WO2010096722A1 - 3-oxo-2,3-dihydro-[1,2,4]triazolo[4, 3-a]pyridines utilisées comme inhibiteurs de l'époxyde hydrolase soluble (eh soluble) - Google Patents

3-oxo-2,3-dihydro-[1,2,4]triazolo[4, 3-a]pyridines utilisées comme inhibiteurs de l'époxyde hydrolase soluble (eh soluble) Download PDF

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WO2010096722A1
WO2010096722A1 PCT/US2010/024829 US2010024829W WO2010096722A1 WO 2010096722 A1 WO2010096722 A1 WO 2010096722A1 US 2010024829 W US2010024829 W US 2010024829W WO 2010096722 A1 WO2010096722 A1 WO 2010096722A1
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trifluoromethoxy
pyridine
oxo
triazolo
dihydro
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PCT/US2010/024829
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English (en)
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Jun Feng
Walter Keung
Wolfgang Reinhard Ludwig Notz
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Takeda Pharmaceutical Company Limited
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    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/34—Ethylene-urea

Definitions

  • the present invention relates to medicinal chemistry and pharmaceutical science.
  • compounds that inhibit soluble epoxide hydrolase (sEH) are provided herein.
  • Soluble epoxide hydrolase acts upon lipid epoxides, including those of arachidonic acid known as epoxyeicosatrienoic acids (EETs). These lipid epoxides are known effectors of blood pressure and modulators of vascular permeability. The vasodilatory properties of lipid epoxides are associated with an increased open-state probability of calcium-activated potassium channels leading to hyperpolarization of the vascular smooth muscle. Hydrolysis of lipid epoxides by sEH diminishes this activity.
  • EETs epoxyeicosatrienoic acids
  • sEH is a modulator of a large number of pathological conditions including hypertension, diabetes, metabolic syndrome, atherosclerosis, coronary artery disease, angina, ischemia, ischemic stroke, Raynaud's disease, inflammatory processes, genitourinary disorders, conditions of the eye, and renal disease.
  • inhibitors of sEH would have a therapeutic effect in such disorders.
  • Ri is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 4-14 aryl, optionally substituted C3-8 cycloalkyl, optionally substituted
  • Ci- 1 0 heteroaryl, and optionally substituted C3-6 heterocycloalkyl
  • Ar is selected from the group consisting Of C 5-14 aryl and C 1-10 heteroaryl;
  • R 2 is selected from the group consisting of optionally substituted Ci_ 6 alkyl, Ci_s sulfonyl, optionally substituted C 2 - 4 alkenyl, optionally substituted C 1-4 alkoxy, optionally substituted
  • Wi is selected from the group consisting of N and CR 3 ;
  • W 2 is selected from the group consisting of N and CR 3 ;
  • W 3 is selected from the group consisting of N and CR 3 ; provided that no more than one of Wi, W 2 , and W 3 is N; each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2 - 4 alkenyl, cyano, C 3 _8 cycloalkyl, halo, and hydroxy; and the pharmaceutically acceptable salts thereof.
  • compositions comprising: a compound of formula I and a pharmaceutically acceptable excipient.
  • the compounds of the invention are inhibitors of sEH they are useful for the treatment of conditions associated with sEH, including hypertension.
  • the invention provides methods of treating conditions associated with sEH, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
  • the present invention provides for the use of compounds of formula I for the manufacture of a medicament, including specifically for the treatment of particular conditions associated with sEH.
  • the present invention also provides an article of manufacture: comprising at least one compound of formula I and a label. Also provided are kits comprising at least one compound of the invention, a label, and apparatus for administration of the inhibitor. [0009] The present invention also provides processes from making sEH inhibitors and intermediates thereof.
  • C 2 - 4 alkenyl refers to a straight or branched alkenyl chain having from two to four carbon atoms and one or more carbon-carbon double bonds, and includes ethylene, propylene, iso-propylene, butylene, iso-butylene, sec-butylene, and the like.
  • optionally substituted C 2 - 4 alkenyl refers to a C 2 - 4 alkenyl optionally having from 1 to 3 substituents independently selected from the group consisting of C 1-4 alkoxy, C 1 -9 amide, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_ 4 alkyl refers to a straight or branched alkyl chain having from one to four carbon atoms.
  • Ci_ 4 alkyl refers to a Ci_ 4 alkyl optionally having from 1 to 5 substituents independently selected from the group consisting of amino, C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C 3 _ 8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C 3 _ 6 hetero cycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C 1-6 alkyl refers to a straight or branched alkyl chain having from one to six carbon atoms.
  • optionally substituted C 1-6 alkyl refers to a C 1-6 alkyl optionally having from 1 to 7 substituents independently selected from the group consisting of amino, C 1-8 alkylamino, C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C 1-8 sulfonyl refers to a sulfonyl linked to a C 1-6 alkyl group, C3-8 cycloalkyl, or an optionally substituted phenyl.
  • C 1-4 alkoxy refers to a C 1-4 alkyl attached through an oxygen atom.
  • Ci_ 4 alkoxy refers to a Ci_ 4 alkoxy optionally having from 1 to 6 substituents independently selected from the group consisting of C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl. It is understood that where the optional substituent is Ci_ 4 alkoxy, cyano, halo, or hydroxy then the substituent is not alpha to the alkoxy attachment point.
  • C 2 -6 alkynyl refers to a straight or branched alkynyl chain having from two to six carbon atoms and one or more carbon-carbon triple bonds.
