WO2004072069A1 - Carboxamide derivatives - Google Patents

Carboxamide derivatives Download PDF

Info

Publication number
WO2004072069A1
WO2004072069A1 PCT/GB2004/000543 GB2004000543W WO2004072069A1 WO 2004072069 A1 WO2004072069 A1 WO 2004072069A1 GB 2004000543 W GB2004000543 W GB 2004000543W WO 2004072069 A1 WO2004072069 A1 WO 2004072069A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
compound according
compound
halo
Prior art date
Application number
PCT/GB2004/000543
Other languages
French (fr)
Inventor
Gregor James Macdonald
Darren Jason Mitchell
Harshad Kantilal Rami
Leontine Saskia Trouw
Mervyn Thompson
Susan Marie Westaway
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0303464A external-priority patent/GB0303464D0/en
Priority claimed from GB0305163A external-priority patent/GB0305163D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AT04710422T priority Critical patent/ATE450533T1/en
Priority to US10/545,283 priority patent/US7531558B2/en
Priority to EP04710422A priority patent/EP1606289B1/en
Priority to DE602004024375T priority patent/DE602004024375D1/en
Priority to JP2006502267A priority patent/JP4909068B2/en
Publication of WO2004072069A1 publication Critical patent/WO2004072069A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel amide derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in medicine, especially in the treatment of various disorders.
  • Vanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. Vanilloid Receptor (VR1), whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51 , No. 2.).
  • Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Numbers WO 92/09285, WO 02/100819 and WO 02/076946.
  • Vanilloid compounds or Vanilloid receptor modulators are capsaicin or trans 8-methyl-N- vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or N-(4-hydroxy-3- methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595).
  • P is aryl, heteroaryl, heterocyclyl or cycloalkyl
  • W, X and Y form a 5-membered nitrogen containing heteroaromatic ring wherein W, X and Y may be selected from CR 1a , NR 1b , N, S and O;
  • R 1a and R 1b independently are -H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl,- (CH 2 ) x OR 4 or -(CH 2 ) X NR 4 R 5 ;
  • R 2 is -H, alkyl, alkoxy or halo;
  • R 2a is alkyl, alkoxy, halo or CF 3
  • R 2b is alkyl, alkoxy, halo or CF 3 ;
  • R 3 is -H, halo, alkyl, alkoxy, cycloalkyl, or aryl wherein said aryl group may be optionally substituted by one or more groups R 2a ; heteroaryl wherein said heteroaryl group may be optionally substituted by one or more groups R 2b ; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N0 2 , -OH, -OCF 3 , -CF 3 , - NR 4 R 5 , -S(0) m R 6 , -S(0) 2 NR 4 R 5 , -OS(0) 2 R 6 , -OS(0) 2 CF 3 , -0(CH 2 ) x NR 4 R 5 , - O(CH 2 ) ⁇ OR 4 -C(0)CF 3 , -C(0)alkyl, -C(0)cycloalkyl, -C(0)aralkyl, -
  • R 4 and R 5 may be the same or different and represent -H or alkyl or R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
  • R 6 is -H, alkyl or aryl
  • R 7 is -H , alkyl or aryl
  • Ar is aryl or heteroaryl
  • m is 0, 1 or 2
  • r is O, 1 , 2 or 3
  • s is O, 1 , 2, 3, 4, 5 or 6
  • x is O, 1 , 2, 3, 4, 5 or 6;
  • Z is a bond, O, S, NR 7 or CH 2 .
  • the invention embraces compounds represented by the formula (I) given above and tautomers thereof.
  • P is phenyl, pyridyl (eg pyrid-3-yl), pyrimidinyl (eg pyrimidin-5- yl), piperazinyl (eg piperazin-1-yl) or cyclohexyl; more preferably pyridyl e.g. pyrid-3-yl.
  • pyridyl e.g. pyrid-3-yl
  • pyrimidinyl eg pyrimidin-5- yl
  • piperazinyl eg piperazin-1-yl
  • cyclohexyl more preferably pyridyl e.g. pyrid-3-yl.
  • the 5-membered nitrogen containing heteroaromatic ring formed from W
  • X and Y and the phenyl ring to which it is fused preferably form a benzothiazole, benzotriazole, benzimidazole or indazole group. Further examples include benzisoxazole and benzoxazole.
  • R 1a is -H or alkyl, particularly R 1a is -H or methyl especially methyl.
  • R 1 is -H or alkyl, particularly R 1 is -H or methyl especially -H.
  • R 2 is alkyl (eg CF 3 ), alkoxy or halo.
  • R 2a represents halo eg fluoro or chloro especially fluoro.
  • R 2b represents alkyl (eg methyl).
  • R 3 is halo, alkyl, aryl e.g. phenyl, wherein said aryl group may be optionally substituted by one or more halo atoms e.g. fluoro or chloro, or heteroaryl e.g. pyridyl or pyrazolyl wherein said heteroaryl group may be optionally substituted by alkyl e.g. methyl. More preferably one of R 3 is phenyl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by alkyl
  • R 4 represents methyl or hydrogen.
  • R 5 represents methyl or hydrogen.
  • R 6 represents methyl.
  • R 7 is -H or alkyl especially -H or methyl.
  • r is 0, 1 or 2, more preferably r is 0 or 1 , particularly r is 0.
  • s is 1 or 2.
  • R is preferably phenyl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by alkyl.
  • one R 3 is preferably phenyl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by alkyl and the other is preferably alkyl e.g. methyl.
  • x is 0, 1 , 2 or 3, especially 1 , 2 or 3.
  • Compounds according to this invention include Examples 1-18 or pharmaceutically acceptable salts or solvates thereof.
  • R 1 represents -H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl,- (CH 2 ) x OR 4 or -(CH 2 ) X NR 4 R 5 ;
  • R 2 represents -H, alkyl, alkoxy or halo
  • R 3 represents -H, halo, alkyl, alkoxy, cycloalkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N0 2 , -OH, -OCF 3 , -CF 3 , -NR 4 R 5 , -S(0) m R 6 , -S(0) 2 NR 4 R 5 , -OS(0) 2 R 6 , -OS(0) 2 CF 3 , -0(CH 2 ) x NR R 5 , -0(CH 2 ) x OR 4 , -C(0)CF 3 , -C(0)alkyl, -C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, -C(0)(CH 2 ) x OR 6 , - C(0)(
  • R 4 and R 5 may be the same or different and represent -H or alkyl or R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
  • R 6 represents -H, alkyl or aryl
  • R 7 represents -H or methyl
  • Ar represents aryl or heteroaryl; x represents an integer 0, 1 , 2, 3, 4, 5 or 6; m is 0, 1 or 2;
  • W, X and Y form a 5-membered nitrogen containing aromatic heterocyclic ring
  • Z represents a bond, O, S, NR 7 or CH 2 ; and s is an integer value from 1 to 6.
  • Examples of the 5-membered nitrogen containing aromatic heterocyclic ring formed by W, X and Y (taken together with the phenyl ring) include benzotriazole, benzimidazole and indazole.
  • P represents phenyl or heteroaryl, more suitably phenyl or pyridyl, especially pyridyl, most especially pyrid-3-yl.
  • R 1 represents -H or alkyl, especially -H or methyl.
  • R 2 represents hydrogen.
  • R 3 represents hydrogen, halo, alkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms (e.g. fluoro); or - O(CH 2 ) x OR 4 , more suitably methyl or aryl (eg phenyl) optionally substituted by one or more halo atoms.
  • s represents 1 or 2.
  • x represents 0, 1 , 2 or 3, especially 1 , 2 or 3.
  • the 5-membered nitrogen containing aromatic heterocyclic ring formed by W, X and Y is a benzimidazol-5- yl, benzimidazol-6-yl, benzotriazol-5-yl or indazol-6-yl group.
  • Another example is indazol-5-yl.
  • R 4 represents methyl or hydrogen.
  • R 5 represents methyl or hydrogen.
  • R 6 represents methyl.
  • R 7 represents methyl or hydrogen.
  • Z represents a bond.
  • Ar represents phenyl.
  • the moiety -P-(R 3 ) S represents -2-methyl-6-(4-fluorophenyl) pyridin-3-yl (this numbering defining the pyridine nitrogen as position 1).
  • P is aryl or heteroaryl
  • R 1 is -H or alkyl
  • R 2 is halo
  • R 3 is halo, alkyl, alkoxy, cycloalkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N0 2 , -OH, -OCF 3 , -CF 3 , -NR 4 R 5 , -S(0) m R 6 -S(0) 2 NR 4 R 5 , -OS(0) 2 R 6 , -0(CH 2 ) x NR 4 R 5 , -0(CH 2 ) x OR 4 , -C(0)CF 3 , -C(0)alkyl, - C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, -C(0)-(CH 2 ) x OR 4 , -C(0)-(CH 2 ) x NR 4 R 5 ,
  • R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring
  • R 6 is alkyl or aryl
  • R 7 is -H, alkyl or aryl; Ar is aryl or heteroaryl; x is O, 1 , 2, 3, 4, 5 or 6;
  • Z is a bond, O, S, NR 7 or CH 2 ; m is 0, 1 or 2; r is 0, 1 or 2; and s is an integer value from 1 to 6.
  • P is phenyl.
  • P is heteroaryl. More suitably, P is pyridyl e.g. 3-pyridyl.
  • R 1 is -H or methyl.
  • R 3 is halo, alkyl or aryl wherein said aryl group may be optionally substituted by one or more halo (eg fluoro) atoms.
  • n 0.
  • x is 0, 1 , 2 or 3, especially 1 , 2 or 3.
  • r is 0.
  • s is 1 or 2.
  • the compounds of formula (IB) are preferably benzothiazol-5-yl derivatives.
  • Certain of the carbon atoms of formula (I) are chiral carbon atoms, and therefore compounds of formula (I) may exist as stereoisomers.
  • the invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers and mixtures thereof, such as racemates.
  • the different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses.
  • the compounds of formula (I) can form salts, especially pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts are those used conventionally in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts.
  • Suitable pharmaceutically acceptable salts include acid addition salts.
  • Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.
  • salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form another aspect of the present invention.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally hydrated or solvated.
  • This invention includes in its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates.
  • Solvates include stoichiometric solvates and non-stoichiometric solvates.
  • alkyl as a group or part of a group refers to a straight or branched chain saturated aliphatic hydrocarbon radical containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms.
  • alkyl groups in particular include methyl ("Me”), ethyl ("Et”), n-propyl (“Pr n "), /so-propyl (“Pr'”), n-butyl (“Bun”), sec-butyl (“Bu s "), terf-butyl ("But”), pen tyl and hexyl.
  • cycloalkyl refers to a saturated alicyclic hydrocarbon radical containing 3 to 12 carbon atoms, suitably 3 to 6 carbon atoms.
  • alkyl groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF 3 , -OH, - OCF3, C 2 _6 alkenyl, C 3-6 alkynyl, C ⁇ -6 alkoxy, aryl and di- C ⁇ -6 alkylamino.
