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US20040192728A1 - Quinoline-derived amide modulators of vanilloid VR1 receptor - Google Patents

Quinoline-derived amide modulators of vanilloid VR1 receptor Download PDF

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US20040192728A1
US20040192728A1 US10/770,204 US77020404A US2004192728A1 US 20040192728 A1 US20040192728 A1 US 20040192728A1 US 77020404 A US77020404 A US 77020404A US 2004192728 A1 US2004192728 A1 US 2004192728A1
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Prior art keywords
quinolin
benzamide
neuralgia
methyl
phenyl
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Inventor
Ellen Codd
Scott Dax
Michele Jetter
Mark McDonnell
James McNally
Mark Youngman
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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Priority to AU2004209456A priority Critical patent/AU2004209456A1/en
Priority to US10/770,204 priority patent/US20040192728A1/en
Priority to JP2006502488A priority patent/JP2007527363A/ja
Priority to CA002514940A priority patent/CA2514940A1/fr
Priority to PCT/IB2004/000785 priority patent/WO2004069792A2/fr
Assigned to JANSSEN PHARMACEUTICA N.V. reassignment JANSSEN PHARMACEUTICA N.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DAX, SCOTT L., JETTER, MICHELE, MCDONNELL, MARK, MCNALLY, JAMES J., YOUNGMAN, MARK, CODD, ELLEN
Publication of US20040192728A1 publication Critical patent/US20040192728A1/en
Priority to US12/174,017 priority patent/US8394828B2/en
Abandoned legal-status Critical Current

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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
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    • 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
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention is directed to novel vanilloid receptor VR1 ligands. More particularly, this invention relates to novel quinoline-derived amides that are potent antagonists or agonists of VR1 and exhibit activity in animal models of hyperalgesia and colitis, and are useful for the treatment and prevention of pain conditions in humans including arthritis, and for the treatment of irritable-bowel syndrome and associated conditions.
  • Noxious chemical, thermal and mechanical stimuli excite peripheral nerve endings of small diameter sensory neurons (nociceptors) in sensory ganglia (e. g., dorsal root, nodose and trigeminal ganglia) and initiate signals that are perceived as pain.
  • sensory ganglia e. g., dorsal root, nodose and trigeminal ganglia
  • These neurons are crucial for the detection of harmful or potentially harmful stimuli (heat) and tissue damage (local tissue acidosis and/or stretch) that arise from changes in the extracellular space during inflammatory or ischaemic conditions (Wall, P. D., and Melzack, R., Textbook of Pain, 1994, New York: Churchill Livingstone).
  • Nociceptors transduce noxious stimuli into membrane depolarization that triggers action potential, conducts the action potential from the sensory sites to the synapses in the CNS, and conversion of action potentials invokes a perception of pain, discomfort, and appropriate mechanical/physical protective reflexes.
  • nociception is carried out by ion channels or receptors.
  • Plant derived vanilloid compounds (capsaicin and its ultrapotent analog, resiniferatoxin, etc.) are known to selectively depolarize nociceptors and elicit sensations of burning pain—the sensation that is typically obtained by hot chili peppers. Therefore, capsaicin mimics the action of physiological/endogenous stimuli that activates the “nociceptive pathway”.
  • U.S. Pat. No. 4,786,644 discloses 1-aryl-3-quinoline carboxamides as analgesics and antiinflammatory agents. This patent, however, does not disclose or suggest the compounds, compositions or methods of the present invention.
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m is 0 , 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a direct bond or C 1-4 alkyldiyl optionally substituted with a substituent selected from the group consisting of C 1-8 alkanyl, C 3-8 cycloalkanyl and phenyl optionally substituted with one to three substituents independently selected from the group consisting of C 1-8 alkanyl, halogen, C 1-8 alkanyloxy, hydroxy, fluorinated alkanyl, fluorinated alkanyloxy, amino, di(C 1-3 )alkanylamino, and C 1-3 alkanylamino;
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-12 alkanyl, C 4-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkanyl, and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a C 1-4 alkyldiyl optionally substituted with a substituent selected from the group consisting of C 1-8 alkanyl, C 3-8 cycloalkanyl and phenyl optionally substituted with one to three substituents independently selected from the group consisting of C 1-8 alkanyl, halogen, C 1-8 alkanyloxy, hydroxy, fluorinated alkanyl, fluorinated alkanyloxy, amino, di(C 1-3 )alkanylamino, and C 1-3 alkanylamino;
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-12 alkanyl, C 4-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkanyl, and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m is 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a direct bond or C 1-4 alkyldiyl optionally substituted with a substituent selected from the group consisting of C 1-8 alkanyl, C 3-8 cycloalkanyl and phenyl optionally substituted with one to three substituents independently selected from the group consisting of C 1-8 alkanyl, halogen, C 1-8 alkanyloxy, hydroxy, fluorinated alkanyl, fluorinated alkanyloxy, amino, di(C 1-3 )alkanylamino, and C 1-3 alkanylamino;
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-12 alkanyl, C 1-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkanyl and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino; cyan
  • m is 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a direct bond or C 1-4 alkyldiyl optionally substituted with a substituent selected from the group consisting of C 1-8 alkanyl, C 3-8 cycloalkanyl and phenyl optionally substituted with one to three substituents independently selected from the group consisting of C 1-8 alkanyl, halogen, C 1-8 alkanyloxy, hydroxy, fluorinated alkanyl, fluorinated alkanyloxy, amino, di(C 1-3 )alkanylamino, and C 1-3 alkanylamino;
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-8 alkanyl, C 1-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkyl, and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m is 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is ethen-1,2-diyl
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-12 alkanyl, C 4-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkanyl, halogen, and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a direct bond
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, and cyclohexyl;
  • R 4 is selected from the group consisting of C 1-12 alkanyl, C 4-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkanyl and —N(R 5 )(R 6 ), wherein the alkanyls in any of the foregoing alkanyl-containing substituents of R 4 is optionally substituted with thienyl or phenyl; or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • the present invention is directed to pharamceutical compositions containing compounds of Formula (I), as well as to methods of treatment of diseases and conditions by administration of these compositions, and also to pharmaceutical kits containing them.
  • FIG. 1 Effect of a compound of the invention on Colon Weight Loss. Data presented are mean % inhibition ⁇ s.e. of colon weight loss from 3 experiments following twice daily oral administration of the compound at the doses indicated.
  • FIG. 2 Effect of a compound of the invention on Colon Length. Data presented are mean % inhibition ⁇ s.e. of colon shrinkage from 3 experiments following twice daily oral administration of the compound at the doses indicated
  • FIG. 3 Effect of a compound of the invention on Colon Damage Score. Data presented are mean % inhibition ⁇ s.e. of macroscopic colon damage scores from 3 experiments following twice daily oral administration of the compound at the doses indicated.