  • optionally substituted C 2 -6 alkynyl refers to a C 2 -6 alkynyl optionally having from 1 to 3 substituents independently selected from the group consisting of C 1-4 alkoxy, C 1 -9 amide, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_ 9 amide refers to a primary amide or one having one or two Ci_ 4 alkyls, for example, -CONH 2 , -CONHCH 3 , and -CON(CH 3 ) 2 .
  • Ci_8 alkylamino refers to an amino having one or two Ci_ 4 alkyl.
  • C 4-14 aryl refers to a monocyclic and polycyclic unsaturated, conjugated hydrocarbon having aromatic character and having four to fourteen carbon atoms, and includes phenyl, biphenyl, indenyl, cyclopentyldienyl, fluorenyl, and naphthyl.
  • C 4-14 aryl refers to a C 4-14 aryl optionally having 1 to
  • substituents independently selected from the group consisting of amino, C 1 -9 amide, C 1-8 alkylamino, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro, and C 1-8 sulfonyl.
  • C 4-14 aryloxy refers to a C 4-14 aryl attached through an oxygen atom.
  • optionally substituted C 4-14 aryloxy refers to a C 4-14 aryloxy optionally having 1 to 5 substituents independently selected from the group consisting of amino, C 1-8 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro, C 1-8 sulfonyl, and trifluoromethyl.
  • optionally substituted benzyl refers to a benzyl group optionally having 1 to 3 groups independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, and nitro.
  • C 1-5 oxycarbonyl refers to a oxycarbonyl group (-CO 2 H) and C 1-4 alkyl ester thereof.
  • C 3 _s cycloalkyl refers to an alkyl ring having from three to eight carbon atoms, and includes cyclopropyl, 2-methyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • optionally substituted C3-8 cycloalkyl refers to a C3-8 cycloalkyl optionally having from 1 to 6 substituents independently selected from the group consisting of optionally substituted C 1-4 alkyl, C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C 3 _ 8 cycloalkoxy refers to a C 3 _ 8 cycloalkyl attached through an oxygen atom.
  • halogen and “halo” refers to a chloro, fluoro, bromo or iodo atom.
  • C3_6 heterocycloalkyl refers to a 4 to 10 membered monocyclic saturated ring having one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran, and the like.
  • optionally substituted C3-6 heterocycloalkyl refers to a heteroC3_6 cycloalkyl optionally substituted on the ring carbons with 1 to 4 substituents independently selected from the group consisting of optionally substituted C 1-4 alkyl, C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, and optionally substituted phenyl; and optionally substituted on any ring nitrogen with a substituent selected from the group consisting of optionally substituted C 1-4 alkyl, C 2 - 4 alkenyl, C3-8 cycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C 1-10 heteroaryl refers to a five to twelve membered monocyclic and polycyclic having unsaturated, conjugated ring(s) having aromatic character and having one to ten carbon atoms and one or more, typically one to four, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes azepine, diazepine, furan, thiophene, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, thiazole, thiadiazole, triazole, tetrazole, benzazepine, benzodiazepine, benzofuran, benzo thiophene, benzimidazole, imidazopyridine, pyrazolopyridine, quinazoline, thienopyridine, indolizine, imidazopyridine, quinoline, isoquinoline, indole, isoindole, benzoxazole, benzopyrazole, benzothiazole, and the like.
  • optionally substituted C 1-10 heteroaryl refers to a C 1-10 heteroaryl optionally having 1 to 5 substituents on carbon independently selected from the group consisting of amino, C 1 ⁇ amide, C 1-8 alkylamino, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro, and C 1-8 sulfonyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted Q_ 4 alkyl, Ci_s sulfonyl, and optionally substituted phenyl.
  • oxo refers to an oxygen atom having a double bond to the carbon to which it is attached to form the carbonyl of a ketone or aldehyde. It is understood that as the term is used herein oxo refers to doubly bonded oxygen attached to the group which has the oxo substituent, as opposed to the oxo group being pendant as a formyl group.
  • an acetyl radical is contemplated as an oxo substituted alkyl group and a pryidone radical is contemplated as oxo substituted C 1-10 heteroaryl.
  • C 1-10 heteroaryloxy refers to a C 1-10 heteroaryl attached through an oxygen.
  • optionally substituted C 1-10 heteroaryloxy refers to a C 1-10 heteroaryl optionally having 1 to 5 substituents on carbon independently selected from the group consisting Of C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro, oxo, C 1-8 sulfonyl, and trifiuoromethyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted C 1-4 alkyl, C 1 -S sulfonyl, and optionally substituted phenyl.
  • optionally substituted phenyl refers to a phenyl group optionally having 1 to 5 substituents independently selected from the group consisting of amino, C2-4 alkenyl, C 1-4 alkyl, C 1-4 alkoxy, C 1 ⁇ amide, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halogen, hydrogen, hydroxyl, nitro, C 1-8 sulfonyl, and trifluoromethyl.
  • pharmaceutically acceptable salt refers to salts of pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and includes those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). Examples are the hydrochloride and mesylate salts.
  • salt refers to organic acids and bases or inorganic acids and bases and included pharmaceutically accpeptable salts and extends to acids and bases that are not generally used in pharmaceuticals, for example the oxalic acid salts.
  • salt refers to organic acids and bases or inorganic acids and bases and included pharmaceutically accpeptable salts and extends to acids and bases that are not generally used in pharmaceuticals, for example the oxalic acid salts.