  • Alkyl groups are preferably unsubstituted or substituted by fluoro.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is defined above.
  • alkoxy groups in particular include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, /so-butoxy, sec-butoxy and te f-butoxy.
  • alkoxy groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF 3 , -OH, -OCF 3 , C ⁇ -6 alkyl, C 2- e alkenyl, C 3-6 alkynyl, aryl and di- C-i -6 alkylamino.
  • Alkoxy groups are preferably unsubstituted.
  • aryl as a group or part of a group refers to a carbocyclic aromatic radical (“Ar").
  • aryl groups are 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups, especially phenyl ("Ph”), biphenyl and naphthyl, particularly phenyl.
  • Ph phenyl
  • naphthyl is used herein to denote, unless otherwise stated, both naphth-1-yl and naphth-2-yl groups.
  • heteroaryl as a group or part of a group refers to a stable 5- 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 ,5,2-dithiazinyl, dihydrobenzofuranyl, furanyl, furazanyl, imidazolyl, 1 H-indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl,
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl but preferably denotes 3-pyridyl.
  • Aryl and heteroaryl groups contained within the moieties R 1 and Ar may optionally be substituted with one or more substituents selected from the list consisting of halo, hydroxyl, carbonyl, alkoxy, alkyl, e.g. CF 3 , NR 4 R 5 and S0 2 R 6 more suitably the list consisting of halo, hydroxyl, alkoxy, alkyl, e.g. CF 3 , NR 4 R 5 and S0 2 R b
  • the terms "heterocyclyl” and “heterocyclic” as a group or part of a group refer to stable heterocyclic non-aromatic single and fused rings containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a fused heterocyclyl ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • suitable heterocyclyl groups include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl, pyrrolidinyl and morpholinyl.
  • halo is used herein to describe, unless otherwise stated, a group selected from fluorine ("fluoro"), chlorine (“chloro”), bromine (“bromo”) or iodine ("iodo").
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which process comprises: (a) reacting a compound of formula (II),
  • P, R 3 and s are as defined in relation to formula (I) and thereafter, as necessary, carrying out one or more of the following reactions: (i) converting one compound of formula (I) into another compound of formula (I); (ii) removing any protecting group; (iii) preparing a salt or a solvate of the compound so formed.
  • reaction between a compound of formula (II) and a compound of formula (III) may be effected using conventional methods for the formation of an amide bond, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 419-421.
  • the reaction may be carried out in a solvent such as dichloromethane, in the presence of a suitable diimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • a compound of formula (III) may be converted into the corresponding acyl chloride with a suitable chlorinating agent such as oxalyl chloride, followed by reaction with a compound of formula (II) in the presence of a suitable base such as pyridine in an inert solvent such as dichloromethane.
  • a suitable chlorinating agent such as oxalyl chloride
  • a compound of formula (II) in the presence of a suitable base such as pyridine in an inert solvent such as dichloromethane.
  • the reaction between a compound of formula (II) and a compound of formula (IV) may be effected using conventional methods for the formation of a urea derivative, for example, by treatment of a compound of formula (II) with a suitable activating reagent, such as phosgene, triphosgene, di-tertbutyl tricarbonate, or phenylchloroformate and a suitable base, followed by treatment with a compound of formula (IV).
  • a suitable activating reagent such as phosgene, triphosgene, di-tertbutyl tricarbonate, or phenylchloroformate and a suitable base
  • the reaction may be carried out in a suitable solvent such as dichloromethane.
  • a suitable base is triethylamine.
  • R 2 and r are as defined in relation to formula (I), with a suitable reducing agent.
  • a suitable reducing agent may be effected by methods well known in the art, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 1216-1218.
  • Suitable reducing agents include (a) iron or zinc metal in hydrochloric acid, or (b) hydrogen in the presence of a suitable catalyst, such as, 5% palladium on charcoal. Reduction using hydrogen may conveniently be performed in a solvent such as methanol or ethanol.
  • the above-mentioned conversions of a compound of formula (I) into another compound of formula (I) include any conversion, which may be effected using conventional procedures, but in particular the said conversions include any combination of: (i) converting one group R 1 into another group R 1 ; (ii) converting one group R 2 into another group R 2 ; and (iii) converting one group R 3 into another group R 3 .
  • Suitable conversions of one group R 1 into another group R 1 include,
  • Standard protection and deprotection techniques such as those described in Greene T.W. ' Protective groups in organic synthesis', New York, Wiley (1981), can be used.
  • primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives.
  • Carboxylic acid groups can be protected as esters.
  • Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures known in the art.
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • Vanilloid receptor antagonist Vanilloid receptor antagonist
  • V1 Vanilloid receptor antagonist
  • neuropathic pain neuropathic pain
  • postoperative pain postrheumatoid arthritic pain
  • osteoarthritic pain back pain
  • visceral pain cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, broncho constriction, inflammatory disorders, oesophagitis, heart burn, Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder (GERD), stomach
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance, in particular, in the treatment and/or prophylaxis of the Disorders of the Invention.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of pain.
  • the invention further provides a method for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial, in particular the Disorders of the Invention, in mammals including humans, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial, particularly the Disorders of the Invention.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient therefor.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral, rectal administration or intravesical adminstration to the bladder and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions, suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound in preparing solutions, can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20, 20 to 250, or 0.1 to 500.0 mg, for example 0.2 to 5 and 0.1 to 250 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 1000 mg; and such therapy may extend for a number of weeks or months.
  • 6-(2,4-Difluorophenyl)nicotinic acid The title compound was prepared from 2',4'-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
  • the title compound was prepared from 3',4'-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
  • the title compound was prepared from 2',3'-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
  • Example 11 N-(1H-Benzimidazol-6-yl)-6-(4-fluorophenyl)-2-methyl-nicotinamide 6-Amino-1 H-benzimidazole (27mg, 0.20mmol), 6-(4-fluorophenyl)-nicotinic acid (D3) (46mg, 0.20mmol), 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (46mg, 0.24mmol) and 4-dimethylaminopyridine (12mg, O.IOmmol) in DCM (1.6ml) were stirred at room temperature overnight. The reaction mixture was purified directly by column chromatography, eluting with a 0-5%MeOH/DCM gradient to give the title compound. MS(ES): MH + 347, M-H + 345.
  • Example 16 4-(2-Fluorophenyl)- ⁇ /-(2-methylbenzothiazol-5-yl)-1-piperazine carboxamide To a stirred solution of 5-amino-2-methylbenzothiazole (100mg, 0.61mmol) and triethylamine (170ul, 1.22mmol) in DCM (5mi) at 0°C under an argon atmosphere was added triphosgene (60mg, 0.2mmol). The mixture was warmed to room temp, and stirred for 1 h. 4-(2-Fluorophenyl)piperazine (110mg, 0.61 mmol) was added and the reaction was stirred at room temp, overnight.
  • the compounds of the invention are Vanilloid receptor (VR1) antagonists and hence have useful pharmaceutical properties.
  • Vanilloid receptor (VR1) antagonist activity can be confirmed and demonstrated for any particular compound by use of conventional methods, for example those disclosed in standard reference texts such as D. Le Bars, M. Gozarin and S. W.
  • the screen used for the compounds of this invention was based upon a FLIPR based calcium assay, similar to that described by Smart et al. (British
  • the cells were pre-incubated with compound or buffer control at room temperature for 30 minutes. Capsaicin (Sigma) was then added to the cells.
  • FCA-induced hyperalgesia in the Guinea pig 100 ⁇ l of 1mg/ml FCA was injected intraplantar into the left paw of 4 groups of 8 male Dunkin Hartley guinea-pigs (batch: 6282434, average weight 340g). 24 hours later compounds were administered orally at 0 (vehicle), 3, 10 30mg/kg with vehicle as 1% methylcellulose and dosing volume being 2ml/kg and dosing straight into the stomach. The methylcellulose was added gradually to the compound into the pestle and mortar and ground together.
  • Behavioural readouts of mechanical hyperalgesia were obtained before FCA administration (na ⁇ ve reading), after FCA but before drug administration (predose reading) and 1 hour after drug administration.
  • the readout used was paw pressure (Randall-Sellito) and the end point was paw withdrawal.
  • the paw pressure equipment also had one silver disc placed on the point to increase the markings by a factor of 2.
  • Examples 1 , 2, 3, 4, 5 and 16 were tested in this model and shown to be active.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Oncology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)