  • FIG. 4 Effect of a compound of the invention on Stool Score. Data presented are mean % inhibition ⁇ s.e. of stool scores from 3 experiments following twice daily oral administration of the compound at the doses indicated.
  • FIG. 5 Effect of a compound of the invention on Total Score. Data presented are mean % inhibition ⁇ s.e. of total scores from 3 experiments following twice daily oral administration of the compound at the doses indicated.
  • FIG. 6 Effect of a compound of the invention on MPO. Data presented are mean % inhibition ⁇ s.e. of MPO accumulation from 3 experiments following twice daily oral administration of the compound at the doses indicated.
  • FIG. 7 Effect of a compound of the invention on guinea pig bronchial ring constriction.
  • C a-b refers to a radical containing from a to b carbon atoms inclusive.
  • C 1-3 denotes a radical containing 1, 2 or 3 carbon atoms.
  • “Fluorinated alkyl” refers to a saturated branched or straight chain hydrocarbon radical derived by removal of 1 hydrogen atom from the parent alkane; the parent alkane contains from 1 to 6 carbon atoms with 1 or more hydrogen atoms substituted with fluorine atoms up to and including substitution of all hydrogen atoms with fluorine.
  • Preferred fluorinated alkyls include trifluoromethyl substituted alkyls and perfluorinated alkyls; more preferred fluorinated alkyls include trifluoromethyl, perfluoroethyl, 2,2,2-trifluoroethyl, perfluoropropyl, 3,3,3-trifluoroprop-1-yl, 3,3,3-trifluoroprop-2-yl, 1,1,1,3,3,3-hexafluoroprop-2-yl; a particularly preferred fluorinated alkyl, is trifluoromethyl.
  • Fluorinated alkanyloxy refers to a radical derived from a fluorinated alkyl, radical attached to an oxygen atom with the oxygen atom having one open valence for attachment to a parent structure.
  • Alkyl refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2- methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, buta-1,3die
  • alkanyl alkenyl
  • alkynyl alkynyl
  • alkanyl refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls such as butan-1-yl, butan-2-yl, 2methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like.
  • the alkanyl groups are (C 1-8 ) alkanyl, with (C 1-3 ) being particularly preferred.
  • Alkenyl refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent-alkene.
  • the radical may be in either the cis or trans conformation about the double bond(s).
  • alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.
  • the alkenyl group is (C 2-8 ) alkenyl, with (C 2-3 )
  • Alkynyl refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.
  • the alkynyl group is (C 2-8 ) alkynyl, with (C 2-3 ) being particularly preferred.
  • Alkyldiyl refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne.
  • the two monovalent radical centers can form bonds with the same or different atoms.
  • Typical alkyldiyls include, but are not limited to methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,2-diy
  • alkandiyl alkendiyl and/or alkyndiyl
  • the alkyldiyl group is (C 1-8 ) alkyldiyl, with (C 1-8 ) being particularly preferred.
  • saturated acyclic alkandiyl radicals in which the radical centers are at the terminal carbons e.g., methandiyl; ethan-1,2-diyl; propan-1,3-diyl; butan-1,4-diyl; and the like (also referred to as alkylenos, as defined infra).
  • Vic Alkyldiyl refers to a saturated or unsaturated, branched, straight-chain or cyclic hydrocarbon radical having two adjacent monovalent radical centers derived by the removal of one hydrogen atom from each of two adjacent carbon atoms of a parent alkane, alkene or alkyne. The two monovalent radical centers can form bonds with the same or different atom(s).
  • Typical vic alkyldiyls include, but are not limited to vic ethyldiyls such as ethan-1,2-diyl, ethen-1,2-diyl; vic propyldiyls such as propan-1,2-diyl, cyclopropan-1,2-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, cycloprop-1-en-1,2-diyl, etc.; vic butyldiyls such as butan-1,2-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,2-diyl, but-1-en-1,2-diyl, cyclobut-1-en-1,2-diyl, buta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, but-3-yn-1,2-diy
  • the nomenclature vic alkandiyl, vic alkendiyl and/or vic alkyndiyl is used.
  • the vic alkyldiyl group is (C 2-8 ) vic alkyldiyl, with (C 2-3 ) being particularly preferred.
  • Gam Alkyldiyl refers to a saturated or unsaturated, branched, straight-chain or cyclic hydrocarbon radical having one divalent radical center derived by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The divalent radical center forms bonds with two different atoms.
  • Typical gem alkyldiyls include, but are not limited to gem methanyldiyl; gem ethyldiyls such as ethan-1,1-diyl,ethen-1,1-diyl; gem propyldiyls such as propan-1,1-diyl, propan-2,2-diyl, cyclopropan-1,1-diyl, prop-1-en-1,1-diyl, cycloprop-2-en-1,1-diyl, prop-2-yn-1,1-diyl, etc.; butyldiyls such as butan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl, but-1-en-1,1-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methyl-prop-2-en-1,1
  • the nomenclature gem alkandiyl, gem alkendiyl and/or gem alkyndiyl is used.
  • the gem alkyldiyl group is (C 1-6 ) gem alkyldiyl, with (C 1-3 ) being particularly preferred.
  • Alkyleno refers to a saturated or unsaturated, straight-chain or branched acyclic bivalent hydrocarbon bridge radical derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of an acyclic parent alkane, alkene or alkyne.
  • Typical alkyleno groups include, but are not limited to, methano; ethylenos such as ethano, etheno, ethyno; propylenos such as propano, propeno, prop-1,2-dieno, propyno, etc.; butylenos such as butano, 2-methyl-propano, but-1-eno, but-2-eno, 2-methyl-prop-1-eno, 2-methanylidene-propano, but-1,3-dieno, but-1-yno, but-2-yno, but-1,3-diyno, etc.; and the like.
  • alkano alkeno and/or alkyno
  • the alkyleno group is (C 1-8 ) alkyleno, with (C 1-3 ) being particularly preferred.
  • straight-chain saturated alkano radicals e.g., methano, ethano, propano, butano, and the like.
  • Alkylidene refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by removal of two hydrogen atoms from the same carbon atom of a parent alkane, alkene or alkyne. The divalent radical center forms a double bond with a single atom.
  • Typical alkylidene radicals include, but are not limited to, methanylidene, ethylidenes such as ethanylidene, ethenylidene; propylidenes such as propan-1-ylidene, propan-2-ylidene, cyclopropan-1-ylidene, prop-1-en-1-ylidene, prop-2-en-1-ylidene, cycloprop-2-en-1-ylidene, etc.; butylidenes such as butan-1-ylidene, butan-2-ylidene, 2-methyl-propan-1-ylidene, cyclobutan-1-ylidene, but-1-en-1-ylidene, but-2-en-1-ylidene, but-3-en-1-ylidene, buta-1,3-dien-1-ylidene; cyclobut-2-en-1-ylidene, etc.; and the like.
