WO2004048319A1 - Nouveaux composes de benzamide destines a etre utilises dans des troubles associes au recepteur de mch - Google Patents

Nouveaux composes de benzamide destines a etre utilises dans des troubles associes au recepteur de mch Download PDF

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WO2004048319A1
WO2004048319A1 PCT/DK2003/000234 DK0300234W WO2004048319A1 WO 2004048319 A1 WO2004048319 A1 WO 2004048319A1 DK 0300234 W DK0300234 W DK 0300234W WO 2004048319 A1 WO2004048319 A1 WO 2004048319A1
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groups
compound according
benzamide
phenyl
methoxy
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PCT/DK2003/000234
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English (en)
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Thomas Högberg
Emelie Bjurling
Jean-Marie Receveur
Trond Ulven
Paul Brian Little
Christian E. Elling
Pia Karina NØRREGAARD
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7Tm Pharma A/S
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Priority to AU2003226929A priority Critical patent/AU2003226929A1/en
Publication of WO2004048319A1 publication Critical patent/WO2004048319A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
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    • 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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • 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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—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 no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to novel compounds that interact with a melanin- concentrating hormone receptor, a MCH receptor.
  • the compounds have modulating activity on the MCH receptor such as e.g. antagonistic, agonistic or allosteric activity and are useful for medicinal or cosmetic purposes such as, e.g. in the treatment or prevention of feeding disorders like obesity, metabolic syndrome, Type II diabetes, bulimia etc. or in the treatment or prevention of depression.
  • the invention also relates to therapeutic and/or prophylactic use of the compounds, to processes for the preparation of the novel compounds, to pharmaceutical compositions comprising the compounds, to the manufacture of such compositions and to methods for the treatment and/or prevention of MCH receptor related disorders.
  • MCH Melanin-concentrating hormone
  • MCH receptors The biological effects of MCH are believed to be mediated by specific MCH receptors, and the MCH1 and MCH2 receptors have been described.
  • Antagonists of MCH receptor e.g. MCH1 receptor
  • MCH1 receptor may be suitable for use as obesity or weight reducing agents and they are also believed to have antidepressant and/or anxiolytic properties.
  • the present invention provides novel compounds that have a MCH modulating activity, i.e. antagonistic, inverse agonistic/negative antagonism, allosteric modulator, partial agonist or agonistic action.
  • a MCH modulating activity i.e. antagonistic, inverse agonistic/negative antagonism, allosteric modulator, partial agonist or agonistic action.
  • the present invention relates to a compound with the following structure (Formula I)
  • -A- is a linker, which is selected from the group consisting of
  • linker may be attached via either of the two free bonds to the Ar1 group
  • R7 is the same or different and is hydrogen or a straight or branched C- ⁇ -C alkyl or alkenyl group
  • An is an aryl or heteroaryl group such as, e.g. phenyl, pyridine, pyrimidine, pyrazine, thiophene, oxazole, isothiazole, pyrazole, pyrrole, imidazole, indole, benzimidazole, quinoline, isoquinoline, furan, benzofuran, benzothiophene, benzothiazole, indazole, thiazole, isoxazole, oxadiazole, indan;
  • R1 is hydrogen or a lower alkoxy group alkyl-O- with one to four carbon atoms and preferably one carbon, and in the case of R1 being ethoxy or propoxy it may be annelated with the benzene ring;
  • Q is selected from the group consisting of:
  • R3 or R4 may optionally be linked to each other, when possible, as indicated in Formula I; and oxygen or nitrogen atoms may be inserted in the chain or ring in a chemically stable position;
  • Alk is the same or a different alkyl, alkenyl or alkynyl group
  • R5 may the same or different selected from hydrogen, halogen atoms, alkoxy groups (AlkO-), hydroxy, alkylamino groups (AlkNH-), dialkylamino groups (Alk 2 N-), hydroxylalkyl groups, carboxamido groups (-CONH 2 , -CONHAIk, -CONAIk 2 ), acylamido groups (-NHCO- Alk), acyl groups (-CO-Alk), -CHO, nitrile, alkyl, alkenyl or alkynyl groups, -SCH 3 , partially or fully fluorinated alkyl, alkoxy or thioalkoxy groups such as -CH 2 CF 3 , -CF 2 CF 3 , -CF 3 , - OCF 3 , -SCF 3 ; -SO 2 NH 2 , -SO 2 NHAIk, -SO 2 NAIk 2 , -SO 2 Alk;
  • R8 is hydrogen, halogen atoms, alkyl, alkenyl or alkynyl groups, cycloalkyl groups with 3-7 carbons, alkylcycloalkyl groups, alkoxy groups (AlkO-), dialkylamino groups (Alk 2 N-), - CONHAIk, -CONAIk 2 , -NHCO-Alk, -CO-Alk, -SCH 3 , partially or fully fluorinated alkyl, alkoxy or thioalkoxy groups such as -CH 2 CF 3 , -CF 2 CF 3 , -CF 3 , -OCF 3 , -SCF 3
  • R5 group same or different, may be present on Ar1; when more than one R5 or when one R5 and one R8 group are present they could be connected to each other, directly or with a suitable connecting moiety, to form rings.
