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WO2004089877A1 - Hydroxynaphtylamides - Google Patents

Hydroxynaphtylamides Download PDF

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Publication number
WO2004089877A1
WO2004089877A1 PCT/SE2004/000573 SE2004000573W WO2004089877A1 WO 2004089877 A1 WO2004089877 A1 WO 2004089877A1 SE 2004000573 W SE2004000573 W SE 2004000573W WO 2004089877 A1 WO2004089877 A1 WO 2004089877A1
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WIPO (PCT)
Prior art keywords
alkyl
naphthyl
hydroxy
formula
acetamide
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PCT/SE2004/000573
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English (en)
Inventor
Yevgeni Besidski
Didier Rotticci
Shawn Johnstone
Original Assignee
Astrazeneca Ab
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Publication date
Priority claimed from SE0301120A external-priority patent/SE0301120D0/xx
Priority claimed from SE0400102A external-priority patent/SE0400102D0/xx
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2004089877A1 publication Critical patent/WO2004089877A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a new class of compounds, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
  • the present invention further relates to processes for the preparation of said compounds.
  • VRl vanilloid receptor 1
  • VRi Functional studies using VRi indicate that it is also activated by noxious heat , tissue acidification) and other inflammatory mediators (Tominaga,M., Caterina,M.J. et.al. Neuron (1998) v.21, p.531-543).
  • Expression of VRl is also regulated after peripheral nerve damage of the type that leads to neuropathic pain. These properties of VRl make it a highly relevant target for pain and for diseases involving inflammation.
  • agonists of the VRl receptor can act as analgesics through nociceptor destruction, the use of agonists, such as capsaicin and its analogues, is limited due to their pungency, neurotoxicity and induction of hypothermia.
  • agents that block the activity of VRl should prove more useful.
  • Antagonists would maintain the analgesic properties, but avoid pungency and neurotoxicity side effects.
  • Compounds with VRl inhibitor activity are believed to be of potential use for the treatment and/or prophylaxis of disorders such as pain, especially that of inflammatory or traumatic origin such as arthritis, ischaemia, cancer, fibromyalgia, low back pain and post-operative pain (Walker et al J Pharmacol Exp Ther. (2003) Jan;304(l):56-62).
  • VRl inhibitors are also of potential use for the treatment and/or prophylaxis of the effects of exposure to VRl activators like capsaicin or tear gas, acids or heat (Szallasi ibid). . : ⁇ :• . . > A further portential use relates to the treatment of tolerance to VRl activators.
  • the object of the present invention is to provide novel hydroxynaphthyl amides-derivatives with surprisingly improved characteristics, carrying other substituents in the amino group at the naphtyl ring as previously described.
  • WO 03/014064 discloses phenyl-naphtyl urea derivatives having a vanilloid receptor antagonistic activity. These compounds differ among others, from the compounds of the present invention in a different substitution pattern at the amino group.
  • the object of the present invention is to provide compounds exhibiting an inhibitory activity at vanilloid receptor 1 (VRl).
  • the present invention provides a compound of formula I
  • R 1 is H
  • R 2 is CHR 7 NR 8 R 9 , arylCo-ealkyl or heteroarylCo- 6 alkyl, whereby the aryl and heteroaryl may be fused with a 5 or 6 membered ring and said arylCo- ⁇ alkyl or heteroarylCo -6 alkyl • may be optionally substituted by one or more A;
  • R 3 is H
  • R 4 and R 5 are independently selected from the group consisting of H, halo, nitro and COR 7 ;
  • R 7 is H or C 1-4 alkyl
  • R 8 is H or C ⁇ -4 alkyl
  • R 9 is arylCo- ⁇ alkyl substituted by one or more A, or arylCo- 6 alkyl, which is fused with a 5 or 6 membered ring and said aryl and 5 or 6 membered ring may be optionally substituted by one or more A, or
  • R 8 and R 9 form together a 5, 6 or 7 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which is fused with a 5 or 6 membered ring and said heterocyclic ring and 5 or 6 membered ring may be optionally substituted by one or more A;
  • A is halo, nitro, CHO, CN, OR 7 , COR 14 , R 14 , C ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
  • R 14 and R 15 are independently selected from the group consisting of H, C 1-4 alkyl, heteroarylC 0 - 6 alkyl and arylC 0-6 alkyl; or salts, solvates or solvated salts thereof.