  • alkanylidene alkenylidene and/or alkynylidene
  • the alkylidene group is (C 1-8 ) alkylidene, with (C 1-3 ) being particularly preferred.
  • acyclic saturated alkanylidene radicals in which the divalent radical is at a terminal carbon e.g., methanylidene, ethan-1-ylidene, propan-1-ylidene, butan-1-ylidene, 2-methyl-propan-1-ylidene, and the like.
  • Alkylidyne refers to a saturated or unsaturated, branched or straight-chain trivalent hydrocarbon radical derived by removal of three hydrogen atoms from the same carbon atom of a parent alkane, alkene or alkyne. The trivalent radical center forms a triple bond with a single atom.
  • Typical alkylidyne radicals include, but are not limited to, methanylidyne; ethanylidyne; propylidynes such as propan-1-ylidyne, prop-2-en-1-ylidyne, prop-2-yn-1-ylidyne; butylidynes such as butan-1-ylidyne, 2-methyl-propan-1-ylidyne, but-2-en-1-ylidyne, but-3-en-1-ylidyne, buta-2,3-dien-1-ylidyne, but-2-yn-1-ylidyne, but-3-yn-1-ylidyne, etc.; and the like.
  • alkanylidyne alkenylidyne and/or alkynylidyne
  • alkylidyne group is (C 1-8 ) alkylidyne, with (C 1-3 ) being particularly preferred.
  • saturated alkanylidyne radicals e.g., methanylidyne, ethanylidyne, propan-1-ylidyne, butan-1-ylidyne, 2-methyl-propan-1-ylidyne, and the like.
  • heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkynyl, heteroalkylidene, heteroalkylidyne, heteroalkyldiyl, vic heteroalkyldiyl, gem heteroalkyldiyl, heteroalkyleno and heteroalkyldiylidene radicals can contain one or more of the same or different heteroatomic groups, including, by way of example and not limitation, epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio (—SS—), epoxythio (—O—S—), epoxylmino (—O—NR′—), imino (—NR′—), biimmino (—NR′—NR′—), azino ( ⁇ N—N ⁇ ), azo (—O—O—), epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio (—SS—), epoxythio (—O
  • Parent aromatic ring system refers to an unsaturated cyclic or polycyclic ring system having a conjugated ⁇ electron system. Specifically included within the definition of “parent aromatic ring system” are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, indane, indene, phenalene, etc.
  • Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like
  • Aryl refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, ple
  • Arylalkyl refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • arylalkanyl arylakenyl and/or arylalkynyl
  • the arylalkyl group is (C 6 - 26 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 6-26 ) and the aryl moiety is (C 5 - 20 ).
  • the arylalkyl group is (C 6 - 13 ), e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1-3 ) and the aryl moiety is (C 5-10 ). Even more preferred arylalkyl groups are phenylalkanyls.
  • alkanyloxy refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen of the alcohol.
  • Typical alkanyloxy groups include, but are not limited to, methanyl; ethanyloxy; propanyloxy groups such as propan-1-yloxy (CH 3 CH 2 CH 2 O—), propan-2-yloxy ((CH 3 ) 2 CHO—), cyclopropan-1-yloxy, etc.; butyanyloxy groups such as butan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy, 2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc.; and the like.
  • the alkanyloxy groups are (C 1-8 ) alkanyloxy groups, with (C 1-3 ) being particularly preferred.
  • Parent Heteroaromatic Ring System refers to a parent aromatic ring system in which one or more carbon atoms are each independently replaced with a heteroatom. Typical heteratoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si etc. Specifically included within the definition of “parent heteroaromatic ring systems” are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, arsindole, chromane, chromene, indole, indoline, xanthene, etc.
  • Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thi
  • Heteroaryl refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, radicals derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole
  • the heteroaryl group is a 5-20 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Specific preferred heteroaryls for the present invention are quinoline, isoquinoline, pyridine, pyrimidine, furan, thiophene and imidazole.
  • “Substituted:” refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • Typical substituents include, but are not limited to, —X, —R, —O ⁇ , ⁇ O, —OR, —O—OR, —SR, —S ⁇ , ⁇ S, —NRR, ⁇ NR, —CX 3 , —CN, —OCN, —SCN, —NCO, —NCS, —NO, —NO 2 , ⁇ N 2 , —N 3 , —NHOH, —S(O) 2 O ⁇ , —S(O) 2 OH, —S(O) 2 R, —P(O)(O ⁇ ) 2 , —P(O)(OH) 2 , —C(O)R, —C(O)X, —C(S)R, —C(S)X,
  • Preferred substituents include hydroxy, halogen, C 1-8 alkyl, C 1-8 alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl, C 1-8 alkylthio, C 3-8 cycloalkyl, C 3-8 cycloalkanyloxy, nitro, amino, C 1-8 alkylamino, C 1-8 dialkylamino, C 3-8 cycloalkylamino, cyano, carboxy, C 1-7 alkanyloxycarbonyl, C 1-7 alkylcarbonyloxy, formyl, carbamoyl, phenyl, aroyl, carbamoyl, amidino, (C 1-8 alkylamino)carbonyl, (arylamino)carbonyl and aryl(C 1-8 alkyl)carbonyl.
  • Aroyl refers to arylacyl substituents.
