invention and preferred embodiments thereof.
  • preferred embodiments of the compound according to the invention of general formula (T) have general formulae (T3-b), (T3-b-1 ) and/or (T3-b-2):
  • Especially preferred embodiments of the compound of the present invention have general formulae (T2-a), (T2-a-1 ), (T2-a-2), (T2-b), (T2-b-1 ) (T2-b-2), (T3-a), (T3-a-1 ), (T3-a-2), (T3- b), (T3-b-1 ) and/or (T3-b-2).
  • radical R 0 in the compound of general formula (T), (T1 -a), (T1 -a-1 ), (T1 -b), (T1 -b-1 ), (T2-a), (T2-a-1 ), (T2-b), (T2-b-1 ), (T3-a), (T3-a-1 ), (T3-b) and/or (T3-b-1 ) represents F, CI, CF 3 or O-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 (T), (T1 -a), (T1 -a-2), (T1 -b), (T1 -b-2), (T2-a), (T2-a-2), (T2-b), (T2-b-2), (T3-a), (T3-a-2), (T3-b) and/or (T3-b-2) represents F, CF 3 or 0-CH 3 , 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.
  • 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
  • the present invention therefore further relates to a pharmaceutical composition containing at least one compound according to the invention, in each case if appropriate in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and/or diastereomers, in any desired mixing ratio, or respectively in the form of a corresponding salt, or respectively in the form of a corresponding solvate, and also if appropriate one or more pharmaceutically compatible auxiliaries.
  • compositions according to the invention are suitable in particular for vanilloid receptor 1 -(VR1/TRPV1 ) regulation, preferably for vanilloid receptor 1 -(VR1/TRPV1 ) inhibition and/or for vanilloid receptor 1 -(VR1 /TRPV1 ) stimulation, i.e. they exert an agonistic or antagonistic effect.
  • compositions according to the invention are preferably suitable for the prophylaxis and/or treatment of disorders or diseases which are mediated, at least in part, by vanilloid receptors 1 .
  • the pharmaceutical composition according to the invention is suitable for administration to adults and children, including toddlers and babies.
  • the pharmaceutical composition according to the invention may be found as a liquid, semisolid or solid pharmaceutical form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and also be administered as much.
  • the pharmaceutical composition according to the invention conventionally contains further physiologically compatible pharmaceutical auxiliaries which can for example be selected from the group consisting of excipients, fillers, solvents, diluents, surface-active substances, dyes, preservatives, blasting agents, slip additives, lubricants, aromas and binders.
  • physiologically compatible auxiliaries and also the amounts thereof to be used depend on whether the pharmaceutical composition is to be applied orally, subcutaneously, parenterally, intravenously, intraperitoneal ⁇ , intradermal ⁇ , intramuscularly, intranasally, buccally, rectally or locally, for example to infections of the skin, the mucous membranes and of the eyes.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral application; solutions, suspensions, easily reconstitutable dry preparations and also sprays are preferably suitable for parenteral, topical and inhalative application.
  • substituted compounds according to the invention used in the pharmaceutical composition according to the invention in a repository in dissolved form or in a plaster, agents promoting skin penetration being added if appropriate, are suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the respective substituted compound according to the invention also in a delayed manner.
  • compositions according to the invention are prepared with the aid of conventional means, devices, methods and process known in the art, such as are described for example in exceedingRemington's Pharmaceutical Sciences", A.R. Gennaro (Editor), 17 th edition, Mack Publishing Company, Easton, Pa, 1985, in particular in Part 8, Chapters 76 to 93.
  • the corresponding description is introduced herewith by way of reference and forms part of the disclosure.
  • the amount to be administered to the patient of the respective substituted compounds according to the invention of the above-indicated general formula I may vary and is for example dependent on the patient's weight or age and also on the type of application, the indication and the severity of the disorder. Conventionally 0.001 to 100 mg/kg, preferably 0.05 to 75 mg/kg, particularly preferably 0.05 to 50 mg of at least one such compound according to the invention are applied per kg of the patient's body weight.
  • the pharmaceutical composition according to the invention is preferably suitable for the treatment and/or prophylaxis of one or more disorders and/or diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal injuries; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiency states, particularly preferably memory disorders; epilepsy; respiratory diseases, preferably selected from the group consisting of asthma, bronchitis and pulmonary inflammation; coughs; urinary incontinence; overactive bladder (OAB); disorders and/or injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoria
  • the pharmaceutical composition according to the invention is suitable for the treatment and/or prophylaxis of one or more disorders and/or diseases selected from the group consisting of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; migraine; depression; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive dysfunctions, preferably cognitive deficiency states, particularly preferably memory disorders; inflammations, preferably inflammations of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; urinary incontinence; overactive bladder (OAB); medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication, preferably development of tolerance to natural or synthetic opioids; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency.
  • the pharmaceutical composition according to the invention is suitable for the treatment and/or prophyl
  • 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 (T-ll),
  • T-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 (T-IV) is reacted with a compound of general formula (T-V),
  • T-V in which R 7 , R 9 , R 08 and t 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 (T),
  • a reaction medium preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol,
  • T-ll The compounds of the above-indicated formulae (T-ll), (T-lll), (T-IV), and (T-V) are each commercially available and/or can be prepared using conventional processes known to the person skilled in the art.