Abstract

Compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein P, W, X, Y, R2, R3, r and s are as defined in the specification, processes for preparing such compounds, pharmaceutical compositions comprising such compounds and their use in therapy.

Description

CARBOXAMIDE DERIVATIVES
This invention relates to novel amide derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in medicine, especially in the treatment of various disorders.
Vanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. Vanilloid Receptor (VR1), whose function is modulated by such compounds, has been widely studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51 , No. 2.).
A wide variety of Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Numbers WO 92/09285, WO 02/100819 and WO 02/076946. Particularly notable examples of Vanilloid compounds or Vanilloid receptor modulators are capsaicin or trans 8-methyl-N- vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or N-(4-hydroxy-3- methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595).
International Patent Application, Publication Number WO 02/08221 discloses diaryl piperazine derivatives which bind with high selectivity and high affinity to vanilloid receptors, especially Type I Vanilloid receptors, also known as capsaicin or VR1 receptors. The compounds are said to be useful in the treatment of chronic and acute pain conditions, itch and urinary incontinence. International Patent Application, Publication Number WO 03/068749 (published after the priority date of the present application) discloses carboxamide derivatives as Vanilloid receptor modulators and their use for the treatment of chronic and acute pain conditions. According to a first aspect of the present invention, there is provided a compound of formula (I),
Figure imgf000003_0001
(I)
or a pharmaceutically acceptable salt or solvate thereof, wherein, P is aryl, heteroaryl, heterocyclyl or cycloalkyl;
W, X and Y form a 5-membered nitrogen containing heteroaromatic ring wherein W, X and Y may be selected from CR1a, NR1b, N, S and O;
R1a and R1b independently are -H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl,- (CH2)xOR4 or -(CH2)X NR4R5; R2 is -H, alkyl, alkoxy or halo;
R2a is alkyl, alkoxy, halo or CF3; R2b is alkyl, alkoxy, halo or CF3;
R3 is -H, halo, alkyl, alkoxy, cycloalkyl, or aryl wherein said aryl group may be optionally substituted by one or more groups R2a; heteroaryl wherein said heteroaryl group may be optionally substituted by one or more groups R2b; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N02, -OH, -OCF3, -CF3, - NR4R5, -S(0)mR6, -S(0)2NR4R5, -OS(0)2R6, -OS(0) 2CF3, -0(CH2)xNR4R5, - O(CH2)χOR4 -C(0)CF3, -C(0)alkyl, -C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, - C(0)(CH2)xOR6, -C(0)(CH2)xNR4R5, -C(0)alkoxy, -C(0)NR4R5, - (CH2)xC(0)alkoxy, -(CH2)xOC(0)R6, -(CH2)xOR6, -(CH2)XNR4R5, - (CH2)xC(0)NR4R5, -(CH2)xN(R4)C(0)R6, -(CH2)xS(0)2NR4R5, - (CH2)xN(R4)S(0)2R6, -ZAr, -(CH2)xS(0)2R6, -(OCH2)xS(0)2R6, -0(CH2)xS(0)2R6, - N(R4)S(0)2R6, -N(R4)C(0)R6 or -(CH2)xC(0)alkyl;
R4 and R5 may be the same or different and represent -H or alkyl or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
R6 is -H, alkyl or aryl; R7 is -H , alkyl or aryl; Ar is aryl or heteroaryl; m is 0, 1 or 2; r is O, 1 , 2 or 3; s is O, 1 , 2, 3, 4, 5 or 6; x is O, 1 , 2, 3, 4, 5 or 6; and
Z is a bond, O, S, NR7 or CH2. The invention embraces compounds represented by the formula (I) given above and tautomers thereof.
Preferably P is phenyl, pyridyl (eg pyrid-3-yl), pyrimidinyl (eg pyrimidin-5- yl), piperazinyl (eg piperazin-1-yl) or cyclohexyl; more preferably pyridyl e.g. pyrid-3-yl. The 5-membered nitrogen containing heteroaromatic ring formed from W,
X and Y and the phenyl ring to which it is fused preferably form a benzothiazole, benzotriazole, benzimidazole or indazole group. Further examples include benzisoxazole and benzoxazole.
Preferably R1a is -H or alkyl, particularly R1a is -H or methyl especially methyl.
Preferably R1 is -H or alkyl, particularly R1 is -H or methyl especially -H.
Preferably R2 is alkyl (eg CF3), alkoxy or halo.
Specific examples of W-X=Y include S-CMe=N, S-CH=N, NH-CH=N, NMe-CH=N, NH-N=CH, NH-N=N and NMe-N=CH. Preferably R2a represents halo eg fluoro or chloro especially fluoro.
Preferably R2b represents alkyl (eg methyl).
Preferably R3 is halo, alkyl, aryl e.g. phenyl, wherein said aryl group may be optionally substituted by one or more halo atoms e.g. fluoro or chloro, or heteroaryl e.g. pyridyl or pyrazolyl wherein said heteroaryl group may be optionally substituted by alkyl e.g. methyl. More preferably one of R3 is phenyl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by alkyl
Preferably R4 represents methyl or hydrogen.
Preferably R5 represents methyl or hydrogen. Preferably R6 represents methyl.
Preferably R7 is -H or alkyl especially -H or methyl.
Preferably r is 0, 1 or 2, more preferably r is 0 or 1 , particularly r is 0. Preferably s is 1 or 2. When s is 1 , R is preferably phenyl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by alkyl. When s is 2, one R3 is preferably phenyl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by alkyl and the other is preferably alkyl e.g. methyl.
Preferably x is 0, 1 , 2 or 3, especially 1 , 2 or 3.
When P represents piperazin-1-yl substituted on the 4-position by aryl or heteroaryl, then preferably W-X=Y does not represent NR1-CR1=N or 0-N=CR1.
Compounds according to this invention include Examples 1-18 or pharmaceutically acceptable salts or solvates thereof.
A group of compounds which may be mentioned are those of formula (IA),
Figure imgf000005_0001
(IA) or a pharmaceutically acceptable salt or solvate thereof, wherein, P is aryl or heteroaryl;
R1 represents -H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl,- (CH2)xOR4 or -(CH2)XNR4R5;
R2 represents -H, alkyl, alkoxy or halo;
R3 represents -H, halo, alkyl, alkoxy, cycloalkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N02, -OH, -OCF3, -CF3, -NR4R5, -S(0)mR6, -S(0)2NR4R5, -OS(0)2R6, -OS(0)2CF3, -0(CH2)xNR R5, -0(CH2)xOR4, -C(0)CF3, -C(0)alkyl, -C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, -C(0)(CH2)xOR6, - C(0)(CH2)xNR4R5, -C(0)alkoxy, -C(0)NR R5, -(CH2)xC(0)alkoxy, - (CH2)xOC(0)R6, -(CH2)xOR6, -(CH2)XNR4R5, -(CH2)xC(0)NR4R5, -
(CH2)xN(R4)C(0)R6, -(CH2)xS(O)2NR R5, -(CH2)xN(R4)S(0)2R6, -ZAr, - (CH2)xS(0)2R6, -(OCH2)xS(0)2R6, -N(R4)S(0)2R6, -N(R4)C(0)R6 or - (CH2)xC(0)alkyl; R4 and R5 may be the same or different and represent -H or alkyl or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
R6 represents -H, alkyl or aryl; R7 represents -H or methyl;
Ar represents aryl or heteroaryl; x represents an integer 0, 1 , 2, 3, 4, 5 or 6; m is 0, 1 or 2;
W, X and Y form a 5-membered nitrogen containing aromatic heterocyclic ring;
Z represents a bond, O, S, NR7 or CH2; and s is an integer value from 1 to 6.
In formula (IA):
Examples of the 5-membered nitrogen containing aromatic heterocyclic ring formed by W, X and Y (taken together with the phenyl ring) include benzotriazole, benzimidazole and indazole.
Suitably P represents phenyl or heteroaryl, more suitably phenyl or pyridyl, especially pyridyl, most especially pyrid-3-yl.
Suitably R1 represents -H or alkyl, especially -H or methyl. Suitably R2 represents hydrogen.
Suitably, R3 represents hydrogen, halo, alkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms (e.g. fluoro); or - O(CH2)xOR4, more suitably methyl or aryl (eg phenyl) optionally substituted by one or more halo atoms. Suitably, s represents 1 or 2.
Suitably, x represents 0, 1 , 2 or 3, especially 1 , 2 or 3.
Suitably the 5-membered nitrogen containing aromatic heterocyclic ring formed by W, X and Y (taken together with the phenyl ring) is a benzimidazol-5- yl, benzimidazol-6-yl, benzotriazol-5-yl or indazol-6-yl group. Another example is indazol-5-yl.
Suitably R4 represents methyl or hydrogen.
Suitably R5 represents methyl or hydrogen.
Suitably R6 represents methyl. Suitably R7 represents methyl or hydrogen. Suitably Z represents a bond. Suitably Ar represents phenyl.
Suitably the moiety -P-(R3)S represents -2-methyl-6-(4-fluorophenyl) pyridin-3-yl (this numbering defining the pyridine nitrogen as position 1).
A further group of compounds which may be mentioned are those of formula (IB),
Figure imgf000007_0001
(IB)
or a pharmaceutically acceptable salt or solvate thereof, wherein,
P is aryl or heteroaryl;
R1 is -H or alkyl; R2 is halo;
R3 is halo, alkyl, alkoxy, cycloalkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N02, -OH, -OCF3, -CF3, -NR4R5, -S(0)mR6 -S(0)2NR4R5, -OS(0)2R6, -0(CH2)xNR4R5, -0(CH2)xOR4, -C(0)CF3, -C(0)alkyl, - C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, -C(0)-(CH2)xOR4, -C(0)-(CH2)xNR4R5, - C(0)alkoxy, -C(0)NR4R5, -(CH2)xC(0)alkoxy, -(CH2)xOC(0)R4, -(CH2)xOR4, - (CH2)XNR4R5, -(CH2)xC(0)NR4R5, -(CH2)xN(R4)C(0)R4, -(CH2)xS(0)2NR4R5, - (CH2)xN(R4)S(0)2R6, -ZAr, -(CH2)xS(0)mR6, -0(CH2)xS(0)mR6, -N(R4)S(0)2R6, - N(R4)C(O)R4 or -(CH2)xC(0)alkyl; R4 and R5 may be the same or different and represent -H, alkyl or aryl or
R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
R6 is alkyl or aryl;
R7 is -H, alkyl or aryl; Ar is aryl or heteroaryl; x is O, 1 , 2, 3, 4, 5 or 6;
Z is a bond, O, S, NR7 or CH2; m is 0, 1 or 2; r is 0, 1 or 2; and s is an integer value from 1 to 6.
In formula (IB):
Suitably P is phenyl. Suitably, P is heteroaryl. More suitably, P is pyridyl e.g. 3-pyridyl.
Suitably R1 is -H or methyl. Suitably R3 is halo, alkyl or aryl wherein said aryl group may be optionally substituted by one or more halo (eg fluoro) atoms.
Suitably m is 0.
Suitably x is 0, 1 , 2 or 3, especially 1 , 2 or 3.
Suitably r is 0. Suitably s is 1 or 2.
The compounds of formula (IB) are preferably benzothiazol-5-yl derivatives.
Certain of the carbon atoms of formula (I) are chiral carbon atoms, and therefore compounds of formula (I) may exist as stereoisomers. The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereospecific or asymmetric syntheses. As indicated above, the compounds of formula (I) can form salts, especially pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts are those used conventionally in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts.
Suitable pharmaceutically acceptable salts include acid addition salts. Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.
The salts and/or solvates of the compounds of the formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the preparation of pharmaceutically acceptable salts and/or solvates of compounds of formula (I) or the compounds of the formula (I) themselves, and as such form another aspect of the present invention.
The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally hydrated or solvated. This invention includes in its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
Suitable solvates include pharmaceutically acceptable solvates, such as hydrates.