  • X being the same or different H, F, Cl, Br, I, -SCH 3 , partially or fully fluorinated alkyl, alkoxy or thioalkoxy groups such as -CH 2 CF 3 , -CF 2 CF 3 , -CF 3 , -OCF 3 , -SCF 3 ; OCH 3 or lower alkyl or alkenyl group;
  • n 1 ,2 or 3
  • the alkyl chain connecting the amide nitrogen and the aliphatic nitrogen may optionally be substituted with one or more R7, alkyl or heteroalkyl groups, which optionally may form a ring;
  • alkyl is intended to indicate a branched or straight-chain, saturated chemical group containing 1-8 carbon atoms such as, e.g. 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl efc.
  • 1-8 carbon atoms such as, e.g. 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl efc.
  • lower alkyl is intended to indicate an alkyl group containing 1-6 carbon atoms, unless otherwise specified.
  • lower alkenyl and lower alkynyl are intended to indicate alkenyl and alkynyl groups, respectively containing 2-6 carbon atoms.
  • alkenyl is intended to indicate an unsaturated alkyl group having one or more double bonds and 2-8 carbon atoms unless otherwise specified.
  • alkynyl is intended to indicate an unsaturated alkyl group having one or more triple bonds and 2-8 carbon atoms unless otherwise specified.
  • cycloalkyl is intended to denote a cyclic, saturated alkyl group of 3-7 carbon atoms.
  • cycloalkenyl is intended to denote a cyclic, unsaturated alkyl group of 5-7 carbon atoms having one or more double bonds.
  • alkoxy is intended to indicate the group alkyl-O-.
  • aryl is intended to denote an aromatic (unsaturated), typically 6-membered, ring, which may be a single ring (e.g. phenyl) or fused with other 5- or 6-membered rings (e.g. naphthyl or indole).
  • heteroaryl is intended to denote an aromatic (unsaturated), 5- or 6-membered, ring, which may be a single ring (e.g. pyridyl) or fused with other 5- or 6-membered rings (e.g. quinoline or indole).
  • heterocyclyl is intended to indicate a cyclic unsaturated (heteroalkenyl), aromatic (“heteroaryl”) or saturated (“heterocycloalkyl”) group comprising at least one heteroatom.
  • the present invention relates to a compound with the following structure (Formula la)
  • Ar 1 ; A, B, R1 , R3, R4, R5, R8, n and X are as defined herein.
  • the present invention also relates to a compound as described above wherein Q is
  • -A- may be selected from the group consisting of
  • -A- may be selected from the group consisting of
  • -A- may be selected from the group consisting of
  • R8 is -SCH 3 , partially or fully fluorinated alkyl, alkoxy or thioalkoxy groups such as -CH 2 CF 3 , -CF 2 CF 3 , -CF 3 , -OCF 3 , -SCF 3 .
  • a ⁇ is an aryl or heteroaryl group such as, e.g. phenyl, pyridine, thiophene.
  • X is H, F, Cl, or lower alkyl.
  • R5 is selected from hydrogen, halogen atoms, alkoxy groups (AlkO-), alkylamino groups (AlkNH-), dialkylamino groups (Alk 2 N-), carboxamido groups (-CONH 2 , -CONHAIk, -CONAIk 2 ), acylamido groups (-NHCO-Alk), nitrile, lower alkyl groups, -CF 3 , -OCF 3 , -SCF 3 , -SCH 3 .
  • the present invention relates to a compound as described herein, having one of the following structures
  • R8 may be -F or partially or fully fluorinated alkyl, alkoxy or thioalkoxy groups such as -CH 2 CF 3 , -CF 2 CF 3 , -CF 3 , -OCF 3 , -SCF 3 and in particular -CF 3 , -OCF 3 or - F.
  • R1 may be a methoxy group.
  • R1 may be a methoxy group and R8 may be -CF 3 , -OCF 3 or -F.
  • the R3 and R4 groups being lower alkyl groups or being joined to each other to form a piperidine, a pyrrolidine or a morpholine ring.
  • X may be hydrogen or fluorine.
  • urea bonds -A- can be formed by reaction of II having A ' as isocyanate with III having A " equal to NH-R7 using appropriate catalysis by base or acid.
  • III having A" as isocyanate with II having A' equal to NH-R7 can also be applied.
  • carbamates can for example be made by reaction of II having A ' as isocyanate with III having A" equal to OH or the reverse use of OH and isocyanate in A ' and A " .
  • bonds in either direction between Ar1 and the benzamide can be made by N-, O- or S- alkylations of compound II with A' being OH, NH-R7, or SH with compound III with A " being a CH 2 -L wherein L being a suitable leaving group such as halogen (Cl, Br, I), tosyl or mesyl using appropriate catalysts and conditions.