  • processes to prepare these compounds are e.g. disclosed in WO 2010/127855-A2, and WO 2010/127856-A2.
  • WO 2010/127855-A2 discloses processes to prepare these compounds.
  • WO 2010/127856-A2 The corresponding parts of these references are hereby deemed to be part of the disclosure.
  • All reactions which can be applied for synthesizing the compounds according to the present invention can each be carried out under the conventional conditions with which the person skilled in the art is familiar, for example with regard to pressure or the order in which the components are added. If appropriate, the person skilled in the art can determine the optimum procedure under the respective conditions by carrying out simple preliminary tests.
  • the intermediate and end products obtained using the reactions described hereinbefore can each be purified and/or isolated, if desired and/or required, using conventional methods known to the person skilled in the art. Suitable purifying processes are for example extraction processes and chromatographic processes such as column chromatography or preparative chromatography.
  • All of the process steps of the reaction sequences which can be applied for synthesizing the compounds according to the present invention as well as the respective purification and/or isolation of intermediate or end products, can be carried out partly or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.
  • substituted compounds according to the invention can be isolated both in the form of their free bases, and also in the form of corresponding salts, in particular physiologically acceptable salts, and further in the form of a solvate such as hydrate.
  • the free bases of the respective substituted compounds according to the invention can be converted into the corresponding salts, preferably physiologically acceptable salts, for example by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1 -sulphonic acid, nicotinic acid, 2, 3 or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, oc-lipoic acid, acetyl glycine, hippuric acid, phosphoric acid and/or aspartic acid.
  • an inorganic or organic acid preferably
  • the free bases of the respective inventive substituted compounds and of corresponding stereoisomers can likewise be converted into the corresponding physiologically acceptable salts using the free acid or a salt of a sugar additive, such as for example saccharin, cyclamate or acesulphame.
  • a sugar additive such as for example saccharin, cyclamate or acesulphame.
  • the substituted compounds according to the invention such as the free acids of the substituted compounds according to the invention can be converted into the corresponding physiologically acceptable salts by reaction with a suitable base.
  • substituted compounds according to the invention and of corresponding stereoisomers can if appropriate, like the corresponding acids, the corresponding bases or salts of these compounds, also be obtained in the form of their solvates, preferably in the form of their hydrates, using conventional methods known to the person skilled in the art.
  • substituted compounds according to the invention are obtained, after preparation thereof, in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and/or diastereomers, they can be separated and if appropriate isolated using conventional processes known to the person skilled in the art. Examples include chromatographic separating processes, in particular liquid chromatography processes under normal pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallisation processes.
  • step j01 an acid halide J-0, in which Hal preferably represents CI or Br, can be esterified using methanol to form the compound J-l by means of methods with which the person skilled in the art is familiar.
  • step j02 the methyl pivalate J-l can be converted into an oxoalkylnitrile J-l I by means of methods known to the person skilled in the art, such as for example using acetonitrile CH 3 - CN, if appropriate in the presence of a base.
  • step j03 the compound J-ll can be converted into an amino-substituted pyrazolyl derivative J-lll by means of methods known to the person skilled in the art, such as for example using hydrazine hydrate, with cyclization.
  • step j04 the amino compound J-lll can first be converted into a diazonium salt by means of methods known to the person skilled in the art, such as for example using nitrite, and the diazonium salt can be converted into a cyano-substituted pyrazolyl derivative J-IV with elimination of nitrogen using a cyanide, if appropriate in the presence of a coupling reagent.
  • step j05 the compound J-IV can be substituted in the N position by means of methods known to the person skilled in the art, for example using a halide of part structure (TS2), i.e. Hal-(TS2), 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 (TS2) 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-(TS2)
  • Hal is preferably CI, Br or I
  • a boronic acid B(OH) 2 (TS2) 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 (T-ll) can in this way be obtained.
  • a suitable catalyst such as palladium/activated carbon or using suitable hydrogenation reagents
  • step j07 the compound (T-ll) can be converted into the compound (T-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 (T-V) can be converted into the compound (T-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.
  • This can be achieved by reaction with (T-Va) by means of methods with which the person skilled in the art is familiar, if appropriate in the presence of 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.
  • Step k02 The aldehyde (K-l) (2 equivalents, 300 mL) obtained from k01 and (3- chlorophenyl)hydrazine (K-IV) (1 equivalent, 20 g) were placed in ethanol (200 mL) and refluxed for 5 h. The solvent was removed under vacuum, the residue was purified by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane) and the product (25 g, 72 %) K-ll was obtained as a brown oil.
  • Step k03 The hydrazine K-ll (1 equivalent, 25 g) was dissolved in dimethylformamide (125 mL). N-chlorosuccinimide (1 .3 equivalents, 19.5 g) was added portionwise at room temperature within 15 min and the mixture was stirred for 3 h. The dimethylformamide was removed by distillation and the residue was taken up in ethyl acetate. The ethyl acetate was removed under vacuum, the residue obtained was purified by column chromatography (silica gel: 100-200 mesh, eluent: n-hexane) and the product K-lll (26.5 g, 92 %) was obtained as a pink-coloured oil.