Solvates include stoichiometric solvates and non-stoichiometric solvates. As used herein the term "alkyl" as a group or part of a group refers to a straight or branched chain saturated aliphatic hydrocarbon radical containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms. Such alkyl groups in particular include methyl ("Me"), ethyl ("Et"), n-propyl ("Prn"), /so-propyl ("Pr'"), n-butyl ("Bun"), sec-butyl ("Bus"), terf-butyl ("But"), pentyl and hexyl. The term "cycloalkyl" as a group or part of a group refers to a saturated alicyclic hydrocarbon radical containing 3 to 12 carbon atoms, suitably 3 to 6 carbon atoms. Where appropriate, such alkyl groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, - OCF3, C2_6 alkenyl, C3-6 alkynyl, Cι-6 alkoxy, aryl and di- Cι-6 alkylamino. Alkyl groups are preferably unsubstituted or substituted by fluoro.
As used herein, the term "alkoxy" as a group or part of a group refers to an alkyl ether radical, wherein the term "alkyl" is defined above. Such alkoxy groups in particular include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, /so-butoxy, sec-butoxy and te f-butoxy. Where appropriate, such alkoxy groups may be substituted by one or more groups selected from halo (such as fluoro, chloro, bromo), -CN, -CF3, -OH, -OCF3, Cι-6 alkyl, C2-e alkenyl, C3-6 alkynyl, aryl and di- C-i-6 alkylamino. Alkoxy groups are preferably unsubstituted. As used herein, the term "aryl" as a group or part of a group refers to a carbocyclic aromatic radical ("Ar"). Suitably such aryl groups are 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups, especially phenyl ("Ph"), biphenyl and naphthyl, particularly phenyl. The term "naphthyl" is used herein to denote, unless otherwise stated, both naphth-1-yl and naphth-2-yl groups.
As used herein, the term "heteroaryl" as a group or part of a group refers to a stable 5- 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of suitable heteroaryl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 ,5,2-dithiazinyl, dihydrobenzofuranyl, furanyl, furazanyl, imidazolyl, 1 H-indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1 ,2,5-thiadiazinyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,5- triazolyl, 1 ,3,4-triazolyl and xanthenyl.
The term "pyridyl" includes 2-pyridyl, 3-pyridyl and 4-pyridyl but preferably denotes 3-pyridyl.
Aryl and heteroaryl groups contained within the moieties R1 and Ar may optionally be substituted with one or more substituents selected from the list consisting of halo, hydroxyl, carbonyl, alkoxy, alkyl, e.g. CF3, NR4R5 and S02R6 more suitably the list consisting of halo, hydroxyl, alkoxy, alkyl, e.g. CF3, NR4R5 and S02Rb As used herein, the terms "heterocyclyl" and "heterocyclic" as a group or part of a group refer to stable heterocyclic non-aromatic single and fused rings containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. A fused heterocyclyl ring system may include carbocyclic rings and need include only one heterocyclic ring. Examples of suitable heterocyclyl groups include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl, pyrrolidinyl and morpholinyl.
The term "halo" is used herein to describe, unless otherwise stated, a group selected from fluorine ("fluoro"), chlorine ("chloro"), bromine ("bromo") or iodine ("iodo").
The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which process comprises: (a) reacting a compound of formula (II),
Figure imgf000011_0001
(II)
wherein, W, X, Y, R2 and r are as defined in relation to formula (I), with a compound of formula (III),
Figure imgf000011_0002
(III)
wherein, P, R3 and s are as defined in relation to formula (I) and thereafter, as necessary, carrying out one or more of the following reactions: (i) converting one compound of formula (I) into another compound of formula (I); (ii) removing any protecting group; (iii) preparing a salt or a solvate of the compound so formed.
The reaction between a compound of formula (II) and a compound of formula (III) may be effected using conventional methods for the formation of an amide bond, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 419-421. Typically, the reaction may be carried out in a solvent such as dichloromethane, in the presence of a suitable diimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Alternatively a compound of formula (III) may be converted into the corresponding acyl chloride with a suitable chlorinating agent such as oxalyl chloride, followed by reaction with a compound of formula (II) in the presence of a suitable base such as pyridine in an inert solvent such as dichloromethane.
According to a further aspect of the present invention there is provided an an alternative process for the preparation of a compound of formula (I) where P is heterocyclyl (e.g. piperazinyl), or a pharmaceutically acceptable salt or solvate thereof, which process comprises reacting a compound of formula (II) with a compound of formula (IV):
Figure imgf000012_0001
(IV)
wherein, P is heterocyclyl and R3 and s are as defined in relation to formula (I); and thereafter, as necessary, carrying out one or more of the following reactions:
(i) converting one compound of formula (I) into another compound of formula (I); (ii) removing any protecting group;
(iii) preparing a salt or a solvate of the compound so formed.
The reaction between a compound of formula (II) and a compound of formula (IV) may be effected using conventional methods for the formation of a urea derivative, for example, by treatment of a compound of formula (II) with a suitable activating reagent, such as phosgene, triphosgene, di-tertbutyl tricarbonate, or phenylchloroformate and a suitable base, followed by treatment with a compound of formula (IV). The reaction may be carried out in a suitable solvent such as dichloromethane. A suitable base is triethylamine.
Compounds of formula (II) are commercially available or may be prepared by the reaction of a compound of formula (V),
Figure imgf000013_0001
(V)
wherein, R2 and r are as defined in relation to formula (I), with a suitable reducing agent. The reaction of a compound of formula (V) with a reducing agent may be effected by methods well known in the art, such as those described in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 1216-1218. Suitable reducing agents include (a) iron or zinc metal in hydrochloric acid, or (b) hydrogen in the presence of a suitable catalyst, such as, 5% palladium on charcoal. Reduction using hydrogen may conveniently be performed in a solvent such as methanol or ethanol.
Compounds of formula (V) are commercially available or may be prepared according to literature methods.
Compounds of formula (III) are commercially available or may be prepared according to a variety of known methods in accordance with the nature of the moiety, P. For example, compounds of formula (III) or their corresponding esters, where P is phenyl or heteroaryl may be prepared in accordance with methods described in J. Hassan et al., Chem. Rev., 2002, 102, 1359. Hydrolysis of the corresponding ester compounds to compounds of formula (III) may be carried out in accordance with methods disclosed in J March, Advanced Organic Chemistry, 4th edition, J Wiley & Sons, 1992, p. 378-383. Compounds of formula (III) where P is heteroaryl may also be prepared in accordance with, for example, methods disclosed in the following references: H. Vorbruggen, Adv. Het. Chem., 1990, 49, 117 and E. Graf et al, Synthesis, 1999, 7,1216. The above-mentioned conversions of a compound of formula (I) into another compound of formula (I) include any conversion, which may be effected using conventional procedures, but in particular the said conversions include any combination of: (i) converting one group R1 into another group R1; (ii) converting one group R2 into another group R2; and (iii) converting one group R3 into another group R3.
The above-mentioned conversions (i), (ii) and (iii) may be performed using any appropriate method under conditions determined by the particular groups chosen.
Suitable conversions of one group R1 into another group R1, as in conversion (i) above, include,
(a) converting a group R1 which represents -H, into another group R1 which represents alkyl, such as methyl. Such a conversion may be performed using an appropriate alkylation procedure, for example, by treating a compound of formula (I) wherein R1 is -H with an agent, R1-Z, where R1 is alkyl and Z is halo, such as bromo, chloro or iodo, or -OS02CF3.
It will be appreciated by those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques, such as those described in Greene T.W. ' Protective groups in organic synthesis', New York, Wiley (1981), can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures known in the art.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
Compounds of formula (I) and their pharmaceutically acceptable salts and solvates thereof have Vanilloid receptor antagonist (VR1) activity and are believed to be of potential use for the treatment or prophylaxis of certain disorders, or treatment of the pain associated with them, such as: pain, chronic pain, neuropathic pain, postoperative pain, postrheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, broncho constriction, inflammatory disorders, oesophagitis, heart burn, Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder (GERD), stomach and duodenal ulcers, functional dyspepsia, irritable bowel syndrome, inflammatory bowel disease, colitis, Crohn's disease, pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic, urinary incontinence, cystitis, burns, itch, psoriasis, pruritis, emesis (hereinafter referred to as the "Disorders of the Invention").
Accordingly, the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance, in particular, in the treatment and/or prophylaxis of the Disorders of the Invention.
In particular, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of pain.
The invention further provides a method for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial, in particular the Disorders of the Invention, in mammals including humans, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial, particularly the Disorders of the Invention. In order to use the compounds of the invention in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient therefor.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral, rectal administration or intravesical adminstration to the bladder and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions, suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants. For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. For systemic administration, dosage levels from 0.01 mg to 100mg per kilogramme of body weight are useful in the treatment of pain. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20, 20 to 250, or 0.1 to 500.0 mg, for example 0.2 to 5 and 0.1 to 250 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 1000 mg; and such therapy may extend for a number of weeks or months.