  • a “phenylC 1-6 alkanylaminocarbonylC 1-6 alkyl” substituent refers to a group of the formula
  • the present invention is directed to a compound of Formula (I):
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a direct bond or C 1-4 alkyldiyl optionally substituted with a substituent selected from the group consisting of C 1-8 alkanyl, C 3-8 cycloalkanyl and phenyl optionally substituted with one to three substituents independently selected from the group consisting of C 1-8 alkanyl, halogen, C 1-8 alkanyloxy, hydroxy, fluorinated alkanyl, fluorinated alkanyloxy, amino, di(C 1-3 )alkanylamino, and C 1-3 alkanylamino;
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 4-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or optionally R 5 and R 6 taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m is 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a C 1-4 alkyldiyl optionally substituted with a substituent selected from the group consisting of C 1-8 alkanyl, C 3-8 cycloalkanyl and phenyl optionally substituted with one to three substituents independently selected from the group consisting of C 1-8 alkanyl, halogen, C 1-8 alkanyloxy, hydroxy, fluorinated alkanyl, fluorinated alkanyloxy, amino, di(C 1-3 )alkanylamino, and C 1-3 alkanylamino;
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-8 alkanyl, C 4-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m is 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a direct bond or C 1-4 alkyldiyl optionally substituted with a substituent selected from the group consisting of C 1-8 alkanyl, C 3-8 cycloalkanyl and phenyl optionally substituted with one to three substituents independently selected from the group consisting of C 1-8 alkanyl, halogen, C 1-8 alkanyloxy, hydroxy, fluorinated alkanyl, fluorinated alkanyloxy, amino, di(C 1-3 )alkanylamino, and C 1-3 alkanylamino;
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-8 alkanyl, C 1-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkyl, and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is ethen-1,2-diyl
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-12 alkanyl, C 4-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkyl, halogen, and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino; cyan
  • m is 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a direct bond or C 1-4 alkyldiyl optionally substituted with a substituent selected from the group consisting of C 1-8 alkanyl, C 3-8 cycloalkanyl and phenyl optionally substituted with one to three substituents independently selected from the group consisting of C 1-8 alkanyl, halogen, C 1-8 alkanyloxy, hydroxy, fluorinated alkanyl, fluorinated alkanyloxy, amino, di(C 1-3 )alkanylamino, and C 1-3 alkanylamino;
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl and cyclohexyl;
  • R 4 is independently selected from the group consisting of C 1-8 alkanyl, C 1-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkyl, and —N(R 5 )(R 6 ); or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • the present invention is directed to a compound of Formula (I) wherein:
  • R 1 is a substituent independently selected from the group consisting of hydrogen; hydroxy; halogen; C 1-8 alkanyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 1-8 alkanyloxy optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl; C 1-8 alkanylthio optionally substituted with one or more substituents independently selected from the group consisting of halogen, fluorinated alkanyl and C 1-8 alkanyloxy; C 3-8 cycloalkanyl; C 3-8 cycloalkanyloxy; nitro; amino; C 1-8 alkanylamino; C 1-8 dialkanylamino; C 3-8 cycloalkanylamino;
  • m is 0, 1 or 2;
  • R 2 is hydrogen or C 1-8 alkanyl
  • L is a direct bond
  • R 3 is selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, and cyclohexyl;
  • R 4 is selected from the group consisting of C 1-8 alkanyl, C 4-8 alkanyloxy, C 3-8 cycloalkanyloxy, C 1-8 alkanylamino, C 3-8 cycloalkanylamino, C 3-14 cyclic heteroalkanyl, C 1-6 fluorinated alkyl, and —N(R 5 )(R 6 ), wherein the alkanyls in any of the foregoing alkanyl-containing substituents of R 4 is optionally substituted with thienyl or phenyl; or when n is 2 or 3, optionally two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkanyl;
  • R 5 is hydrogen, C 1-16 alkyl, alkanylcarbonyl or arylcarbonyl;
  • R 6 is C 4-16 alkyl, alkanylcarbonyl, C 1-3 alkyl substituted with a substituent selected from the group consisting of pyrrolyl, pyridyl, furyl, thienyl, phenyl, and furyl, or arylcarbonyl; or optionally R 6 and one of R 4 taken together form a saturated or partially unsaturated cyclic heteroalkyl or a heteroaryl; or R 5 and R 6 optionally taken together form a bridged or non-bridged cyclic heteroalkanyl, wherein said heteroalkanyl is optionally substituted with C 1-6 alkanylcarbonyl;
  • alkanyls in any of the foregoing alkanyl-containing substituents of R 4 , R 5 or R 6 are optionally and independently substituted with pyrrolyl, pyridyl, furyl, thienyl, phenyl, furyl, C 1-4 alkylpyrrolyl, C 1-4 alkylpyridyl, C 1-4 alkylthienyl, C 1-4 alkylphenyl, or C 1-4 alkylfuryl;
  • n 1, 2 or 3;
  • Z is O or S
  • Embodiments of the present invention also include those wherein for compounds of Formula (I):
  • L is C 1-4 alkyldiyl
  • L is ethen-1,2-diyl, and one R 4 is C 1-6 fluorinated alkanyl;
  • L is ethen-1,2-diyl, and one R 4 is halogen
  • L is ethen-1,2-diyl, n is 2, one R 4 is halogen and the other R 4 is C 1-6 fluorinated alkanyl;
  • R 3 is phenyl
  • R 3 is pyridyl
  • R 3 is thienyl
  • R 3 is furyl
  • R 3 is cyclohexyl
  • n 2 or 3 and R 4 is C 1-12 alkanyl
  • R 4 is —N(R 5 )(R 6 );
  • L is C 1-4 alkyldiyl, R 3 is phenyl, n is 1 and R 4 is C 1-12 alkanyl;
  • R 3 is phenyl, n is 1 and R 4 is —N(R 5 )(R 6 );
  • R 3 is phenyl, n is 2 or 3, and two R 4 substituents taken together form a C 3-14 cyclic heteroalkyl or C 3-14 cyclic alkyl;
  • R 2 is hydrogen
  • the present invention is also directed to a compound selected from the group consisting of
  • the present invention is also directed to a compound selected from the group consisting of
  • the present invention is also directed to a compound selected from the group consisting of
  • the present invention is also directed to a compound selected from the group consisting of
  • the present invention is also directed to a compound selected from the group consisting of
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” ( Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm.Sci., 1997 (Jan), 66, 1, 1).
  • Other salts well known to those in the art may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.
  • Organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as ( ⁇ )-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1999.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
  • a pharmaceutical carrier excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
  • the present invention is directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilising agent(s).
  • Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • the compounds of the general Formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • An alternative means of transdermal administration is by use of a skin patch.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
  • compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or coloring agents.
  • compositions can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously.
  • the compositions will comprise a suitable carrier or diluent.
  • compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate the major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • a therapeutically effective amount for use of the instant compounds or a pharmaceutical composition thereof comprises a dose range of from about 0.001 mg to about 1,000 mg, in particular from about 0.1 mg to about 500 mg or, more particularly from about 1 mg to about 250 mg of active ingredient per day for an average (70 kg) human.
  • a pharmaceutical composition is preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • the therapeutically effective dose for active compounds of the invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of the invention as vanilloid receptor modulators is required for a subject in need thereof.
  • the invention also provides a pharmaceutical or veterinary pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the compounds of Formula (I) are useful in methods for treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of one or more vanilloid receptors. Such methods comprises administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of Formula (I).
  • the compounds of Formula (I) are useful in methods for preventing or treating a chronic- or acute-pain causing diseases or conditions and pulmonary dysfunction, and more particulalry, in treating diseases or conditions that cause inflammatory pain, burning pain, itch or urinary incontinence, and chronic obstructive pulmonary disease.
  • the compounds of Formula (I) are useful for treating diseases and conditions selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite (in particular, venomous snake bite), spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, urinary tract infection, cough asthma, pharyngitis, mucositis, pancreatitis, enteritis, cellulites, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, post-operative ileus, Irritable Bowel Syndrome, Inflammatory Bowel Diseases such as Crohn's Disease and ulcerative colitis,
  • one embodiment of the present invention is a method of treating or preventing ulcerative colitis comprising administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of formulae (I), (II), (III), or (IV).