  • the skilled artisan will appreciate that certain of the compounds of the present invention exist as isomers. All mixtures of stereoisomers, in any ratio, and specific geometric isomers, enantiomers, and diastereomers of the compounds of the invention are contemplated to be within the scope of the present invention.
  • the compounds of the invention include a compound of formula I wherein Ar is C 4-14 aryl.
  • Another embodiment relates to any of the embodiments above or below wherein n is 1.
  • Another embodiment relates to any of the embodiments above or below wherein m is 1 or 2 and at least one of R 2 is selected from the group consisting of hydrogen, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C3-6 heterocycloalkyl and optionally substituted C 4-14 aryl.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is hydrogen.
  • Ri is optionally substituted C 1-4 alkyl having from 1 to 4 substituents independently selected from the group consisting of cyano, halo, hydroxy, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Another embodiment relates to any of the embodiments above or below wherein Ri optionally substituted C 1-4 alkyl having an optionally substituted C 1-10 heteroaryl and the C 1-10 heteroaryl is selected from the group consisting of furan, thiophene, imidazole, pyrazine, pyridazine, pyridine, pyrimidine, thiazole, and quinoline.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_ 4 alkyl having a cyano.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_4 alkyl having a hydroxy.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_ 4 alkyl having from 1 to 4 halo.
  • Another embodiment relates to any of the embodiments above or below wherein m is
  • R 2 is optionally substituted C 1-4 alkoxy.
  • Another embodiment relates to any of the embodiments above or below wherein m is
  • R 2 is C 1-4 alkoxy.
  • Another embodiment relates to any of the embodiments above or below wherein m is
  • R 2 is cyano
  • Another embodiment relates to any of the embodiments above wherein m is 1 or 2 and at least one of R 2 is halo.
  • the compounds of the invention can be prepared by a variety of procedures, some of which are described below. All substituents, unless otherwise indicated, are as previously defined.
  • the products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like.
  • the procedures may require protection of certain groups, for example hydroxy, amino, or carboxy groups to avoid unwanted reactions.
  • the selection, use, and removal of protecting groups is well known and appreciated as standard practice, for examples see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
  • step 1 depicts the reaction of an appropriate compound of formula (a) with an appropriate compound of formula H 2 N-(CH 2 ) n -Ar-(Pv 2 ) m to give a compound of formula (b).
  • An appropriate compound of formula (a) is one in which W 1 , W 2 , and W 3 are as desired in the final compound of formula I or give rise to W 1 , W 2 , and W 3 are as desired in the final compound of formula I and
  • X 1 is a hydroxyl or a leaving group, such as chloro, bromo, or imidazolyl, an activating moiety, a mixed anhydride of another carboxylic acid, such as formic acid, acetic acid, or a substituted or unsubstituted benzoic acid, or X 1 represents the other part of a symmetrical anhydride formed from two compounds of formula (a) in which Xi is hydroxyl.
  • standard amide forming conditions can be used, such as those using coupling agents, including those used in peptide couplings, such as 2-(lH-7-azabenzotriazol-l-yl)- 1,1,3,3- tetramethyl uronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • an additive such as 4-(dimethylamino)pyridine, 1- hydroxybenzotriazole, and the like may be used to facilitate the reaction.
  • reaction is generally carried out using a base, such as N-methylmorpholine or triethylamine, in a wide variety of suitable solvents such as dichloromethane, dimethylformamide (DMF), N- methylpyrrolidone (NMP), dimethylacetamide (DMAc), tetrahydrofuran (THF), and the like.
  • a base such as N-methylmorpholine or triethylamine
  • suitable solvents such as dichloromethane, dimethylformamide (DMF), N- methylpyrrolidone (NMP), dimethylacetamide (DMAc), tetrahydrofuran (THF), and the like.
  • DMF dimethylformamide
  • NMP N- methylpyrrolidone
  • DMAc dimethylacetamide
  • THF tetrahydrofuran
  • a compound of formula (b) is reacted with hydrazine in a solvent using a suitable base.
  • the reaction can be carried out using an excess of hydrazine.
  • the reaction is carried out in a suitable solvent, such as a lower alcohol, water, and mixtures thereof.
  • the reaction is carried out at temperatures of about 60 0 C to 150 0 C.
  • the reaction mixture may be sealed as a matter of convenience.
  • Ri is as described above and R is selected from the group consisting of C1-4 alkyl, 2,2,2-trichloroethyl, and optionally substituted benzyl followed by cyclization to directly give a compound of formula I.
  • a compound of formula (b) is reacted with a compound of formula (g) in solvent.
  • Typical solvents include water and lower alcohols and mixtures thereof.
  • the reaction is carried out using a suitable base. It will be appreciated the reaction can be carried out without a base, but if a base is not used in the first step, a base will be introduced to facilitate the cyclization to give a compound of formula (e).
  • the cyclization reaction is carried out in a suitable solvent, such as a water and mixtures of water and lower alcohol and mixtures of water and acetic acid. The reaction is carried out at temperatures of about 60 0 C to 150 0 C.
  • Scheme A depicts a ring forming reaction of an appropriate compound of formula (c) with suitable carbonyl reagent to give a compound of formula I in which Ri is hydrogen.
  • suitable carbonyl reagents include carbonyl dichloride, carbonyl dibromide, carbonyl diimidazole, and the like.