No unacceptable toxicological effects are indicated with compounds of the invention when administered in accordance with the invention.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The following Descriptions and Examples illustrate the preparation of the compounds of the invention.
Abbreviations
tβuOH = te/f-Butanol DCM = Dichloromethane DMF = N,N-Dimethylformamide EtOAc = Ethyl acetate MeOH = Methanol MgS04 = Magnesium sulfate HCI - Hydrochloric acid
Description 1 (D1) 3-Dimethylamino-4'-fluoropropiophenone hydrochloride To a solution of 4'-fluoroacetophenone (5g, 36.2mmol) in propan-2-ol (90ml) was added paraformaldehyde (4.35g, 0.145mol), dimethylamine hydrochloride (54.2mmol) and concentrated HCI (0.8ml). The reaction was heated at reflux for 18h and on cooling the solvent was removed in vacuo. The residue was treated with acetone giving a white precipitate which was collected by filtration and dried in vacuo to give the title compound as a white solid (7.9g). MS (ES): MH+ 196.
Description 2 (D2)
Ethyl 6-(4-fluorophenyl)-2-methyl nicotinate
A solution of 3-dimethylamino-4'-fluoropropiophenone hydrochloride (D1) (2.4g, 9.3mmol) and ethyl 3-aminocrotonate (1.74ml, 13.8mmol) in absolute ethanol
(30ml) was heated at reflux for 18h. On cooling, the solvent was removed in vacuo to give an orange oil which was purified by column chromatography.
Elution with 0-5% EtOAc/40-60 pet. ether gradient gave the title compound as a pale yellow solid (1.3g). MS(ES): MH+ 260.
Description 3 (D3)
6-(4-Fluorophenyl)nicotinic acid
A solution of ethyl 6-(4-fluorophenyl)-2-methyl nicotinate (D2) (0.63g, 2.4mmol) in
MeOH (12ml) was treated with 2M sodium hydroxide (6ml) for 18h. The mixture was diluted with water and the methanol removed in vacuo. The aqueous residue was extracted with EtOAc then 20% *BuOH/EtOAc and the combined organics were dried over MgSθ4 then concentrated in vacuo to give the title compound as a pale yellow solid (0.40g). MS(ES): MH+ 232, M-H+ 230
Description 4 (D4)
6-(2,4-Difluorophenyl)nicotinic acid The title compound was prepared from 2',4'-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
Description 5 (D5) 6-(3,4-Difluorophenyl)nicotinic acid
The title compound was prepared from 3',4'-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
Description 6 (D6) 6-(2,3-Difluorophenyl)nicotinic acid
The title compound was prepared from 2',3'-difluoroacetophenone using the procedures outlined for 6-(4-fluorophenyl)nicotinic acid (D1-D3).
Description 7 (D7) 2-Phenyl-5-pyrimidinecarboxylic acid
The title compound was prepared using a procedure similar to that outlined in P. Zhichkin, D.J. Fairfax & S.A. Eisenbeis, Synthesis 2002, 6, 720.
Description 8 (D8) 4-Methyl-2-phenyl-5-pyrimidinecarboxylic acid
The title compound was prepared using a procedure similar to that outlined in P. Schenone, L. Sansebastiano & L. Mosti, J. Heterocycl. Chem., 1990, 27, 295.
Description 9 (D9) 2-(4-Fluorophenyl)-4-methyl-5-pyrimidinecarboxylic acid
The title compound was prepared using a procedure similar to that outlined in P. Schenone, L. Sansebastiano & L. Mosti, J. Heterocycl. Chem., 1990, 27, 295 for the synthesis of D8.
Description 10 (D10)
4-(6- ethyl-2-pyridinyl)benzoic acid The title compound was prepared using the procedure outlined in H.K. Rami, M. Thompson, G.J. Macdonald, S.M. Westaway & D.J. Mitchell, International Patent Application, Publication Number WO 03/068749.
Description 11 (D11) 5-Aminobenzothiazole
The title compound was prepared using the procedure outlined in T.L. Cupps ef al, International Patent Application, Publication Number WO 98/23612.
Description 12 (D12)
6-Amino-1 -methyl-1 H-benzimidazole
The title compound was prepared using the procedure outlined in Y.T. Jeon ef al, International Patent Application, Publication Number WO 96/04270.
The following compounds are commercially available:
5-Amino-2-methylbenzothiazole dihydrochloride
5-Amino-2-methylbenzothiazole
6-Amino-(1 H)-benzimidazole
6-Aminoindazole 5-Aminobenzotriazole
4-(4-Chlorophenyl)-cyclohexane-1 -carboxylic acid
4-(2-Fluorophenyl)piperazine
4-(2,4-Difluorophenyl)piperazine
5-Amino-1 -methylindazole
Example 1
6-(4-Fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide
5-Amino-2-methylbenzothiazole dihydrochloride (98mg, 0.41 mmol), 6-(4- fluorophenyl)-2-methylnicotinic acid (D3) (96mg, 0.42mmol), 1-(3-dimethyl- aminopropyl)-3-ethylcarbodiimide hydrochloride (119mg, 0.62mmol) and 4- dimethylaminopyridine (25mg, 0.21 mmol) in DCM (2ml) were stirred at room temperature overnight. The reaction mixture was purified directly by column chromatography, eluting with a 0-10%MeOH/DCM gradient to give the title compound as a white solid. 1H NMR (400MHz, DMSO) δ (ppm): 8.42 (d, 1H), 8.21 (dd, 2H), 8.02 (d, 1H), 7.98 (d, 1H), 7.94 (d, 1H), 7.71 (dd, 1H), 7.34 (t, 2H), 2.80 (s, 3H), 2.67 (s, 3H). MS(ES): MH+ 378, M-H+ 376.
The compounds shown in Table 1 were prepared using methods analogous to that described in Example 1.
Table 1
Figure imgf000021_0001
Example 11 N-(1H-Benzimidazol-6-yl)-6-(4-fluorophenyl)-2-methyl-nicotinamide 6-Amino-1 H-benzimidazole (27mg, 0.20mmol), 6-(4-fluorophenyl)-nicotinic acid (D3) (46mg, 0.20mmol), 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (46mg, 0.24mmol) and 4-dimethylaminopyridine (12mg, O.IOmmol) in DCM (1.6ml) were stirred at room temperature overnight. The reaction mixture was purified directly by column chromatography, eluting with a 0-5%MeOH/DCM gradient to give the title compound. MS(ES): MH+ 347, M-H+ 345.
The compounds shown in Table 2 were prepared using methods analogous to that described in Example 11.
Table 2
Figure imgf000022_0001
Example 15 4-(4-Chlorophenyl)-Λ/-(2-methylbenzothiazol-5-yl)cyclohexane-1- carboxamide.
A suspension of 4-(4-chlorophenyl)-cyclohexane-1-carboxylic acid (100mg, 0.42mmol) in DCM (10ml) was treated with catalytic DMF and oxalyl chloride (110ul, 1.26mmol) at 0°C and the mixture was then stirred at room temp, for 1h and at 45°C for 2h. The solvent and excess oxalyl chloride was removed in vacuo and the residue resuspended in DCM (5ml). To this was added pyridine (35ul, 0.42mmol) and 5-amino-2-methylbenzothiazole (63mg, 0.38mmol) and the reaction stirred at room temp, overnight. MeOH (1ml) was added and the mixture was washed with sat. aq. sodium bicarbonate solution and brine then dried (MgS0 ) and concentrated to give the title compound as an off-white solid (148mg). 1H NMR (400MHz, DMSO) δ (ppm): 8.37 (d, 1 H), 7.96 (d, 1H), 7.63 (dd, 1 H), 7.40 (d, 2H), 7.38 (d, 2H), 2.83 (s, 3H), 2.49-2.63 (m, 2H), 2.04 (m, 2H), 1.94 (m, 2H), 1.69 (m, 2H), 1.53 (m, 2H). MS(ES): MH+ 385/387, M-H+ 383/385.
Example 16 4-(2-Fluorophenyl)-Λ/-(2-methylbenzothiazol-5-yl)-1-piperazine carboxamide To a stirred solution of 5-amino-2-methylbenzothiazole (100mg, 0.61mmol) and triethylamine (170ul, 1.22mmol) in DCM (5mi) at 0°C under an argon atmosphere was added triphosgene (60mg, 0.2mmol). The mixture was warmed to room temp, and stirred for 1 h. 4-(2-Fluorophenyl)piperazine (110mg, 0.61 mmol) was added and the reaction was stirred at room temp, overnight. The solvent was removed in vacuo and the residue purified by chromatography eluting with a 0- 100% EtOAc/petroIeum ether gradient to give the title compound as a pale yellow solid (69mg). 1H NMR (400MHz, CDCI3) δ (ppm): 7.82 (d, 1 H), 7.71 (d, 1 H), 7.53 (dd, 1 H), 6.92-7.10 (m, 4H), 6.65 (s, 1 H), 3.69 (m, 2H), 3.13 (m, 2H), 2.81 (s, 3H). MS(ES): MH+ 371 , M-H+ 369.
Example 17
4-(2,4-Difluorophenyl)-Λ/-(2-methylbenzothiazol-5-yl)-1-piperazine carboxamide Using the procedure outlined in Example 16, the title compound was prepared from 5-amino-2-methylbenzothiazole (100mg, 0.61 mmol) and 4-(2,4- difluorophenyl)piperazine (121mg, 0.61mmol) as a pale yellow solid (95mg). 1H NMR (400MHz, CDCI3) δ (ppm): 7.82 (d, 1 H), 7.71 (d, 1 H), 7.52 (dd, 1 H), 6.76- 6.94 (m, 3H), 6.74 (s, 1 H), 3.68 (m, 2H), 3.04 (m, 2H), 2.80 (s, 3H).
Example 18
6-(4-Fluorophenyl)-2-methyl-Λ/-(1-methylindazol-5-yl)nicotinamide Using the procedure outlined in Example 15, the title compound was prepared from 6-(4-fluorophenyl)nicotinic acid (D3) (100mg, 0.43mmol) and 5-amino-1- methylindazole (58mg, 0.39mmol) as a white solid (21 mg). MS (ES): MH+ 361 , (M-HV 359.
Pharmacological Data (a) In vitro assay
As referenced above, the compounds of the invention are Vanilloid receptor (VR1) antagonists and hence have useful pharmaceutical properties.
Vanilloid receptor (VR1) antagonist activity can be confirmed and demonstrated for any particular compound by use of conventional methods, for example those disclosed in standard reference texts such as D. Le Bars, M. Gozarin and S. W.
Cadden, Pharmacological Reviews, 2001 , 53(4), 597-652] or such other texts mentioned herein.
The screen used for the compounds of this invention was based upon a FLIPR based calcium assay, similar to that described by Smart et al. (British
Journal of Pharmacology, 2000, 129, 227-230).
Transfected astrocytoma 1321 N1 cells, stably expressing human VR1 , were seeded into FLIPR plates at 25,000cells/well (96-well plate) and cultured overnight. The cells were subsequently loaded in medium containing 4μM Fluo-3
AM (Molecular Probes) for 2 hours, at room temperature, in the dark. The plates were then washed 4 times with Tyrode containing 1.5mM calcium, without probenecid.
The cells were pre-incubated with compound or buffer control at room temperature for 30 minutes. Capsaicin (Sigma) was then added to the cells.
Compounds having antagonist activity against the human VR1 were identified by detecting differences in fluorescence when measured after capsaicin addition, compared with no compound buffer controls. Thus, for example, in the buffer control capsaicin addition results in an increase in intracellular calcium concentration resulting in fluorescence. A compound having antagonist activity blocks the capsaicin binding to the receptor, there is no signalling and therefore no increase in intracellular calcium levels and consequently lower fluorescence. pKb values are generated from the IC50 values using the Cheng-Prusoff equation. All the examples when tested by the above methodology gave a pKb >
7.0.
(b) FCA-induced hyperalgesia in the Guinea pig 100μl of 1mg/ml FCA was injected intraplantar into the left paw of 4 groups of 8 male Dunkin Hartley guinea-pigs (batch: 6282434, average weight 340g). 24 hours later compounds were administered orally at 0 (vehicle), 3, 10 30mg/kg with vehicle as 1% methylcellulose and dosing volume being 2ml/kg and dosing straight into the stomach. The methylcellulose was added gradually to the compound into the pestle and mortar and ground together.
Behavioural readouts of mechanical hyperalgesia were obtained before FCA administration (naϊve reading), after FCA but before drug administration (predose reading) and 1 hour after drug administration. The readout used was paw pressure (Randall-Sellito) and the end point was paw withdrawal. The paw pressure equipment also had one silver disc placed on the point to increase the markings by a factor of 2.
Examples 1 , 2, 3, 4, 5 and 16 were tested in this model and shown to be active.

