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WO2006038041A1 - Sels de besylate d’amino-heterocycles a six elements en tant qu’antagonistes du recepteur vanilloide-1 pour le traitement de la douleur - Google Patents

Sels de besylate d’amino-heterocycles a six elements en tant qu’antagonistes du recepteur vanilloide-1 pour le traitement de la douleur Download PDF

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Publication number
WO2006038041A1
WO2006038041A1 PCT/GB2005/050172 GB2005050172W WO2006038041A1 WO 2006038041 A1 WO2006038041 A1 WO 2006038041A1 GB 2005050172 W GB2005050172 W GB 2005050172W WO 2006038041 A1 WO2006038041 A1 WO 2006038041A1
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Prior art keywords
amine
pyrimidin
trifluoromethylphenyl
quinolin
alkyl
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PCT/GB2005/050172
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English (en)
Inventor
Dongwei Cai
A. Brian Jones
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Merck Sharp & Dohme Limited
Merck & Co., Inc.
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Publication of WO2006038041A1 publication Critical patent/WO2006038041A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention is concerned with the besylate salts of substituted nitrogen-containing six- membered amino-heterocycles and analogues and derivatives thereof, which are useful as therapeutic compounds, particularly in the treatment of pain and other conditions ameliorated by the modulation of the function of the vanilloid-1 receptor (VRl).
  • VRl vanilloid-1 receptor
  • the pharmacologically active ingredient of chilli peppers has been recognised for some time to be the phenolic amide capsaicin.
  • the beneficial effects of topical administration of capsaicin as an analgesic is also well established.
  • understanding of the underlying molecular pharmacology mediating these responses to capsaicin has been a more recent development.
  • VRl receptor The receptor for capsaicin, termed the vanilloid VRl receptor, was cloned by Caterina and colleagues at UCSF in 1997 (Nature, 398:816, 1997).
  • VRl receptors are cation channels that are found on sensory nerves that innervate the skin, viscera, peripheral tissues and spinal cord. Activation of VRl elicits action potentials in sensory fibres that ultimately generate the sensation of pain.
  • the VRl receptor is activated not only by capsaicin but also by acidic pH and by noxious heat stimuli. It is also sensitized by a number of inflammatory mediators and thus appears to be a polymodal integrator of painful stimuli.
  • the prototypical VRl antagonist is capsazepine (Walpole et al., J. Med. Chem., 37:1942, 1994) - VRl IC 50 of 42OnM.
  • a novel series of sub-micromolar antagonists has also been reported recently (Lee et al, Bioorg. Med. Chem., 9:1713, 2001), but these reports provide no evidence for in vivo efficacy.
  • a much higher affinity antagonist has been derived from the 'ultra-potent' agonist resiniferatoxin.
  • Iodo-resiniferatoxin (Wahl et al, MoI. Pharmacol, 59:9, 2001) is a nanomolar antagonist of VRl but does not possess properties suitable for an oral pharmaceutical.
  • the present invention provides compounds of formula I: Y-J-L-Z
  • L is NR 1 , O, S or CH 2 ;
  • J is a six-membered heterocycle containing one, two or three nitrogen atoms which is unsubstituted or substituted with up to three substituents, depending on the number of nitrogen atoms present, chosen independently from: halogen; hydroxy; nitro; cyano; isonitrile; C 3 . 7 cycloa]kyl; C ⁇ alkyl; C 2 - 6 alkenyl; C 2 _ 6 alkynyl; C ⁇ alkoxy; C 3 .
  • Q is phenyl, a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, or a six-membered heterocyclic ring containing one, two or three nitrogen atoms, optionally substituted by halogen, C ⁇ alkyl or haloC 1 .
  • Y is naphthalene or a fused 9- or 10-membered heteroaromatic system containing a six- membered heterocyclic ring, as defined above, or a phenyl ring, or a six-membered nitrogen-containing partially saturated ring, fused either to a six-membered heterocyclic ring as defined above or to a five- membered heterocyclic ring as defined above, Y being unsubstituted or substituted with one, two or three groups independently chosen from halogen, hydroxy, cyano, nitro, isonitrile, C ⁇ alkyl, C 2 . 6 alkenyl, C 2 .