  • R 1 is H
  • R 2 is CHR 7 NR 8 R 9 , arylCo- ⁇ alkyl or heteroarylCo- 6 alkyl s whereby the heteroaryl may be fused with a 5 or 6 membered ring and said arylCo -6 alkyl or heteroarylCo -6 alkyl may be optionally substituted by one or more A;
  • R 3 is H
  • R 4 and R 5 are H;
  • R 7 is H or C ⁇ -4 alkyl;
  • R 8 is H or C ⁇ -4 alkyl
  • R 9 is arylCo-ealkyl substituted by one or more A, or arylCo -6 alkyl, which is fused with a 5 membered ring, or
  • R 8 and R 9 form together a 5, 6 or 7 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which is fused with a 6 membered ring and said heterocyclic ring and 5 or 6 membered ring may be optionally substituted by one or more A;
  • A is halo, nitro, CHO, CN, OR 7 , COR 14 , R 14 , C ⁇ -6 alkyl, C 3-6 cycloalkylC 0 - 6 alkyl,
  • Another embodiment of the invention relates to the compound of formula I, wherein R ⁇ R 3 , R 4 , R 5 and R 7 are H.
  • One embodiment of the invention relates to the compound of formula I wherein A is halo, nitro, OR 7 , COR 14 , R 14 , C ⁇ -6 alkyl, C 0 - 6 alkylC 3-6 cycloalkyl, OC 1-4 haloalkyl or
  • a further embodiment of the invention relates to the compound of formula I wherein: R 1 is H; R 2 is CHR 7 NR 8 R 9 ; and R 7 is H or C ⁇ -2 alkyl; R 8 is H or C 1-2 alkyl; R 9 is arylCo- ⁇ alkyl substituted by one or more A, or arylCo- ⁇ alkyl, which is fused with a 5 or 6 membered ring and said aryl and 5 or 6 membered ring may be optionally substituted by one or more A, or R 8 and R 9 form together a 5, 6 or 7 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which is fused with a 5 or 6 membered ring and said heterocyclic ring and 5 or 6 membered ring may be optionally substituted by*. one or more A.
  • Another embodiment of the invention relates to the compound of formula I, wherein R 8 is H.
  • a further embodiment of the invention relates to the compound of formula I, wherein
  • R 9 is aryl substituted by one or more A.
  • R 9 is phenyl substituted by one or more A.
  • R 9 is phenyl substituted by one or more A, whereby A is independently selected from the group consisting of halo, COR 14 , C 1-4 alkyl or C 0-6 alkylNR 14 R 15 .
  • R 14 and R 15 are C 1-4 alkyl. In a further embodiment R 14 and R 15 are methyl.
  • A is chloro, fluoro, methyl, t-butyl, acetyl and/or dimethylamino.
  • R 9 is phenylmethyl substituted by one or more A, whereby A is halo. In one embodiment A is fluoro. In a further embodiment R 9 is arylCo -6 alkyl, which is fused with a 5 or 6 membered ring and said aryl and 5 or 6 membered ring may be optionally substituted by one or more A. In another embodiment R 9 is phenyl fused with a 5 membered ring.
  • R and R form together a 5 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which is fused with a 6 membered ring and said 6 membered ring may be optionally substituted by one A.
  • R 9 and R 8 form together a 5 membered heterocyclic ring containing one N atom, which is fused with phenyl and optionally substituted by one A.
  • A is nitro.
  • R 2 is fluoromethylphenylamino, dihydroindolyl, indanylamino, (chlorophenyl)methylamino, nitro-dihydro-1-indolyl, (difluorophenyl)methyl]amino, (chlorofluorophenyl)amino, (acetylphenyl)amino, (dimethylamino)phenyl] amino, (butylphenyl)amino, or (difluorophenyl)amino.
  • R 1 is H
  • R 2 is arylCo -6 alkyl or heteroarylC 0-6 alkyl, whereby the aryl or heteroaryl may be fused with a 5 or 6 membered ring and said arylCo- 6 alkyl or heteroarylCo- ⁇ alkyl may be optionally substituted by one or more A.
