WO2003014064A1 - Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists - Google Patents

Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists Download PDF

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WO2003014064A1
WO2003014064A1 PCT/EP2002/008493 EP0208493W WO03014064A1 WO 2003014064 A1 WO2003014064 A1 WO 2003014064A1 EP 0208493 W EP0208493 W EP 0208493W WO 03014064 A1 WO03014064 A1 WO 03014064A1
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Prior art keywords
straight
branched
chain
represents hydrogen
hydroxy
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PCT/EP2002/008493
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English (en)
French (fr)
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WO2003014064A8 (en
Inventor
Takeshi Yura
Muneto Mogi
Yuka Ikegami
Tsutomu Masuda
Toshio Kokubo
Klaus Urbahns
Timothy B. Lowinger
Nagahiro Yoshida
Joachim Freitag
Heinrich Meier
Reilinde Nopper
Makiko Marumo
Masahiro Shiroo
Masaomi Tajimi
Keisuke Takeshita
Toshiya Moriwaki
Yasuhiro Tsukimi
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Bayer Healthcare Ag
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Priority claimed from JP2001232503A external-priority patent/JP2003055209A/ja
Application filed by Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Priority to JP2003524319A priority Critical patent/JP2005501873A/ja
Priority to EP02758413A priority patent/EP1414788A1/en
Priority to US10/485,481 priority patent/US20040259875A1/en
Priority to AU2002325381A priority patent/AU2002325381A1/en
Priority to CA002455754A priority patent/CA2455754A1/en
Publication of WO2003014064A1 publication Critical patent/WO2003014064A1/en
Publication of WO2003014064A8 publication Critical patent/WO2003014064A8/en

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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to an amine derivative, which is useful as an active ingredient of pharmaceutical preparations.
  • the amine derivatives of the present invention have vanilloid receptor 1 (VRl) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with VRl activity, in particular for the treatment of urinary incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and/or inflammatory disorders.
  • VRl vanilloid receptor 1
  • Vanilloid compounds are characterized by the presence of vanillyl group or a functionally equivalent group.
  • vanilloid compounds or vanilloid receptor modulators are vanillin (4-hydroxy-3-methoxy-benzaldehyde), guaiacol (2- methoxy-phenol), zingerone (4-/4-hydroxy-3-methoxyphenyl/-2-butanon), eugenol
  • capsaicin the main pungent ingredient in "hot” chili peppers
  • capsaicin is a specific neurotoxin that desensitizes C-fiber afferent neurons.
  • Capsaicin and its analogues such as resiniferatoxin, are shown to be effective in the treatment of urological disorder e.g., urinary incontinence and overactive bladder, due to the desensitization of C-fiber afferent neurons [(Michael B Chancellor and William C. de Groat, The Journal of Urology Vol. 162, 3-11, 1999) and (K.E. Andersson et al., BJU International, 84, 923-947, 1999)].
  • the mechanism in which capsaicin and other analogues cause the desensitization of C-fiber afferent neurons is very complicated.
  • Vanilloid receptor is a specific neuronal membrane recognition site for capsaicin. It is expressed almost exclusively by primary sensory neurons involved in nociception and neurogenic inflammation. The VR functions as a cation-selective ion channel with a preference for calcium. Capsaicin interacts with VRl, which is a functional subtype of the VR and predominantly expressed in cell bodies of dorsal root ganglia (DRG) or nerve endings of afferent sensory fibers including C-fiber nerve endings [Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H,
  • VRl can therefore be viewed as a molecular integrator of chemical and physical stimuli that elicit neuronal signals in a pathological conditions or diseases.
  • antagonists of the VRl can be used for prophylaxis and treatment of the condition and diseases including urology disorder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and inflammatory disorders.
  • Urology disorder used herein refers to e.g., urinary incontinence and overactive bladder.
  • Urinary incontinence and overactive bladder encompass detrusor hyper-reflexia, detrusor instability and urgency/- frequency syndrome, such as urge urinary incontinence and the like.
  • WO 00/50387 discloses the compounds having a vanilloid receptor agonist activity represented by the general formula:
  • X p is an oxygen or sulfur atom
  • a p is -NHCH 2 - or -CH 2 -;
  • R a is a substituted or unsubstituted C 1-4 alkyl group, or R aI CO-;
  • R al is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or substituted or unsubstituted aryl group having 6 to 10 carbon atoms;
  • R b is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or a halogen atom;
  • R is a hydrogen atom, an alkyl group having 1 to 4 carbon atom, an aminoalkyl, a diacid monoester or ⁇ -alkyl acid;
  • the asteric mark * indicates a chiral carbon atom, and their pharmaceutically acceptable salts.