  • Z is phenyl, naphthyl, a six-membered heterocyclic ring containing one, two, or three nitrogen atoms or a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, Z being unsubstituted or substituted with one, two or three substituents independently chosen from halogen, hydroxy, cyano, nitro, isonitrile, C ⁇ alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, ImIoC 1 _ 6 alkyl, hydroxyC ⁇ alkyl, aminoCu ⁇ alkyl, Ci.
  • L is preferably NR 1 , particularly NH.
  • L may be CH 2 or NR 1 .
  • J is preferably unsubstituted or substituted by one or two substituents. Most preferably J is unsubstituted or monosubstituted. J may be disubstituted.
  • J is thus preferably an unsubstituted or substituted pyrimidine, pyrazine, pyridazine or triazine. Pyrimidine is particularly favoured. J may be pyridine, which is unsubstituted or substituted, such as unsubstituted pyridine. Substituents on J are preferably chosen independently from halogen, hydroxy, nitro, cyano,
  • Substituents on J may be chosen independently from halogen, hydroxy, nitro, cyano, C ⁇ alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, C ⁇ alkoxy, hydroxyC ⁇ alkyl, aminoC ⁇ alkyl, haloC ⁇ alkyl, haloC ⁇ alkoxy, C ⁇ alkoxycarbonyl, -NR 2 R 3 , -(CH 2 ) P NR 2 R 3 , -CONR 2 R 3 and -CO 2 H.
  • substituents are independently chosen from halogen, hydroxy, nitro, amino, Ci_ 4 alkyl, haloCi 4 alkyl, C 3 5 cycloalkyl and Ci 4 alkoxy.
  • substituents can be chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro, amino, tertiarybutyl, hydroxymethyl, 2,6-dimethylmorpholino, bromo, methylthio, cyano, 2-methylpyrrolidino, morpholino, trifluoromethoxy, hydroxy, N-phenylpiperazinyl, 2,2,2-trifluoroethyl, morpholinomethyl, imidazomethyl, cyclopropylmethoxy, pyridomethoxy, morpholinoethoxy and tetrazolyl.
  • any substituents are chosen from chloro, fluoro, methyl, e
  • any substituents are independently chosen from halogen, hydroxy, nitro, amino, Ci_ 4 alkyl and Ci. 4 alkoxy. Most preferably the substituent is fluoro, methyl, methoxy, nitro or amino.
  • J are pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, pyrimidin-4-yl, pyridazin-4-yl, l,3,5-triazin-2-yl, 5-methoxypyrimidin-4-yl, 5-methylpyrimidin-4-yl, 5-fluoropyrimidin- 4-yl, 2-methoxypyrimidin-4-yl, 2-methylpyrimidin-4-yl, 5-nitropyrimidin-4-yl and 5-aminopyrimidin-4- yl.
  • J are 5-tertiarybutylpyrimidin-4-yl, 2-trifluoromethylpyrimidin-4- yl, 2-hydroxymethylpyrimidin-4-yl, (cis-2,6-dimethy]mo ⁇ holin-4-yl)methylpyrimidin-4-yl, 5- bromopyrimidin-4-yl, 2-methylthio-5-methylpyrimidin-4-yl, 2-cyano-5-methylpyrimidin-4-yl, 2-(2- methylpyrrolidin- l-yl)-5-methylpyrimidin-4-yl, 2-(morpholin-4-yl)-5-methylpyrimidin-4-yl, 2-(2,2,2- trifluoroethoxy)-5-methylpyrimidin-4-yl, 2-methyl-5-aminopyrimidin-4-yl, 2-hydroxypyrimidin-4-yl, 2- cyanopyrimidin-4-yl, 2-(morpholin-4-yl)pyrimidin-4-yl, 2-(morpholin-4-yl)pyrimidin-4
  • J may also be 2-chloropyrimidin-4-yl, 5-trifluoromethylpyridin-4-yl, 5-ethylpyrimidin-4-yl, 2- cyclopropyl-5-methylpyrimidm-4-yl, 5-isopropylpyrimidin-4-yl or pyridin-4-yl.