  • a compound of formula (c) is reacted with, generally, 1 equivalent of a suitable carbonyl reagent in a suitable solvent such as DMSO and may be carried out using a suitable base, such as triethylamine, diisopropylethylamine, and the like.
  • a suitable base such as triethylamine, diisopropylethylamine, and the like.
  • the reaction typically is carried out at temperatures of from -20 0 C to ambient temperature and require about 1 hour to 2 days.
  • Scheme A depicts the reaction of a compound of formula I in which Ri is hydrogen with a suitable RiX 2 to give a compound of formula I.
  • Suitable compounds of formula RiX 2 are ones in which Ri is as desired in the final compound of formula I or gives rise to Ri as desired.
  • X 2 is a suitable leaving group, the nature of which may vary with the Ri group to be introduced but generally will be a halogen or sulfonate ester.
  • a suitable X 2 may be a halide, such as chloro, bromo, or iodo or a sulfonate ester, such as tosylate, besylate, nosylate, trifluoromethanesulfonate, and the like.
  • a suitable X 2 may be a halide, such as fluoro, chloro, or bromo.
  • a compound of formula I in which Ri is hydrogen is reacted with a molar excess of a compound of formula RiX 2 in a suitable solvent such as DMSO, DMF, THF and the like and may be carried out using a suitable base, such as cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, and the like.
  • a suitable solvent such as DMSO, DMF, THF and the like
  • a suitable base such as cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, and the like.
  • the reaction is generally carried out using from 0.9 to 2 equivalents of a compound of formula RiX 2 .
  • the reaction typically is carried out at temperatures of from 0 0 C to 8O 0 C and require about 1 hour to 3 days.
  • a compound of formula (e) can be prepared by a process characterized by the reaction of a compound of formula (g) with a compound of formula (d) Such a reaction is followed by cychzation to give a compound of formula (e)
  • a compound of formula (e) can undergo an optional reaction as described in Scheme A, step 4 using a suitable RiX 2 , followed by deprotection, if required, to give a compound of formula (e) in which Ri is not hydrogen
  • a compound of formula (e) in which Ri is as desired in the final compound of formula I can, either as the carboxylic acid or after activation to -C(O)Xi, undergo an amide forming reaction as described in Scheme A, step 1, with an appropriate compound of formula (f), H 2 N- (CH 2 ) n -Ar-(R 2 ) m , to give a compound of formula I
  • a compound of formula (e) in which Ri is hydrogen can, either as the carboxylic acid or after activation to -C(O)Xi, undergo an amide forming reaction as described in Scheme A, step 1, with an appropriate compound of formula H 2 N-(CH 2 )I 1 -Ar-(R 2 )In to give a compound of formula I in which Ri is hydrogen.
  • step 4 to give a compound of formula I in which Ri is other than hydrogen.
  • compounds of formula (f) can be prepared by a variety of methods as described herein or by methods analogous to those described herein and in the art. Specifically, a compound of formula (f) in which n is 1 can be prepared by reduction of a nitrile or an amide or by halogenations of a methyl (in a toluene derivative) followed by displacement by ammonia or a protected amine, for example NH 2 NBoC or phthalimide.
  • R 2 groups are commercially available or can be installed by various methodologies, for example, hydrolysis, oxidation, reduction, alkylation, amidations, sulfonations, alkynations, alkyenations, arylations such as Suzuki coupling, and the like.
  • Compounds of formula (f) that are included in the present invention are 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile, (4-nitro-2-(trifluoromethoxy)phenyl)methanamine, (4-iodo-2-
  • Example 1 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carboxamide
  • Example 2 2-(cyanomethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 3 2-(3-oxo-6-(2-(trifluoromethoxy)benzylcarbamoyl)-[l,2,4]triazolo[4,3- a]pyridin-2(3H)-yl)acetic acid
  • Example 4 2-(2-amino-2-oxoethyl)-3-oxo-N-(2-(trifiuoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 7 N-(2,3-dimethoxybenzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carboxamide
  • Example 11 3-oxo-2-(pyridin-2-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 12 2-(2-(diethylamino)ethyl)-3-oxo-N-(2-(trifiuoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 13 2-(2-(dimethylamino)ethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 14 2-(2-morpholinoethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 15 2-(2-(lH-imidazol-l-yl)ethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l-(2-bromoethyl)-lH-imidazole. Purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt.
  • Example 17 (S)-3-oxo-2-((5-oxopyrrolidin-2-yl)methyl)-N-(2- (trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 18 2-ethyl-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 20 2-(2-hydroxyethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 21 2-(2,3-dihydroxypropyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized fromN-(2,3-dimethoxybenzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoacetonitrile. Purified by Mass-triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA).
  • Example 24 3-oxo-2-(2,2,2-trifluoroethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 25 2-((l-methyl-lH-imidazol-2-yl)methyl)-3-oxo-N-(2- (trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-(bromo methyl)- 1 -methyl- lH-imidazole. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt.
  • Example 26 3-oxo-2-(pyridin-4-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 27 3-oxo-2-(pyridin-3-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 3-(bromomethyl)pyridine. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt.
  • Example 28 3-oxo-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 30 N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized by a method similar to Example 1 by using (4- methoxy-2-(trifluoromethoxy)phenyl)methanamine as amine. Purified by Mass-triggered HPLC (Gradient: 30-40% ACN containing 0.035% TFA in water containing 0.05% TFA).