  • /61581 discloses amine derivatives represented by the general formula:
  • R R represent (F, F), (CF 3 , H), or (iPr, iPr)
  • R 90 is hydrogen, C 1-12 alkyl, C 3-8 cycloalkyl, or the like, and R 91 is amino-C 1-6 alkyl, aminocarbonyl-C 1-6 alkyl, or hydroxyamino- carbonyl C 1-6 alkyl; and
  • R 90 and R 91 are independently selected from the group consisting of H, C ⁇ - 6 alkyl, C ⁇ -6 alkylthio, C ⁇ -6 alkoxy, fluoro, chloro, bromo, iodo, and nitro;
  • This invention is to provide the following general formula (I), its tautomeric or stereoisomeric form, and the salts thereof:
  • X represents C 3-8 cycloalkyl optionally fused by benzene, t ienyl, thienyl straight alkyl, quinolyl, 1,2-oxazolyl substituted by R 1 , naphthyl optionally substituted by R 4 and R 5 , phenyl fused by C 4-8 cycloalkyl, phenyl fused by saturated C 4-8 heterocycle having one or two O atoms, carbazolyl of which N-H is substituted by N-R 1 , phenyl fused by indanone, phenyl fused by indan, phenyl fused by cyclohexanone, phenyl fused by dihydrofuranone, phenyl substituted by R 1 , R 2 and R 3 , phenyl C 1-6 straight alkyl of which phenyl is substituted by R 1 , R 2 and
  • R 3 phenyl fused by unsaturated 5-6 membered hetero ring having one or two hetero atoms selected from the group consisting of N, O, S, and SO , wherein the hetero ring is optionally substituted by R 1 ,
  • R 1 , R 2 and R 3 are identical or different and represent hydrogen, halogen, straight-chain or branched C ⁇ -6 alkyl, straight-chain or branched Cj -6 alkylcarbamoyl, carbamoyl, straight-chain or branched Cj -6 alkoxy, carboxyl, nitro, amino, straight-chain or branched C ⁇ -6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, morpholino, straight-chain or branched C 1-6 alkoxycarbonyl, benzyl, phenoxy, halogen substituted phenoxy, straight-chain or branched C 1-6 alkylthio, straight-chain or branched C 1-6 alkanoyl, straight-chain or branched C 1-6 alkanoylamino, hydroxy substituted straight-chain or branched C 1-6 alkyl, mono-, di- or tri- halogen substituted straight-chain or branched C
  • the substituents are each identical or different and selected from the group consisting of hydrogen, halogen, straight-chain or branched C ⁇ - 6 alkoxy, straight-chain or branched C 1-6 alkyl, straight-chain or branched C 1-6 alkanoyl, and carboxy;
  • R represents hydrogen, hydroxy, or straight-chain or branched C 1-6 alkoxy
  • R 5 represents hydrogen, hydroxy, or straight-chain or branched C 1-6 alkoxy
  • Q represents CH or N
  • R 6 represents hydrogen or methyl
  • R 7 represents hydrogen or methyl
  • R represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3- cycloalkyl- methoxy, straight-chain or branched C 2-6 alkenyloxy, benzoyloxy, amino, straight-chain or branched C 1-6 alkylamino, phenyl C 1-6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, straight-chain or branched C 1-6 alkanoylamino, formylamino, C 1-6 alkylsulfonamino, or the group represented by the formula
  • R and R 81 are each identical or different and represent hydrogen, halogen, or straight-chain or branched C 1-6 alkoxy;
  • R 8a represents hydrogen or halogen
  • R 9 and R ⁇ are each identical or different and represent hydrogen, halogen, or nitro
  • R 10 represents hydrogen, halogen, carboxy, carbamoyl, cyano, or straight-chain or branched C 1-6 alkyl optionally substituted by the substituent, which substituent is selected from the group consisting of hydroxy, amino, di(straight-chain or branched C 1-6 alkyl)amino, piperidino, morpholino, and methyl- piperazino.
  • the compounds of the present invention suprisingly show excellent VRl antagonistic activity. They are, therefore, suitable especially as VRl antagonists and in particular for the production of medicament or medical composition, which may be useful to treat urological disorder. Since the amine derivatives of the present invention antagonize VRl activity, they are useful for treatment and prophylaxis of diseases as follows: urology disorder (e.g., urinary incontinence and overactive bladder), chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence and/or inflammatory disorders.
  • urology disorder e.g., urinary incontinence and overactive bladder
  • chronic pain e.g., neuropathic pain, postoperative pain, rheumatoid arthritic pain
  • neuralgia e.g., nerve injury, ischaemia, neurodegeneration, stroke,
  • the amine derivative of the formula (I) is those wherein;
  • R , R and R are different or identical and represent hydrogen, halogen, straight-chain or branched d- 6 alkyl, straight-chain or branched C 1-6 alkylcarbamoyl, carbamoyl, straight-chain or branched C 1-6 alkoxy, carboxyl, nitro, amino, straight-chain or branched C 1-6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, morpholino, straight-chain or branched C 1-6 alkoxycarbonyl, benzyl, phenoxy, halogen substituted phenoxy, straight-chain or branched C 1-6 alkylthio, straight-chain or branched C 1-6 alkanoyl, straight-chain or branched C 1-6 alkanoylamino, hydroxy substituted straight-chain or branched C 1-6 alkyl, mono-, di- or tri- halogen substituted straight-chain or branched C 1-6 alkyl,
  • the substituents are each different or identical and selected from the group consisting of hydrogen, halogen, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C ⁇ -6 alkyl, straight-chain or branched C 1-6 alkanoyl, and carboxy;
  • R 4 represents hydrogen, hydroxy, or straight-chain or branched C 1-6 alkoxy;
  • R 5 represents hydrogen, hydroxy, or straight-chain or branched C ⁇ -6 alkoxy
  • R .6 represents hydrogen or methyl
  • R 7 represents hydrogen or methyl
  • R 8 represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3-6 C 3-6 cycloalkylmethoxy, straight-chain or branched C 2-6 alkenyloxy, benzoyloxy, amino, straight-chain or branched Cj -6 alkylamino, phenyl C 1-6 alkylamino, di(straight-chain or branched C ⁇ -6 alkyl)amino, straight-chain or branched C 1-6 alkanoylamino, formylamino, straight-chain or branched C ⁇ -6 alkylsulfonamino, or the group represented by the formula wherein
  • R 80 and R 81 are each identical or different and represent hydrogen, halogen, or straight-chain or branched Cj_ 6 alkoxy;
  • R 8a represents hydrogen or halogen
  • R 9 represents hydrogen or halogen
  • R 10 represents hydrogen, halogen, or straight-chain or branched C 1-6 alkyl optionally substituted by hydroxy
  • R u represents hydrogen, halogen, or nitro
  • the amine derivative of the formula (I) is those wherem;
  • R 6 represents hydrogen
  • R represents hydrogen
  • R 8 represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight- chain or branched C ⁇ -6 alkanoyloxy, C 3- C 3-6 cycloalkylmethoxy, straight-chain or branched C -6 alkenyloxy, benzoyloxy, amino, straight-chain or branched C 1-6 alkylamino, phenyl C 1-6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, straight-chain or branched C 1-6 alkanoylamino, formylamino, or C 1-6 alkylsulfonamino;
  • R , 8a represents hydrogen, chloro, or fluoro
  • R represents hydrogen or halogen
  • R .10 represents hydrogen, halogen or straight-chain or branched C 1-6 alkyl optionally substituted by hydroxy
  • R l represents hydrogen or halogen
  • the amine derivative of the formula (I) is those wherein;
  • R represents hydrogen