  • the alkene linkage can be made by a Wittig reaction with compound II with A ' being CHO and compound III with A " being CH 2 - PPh 3 .
  • the reverse use of A ' and A " in II and III can be applied as well to form the linker in the opposite direction.
  • 1 ,2,4-triazole can be made from II with A ' being acylhydrazide with III with A " being amide or thioamide or the reverse orientation of A ' and A " .
  • 1,2,4-Oxadiazole can be formed from II with A ' being amidoxime with III with A" being carboxylic ester or the reverse orientation of A ' and A " .
  • 1 ,3,4- Oxadiazole can be formed from II with A ' being acylhydrazide with III with A " being carboxylic ester or the reverse orientation of A ' and A " .
  • Aromatic substituents R4, R5 and R8 are preferably introduced prior to formation of the A- or B-linkage either direct or via a masked functionality that is compatible with the subsequent synthetic steps.
  • the benzamide bond is formed by reacting a suitably activated carboxylic acid VI (e.g. acid chloride) with the corresponding amines VII in the presence of a base or using suitable coupling reagents such as DCC in presence of promoting agents and a suitable base.
  • a suitably activated carboxylic acid VI e.g. acid chloride
  • suitable coupling reagents such as DCC
  • compounds of formula I can be made by N-alkylation of compounds of formula I having R3 and R4 being hydrogen using well-known synthetic routes such as reductive alkylation or alkylation with alkyl halides in case the functionalisation of the molecule is compatible with this type of reactions (Route 3).
  • compound (lb) having NHCON-R7 as linker A with R7 defined as hydrogen or lower alkyl or alkenyl group can be produced, for instance, by the following urea reaction.
  • inert solvents can be ether solvents, halogenated hydrocarbon solvents, nitrile solvents and aromatic solvents.
  • Reaction temperature is usually room temperature and the reaction time is 2 hours to 1 day.
  • Compound lla can be produced from the corresponding carboxylic acid.
  • 4- phenoxyphenylisocyanate can be produced in accordance with methods such as described in "Comprehensive Organic Transformation", 2 nd Edition (Wiley); R.C. Larock.
  • Compound Ic having N-AlkCON-R7 as linker A with R7 defined as hydrogen or lower alkyl or alkenyl group can be produced, for instance, by the following urea reaction.
  • Suitable inert solvents can be ether solvents, halogenated hydrocarbon solvents, nitrile solvents and aromatic solvents.
  • a base can be used for instance triethylamine, diisopropylethylamine and sodium carbonate.
  • the reaction temperature is 0 °C to room temperature and the reaction time is 1 hour to 1 day.
  • Compound lib can be produced from the corresponding N-alkyl aromatic amine by well- known methods.
  • N-methyl-N-4-phenoxyphenylcarbamoyl chloride can be produced in accordance with methods such as described in J. Labelled Compd. Radiopharma 29(2), 149-155, 1991.
  • Compound Ii having CON-R7 as linker A with R7 defined as hydrogen or lower alkyl or alkenyl group can be produced by the following amidation reaction.
  • the amide bonds are formed by reacting a suitably activated carboxylic acid lie (acid chloride, mixed anhydrides, esters with phenol bearing electron withdrawing substituents, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 2-hydroxypyridine) with anilines Ilia in an inert solvent in the presence of a base.
  • inert solvents can be used ether solvents, amide solvents and halogenated hydrocarbon solvents.
  • Suitable bases that can be used are triethylamine, diiisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP) and sodium carbonate.
  • the reaction temperature is usually between 0°C to 30°C and reaction time is 1 hour to 1 day.
  • the coupling can also be performed directly from lie using suitable coupling reagents such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethyl-cabodiimide (EDCI), N-ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (EEDQ) preferably in presence of promoting agents capable of forming an active ester such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, 2-hydroxypyridine in an inert solvent in the presence of a base.
  • inert solvents can be used ether solvents, amide solvents and halogenated hydrocarbon solvents.
  • Suitable bases that can be used are triethylamine, diiisopropylethylamine, pyridine, N-ethyldiisopropylamine, and 4-methylmorpholine.
  • the reaction temperature is usually between 0°C to 30°C and reaction time is 1 hour to 1 day.
  • bonds can be made via the corresponding reaction of Ar-NH-R7 (Ilia) with activated forms of sulphonic acids, such sulphonyl chlorides, in the presence of base.
  • Compound Ig is reacted in an inert solvent with or without the presence of a suitable base or acid (e.g. N-tetrabutyl ammonium fluoride, sodium hydride, sodium ethoxide or polyphosphoric acid) in accordance with standard methods such as described in Tetrahedron Lett. 42, 1441-1443, 2001 ; Tetrahedron Lett. 42, 1495-1498, 2001.