  • compositions comprising one or more of the compounds of Formula (I) While the present invention also comprises compositions comprising intermediates used in the manufacture of compounds of Formula (I).
  • the respective product of each process step be separated from other components of the reaction mixture and subjected to purification before its use as a starting material in a subsequent step.
  • Separation techniques typically include evaporation, extraction, precipitation and filtration.
  • Purification techniques typically include column chromatography (Still, W. C. et. al., J. Org. Chem. 1978, 43, 2921), thin-layer chromatography, crystallization and distillation.
  • the structures of the final products, intermediates and starting materials are confirmed by spectroscopic, spectrometric and analytical methods including nuclear magnetic resonance (NMR), mass spectrometry (MS) and liquid chromatography (HPLC).
  • ethyl ether, tetrahydrofuran and dioxane are common examples of an ethereal solvent; benzene, toluene, hexanes and cyclohexane are typical hydrocarbon solvents and dichloromethane and dichloroethane are representative halogenhydrocarbon solvents.
  • the free base may be obtained by techniques known to those skilled in the art.
  • the salt may contain one or more equivalents of the acid.
  • HBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • a suitably substituted benzene (IA) was reacted with hexamethylenetetramine and an acid such as trifluoroacetic acid at an elevated temperature preferably at a temperature in the range of 80-100° C., to yield the corresponding compound of formula (IIA).
  • a compound of formula (IIA), prepared as described above was reacted with a Wittig reagent such as ethyl(triphenylphosphoranylidene)acetate (purchased from Aldrich Chemicals) in a suitable solvent such as benzene or toluene at an elevated temperature, preferably at a temperature in a range of 80-100° C. to yield the compound of formula (IB).
  • a Wittig reagent such as ethyl(triphenylphosphoranylidene)acetate (purchased from Aldrich Chemicals) in a suitable solvent such as benzene or toluene at an elevated temperature, preferably at a temperature in a range of 80-100° C.
  • the compound of formula (IB) was reduced by treating with hydrogen gas at an elevated pressure in the range of about 40-50 psi in a suitable solvent such as ethanol or methanol and the like, in the presence of a catalyst such as 10% palladium on carbon at ambient temperature to yield the corresponding compound of formula (IIB).
  • the compound of formula (IIB) was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (IIIB).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a compound of formula (IIA), prepared as described above, was reacted with a Wittig reagent such as (2-carboxyethyl)triphenylphosphonium chloride (prepared as described in the literature, Journal of Organic Chemistry 1962, 3407) in the presence of a strong base such as potassium t-butoxide in a suitable solvent such a tetrahydrofuran or diethylether and the like at a temperature ranging from 0° C. to ambient temperature to yield the compound of formula (IC).
  • a Wittig reagent such as (2-carboxyethyl)triphenylphosphonium chloride (prepared as described in the literature, Journal of Organic Chemistry 1962, 3407)
  • a strong base such as potassium t-butoxide
  • a suitable solvent such as a tetrahydrofuran or diethylether and the like
  • the compound of formula (IC) was reduced by treating with hydrogen gas at an elevated pressure in the range of about 40-50 psi in a suitable solvent such as ethanol or methanol and the like, in the presence of a catalyst such as 10% palladium on carbon at ambient temperature to yield the corresponding compound of formula (IIIC).
  • the compound of formula (VD) was reacted with a Wittig reagent such as ethyl(triphenylphosphoranyl idene)acetate (purchased from Aldrich Chemicals) in a suitable solvent such a benzene or toluene at an elevated temperature, preferably at a temperature in a range of 80-100° C. to yield the compound of formula (VID).
  • a Wittig reagent such as ethyl(triphenylphosphoranyl idene)acetate (purchased from Aldrich Chemicals) in a suitable solvent such a benzene or toluene at an elevated temperature, preferably at a temperature in a range of 80-100° C.
  • the compound of formula (VID) was reduced by treating with hydrogen gas at an elevated pressure in the range of about 40-50 psi in a suitable solvent such as ethanol or methanol and the like, in the presence of a catalyst such as 10% palladium on carbon at ambient temperature to yield the corresponding compound of formula (VIID).
  • the compound of formula (VIID) was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (VIIID).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • the compound of formula (IVE) was reduced by treating with hydrogen gas at an elevated pressure in the range of about 40-50 psi in a suitable solvent such as ethanol or methanol and the like, in the presence of a catalyst such as 10% palladium on carbon at ambient temperature to yield the corresponding compound of formula (VE).
  • the compound of formula (VE) was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (VIE).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a suitably substituted cyano-bromobenzene was reacted with a Grignard reagent such as phenethyl magnesium chloride in a suitable solvent such as diethylether, tetrahydrofuran and the like to yield the corresponding ketone of formula (IF).
  • a Grignard reagent such as phenethyl magnesium chloride
  • a suitable solvent such as diethylether, tetrahydrofuran and the like
  • the compound of formula (IIF) underwent a Heck reaction with an unsaturated substrate such as methyl acrylate in the presence of a palladium catalyst such as palladium acetate and a ligand such as tri-o-tolylphosphine or triphenylphosphine in a solvent such as THF, ether and the like at an elevated temperature, preferably at a temperature in a range of 80-100° C. to yield the corresponding compound of formula (IIIF).
  • a palladium catalyst such as palladium acetate
  • a ligand such as tri-o-tolylphosphine or triphenylphosphine
  • the compound of formula (IIIF) was reduced by treating with hydrogen gas at an elevated pressure in the range of about 40-50 psi in a suitable solvent such as ethanol or methanol and the like, in the presence of a catalyst such as 10% palladium on carbon at ambient temperature to yield the corresponding compound of formula (IVF).
  • the compound of formula (IVF) was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (VF).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a suitably substituted quinoline ester is reacted with an alkyl triflate such as methyl, n-butyl or n-pentyl triflate to yield the corresponding compound of formula (IG).
  • an alkyl triflate such as methyl, n-butyl or n-pentyl triflate
  • the compound of formula (IG) was reduced by treating with hydrogen gas at an elevated pressure in the range of about 40-50 psi in a suitable solvent such as ethanol or methanol and the like, in the presence of a catalyst such as 10% palladium on carbon at ambient temperature to yield the corresponding compound of formula (IIG).
  • the compound of formula (IIG) was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (IIIG).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a suitably substituted nitro-cinnamate was reduced by treating with hydrogen gas at an elevated pressure in the range of about 40-50 psi in a suitable solvent such as ethanol or methanol and the like, in the presence of a catalyst such as 10% palladium on carbon at ambient temperature to yield the corresponding compound of formula (IH).
  • the compound of formula (IH) was reacted with an appropriately substituted aldehyde or ketone in the presence of a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like in a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of about 70-100 ° C. to yield the corresponding amine of formula (IIH).