  • R represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3-6 C 3-6 cycloalkylmethoxy, straight-chain or branched C -6 alkenyloxy, benzoyloxy, amino, straight-chain or branched C 1-6 alkylamino, phenyl C 1-6 alkylamino, di(straight-chain or branched C 1-6 alkyl)amino, straight-chain or branched C 1-6 alkanoylamino, formylamino, or straight-chain or branched C 1-6 alkylsulfonamino;
  • R a represents hydrogen
  • R represents hydrogen, bromo, chloro, or fluoro
  • R 10 represents hydrogen,halogen or straight-chain or branched C 1-6 alkyl optionally substituted by hydroxy
  • R 1 ' represents hydrogen, chloro, or fluoro
  • the amine derivative of the fo ⁇ nula (I) is those wherein;
  • R ) 6 represents hydrogen
  • R 7 represents hydrogen
  • R represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3-6 cyclo- alkylmethoxy, straight-chain or branched C 2-6 alkenyloxy, benzoyloxy, amino, or straight-chain or branched C 1-6 alkylamino;
  • R a represents hydrogen
  • R ,9 represents bromo or chloro
  • R , 10 represents bromo, chloro, or straight-chain or branched C 1-6 alkyl optionally substituted by hydroxy
  • R , ⁇ represents hydrogen
  • the amine derivative of the formula (I) is those wherein;
  • R > 6 represents hydrogen
  • R 7 represents hydrogen
  • R represents hydroxy, straight-chain or branched C 1-6 alkoxy, straight-chain or branched C 1-6 alkanoyloxy, C 3-6 cycloalkyl- methoxy, straight-chain or branched C 2-6 alkenyloxy, benzoyloxy, amino, or straight-chain or branched C 1-6 alkylamino;
  • R ,8a represents hydrogen
  • R represents chloro
  • R , 10 represents chloro
  • R 11 represents hydrogen
  • the present invention further provides the medicament having one of the compounds mentioned-above and one or more pharmaceutically acceptable excipients.
  • the compound of the formula (I) of the present invention can be, but not limited to be, prepared by the general methods [A]-[K] below.
  • one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (3 rd Edition, John Wiley, New York, 1999)" by Greene and Wuts.
  • the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloro- ethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloro- ethane; ethers such as diethylether, dioxane, tetrahydrofuran (
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 100°C.
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
  • the substituted naphthylamine and isocyanate are commercially available or can be prepared by the use of known techniques.
  • the compound [I-b] and the compound [I-b ], wherein R 6 , R 7 , R 8a , R 8 ', R 9 , R 10 , R 11 , and X are the same as defined above, can be prepared by (1) reacting a substituted naphthylamine and phenylchloroformate, and (2) adding amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above) to the reaction mixture.
  • the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chlorofo ⁇ n and 1,2-dichloro- ethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chlorofo ⁇ n and 1,2-dichloro- ethane; ethers such as diethylether, dioxane, te
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 50°C.
  • the reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.
  • the reaction can be advantageously carried out in the presence of a base including, for instance, an alkali metal hydride such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N- diisopropylethylamine, and others.
  • a base including, for instance, an alkali metal hydride such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N- diisopropylethylamine, and others.
  • the reaction (2) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N,N- dimethylaceta ide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (TH
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 120°C.
  • the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
  • substituted naphthylamine, phenylchloroformate and amine are commercially available or can be prepared by the use of known techniques.
  • X are the same as defined above, can be prepared by the reaction of a substituted naphthylamine carbamate and amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above).
  • the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloro- form and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran
  • THF 1,2-dimethoxyethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ketones such as acetone
  • nitriles such as acetonitrile
  • amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone
  • sulfoxides such as dimethylsulfoxide (DMSO); and others.
  • two or more of the solvents selected from the listed above can be mixed and used.
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 120°C.
  • the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
  • the compound [I-d] and the compound [I-d ' ] 5 wherein R 6 , R 7 , R 8a , R 9 , R 10 , R ⁇ , and X are the same as defined above, can be prepared by (1) reacting a substituted naphthylamine carbamate and amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above), and (2) adding base to the reaction mixture.
  • the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF)
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 120°C.
  • the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
  • the reaction (2) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); alcohol such as tert-butanol, methanol and ethanol; water, and others.
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
  • ethers such as diethylether, dioxan
  • two or more of the solvents selected from the listed above can be mixed and used.
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 30°C to 100°C.
  • the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
  • the base used in the reaction (2) can be, for instance, alkali metal alkoxide such as sodium methoxide and sodium ethoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, and others.
  • the compound [I-e] and the compound [I-e ' ], wherein R 7 , R 8' , R 8a , R 9 , R 10 , R 11 , and X are the same as defined above, can be prepared by (1) reacting amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above) and 1,1'- carbonyldi(l,2,4-triazole) (CDT) and (2) adding substituted naphthylamine to the reaction mixture.
  • amine represented by the formula X-NH-R 6 wherein R 6 and X are the same as defined above
  • CDT 1,1'- carbonyldi(l,2,4-triazole)
  • the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2- dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 100°C.
  • the reaction may be conducted for, usually, 30 minutes to 40 hours and preferably 1 to 24 hours.
  • the reaction (2) may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
  • ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 30°C to 100°C.
  • the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
  • the compound [I-fJ and the compound [l-f ], wherein R 6 , R 7 , R 8' R 8a , R 9 , R 10 , R 11 and X is the same as defined above, can be prepared by (1) reacting a substituted naphthylamine and l,l '-carbonyldi(l,2,4-triazole) (CDT), and (2) adding amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above) to the reaction mixture.
  • the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydro- furan (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydro- furan (
  • the reaction temperature can be optionally set depending on The reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 100°C.
  • the reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.
  • the reaction (2) may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (TH
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 100°C.