  • a suitable base or acid e.g. N-tetrabutyl ammonium fluoride, sodium hydride, sodium ethoxide or polyphosphoric acid
  • Suitable, inert solvents can be ether solvents, amide solvents and aromatic solvents.
  • the reaction temperature is usually room temperature to 100°C and the reaction time is 1 hour to 3 days.
  • Compound Ig can be produced by reacting an activated derivative of compound lid with 1 equivalent of compound I lie in an inert solvent in the presence of a base.
  • inert solvents can be used ether solvents, amide solvents and halogenated hydrocarbon solvents.
  • bases that can be used are triethylamine, diiisopropylethylamine, pyridine and sodium carbonate.
  • Appropriate examples of the activated derivatives of compound lid include active esters (e.g. esters with phenol bearing electron withdrawing substituents, 1-hydroxybenzotriazole, N-hydroxysuccinamide), acid chlorides, symmetrical or unsymmetrical anhydrides and orthoesters.
  • the reaction temperature is usually between 0°C to 30°C and reaction time is 1 hour to 1 day.
  • Compound 11 lo can be produced from the corresponding amino compound lllb by well known methods such as described in "Comprehensive Organic Transformation”, 2 nd Edition (Wiley), R.C. Larock; In “Handbook of Heterocyclic Chemistry”, 2 nd Edition (Pergamon), A.R. Katritzky).
  • Benzamide bonds are formed by reacting a suitably activated carboxylic acid VI (acid chloride, mixed anhydrides, esters with phenol bearing electron withdrawing substituents, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 2-hydroxypyridine) with the corresponding amines VII in an inert solvent in the presence of a base.
  • inert solvents can be used ether solvents, amide solvents and halogenated hydrocarbon solvents.
  • Suitable bases that can be used are triethylamine, diiisopropylethylamine, pyridine, 4-dimethylamino- pyridine (DMAP) and sodium carbonate.
  • the reaction temperature is usually between 0°C to 30°C and reaction time is 1 hour to 1 day.
  • the coupling can also be performed by using suitable coupling reagents such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethyl-cabodiimide (EDCI), N-ethoxycarbonyl-2-ethoxy-1 ,2-dihydroquinoline (EEDQ) preferably in presence of promoting agents capable of forming an active ester such as 1 -hydroxybenzotriazole, N- hydroxysuccinimide, 2-hydroxypyridine in an inert solvent in the presence of a base.
  • inert solvents can be used ether solvents, amide solvents and halogenated hydrocarbon solvents.
  • Suitable bases that can be used are triethylamine, diiisopropylethylamine, pyridine, N-ethyldiisopropylamine, and 4-methylmorpholine.
  • the reaction temperature is usually between 0°C to 30°C and reaction time is 1 hour to 1 day.
  • N-alkylated derivative Ilia may be obtained via reductive alkylation of lllb.
  • the carboxylic acids VIII are produced by well-known organic reactions including electrophilic substitutions or organometallic reactions such as ortho-lithiation and halogen- metal exchange followed by capture with electrophilic reagents.
  • the aniline nitrogen may be introduced by a benzyne reaction.
  • one part of the molecule such as e.g. the amine group, the linker -A-, the Ar-i group, the R1 , R4, R5, R8 group or the chain length is varied, while the other parts are conserved.
  • the invention also includes all compounds wherein all variations in one part of the molecule, e.g. linker -A- is combined with all variations in another of the features, e.g. variation in the Ar-, group.
  • the invention also relates to physiologically acceptable salts, complexes, solvates or prodrugs of the compounds of the invention.
  • a compound of the invention When a compound of the invention possesses a basic functional group it can form a salt with an inorganic or organic acid.
  • physiologically acceptable salts of the compounds according to the invention include salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid (to form e.g. a nitrate or a nitrite), sulfuric acid (to form e.g., a H 2 SO 3 salt, a sulfate or a H 2 SO 5 salt) and phosphoric acid (to form e.g. a H 3 PO 3 salt or a H 3 PO 4 salt)
  • salts with organic acids include salts with formic acid, acetic acid, propionic acid, butyric acid, pentanoic acid, oxalic acid, tartaric acid, malonic acid, succinic acid, citric acid, C 4 H 8 (COOH) 2 , C 5 H ⁇ 0 (COOH) 2 , acrylic acid, malic acid, fumaric acid, H 2 CO 3 , lactic acid, ascorbic acid, benzoic acid, salicylic acid and phthalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 3-chlorobenzoic acid.
  • salts with acidic amino acids include salts with aspartic acid and glutamic acid.
  • a compound of the invention contains optical isomers, diastereomers or other stereroisomers these are included as a compound of the invention as well as the racemate, i.e. mixture of enantiomers.
  • optical isomer can be obtained using an optically active synthetic intermediate, an asymmetric synthesis or subjecting the racemic mixture of the final product or a suitable intermediate to optical resolution in accordance with known methods such as, e.g., fractional recrystallisation method, chiral column method, diastereomer method etc.