Claims

1. A compound of formula (I),
Figure imgf000026_0001
(I) or a pharmaceutically acceptable salt or solvate thereof, wherein, P is aryl, heteroaryl, heterocyclyl or cycloalkyl;
W, X and Y form a 5-membered nitrogen containing heteroaromatic ring wherein W, X and Y may be selected from CR1a, NR1b, N, S and O; R1a and R1b independently are -H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl,- (CH2)xOR4 or -(CH2)X NR4R5; R2 is -H, alkyl, alkoxy or halo; R2a is alkyl, alkoxy, halo or CF3; R2b is alkyl, alkoxy, halo or CF3; R3 is -H, halo, alkyl, alkoxy, cycloalkyl, or aryl wherein said aryl group may be optionally substituted by one or more groups R2a; heteroaryl wherein said heteroaryl group may be optionally substituted by one or more groups R2b; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N02, -OH, -OCF3, -CF3, - NR4R5, -S(0)mR6, -S(0)2NR4R5, -OS(0)2R6, -OS(0) 2CF3, -0(CH2)χNR4R5, - 0(CH2)xOR4 -C(0)CF3, -C(0)alkyl, -C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, - C(0)(CH2)xOR6, -C(0)(CH2)xNR4R5, -C(0)alkoxy, -C(0)NR4R5, - (CH2)xC(0)alkoxy, -(CH2)xOC(0)R6, -(CH2)xOR6, -(CH2)XNR4R5, - (CH2)xC(0)NR4R5, -(CH2)xN(R4)C(0)R6, -(CH2)xS(0)2NR4R5, - (CH2)xN(R4)S(0)2R6, -ZAr, -(CH2)xS(0)2R6, -(OCH2)xS(0)2R6, -0(CH2)xS(0)2R6, - N(R4)S(0)2R6, -N(R4)C(0)R6 or -(CH2)xC(0)alkyl;
R4 and R5 may be the same or different and represent -H or alkyl or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
R6 is -H, alkyl or aryl; R7 is -H , alkyl or aryl; Ar is aryl or heteroaryl; m is 0, 1 or 2; r is 0, 1 , 2 or 3; s is O, 1 , 2, 3, 4, 5 or 6; x is 0, 1 , 2, 3, 4, 5 or 6; and
Z is a bond, O, S, NR7 or CH2.
2. A compound according to claim 1 wherein P is phenyl, pyridyl, pyrimidinyl, piperazinyl or cyclohexyl.
3. A compound according to claim 1 or 2 wherein the 5-membered nitrogen containing heteroaromatic ring formed from W, X and Y and the phenyl ring to which it is fused form a benzothiazole, benzotriazole, benzimidazole, indazole, benzisoxazole or benzoxazole group.
4. A compound according to any one of the preceding claims wherein R1a and R1b are selected from -H or alkyl.
5. A compound according to any one of the preceding claims wherein R2 is alkyl, alkoxy or halo.
6. A compound according to any one of the preceding claims wherein R3 is halo, alkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms.or heteroaryl wherein said heteroaryl group may be optionally substituted by alkyl.
7. A compound according to any one of the preceding claims wherein r is 0.
8. A compound according to any one of the preceding claims wherein s is 1 or 2.
9. A compound according to claim 8 wherein when s is 1 , R3 is phenyl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by alkyl, and when s is 2, one R3 is phenyl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by alkyl and the other is alkyl.
10. A compound according to claim 1 which is a compound of formula (IA):
Figure imgf000028_0001
(IA) or a pharmaceutically acceptable salt or solvate thereof, wherein, P is aryl or heteroaryl; R1 represents -H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl,- (CH2)xOR4 or -(CH2)XNR4R5;
R2 represents -H, alkyl, alkoxy or halo;
R3 represents -H, halo, alkyl, alkoxy, cycloalkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N02, -OH, -OCF3, -CF3, -NR4R5, -S(0)mR6, -S(0)2NR4R5, -OS(0)2R6, -0S(0)2CF3) -0(CH2)xNR R5, -0(CH2)xOR4, -C(0)CF3, -C(0)alkyl, -C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, -C(0)(CH2)xOR6, - C(0)(CH2)χNR4R5, -C(0)alkoxy, -C(0)NR4R5, -(CH2)xC(0)alkoxy, - (CH2)xOC(0)R6, -(CH2)xOR6, -(CH2)XNR4R5, -(CH2)xC(0)NR4R5, - (CH2)xN(R4)C(0)R6, -(CH2)xS(0)2NR4R5, -(CH2)xN(R4)S(0)2R6, -ZAr, - (CH2)xS(0)2R6, -(OCH2)xS(0)2R6, -N(R4)S(0)2R6, -N(R4)C(0)R6, or - (CH2)xC(0)alkyl;
R4 and R5 may be the same or different and represent -H or alkyl or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
R6 represents -H, alkyl or aryl; R7 represents -H or methyl; Ar represents aryl or heteroaryl; x represents an integer 0, 1 , 2, 3, 4, 5 or 6; m is O, 1 or 2;
W, X and Y form a 5-membered nitrogen containing aromatic heterocyclic ring;
Z represents a bond, O, S, NR7 or CH2; and s is an integer value from 1 to 6.
11. A compound according to claim 10 wherein the 5-membered nitrogen containing aromatic heterocyclic ring formed by X, Y and Y (taken together with the phenyl ring) is selected from benzotriazole, benzimidazole or indazole.
12. A compound according to claim 10 or claim 11 wherein P represents phenyl or pyridyl.
13. A compound according to any one of claims 10 to 12 wherein R1 represents hydrogen or alkyl.
14. A compound according to any one of claims 10 to 13 wherein R2 represents hydrogen.
15. A compound according to any one of claims 10 to 14 wherein R3 represents hydrogen, halo, alkyl, aryl wherein said aryl group may be optionally substituted by one or more halo groups; or -0(CH2)xOR4.
16. A compound according to claim 10 which is defined by any one of Examples 11-14 or a pharmaceutically acceptable salt or solvate thereof.
17. A compound according to claim 1 which is a compound of formula (IB):
Figure imgf000029_0001
(IB) or a pharmaceutically acceptable salt or solvate thereof, wherein, P is aryl or heteroaryl; R1 is -H or alkyl;
R2 is halo;
R3 is halo, alkyl, alkoxy, cycloalkyl, aryl wherein said aryl group may be optionally substituted by one or more halo atoms; aralkyl, aralkoxy, cycloalkylalkyl, cycloalkylaikoxy, -CN, -N02, -OH, -OCF3, -CF3, -NR4R5, -S(0)mR6, -S(0)2NR4R5, -OS(0)2R6, -0(CH2)xNR4R5, -0(CH2)xOR4, -C(0)CF3, -C(0)alkyl, - C(0)cycloalkyl, -C(0)aralkyl, -C(0)Ar, -C(0)-(CH2)xOR4, -C(0)-(CH2)xNR4R5, - C(0)alkoxy, -C(0)NR4R5, -(CH2)xC(0)alkoxy, -(CH2)xOC(0)R4, -(CH2)xOR4, - (CH2)XNR4R5, -(CH2)xC(0)NR4R5, -(CH2)xN(R4)C(0)R4, -(CH2)xS(0)2NR4R5, - (CH2)χN(R4)S(0)2R6, -ZAr, -(CH2)xS(0)mR6, -0(CH2)xS(0)mR6, -N(R4)S(0)2R6, - N(R4)C(0)R4 or -(CH2)xC(0)alkyl; R4 and R5 may be the same or different and represent -H, alkyl or aryl or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
R6 is alkyl or aryl; R7 is -H, alkyl or aryl;
Ar is aryl or heteroaryl; x is O, 1 , 2, 3, 4, 5 or 6;
Z is a bond, O, S, NR7 or CH2; m is 0, 1 or 2; r is 0, 1 or 2; and s is an integer value from 1 to 6.
18. A compound according to claim 17 wherein P represents phenyl or pyridyl.
19. A compound according to claim 17 or claim 18 wherein r represents 0.
20. A compound according to any one of claims 17 to 19 wherein R3 represents halo, alkyl or aryl wherein said aryl group may be optionally substituted by one or more halo atoms.
21. A compound according to claim 17 which is defined by any one of Examples 1-4 or a pharmaceutically acceptable salt thereof.
22. A compound according to claim 1 as defined in any one of Examples 5-10 and 15-18 or a pharmaceutically acceptable salt or solvate thereof.
23. A compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt or solvate thereof for use as an active therapeutic substance.
24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.
25. A method for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial in mammal, which method comprises administering to a mammal in need thereof a therapeutically acceptable amount of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt or solvate thereof.
26. The use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of disorders in which antagonism of the Vanilloid (VR1) receptor is beneficial.
27. The method according to claim 25 or the use according to claim 26 wherein the disorder is selected from pain, chronic pain, neuropathic pain, postoperative pain, postrheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, broncho constriction, inflammatory disorders, oesophagitis, heart burn, Barrett's metaplasia, dysphagia, gastroeosophageal relux disorder (GERD), stomach and duodenal ulcers, functional dyspepsia, irritable bowel syndrome, inflammatory bowel disease, colitis, Crohn's disease, pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic, urinary incontinence, cystitis, burns, itch, psoriasis, pruritis and emesis.
28. A process for the production of a compound according to any one of claims 1 to 22 which process comprises:
(a) reacting a compound of formula (II),
Figure imgf000031_0001
GO
wherein, W, X, Y, R2 and r are as defined in claim 1, with a compound of formula
(HI),
Figure imgf000031_0002
(III)
wherein, P, R3 and s are as defined in claim 1; (b) converting a compound of formula (III) into the corresponding acyl chloride with a suitable chlorinating agent, followed by reaction with a compound of formula (II) in the presence of a suitable base in an inert solvent;
(c) where P is heterocyclyl reacting a compound of formula (II) with a compound of formula (IV):
Figure imgf000032_0001
(iv) wherein, P is heterocyclyl and R3 and s are as defined in claim 1 ; and thereafter, as necessary, carrying out one or more of the following reactions: (i) converting one compound of formula (I) into another compound of formula
(i);
(ii) removing any protecting group; or
(iii) preparing a salt or a solvate of the compound so formed.
PCT/GB2004/000543 2003-02-14 2004-02-12 Carboxamide derivatives WO2004072069A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AT04710422T ATE450533T1 (en) 2003-02-14 2004-02-12 CARBOXAMIDE DERIVATIVES
US10/545,283 US7531558B2 (en) 2003-02-14 2004-02-12 Carboxamide derivatives
EP04710422A EP1606289B1 (en) 2003-02-14 2004-02-12 Carboxamide derivatives
DE602004024375T DE602004024375D1 (en) 2003-02-14 2004-02-12 carboxamide
JP2006502267A JP4909068B2 (en) 2003-02-14 2004-02-12 Carboxamide derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0303464.2 2003-02-14
GB0303464A GB0303464D0 (en) 2003-02-14 2003-02-14 Novel compounds
GB0305163.8 2003-03-06
GB0305163A GB0305163D0 (en) 2003-03-06 2003-03-06 Novel compounds

Publications (1)

Publication Number Publication Date
WO2004072069A1 true WO2004072069A1 (en) 2004-08-26

Family

ID=32870953

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/000543 WO2004072069A1 (en) 2003-02-14 2004-02-12 Carboxamide derivatives

Country Status (7)

Country Link
US (1) US7531558B2 (en)
EP (1) EP1606289B1 (en)
JP (1) JP4909068B2 (en)
AT (1) ATE450533T1 (en)
DE (1) DE602004024375D1 (en)
ES (1) ES2337254T3 (en)
WO (1) WO2004072069A1 (en)