  • the reaction may be conducted for, usually, 1 hour to 48 hours and preferably 2 to 24 hours.
  • the substituted naphthylamine, l,l'-carbonyldi(l,2,4-triazole) (CDT) and amine are commercially available or can be prepared by the use of known techniques.
  • the reaction may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (TH
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 20°C to 100°C.
  • the reaction may be conducted for, usually, 30 minutes to 40 hours and preferably 1 to 24 hours.
  • the reaction can be advantageously conducted in the presence of substance having catalytic activity.
  • substances include, but not limited to, copper salts, such as copper (II) acetate, or the like.
  • the reaction can also be advantageously carried out in the presence of a base including, for instance, organic amines such as triethylamine and N,N-diiso- propylethylamine, and the others.
  • arylboronic acid and coper salts are commercially available or can be prepared by the use of known techniques.
  • the compound [I-h] and the compound [I-h'], wherein R 82 is hydrogen, or straight- chain or branched C 1-6 alkyl, R 83 is hydrogen, straight-chain or branched C 1-6 alkyl, or phenyl Cj -6 alkyl, R 8a is halogen, R 9 , R 10 and X are the same as defined above, can be prepared by reacting a substituted naphthylamine and suitable halogenating agents, for instance, N-halosuccinimides such as N-chlorosuccinimide and N-bromo- succinimide; and N-fluoro-pyridium salts such as N-fluoro-4-methylpyridinium-2- sulfonate, and others.
  • suitable halogenating agents for instance, N-halosuccinimides such as N-chlorosuccinimide and N-bromo- succinimide; and N-fluoro-pyridium salts such as N-fluor
  • the reaction may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, and others.
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
  • ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane
  • aromatic hydrocarbons such as benzene, and others.
  • two or more of the solvents selected from the listed above can be mixed and used.
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 60°C.
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
  • substituted naphthylamine and halogenating agents are commercially available or can be prepared by the use of known techniques.
  • the compound [I-i] and the compound [I-i'], wherein R 85 represents hydrogen or straight-chain or branched C 1-6 alkyl and R 6 , R 7 , R 8a , R 9 , R 10 , R 11 and X is the same as defined above, can be prepared by reacting a substituted naphthylamine and suitable acylating agents, for instance, carboxylic anhydrides such as formic anhydride, and acetic anhydride; acyl halides such as acetyl chloride, and others.
  • suitable acylating agents for instance, carboxylic anhydrides such as formic anhydride, and acetic anhydride; acyl halides such as acetyl chloride, and others.
  • the reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF)
  • the reaction can be advantageously ca ⁇ ied out in the presence of a base including, for instance, alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • a base including, for instance, alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 100°C.
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 10 hours.
  • substituted naphthylamine and acylating agents are commercially available or can be prepared by the use of known techniques.
  • the compound [I-j]and the compound [I-j'], wherein R 86 is straight-chain or branched C ⁇ -6 alkyl and R 6 , R 7 , R 8a , R 9 , R 10 , R 11 and X is the same as defined above, can be prepared by reacting a substituted naphthylamine and alkylsulfonyl chloride such as methanesulfonyl chloride, ethanesulfonyl chloride and others.
  • the reaction may be ca ⁇ ied out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (TH
  • the reaction can be advantageously carried out in the presence of a base including, for instance, alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • a base including, for instance, alkali metal carbonates such as sodium carbonate or potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 100°C.
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
  • substituted naphthylamine and alkylsulfonyl chlorides are commercially available or can be prepared by the use of known techniques.
  • the compound [I-k] and the compound [I-k'], wherein R 6 , R 7 , R 9 , R 10 , R 11 , and X are the same as defined above, can be prepared by (l)the reacting a substituted naphthalene and amine represented by the formula X-NH-R 6 (wherein R 6 and X are the same as defined above) (2) adding fluoride salts, such as tetrabutylamonium fluoride to the reaction mixture.
  • the reaction (1) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxy ethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide
  • DMSO dimethylethyl-N-(2-amino- ⁇ ropyl)-3-ethylcarbodiimide
  • coupling agent including, for instance, carbodiimides such as N, N-dicyclohexylcarbodiimide and l-(3-dimethylamino- ⁇ ropyl)-3-ethylcarbodiimide, and others.
  • the reaction may be advantageously ca ⁇ ied out in the presence of a base including, for instance, organic amines such as pyridine, 4-dimethlyaminopyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • a base including, for instance, organic amines such as pyridine, 4-dimethlyaminopyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 60°C.
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 1 to 24 hours.
  • the reaction (2) may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; ketones such as acetone; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpy ⁇ olidone; sulfoxides such as dimethylsulfoxide
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
  • ethers such as diethylether, dioxane, tetrahydrofuran (THF) and 1,2-dimethoxyethane
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0°C to 100°C.
  • the reaction may be conducted for, usually, 30 minutes to 10 hours and preferably 1 to 24 hours.
  • substituted naphthalene, amine, and fluoride salt are commercially available or can be prepared by the use of known techniques.
  • compound shown by the formula (I) or a salt thereof has tautomeric isomers and/or stereoisomers (e.g., geometrical isomers and conformational isomers), each of their separated isomer and mixtures are also included in the scope of the present invention.
  • Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.
  • Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like
  • organic acids such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like.
  • inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.
  • the compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts.
  • the compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
  • the dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.
  • the compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients.
  • Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
  • compositions of the present invention are pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically- acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefore.
  • the active ingredient may be mixed with a diluent, or enclosed within a ca ⁇ ier, which may be in the form of a capsule, sachet, paper, or other container.
  • the ca ⁇ ier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • a diluent which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the active ingredient may be combined with an oral, and nontoxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium
  • the ca ⁇ ier may be a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets.
  • the powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention.
  • Suitable solid ca ⁇ iers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.
  • Sterile liquid formulations include suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
  • the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
  • a suitable organic solvent for example, aqueous propylene glycol.
  • Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in suitable oil.
  • the formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals.
  • a unit dosage form can be a capsule or tablets, or a number of capsules or tablets.