  • Example 32 N-(4-methoxy-2-(trifiuoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H- pyran-4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 4-iodotetrahydro-2H-pyran. Purified by Mass-triggered HPLC (Gradient: 20-60% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound.
  • the title compound was synthesized fromN-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoethanol. Purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound.
  • Example 34 (R)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2-((5- oxopyrrolidin-2-yl)methyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 36 2-(l-cyanoethyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromopropanenitrile. Purified by Mass-triggered HPLC (Gradient: 40- 60% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound.
  • Example 37 2-(2,3-dihydroxypropyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 38 2-(l -amino- 1 -oxopropan-2-yl)-N-(4-methoxy-2- (trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 40 N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 41 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 43 N-(4-(6-aminopyridin-3-yl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 45 N-(4-(3-hydroxyprop-l-ynyl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 47 N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • a title compound was synthesized from N-(4-bromo-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoethanol. Purified by Mass-triggered HPLC (Gradient: 30-50% ACN containing 0.035% TFA in water containing 0.05% TFA).
  • Example 48 2-(2-hydroxyethyl)-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 49 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2- hydroxyethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 50 N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 51 2-(2-cyanoethyl)-N-(4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 52 N-(4-(2-aminopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2-(2- cyanoethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 55 N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • N-(4-bromo-2-(trifluorometho xy )benzyl)-3-oxo-2,3-dihy dro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide 550 mg, 1.28 mmol
  • Cs 2 CO 3 623 mg, 1.92 mmol
  • 1,1- difluoro-2-iodoethane 370 mg, 1.92 mmol
  • Example 58 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2,2- difluoroethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 59 N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H-pyran- 4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 60 N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H-pyran- 4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 61 N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-morpholinoethyl)-3-oxo-
  • Example 62 N-(4-methoxy-2-(trifiuoromethoxy)benzyl)-2-(2-morpholinoethyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 64 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2- morpholinoethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 66 N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the organic layer was dried with MgSO4 and evaporates to a volume of about 2OmL to give a solid.
  • the solid was collected by filtration and washed with EtOAc/Hexane (1 :1) and further purified by dissolving in 10OmL EtOAc (refluxing) and titration with hexane to about 1 to 1 ratio of EtOAc to Hexane at room temperature. The solid was collected by filtration to give 1.5 g (62.5%) of the title compound.
  • Example 67 (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine [0216] To a mixture of 4-methoxy-2-(trifluoromethoxy)benzaldehyde (10Og, 450 mmol) in 1000 mL of EtOH was added hydroxylamine hydrochloride (38 g, 550 mmol) and potassium acetate (49 g, 500 mmol). The mixture was stirred at 50 0 C for 5 h. The solvent was then removed on rotoray evaporator to give a white solid which was collected by filtration and washed with 2 potions of water. The solid product was dried overnight in vacuum to give 81 grams of the crude 4-methoxy-2-(trifluoromethoxy)benzaldehyde oxime (yield: 75%) that was used in next step without purification.
  • Example 68 N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 69 2-(2 -hydroxy ethyl)-N-(4-methoxy-2-(trifluoro methoxy)benzyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 70 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile
  • a mixture of (4-bromo-2-(trifluoromethoxy)phenyl)methanamine HCl salt (2 g, 6.53 mmol), di-tert-butyl dicarbonate (2.85 g, 13.05 mmol) and NaHCO 3 (5.48 g, 65.3 mmol) in dioxane was stirred overnight, then the solvent was removed in vacuum to give a residue.
  • Example 72 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonyl chloride [0235] To a solution of 6-chloronicotinic acid (20 g, 127 mmol) in 200 mL of EtOH was added hydrazine hydrate (14.8 mL, 317 mmol). The mixture was refluxed overnight, then cooled to room temperature to give a solid, which was collected by filtration, washed with petroleum ether/EA (2: 1) to give 18 g of 6-hydrazinylnicotinic acid as a yellow solid (Yield: 91%).
  • Example 74 N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 75 2-(2-cyanoethyl)-N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using 3-bromopropanenitrile. Purified by prep HPLC (Column: XB-Cl 8(5uM) 21.2 mm x 150mm) eluting with a gradient 10-60% ACN containing 0.0355 TFA in water containing 0.1% TFA) to give the title compound.
  • Example 76 2-(2,2-difluoroethyl)-N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from N-((2-(4-fluorophenyl)pyridin-3- yl)methyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using 2-bromoethanol. Purified by TLC eluted with Pentane/EtOAc (2/1) to give 25 mg of the title compound.
  • reaction mixture was refluxed overnight before slowly adding consecutively 15 mL of H 2 O, 5.7 mL of 15% aq. NaOH solution and 5 mL of H 2 O for quench.
  • the resulting mixture was filtered, and filtrate was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the crude title compound as a brown oil which was used without the further purification.
  • Example 80 N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 81 2-(2,2-difluoroethyl)-N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 82 N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-2-(2 -hydroxy ethyl)-3-oxo-
  • Example 83 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile
  • a solution of 4-bromo-l-iodo-2-(trifluoromethoxy)benzene (4.95 g, 13.49 mmol) in THF (80 mL) was cooled in a dry ice/acetone bath under an atmosphere of nitrogen.
  • n-BuLi (16.86 mL, 27.0 mmol) dropwise over 13 min while maintaining an internal temperature ranging from -112° C to -65.5 0 C.
  • the reaction was stirred at -77°C for 60 min.