  • Step k04 At room temperature the hydrazonoyl chloride K-lll (1 equivalent, 10 g) was taken up in toluene (150 mL) and mixed with 2-chloroacrylonitrile (2 equivalents, 6.1 mL) and triethylamine (2 equivalents, 10.7 mL). This reaction mixture was stirred for 20 h at 80 ' ⁇ . The mixture was then diluted with water (200 mL) and the phases were separated. The organic phase was dried over magnesium sulphate and the solvent was removed under vacuum.
  • Step j06 ⁇ method 3
  • Step a To a solution of (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5-yl)methanamine (5 g, 18 mmol) in dimethylformamide (25 mL), potassium carbonate (9.16 g, 66 mmol, 3.5 eq) was added and cooled the contents to O'C. Then phenyl chloroformate (3.28 g (2.65 mL), 20 mmol, 1 .1 equivalents) was added dropwise for 15 minutes and the overall reaction mixture was stirred for another 15 minutes at 0 °C. Progress of the reaction was monitored by TLC (20 % ethyl acetate-n-hexane).
  • 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 (T-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 (T-lll) is in this way converted into the corresponding acid chloride.
  • a chlorinating agent preferably with thionyl chloride
  • the amine of general formulae (T-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 (T) is in this way obtained.
  • the exemplary compounds D1 -D10 were obtained using one of the methods described hereinbefore.
  • the exemplary compounds D1 1 -D25 can be obtained using one of the methods described hereinbefore.
  • Step j07/step v1 The amine of general formula (T-ll) or (T-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 (T-IV) or (T-Va) is in this way obtained.
  • Step j08/step v2 The carbamic acid phenyl ester (T-IV) or (T-Va) obtained (1 equivalent) and the corresponding amine (T-V) or (T-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 (T) is in this way obtained.
  • the exemplary compounds D26-D29, D31 and D33 were obtained using one of the methods described hereinbefore.
  • the exemplary compounds D30 and D32 can be prepared by using one of the methods described hereinbefore.
  • Step 1 To 2-fluorobenzenethiol (4.8 g (3.6 ml_), 0.03 mol), sodium hydroxide (1 .8 g) was added at room temperature. Dimethyl sulphide (4.7 g, 1 eq) was neutralized with potassium carbonate and added to the above contents at room temperature. The overall reaction mixture was stirred for 3 h at room temperature. Progress of the reaction was monitored by TLC (5% ethyl acetate/hexane, R f ⁇ 0.8). On completion of the reaction, cold water was added to the contents and the compound extracted with ethyl acetate (2 ⁇ 50 ml_). Combined extract was dried over sodium sulfate and concentrated under reduced pressure to (2- fluorophenyl)(methyl)sulfane as a pale blue colored liquid (5 g, crude). The crude obtained was directly used for the next step.
  • Step 2 To a solution of AICI 3 (9.2 g, 0.06 mol, 2 eq) in chloroform (50 ml_) cooled at 0 Q C, ethyl (chlorocarbonyl)formate (7.3 g, 0.05 mol, 1 .6 eq) was added drop wise and the reaction mixture was stirred for 30 ⁇ 15 min at the same temperature. (2-fluorophenyl)(methyl)sulfane (5 g, crude) was added at 0 Q C and the reaction mixture was stirred for 4 h at room temperature. Progress of the reaction was monitored by TLC (5% ethyl acetate in n-hexane, R f ⁇ 0.5).
  • Step 3 To a solution of ethyl 2-(3-fluoro-4-(methylthio)phenyl)-2-oxoacetate (5.5 g, 0.02 mol) in toluene (55 ml_, 10 times), 3 M sodium hydroxide solution (9.09 ml_) was added at 50 Q C and the reaction mixture was stirred for 3 h at the same temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, R f ⁇ 0.1 ). On completion of the reaction, the contents were cooled to 0 Q C, the mixture was acidified with diluted HCI and the solid precipitated was filtered. The crude 2-(3-fluoro-4-(methylthio)phenyl)-2-oxoacetic acid obtained as an yellow colored solid (4.5 g, crude) was directly used for the next step.
  • Step 4 2-(3-Fluoro-4-(methylthio)phenyl)-2-oxoacetic acid (4.5 g, crude) was added to hydrazine hydrate (5.1 mL, 5 eq) at -50 Q C. The contents were heated to 80 Q C, KOH (2.7 g, 2.3 eq) was added and the overall reaction mixture was stirred for 12 h at 100 Q C. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, R f ⁇ 0.8). On completion of the reaction, to the contents was added water and ethyl acetate and the layers were separated.
  • TLC 50% ethyl acetate/hexane, R f ⁇ 0.8
  • the aqueous layer was acidified with diluted HCI at 0-5 Q C, the precipitate was filtered and dried to yield 2-(3-fluoro-4-(methylthio)phenyl)acetic acid as a white colored solid (3 g, 71 %).
