WO2007018508A1 - Nouveaux antagonistes du récepteur muscarinique m3 de l’acétylcholine - Google Patents

Nouveaux antagonistes du récepteur muscarinique m3 de l’acétylcholine Download PDF

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WO2007018508A1
WO2007018508A1 PCT/US2005/026756 US2005026756W WO2007018508A1 WO 2007018508 A1 WO2007018508 A1 WO 2007018508A1 US 2005026756 W US2005026756 W US 2005026756W WO 2007018508 A1 WO2007018508 A1 WO 2007018508A1
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carbonyl
methyl
amino
phenyl
piperidiniumyl
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PCT/US2005/026756
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English (en)
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Jakob Busch-Petersen
Wei Fu
Jian Jin
Michael Lee Moore
Ralph A. Rivero
Dongchuan Shi
Feng Wang
Yonghui Wang
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—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
    • 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
    • C07D211/08—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • This invention relates to novel derivatives of cyclic quaternary ammonium salts, pharmaceutical compositions, processes for their preparation, and use thereof in treating M3 muscarinic acetylcholine receptor mediated diseases.
  • mAChRs Muscarinic acetylcholine receptors
  • M5 Muscarinic acetylcholine receptors are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, bladder and gastrointestinal tract, M3 mAChRs mediate contractile responses. For review, please see ⁇ Brown 1989 247 /id ⁇ .
  • Muscarinic acetylcholine receptor dysfunction has been noted in a variety of different pathophysiological states. For instance, in asthma and chronic obstructive pulmonary disease (COPD), inflammatory conditions lead to loss of inhibitory M2 muscarinic acetylcholine autoreceptor function on parasympathetic nerves supplying the pulmonary smooth muscle, causing increased acetylcholine release following vagal nerve stimulation. This mAChR dysfunction results in airway hyperreactivity mediated by increased stimulation of M3 mAChRs ⁇ Costello,
  • Incontinence due to bladder hypercontractility has also been demonstrated to be mediated through increased stimulation of M3 mAChRs ⁇ Hegde & Eglen 1999 251 /id ⁇ .
  • identification of subtytpe-selective mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
  • This invention relates to compounds of Formula I
  • R3 is selected from the group consisting of hydrogen, C-) -Cg branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, unsubstituted or substituted phenyl, or unsubstituted or substituted phenyl C1-C3 lower alkyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C ⁇ -Cs alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl and C3-C8 cycloalkyl lower alkyl; q is an interger from 0 to 7; h is O
  • Z " is selected from the group consisting of I “ , Br ' , Cl “ , F “ , CF3COO “ , mesylate, tosylate, and any other pharmaceutically acceptable counter ion;
  • V is selected from the group consisting of phenyl, thiophenyl, furanyl, pyridinyl, naphthyl, quinolinyl, indolyl, benzothiophenyl and benzofuranyl;
  • R4 is selected from the group consisting of hydrogen, hydroxy, amino, halo, cyano, trifluoromethyl, C-
  • T is selected from the group consisting of an unsubstituted or substituted following group: phenyl, thiophenyl, furanyl, pyridinyl, naphthyl, quinolinyl, indolyl, benzothiophenyl, and benzofuranyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-
  • R5 is selected from the group consisting of COOR6, CONH R6, COR6, CON(R6)2, COG, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted phenoxy, or cyano; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C ⁇ -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl, C-
  • R6 is selected from the group consisting of C ⁇ -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted phenyl C1-C3 lower alkyl, unsubstituted or substituted naphthyl, or unsubstituted or substituted naphthyl C1-C3 lower alkyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C ⁇ -Cs alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl;
  • G is selected from the group consisting of an unsubstituted or substituted following group: pyrrolidinyl, piperdinyl, dihydroindolyl, tetrohydroquinolinyi, morpholino, azetidinyl, hexahydroazepinyl, or octahydroazocinyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of Ci-Cs alkoxy, hydroxy, amino, C-
  • R1 is selected from the group consisting of an unsubstituted or substituted following group: phenyl, phenyl C1-C6 lower alkyl, thiophenyl, thiophen
  • the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
  • Prodrugs are any covalently bonded compounds that release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
  • Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
  • basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, be
  • C-i-Cs alkyl and “C- ⁇ Cg alkyl” is used herein includes both straight or branched chain radicals of 1 to 6 or 8 carbon atoms. By example this term includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, t ⁇ /t-butyl, pentyl, hexyl, heptyl, octyl and the like. "Lower alkyl” has the same meaning as C-j.Cs alkyl.