  • the invention also encompasses a compound in amorphous, any polymorphous or any crystalline form.
  • the compounds according to the invention can be used in medicine and modulate the activity of a MCH receptor.
  • the compounds may be used as agents for preventing or treating diseases caused by or involving a melanin-concentrating hormone, i.e. they are useful for treating or preventing a MCH or MCH receptor related disorder or abnormality in a subject such as, e.g., an animal or a mammal such as, e.g., a human.
  • the compounds according to the invention may have antagonistic, inverse agonistic, agonistic or allosteric activity against a MCH receptor, normally antagonistic activity.
  • an agonist is defined as a compound that increases the functional activity of a MCH receptor (e.g. the signal transduction through a receptor).
  • agonist includes partial agonist, i.e. which increases the functional activity of the receptor to a submaximal level.
  • An inverse agonist is defined as a compound that decreases the basal functional activity of a MCH receptor.
  • An allosteric compound is defined as a compound that enhances or diminishes the effects of other receptor ligands.
  • An antagonist is defined as a compound that decreases the functional activity of a MCH receptor either by inhibiting the action of an agonist or by its own intrinsic activity.
  • the MCH receptors mentioned in the invention include MCH1 and MCH2 receptors. It also includes MCH receptors having at least about 80% such as, e.g. at least about 85% or at least about 90% homology to the amino acid sequences CTLITAMDAN or CTIITSLDTC.
  • the MCH receptors may be an animal or a mammalian or non-mammalian receptor, such as a human receptor.
  • a MCH receptor such as, e.g. a MCH1 receptor alleviates a MCH-related disorder or abnormality.
  • the disorder is a steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, a muscoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder such as, e.g., Alzheimer's disease, a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as, e.g.
  • Parkinson's disease a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, an affective disorder such as, e.g. depression, a stress-related disorder, a fluid-balance disorder, a urinary disorder such as, e.g., urinary incontinence, a seizure disorder, pain, psychotic behaviour such as, e.g., schizophrenia, morphine or opioid tolerance, opiate addiction or migraine.
  • the compounds of the invention are useful for the treatment or prevention of feeding disorders such as, e.g., overweight, adiposity, obesity and bulimia (e.g. malignant mastocytosis, exogeneous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophyseal adposity, hypoplasmic obesity, hypophysal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity etc.), hyperfagia, emotional disorders, dementia or hormonal disorders.
  • feeding disorders such as, e.g., overweight, adiposity, obesity and bulimia (e.g. malignant mastocytosis, exogeneous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophyseal adposity, hypoplasmic obesity, hypophysal adiposity, hypoplasmic obesity,
  • body mass index is defined as body weight
  • overweight is intended to indicate a BMI in a range from about 25 to about 29.9, whereas obesity is intended to indicate a BMI, which is at least about 30.
  • a compound of the invention is also useful as an agent for preventing or treating lifestyle diseases such as, e.g., diabetes, diabetic complications (e.g. retinopathy, neuropathy, nephropathy etc.), arteriosclerosis and gonitis.
  • lifestyle diseases such as, e.g., diabetes, diabetic complications (e.g. retinopathy, neuropathy, nephropathy etc.), arteriosclerosis and gonitis.
  • the present invention further relates to a cosmetic method for reducing overweight and/or for treating of and/or preventing overweight, bulimia, bulimia nervosa, obesity and/or complications thereto, the method comprising administering to an animal such as, e.g. a human in need thereof, an effective amount of a compound according to the invention
  • the invention also relates to a method for the treatment and/or prophylaxis of diseases caused by a melanin-concentrating hormone, the method comprising administering to a mammal in need thereof an efficient amount of a compound according to the invention.
  • the MCH-related disorders may be a feeding disorder.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases caused by feeding disorders, the method comprising administering to a mammal in need thereof an efficient amount of a compound according to the invention.
  • the invention also relates to a method for modifying the feeding behaviour of a mammal, the method comprising administering to a mammal in need thereof an efficient amount of a compound according to the invention.
  • the invention relates to a method for the reduction of body mass, the method comprising administering to a mammal in need thereof an efficient amount of a compound according to the invention.
  • the invention relates to a method for the treatment and/or prophylaxis of Syndrome X (metabolic syndrome) or any combination of obesity, insulin resistance, dyslipidemia, impaired glucose tolerance and hypertension, the method comprising administering to a mammal in need thereof an efficient amount of a compound according to the invention.
  • Syndrome X metabolic syndrome
  • Another aspect of the invention is a method for the treatment and/or prophylaxis of Type II diabetes or Non Insulin Dependent Diabetes Mellitus (NIDDM), the method comprising administering to a mammal in need thereof an efficient amount of a compound according to the invention.