  • a "unit dose" is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients.
  • the quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more accordmg to the particular treatment involved.
  • Typical oral dosages of the present invention when used for the indicated effects, will range from about 0.0 lmg /kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day.
  • parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to lOOmg /kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
  • Fig. 1 presents charts showing bladder capacity and voiding frequency in normal rats, cyclophosphamide treated rats (vehicle) and CYP-VR1 antagonist treated rats.
  • Fig. 2 presents graphs which shows the bladder capacity in normal rats, cyclophosphamide treated rats (vehicle), and CYP-VR1 antagonist treated rats.
  • Fig. 3 presents graphs which shows the micturition frequency in normal rats, cyclophosphamide treated rats (vehicle), and CYP-VR1 antagonist treated rats.
  • Human vanilloid receptor (hVRl) cDNA was cloned from libraries of axotomized dorsal root ganglia (WO2000/29577). The cloned hVRl cDNA was constructed with pcDNA3 vector and transfected into a CHOluc9aeq cell line. The cell line contains aequorin and CRE-luciferase reporter genes as read-out signals.
  • the transfectants were cloned by limiting dilution in selection medium (DMEM/F12 medium (Gibco BRL) supplemented with 10% FCS, 1.4 mM Sodium pyruvate, 20 mM HEPES, 0.15% Sodium bicarbonate, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, non-essential amino acids and 2 mg/ml G418). Ca 2+ influx was examined in the capsaicin-stimulated clones. A high responder clone was selected and used for further experiments in the project.
  • the human VRl-CHOluc9aeq cells were maintained in the selection medium and passaged every 3-4 days at l-2.5xl0 5 cells/flask (75 mm 2 ).
  • Human VRl-CHOluc9aeq cells were suspended in a culture medium which is the same as the selection medium except for G418 and seeded at a density of 1,000 cells per well into 384-well plates (black walled clear-base / Nalge
  • DRG dorsal root ganglia
  • DRG was incubated with 0.1% trypsin (Gibco BRL) in PBS(-) (Gibco BRL) for 30 min at 37°C, then a half volume of fetal calf serum (FCS) was added and the cells were spun down.
  • FCS fetal calf serum
  • the DRG neuron cells were resuspended in Ham F12/5% FCS/5% horse serum (Gibco BRL) and dispersed by repeated pipetting and passing through 70 ⁇ m mesh (Falcon). The culture plate was incubated for 3 hours at 37°C to remove contaminating Schwann cells.
  • Non-adherent cells were recovered and further cultured in laminin-coated 384 well plates (Nunc) at lxlO 4 cells/50 ⁇ l/well for 2 days in the presence of 50 ng/ml recombinant rat NGF (Sigma) and 50 ⁇ M 5- fluorodeoxyuridine (Sigma).
  • Bladder strips were equilibrated for 60 min before each stimulation. Contractile response to 80 mM KCl was determined at 15 min intervals until reproducible responses were obtained. The response to KCl was used as an internal standard to evaluate the maximal response to capsaicin. The effects of the compounds were investigated by incubating the strips with compounds for 30 min prior to the stimulation with 1 ⁇ M of capsaicin (Nacalai Tesque) (vehicle: 80% saline, 10% EtOH, and 10% Tween 80). One of the preparations made from the same animal was served as a control while the others were used for evaluating compounds. Ratio of each capsaicin-induced contraction to the internal standard (i.e. KCl-induced contraction) was calculated and the effects of the test compounds on the capsaicin-induced contraction were evaluated.
  • capsaicin Nacalai Tesque
  • Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.2 g/kg.
  • the abdomen was opened through a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder tlirough the dome.
  • a polyethylene catheter (Hibiki, size 5) filled with 2 IU / ml of heparin (Novo Heparin, Aventis Pharma, France) in saline (Otsuka) was inserted into a femoral vein.
  • the bladder catheter was connected via T-tube to a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a microinj ection pump (TERUMO). Saline was infused at room temperature into the bladder at a rate of 3.6 ml/hr. Intravesical pressure was recorded continuously on a chart pen recorder (Yokogawa). At least three reproducible micturition cycles, conesponding to a 20-minute period, were recorded before a test compound administration and used as baseline values. (4) Administration of test compounds and stimulation of bladder with capsaicin
  • the saline infusion was stopped before administrating compounds.
  • a testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1 : 1 : 8, v/v/v) was administered intraarterially at 3mg/kg or
  • saline including 30 ⁇ M of capsaicin (Nacalai Tesque) was infused at room temperature into the bladder at a rate of 3.6 ml/hr.
  • capsaicin-induced intravesical pressure were analyzed from the cystometry data.
  • the capsaicin-induced bladder pressures were compared with the maximum bladder pressure during micturition without the capsaicin stimulation.
  • the testing compounds-mediated inhibition of the increased bladder pressures was evaluated using Student's t- test. A probability level less than 5% was accepted as significant difference.
  • Cyclophosphamide (CYP) dissolved in saline was administered intra- peritoneally at 150 mg/kg 48 hours before experiment.
  • Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.25 g/kg. The abdomen was opened through a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder through the dome. In parallel, the inguinal region was incised, and a polyethylene catheter (BECTON DICKINSON, PE50) filled with saline (Otsuka) was inserted into a femoral vein. After the bladder was emptied, the rats were left for 1 hour for recovery from the operation.
  • urethane Sigma
  • the bladder catheter was connected via T-tube to a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a microinj ection pump (TERUMO). Saline was infused at room temperature into the bladder at a rate of 3.6 ml/hr for 20 min. Intravesical pressure was recorded continuously on a chart pen recorder (Yokogawa). At least three reproducible micturition cycles, conesponding to a 20-minute period, were recorded before a test compound administration.
  • a testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1 : 1 : 8, v/v/v) was administered intravenously at 0.05 mg/kg, 0.5 mg/kg or 5 mg/kg. 3min after the administration of the compound, saline (Nacalai Tesque) was infused at room temperature into the bladder at a rate of 3.6 ml/hr.