  • R is arylC ⁇ -3 alkyl optionally substituted by one or more A. 7
  • R is arylC ⁇ -3 alkyl substituted by one or more OR , C 3-6 cycloalkyl or phenyl. 7
  • R is phenylmethyl substituted by one or more OR , C 3-6 cycloalkyl or phenyl.
  • R 2 is aryl optionally substituted by one or more A. In yet a further embodiment R 2 is phenyl optionally substituted by one or more A. In one embodiment R 2 is phenyl substituted by one or more COR 14 , wherein R 14 is aryl.
  • R 2 is phenyl substituted by one or more R 14 , wherein R 14 is heteroarylC 0-6 alkyl containing one N atom.
  • R 2 is phenyl substituted by one or more R 14 , wherein R 14 is imidazole or pyrolle.
  • R 2 is phenyl substituted by one or more OR 7 wherein R 7 is .
  • R 2 is phenyl substituted by one or more OC 1-2 haloalkyl.
  • R 2 is heteroaryl which is fused with a 6 membered ring and said heteroaryl may be optionally substituted by one or more A. In another embodiment R 2 is heteroaryl which is fused phenyl.
  • R 2 is imidazolyl-benzamide, (methoxyphenyl)-cyclopropanecarboxylic acid, diphenyl, benzo[b]thiophene-2-carboxylic acid, benzoyl, trifluoromethoxy-benzamide or pyrrolyl- benzamide.
  • Another embodiment of the invention relates to compounds selected from the group 2-[(3-fluoro-4-methylphenyl)amino]-N-(7-hydroxy- 1 -naphthyl)-acetamide, 2-[(2,3-Dihydroindol- 1 -yl)]-N-(7-hydroxy- 1 -naphthyl)-acetamide, N-(7-Hydroxy- 1 -naphthyl)-2-(indan-5-ylamino)-acetamide, 2-[(4-cMorophenyl)methylamino]-N-(7-hydroxy-l-naphthyl)-acetamide, 2- [(5-nitro-2,3-dihydro- 1 -indolyl)]-N-(7-hydroxy- 1 -naphthyl)-acetamide, 2-[[[(3,4-difluorophenyl)methyl]amino]
  • Yet a further embodiment of the invention relates to the compound (7-hydroxy-l- naphthyl)-carbamic acid 4-methoxybenzyl ester, or salts, solvates or solvated salts thereof.
  • R 1 is H when R 2 is OR 6 , CHR 7 NR 8 R 9 , arylCo -6 alkyl or heteroarylC 0-6 alkyl, whereby the aryl may be fused with a 5 or 6 membered ring and said arylC 0-6 alkyl or heteroarylC 0-6 alkyl may be optionally substituted by one or more A;
  • R 3 is H; R and R are independently selected from the group consisting of H, halo, nitro and
  • R is H or arylCo -6 alkyl optionally substituted by one or more A;
  • R 14 and R 15 are C 1- alkyl and form together a ring
  • A is halo, nitro, CHO, CN, OR 7 , COR 14 , R 14 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0 . 6 alkylC 3-6 cycloalkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, C 0-6 alkylNR 14 R 15 ,
  • alkyl includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i- hexyl or t-hexyl.
  • C ⁇ -3 alkyl having 1 to 3 carbon atoms may be methyl, ethyl, n- propyl or i-propyl.
  • cycloalkyl refers to an optionally substituted, saturated cyclic hydrocarbon ring system.
  • C 3-7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • alkenyl includes both straight and branched chain alkenyl groups.
  • C 2 - 6 alkenyl having 2 to 6 carbon atoms and one or two double bonds may be, but is not limited to vinyl, allyl, propenyl, butenyl, crotyl, pentenyl, or hexenyl.
  • a butenyl group may for example be, buten-2-yl, buten-3-yl or buten-4-yl.
  • alkynyl includes both straight and branched chain alkynyl groups.
  • the term C 2 - 6 alkynyl having 2 to 6 carbon atoms and one or two trippel bonds, may be, but is not limited to etynyl, propargyl, pentynyl or hexynyl.
  • a butynyl group may for example be, butyn-3-yl or butyn-4-yl.
  • aryl and heteroaryl refer to an optionally substituted monocyclic hydrocarbon unsaturated aromatic ring system.