  • p can be one or two.
  • Q can be pyridyl or phenyl. Q can be unsubstituted.
  • Y is thus preferably an unsubstituted or substituted quinoline, quinazoline, quinoxaline, phthalazine, isoquinoline, cinnoline, naphthyridine, indole, indazole, benzimidazole, benzothiazole, benzoxazole, imidazopyridine, imidazopyridazine, imidazopyrimidine, pyrazolopyridine, pyrazolopyridazine, pyrazolopyrimidine or triazolopyridine.
  • Y may be substituted benzimidazole attached to J via the benzene portion.
  • Y may be quinoxaline attached to L via the benzene portion.
  • Y may be naphthyridine such as 1,8-naphthyridine or 1,5-naphthyridine.
  • Y is most preferably an unsubstituted or substituted quinoline or isoquinoline, particularly a quinoline.
  • Substituents on Y are preferably independently chosen from halogen, hydroxy, cyano, nitro, amino, C ⁇ alkyl, C 2 . 4 alkenyl, C 2 ⁇ alkynyl, haloC ⁇ alkyl, hydroxyC ⁇ alkyl, aminoC ⁇ alkyl, C ⁇ alkoxy and haloCi 4 alkoxy.
  • substituents are hydroxy, halogen, Ci 4 alkyl and haloCi 4 alkyl such as hydroxy, fluorine, methyl, ethyl and trifluoromethyl.
  • the substituents can be halogen, d_ 4 alkyl and haloC ⁇ alkyl such as fluorine, methyl and trifluoromethyl.
  • Y is preferably unsubstituted or substituted with one or two substituents. More preferably Y is unsubstituted or monosubstituted. Y may be naphthalene or a fused 10-membered heteroaromatic ring. Y is generally a fused 10-membered heteroaromatic system.
  • Y include quinolin-8-yl, quinoline -7-yl, 3-methylquinolin-7-yl, quinolin-5-yl, quinolin-6-yl, 6-fluoroquinolin-7-yl, 8-fluoroquinolin-7-yl, 6-trifluoromethylquinolin-7-yl, 8- fluoroquinolin-7-yl and isoquinolin-7-yl.
  • Y include 8-ethylquinolin-7-yl, 1,8- naphthyridin-7-yl, 4-trifluoromethylquinolin-7-yl, 5-fluoroquinolin-7-yl, l,5-naphthyridin-7-yl, 1-methyl- lH-benzimidazol-5-yl, lH-benzimidazol-6-yl, 3-fluoroquinolin-7-yl, 4-hydroxyquinolin-7-yl and quinoxalin-6-yl.
  • Z is preferably a six-membered ring such as pyridazinyl, phenyl or pyridyl preferably phenyl or pyridyl Z is preferably monosubstituted, particular para to the attachment to L.
  • Particular embodiments of Z include 4-trifluoromethylphenyl, 3-trifluoromethylpyrid-6-yl and 2-trifluoromethylpyrid-5-yl. Further embodiments include 4-trifluoromethoxyphenyl and 2-fluoro- 4-trifluoromethylphenyl. Yet further embodiments include 3-trifluoromethylpyridazin-6-yl and 3-fluoro-5-trifluorcmethylpyridin-2-yl.
  • Substituents on Z are preferably independently chosen from halogen, amino, Ci 4 alkyl, haloC ⁇ alkyl, hydroxyC ⁇ alkyl, aminoC ⁇ alkyl, C ⁇ alkoxy and haloCi_ 4 alkoxy. Particular substituents are haloCi_ 4 alkyl such as trifluoromethyl.
  • Z may be substituted by halogen, haloC ⁇ alkyl or haloC 1 . 4 alkoxy. Thus Z may be substituted by trifluoromethyl, rrifluoromethoxy or fluorine.
  • Each R 1 is preferably hydrogen or Ci_ 4 alkyl such as methyl. R 1 is particularly hydrogen.