  • the cystometry parameters were analyzed as described previously [ Lecci A et al: Eur. J. Pharmacol. 259: 129-135, 1994].
  • the micturition frequency calculated from micturition interval and the bladder capacity calculated from a volume of infused saline until the first micturition were analyzed from the cystometry data.
  • the testing compounds-mediated inhibition of the frequency and the testing compounds-mediated increase of bladder capacity were evaluated using unpaired Student's t-test. A probability levels less than 5% was accepted as significant difference. Data were analyzed as the mean + SEM from 4 - 7 rats.
  • Human P2X1 -transfected CHOluc9aeq cell line was established and maintained in Dulbecco's modified Eagle's medium (DMEM/F12) supplemented with 7.5% FCS, 20 mM HEPES-KOH (pH 7.4), 1.4 mM sodium pyruvate, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine (Gibco BRL) and 0.5 Units/ml apyrase (grade I, Sigma).
  • the suspended cells were seeded in each well of 384-well optical bottom black plates (Nalge Nunc International) at 3 x IO 3 / 50 ⁇ l / well. The cells were cultured for following 48 hrs to adhere to the plates.
  • P2X1 receptor agonist-mediated increases in cytosolic Ca levels were measured using a fluorescent Ca 2+ chelating dye, Fluo-3 AM (Molecular Probes).
  • the plate-attached cells were washed twice with washing buffer (HBSS, 17 mM HEPES-KOH (pH 7.4), 0.1% BSA and 0.5 units/ml apyrase), and incubated in 40 ⁇ l of loading buffer (1 ⁇ M Fluo-3 AM, 1 mM probenecid, 1 ⁇ M cyclosporin A, 0.01% pluronic (Molecular Probes)in washing buffer) for 1 hour in a dark place.
  • IC 50 value of equal to or below 10 nM.
  • the compounds of the present invention also show excellent selectivity, and strong activity in other assays (2)-(4) described above.
  • N,N-dimethylformamide 100 mL
  • Phosphorus oxychloride 61.2 g, 399.2 mmol
  • N,N-dibenzyl-7-(benzyloxy)-l-naphthalenamine 49.0 g, 114.1 mmol
  • the mixture was stined at room temperature for 16 hours, and then poured into ice- water.
  • the product mixture was extracted with dichloromethane, and the organic layer was washed with water, aqueous sodium bicarbonate, and brine.
  • N,N-dimethylformamide 100 mL
  • Phosphorus oxychloride 61.2 g, 399.2 mmol
  • N,N-dibenzyl-7-(benzyloxy)-l-naphthalenamine 49.0 g, 114.1 mmol
  • the mixture was stined at room temperature for 16 hours, and then poured into ice- water.
  • the product mixture was extracted with dichloromethane, and the organic layer was washed with water, aqueous sodium bicarbonate, and brine.
  • This example was performed according to the general method A.
  • This example was performed according to the general method B.
  • N-(l, -biphenyl-3-yl)-N'-(2-chloro-7-hydroxy-l-naphthyl)urea 102.1 mg, 87.5 %).
  • This example was performed according to the general method C.
  • This example was performed according to the general method D.
  • This example was performed according to the general method E.
  • This example was performed according to said method F.
  • Methyl 3-aminobenzoate (60.5mg, 0.4mmol) was added to the suspension at room temperature. The reaction mixture was stirred at 50°C for 15hrs. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and ethanol (1:1), and it was passed through a silicagel short cartridge (lg Si / 6ml). The cartridge was washed with a mixture of ethyl acetate and ethanol (1:1). The combined filtrates were concentrated to give the dark purple solid.
  • This example was performed according to the general method H.
  • the compounds of the present invention inhibit the capsaicin-induced increase of intracellular calcium levels (Ca 2+ flux) in the cell line expressing human VRl in a concentration dependent manner with IC 5 o values.
  • Functional activity (Ca 2+ flux) in the capsaicin-stimulated rat DRG cells is inhibited by the tested compounds.
  • Significant inhibition of the capsaicin-induced rat bladder detrusor contraction is observed for most of the tested compounds.
  • Selectivity over other ion channel receptors such as P2X1 and P2X3 is high - more than 100 fold.
  • the effect of one of the compound of the present invention (VRl antagonist) on the capsaicin-induced overactive bladder in vivo in anesthetized rats is investigated.
  • the overactive bladder is induced by intravesical infusion of capsaicin solution.
  • the frequency of the micturition is compared.
  • VRl antagonist inhibits the capsaicin-induced increase of micturition reflex at 3 or 10 mg/kg.
  • assay 5 the effect of VRl antagonists of the present invention on cyclophosamide induced cystitis in anesthetized rats is investigated.
  • Significant improvement of both bladder capacity (Fig. 1 and Fig. 2) and micturition frequency (Fig. 1 and Fig. 3) is observed at a dosage of 0.5 mg/kg, i.v. and 5 mg/kg, i.v.
PCT/EP2002/008493 2001-07-31 2002-07-31 Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists WO2003014064A1 (en)

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EP02758413A EP1414788A1 (en) 2001-07-31 2002-07-31 Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists
US10/485,481 US20040259875A1 (en) 2001-07-31 2002-07-31 Amine derivatives
AU2002325381A AU2002325381A1 (en) 2001-07-31 2002-07-31 Naphthylurea and naphthylacetamide derivatives as vanilloid receptor 1 (vr1) antagonists
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Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055848A2 (en) * 2001-12-26 2003-07-10 Bayer Healthcare Ag Urea derivatives as vr1- antagonists
WO2003070247A1 (en) * 2002-02-20 2003-08-28 Abbott Laboratories Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor
WO2003080578A1 (en) * 2002-03-22 2003-10-02 Merck Sharp & Dohme Limited Heteroaromatic urea derivatives as vr-1 receptor modulators for treating pain
WO2004007459A2 (en) * 2002-07-12 2004-01-22 Janssen Pharmaceutica N.V. Naphthol, quinoline and isoquinoline-derivatives as modulators of vanilloid vr1 receptor
WO2004028440A2 (en) * 2002-09-24 2004-04-08 Bayer Healthcare Ag Vr1 antagonists for the treatment of urological disorders
WO2004052846A1 (en) * 2002-12-06 2004-06-24 Bayer Healthcare Ag Tetrahydro-naphthalene derivatives
WO2004089881A1 (en) * 2003-04-14 2004-10-21 Astrazeneca Ab New sulfonyl derivatives of aminonaphtols
WO2004096784A1 (en) * 2003-04-28 2004-11-11 Astrazeneca Ab New heterocyclic amides exhibiting an inhibitory activity at the vanilloid receptor 1 (vr1).