  • NIDDM Non Insulin Dependent Diabetes Mellitus
  • a still further aspect of the invention is a method for the treatment and/or prophylaxis of bulimia, bulimia nervosa and/or obesity, the method comprising administering to a mammal in need thereof an efficient amount of a compound according to the invention.
  • the invention relates to a method for the treatment and/or prophylaxis of depression and/or anxiety, the method comprising administering to a mammal in need thereof an efficient amount of a compound according to the invention.
  • the compounds for use in the methods according to the invention are normally presented in the form of a pharmaceutical or a cosmetic composition comprising the specific compound or a physiologically acceptable salt thereof together with one or more physiologically acceptable excipients.
  • the compounds may be administered to the animal including a mammal such as, e.g., a human by any convenient administration route such as, e.g., the oral, buccal, nasal, ocular, pulmonary, topical, transdermal, vaginal, rectal, ocular, parenteral (including inter alia subcutaneous, intramuscular, and intravenous), route in a dose that is effective for the individual purposes.
  • a mammal such as, e.g., a human by any convenient administration route such as, e.g., the oral, buccal, nasal, ocular, pulmonary, topical, transdermal, vaginal, rectal, ocular, parenteral (including inter alia subcutaneous, intramuscular, and intravenous), route in a dose that is effective for the individual purposes.
  • a mammal such as, e.g., a human by any convenient administration route such as, e.g., the oral, buccal, nasal, ocular, pulmonary, topic
  • the pharmaceutical or cosmetic composition comprising a compound according to the invention may be in the form of a solid, semi-solid or fluid composition.
  • the solid composition may be in the form of tablets such as, e.g. conventional tablets, effervescent tablets, coated tablets, melt tablets or sublingual tablets, pellets, powders, granules, granulates, particulate material, solid dispersions or solid solutions.
  • a semi-solid form of the composition may be a chewing gum, an ointment, a cream, a liniment, a paste, a gel or a hydrogel.
  • the fluid form of the composition may be a solution, an emulsion including nano- emulsions, a suspension, a dispersion, a liposomal composition, a spray, a mixture, a syrup or a aerosol.
  • Fluid compositions which are sterile solutions or dispersions can utilized by for example intraveneous, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection of infusion.
  • the compounds may also be prepared as a sterile solid composition, which may be dissolved or dispersed before or at the time of administration using e.g. sterile water, saline or other appropriate sterile injectable medium.
  • suitable dosages forms of the pharmaceutical compositions according to the invention may be vagitories, suppositories, plasters, patches, tablets, capsules, sachets, troches, devices etc.
  • the dosage form may be designed to release the compound freely or in a controlled manner e.g. with respect to tablets by suitable coatings.
  • the pharmaceutical composition may comprise a therapeutically effective amount of a compound according to the invention.
  • the content of a compound of the invention in a pharmaceutical composition of the invention is e.g. from about 0.1 to about 100% w/w of the pharmaceutical composition.
  • compositions may be prepared by any of the method well known to a person skilled in pharmaceutical or cosmetic formulation.
  • the compounds are normally combined with a pharmaceutical excipient, i.e. a therapeutically inert substance or carrier.
  • the carrier may take a wide variety of forms depending on the desired dosage form and administration route.
  • the pharmaceutically or cosmetically acceptable excipients may be e.g. fillers, binders, disintegrants, diluents, glidants, solvents, emulsifying agents, suspending agents, stabilizers, enhancers, flavours, colors, pH adjusting agents, retarding agents, wetting agents, surface active agents, preservatives, antioxidants etc. Details can be found in pharmaceutical handbooks such as, e.g., Remington's Pharmaceutical Science or Pharmaceutical Excipient Handbook.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the composition, the route of administration, the frequency of administration, the age, weight, gender, diet and condition of the subject to be treated and the condition being treated and the advancement of the disease condition etc.
  • Suitable dosages may be from about 0.001 mg to about 1 g such as, e.g. from about 0.005 to about 750 mg, from about 0.01 to about 500 mg, from about 0.05 to about 500 mg, from about 0.1 to about 250 mg, from about 0.1 to about 100 mg or from about 0.5 to about 50 mg.
  • the amounts can be divided into one or several doses for administration daily, every second day, weekly, every two weeks, monthly or with any other suitable frequency. Normally, the administration is daily.
  • a compound or a pharmaceutical composition according to the invention may be used in combination with other drug substances such as agents for treating disorders like e.g. diabetes, diabetes complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, arthritis, anxiety, and/or depression etc.
  • agents for treating disorders like e.g. diabetes, diabetes complications, obesity, hypertension, hyperlipidemia, arteriosclerosis, arthritis, anxiety, and/or depression etc.