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016922A1 (en) * 2003-08-14 2005-02-24 Glaxo Group Limited Carbazole-2-carboxamide derivatives having vanilloid receptor antagonist activity
WO2005016915A1 (en) * 2003-08-14 2005-02-24 Glaxo Group Limited Piperidine/cyclohexane carboxamide derivatives for use as vanilloid receptor modulators
WO2006072736A1 (en) * 2005-01-07 2006-07-13 Sanofi-Aventis N- (heteroaryl) -1h-indole-2-carb0xamide derivatives and their use as vanilloid trpv1 receptor ligands
DE102005012872A1 (en) * 2005-03-19 2006-09-28 Sanofi-Aventis Deutschland Gmbh Substituted, bicyclic 8-pyrrolidino-benzimidazoles, process for their preparation and their use as medicaments
WO2007010144A1 (en) * 2005-07-22 2007-01-25 Sanofi-Aventis N-(heteroaryl)-1-heteroarylalkyl-1h-indole-2-carboxamide derivatives, preparation and use thereof
WO2007010138A2 (en) * 2005-07-22 2007-01-25 Sanofi-Aventis N(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof
WO2007041634A1 (en) * 2005-10-04 2007-04-12 Aventis Pharmaceuticals Inc. Pyrimidine amide compounds as pgds inhibitors
US7384969B2 (en) 2004-08-05 2008-06-10 Sanofi-Aventis N-(1H-indolyl)-1H-indole-2-carboxamide derivatives, their preparation and their therapeutic use
FR2911604A1 (en) * 2007-01-19 2008-07-25 Sanofi Aventis Sa New N-(benzo-heterocyclyl)-1H-indole-2-carboxamides, are TRPV1 receptor antagonists useful e.g. for treating pain, inflammation or gynecological, gastrointestinal or respiratory disorders,
EP1955697A1 (en) * 2005-11-30 2008-08-13 Astellas Pharma Inc. 2-aminobenzamide derivative
FR2919610A1 (en) * 2007-08-02 2009-02-06 Sanofi Aventis Sa New tricyclic N-heteroaryl carboxamide derivatives are transient receptor potential vanilloid 1 inhibitors useful to prevent/treat e.g. pain, inflammation, metabolic disorders, urological disorders, gastrointestinal disorders and psoriasis
US7585878B2 (en) 2003-06-12 2009-09-08 Astellas Pharma Inc. Benzamide derivative or salt thereof
US7772254B2 (en) 2003-09-22 2010-08-10 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US7799807B2 (en) 2003-09-22 2010-09-21 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8153650B2 (en) 2006-12-26 2012-04-10 Sanofi-Aventis N-(amino-heteroaryl)-1H-pyrrolopyridine-2-carboxamides derivatives preparation thereof and their use in therapy
US8557872B2 (en) 2008-01-28 2013-10-15 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
WO2017207340A1 (en) 2016-05-31 2017-12-07 Bayer Pharma Aktiengesellschaft Novel substituted benzimidazole, methods for the production thereof, pharmaceutical preparations containing same, and use thereof to produce medicaments
WO2018060072A1 (en) 2016-09-29 2018-04-05 Bayer Pharma Aktiengesellschaft New substituted benzimidazoles, methods for the production of same, pharmaceutical preparations containing same, and use of same to produce drugs
WO2018060174A1 (en) 2016-09-29 2018-04-05 Bayer Pharma Aktiengesellschaft Substituted benzimidazoles, pharmaceutical preparations containing same, and use of same to produce drugs
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10266530B2 (en) 2016-09-09 2019-04-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
CN115244043A (en) * 2020-04-22 2022-10-25 杰迈肯有限公司 Benzimidazolonyl cinnamamide derivative as TRPV1 antagonist and pharmaceutical composition for treating or preventing pain containing the same as active ingredient
US11591544B2 (en) 2020-11-25 2023-02-28 Akagera Medicines, Inc. Ionizable cationic lipids
WO2023091456A1 (en) * 2021-11-17 2023-05-25 Chdi Foundation, Inc. N-(2h-indazol-5-yl)pyrazine-2-carboxamide derivatives and similar compounds as htt modulators for the treatment of huntington's disease
DE102022104759A1 (en) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-crystal screening method, in particular for the production of co-crystals

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040192738A1 (en) * 2003-03-18 2004-09-30 Aventis Pharma Deutschland Gmbh 2-(Butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridin-3-yl)propyl] benzamide, its use as a medicament, and pharmaceutical preparations comprising it
AR045979A1 (en) * 2003-04-28 2005-11-23 Astrazeneca Ab HETEROCICLIC AMIDAS
JP2007518816A (en) * 2004-01-23 2007-07-12 アムジエン・インコーポレーテツド Vanilloid receptor ligands and their use in the treatment of inflammatory and neuropathic pain
WO2007095124A2 (en) * 2006-02-10 2007-08-23 Transtech Pharma, Inc. Benzazole derivatives, compositions, and methods of use as aurora kinase inhibitors
US8759362B2 (en) * 2008-10-24 2014-06-24 Purdue Pharma L.P. Bicycloheteroaryl compounds and their use as TRPV1 ligands
US8703962B2 (en) * 2008-10-24 2014-04-22 Purdue Pharma L.P. Monocyclic compounds and their use as TRPV1 ligands
US8546388B2 (en) * 2008-10-24 2013-10-01 Purdue Pharma L.P. Heterocyclic TRPV1 receptor ligands
MX2012000435A (en) 2009-07-08 2012-06-01 Dermira Canada Inc Tofa analogs useful in treating dermatological disorders or conditions.
JP6249517B2 (en) * 2012-11-08 2017-12-20 花王株式会社 External preparation for reducing the temperature

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027819A2 (en) * 1998-11-10 2000-05-18 Schering Aktiengesellschaft Antrhranilic acid amides and the use thereof as medicaments
WO2000069849A1 (en) * 1999-05-12 2000-11-23 Ortho-Mcneil Pharmaceutical, Inc. Pyrazole carboxamides useful for the treatment of obesity and other disorders
WO2002008221A2 (en) * 2000-07-20 2002-01-31 Neurogen Corporation Capsaicin receptor ligands
WO2002076946A2 (en) * 2001-03-26 2002-10-03 Novartis Ag Fused pyridine derivatives for use as vanilloid receptor antagonists for treating pain.

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69028934T2 (en) * 1989-02-02 1997-03-20 Yamanouchi Pharma Co Ltd Tetrahydrobenzimidazole derivatives
JP2000095767A (en) * 1998-09-28 2000-04-04 Takeda Chem Ind Ltd Antagonist for gonadotrophic hormone-releasing hormone
JP2001328938A (en) * 2000-03-17 2001-11-27 Yamanouchi Pharmaceut Co Ltd Pharmaceutical containing cyanophenyl derivative as active ingredient
US6897231B2 (en) * 2000-07-31 2005-05-24 Signal Pharmaceuticals, Inc. Indazole derivatives as JNK inhibitors and compositions and methods related thereto
EP1403255A4 (en) * 2001-06-12 2005-04-06 Sumitomo Pharma Rho KINASE INHIBITORS
KR100713137B1 (en) * 2001-06-28 2007-05-02 동화약품공업주식회사 Novel 2,4-difluorobenzamide derivatives
CA2465207C (en) * 2001-11-01 2011-01-04 Icagen, Inc. Pyrazole-amides and -sulfonamides
EP1314733A1 (en) 2001-11-22 2003-05-28 Aventis Pharma Deutschland GmbH Indole-2-carboxamides as factor Xa inhibitors
SI1557411T1 (en) * 2002-07-12 2013-01-31 Astellas Pharma Inc
AU2003252715B2 (en) * 2002-07-30 2009-06-04 Banyu Pharmaceutical Co., Ltd. Antagonist of melanin-concentrating hormone receptor comprising benzimidazole derivative as active ingredient
AU2003299797A1 (en) * 2002-12-19 2004-07-14 Neurogen Corporation Substituted biphenyl-4-carboxylic acid arylamide analogues as capsaicin receptor modulators

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000027819A2 (en) * 1998-11-10 2000-05-18 Schering Aktiengesellschaft Antrhranilic acid amides and the use thereof as medicaments
WO2000069849A1 (en) * 1999-05-12 2000-11-23 Ortho-Mcneil Pharmaceutical, Inc. Pyrazole carboxamides useful for the treatment of obesity and other disorders
WO2002008221A2 (en) * 2000-07-20 2002-01-31 Neurogen Corporation Capsaicin receptor ligands
WO2002076946A2 (en) * 2001-03-26 2002-10-03 Novartis Ag Fused pyridine derivatives for use as vanilloid receptor antagonists for treating pain.

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMCATS [online] 15 November 2001 (2001-11-15), "benzamide, 2-methyl-N-(2-methyl-5-benzothiazolyl)", XP002280691, retrieved from CHEMCATS Database accession no. 2000:949382 *
JANUSZ, JOHN ET AL.: "Vanilloids - Analogues of Capsaicin with antinociceptive /antiinflammatory activity", J. MED. CHEM., vol. 36, - 1993, pages 2595 - 2604, XP001008868 *