  • a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like
  • a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of about 70-100 ° C
  • the compound of formula (IIH) could be reacted with a suitably substituted aldehyde and a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like in a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of about 70-100° C. to yield the corresponding amine of formula (IIIH).
  • a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like
  • the compound of formula (IIIH) was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (IVH).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a suitably substituted amino-cinnamate was reacted initially with a suitably substituted aldehyde or ketone and a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like in a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of about 70-100° C.
  • a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like
  • This reaction could be followed, in the same reaction vessel, by reaction with a suitably substituted aldehyde and a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like in a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of about 70-100° C. to yield the corresponding amine of formula (II).
  • a suitably substituted aldehyde and a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like
  • a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of
  • the compound of formula (II) was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (III).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a compound of formula (IH), obtained as described above, was reacted with a suitably substituted aldehyde and a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like in a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of about 70-100° C. to yield the corresponding tertiary amine of formula (IJ).
  • a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like
  • the compound of formula (IJ) was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (IIJ).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a compound of formula (IIA), prepared as described above, was saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (IK).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a suitable substituted aldehyde of formula (IIA) was reacted with the reagent tosylmethylisocyanide (TosMIC) in the presence of a strong base such as potassium t-butoxide or sodium t-butoxide in a solvent such as dimethoxyethane or tetrahydrofuran and the like at a temperature in the range of ⁇ 50° C. to 100° C. to yield the corresponding compound of formula (IL).
  • a strong base such as potassium t-butoxide or sodium t-butoxide
  • a solvent such as dimethoxyethane or tetrahydrofuran and the like
  • the compound of formula (IL) was hydrolyzed by reaction with suitable base such as sodium hydroxide, potassium hydroxide and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at an elevated temperature, preferably a temperature in the range of about 70-100° C. to yield the corresponding compound of formula (IIL).
  • suitable base such as sodium hydroxide, potassium hydroxide and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • the compound of formula (IIL) was reacted with a suitably substituted 3-aminoquinoline with a suitable coupling agent such as HATU, HBTU, 1,1′-carbonyl diimidazole and the like in the presence of an organic base such as diisopropylethylamine or triethylamine and the like, in a suitable solvent such as methylene chloride, dichloroethane, DMF and the like, to yield the corresponding compound of formula (IIIL).
  • a suitable coupling agent such as HATU, HBTU, 1,1′-carbonyl diimidazole and the like
  • organic base such as diisopropylethylamine or triethylamine and the like
  • a suitable solvent such as methylene chloride, dichloroethane, DMF and the like
  • a suitably substituted benzaldehyde ester and the aldehyde portion was reductively aminated with an appropriately substituted amine in the presence of a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like in a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of about 70-100° C. to yield the corresponding amine of formula (IM).
  • a reducing agent such as tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like
  • a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a
  • the compound of formula (IM) was then saponified by reaction with suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding compound of formula (IIM).
  • suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a compound of formula (IN) was reacted with a suitably substituted 3-aminoquinoline with a suitable coupling agent such as HATU, HBTU, 1,1′-carbonyl diimidazole and the like in the presence of an organic base such as diisopropylethylamine or triethylamine and the like, in a suitable solvent such as methylene chloride, dichloroethane, DMF and the like, to yield the corresponding compound of formula (IIIN).
  • a suitable coupling agent such as HATU, HBTU, 1,1′-carbonyl diimidazole and the like
  • organic base such as diisopropylethylamine or triethylamine and the like
  • a suitable solvent such as methylene chloride, dichloroethane, DMF and the like
  • a compound of formula (IIIN) was reacted with a sulfurizing agent such as Lawesson's reagent or phosphorous pentasulfide in a suitable solvent such as benzene, toluene and the like at an elevated temperature, preferably a temperature in the range of about 70-100° C. to yield the corresponding compound of formula (IO).
  • a sulfurizing agent such as Lawesson's reagent or phosphorous pentasulfide
  • a suitable solvent such as benzene, toluene and the like
  • a compound of formula (IJ), obtained as described above, was reacted with glutaraldehyde in the presence of a reducing agent such as sodium borohydride, tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like in a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like at a temperature in the range of ambient temperature to a temperature of about 70-100° C. to yield the corresponding tertiary amine of formula (IO).
  • a reducing agent such as sodium borohydride, tetramethylammonium triacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like
  • a suitable solvent such as dichloroethane, dichloromethane, chloroform, methanol, tetrahydrofuran and the like
  • the compound of formula (IO) was saponified by reaction with suitable base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like in a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like, at a temperature from ambient temperature to a temperature of about 70-100° C. to yield the corresponding carboxylic acid of formula (IIO).
  • suitable base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like
  • a solvent such as ethanol, methanol, aqueous tetrahydrofuran and the like
  • a suitably substituted 3-aminoquinoline (IAA) and a suitably substituted ester was treated with trimethylaluminum in an aprotic solvent, such as 1,2-dichloroethane or toluene, at a temperature in the range of 0-100° C., to yield the corresponding compound of the formula IVAA or VAA.
  • an aprotic solvent such as 1,2-dichloroethane or toluene
  • an acid of the formula (IIBB) was activated with a suitable activating reagent, such as HBTU or CDI or HATU, and a suitable base, such as TEA or DIEA, in a suitable solvent, such as acetonitrile or DMF or dichloromethane, at a temperature range 0-200° C., and subsequently treated with a suitably substituted 3-aminoquinoline (IBB), at a temperature range of 0-200° C. to yield the corresponding compound of the formula (IIIBB).
  • a suitable activating reagent such as HBTU or CDI or HATU
  • a suitable base such as TEA or DIEA
  • a suitable solvent such as acetonitrile or DMF or dichloromethane
  • a suitably substituted aminobenzoic acid was treated with di-tert-butyl dicarbonate and a suitable base, such as sodium hydroxide or sodium carbonate, in a suitable solvent, such as water or dioxane, at a temperature range of 0-100° C., to yield the corresponding compound of the formula (IICC).
  • a suitable base such as sodium hydroxide or sodium carbonate
  • a suitable solvent such as water or dioxane
  • An acid of the formula (IICC) was activated with and a suitable activating reagent, such as HBTU or CDI or HATU, and a suitable base, such as TEA or DIEA, in a suitable solvent, such as acetonitrile or DMF or dichloromethane, at a temperature range 0-200° C., and subsequently treated with a suitably substituted 3-aminoquinoline, at a temperature range of 0-200° C. to yield the corresponding compound of the formula (IIICC).