  • C1.C3 lower alkyl includes methyl, ethyl, n- propyl, and isopropyl.
  • Ci-Ce a'koxy includes straight and branched chain radicals of the likes of -O-CH3, -O-CH2CH3, and the n-propoxy, isopropoxy, n-butoxy, sec- butoxy, isobutoxy, terf-butoxy, pentoxy, and hexoxy, and the like.
  • C3-C8-cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane, and the like.
  • Alkenyl is used herein at all occurrences to mean straight or branched chain moiety of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methy!-1-propenyl, 1-butenyl, 2-butenyI and the like.
  • Halogen or "halo" means F, Cl, Br, and I.
  • the preferred compounds of Formula I include those compounds wherein: When X is carbon, n is 1 , 2, or 3; m is 1 , 2, or 3; p is 0, or 1 ; When X is oxygen, n is 1 ; m is 2; p is 1 ;
  • W is O;
  • U is NR3;
  • R3 is selected from the group consisting of hydrogen, C-j-Cs branched or unbranched alkyl, C3-C-8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, or phenyl C1-C3 lower alkyl;
  • q is O;
  • h is 0;
  • g is 1 ;
  • Z " is selected from the group consisting of I “ , Br ' , Cl “ , F “ , CF3COO “ , mesylate, tosylate, or any other pharmaceutically acceptable counter ion;
  • V is selected from the group consisting of phenyl, thiophenyl, furanyl, naphthyl, benzothiophenyl or benzofuranyl;
  • R4 is selected from the group consisting of hydrogen, hydroxy, amino, halo, cyano, trifluoromethyl, C-j-Cs alkoxy, C-j-Cs alkyl, C3-C8 cycloalkyl, C3-C-8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, phenylcarbonyl; k is 1 , 2, 3, 4, or 5; T is selected from the group consisting of an unsubstituted or substituted following group: phenyl, thiophenyl, furanyl, naphthyl, benzo-thiophenyl, and benzofuranyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-
  • R5 is selected from the group consisting of COOR6, CONHR6, COR6, CON(R6)2, COG, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted phenoxy, or cyano; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of Ci-Cs alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl and trifluoromethyl;
  • R6 is selected from the group consisting of Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, naphthyl, or naphthyl C1-C3 lower alkyl;
  • G is selected from the group consisting of pyrrolidinyl, piperdinyl, dihydroindolyl, tetrohydroquinolinyl, morpholino, azetidinyl, hexahydroazepinyl, or octahydroazocinyl;
  • R1 is selected from the group consisting of an unsubstituted or substituted following group: phenyl C1 -C6 lower alkyl, thiophenyl C1 -C6 lower alkyl, furanyl C1-C6 lower alkyl, pyridinyl C1-C6 lower alkyl, imidazolyl C1-C6 lower alkyl, naphthyl C1-C6 lower alkyl, quinolinyl C1-C6 lower alkyl, indolyl C1-C6 lower alkyl, benzothiophenyl C1-C6 lower alkyl, benzofuranyl C1-C6 lower alkyl, benzoimidazolyl C1-C6 lower alkyl, C-j-Cs branched or unbranched alkyl, C3-C-8 cycloalkyl, C3-C8 cycloalkyl C ⁇ -CQ lower alkyl, or C3-C8 alkenyl
  • R2 is selected from the group consisting of C-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, C3-C8 alkenyl, or unsubstituted or substituted phenyl C1-C3 lower alkyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-
  • U is NR3
  • R3 is hydrogen; q is 0; h is O; g is 1 ;
  • Z " is selected from the group consisting of I “ , Br ' , Cl “ , F “ , CF3COO ' , mesylate, tosylate, or any other pharmaceutically acceptable counter ion;
  • V is selected from the group consisting of phenyl, or naphthyl
  • R4 is selected from the group consisting of hydroxy, amino, halo, cyano, trifluoromethyl, C-
  • T is selected from the group consisting of unsubstituted or substituted phenyl, and thiophenyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-
  • R5 is COOR6, CONHR6, COR6, CON(R6)2, COG, unsubstituted or substituted oxadiazolyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C ⁇ -Cg alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl;