  • aryl may be, but are not limited to, phenyl or naphthalenyl.
  • heteroaryl may be, but are not limited to, furan, thiophene, pyrrole, triazole, pyrazole, pyridazine, pyrimidine, pyrazine, triazine or pyran.
  • arylalkyl and “heteroarylalkyl” refer to a substituent that is attached via the alkyl to an aryl group.
  • heterocyclic ring containing one or more heteroatoms independently selected from N, O or S includes both heteroaromatic rings and heterocyclic rings that are saturated or unsaturated.
  • heterocyclic rings may be, but is not limited to imidazolidinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrrolidinyl or tetrahydropyranyl.
  • the term “5 or 6 membered saturated or partially saturated heterocyclic ring containing one or more heteroatoms independently selected from N, O or S,” may be, but is not limited to morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrrolidinyl or tetrahydropyranyl.
  • the terms “5 or 6 membered ring” includes both aromatic, heteroaromatic rings and heterocyclic rings that are saturated or unsaturated.
  • rings may be, but are not limited to, cyclopentyl, cyclohexyl, furyl, thiophenyl, pyrollyl, pyrolinyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyryl, pyridinyl, piperidinyl, morpholinyl, pyrimidinyl, pyridazinyl or pyrazinyl.
  • the terms "5, 6 or 7 membered heterocyclic ring containing one or more heteroatoms independently selected from N, O or S, which is fused with a 5 or 6 membered ring", or "aryl or heteroaryl which is fused with a 5 or 6 membered ring” includes both aromatic, heteroaromatic rings and heterocyclic rings that are saturated or unsaturated.
  • rings may be, but are not limited to, indoline, indole, indolizine, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, purine, quinoline, quinolizine, isoquinoline, quinozoline, quinoxaline, naphthalene, indene, azulene, oxindole, cinnoline, chroman or isochroman. -
  • haloalkyl refers to an alkyl group as defined above, which is substituted with halo.
  • C 1-6 haloalkyl may be, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or bromopropyl.
  • OC ⁇ -4 haloalkyl may be, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
  • the present invention relates to the use of compounds of formula I as hereinbefore defined as well as to the salts, solvates or solvated salts thereof.
  • Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example an inorganic or organic acid salt.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base.
  • Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomeric and geometric isomers.
  • the invention also relates to any and all tautomeric forms of the compounds of formula I. .
  • Another aspect of the present invention provides processes for preparing compounds of formula I, or salts, solvates or solvated salts thereof. .. . , " •
  • Another embodiment of the invention relates to processes for the preparation of compounds of formula I according to Method A to C, wherein R 1 to R 15 , unless otherwise specified, are defined as in formula I, comprising; Method A
  • Suitable solvents to be used for this reaction may be halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane or amides such as dimethylformamide and dimethylacetamide or aromatic and heteroaromatic compounds such as benzene, toluene, xylene, pyridine and lutidine of ethers such as ethyl ether, tetrahydrofuran and ., dioxan or any mixtures thereof. ' " ⁇ ⁇ - .
  • Catalysts such as heteroaromatic bases like pyridine and lutidine or tertiary amines like triethylamine, N-methylmorpholine and ethyl diisopropylamine may be used as well.
  • the temperature may be between 0 and 80°C and the reaction time between 1 and 30 h.
  • Method B
  • Suitable solvents to be used for this reaction may be halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, or aromatic and heteroaromatic compounds such as benzene, toluene, xylene, pyridine and lutidine or ethers such as ethyl ether, tetrahydrofuran and dioxan or mixtures thereof.
  • halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane
  • aromatic and heteroaromatic compounds such as benzene, toluene, xylene, pyridine and lutidine or ethers such as ethyl ether, tetrahydrofuran and dioxan or mixtures thereof.
  • Catalysts such as tertiary amines like triethylamine, N-methylmorpholine and ethyl diisopropylamine may also be used.
  • the temperature may be between -40 and 20°C and the reaction time between 0.3 and 30 h.
  • Suitable solvents to be used in the second step may be halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane or amides such as dimethylformamide and dimethylacetamide or aromatic and heteroaromatic compounds such as benzene, toluene, xylene, pyridine and lutidine or ethers such as ethyl ether, tetrahydrofuran and dioxin or alcohols such as methanol, ethanol, isopropanol, n-butanol, and the like or mixtures thereof.
  • halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane or amides such as dimethylformamide and dimethylacetamide or aromatic and heteroaromatic compounds such as benzene, toluene, xylene, pyridine and lutidine or ethers such as ethyl ether, tetrahydrofuran and dioxin or alcohol
  • Catalysts such as tertiary amines like triethylamine, N-methylmorpholine and ethyl diisopropylamine may also be used.
  • the temperature may be between 2,0 and 120°C and the reaction time between 1 and 40 h. .
  • the reaction may be carried out in a solvent including halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane or amides such as dimethylformamide and dimethylacetamide or aromatic and heteroaromatic compounds such as benzene, toluene, xylene, pyridine and lutidine or ethers such as ethyl ether, tetrahydrofuran and dioxan.
  • the temperature may be between 0 and 50°C and the reaction time between 1 and 40 h.
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I, or salts, solvates or solvated salts thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • the composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution suspension or emulsion
  • topical administration e.g. as an ointment, patch or cream
  • rectal administration e.g. as a suppository.
  • the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.
  • Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg kg bodyweight at parenteral administration.
  • the typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.
  • compositions may be obtained by conventional procedures well known in the pharmaceutical art.
  • the compounds according to the present invention are useful in therapy.
  • the compounds may be used to produce an inhibitory effect of VRl in mammals, including man.
  • VRl are highly expressed the peripheral nervous system and in other tissues.
  • the compounds of the invention are well suited for the treatment of VRl mediated disorders.
  • the compounds of formula I are expected to be suitable for the treatment of acute and chronic pain, acute and chronic neuropathic, pain and acute and chronic inflammatory pain.
  • Examples of such disorder may be selected from the group comprising arthritis, fibromyalgia, low back pain, post-operative pain, visceral pains like chronic pelvic pain, cystitis, including interstitial cystitis, bowel syndrome (IBS), pancreatitis, ischeamic, sciatia, diabetic neuropathy, multiple sclerosis, HIV neuropathy, asthma, cough and inflammatory bowel disease (IBD).
  • arthritis fibromyalgia
  • low back pain post-operative pain
  • visceral pains like chronic pelvic pain
  • cystitis including interstitial cystitis, bowel syndrome (IBS), pancreatitis, ischeamic, sciatia, diabetic neuropathy, multiple sclerosis, HIV neuropathy, asthma, cough and inflammatory bowel disease (IBD).
  • GSD gastro-esophageal reflux disease
  • psoriasis cancer
  • emesis urinary incontinence
  • hyperactive bladder Other relevant disorders are related to respiratory diseases and may be selected from the group comprising asthma, chronic obstructive lung disease and emphysema, lung fibrosis and interstitial lung disease.
  • the VRl inhibitor(s) may be administrated by either an oral or inhaled route.
  • the respiratory disease may be an acute and chronic illness and may be related to infection(s) and/or exposure to environmental pollution and/or irritants.
  • the compounds of formula I may also be used as antitoxin to treat (over-) exposure to VRl activators like capsaicin, tear gas, acids or heat. Regarding heat, there is a potential use for VRl antagonists in (sun-) burn induced pain, or inflammatory pain resulting from bran injuries.
  • the compounds may further be used for treatment of tolerance to VRl activators.
  • One embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, in therapy.
  • Another embodiment of the invention relates to the use of the compounds of formula I as 5 hereinbefore defined, for treatment of VRl mediated disorders.
  • a further embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of acute and chronic pain disorders.
  • Yet another embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of acute and chronic neuropathic pain.
  • Yet a further embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of acute and chronic inflammatory pain.
  • One embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of arthritis, fibromyalgia, low back pain, post-operative pain, visceral pains like chronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic.
  • Another embodiment of the invention relates to the use of the compounds of formula I as hereinbefore defined, for treatment of sciatia, diabetic neuropathy, multiple sclerosis or HIV neuropathy.
  • a further embodiment of the invention relates to the use of the compounds of formula I as 25 hereinbefore defined, for treatment of asthma, cough, IBD, psoriasis, gastro-esophageal reflux disease (GERD), psoriasis, cancer, emesis, urinary incontinence or hyperactive bladder.