WO2004111009A1 (en) * 2003-06-12 2004-12-23 Abbott Laboratories Fused compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor
WO2005013914A2 (en) 2003-08-08 2005-02-17 Vertex Pharmaceuticals Incorporated Heteroarylaminosulfonylphenyl derivatives for use as sodium or calcium channel blockers in the treatment of pain
WO2005016922A1 (en) * 2003-08-14 2005-02-24 Glaxo Group Limited Carbazole-2-carboxamide derivatives having vanilloid receptor antagonist activity
WO2005016890A1 (en) * 2003-02-11 2005-02-24 Abbott Laboratories Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (vr1) receptor
WO2005040119A1 (en) * 2003-10-01 2005-05-06 Bayer Healthcare Ag Tetrahydro-naphthalene and urea derivatives
WO2005040100A1 (en) * 2003-10-15 2005-05-06 Bayer Healthcare Ag Tetrahydro-naphthalene and urea derivatives
WO2005049613A1 (en) 2003-11-14 2005-06-02 Merck Sharp & Dohme Limited Bicyclic pyrimidin-4-(3h)-ones and analogues and derivatives thereof which modulate the function of the vanilloid-1 receptor (vr1)
WO2005120510A1 (en) * 2004-06-08 2005-12-22 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US6984647B2 (en) 2002-05-17 2006-01-10 Janssen Pharmaceutica N.V. Aminotetralin-derived urea modulators of vanilloid VR1 receptor
US7067553B2 (en) 2000-08-21 2006-06-27 Pacific Corporation Thiourea compounds and the pharmaceutical compositions containing the same
US7074805B2 (en) 2002-02-20 2006-07-11 Abbott Laboratories Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
US7074799B2 (en) 2002-01-17 2006-07-11 Neurogen Corporation Substituted quinazolin-4-ylamine analogues
EP1684762A2 (en) * 2003-11-13 2006-08-02 Ambit Biosciences Corporation Urea derivatives as kinase modulators
WO2006100520A1 (en) * 2005-03-24 2006-09-28 Merck Sharp & Dohme Limited 2,3-substituted fused pyrimidin-4(3h)-ones as vr1 antagonists
WO2007002635A2 (en) 2005-06-27 2007-01-04 Bristol-Myers Squibb Company C-linked cyclic antagonists of p2y1 receptor useful in the treatment of thrombotic conditions
JP2007511479A (ja) * 2003-11-08 2007-05-10 バイエル・ヘルスケア・アクチェンゲゼルシャフト 二環式アミド、カルバメートまたは尿素誘導体
WO2008050199A2 (en) 2006-10-23 2008-05-02 Pfizer Japan Inc. Substituted phenylmethyl bicyclocarboxyamide compounds
US7375126B2 (en) 2003-06-12 2008-05-20 Abbott Laboratories Fused compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor
US7550499B2 (en) 2004-05-12 2009-06-23 Bristol-Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7585878B2 (en) 2003-06-12 2009-09-08 Astellas Pharma Inc. Benzamide derivative or salt thereof
WO2009128661A2 (ko) 2008-04-18 2009-10-22 주식회사 대웅제약 신규 벤조옥사진 벤즈이미다졸 유도체, 이를 포함하는 약학 조성물 및 이의 용도
US7618993B2 (en) 2005-12-23 2009-11-17 Astrazeneca Ab Compounds
US7645778B2 (en) 2005-01-19 2010-01-12 Bristol-Myers Squibb Company Heteroaryl compounds as P2Y1 receptor inhibitors
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US7683076B2 (en) 2003-11-08 2010-03-23 Bayer Schering Pharma Aktiengesellschaft Tetrahydro-quinolinylurea derivatives
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US7728005B2 (en) 2003-10-14 2010-06-01 Ajinomoto Co., Inc. Ether derivative
US7728008B2 (en) 2005-06-27 2010-06-01 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7767705B2 (en) 2006-08-25 2010-08-03 Abbott Laboratories Compounds that inhibit TRPV1 and uses thereof
US7816382B2 (en) 2005-06-27 2010-10-19 Bristol-Myers Squibb Company Linear urea mimics antagonists of P2Y1 receptor useful in the treatment of thrombotic condition
US7879866B2 (en) 2004-07-19 2011-02-01 Dorte Xenia Gram Inhibition of the activity of the capsaicin receptor in the treatment of obesity or obesity-related diseases and disorders
US7906654B2 (en) 2006-08-11 2011-03-15 Astrazeneca Ab Benzimidazole derivatives
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7964732B2 (en) 2006-11-17 2011-06-21 Pfizer Inc. Substituted bicyclocarboxyamide compounds
US8026256B2 (en) 2003-06-12 2011-09-27 Abbott Laboratories Fused compounds that inhibit vanilloid subtype 1 (VR1) receptor
US8026235B1 (en) 2010-10-13 2011-09-27 Daewoong Pharmaceutical Co., Ltd. Pyridyl benzoxazine derivatives, pharmaceutical composition comprising the same, and use thereof
US8030504B2 (en) 2006-12-20 2011-10-04 Abbott Laboratories Antagonists of the TRPV1 receptor and uses thereof
US8071650B2 (en) 2000-08-21 2011-12-06 Pacific Corporation Thiourea derivatives and the pharmaceutical compositions containing the same
US8178558B2 (en) 2006-09-15 2012-05-15 Pfizer Inc. Substituted pyridylmethyl bicycliccarboxyamide compounds
US8232411B2 (en) 2008-03-20 2012-07-31 Abbott Laboratories Methods for making central nervous system agents that are TRPV1 antagonists
US9199965B2 (en) 2005-01-28 2015-12-01 Daewoong Co., Ltd. Benzoimidazole derivatives and pharmaceutical composition comprising the same