  • R6 is selected from the group consisting of C-
  • G is selected from the group consisting of pyrrolidinyl, piperdinyl, dihydroindolyl, tetrohydroquinolinyl, morpholino, azetidinyl, hexahydroazepinyl, or octahydroazocinyl;
  • R1 is selected from the group consisting of an unsubstituted or substituted following group: phenyl C1-C6 lower alkyl, thiophenyl C1-C6 lower alkyl, furanyl C1-C6 lower alkyl, pyridinyl C1-C6 lower alkyl, imidazolyl C1-C6 lower alkyl, naphthyl C1-C6 lower alkyl, quinolinyl C1-C6 lower alkyl, indolyl C1-C6 lower alkyl, benzothiophenyl C1-C6 lower alkyl, benzofuranyl C1-C6
  • the preferred compounds are selected from the group consisting of: /V-[( ⁇ 4-[(ethyloxy)carbonyl]phenyl ⁇ amino)carbonyl]- ⁇ /- ⁇ 1-[(4-hydroxyphenyl)methyl]- 1 -methyl-3-pyrrolidiniumyl ⁇ -L-tyrosinamide trifluoroacetate;
  • the most preferred compounds are selected from the group consisting of:
  • the compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below.
  • the synthesis provided for these Schemes is applicable for producing compounds of Formula (I) having a variety of different R1 , R2, R3, R4, R5 and R6, which are reacted, employing substituents which are suitable protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. While some Schemes are shown with specific compounds, this is merely for illustration purpose only.
  • Resin-bound amines 3 were prepared by reductive alkylation of 2,6- dimethoxy-4-polystyrenebenzyloxy-benzaldehyde (DMHB resin) with N-protected diamine HCI salts 2, which were prepared from Boc-protected diamines 1 (Scheme 1). Reactions of 3 with Fmoc-protected amino acids, followed by removal of the protecting group, provided resin-bound intermediates 4. Reactions of 4 with isocyanates afforded the corresponding resin-bound ureas, which were subsequently treated with potassium carbonate and thiophenol to give secondary amines 5. Reductive alkylation of 5 with aldehydes produced resin-bound tertiary amines 6.
  • Example 1 The following examples are provided as illustrative of the present invention but not limiting in any way: Example 1
  • the above resin (0.860 mmol) was treated with 15 mL of 20% piperidine in anhydrous 1-methyl-2-pyrrolidinone solution. After the mixture was shaken at rt for 15 min, the solution was drained and another 15 mL of 20% piperidine in anhydrous 1-methyl-2-pyrrolidinone solution was added. The mixture was shaken at rt for another 15 min. The solution was drained and the resin was washed with DMF (3 x 25 mL), CH 2 CI 2 /MeOH (1 :1 , 3 x 25 mL) and MeOH (3 x 25 mL).
  • Resin-bound secondary amines 5 were treated with alkyl dihalides to give the corresponding resin-bound quaternary ammonium salts, which were then cleaved with 50% trifluoroacetic acid in 1 ,2-dichloroethane to afford targeted compounds 8 (Scheme 2).
  • the dry resin was treated with 4 ml_ of 50% trifluoroacetic acid in dichloroethane at rt for 1 h. After the cleavage solution was collected, the resin was treated with another 4 ml_ of 50% trifluoroacetic acid in dichloroethane at rt for 30 min. The combined cleavage solutions were concentrated in vacuo.
  • Resin-bound amines 3 were prepared in the same way as described in preparation 1. Reactions of 3 with Fmoc-Try(tBu)-OH, followed by removal of the Fmoc protecting group, provided resin-bound intermediates 9. A variety of 4- substituted anilines were reacted with 1 ,1 '-carbonyldiimidazole to give the intermediates which in turn were reacted with 9 to afford the corresponding resin- bound ureas. The ureas were subsequently treated with potassium carbonate and thiophenol to give secondary amines 10. Reductive amination of 10 with appropriate aldehydes produced resin-bound tertiary amines 11.