  • Example 84 2-(2-hydroxyethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid
  • reaction mixture was then heated back to about 94 0 C and stirred at this temperature for about 48 hours.
  • the mixture was then cooled to about 46 0 C and cone HCl (400 mL) was added over 1-2 minutes to give a pH ⁇ 0.
  • the reaction mixture was cooled to room temperature, the solid filtered, the filter cake was rinsed with water (3x250 mL), dried first by suction, then in vacuo at 100 0 C, to afford 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid (449.86 g, 2498 mmol, 85 % yield).
  • Example 85 N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 86 N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • isopropanol 1000 mL was added and atmospheric distillation was continued. After about 720 mL of distillate had been collected, more isopropanol (1000 mL) was added. As the distillation progressed, the internal temperature increased to about 84 0 C. After a total of about 1680 mL of distillate had been collected, the heating was removed and isopropanol (500 mL) was added. The mixture was cooled back to room temperature and acidified with cone HCl (45 mL).
  • Example 87 N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide sulfate [0281] A suspension of N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (702 mg, 1.498 mmol) in acetonitrile (60 mL) was heated close to reflux until a clear solution was obtained; then the solution was stirred while cooling.
  • Example 88 N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide hydrochloride [0283] N-(4-Cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (3.4 g, 7.26 mmol) was suspended in acetonitrile (250 mL) and heated to reflux, upon which dissolution occurred.
  • Reaction was diluted with 15mL water to give a solid.
  • the solid product was filtered and dried by suction.
  • Solid product was added into 1OmL 30% isopropanol in water, broke up with a spatula, sonicated, and then heated to 65 0 C.
  • An additional 3mL isopropanol was added and again the solid was broken up with a spatula, the mixture was sonicated, then heated to 65 0 C to give a suspension which was allowed to cool to room temperature.
  • the solid was collected by filtration, washed with 1OmL 30% isopropanol in water and dried by suction to give 77.6 mg of the title compound.
  • the compounds of the invention can be administered alone or in the form of a pharmaceutical composition.
  • the compounds of the invention are usually administered in the form of pharmaceutical compositions, that is, in admixture with pharmaceutically acceptable excipients the proportion and nature of which are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.
  • the present invention provides pharmaceutical compositions comprising: a compound of invention and a pharmaceutically acceptable excipient.
  • a compound of the invention can be administered in any form and route which makes the compound bioavailable.
  • the compounds of the invention can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.
  • routes including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally,
  • compositions of the invention may be administered to the patient, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, and suspensions.
  • the pharmaceutical compositions of the present invention are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient.
  • the amount of a compound of the present invention may be varied depending upon its particular form and may conveniently be between 1 % to about 70% of the weight of the unit dosage form.
  • pharmaceutically acceptable excipient refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semisolid, or liquid material which can serve as a vehicle or medium for the active ingredient.
  • compositions include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.
  • the present pharmaceutical compositions are preferably formulated in a unit dosage form, each dosage typically containing from about 0.5 mg to about 200 mg of the compounds of the invention.
  • unit dosage form refers to a physically discrete unit suitable as a single dosage, each unit containing a predetermined quantity of active ingredient, in association with a suitable pharmaceutical excipient, by which one or more is used throughout the dosing regime to produce the desired therapeutic effect.
  • the composition is a pharmaceutical composition adapted for oral administration, such as a liquid formulation, for example, a solution or suspension, adapted for oral administration or a tablet or a capsule.
  • the pharmaceutical composition is a liquid formulation adapted for parenteral administration.
  • the invention provides methods of treating conditions associated with sEH, comprising: administering to a patient in need thereof an effective amount of a compound of the invention.
  • the invention provides a method of inhibiting a sEH: comprising, contacting the enzyme with a compound of the invention.
  • the invention provides a method of inhibiting a sEH: comprising, administering a compound of the invention to a patient in order to inhibit the enzyme in vivo.
  • the invention provides a method of inhibiting a sEH: comprising, administering a first compound to a subject that is converted in vivo to a compound of the invention.
  • compounds of the invention including the compound of formula I, are provided for use as a medicament.
  • the invention also provides the use of compounds of the invention for the manufacture of a medicament to treat the conditions associated with sEH described herein.
  • the compounds of the present invention are stable and are relatively safe in their end use.
  • the compounds of the present invention are useful as sEH inhibitors for a variety of subjects (e.g., humans, non-human mammals and non-mammals).
  • conditions As used herein terms "condition,” “disorder,” and “disease” relate to any unhealthy or abnormal state.
  • condition associated with sEH includes disorders and diseases in which the inhibition of sEH provides a therapeutic benefit, such hypertension, metabolic syndrome, obesity, elevated triglycerides, elevated cholesterol, glucose intolerance, atherosclerosis, coronary artery disease, cardiac fibrosis, angina, ischemia, stroke, renal disease, inflammation, including arthritis, renal inflammation, hepatic inflammation, vascular inflammation, and respiratory inflammation, adult respiratory distress syndrome and chronic obstructive pulmonary disease, emphysema, chronic bronchitis, interstitial lung disease, and idiopathic pulmonary fibrosis, systematic inflammatory response syndrome, pain, itching, irritation of the skin, dermatoses, sunburn, mild burns, prurtius, genitourinary disorders, overactive bladder, outlet obstructions, outlet insufficiency, benign prostatic hyperplasia, interstitial cystitis, erectile dysfunction, incontinence, and the like.