  • Each R 2 and R 3 is preferably independently hydrogen or C ⁇ alkyl such as methyl.
  • R 2 and R 3 are preferably hydrogen.
  • R 2 and R 3 may form a piperidine, piperazine or morpholine ring, R 2 and R 3 may then be substituted by C ⁇ alkyl, phenyl or pyridyl, particularly when they form a piperazine ring.
  • a particularly preferred subclass of compounds is of formula Ia:
  • Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from hydroxy, halogen, 1IaIoC 1 _ 4 alkyl, Ci_ 4 alkyl, Ci_ 4 alkoxy, haloCi_ 4 alkoxy, nitro and amino;
  • J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from hydroxy, halogen, haloCi_ 4 alkyl, Ci_ 4 alkyl, C 3 .
  • Q is phenyl, a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, or a six-membered heterocyclic ring containing one, two or three nitrogen atoms, optionally substituted by C ⁇ alkyl; each R 2 and R 3 is chosen from H and Ci_ 4 alkyl, or R 2 and R 3 , together with the nitrogen atom to which they are attached, may form a six-membered ring optionally containing an oxygen atom or a further nitrogen atom, which ring is optionally substituted by Ci_ 4 alkyl or Q; p is 1, 2 or 3; as the besylate salt.
  • each R 2 and R 3 is chosen from H and Ci_ 4 alkyl, or R 2 and R 3 , together with the nitrogen atom to which they are attached, may form a six-membered ring optionally containing an oxygen atom or a further nitrogen atom, which ring
  • Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloCi_ 4 alkyl, C ⁇ alkyl, C ⁇ alkoxy, haloCi_ 4 alkoxy, nitro and amino;
  • J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from halogen, haloQ ⁇ alkyl, C ⁇ alkyl, C 3 .
  • Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloC ⁇ alkyl, C ⁇ alkyl, C ⁇ alkoxy, haloCi_ 4 alkoxy, nitro and amino;
  • J is pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from halogen, haloC 1 . 4 alkyl, Q ⁇ alkyl, C 1 ⁇ aIkOXy, haloCi. 4 alkoxy, nitro and amino; wherein J is substituted at positions meta to each other by NH and Y;
  • Z is phenyl or pyridyl optionally substituted with one or two substituents independently selected from halogen, hak>Ci_ 4 alkyl, Q ⁇ alkyl, C 1 ⁇ aIk oxy, haloC ⁇ alkoxy, nitro and amino; as the besylate salt.
  • Y is particularly quinoline or isoquinoline and is unsubstituted or monosubstituted.
  • Preferred substituents include hydroxy, trifluoromethyl, fluorine, methyl and ethyl such as fluoro and methyL Y may be quinoline.
  • J can be unsubstituted, monosubstituted or disubstituted with substituents preferably chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro, amino, tertiarybutyl, hydroxymethyl, 2,6- dime thy lmorpholino, bromo, methylthio, cyano, 2-methylpyrrolidino, morpholino, trifluoromethoxy, hydroxy, N-phenylpiperazinyl, 2,2,2-trifluoroethyl, morpholinomethyl, imidazomethyl, cyclopropylmethoxy, pyridomethoxy, morpholinoethoxy and tetrazolyl.
  • the substituents are preferably chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy,
  • J is preferably unsubstituted or monosubstituted with fluorine, methoxy, methyl, amino or nitro.
  • J is preferably pyrimidine.
  • J may be pyridine.
  • J may be triazine.
  • Z is preferably monosubstituted at a position para to the point of attachment to NH. Z may be substituted by F, CF 3 or OCF 3 . The substituent is preferably CF 3 .
  • Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloCi_ 4 alkyl, Q ⁇ alkyl, C ⁇ alkoxy, haloCi_ 4 alkoxy, nitro and amino; J is pyrimidine optionally substituted with one or two substituents independently chosen from halogen, haloCi_ 4 alkyl, Ci. 4 alkyl, C 3 . 5 cycloalkyl, d_ 4 alkoxy, ImIoC 1 .