  • Resin-bound secondary amines 10 were treated with alkyl dihalides to give the corresponding resin-bound quaternary ammonium salts, which were then cleaved with 50% trifluoroacetic acid in 1 ,2-dichloroethane to afford targeted compounds 13 (Scheme 4).
  • Scheme 4
  • DMHB resin-bound 1 -methylethyl 4- ⁇ [( ⁇ (1 S)-1-( ⁇ 4-[(1 ,1-dimethylethyl) oxy]phenyI ⁇ methyl)-2-oxo-2-[(3S)-3- piperidinylamino]ethyl ⁇ amino)carbonyl]amino ⁇ benzoate was prepared in the same way as described in example 134. To 80 mg (0.36mmol/g, 0.029 mmol) of this resin in acetonitrile (6.4 ml_) was added (0.488ml_, 3.2 mmol) of 1 ,6- dibromohexane. The mixture was shaken at 75 0 C for overnight.
  • the resin was dried in vacuum oven at 35 0 C for 24 h.
  • the dry resin was treated with 2 ml_ of 50% trifluoroacetic acid in 1 ,2- dichloroethane at rt for 1 h.
  • the resin was treated with another 2 ml_ of 50% trifluoroacetic acid in 1 ,2-dichloroethane at rt for 30 min.
  • the combined cleavage solutions were concentrated in vacuo.
  • thiophene ester and amide antagonist compounds were prepared.
  • 5-Nitro-2-thiophenecarboxylic acid was treated with oxalyl chloride to form acid chloride, which reactied with a series of cycloalkyl alcohols and amines to provide corresponding esters and amides 14.
  • the nitro group in 14 was converted to amine by hydrogenation via 10% palladium on carbon.
  • the amines 15 were coupled with resin-bound intermediate 9 to afford the corresponding resin-bound ureas 16.
  • the ureas were subsequently treated with benzenethiolate to give the secondary amines, which underwent reductive amination with appropriate aldehydes to produce resin-bound tertiary amines 17.
  • Amines 17 were then treated with alkyl halides to form the corresponding quaternary ammonium salts.
  • the resin was then cleaved by 50% trifluoroacetic acid in dichloromethane to afford targeted compounds 18 (Schem
  • Oxalyl chloride in methylene chloride (2.0 M, 32.3 ml_) was added at room temperature followed by one drop of dimethyl formamide (0.1 mL). The reaction mixture was stirred at RT for 1 hr and concentrated. Methylene chloride (100 mL) was added, concentrated again and redissolved in methylene chloride (60 mL). N, N'-Dimethylaminopyridine (652 mg, 5.33 mmol) , triethyl amine(4.47 mL, 32 mmol) and cyclohexanol (2.54 mL, 24 mmol) were added to reaction mixture and stirred at room temperature overnight.
  • Resin-bound tertiary amine 17 was treated with alkyl halides to give the corresponding symmetric resin-bound quaternary ammonium salts, which was then cleaved with 50% trifluoroacetic acid in dichloromethane to afford targeted compounds 19 (Scheme 6).
  • DMHB resin-bound ethyl 5- ⁇ [( ⁇ (1 S)-2-( ⁇ (3S)-1-[(3-chlorophenyl)methyl]-3- piperidinyl ⁇ amino)-1-[(4-hydroxyphenyl)methyl]-2-oxoethyl ⁇ amino)carbonyl]amino ⁇ - 2-thiophenecarboxylate was prepared in the same way as described in example 247. To 60 mg (0.048 mmol) of this resin in acetonitrile (6.4 ml_) was added
  • inhibitory effects of compounds at the M3 mAChR of the present invention are determined by the following in vitro and in vivo assays:
  • a CHO (Chinese hamster ovary) cell line stably expressing the human M3 muscarinic acetylcholine receptor is grown in DMEM plus 10% FBS, 2 mM Glutamine and 200 ug/ml G418. Cells are detached for maintenance and for plating in preparation for assays using either enzymatic or ion chelation methods.
  • the day before the FLIPR (fluorometric imaging plate reader) assay cells are detached, resuspended, counted, and plated to give 20,000 cells per 384 well in a 50 ul volume.
  • the assay plates are black clear bottom plates, Becton Dickinson catalog number 35 3962.