  • the cDNA encoding the human MCH-1 receptor was cloned from a human brain cDNA library and cloned into the eukaryotic expression vector pcDNA3.1 (Invitrogen). Assays were performed on transiently transfected COS-7 cells or stably transfected CHO (Chinese Hamster Ovary) cells, expressing the human MCH-1 receptor in pcDNA3.1. Stable MCH-1 receptor transfectants of CHO cells were obtained using 5 ⁇ g plasmid cDNA and a standard calcium phosphate transfection method
  • COS-7 cells were grown in Dulbecco ' s modified Eagle ' s medium (DMEM) 1885 (Invitrogen) supplemented with 10 % fetal calf serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, and were transiently transfected by a standard calcium phosphate transfection method (Johansen et al., 1990; Gether et al., 1992) two days before assay.
  • DMEM Dulbecco ' s modified Eagle ' s medium
  • Radioligand Binding Assay Transiently transfected COS-7 cells or stably transfected CHO cells, expressing human MCH-1 receptor were seeded in multi-well culture plates one day before the assay. The number of cells per well was determined by the apparent expression efficiency of the cell line aiming at 5 - 10 % binding of the added radioligand.
  • Cells were assayed by competition binding for 3 hours at room temperature using 15 pM [ 125 I]-MCH (Amersham Pharmacia Biotech) plus variable amounts of unlabeled ligand in 0.5 ml of a 25 mM Hepes buffer, pH 7.4, supplemented with 10 mM MgCI 2 , 5 mM MnCI 2 , 10 mM NaCI, 0.1 % (w/v) bovine serum albumin (BSA), 100 ⁇ g/ml bacitracin. The assay was performed in duplicate. Nonspecific binding was determined as the binding in the presence of 1 ⁇ M MCH (Bachem).
  • BSA bovine serum albumin
  • Phosphatidylinositol assay - To assay phosphatidylinositol turnover, transiently transfected COS-7 cells or stably transfected CHO cells, expressing human MCH-1 receptor (2x10 5 cells/well) were incubated for 24 h with 5 ⁇ Ci of [ 3 H]-myo-inositol (Amersham Pharmacia Biotech) in 0.5 ml inositol-free culture medium.
  • Pl-buffer 20 mM HEPES, pH 7.4, supplemented with 140 mM NaCI, 5 mM KCI, 1 mM MgSO 4 , 1 mM CaCI 2 , 10 mM glucose, 0.02% (w/v) bovine serum; and were incubated in 0.5 ml Pl-buffer supplemented with 10 mM LiCI at 37 °C for 45 min. Phosphatidylinositol turnover was stimulated by submaximal concentrations of MCH, i.e. 10 nM in the presence of increasing amounts of ligand. The ligand was added 5 min. before adding the agonist (MCH).
  • MCH agonist
  • the binding buffer contained 50 mM Tris (pH 7.4), 8 mM MgCI2, 12% glycerol, 0.1% (w/v) bovine serum albumin (BSA), and protease inhibitors (Complete protease inhibitor cocktail tablets, Roche).
  • EtOAc 3 x 70 mL
  • Ex 93 50 mg, 0.117 mmol
  • Ex 96 30 mg, 0.117 mmol
  • the reaction mixture was refluxed at 70°C overnight under N 2 .
  • the reaction mixture was partitioned between a 2 M NaHSO 3 -solution (20 ml) and EtOAc (20 ml).
  • the aqueous phase was extracted with EtOAc (2 x 20 ml).
  • the combined organic extracts were dried over MgSO and concentrated in vacuo.
  • the crude was purified over silica gel chromatography (eluted with DCM/MeOH/NH 3 (100:10:1)) to give the title compound Ex 97 (17.1mg, 0.028 mmol, 24%)

Abstract

L'invention concerne de nouveaux composés de formule (I), qui modulent l'activité de MCH. Dans ladite formule, A est un lieur; Ar1 est un groupe aryle ou hétéroaryle; R1 est hydrogène ou un groupe alcoxy inférieur; Q et carbonyle forment ensemble un groupe amide ultérieurement substitué par un groupe amine; R5 est hydrogène, atomes d'halogène, groupes alcoxy, hydroxy, groupes alkylamino, groupes dialkylamino, groupes hydroxyalkyle, groupes carboxyamido, groupes acylamido, groupes acyle, -CHO, nitrile, alkyle, groupes alcényle ou alkynyle, -SCH3, groupes alkyle, alcoxy ou thioalcoxy partiellement ou complètement fluorés, tels que -CH2CF3, -CF2CF3, -CF3, -OCF3, -SCF3, -SO2NH3, -SO2NHAlk, -SO2NAlk2, -SO2Alk; R8 est hydrogène, atomes d'halogène, alkyle, groupes alcényle ou alkynyle, groupes cycloxyalkyle, groupes alkylcycloxyalkyle, groupes alcoxy, groupes dialkylamino, -CONHAlk, -CONAlk2, -NHCO-Alk, -CO-Alk, -SCH3, groupes alkyle, alcoxy ou thioalcoxy partiellement ou complètement fluorés, tels que -CH2CF3, -CF2CF3, -CF3, -OCF3, -SCF3; X est H, F, Cl, Br, I, -SCH3, groupes alkyle, alcoxy ou thioalcoxy partiellement ou complètement fluorés, tels que -CH2CF3, -CF2CF3, -CF3, -OCF3, -SCF3, -OCH3 ou alkyle inférieur ou groupe alcényle. Les composés de l'invention sont utiles pour le traitement ou la prévention, par exemple, de l'obésité, de la dépression, du diabète, de la boulimie, etc.