  • Particular embodiments of Y, J and Z are described above.
  • Particular embodiments of the invention include the besylate salts of: 4-quinolin-8- y 1-N- [4-trifluoromethylphenyl]pyrimidin - 2-amine ; 6-quinolm-8-yl-N-[4-trifluoromethylphenyl]pyrazm-2-amine;
  • 6-fluoroquinolin -7-yl 6-fluoroquinolin -7-yl) -N- [4-trifluoromethylphenyl]pyrimidin-4-amine
  • 6-fluoroquinolin -7-yl 6-fluoroquinolin -7-yl) -N- [4-trifluoromethylphenyl]pyrimidin - 4-amine
  • Further particular embodiments include the besylate salts of: 6-( 8-fluoroquinolin-7- yl) -5-methyl-N- [5-trifluoromethylpyridin -2- yl]pyrimidin-4-amine ;
  • Further preferred embodiments include the besylate salts of: 5-fert-butyl-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin -4-amine;
  • Particular embodiments include: 7-(5-methyl-6- ⁇ 5-trifluoromethylpyridin-2-ylamino]pyrimidin-4-yl)quinolinium benzenesulfonate;
  • alkyl or "alkoxy" as a group or part of a group means that the group is straight or branched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, i- propyl, n-butyl, s -butyl and t-butyl.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
  • Alkylthio shall be construed in an analogous manner. Examples of
  • C 3 . 7 cycloalkyl groups are cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl and methylcyclopropyl groups.
  • hydroxyC ⁇ alkyl means a C ⁇ alkyl group in which one or more (in particular 1 to 3, and especially 1) hydrogen atoms have been replaced by hydroxy groups.
  • Particularly preferred are hydroxyC 1-3 alkyl groups, for example, CH 2 OH, CH 2 CH 2 OH, CH(CH 3 )OH or C(CH 3 ) 2 OH, and most especially CH 2 OH.
  • AminoC 1 . 6 alkyl shall be construed in an analogous manner.
  • haloC ⁇ alkyl and "ImIoC 1 _ 6 alkoxy” means a C ⁇ alkyl or Ci_ 6 alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms.
  • fluoroCi_ 6 alkyl and HUOTOC 1 . 6 alkoxy groups in particular, fluoroQj alkyl and fluoroC ⁇ alkoxy groups, for example, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 ,
  • alkenyl and alkynyl as a group or part of a group means that the group is straight or branched.
  • suitable alkenyl groups include vinyl and allyl.
  • a suitable alkynyl group is acetylene or propargyl.
  • halogen means fluorine, chlorine, bromine and iodine.
  • the most preferred halogens are fluorine and chlorine, especially fluorine.
  • Suitable examples of such esterified carboxy groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • 6-membered heterocycles examples include pyridine, pyrimidine, pyrazine, pyridazine and triazine.
  • 5-membered heterocycles are thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole and tetrazole.
  • Heterocyclic in the above is interchangeable with “heteroaromatic”.
  • the salts may be formed by conventional means, such as by reacting the free base form of the compound of formula I with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the present invention also includes within its scope N-oxides of the compounds of formula I above.
  • N-oxides may be formed on any available nitrogen atom.
  • the N-oxides may be formed by conventional means, such as reacting the compound of formula I with oxone in the presence of wet alumina.
  • the present invention includes within its scope prodrugs of the compounds of formula I above.
  • prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a prodrug may be a pharmacologically inactive derivative of a biologically active substance (the
  • parent drug or “parent molecule” that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • the present invention includes within its scope solvates of the compounds of formula for example, hydrates.
  • the compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the compounds of formula I may also exist in tautomeric forms and the invention includes within its scope both mixtures and separate individual tautomers.
  • the present invention further provides pharmaceutical compositions comprising one or more compounds of formula I in association with a pharmaceutically acceptable carrier or excipient.
  • compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices, suppositories, creams or gels; for oral, parenteral, intrathecal, intranasal, sublingual, rectal or topical administration, or for administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
  • a pharmaceutical carrier e.g.