  • renal disease includes treatment of kidney disease, albuminuria, diabetic neuropathy, chronic kidney disease, fibrosis of the kidney, amyloidosis, acquired cystic kidney disease, nephritic syndrome, and proteinuria.
  • treatment of inflammatory conditions includes the treatment of arthritis and that arthritis is presently categorized into several more specific disorders, such as osteoarthritis and rheumatic arthritis, and others all of which are contemplated by the invention.
  • Another example is systematic inflammatory response syndrome which is used to describe inflammation events associated with lupus, sepsis, pancreatitis, multiple trauma, lacerations, brain injury or surgery, hemorrhagic shock and immune-mediated organ injuries and others all of which are contemplated by the invention.
  • itching which includes itching of the skin due to insect bites, allergic reaction, and contact dermatitis, pruritus, eczema, hives, chicken pox, impetigo, and others, all of which are contemplated by the invention.
  • treat include improvement of the conditions described herein. Also, it is also recognized that one skilled in the art may affect the conditions by treating a patient presently afflicted with the disorders or by prophylactically treating a patient believed to be susceptible to such conditions with an effective amount of a compound of invention. Thus, the terms “treat,” “treatment,” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition, and is intended to include prophylactic and therapeutic treatment of such disorders.
  • the terms "patient” and “subject” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs. [0301] As used herein, the term “effective amount” refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • the dose a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • An effective amount of the present use invention, including a compound of the invention is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 20 mg/kg/day. Specific amounts can be determined by the skilled person.
  • the present invention provides a method for treating metabolic syndrome, comprising: administering to a patient in need thereof an effective amount of a compound of invention.
  • the present invention provides a method for treating hypertension comprising: administering to a patient in need thereof an effective amount of a compound of the invention.
  • a variety therapeutic agents may have a therapeutic additive or synergistic effect when used in combination with sEH inhibitors according to the present invention.
  • Such combination therapy can include administration concurrently or sequentially with therapy and/or an agent for the treatment of any of the conditions associated with sEH.
  • the present compounds may be combined calcium channel blockers, lipid lowering agents, cholesterol lowering agents, such as statins, fibrates, beta-blockers, ACE inhibitors, platelet aggregation inhibitors, diuretics, glucose lowering agents, insulin, and the like.
  • the invention also provides an article of manufacture: comprising at least one compound of the invention and a label.
  • the label may include information about the manufacturer, doses, conditions to be treated, and the use of the compound or pharmaceutical composition.
  • the invention provides a kit: comprising, at least one compound of the invention, a label, and apparatus for administration.
  • the apparatus may include mixing vials, liquids for forming solutions or suspensions, tubing, syringes, and the like.
  • DNA encoding the full-length sequence of the human enzyme was amplified by PCR and cloned into the pI-SUMOstar (LifeSensors), which incorporates a 6 x His_ SUMO tag at N-terminus.
  • DNA encoding the full-length sequence of the rat enzyme was amplified by PCR and cloned into the pFastBacHTb vector (Invitrogen), which incorporates a 6 x His tag at N-terminus
  • Recombinant protein was isolated from cellular extracts by passage over ProBond Nickel resin (Invitrogen).
  • the N-terminal 6 x His SUMO (human sEH) or 6 x His (rat sEH) tag was removed from partially purified sEH protein by incubating with SunoStar Proteinase 1 (LifeSensor) or rTEV enzyme respectively.
  • Partially purified and tag removed sEHs were purified by high pressure liquid chromatography over a BioSep S3000 gel filtration column for human sEH or by Nickel reverse purification and dialyzation for rat sEH. The purity of sEH proteins was determined on denaturing SDS-PAGE gel.
  • the proteins were either stored at -78 oC or - 20 oC in a buffer containing 25mM TRIS-HCl pH 7.6, 125mM NaCl and 50% glycerol for human sEH or in a buffer containing 5OmM TRIS 7.9, 20OmM NaCl, 50% glycerol for rat sEH .
  • the sEH inhibitory properties of test compounds were determined using a black 384- well-plate format under the following reaction conditions: 20 mM Tris pH 7.0, 0.1 mM EDTA, 0.1 mg/ml BSA, 5 ⁇ M PHOME (substrate from Cayman Chemical), 2 nM sEH enzyme, 1% DMSO (from test compound). Reaction product was determined quantitatively by fluorescence intensity using a Fluorescence plate reader (Molecular Devices Gemini) with an excitation wavelength at 330 nm and emission at 465 nm.
  • the assay reaction was initiated as follows: 2 ⁇ l of 5 times intermediate diluted inhibitor was added to each well of the plate, followed by the addition of 4 ⁇ l of 2.5 x sEH enzyme solution and incubated for 10 minutes at room temperature. After incubation, 4 ul of 2.5X substrate solution was added to initiate the reaction. Fluorescence intensities of the resulting reaction mixtures were measured after 20 minute (human sEH) or 10 minute (rat sEH) incubation at room temperature. A dose-response curve was constructed by diluting the test compound 2-fold in 11 subsequent dilutions and determining the percent inhibition of catalytic activity relative to control for each dilution of a single test compound.
  • a dose-response curve is first constructed by plotting on the Y-axis the percent relative to a control compound exhibiting complete inhibition of enzymatic activity versus the concentration of inhibitor on the X-axis.
  • the IC50 value is extrapolated from the dose-response curve at the concentration of test compound which exhibits 50% inhibition relative to control on the Y-axis.