  • a suitable activating reagent such as HBTU or CDI or HATU
  • a suitable base such as TEA or DIEA
  • a suitable solvent such as acetonitrile or DMF or dichloromethane
  • 4-fluorobenzoic acid was activated with a suitable activating reagent, such as HBTU or CDI or HATU, and a suitable base, such as TEA or DIEA, in a suitable solvent, such as acetonitrile or DMF or dichloromethane, at a temperature range 0-200° C., and subsequently treated with a suitably substituted 3-aminoquinoline (IDD), at a temperature range of 0-200° C., to yield the corresponding compound of the formula (IIDD).
  • a suitable activating reagent such as HBTU or CDI or HATU
  • a suitable base such as TEA or DIEA
  • a suitable solvent such as acetonitrile or DMF or dichloromethane
  • 6-chloronicotinic acid was activated with a suitable activating reagent, such as HBTU or CDI or HATU, and a suitable base, such as TEA or DIEA, in a suitable solvent, such as acetonitrile or DMF or dichloromethane, at a temperature range 0-200° C., and subsequently treated with a suitably substituted 3-aminoquinoline (IEE), at a temperature range of 0-200° C., to yield the corresponding compound of the formula (IIEE).
  • a suitable activating reagent such as HBTU or CDI or HATU
  • a suitable base such as TEA or DIEA
  • a suitable solvent such as acetonitrile or DMF or dichloromethane
  • 5-bromoindoline (IFF) was treated with a suitable ketone or aldehyde and a suitable reducing agent, such as tetramethylammonium triacetoxyborohydride or sodium cyanoborohydride, in a suitable solvent, such as 1,2-dichloroethane or methanol, at a temperature range of 0-100° C., to yield the corresponding compound of the formula (IIFF).
  • a suitable ketone or aldehyde and a suitable reducing agent, such as tetramethylammonium triacetoxyborohydride or sodium cyanoborohydride
  • a suitable solvent such as 1,2-dichloroethane or methanol
  • a compound of the formula (IIIFF) and suitably substituted 3-aminoquinoline was treated with trimethylaluminum in an aprotic solvent, such as 1,2-dichloroethane or toluene, at a temperature in the range of 0-200° C., to yield the corresponding compound of the formula (IVFF).
  • an aprotic solvent such as 1,2-dichloroethane or toluene
  • a compound of the formula (VFF) and suitably substituted 3-aminoquinoline was treated with trimethylaluminum in an aprotic solvent, such as 1,2-dichloroethane or toluene, at a temperature in the range of 0-200° C., to yield the corresponding compound of the formula (VIFF).
  • an aprotic solvent such as 1,2-dichloroethane or toluene
  • a suitable base such as sodium hydride
  • an alkyl halide such as DMF or THF or DMSO
  • a suitable source of hydroxide such as sodium hydroxide or potassium hydroxide
  • a suitable activating reagent such as HBTU or CDI or HATU
  • a suitable base such as TEA or DIEA
  • a suitable solvent such as acetonitrile or DMF or dichloromethane
  • a compound of the formula (IIHH) was treated with a suitable Wittig reagent, such as triethyl phosphonoacetate, a suitable base, such as DBU, and lithium chloride, in a suitable solvent, such as acetonitrile or dichloromethane, at a temperature of 50-200° C., to yield a compound of the formula (IIIHH).
  • a suitable Wittig reagent such as triethyl phosphonoacetate
  • a suitable base such as DBU
  • lithium chloride lithium chloride
  • a compound of the formula (IIIHH) and a suitably substituted 3-aminoquinoline was treated with trimethyl aluminum in a suitable solvent, such as 1,2-dichloroethane or toluene, at a temperature range of 0-200° C., to yield a compound of the formula (IVHH).
  • a suitable solvent such as 1,2-dichloroethane or toluene
  • a compound of the formula (IIIHH) was hydrogenated at 20-80 psi, with a suitable catalyst, such as palladium, in a suitable solvent, such as methanol, at a temperature range of 0-200° C., to yield a compound of the formula (VHH).
  • a suitable catalyst such as palladium
  • a suitable solvent such as methanol
  • a compound of the formula (VHH) and a suitably substituted 3-aminoquinoline was treated with trimethylaluminum in a suitable solvent, such as 1,2-dichloroethane or toluene, at a temperature range of 0-200° C., to yield a compound of the formula (VIHH).
  • a suitable solvent such as 1,2-dichloroethane or toluene
  • a compound of the formula (IJJ) was treated with a suitable oxidizing agent, such as mCPBA, in a suitable solvent, such as dichloromethane, at a temperature range of ⁇ 40-100° C., to yield a compound of the formula (IIJJ).
  • a suitable oxidizing agent such as mCPBA
  • a suitable solvent such as dichloromethane
  • a compound of formula (IKK) was treated with piperazine in a suitable solvent, such as dimethylsulfoxide, at a temperature in the range of 50-250° C., to yield the corresponding compound of the formula (IIKK).
  • a suitable solvent such as dimethylsulfoxide
  • Certain target compounds of the present invention may be prepared according to the process outlined in Scheme LL below.
  • 5-bromoindoline (ILL) was treated with di-tert-butyldicarbonate in a suitable solvent, such as dichloromethane, at a temperature in the range of 0-100° C., to yield the corresponding BOC-protected 5-bromoindoline (IILL).
  • a suitable solvent such as dichloromethane
  • the compound of the formula (IILL) was treated with an appropriate catalyst, such as bistriphenylphosphinopalladium(II) chloride, an appropriate organic base, such as tributylamine, in the presence of carbon monoxide gas at 10 to 1000 psi, in methanol, at a temperature in the range of 20-200° C., to yield a the ester of the formula (IIILL).
  • an appropriate catalyst such as bistriphenylphosphinopalladium(II) chloride
  • an appropriate organic base such as tributylamine
  • a BOC-protected compound of the formula (VLL) was deprotected using an appropriate organic or inorganic acid, such as trifluoroacetic acid or hydrochloric acid, in a suitable solvent, such as dichloromethane or dioxane, at a temperature in the range of 0-100° C., to yield the compound of the formula (VILL).
  • an appropriate organic or inorganic acid such as trifluoroacetic acid or hydrochloric acid
  • a suitable solvent such as dichloromethane or dioxane
  • a compound of the formula (VILL) was treated with an appropriate acid chloride and a suitable organic base, such as N,N-diisopropylethylamine, in a suitable solvent, such as 1,2-dichloroethane or tetrahydrofuran, at a temperature in the range of 0-100° C., to yield the compound of the formula (VIILL) wherein R 5 is an alkanylcarbonyl or arylcarbonyl as defined herein.
  • a suitable organic base such as N,N-diisopropylethylamine
  • a suitable solvent such as 1,2-dichloroethane or tetrahydrofuran
  • Certain target compounds of the present invention may be prepared according to the process outlined in Scheme MM below.