Cited By (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7855198B2 (en) 2003-06-12 2010-12-21 Astellas Pharma Inc. Benzamide derivative or salt thereof
US7585878B2 (en) 2003-06-12 2009-09-08 Astellas Pharma Inc. Benzamide derivative or salt thereof
WO2005016915A1 (en) * 2003-08-14 2005-02-24 Glaxo Group Limited Piperidine/cyclohexane carboxamide derivatives for use as vanilloid receptor modulators
WO2005016922A1 (en) * 2003-08-14 2005-02-24 Glaxo Group Limited Carbazole-2-carboxamide derivatives having vanilloid receptor antagonist activity
US7772254B2 (en) 2003-09-22 2010-08-10 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8129388B2 (en) 2003-09-22 2012-03-06 Purde Pharma L.P. Therapeutic agents useful for treating pain
US7994177B2 (en) 2003-09-22 2011-08-09 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US7964606B2 (en) 2003-09-22 2011-06-21 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US7799807B2 (en) 2003-09-22 2010-09-21 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US7582671B2 (en) 2004-08-05 2009-09-01 Sanofi-Aventis Therapeutic use of N-(1H-indolyl)-1H-indole-2-carboxamide derivatives
US7781477B2 (en) 2004-08-05 2010-08-24 Sanofi-Aventis Therapeutic use of N-(1H-Indolyl)-1H-indole-2-carboxamide derivatives
US7384969B2 (en) 2004-08-05 2008-06-10 Sanofi-Aventis N-(1H-indolyl)-1H-indole-2-carboxamide derivatives, their preparation and their therapeutic use
KR101288698B1 (en) * 2005-01-07 2013-07-22 사노피 N-(heteroaryl)-1h-indole-2-carboxamide derivatives and their use as vanilloid trpv1 receptor ligands
US7407950B2 (en) 2005-01-07 2008-08-05 Sanofi-Aventis N-(heteroaryl)-1H-indole-2-carboxamide derivatives and their use as vanilloid TRPV1 receptor ligands
CN101115718B (en) * 2005-01-07 2011-06-08 赛诺菲-安万特 N- (heteroaryl) -1h-indole-2-carb0xamide derivatives and their use as vanilloid TRPV1 receptor ligands
US7557134B2 (en) 2005-01-07 2009-07-07 Sanofi-Aventis N-(heteroaryl)-1H-indole-2-carboxamide derivatives and their use as vanilloid TRPV1 receptor ligands
EA013264B1 (en) * 2005-01-07 2010-04-30 Санофи-Авентис N-(heteroaryl)-1h-indole-2-carboxamide derivatives and their use as vanilloid trpv1 receptor ligands
FR2880625A1 (en) * 2005-01-07 2006-07-14 Sanofi Aventis Sa N- (HETEROARYL) -1H-INDOLE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
WO2006072736A1 (en) * 2005-01-07 2006-07-13 Sanofi-Aventis N- (heteroaryl) -1h-indole-2-carb0xamide derivatives and their use as vanilloid trpv1 receptor ligands
DE102005012872A1 (en) * 2005-03-19 2006-09-28 Sanofi-Aventis Deutschland Gmbh Substituted, bicyclic 8-pyrrolidino-benzimidazoles, process for their preparation and their use as medicaments
TWI386402B (en) * 2005-07-22 2013-02-21 Sanofi Aventis N-(heteroaryl)-1-heteroarylalkyl-1h-indole-2-carboxamide derivatives, preparation thereof and therapeutic use thereof
US8735432B2 (en) 2005-07-22 2014-05-27 Sanofi N-(Heteroaryl)-1-heteroarylalky1-1H-indole-2-carboxamide derivatives, preparation and therapeutic use thereof
WO2007010138A2 (en) * 2005-07-22 2007-01-25 Sanofi-Aventis N(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof
US8318775B2 (en) 2005-07-22 2012-11-27 Sanofi N-(heteroaryl)-1-heteroarylalkyl-1H-indole-2-carboxamide derivatives, preparation and therapeutic use thereof
KR101257969B1 (en) 2005-07-22 2013-04-24 사노피 N-(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and thetapeutic use thereof
JP2009502766A (en) * 2005-07-22 2009-01-29 サノフイ−アベンテイス N (arylalkyl) -1H-pyrrolopyridine-2-carboxamide derivatives, their preparation and their therapeutic use
US7745467B2 (en) 2005-07-22 2010-06-29 Sanofi-Aventis N-(heteroaryl)-1-heteroarylalkyl-1H-indole-2-carboxamide derivatives, preparation and therapeutic use thereof
EA013747B1 (en) * 2005-07-22 2010-06-30 Санофи-Авентис N(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof
EA013748B1 (en) * 2005-07-22 2010-06-30 Санофи-Авентис N-(heteroaryl)-1-heteroarylalkyl-1h-indole-2-carboxamide derivatives, preparation and use thereof
US7763636B2 (en) 2005-07-22 2010-07-27 Sanofi-Aventis N-(arylalkyl)-1H-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof
JP2009502767A (en) * 2005-07-22 2009-01-29 サノフイ−アベンテイス N- (heteroaryl) -1-heteroarylalkyl-1H-indole-2-carboxamide derivatives, their preparation and their use
WO2007010144A1 (en) * 2005-07-22 2007-01-25 Sanofi-Aventis N-(heteroaryl)-1-heteroarylalkyl-1h-indole-2-carboxamide derivatives, preparation and use thereof
FR2888848A1 (en) * 2005-07-22 2007-01-26 Sanofi Aventis Sa N- (ARYLALKYL) -1H-PYRRROLOPYRIDINE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2888847A1 (en) * 2005-07-22 2007-01-26 Sanofi Aventis Sa N- (HETERIARYL) -1-HETEORARYLALKYL-1H-INDOLE-2-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC APPLICATION
WO2007010138A3 (en) * 2005-07-22 2007-04-12 Sanofi Aventis N(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof
WO2007041634A1 (en) * 2005-10-04 2007-04-12 Aventis Pharmaceuticals Inc. Pyrimidine amide compounds as pgds inhibitors
TWI415839B (en) * 2005-10-04 2013-11-21 Aventis Pharma Inc Pyrimidine amide compounds as pgds inhibitors
KR101457966B1 (en) 2005-10-04 2014-11-04 아벤티스 파마슈티칼스 인크. Pyrimidine amide compounds as PGDS inhibitors
CN101538246A (en) * 2005-10-04 2009-09-23 安万特药物公司 Pyrimidine amide compounds as pgds inhibitors
AU2006299428B2 (en) * 2005-10-04 2012-04-26 Aventisub Llc Pyrimidine amide compounds as PGDS inhibitors
US8202863B2 (en) 2005-10-04 2012-06-19 Aventis Pharmaceuticals Inc. Pyrimidine amide compounds as PGDS inhibitors
JP2009510170A (en) * 2005-10-04 2009-03-12 アベンティス・ファーマスーティカルズ・インコーポレイテツド Pyrimidineamide compounds as PGDS inhibitors
EP1955697A4 (en) * 2005-11-30 2011-01-26 Astellas Pharma Inc 2-aminobenzamide derivative
JP5169220B2 (en) * 2005-11-30 2013-03-27 アステラス製薬株式会社 2-aminobenzamide derivatives
US8106190B2 (en) 2005-11-30 2012-01-31 Astellas Pharma Inc. 2-aminobenzamide derivatives
EP1955697A1 (en) * 2005-11-30 2008-08-13 Astellas Pharma Inc. 2-aminobenzamide derivative
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US8716273B2 (en) 2006-12-26 2014-05-06 Sanofi N-(amino-heteroaryl)-1H-pyrrolopyridine-2-carboxamides derivatives preparation thereof and their use in therapy
US8153650B2 (en) 2006-12-26 2012-04-10 Sanofi-Aventis N-(amino-heteroaryl)-1H-pyrrolopyridine-2-carboxamides derivatives preparation thereof and their use in therapy
US8716272B2 (en) 2006-12-26 2014-05-06 Sanofi N-(amino-heteroaryI)-1H-pyrrolopyridine-2-carboxamides derivatives preparation thereof and their use in therapy
US7868024B2 (en) 2007-01-19 2011-01-11 Sanofi-Aventis Derivatives of N-(heteroaryl)-1-heteroaryl-1H-indole-2-carboxamides, preparation thereof and therapeutic use thereof
WO2008107544A1 (en) * 2007-01-19 2008-09-12 Sanofi-Aventis Derivatives of n-(heteroaryl)-1-heteroaryl-1h-indol-2-carboxamids, preparation thereof and therapeutic use thereof
FR2911604A1 (en) * 2007-01-19 2008-07-25 Sanofi Aventis Sa New N-(benzo-heterocyclyl)-1H-indole-2-carboxamides, are TRPV1 receptor antagonists useful e.g. for treating pain, inflammation or gynecological, gastrointestinal or respiratory disorders,
US8153796B2 (en) 2007-08-02 2012-04-10 Sanofi-Aventis Tricyclic N-heteroaryl-carboxamide derivatives, preparation and therapeutic use thereof
WO2009050348A1 (en) * 2007-08-02 2009-04-23 Sanofis-Aventis Tricyclic n-heteroaryl-carboxamide derivatives, preparation thereof and therapeutic use of same
US8420817B2 (en) 2007-08-02 2013-04-16 Sanofi Tricyclic N-heteroaryl-carboxamide derivatives, preparation and therapeutic use thereof
FR2919610A1 (en) * 2007-08-02 2009-02-06 Sanofi Aventis Sa New tricyclic N-heteroaryl carboxamide derivatives are transient receptor potential vanilloid 1 inhibitors useful to prevent/treat e.g. pain, inflammation, metabolic disorders, urological disorders, gastrointestinal disorders and psoriasis
EA017808B1 (en) * 2007-08-02 2013-03-29 Санофи-Авентис Tricyclic n-heteroarylcarboxamide derivatives, preparation thereof and therapeutic use thereof
US8557872B2 (en) 2008-01-28 2013-10-15 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
WO2017207340A1 (en) 2016-05-31 2017-12-07 Bayer Pharma Aktiengesellschaft Novel substituted benzimidazole, methods for the production thereof, pharmaceutical preparations containing same, and use thereof to produce medicaments
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US10266530B2 (en) 2016-09-09 2019-04-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
US10435405B2 (en) 2016-09-09 2019-10-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10934288B2 (en) 2016-09-09 2021-03-02 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11542265B2 (en) 2016-09-09 2023-01-03 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11891388B2 (en) 2016-09-09 2024-02-06 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11795166B2 (en) 2016-09-09 2023-10-24 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2018060174A1 (en) 2016-09-29 2018-04-05 Bayer Pharma Aktiengesellschaft Substituted benzimidazoles, pharmaceutical preparations containing same, and use of same to produce drugs
WO2018060072A1 (en) 2016-09-29 2018-04-05 Bayer Pharma Aktiengesellschaft New substituted benzimidazoles, methods for the production of same, pharmaceutical preparations containing same, and use of same to produce drugs
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
US11492354B2 (en) 2018-02-20 2022-11-08 Incyte Corporation Indazole compounds and uses thereof
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US11731958B2 (en) 2018-02-20 2023-08-22 Incyte Corporation Carboxamide compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
US11866426B2 (en) 2018-08-08 2024-01-09 Incyte Corporation Benzothiazole compounds and uses thereof
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
US11787784B2 (en) 2019-08-06 2023-10-17 Incyte Corporation Solid forms of an HPK1 inhibitor
CN115244043A (en) * 2020-04-22 2022-10-25 杰迈肯有限公司 Benzimidazolonyl cinnamamide derivative as TRPV1 antagonist and pharmaceutical composition for treating or preventing pain containing the same as active ingredient
US11591544B2 (en) 2020-11-25 2023-02-28 Akagera Medicines, Inc. Ionizable cationic lipids
WO2023091456A1 (en) * 2021-11-17 2023-05-25 Chdi Foundation, Inc. N-(2h-indazol-5-yl)pyrazine-2-carboxamide derivatives and similar compounds as htt modulators for the treatment of huntington's disease
DE102022104759A1 (en) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-crystal screening method, in particular for the production of co-crystals

Also Published As

Publication number Publication date
US20060148855A1 (en) 2006-07-06
US7531558B2 (en) 2009-05-12
ES2337254T3 (en) 2010-04-22
ATE450533T1 (en) 2009-12-15
JP4909068B2 (en) 2012-04-04
EP1606289B1 (en) 2009-12-02
DE602004024375D1 (en) 2010-01-14
EP1606289A1 (en) 2005-12-21
JP2006517574A (en) 2006-07-27

Similar Documents

Publication Publication Date Title
EP1606289B1 (en) Carboxamide derivatives
EP1480954B1 (en) Vanilloid receptor modulators
AU2004264409B2 (en) Heterocyclic N-aryl carboxamides as cytokine inhibitors
JP4865702B2 (en) Cytokine inhibitor
JP4463552B2 (en) New compounds
JP5411927B2 (en) Pyrazole compounds as CCR1 antagonists
RU2411237C2 (en) PYRIDINE-2-CARBOXAMIDE DERIVATIVES AS mGluR5 ANTAGONISTS
CA2941581C (en) Novel compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions comprising the same
WO2005016922A1 (en) Carbazole-2-carboxamide derivatives having vanilloid receptor antagonist activity
US20060264425A1 (en) Novel anthranilamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors
JP5069119B2 (en) Nicotinamide pyridine urea as a vascular endothelial growth factor (VEGF) receptor kinase inhibitor
JP2005516951A (en) Urea derivatives and their use as vanilloid receptor antagonists
SK280356B6 (en) Methanoanthracene derivatives, process for their preparation, intermediates for their preparation and pharmaceutical compositions containing mentioned derivatives
US7514562B2 (en) Urea derivatives and their use as vanilloid receptor antagonists in the treatment of pain
US7528150B2 (en) Urea derivatives having vanilloid receptor antagonist activity
EP1603899B1 (en) Heterocyclic urea derivatives for the treatment of pain
EP1867646A1 (en) Cytokine inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2006148855

Country of ref document: US

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 10545283

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2006502267

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2004710422

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2004710422

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 10545283

Country of ref document: US