PCT/DK2003/000234 2002-11-25 2003-04-08 Nouveaux composes de benzamide destines a etre utilises dans des troubles associes au recepteur de mch WO2004048319A1 (fr)

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WO2006014134A1 (fr) * 2004-08-02 2006-02-09 Astrazeneca Ab Nouveau dérivatif de la pipéridine pour le traitement de la dépression
WO2006018662A2 (fr) * 2004-08-16 2006-02-23 Prosidion Limited Derives d'uree arylique
US7834039B2 (en) 2006-12-15 2010-11-16 Abbott Laboratories Oxadiazole compounds
CN101065372B (zh) * 2004-12-01 2011-05-18 辛根塔参与股份公司 1-炔基-2-芳氧基烷基酰胺类化合物及其作为杀真菌剂的用途
US8357711B2 (en) 2007-03-23 2013-01-22 Pfizer Limited Heterocyclic sulfonamides as inhibitors of ion channels
US9045442B2 (en) 2007-12-21 2015-06-02 University Of Notre Dame Du Lac Antibacterial compounds and methods of using same
CN106831494A (zh) * 2017-03-14 2017-06-13 青岛科技大学 一种邻酰胺基二苯脲类化合物及其用途
CN110054584A (zh) * 2019-05-28 2019-07-26 沈阳药科大学 1-芳基-3-{4-[(吡啶-2-基甲基)硫基]苯基}脲类化合物及应用
US10662164B2 (en) 2014-09-25 2020-05-26 University Of Notre Dame Du Lac Non-beta lactam antibiotics
US11168062B2 (en) 2016-09-12 2021-11-09 University Of Notre Dame Du Lac Compounds for the treatment of Clostridium difficile infection

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WO2001021577A2 (fr) * 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2002070494A1 (fr) * 2001-03-02 2002-09-12 Icos Corporation Uree aryle et heteroaryle utilisee en tant qu'inhibiteur de chk1, a utiliser en tant que radiosensibilisants et chimiosensibilisants

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WO2001021577A2 (fr) * 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2002070494A1 (fr) * 2001-03-02 2002-09-12 Icos Corporation Uree aryle et heteroaryle utilisee en tant qu'inhibiteur de chk1, a utiliser en tant que radiosensibilisants et chimiosensibilisants

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014134A1 (fr) * 2004-08-02 2006-02-09 Astrazeneca Ab Nouveau dérivatif de la pipéridine pour le traitement de la dépression
WO2006018662A2 (fr) * 2004-08-16 2006-02-23 Prosidion Limited Derives d'uree arylique
WO2006018662A3 (fr) * 2004-08-16 2006-12-21 Prosidion Ltd Derives d'uree arylique
JP2008509982A (ja) * 2004-08-16 2008-04-03 プロシディオン・リミテッド アリール尿素誘導体
CN101065372B (zh) * 2004-12-01 2011-05-18 辛根塔参与股份公司 1-炔基-2-芳氧基烷基酰胺类化合物及其作为杀真菌剂的用途
US7834039B2 (en) 2006-12-15 2010-11-16 Abbott Laboratories Oxadiazole compounds
US8357711B2 (en) 2007-03-23 2013-01-22 Pfizer Limited Heterocyclic sulfonamides as inhibitors of ion channels
US8741934B2 (en) 2007-03-23 2014-06-03 Pfizer Limited Inhibitors of ion channels
US9045442B2 (en) 2007-12-21 2015-06-02 University Of Notre Dame Du Lac Antibacterial compounds and methods of using same
US10662164B2 (en) 2014-09-25 2020-05-26 University Of Notre Dame Du Lac Non-beta lactam antibiotics
US11168062B2 (en) 2016-09-12 2021-11-09 University Of Notre Dame Du Lac Compounds for the treatment of Clostridium difficile infection
CN106831494A (zh) * 2017-03-14 2017-06-13 青岛科技大学 一种邻酰胺基二苯脲类化合物及其用途
CN106831494B (zh) * 2017-03-14 2018-04-17 青岛科技大学 一种邻酰胺基二苯脲类化合物及其用途
CN110054584A (zh) * 2019-05-28 2019-07-26 沈阳药科大学 1-芳基-3-{4-[(吡啶-2-基甲基)硫基]苯基}脲类化合物及应用
CN110054584B (zh) * 2019-05-28 2022-03-11 沈阳药科大学 1-芳基-3-{4-[(吡啶-2-基甲基)硫基]苯基}脲类化合物及应用

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