  • Step 5 2-(3-Fluoro-4-(methylthio)phenyl)acetic acid (3 g, 0.01 mol) was dissolved in dry THF (60 mL) and the mixture was cooled to -78 Q C. Lithium bis(trimethylsilyl)amide (45 mL, 3 eq) was added at -78 Q C and the mixture was stirred for 1 h at the same temperature. Methyl iodide (0.93 mL, 1 eq) was added at -78 Q C, the mixture was allowed to come to room temperature and stirred for 3 h at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, R f ⁇ 0.5).
  • Step 6 To a solution of 2-(3-fluoro-4-(methylthio)phenyl)propanoic acid (1 g, 0.009 mol) in acetone (10 mL), potassium carbonate (0.63 g) was added at room temperature. DMS (0.58 g, 1 eq) was neutralized with potassium carbonate and filtered. The filtered DMS was added to the above contents and the overall reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, R f ⁇ 0.9). On completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Step 7 Formic acid (6.5 mL, 1 eq) was added to methyl 2-(3-fluoro-4- (methylthio)phenyl)propanoate (1 g, crude) and the mixture cooled to 0 Q C. Hydrogen peroxide (1 .4 mL, 3 eq) was added drop wise at 0 Q C and the reaction mixture was stirred overnight at room temperature. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, R f ⁇ 0.4). On completion of the reaction, the contents were cooled to 0 Q C, water was added and the mixture was extracted with ethyl acetate (2 ⁇ 25 mL).
  • Step 8 To a solution of methyl 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoate (2.1 g, 0.008 mol) in methanol (21 mL, 10 times), a solution of sodium hydroxide (0.32 g, 1 eq) in water (3 mL) was added at 0 Q C. The contents were allowed to come to room temperature and the mixture was stirred for 2 h. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, R f ⁇ 0.1 ). On completion of the reaction, methanol was distilled off completely and the residue obtained was taken in water.
  • TLC 50% ethyl acetate/hexane, R f ⁇ 0.1
  • Step 9 To a solution of (3-tert-butyl-1 -(3-chloro-4-fluorophenyl)-1 H-pyrazol-5- yl)methanamine (49 mg, 0.189 mmol) in DCM (1 .3 mL) at room temperature and under nitrogen atmosphere was added 1 -chloro-N,N,2-trimethyl-1 -propenylamine (48 ⁇ , 0.369 mmol), After 1 h of stirring were added 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoic acid (93 mg, 0.378 mmol) and N-ethyldiisopropylamine (0.1 1 mL, 0.662 mmol).
  • Step 9 To a solution of 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoic acid (60 mg, 0.244 mmol) in THF(1 .9 ml_) was added 1 -hydroxybenzotriazole (32 mg, 0.244 mmol), 0-(1 H- benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (78 mg, 0.244 mmol), N- ethyldiisopropylamine (0.083 mL, 0.488 mmol) and (1 -(3-chlorophenyl)-3-(trifluoromethyl)- 1 H-pyrazol-5-yl)methanamine (67 mg, 0.244 mmol).
  • Step 1 To a well stirred solution of AICI 3 (16.58 g, 2 eq) in chloroform (100 mL), ethyl (chlorocarbonyl)formate (10.02 g (8.35 mL), 1 .6 eq) was added at 0°C and the contents were allowed to stir for 30 min. Then (2-chlorophenyl)(methyl)sulfane (10 g (8.33 mL), 0.06 mol) was added at 0°C and the overall reaction mass was allowed to stir for 3 - 4 h at room temperature. Progress of the reaction was monitored by TLC (5% ethyl acetate/hexane, R f ⁇ 0.3).
  • Step 2 A solution of ethyl 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetate (12 g, 0.49 mol) in toluene (120 ml_, 10 times) was heated to 50°C.
  • Step 3 To hydrazine hydrate (10 g, 5 eq) cooled at -50°C, 2-(3-chloro-4- (methylthio)phenyl)-2-oxoacetic acid (10 g, 0.04 mol) was added. The contents were initially warmed to room temperature and slowly heated to 80°C. Then KOH (5.59 g, 2.3 eq) was added portion wise at 80°C and the overall reaction mass was allowed to reflux for 12 - 16 h at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, R f ⁇ 0.4). On completion of the reaction, the reaction contents were diluted with a mixture of water and ethyl acetate.
  • Step 4 2-(3-chloro-4-(methylthio)phenyl)acetic acid (2 g, 0.009 mol) was taken in THF (20 ml_, 10 times) and cooled to -78°C. Lithium bis(trimethylsilyl)amide (27.77 mL, 3 eq) was added drop wise at -78°C and allowed to stir for 2 h at the same temperature. Then methyl iodide (1 .31 g, 1 eq) was added drop wise at -78°C and the overall reaction mass was allowed to stir for 3 h at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, R f ⁇ 0.2).
  • reaction mass was warmed to room temperature and allowed to stir for 10 h. Again TLC was monitored and still the reaction was not completed. Then the reaction contents were quenched with saturated ammonium chloride solution and acidified with diluted HCI. THF layer was separated and the aqueous layer was extracted with ethyl acetate (2 ⁇ 50 mL). The combined extract was dried over sodium sulfate, concentrated under reduced pressure and the crude obtained was purified by column chromatography (10% ethyl acetate/n-hexane) to yield 2-(3-chloro-4-(methylthio)phenyl)propanoic acid as a pale yellow colored solid (1 .2 g, 53%).