  • the assay is run the next day.
  • media are aspirated, and cells are washed with 1x assay buffer (145mM NaCI, 2.5mM KCI, 1OmM glucose, 1OmM HEPES, 1.2 mM MgCI 2 , 2.5mM CaCI 2 , 2.5mM probenecid (pH 7.4.)
  • Cells are then incubated with 5OuI of Fluo-3 dye (4uM in assay buffer) for 60 - 90 minutes at 37 degrees C.
  • the calcium- sensitive dye allows cells to exhibit an increase in fluorescence upon response to ligand via release of calcium from intracellular calcium stores.
  • Test compounds and antagonists are added in 25 ul volume, and plates are incubated at 37 degrees C for 5 -30 minutes. A second addition is then made to each well, this time with the agonist challenge, acetylcholine. It is added in 25 ul volume on the FLIPR instrument. Calcium responses are measured by changes in fluorescent units.
  • acetylcholine ligand is added at an ECso concentration, and the antagonist IC 50 can then be determined using dose response dilution curves.
  • the control antagonist used with M3 is atropine.
  • CHO cells stably expressing M3 mAChRs were plated in 96 well black wall/clear bottom plates. After 18 to 24 hours, media was aspirated and replaced with 100 ⁇ l of load media (EMEM with Earl's salts, 0.1% RIA-grade BSA (Sigma, St. Louis MO), and 4 ⁇ M Fluo-3-acetoxymethyl ester fluorescent indicator dye (Fluo-3 AM, Molecular Probes, Eugene, OR) and incubated 1 hr at 37° C.
  • load media EMEM with Earl's salts, 0.1% RIA-grade BSA (Sigma, St. Louis MO)
  • Fluo-3-acetoxymethyl ester fluorescent indicator dye Fluo-3 AM, Molecular Probes, Eugene, OR
  • the dye-containing media was then aspirated, replaced with fresh media (without Fluo-3 AM), and cells were incubated for 10 minutes at 37° C. Cells were then washed 3 times and incubated for 10 minutes at 37° C in 100 ⁇ l of assay buffer (0.1% gelatin (Sigma), 120 mM NaCI, 4.6 mM KCI, 1 mM KH 2 PO 4 , 25 mM NaH CO 3 , 1.0 mM CaCI 2 , 1.1 mM
  • Penh enhanced pause
  • mice were then challenged with an aerosol of methacholine (10 mg/ml) for 2 minutes. Penh was recorded continuously for 7 min starting at the inception of the methacholine aerosol, and continuing for 5 minutes afterward. Data for each mouse were analyzed and plotted by using GraphPad PRISM software.
  • the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis.
  • respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis.
  • the present invention further provides a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative (e.g., salts and esters) thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
  • a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative (e.g., salts and esters) thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
  • active ingredient means a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • Compounds of formula (I) will be administered via inhalation via the mouth or nose.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di- or poly-saccharides (e.g., lactose or starch), organic or inorganic salts (e.g., calcium chloride, calcium phosphate or sodium chloride), polyalcohols (e.g., mannitol), or mixtures thereof, alternatively with one or more additional materials, such additives included in the blend formulation to improve chemical and/or physical stability or performance of the formulation, as discussed below, or mixtures thereof.
  • a suitable powder base such as mono-, di- or poly-saccharides (e.g., lactose or starch),
  • Each capsule or cartridge may generally contain between 20 ⁇ g-10mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient.
  • the compound of the invention may be presented without excipients, or may be formed into particles comprising the compound, optionally other therapeutically active materials, and excipient materials, such as by co- precipitation or coating.
  • the medicament dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), a multi-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI).
  • reservoir dry powder inhaler By reservoir dry powder inhaler (RDPI) it is meant as an inhaler having a reservoir form pack suitable for comprising multiple (un-metered doses) of medicament in dry powder form and including means for metering medicament dose from the reservoir to a delivery position.
  • the metering means may for example comprise a metering cup or perforated plate , which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation.
  • multi-dose dry powder inhaler is meant an inhaler suitable for dispensing medicament in dry powder form, wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple, define doses (or parts thereof) of medicament.
  • the carrier has a blister pack form, but it could also, for example, comprise a capsule-based pack form or a carrier onto which medicament has been applied by any suitable process including printing, painting and vacuum occlusion.