  • pre-formulation compositions containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Favoured unit dosage forms contain from 1 to 500 mg, for example 1, 5, 10, 25, 50, 100, 300 or 500 mg, of the active ingredient.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • a suitable dosage level is about 1.0 mg to 15 g per day, preferably about 5.0 mg to I g per day, more preferably about 5 mg to 500 mg per day, especially 10 mg to 100 mg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • the invention further provides a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, for use in treatment of the human or animal body.
  • said treatment is for a condition which is susceptible to treatment by modulation (preferably antagonism) of VRl receptors.
  • the compounds of the present invention will be of use in the prevention or treatment of diseases and conditions in which pain and/or inflammation predominates, including chronic and acute pain conditions.
  • Such conditions include rheumatoid arthritis; osteoarthritis; post-surgical pain; musculo ⁇ skeletal pain, particularly after trauma; spinal pain; myofascial pain syndromes; headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; episiotomy pain; burns, and especially primary hyperalgesia associated therewith; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, pain associated with cystitis and labour pain, chronic pelvic pain, chronic prostatitis and endometriosis; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve
  • neuropathic pain conditions such as diabetic neuropathy, chemotherapy- induced neuropathy and post-herpetic neuralgia; "non-painful" neuropathies; complex regional pain syndromes; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage, low back pain, sciatica and ankylosing spondylitis; gout; scar pain; irritable bowel syndrome; inflammatory bowel disease; urinary incontinence including bladder detrusor hyper-reflexia and bladder hypersensitivity; respiratory diseases including chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis, asthma and rhinitis, including allergic rhinitis such as seasonal and perennial rhinitis, and non-allergic rhinitis; autoimmune diseases; and immunodefic
  • conditions that can be treated or prevented by the compounds of the present invention include respiratory diseases such as chronic obstructive pulmonary disease (COPD); chronic bronchitis; cystic fibrosis; asthma; and rhinitis, including allergic rhinitis such as seasonal and perennial rhinitis, non-allergic rhinitis and cough.
  • COPD chronic obstructive pulmonary disease
  • chronic bronchitis cystic fibrosis
  • asthma chronic obstructive pulmonary disease
  • rhinitis including allergic rhinitis such as seasonal and perennial rhinitis, non-allergic rhinitis and cough.
  • the compounds of the present invention may also be useful in the treatment of depression. They may also be used to treat gastro- oesophageal reflux disease (GERD), particularly the pain associated with GERD.
  • GSD gastro- oesophageal reflux disease
  • the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of physiological disorders
  • the present invention also provides a method for the treatment or prevention of physiological disorders that may be ameliorated by modulating VRl activity, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates.
  • the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of respiratory diseases such as cough.
  • the present invention also provides a method for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the present invention also provides a method for the treatment or prevention of respiratory diseases, such as cough, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • any of the aforementioned conditions may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition.
  • the compound of formula I and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or separately.
  • the combination may thus be presented as a unit dosage form, for example a single tablet.
  • a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, as well as opioid analgesics, especially morphine, NR2B antagonists, bradykinin antagonists, anti-migraine agents, anticonvulsants such as oxcarbazepine and carbamazepine, antidepressants (such as TCAs, SSRIs, SNRIs, substance P antagonists, etc.), spinal blocks, gabapentin, pregabalin and asthma treatments (such as ⁇ -adrenergic receptor agonists or leukotriene D 4 antagonists (e.g. montelukast).
  • analgesics such as acetaminophen (paracetamol), aspirin and other NSAIDs, including selective cyclooxygenase-2 (COX-2)
  • Specific anti- inflammatory agents include diclofenac, ibuprofen, indomethacin, nabumetone, ketoprofen, naproxen, piroxicam and sulindac, etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib and tilicoxib.
  • Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof.
  • Suitable anti- migraine agents of use in conjunction with a compound of the present invention include CGRP -antagonists, ergotamines or 5-HT 1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan. Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
  • a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment of a condition or disease in which pain and/or inflammation predominates.