  • Step 5 To a solution of 2-(3-chloro-4-(methylthio)phenyl)propanoic acid (3.5 g, 0.015 mol) in acetone (35 ml_), potassium carbonate (2.06 g, 0.01 mol, 1 eq) was added at room temperature. DMS (1 .91 g, 1 eq) was neutralized with potassium carbonate and filtered. The filtered DMS was added to the above contents and the overall reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, R f ⁇ 0.9). On completion of the reaction, filtered the contents and the filtrate was concentrated under reduced pressure.
  • TLC 50% ethyl acetate/hexane, R f ⁇ 0.9
  • Step 6 Formic acid (20.8 ml_, 1 eq) was added to methyl 2-(3-chloro-4- (methylthio)phenyl)propanoate (3.2 g, crude) and cooled to 0 Q C. Hydrogen peroxide (4.48 ml_, 3 eq) was added drop wise at 0 Q C and the reaction mass was stirred for overnight at room temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, R f ⁇ 0.3). On completion of the reaction, the contents were cooled to 0 Q C, water was added and the mixture was extracted with ethyl acetate (2 ⁇ 100 ml_).
  • Step 7 To a solution of methyl 2-(3-chloro-4-(methylsulfonyl)phenyl)propanoate (3.2 g, crude) in methanol (32 ml_, 10 times), a solution of sodium hydroxide (0.46 g, 1 eq) in water (5 ml_) was added at 0 Q C. The contents were warmed to room temperature and allowed to stir for 2 h. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Ptf ⁇ 0.1 ). On completion of the reaction, methanol was distilled off completely and the residue obtained was taken in water.
  • Step 8 To a solution of 2-(3-chloro-4-(methylsulfonyl)phenyl)propanoic acid (60 mg, 0.229 mmol) in THF (1 .9 mL) was added 1 -hydroxybenzotriazole (30 mg, 0.229 mmol), 0-(1 H- benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (74 mg, 0.229 mmol), N- ethyldiisopropylamine (0.078 mL, 0.458 mmol) and (1 -(3-chlorophenyl)-3-(trifluoromethyl)- 1 H-pyrazol-5-yl)methanamine (63 mg, 0.229 mmol).
  • Step 1 To a stirred solution of 4-bromo-2-fluoro-1 -(methylsulfonylmethyl)benzene ( 2 g, 7.487 mmol) in dimethylformamide (1 1 mL) were added ethyl 2-chloropropionate (1 .24 ml_,9.733 mmol), manganese (822 mg, 14.974 mmol) and (2,2'-bipyridine)nickel(ll)- dibromide (196 mg, 0.524 mmol). Trifluoroacetic acid (4 drops) was added. The reaction mixture was stirred overnight at 60 ° C.
  • Step 3 To a stirred solution of 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoic acid (68 mg, 0.231 mmol) and (1 -(3-chlorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methanamine (60 mg, 0.231 mmol) in THF (1 .8 mL) were added 0-(1 H-Benzotriazol-1 -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium tetrafluorborat (73 mg, 0.231 mmol), 1 -hydroxybenzotriazole (30 mg, 0.231 mmol) and N-ethyldiisopropylamine (0.078
  • Exemplary compound D10 was prepared analogously according to D6.
  • Step 3 To a stirred solution of 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)propanoic acid (60 mg, 0.231 mmol) and (3-tert-butyl-1 -(3-chlorophenyl)-1 H-pyrazol-5-yl)methanamine (60 mg, 0.231 mmol) in THF (1 .8 mL) were added 0-(1 H-benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluorborat (73 mg, 0.231 mmol), 1 -hydroxybenzotriazole (30 mg, 0.231 mmol) and N-ethyldiisopropylamine (0.078 mL, 0.462 mmol).
  • Step 1 DMAP (4.25 g, 34 mmol) was added to DCM (3 L) and the contents were cooled to -l O ⁇ . Trifluoroacetic anhydride (765 g , 3.2 mol) was added followed by ethyl vinyl ether (250 g, 3.04 mol) which was added drop wise for 45 min at - 10°C. Then the overall reaction mixture was stirred for 8 h at 0°C and later overnight at room temperature. Progress of the reaction was monitored by TLC (10% ethyl acetate/hexane, R f ⁇ 0.7). On completion of the reaction, the reaction contents were treated with saturated NaHC0 3 solution (600 mL) and the organic layer was separated.
  • Step 2 Hydrazine dihydrochloride (225 g, 2.14 mol) in ethanol (1400 mL) was stirred well. TEA (185.4 mL, 1 .34 mol) was added drop wise for 45 min at ambient temperature. Then (E)-4-ethoxy-1 ,1 ,1 -trifluorobut-3-en-2-one (225 g, crude) was added drop wise at room temperature and the overall reaction mixture was refluxed overnight. Progress of the reaction was monitored by TLC (20 % ethyl acetate/hexane, Rf ⁇ 0.4).