  • the formulation can be pre-metered (eg as in Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg as in Turbuhaler, see EP 69715).
  • An example of a unit-dose device is Rotahaler (see GB 2064336).
  • the Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose.
  • the strip is sufficiently flexible to be wound into a roll.
  • the lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width.
  • the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.
  • the multi-dose pack is a blister pack comprising multiple blisters for containment of medicament in dry powder form. The blisters are typically arranged in regular fashion for ease of release of medicament therefrom.
  • the multi-dose blister pack comprises plural blisters arranged in generally circular fashion on a disk-form blister pack.
  • the multi-dose blister pack is elongate in form, for example comprising a strip or a tape.
  • the multi-dose blister pack is defined between two members peelably secured to one another.
  • US Patents Nos. 5,860,419, 5,873,360 and 5,590,645 describe medicament packs of this general type.
  • the device is usually provided with an opening station comprising peeling means for peeling the members apart to access each medicament dose.
  • the device is adapted for use where the peelable members are elongate sheets which define a plurality of medicament containers spaced along the length thereof, the device being provided with indexing means for indexing each container in turn.
  • the device is adapted for use where one of the sheets is a base sheet having a plurality of pockets therein, and the other of the sheets is a Hd sheet, each pocket and the adjacent part of the lid sheet defining a respective one of the containers, the device comprising driving means for pulling the lid sheet and base sheet apart at the opening station.
  • metered dose inhaler it is meant a medicament dispenser suitable for dispensing medicament in aerosol form, wherein the medicament is comprised in an aerosol container suitable for containing a propellant-based aerosol medicament formulation.
  • the aerosol container is typically provided with a metering valve, for example a slide valve, for release of the aerosol form medicament formulation to the patient.
  • the aerosol container is generally designed to deliver a predetermined dose of medicament upon each actuation by means of the valve, which can be opened either by depressing the valve while the container is held stationary or by depressing the container while the valve is held stationary.
  • Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
  • Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g.
  • the aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvents eg ethanol. Pressurized formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
  • a canister eg an aluminium canister
  • a valve eg a metering valve
  • Medicaments for administration by inhalation desirably have a controlled particle size.
  • the optimum aerodynamic particle size for inhalation into the bronchial system for localized delivery to the lung is usually 1-1 O ⁇ m, preferably 2- 5 ⁇ m.
  • the optimum aerodynamic particle size for inhalation into the alveolar region for achieving systemic delivery to the lung is approximately .5-3 ⁇ m, preferably 1- 3 ⁇ m.
  • Particles having an aerodynamic size above 20 ⁇ m are generally too large when inhaled to reach the small airways.
  • Average aerodynamic particle size of a formulation may measured by, for example cascade impaction.
  • Average geometric particle size may be measured, for example by laser diffraction, optical means.
  • the particles of the active ingredient as produced may be size reduced by conventional means eg by controlled crystallization, micronisation or nanomiiling
  • the desired fraction may be separated out by air classification.
  • particles of the desired size may be directly produced, for example by spray drying, controlling the spray drying parameters to generate particles of the desired size range.
  • the particles will be crystalline, although amorphous material may also be employed where desirable.
  • an excipient such as lactose is employed, generally, the particle size of the excipient will be much greater than the inhaled medicament within the present invention, such that the "coarse" carrier is non-respirable.
  • the excipient When the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90 ⁇ m and not less than 15% will have a MMD of less than 15 ⁇ m.
  • Additive materials in a dry powder blend in addition to the carrier may be either respirable, i.e., aerodynamically less than 10 microns, or non-respirable, i.e., aerodynamically greater than 10 microns.
  • Suitable additive materials which may be employed include amino acids, such as leucine; water soluble or water insoluble, natural or synthetic surfactants, such as lecithin (e.g., soya lecithin) and solid state fatty acids (e.g., lauric, palmitic, and stearic acids) and derivatives thereof (such as salts and esters); phosphatidylcholines; sugar esters.
  • Additive materials may also include colorants, taste masking agents (e.g., saccharine), anti-static-agents, lubricants (see, for example, Published PCT Patent Appl. No. WO 87/905213, the teachings of which are incorporated by reference herein), chemical stabilizers, buffers, preservatives, absorption enhancers, and other materials known to those of ordinary skill.