  • the besylate salts can be prepared by adding benzene sulfonic acid to a solution of the free base of compound I in a solvent, such as an aprotic solvent, such as DMF, generally at a temperature of about 40°C.
  • a solvent such as an aprotic solvent, such as DMF
  • a less polar solvent such as isopropyl acetate
  • the solution is generally aged for about 30 minutes, with further addition of the less polar solvent, followed by further ageing for one or two hours.
  • the reaction mixture is generally cooled to 20-25°C, further aged for about two hours and finally filtered, optionally washed and then dried to yield the desired product generally in crystalline form.
  • the following Examples illustrate the present invention.
  • Example 1 7-(5-Methyl-6- ⁇ 5-trifluoromethylpyridin-2-y]amino]pyrimidin-4- yDquinolinium benzenesulfonate
  • benzenesulfonic acid (1.05 eq., 4.3 g, 27.2 mmoi) at 40 0 C.
  • Isopropyl acetate (10 ml) was added into the solution, which was then seeded with the product (10 mg). The solution was aged for 30 min, then more isopropyl acetate (70 ml) was added over 1-2 hours, keeping the internal temperature at ca.
  • the above specified compounds of the present invention have been tested in the following assay and generally possess an IC 50 ⁇ 30OnM and, in the majority of cases, ⁇ 200 nM.
  • Other assays such as electrophysiology using rat VRl expressed in HEK cells measuring activity at various pH levels, can be used.
  • CHO cells stably expressing recombinant rat or human VRl receptors and plated into black-sided 384- well plates, were washed three times with assay buffer (containing Hepes, NaCl 2 , KCl, MgCt, CaCl 2 , sucrose, glucose and probenecid, pH 7.4) and then incubated with test compound and 4uM Fluo-3-AM for 60 minutes at room temperature in darkness. Cells were washed three times more to remove excess dye, before being placed, along with plates containing capsaicin and test compounds into a Molecular Devices FLEPR 384 . The FLEPR 384 simultaneously performed automated pharmacological additions and recorded fluorescence emission from Fluo-3.
  • assay buffer containing Hepes, NaCl 2 , KCl, MgCt, CaCl 2 , sucrose, glucose and probenecid, pH 7.4
  • Antagonists were ranked by absolute efficacy at a single low concentration vs. activation by either pH 5.5 or capsaicin (500 nM) using a medium-throughput electrophysiology assay.
  • TRPVl activity is initially determined using a 5 second application of 500 nM capsaicin.
  • Agonist either pH 5.5 or capsaicin
  • Inhibition of the agonist response is determined following applications of a single concentration of test compound and inhibition is monitored using repeated agonist activation in the presence of the compound until a stable inhibition state is achieved (up to a maximum of 10 minutes of application).

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Abstract

La présente invention concerne un composé de formule I : Y-J-NH-Z (I) (10), selon laquelle : Y est une quinoline ou isoquinoline éventuellement substituée par un ou deux substituants indépendamment sélectionnés parmi les groupes hydroxy, halogène, haloalkyle en C1-4, alkyle en C1-4, alcoxy en C1-4, haloalcoxy en C1-4, nitro et amino ; J est une pyridine, pyridazine, pyrazine, pyrimidine ou triazine éventuellement substituée par un ou deux substituants 15 indépendamment sélectionnés parmi les groupes hydroxy, halogène, haloalkyle en C1-4, alkyle en C1-4, cycloalkyle en C3-5, alcoxy en C1-4, hydroxyalkyle en C1-4, cyano, hydroxy, cycloalcoxy en C1-4, alkylthio en C1-4, haloalcoxy en C1-4, nitro, Q, (CH2)p Q, -NR2R3 , -(CH2)pNR2R3 et -O(CH2)pNR2R3; J étant substitué à des positions méta l’une par rapport à l’autre par NH et Y ; et Z est un phényle ou pyridyle éventuellement substitué par un ou deux substituants indépendamment sélectionnés (20) parmi les groupes halogène, haloalkyle en C1-4, alkyle en C1-4, alcoxy en C1-4, haloalcoxy en C1-4, nitro et amino ; Q est un phényle, un hétérocycle à cinq éléments contenant un, deux, trois ou quatre hétéroatomes sélectionnés parmi O, N et S, un hétéroatome au plus étant O ou S, ou un hétérocycle à six éléments contenant un, deux ou trois atomes d’azote, éventuellement substitué par un alkyle en C1-4 ; R2 et R3 sont chacun sélectionnés parmi H et un alkyle en C1-4, ou bien R2 et R3 peuvent former, avec l’atome d’azote (25) auquel ils sont liés, un cycle à six éléments contenant éventuellement un atome d’oxygène ou un atome d’azote supplémentaire, lequel cycle est éventuellement substitué par un alkyle en C1-4 ou Q ; p est 1, 2 ou 3 ; en tant que sel de bésylate ; les compositions pharmaceutiques le comprenant ; son utilisation dans des méthodes thérapeutiques ; son utilisation pour la fabrication de médicaments ; et ses méthodes d’utilisation pour le traitement des maladies exigeant l’administration d’un antagoniste VR1 (30), comme la douleur, la toux, le reflux gastro-œsophagien pathologique (GERD) et la dépression.