  • Step 3 NaH (33.08 g (19.85 mol, 60 %) was washed with n-hexane, then dry DMF (500 mL) was added drop wise under N 2 atmosphere and the mixture was stirred well. A solution of 3- (trif luoromethyl)- 1 H-pyrazole (75 g, 0.55 mol) in DMF (125 mL) was added drop wise under N 2 atmosphere. Then a solution of 4-methoxylbenzyl chloride (86.3 g, 0.55 mol) in DMF (125 mL) was added drop wise and the overall reaction mixture was allowed to stir for 12 h at room temperature.
  • the obtained crude was purified by CC with 10% ethyl acetate/n-hexane to yield 1 -(4-methoxybenzyl)-3-(trifluoromethyl)-1 H- pyrazole as a brown colored liquid (98 g, 70 %).
  • Step 4 Diisopropyl amine (28.4 mol, 39.4 mL) was taken in THF (500 mL), stirred well and cooled to 0°C. n-BuLi (234.4 mL) was added drop wise at O 'C and the mixture was stirred for 1 h at 0°C. Then the contents were cooled to -78 ⁇ , a solution of 1 -(4-methoxybenzyl)-3- (trif luoromethyl)- 1 H-pyrazole (62 g, 0.24 mol) in THF (200 mL) was added drop wise for 30 min and the contents were stirred for another h at -78 ⁇ .
  • Step 5 To a solution of 1 -(4-methoxybenzyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxylic acid (50 g, 0.16 mol) in DCM (750 mL), a catalytic amount of DMF was added and the mixture was cooled to ⁇ ' ⁇ . Thionyl chloride (61 mL, 0.83 mol) was added drop wise for 30 min at ⁇ ' ⁇ . The overall reaction mixture was heated to reflux and maintained for 2 h. Progress of the reaction was monitored by TLC (10 % ethyl acetate/hexane, R f ⁇ 0.4). On disappearance of the starting material, DCM was distilled off completely.
  • Step 6 LAH (4.7 g, 0.12 mol) was charged into a flask. THF (250 mL) was added at 0°C. Then a solution of 1 -(4-methoxybenzyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (37 g, 0.12 mol) in THF (120 mL) was added drop wise for 30 min at ⁇ ' ⁇ and reaction mixture was heated to reflux for 5 h. Progress of the reaction was monitored by TLC (50 % ethyl acetate/hexane, R f ⁇ 0.2). As the reaction was not completd, LAH (2.3 g) was added again and the mixture was refluxed for another 4 h.
  • Step 7 To a solution of (1 -(4-methoxybenzyl)-3-(trifluoromethyl)-1 H-pyrazol-5- yl)methanamine (80 g, 0.28 mol) in DCM (600 mL) cooled at 0°C, TEA (30.2 mL, 0.026 mol) was added drop wise for 10 min. Then Boc anhydride (62.5 mL, 0.28 mol) was added drop wise for 20 - 30 min at 0°C. The overall reaction mixture was stirred for 30 min at 0°C and stirred for 1 h at room temperature. Progress of the reaction was monitored by TLC (20 % ethyl acetate/hexane, R f ⁇ 0.6).
  • Step 8 To a stirred solution of tert-butyl (1 -(4-methoxybenzyl)-3-(trifluoromethyl)-1 H-pyrazol- 5-yl)methylcarbamate (20 g, 0.052 mol) in toluene (300 ml_) cooled to 0°C was added aluminum chloride (17.34 g, 0.129 mol) portion wise for 30 min. The reaction mixture was slowly heated to 50 - 60 °C and allowed to stir for 2 h at the same temperature. Progress of the reaction was monitored by TLC (20 % ethyl acetate/hexane, R f ⁇ 0.1 ).
  • Step 9 (3-(Trifluoromethyl)-1 H-pyrazol-5-yl)methanamine (7 g, 42.4 mmol) was dissolved in DCM (7 mL) at room temperature, then to that TEA (5.86 mL, 72.4 mmol ) was added at room temperature and the mixture was stirred for 10 min and cooled to 0-5 'C.
  • (Boc) 2 0 (9.24 g, 42.4 mmol) was added drop wise to reaction mixture for 30 min and maintained for 3 h at 0-5 °C. Progress of the reaction was monitored by the TLC (30 % ethyl acetate/n-hexane).
  • Step 10 To a stirred solution of tert-butyl (3-(trifluoromethyl)-1 H-pyrazol-5-yl)methyl- carbamate (5 g, 18.8 mmol) in MeOH (36 mL) was added HCI in 2-propanol (5.8 mL, 29.2 mmol) and the mixture was stirred for 48 h at room temperature. The reaction mixture was concentrated in vacuo, diethylether (20 mL) was added and the obtained precipitate filtered off and washed with diethylether (5 ml_). After drying (3-(trifluoromethyl)-1 H-pyrazol-5- yl)methanamine hydrochloride was obtained (3.67 g, 97 %).
  • Step 11 To a stirred solution of (3-(trifluoromethyl)-1 H-pyrazol-5-yl)methanamine
  • Step 12 4-Fluorophenylboronic acid (41 mg, 0.295 mmol), 2-(3-fluoro-4- (methylsulfonylmethyl)phenyl)-N-((3-(trifluoromethyl)-1 H-pyrazol-5-yl)methyl)propanamide (60 mg, 0.147 mmol) and copper(ll)-acetate (0.021 ml_, 0.221 mmol) were added to DCM (2.2 ml_). At room temperature was added pyridine (0.238 ml_, 2.946 mmol) and the mixture was stirred for overnight.