  • GFD gastro-esophageal reflux disease
  • psoriasis cancer, emesis, urinary incontinence or hyperactive bladder.
  • One embodiment of the invention relates to the use of the compound of formula I as hereinbefore defined, in the manufacture of a medicament for treatment of VRl mediated disorders and for treatment of acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain and any other disorder mentioned above.
  • Another embodiment of the invention relates to a method of treatment of VRl mediated disorders and acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain and any other disorder mentioned above, comprising administrering to a mammal, including man in need of such treatment, a therapeutically. ' effective amount of the compounds of formula I, as hereinbefore defined.
  • a further embodiment of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as hereinbefore defined, for use in treatment of VRl mediated disorders and for treatment of acute and chronic pain disorders, acute and chronic neuropathic pain and acute and chronic inflammatory pain and any other disorder mentioned above.
  • the term “therapy” and “treatment” includes prevention and prophylaxis, unless there are specific indications to the contrary.
  • the terms “treat”, “therapeutic” and “therapeutically” should be construed accordingly.
  • inhibitor and “antagonist” mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the ligand.
  • disorder means any condition and disease associated with vanilloid receptor activity.
  • the compounds of formula I, or salts, solvates or solvated salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of VRl related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.
  • 2-Methoxyphenyl acetic acid (0.1 mmol) was dissolved in dimethylformamide (1 ml).
  • Transfected CHO cells stably expessing hVRl (15,000 cells/well) are seeded in 50 ul media in a black clear bottom 384 plate (Greiner) and grown in a humidified incubator (37°C, 2% C0 2 ), 24-30 hours prior to experiment. Subsequently, the media is removed from the cell plate by inversion and 2 ⁇ M Fluo-4 is added using a multidrop (Labsystems).
  • the fluorescence is read using FLIPR filter 1 (em 520-545 nM).
  • a cellular baseline recording is taken for 30 seconds, followed by a 20 ⁇ l addition of 10, titrated half-log concentrations of the test compound, yielding cellular concentration ranging from 3 ⁇ M to 0.1 nM.
  • Data is collected every 2 seconds for a further 5 minutes prior to the addition of a VRl agonist solution: either 50 nM solution of capsaicin or MES (2-[N-morpholino] ethanesulfonic acid) buffer (pH 5.2), by the FLIPR pipettor.
  • the FLIPR continues to collect data for a further 4 'minutes.
  • Compounds having antagonistic are described in this specification.
  • DRGs were dissected out from adult Sprague Dawley rats (100-300 g), and placed on ice in L15 Leibovitz medium.
  • the ganglia were enzyme treated with Collagenase 80 U/ml + Dispase 34 U/ml dissolved in DMEM + 5% serum, over night at 37 °C.
  • cells were triturated with fire polished pasteur pipettes, and seeded in the center of 58 mm diameter Nunc cell dishes coated with Poly-D Lysine (1 mg/ml).
  • the DRGs were cultured in a defined medium without foetal bovine serum, containing Dulbecco's MEM / NUT MIX F- 12 (1:1) without L-glutamine but with pyridoxine, 6 mg/ml D(+)-Glucose, 100 ⁇ g/ml apo-transferrin, 1 mg/ml BSA, 20 ⁇ g/ml insulin, 2 mM L-glutamine, 50 IU/ ml Penicillin, 50 ⁇ g/ml Streptomycin and 0.01 ⁇ g/ml NGF-7S. When the cells had grown for 2 days up to 4 weeks, the experiments were done. Cells were chosen based on size and presence of neurites. Small cells with long processes were used for recording (most likely to be C neurons, with native VRl receptors).
  • the cells were recorded with conventional whole cell voltage clamp patch clamp, using the following solutions (calcium ion free); extracellular solution (in mM): NaCl 137, KCl 5, MgCl 2 * H 2 O 1.2, HEPES 10, glucose
  • capsaicin 500 nM
  • a puff of capsaicin 500 nM was used to determine if the cell expressed VRl receptor. If not, a new cell was chosen. If yes, then the compounds were added in increasing doses before the capsaicin pulse (500 nM), to determine the IC 50 value.
  • Typical IC 5 o values as measured in the assays described above are 10 ⁇ M or less.
  • the IC 50 is below 500 nM.