  • Sustained release coating materials e.g., stearic acid or polymers, e.g. polyvinyl pyrolidone, polylactic acid
  • active material or active material containing particles see, for example, Patent Nos. US 3,634,582, GB 1 ,230,087, GB 1 ,381 ,872, the teachings of which are incorporated by reference herein).
  • Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
  • Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
  • Preferred unit dosage formulations are those containing an effective dose, as herein before recited, or an appropriate fraction thereof, of the active ingredient.

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Abstract

L’invention a pour objet des antagonistes du récepteur muscarinique de l’acétylcholine et des méthodes pour leur utilisation.
PCT/US2005/026756 2005-07-28 2005-07-28 Nouveaux antagonistes du récepteur muscarinique m3 de l’acétylcholine WO2007018508A1 (fr)

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US7276521B2 (en) 2003-10-14 2007-10-02 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7384946B2 (en) 2004-03-17 2008-06-10 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US7439255B2 (en) 2003-11-04 2008-10-21 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7488827B2 (en) 2004-04-27 2009-02-10 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7495010B2 (en) 2003-07-17 2009-02-24 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7507747B2 (en) 2003-10-17 2009-03-24 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7598267B2 (en) 2004-05-13 2009-10-06 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
JP2010519299A (ja) * 2007-02-23 2010-06-03 セラヴァンス， インコーポレーテッド ムスカリン受容体アンタゴニストとして有用な第四級アンモニウムジフェニルメチル化合物
US7767691B2 (en) 2005-08-18 2010-08-03 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists containing an azoniabiocyclo[2.2.1] heptane ring system
WO2010094643A1 (fr) 2009-02-17 2010-08-26 Glaxo Group Limited Dérivés de quinoline et applications associées dans la rhinite et l'urticaire
US7932247B2 (en) 2004-11-15 2011-04-26 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8071588B2 (en) 2008-02-06 2011-12-06 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8084449B2 (en) 2008-02-06 2011-12-27 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US10159268B2 (en) 2013-02-08 2018-12-25 General Mills, Inc. Reduced sodium food products
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
WO2022008419A1 (fr) 2020-07-06 2022-01-13 Byondis B.V. Médicaments lieurs d'antifolate et conjugués anticorps-médicament
WO2023126297A1 (fr) 2021-12-30 2023-07-06 Byondis B.V. Médicaments de liaison antifolate et conjugués anticorps-médicament

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US20050137230A1 (en) * 2000-12-16 2005-06-23 Dieter Dorsch Carboxamide derivatives

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US7276521B2 (en) 2003-10-14 2007-10-02 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
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US7906531B2 (en) 2003-11-04 2011-03-15 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
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US9045469B2 (en) 2004-04-27 2015-06-02 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US8853404B2 (en) 2004-04-27 2014-10-07 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7498440B2 (en) 2004-04-27 2009-03-03 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
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US8309572B2 (en) 2004-04-27 2012-11-13 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7598267B2 (en) 2004-05-13 2009-10-06 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7932247B2 (en) 2004-11-15 2011-04-26 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US7767691B2 (en) 2005-08-18 2010-08-03 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists containing an azoniabiocyclo[2.2.1] heptane ring system
JP2010519299A (ja) * 2007-02-23 2010-06-03 セラヴァンス， インコーポレーテッド ムスカリン受容体アンタゴニストとして有用な第四級アンモニウムジフェニルメチル化合物
US8084449B2 (en) 2008-02-06 2011-12-27 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8071588B2 (en) 2008-02-06 2011-12-06 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
WO2010094643A1 (fr) 2009-02-17 2010-08-26 Glaxo Group Limited Dérivés de quinoline et applications associées dans la rhinite et l'urticaire
US10159268B2 (en) 2013-02-08 2018-12-25 General Mills, Inc. Reduced sodium food products
US11540539B2 (en) 2013-02-08 2023-01-03 General Mills, Inc. Reduced sodium food products
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US10961200B2 (en) 2014-12-29 2021-03-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US11247971B2 (en) 2014-12-29 2022-02-15 The Trustees Of The University Of Pennsylvania Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
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