  • Exemplary compounds D14, D15, D22 and D25 were prepared in a similar manner or may be prepared analogously according to D12.
  • Step 1 To a stirred solution of 2-(2-fluoro-4-nitrophenyl)acetic acid (1 g, 5.02 mmol) in tetrahydrofuran (10 mL) was added BH 3 » S(CH 3 ) 2 (7.5 mL, 7.53 mmol) at 0 ° C. The reaction mixture was allowed to stir at room temperature for 10 h. Then reaction mixture was cooled to 0 ° C and the excess of borane was quenched with methanol (10 mL).
  • Step 2 2-(2-Fluoro-4-nitrophenyl)ethanol (0.89 g, 4.8 mmol) was added to a stirred solution of 48% aqueous hydrobromic acid (0.77g, 9.62 mmol) and concentrated sulfuric acid (0.25 mL) under cooling. The reaction mixture was heated to l OO'C for 3 h. The reaction mixture was diluted with water (25 mL) and was extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with brine (25 mL) and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the crude compound.
  • Step 3 To a stirred solution of 1 -(2-bromoethyl)-2-fluoro-4-nitrobenzene (1 g, 4.03 mmol) in isopropanol (15 mL) was added sodium methane sulfinate (2.05g, 20.16 mmol) at room temperature. The reaction mixture was heated to 70 ° C for 10 h. The reaction mixture was cooled to room temperature and was concentrated under reduced pressure to obtain a crude compound which was filtered off and the residue was washed with water (2 x 5 mL) to obtain pure 2-fluoro-1 -(2-(methylsulfonyl)ethyl)-4-nitrobenzene (700 mg, 70 %).
  • Step 4 2-Fluoro-1 -(2-(methylsulfonyl)ethyl)-4-nitrobenzene (700 mg, 2.83 mmol) was dissolved in ethyl acetate (7 mL), and to the solution was added (10 %) Pd / C (70 mg) under argon atmosphere which was subjected to hydrogenation in a Parr apparatus and the reaction was continued to stir for 2 h. The reaction mixture was filtered through celite and was washed thoroughly with ethyl acetate and was concentrated under reduced pressure to obtain 3-fluoro-4-(2-(methylsulfonyl)ethyl)aniline (590 mg, 96 %).
  • Step 5 To a stirred solution of 3-fluoro-4-(2-(methylsulfonyl)ethyl)aniline (200 mg, 0.92 mmol) in acetone / DMF (3 mL + 1 .27 mL), pyridine (0.222 mL, 2.76 mmol) was added dropwise phenyl chloroformate (0.152 mL, 1 .197 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 h. The acetone was evaporated and the residue was diluted with DCM (30 mL). The mixture was washed with saturated NaHC0 3 solution (15 mL) and the organic layer extracted with DCM (2 x 20 mL). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give pure phenyl 3-fluoro-4-(2- (methylsulfonyl)ethyl)phenylcarbamate (260 mg, 84 %).
  • Step 6 To a stirred solution of phenyl 3-fluoro-4-(2-(methylsulfonyl)ethyl)phenylcarbamate (90 mg, 0.267 mmol) and (1 -(3-chlorophenyl)-3-cyclopropyl-1 H-pyrazol-5-yl)methanamine (70 mg, 0.286 mmol) in THF (4 mL) was added N-ethyldiisopropylamine (0.087 mL, 0.507 mmol) and stirred for 1 h in a microwave (150 °C, 7 bar).
  • reaction mixture was concentrated in vacuo and purified by CC (eluent: ethyl acetate/cyclohexane (2:1 )) to give 1 - [[2-(3-chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-methylsulfonyl- ethyl)-phenyl]-urea (30 mg, 23 %).
  • Exemplary compounds D27 - D33 were prepared in a similar manner or may be prepared analogously according to D26. Mass spectrometric data are cited hereinafter by way of example for the following exemplary compounds (Table 1 ):
  • the agonistic or antagonistic effect of the substances to be tested on the rat-species vanilloid receptor 1 can be determined using the following assay.
  • the influx of Ca 2+ through the receptor channel is quantified with the aid of a Ca 2+ -sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
  • a Ca 2+ -sensitive dye type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands
  • FLIPR fluorescent imaging plate reader
  • Complete medium 50 ml_ HAMS F12 nutrient mixture (Gibco Invitrogen GmbH, Düsseldorf, Germany) with 10 % by volume of FCS (foetal calf serum, Gibco Invitrogen GmbH, Düsseldorf, Germany, heat-inactivated); 2mM L-glutamine (Sigma, Kunststoff, Germany); 1 % by weight of AA solution (antibiotic/antimyotic solution, PAA, Pasching, Austria) and 25 ng/mL NGF medium (2.5 S, Gibco Invitrogen GmbH, Düsseldorf, Germany)
  • Cell culture plate Poly-D-lysine-coated, black 96-well plates having a clear base (96-well black/clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Düsseldorf, Germany), the laminin being diluted with PBS (Ca-Mg- free PBS, Gibco Invitrogen GmbH, Düsseldorf, Germany) to a concentration of 100 ⁇ g/mL. Aliquots having a laminin concentration of 100 ⁇ g mL are removed and stored at -20 'C.