  • the values expressed in Table 1 are pIC 50 (negative log (base 10) of the IC50 in moles per liter). All of the exemplified compounds inhibited human sEH in the assay of Example A with a pIC 50 of greater than about 5.8.
  • Illustrative pIC 5 o values are given in Table 1.
  • Example B Determination of sEH inhibition in cellular assay [0314] The cellular sEH activity can be assayed by its hydration of 14,15-EET and producing 14,15-DHET which is secreted out of the cell into the culture medium (Eagle's MEM (ATCC), 10% Fetal Bovine Serum (Hyclone), 1 x NEAA (Invitrogen), 1 x L- Glutamine (Invitrogen)).
  • Eagle's MEM ATCC
  • 10% Fetal Bovine Serum Hyclone
  • 1 NEAA Invitrogen
  • 1 x L- Glutamine Invitrogen
  • HepG2 hepatocellular carcinoma cells (30,000 cells/well) or ACHN renal cell adenocarcinoma (ATCC) (35,000 cells/well) are seeded in 96-well tissue culture cell bind plates. Cultures are incubated overnight at 370C in a 5% CO2 incubator until cells are attached and spread. 14,15-EET (Biomol International) is added to final concentration of 6 uM and inhibitor is added to the desired final concentration in total volume of 200ul per well. Prior to addition to cells compounds are serially diluted (1 :3) from column 1 to 11 and column 12 contained DMSO vehicle. Compounds are diluted into cell growth medium then compound solution is added to cells.
  • DMSO concentration 0.5%). Cultures are incubated for 2 hours at 370C in a 5% CO2 incubator.
  • the resulting 14,15-DHET amount in the cell culture medium can be directly detected using a 14,15-DHET ELISA kit (Detroit R&D, Inc.), and measuring the OD450 nm with a Spectamax microplate reader (Molecular Devices, San Diego, CA).
  • EC50 values are calculated using non-linear curve-fitting of the secreted 14,15-DHET as a function of compound concentration.
  • Test compounds at 3 mg/kg sEH inhibitor in 0.5 % methyl cellulose or the vehicle control is orally administrated to SHR rats (6 rats/group, 13 weeks old males, Charles River Laboratories) daily for two days.
  • Plasma is collected (200 ⁇ l_ in heparinized tubes at 4 h post dose on day 1 and 4, 8 and 24 h post dose on day 2.
  • the samples are frozen at -80 OC until analysis.
  • the lipids are extracted from the plasma sample with acetonitrile which contains
  • 14,15-DHET-dl 1 [80OuL of IOng/mL] as an internal standard, and the extract is blown dry and reconstituted into 100 ul 60/40 water/acetonitrile.
  • 14,15-DHET calibration was obtained by spike in known amount of 14,15-DHET (0.5, 1, 2.5, 20, 25, 100, 200, 500, 1000, 2000ng/mL) into blank plasma and extract the lipids with 80OuL acetonitrile containing IOng/mL 14,15-DHET-dl 1 as internal standard, and the extract was blown dry and reconstituted into lOOuL 60/40 water/acetonitrile.
  • the 14,15-DHET levels are determined by LC/MRM.
  • mice Male Sprague Dawley (SD) rats (7 - 8 weeks old from Harlan) are surgically implanted under isoflurane anesthesia with an osmotic mini-pump (Alzet 2ML2) which administer 1.0 mg/kg/day Angiotensin II subcutaneously for 14 days.
  • the rats are accessible to food and water ad libitum.
  • the rats are randomized on day 13 (6 rats/group) by systolic blood pressure.
  • the rats are orally dosed with 3 or 10 mg/kg of test compound formulated in 0.5% methylcellulose on day 14 and blood pressure is measured at 4 hr post dosing through non-invasive tail-cuff system under light anesthesia.

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Abstract

L'invention concerne des intermédiaires dans la synthèse de N-arylméthyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamides ainsi qu'un procédé (A) permettant d'obtenir l'acide 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylique. Les triazolo[4,3-a]pyridine-6-carboxamides de formule (I) sont utilisés comme inhibiteurs de l'époxyde hydrolase soluble (EH soluble) ayant un effet thérapeutique dans les pathologies telles que l'hypertension, l'accident vasculaire cérébral, les processus inflammatoires, le diabète et diverses maladies cardiovasculaires.
PCT/US2010/024829 2009-02-20 2010-02-19 3-oxo-2,3-dihydro-[1,2,4]triazolo[4, 3-a]pyridines utilisées comme inhibiteurs de l'époxyde hydrolase soluble (eh soluble) WO2010096722A1 (fr)

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AU2019398820B2 (en) * 2018-12-14 2022-09-15 Yuhan Corporation Triazolopyridin-3-ones or their salts and pharmaceutical compositions comprising the same
WO2020121263A1 (fr) * 2018-12-14 2020-06-18 Yuhan Corporation Triazolopyridin-3-ones ou leurs sels et compositions pharmaceutiques les comprenant
US11713308B2 (en) 2018-12-14 2023-08-01 Yuhan Corporation 3,3-difluoroallylamines or salts thereof and pharmaceutical compositions comprising the same
US11820769B2 (en) 2018-12-14 2023-11-21 Yuhan Corporation Triazolopyridin-3-ones or their salts and pharmaceutical compositions comprising the same
WO2024105234A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Inhibiteurs doubles de récepteur sigma-1 et d'époxyde hydrolase soluble et leur utilisation dans le traitement de la douleur

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