PCT/GB2005/050172 2004-10-08 2005-10-04 Sels de besylate d’amino-heterocycles a six elements en tant qu’antagonistes du recepteur vanilloide-1 pour le traitement de la douleur WO2006038041A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013014060A1 (fr) 2011-07-26 2013-01-31 Boehringer Ingelheim International Gmbh Quinoléines substituées et leur utilisation comme médicaments
WO2015140051A1 (fr) 2014-03-19 2015-09-24 Boehringer Ingelheim International Gmbh Inhibiteurs de sik de type hétéroaryle
US11078204B2 (en) 2018-11-13 2021-08-03 Incyte Corporation Heterocyclic derivatives as PI3K inhibitors
US11161838B2 (en) 2018-11-13 2021-11-02 Incyte Corporation Heterocyclic derivatives as PI3K inhibitors
US11396502B2 (en) 2018-11-13 2022-07-26 Incyte Corporation Substituted heterocyclic derivatives as PI3K inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002008221A2 (fr) * 2000-07-20 2002-01-31 Neurogen Corporation Ligands du recepteur de la capsicine
WO2003099284A1 (fr) * 2002-05-22 2003-12-04 Amgen Inc. Amino-pyridine, derives de pyridine et de pyridazine utilises comme ligands de recepteur vanilloide permettant de traiter une douleur

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002008221A2 (fr) * 2000-07-20 2002-01-31 Neurogen Corporation Ligands du recepteur de la capsicine
WO2003099284A1 (fr) * 2002-05-22 2003-12-04 Amgen Inc. Amino-pyridine, derives de pyridine et de pyridazine utilises comme ligands de recepteur vanilloide permettant de traiter une douleur

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013014060A1 (fr) 2011-07-26 2013-01-31 Boehringer Ingelheim International Gmbh Quinoléines substituées et leur utilisation comme médicaments
WO2015140051A1 (fr) 2014-03-19 2015-09-24 Boehringer Ingelheim International Gmbh Inhibiteurs de sik de type hétéroaryle
WO2015140055A1 (fr) 2014-03-19 2015-09-24 Boehringer Ingelheim International Gmbh Inhibiteurs de syk de type hétéroaryle
WO2015140054A1 (fr) 2014-03-19 2015-09-24 Boehringer Ingelheim International Gmbh Inhibiteurs de syk de type hétéroaryle
US11078204B2 (en) 2018-11-13 2021-08-03 Incyte Corporation Heterocyclic derivatives as PI3K inhibitors
US11161838B2 (en) 2018-11-13 2021-11-02 Incyte Corporation Heterocyclic derivatives as PI3K inhibitors
US11396502B2 (en) 2018-11-13 2022-07-26 Incyte Corporation Substituted heterocyclic derivatives as PI3K inhibitors
US12006320B2 (en) 2018-11-13 2024-06-11 Incyte Corporation Heterocyclic derivatives as PI3K inhibitors

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