  • the aliquots are diluted with PBS in a ratio of 1 : 10 to 10 ⁇ g mL of laminin and respectively 50 ⁇ - of the solution are pipetted into a recess in the cell culture plate.
  • the cell culture plates are incubated for at least two hours at 37 °C, the excess solution is removed by suction and the recesses are each washed twice with PBS.
  • the coated cell culture plates are stored with excess PBS which is not removed until just before the feeding of the cells.
  • the vertebral column is removed from decapitated rats and placed immediately into cold HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany), i.e. buffer located in an ice bath, mixed with 1 % by volume (per cent by volume) of an AA solution (antibiotic/antimyotic solution, PAA, Pasching, Austria).
  • HBSS buffer Horco Invitrogen GmbH, Düsseldorf, Germany
  • AA solution antibiotic/antimyotic solution
  • PAA antibiotic/antimyotic solution
  • PAA dorsal root ganglia
  • the DRG from which all blood remnants and spinal nerves have been removed, are transferred in each case to 500 ⁇ _ of cold type 2 collagenase (PAA, Pasching, Austria) and incubated for 35 minutes at 37 ⁇ . After the addition of 2.5 % by volume of trypsin (PAA, Pasching, Austria), incubation is continued for 10 minutes at 37 ⁇ . After complete incubation, the enzyme solution is carefully pipetted off and 500 ⁇ _ of complete medium are added to each of the remaining DRG.
  • the DRG are respectively suspended several times, drawn through cannulae No. 1 , No. 12 and No. 1 6 using a syringe and transferred to a 50 ml_ Falcon tube which is filled up to 15 ml_ with complete medium.
  • each Falcon tube is respectively filtered through a 70 ⁇ Falcon filter element and centrifuged for 1 0 minutes at 1 ,200 rpm and room temperature. The resulting pellet is respectively taken up in 250 ⁇ _ of complete medium and the cell count is determined.
  • the number of cells in the suspension is set to 3 x 1 0 5 per ml_ and 1 50 ⁇ _ of this suspension are in each case introduced into a recess in the cell culture plates coated as described hereinbefore. In the incubator the plates are left for two to three days at 37 °C, 5 % by volume of C0 2 and 95 % relative humidity.
  • the cells are loaded with 2 ⁇ of Fluo-4 and 0.01 % by volume of Pluronic F1 27 (Molecular Probes Europe BV, Leiden, the Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) for 30 min at 37 °C, washed 3 times with HBSS buffer and after further incubation for 1 5 minutes at room temperature used for Ca 2+ measurement in a FLIPR assay.
  • the FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 ⁇ ) are pipetted onto the cells and the Ca 2+ influx is compared with the control (capsaicin 1 0 ⁇ ). This provides the result in % activation based on the Ca 2+ signal after the addition of 1 0 ⁇ of capsaicin (CP). After 5 minutes' incubation, 100 nM of capsaicin are applied and the Ca 2+ influx is also determined.
  • the agonistic or antagonistic effect of the substances to be tested on the vanilloid receptor 1 can also be determined using the following assay.
  • the influx of Ca 2+ through the channel is quantified with the aid of a Ca 2+ -sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
  • a Ca 2+ -sensitive dye type Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands
  • FLIPR fluorescent imaging plate reader
  • CHO K1 cells Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC) United Kingdom) are stably transfected with the VR1 gene. For functional testing, these cells are plated out on poly-D-lysine-coated black 96-well plates having a clear base (BD Biosciences, Heidelberg, Germany) at a density of 25,000 cells/well. The cells are incubated overnight at 37 °C and 5 % C0 2 in a culture medium (Ham's F12 nutrient mixture, 1 0 % by volume of FCS (foetal calf serum), 1 8 ⁇ g ml of L-proline).
  • FCS calcium calf serum
  • the FLIPR protocol consists of 2 substance additions. First the compounds to be tested (10 ⁇ ) are pipetted onto the cells and the Ca 2+ influx is compared with the control (capsaicin 10 ⁇ ) (% activation based on the Ca 2+ signal after the addition of 10 ⁇ of capsaicin). After 5 minutes' incubation, 100 nM of capsaicin are applied and the Ca 2+ influx is also determined.
  • the compounds according to the invention display outstanding affinity to the VR1 /TRPV1 receptor (Table 2).
  • the value after thetician@"symbol indicates the concentration at which the inhibition (as a percentage) was respectively determined.

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BR112014011108A BR112014011108A2 (pt) 2011-11-09 2012-11-08 derivados de carboxamida e ureia à base de pirazolila substituída portando uma porção fenila substituída com um grupo contendo so2 como ligantes do receptor de vaniloides
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MX2014005233A MX2014005233A (es) 2011-11-09 2012-11-08 Derivados de carboxamida y urea a base de pirazolilos sutituidos que contienen una porcion fenilo sustituida con un grupo que contiene so2 como ligandos del receptor de vanilloide.
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