  • a compound of formula (IM) was treated with the appropriate acid chloride and a suitable organic base, such as triethyamine or N,N-diisopropylethylamine, in a suitable solvent, such as 1,2-dichloroethane, at a temperature in the range of 0-100° C., to yield the corresponding compound of the formula (IIMM) wherein R 5 is an alkanylcarbonyl or arylcarbonyl as defined herein.
  • a suitable organic base such as triethyamine or N,N-diisopropylethylamine
  • a suitable solvent such as 1,2-dichloroethane
  • a suitably substituted compound of formula (INN) was treated with diethyl ethoxymethylenemalonate and heated to a temperature in the range of 0-300° C., to yield the corresponding compound of the formula (IINN).
  • a compound of formula (IINN) was added to a high boiling solvent such as diphenylether at a temperature in the range of 200-400° C. to yield the corresponding compound of the formula (IIINN).
  • a compound of formula (IIINN) was treated with thionyl chloride or phosphorous oxychloride at a temperature in the range of 25-200° C., to yield the corresponding compound of the formula (IVNN).
  • a compound of formula (IVNN) was treated in with hydrogen gas over an appropriate catalyst, such as palladium, in an appropriate solvent, such as ethanol or ethyl acetate or tetrahydrofuran at a temperature in the range of 25-200° C., to yield the corresponding compound of the formula (VNN).
  • an appropriate catalyst such as palladium
  • an appropriate solvent such as ethanol or ethyl acetate or tetrahydrofuran at a temperature in the range of 25-200° C.
  • a compound of the formula (VNN) was treated with a source of hydroxide ion, such as sodium hydroxide, in an appropriate solvent, such as methanol or water, or mixture of solvents, such as methanol and water, at a temperature in the range of 0-200° C., to yield the corresponding compound of the formula (VINN).
  • a compound of the formula (VINN) was treated with diphenylphosphoryl azide in the presence of a base, such as TEA or diisopropylethylamine, in t-butanol at a temperature in the range of 25-300° C. to yield the corresponding compound of the formula (VIINN).
  • a compound of the formula (VIINN) was treated with an acid, such as trifluoroacetic acid or hydrochloric acid or trifluoroacetic acid with water, with or without a solvent, such as DCE or DCM or THF or methanol, at a temperature in the range of 0-200° C., to yield the corresponding compound of the formula (VIIINN).
  • an acid such as trifluoroacetic acid or hydrochloric acid or trifluoroacetic acid with water
  • a solvent such as DCE or DCM or THF or methanol
  • a compound of the formula (VIIINN) was treated with the appropriate ester and trimethylaluminum in an appropriate aprotic solvent or mixture of solvents, such as DCE or DCM or toluene at a temperature in the range of 25-300° C., to yield the corresponding compound of the formula (IXNN).
  • an appropriate aprotic solvent or mixture of solvents such as DCE or DCM or toluene at a temperature in the range of 25-300° C.
  • an ester of the formula (IOO) and an aminoquinoline of the formula (IIOO) was treated with the trimethylaluminum in an appropriate aprotic solvent or mixture of solvents, such as DCE or DCM or toluene, at a temperature in the range of 25-300° C., to yield the corresponding compound of the formula (IIIOO).
  • an appropriate aprotic solvent or mixture of solvents such as DCE or DCM or toluene
  • reaction mixture was diluted with 100 mL diethylether and washed once with saturated ammonium chloride (50 mL), once with 1N HCl (50 mL), once with 1N NaOH (50 mL) and once with brine (50 mL). The organics were then dried over Na 2 SO 4 , filtered and concentrated in vacuo to yield the crude product, which was used without further purification.
  • [0889] B 4-[4-(1,1-Dimethyl-pentyl)-phenyl]-but-3-enoic acid quinolin-3-ylamide.
  • the 4-[4-(1,1-dimethyl-pentyl)-phenyl]-but-3-enoic acid from step A (0.130 g, 0.50 mmol) was dissolved in 5 mL DMF with stirring. To this was added Et 3 N (0.08 mL, 0.57 mmol), 3-aminoquinoline (0.077 g, 0.53 mmol) and lastly HBTU (0.204 g, 0.54 mmol).
  • step E 3-[4-(1,1-Dimethyl-propyl)-2,6-dimethoxy-phenyl]-propionic acid ethyl ester.
  • step G 3-[4-(1,1-Dimethyl-propyl)-2,6-dimethoxy-phenyl]-N-quinolin-3-yl-propionamide.
  • the product obtained in step G 3-[4-(1,1-dimethyl-propyl)-2,6-dimethoxy-phenyl]-propionic acid (0.422 g, 1.51 mmol), iPr 2 NEt (0.29 mL, 1.66 mmol), 3-aminoquinoline (0.218 g, 1.51 mmol) and lastly PyBroP (0.713 g, 1.53 mmol).

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US10/770,204 2003-02-03 2004-02-02 Quinoline-derived amide modulators of vanilloid VR1 receptor Abandoned US20040192728A1 (en)

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AU2004209456A AU2004209456A1 (en) 2003-02-03 2004-02-02 Quinoline-derived amide modulators of vanilloid VR1 receptor
US10/770,204 US20040192728A1 (en) 2003-02-03 2004-02-02 Quinoline-derived amide modulators of vanilloid VR1 receptor
JP2006502488A JP2007527363A (ja) 2003-02-03 2004-02-02 バニロイドｖｒ１受容体のモジュレーターであるキノリン誘導アミド
CA002514940A CA2514940A1 (fr) 2003-02-03 2004-02-02 Amides derives quinoliniques modulant le recepteur vr1 vanilloide
PCT/IB2004/000785 WO2004069792A2 (fr) 2003-02-03 2004-02-02 Amides derives quinoliniques modulant le recepteur vr1 vanilloide
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US20100273781A1 (en) * 2009-04-27 2010-10-28 Boehringer Ingelheim International Gmbh Cxcr3 receptor antagonists
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US7312233B2 (en) * 2005-03-14 2007-12-25 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US20080096919A1 (en) * 2005-03-14 2008-04-24 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
WO2009055730A1 (fr) * 2007-10-25 2009-04-30 Genentech, Inc. Procédé de préparation de composés de thiénopyrimidine
US8431694B1 (en) * 2007-10-25 2013-04-30 Genentech, Inc. Process for making thienopyrimidine compounds
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JP2007527363A (ja) 2007-09-27
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AU2004209456A1 (en) 2004-08-19
WO2004069792A3 (fr) 2005-01-20
TW200505450A (en) 2005-02-16
AR043015A1 (es) 2005-07-13
EP2308848A1 (fr) 2011-04-13
EP1603883B1 (fr) 2012-03-28
US20080300236A1 (en) 2008-12-04
EP1603883A2 (fr) 2005-12-14
CA2514940A1 (fr) 2004-08-19
ATE551324T1 (de) 2012-04-15
US8394828B2 (en) 2013-03-12
CL2004000179A1 (es) 2005-01-07

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