  • the IC 50 is below 100 nM.
  • the IC 50 is below 10 nM.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule I, dans laquelle R1, R2, R3, R4 et R5 sont tels que définis, y compris les sels, solvates ou sels solvatés correspondants. L'invention concerne également un procédé d'élaboration correspondant, des compositions pharmaceutiques renfermant ces composés, et l'utilisation des composés en question à des fins thérapeutiques. Lesdits composés sont des inhibiteurs de récepteur vanilloïde 1 (VR1) et ils sont utiles dans le traitement d'un certain nombre de troubles, par exemple la douleur neuropathique et inflammatoire aiguë et chronique.
PCT/SE2004/000573 2003-04-14 2004-04-13 Hydroxynaphtylamides WO2004089877A1 (fr)

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SE0301120A SE0301120D0 (sv) 2003-04-15 2003-04-15 New compounds
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WO2006094627A3 (fr) * 2005-03-05 2006-12-07 Bayer Healthcare Ag Utilisation de derives d'hydroxy-tetrahydro-naphthalene
US7994167B2 (en) 2005-05-20 2011-08-09 Gruenenthal Gmbh Pentafluorosulphanyl-substituted compound and its use for producing medicaments
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
US9206182B2 (en) 2009-07-15 2015-12-08 Intellikine Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9290497B2 (en) 2011-01-10 2016-03-22 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US9527847B2 (en) 2012-06-25 2016-12-27 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US9822131B2 (en) 2008-01-04 2017-11-21 Intellikine Llc Certain chemical entities, compositions and methods
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies
US20220313631A1 (en) * 2019-06-07 2022-10-06 The Board Of Trustees Of The University Of Illinois Compounds and methods for the treatment of parasitic infections
DE102022104759A1 (de) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-Kristall-Screening Verfahren, insbesondere zur Herstellung von Co-Kristallen
US12213983B2 (en) 2012-11-01 2025-02-04 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators

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US20130053392A1 (en) * 2010-02-12 2013-02-28 Peter Ebbesen Carbonic anhydrase inhibitors

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006094627A3 (fr) * 2005-03-05 2006-12-07 Bayer Healthcare Ag Utilisation de derives d'hydroxy-tetrahydro-naphthalene
US7994167B2 (en) 2005-05-20 2011-08-09 Gruenenthal Gmbh Pentafluorosulphanyl-substituted compound and its use for producing medicaments
US9822131B2 (en) 2008-01-04 2017-11-21 Intellikine Llc Certain chemical entities, compositions and methods
US9216982B2 (en) 2008-01-04 2015-12-22 Intellikine Llc Certain chemical entities, compositions and methods
US11433065B2 (en) 2008-01-04 2022-09-06 Intellikine Llc Certain chemical entities, compositions and methods
US9655892B2 (en) 2008-01-04 2017-05-23 Intellikine Llc Certain chemical entities, compositions and methods
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
US9206182B2 (en) 2009-07-15 2015-12-08 Intellikine Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9522146B2 (en) 2009-07-15 2016-12-20 Intellikine Llc Substituted Isoquinolin-1(2H)-one compounds, compositions, and methods thereof
USRE46621E1 (en) 2011-01-10 2017-12-05 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US9840505B2 (en) 2011-01-10 2017-12-12 Infinity Pharmaceuticals, Inc. Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1 (2H)-one and methods of use thereof
US10550122B2 (en) 2011-01-10 2020-02-04 Infinity Pharmaceuticals, Inc. Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and methods of use thereof
US11312718B2 (en) 2011-01-10 2022-04-26 Infinity Pharmaceuticals, Inc. Formulations of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one
US9290497B2 (en) 2011-01-10 2016-03-22 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US9527847B2 (en) 2012-06-25 2016-12-27 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US12213983B2 (en) 2012-11-01 2025-02-04 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11944631B2 (en) 2014-04-16 2024-04-02 Infinity Pharmaceuticals, Inc. Combination therapies
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies
US20220313631A1 (en) * 2019-06-07 2022-10-06 The Board Of Trustees Of The University Of Illinois Compounds and methods for the treatment of parasitic infections
DE102022104759A1 (de) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-Kristall-Screening Verfahren, insbesondere zur Herstellung von Co-Kristallen

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