CN105906564A (zh) * 2016-05-05 2016-08-31 海南省药物研究所 化合物、制备方法及其用途
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Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052845A1 (en) * 2002-12-09 2004-06-24 Bayer Healthcare Ag Tetrahydro-naphthalene derivatives as vanilloid receptor antagonists
TW200510373A (en) * 2003-07-14 2005-03-16 Neurogen Corp Substituted quinolin-4-ylamine analogues
GB0319150D0 (en) * 2003-08-14 2003-09-17 Glaxo Group Ltd Novel compounds
KR20050039573A (ko) * 2003-10-23 2005-04-29 주식회사 태평양 티오우레아계 유도체의 용해성과 생체이용률이 개선된약제학적 조성물
GB0509573D0 (en) * 2005-05-11 2005-06-15 Merck Sharp & Dohme Therapeutic compounds
WO2010095227A1 (ja) * 2009-02-19 2010-08-26 富士通株式会社 新規化合物、並びに、結合阻害剤、抗アレルギー剤、抗喘息剤、及び抗炎症剤
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CN114736099B (zh) * 2022-05-18 2023-06-06 江苏南大光电材料股份有限公司 1-（叔丁基）-3-氯萘的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050387A1 (en) * 1999-02-22 2000-08-31 Pacific Corporation Vanilloid analogues containing resiniferatoxin pharmacophores as potent vanilloid receptor agonists and analgesics, compositions and uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000050387A1 (en) * 1999-02-22 2000-08-31 Pacific Corporation Vanilloid analogues containing resiniferatoxin pharmacophores as potent vanilloid receptor agonists and analgesics, compositions and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANDRIEUX, J. ET AL: "Synthesis of new naphthalene analogs of serotonin", CHIM. THERAP. (1966), (2), 57-61, XP009000513 *
DRAY A: "NEUROPHARMACOLOGICAL MECHANISMS OF CAPSAICIN AND RELATED SUBSTANCES", BIOCHEMICAL PHARMACOLOGY, PERGAMON, OXFORD, GB, vol. 44, no. 4, 18 August 1992 (1992-08-18), pages 611 - 615, XP000576776, ISSN: 0006-2952 *
HONMA, TERUKI ET AL: "Structure-Based Generation of a New Class of Potent Cdk4 Inhibitors: New de Novo Design Strategy and Library Design", JOURNAL OF MEDICINAL CHEMISTRY (2001), 44(26), 4615-4627, XP002220243 *
LECLERC, VERONIQUE ET AL: "Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands", BIOORGANIC & MEDICINAL CHEMISTRY (1998), 6(10), 1875-1887, XP002220244 *

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US7285563B2 (en) 2002-03-22 2007-10-23 Rebecca Elizabeth Brown Heteroaromatic urea derivatives as VR-1 receptor modulators for treating pain
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US6984647B2 (en) 2002-05-17 2006-01-10 Janssen Pharmaceutica N.V. Aminotetralin-derived urea modulators of vanilloid VR1 receptor
US7678812B2 (en) 2002-05-17 2010-03-16 Janssen Pharmaceutica Nv Aminotetralin-derived urea modulators of vanilloid VR1 receptor
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WO2004007459A2 (en) * 2002-07-12 2004-01-22 Janssen Pharmaceutica N.V. Naphthol, quinoline and isoquinoline-derivatives as modulators of vanilloid vr1 receptor
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US7728005B2 (en) 2003-10-14 2010-06-01 Ajinomoto Co., Inc. Ether derivative
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US8815930B2 (en) 2006-08-25 2014-08-26 Abbvie Inc. Compounds that inhibit TRPV1 and uses thereof
US7767705B2 (en) 2006-08-25 2010-08-03 Abbott Laboratories Compounds that inhibit TRPV1 and uses thereof
US8178558B2 (en) 2006-09-15 2012-05-15 Pfizer Inc. Substituted pyridylmethyl bicycliccarboxyamide compounds
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US8158650B2 (en) 2006-10-23 2012-04-17 Pfizer Inc. Substituted phenylmethyl bicyclocarboxyamide compounds
WO2008050199A2 (en) 2006-10-23 2008-05-02 Pfizer Japan Inc. Substituted phenylmethyl bicyclocarboxyamide compounds
US7964732B2 (en) 2006-11-17 2011-06-21 Pfizer Inc. Substituted bicyclocarboxyamide compounds
US8350083B2 (en) 2006-12-20 2013-01-08 Abbvie Inc. Antagonists of the TRPV1 receptor and uses thereof
US8030504B2 (en) 2006-12-20 2011-10-04 Abbott Laboratories Antagonists of the TRPV1 receptor and uses thereof
US8232411B2 (en) 2008-03-20 2012-07-31 Abbott Laboratories Methods for making central nervous system agents that are TRPV1 antagonists
WO2009128661A2 (ko) 2008-04-18 2009-10-22 주식회사 대웅제약 신규 벤조옥사진 벤즈이미다졸 유도체, 이를 포함하는 약학 조성물 및 이의 용도
US8026235B1 (en) 2010-10-13 2011-09-27 Daewoong Pharmaceutical Co., Ltd. Pyridyl benzoxazine derivatives, pharmaceutical composition comprising the same, and use thereof
CN105906564A (zh) * 2016-05-05 2016-08-31 海南省药物研究所 化合物、制备方法及其用途
DE102022104759A1 (de) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-Kristall-Screening Verfahren, insbesondere zur Herstellung von Co-Kristallen

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AU2002325381A1 (en) 2003-02-24
CA2455754A1 (en) 2003-02-20
EP1414788A1 (en) 2004-05-06
JP2005501873A (ja) 2005-01-20
WO2003014064A8 (en) 2003-11-27

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