WO2007018514A1 - Novel m3 muscarinic acetylcholine receptor antagonists - Google Patents

Novel m3 muscarinic acetylcholine receptor antagonists Download PDF

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WO2007018514A1
WO2007018514A1 PCT/US2005/026877 US2005026877W WO2007018514A1 WO 2007018514 A1 WO2007018514 A1 WO 2007018514A1 US 2005026877 W US2005026877 W US 2005026877W WO 2007018514 A1 WO2007018514 A1 WO 2007018514A1
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amino
methyl
lower alkyl
carbonyl
hydroxyphenyl
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PCT/US2005/026877
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French (fr)
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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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Priority to PCT/US2005/026877 priority Critical patent/WO2007018514A1/en
Publication of WO2007018514A1 publication Critical patent/WO2007018514A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D203/00Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
    • C07D203/12Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic 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
    • C07D207/04Heterocyclic 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
    • C07D207/10Heterocyclic 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
    • C07D207/14Nitrogen atoms not forming part of a nitro radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic 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
    • C07D211/36Heterocyclic 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
    • C07D211/56Nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D223/00Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06Heterocyclic 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
    • C07D223/12Nitrogen atoms not forming part of a nitro radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D265/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/281,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/301,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/06Heterocyclic 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

Definitions

  • This invention relates to novel derivatives of cyclic amines, 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
  • W is O, S, or NH
  • U is NR3, O, or bond
  • R3 is selected from the group consisting of hydrogen, C-] -Cs branched or unbranched alkyl, C3-C-8 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 C1-C8 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-i-Cs branched or unbranched alkyl, C3-C8 cycloalkyl and C3-C8 cycloalkyl lower alkyl; q is an integer from 0 to 7; h is O, 1 , or 2; g is 1 , 2, or 3;
  • 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, Ci-Cs alkoxy, C-
  • R5 is selected from the group consisting of COOR6, CONHR6, 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-
  • G is selected from the group consisting of an unsubstituted or substituted following group: pyrrolidinyl, piperdinyl, dihydroindolyl, tetrohydroquinolinyl, morpholino, azetidinyl, hexahydroazepinyl, or octahydroazocinyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-i-Cs alkoxy, hydroxy, amino, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C-8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl;
  • R1 is selected from the group consisting of an unsubstituted or substituted following group: hydrogen, phenyl, phenyl C1-C6 lower alkyl, thiophenyl, thi
  • 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.
  • 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-C ⁇ alk y' and "C-) .CQ 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, tert-butyl, pentyl, hexyl, heptyl, octyl and the like. "Lower alkyl” has the same meaning as C-i-C ⁇ alkyl.
  • C-1-C3 lower alkyl is used herein includes methyl, ethyl, n- propyl, and isopropyl.
  • Cg 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, fert-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-methyl-1-propenyl,
  • Halogen or halo means F, Cl, Br, and I.
  • the preferred compounds of Formula I include those compounds wherein: When X and Y are carbons, n is 1 , or 2; m is 1 , 2, or 3; p is 0, or 1 ; When X is oxygen and Y is carbon, n is 1 ; m is 2; p is 1 ; When X is carbon and Y is nitrogen, n is 2; m is 1 ; p is 2;
  • W is O;
  • U is NR3;
  • R3 is selected from the group consisting of hydrogen, C-j-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, and phenyl C1- C3 lower alkyl;
  • q is O;
  • h is O;
  • g is 1 ;
  • V is selected from the group consisting of phenyl, thiophenyl, furanyl, naphthyl, benzothiophenyl and benzofuranyl;
  • R4 is selected from the group consisting of hydrogen, hydroxy, amino, halo, cyano, trifluoromethyl, Ci-Cs alkoxy, Ci-Ce alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, phenylcarbonyl;
  • k is an integer from 1 to 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 Ci-Cs
  • 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, and 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, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C- ⁇ -CQ lower alkyl, or C3-C8 alkenyl
  • X and Y are carbons; n is 1 , or 2; m is 1 , 2, or 3; p is 0, or 1 ;
  • W is O
  • U is NR3
  • R3 is hydrogen; q is 0; h is O; g is 1 ;
  • 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 Ci-Cs alkoxy, halo, hydroxy, amino, trifluoromethyl, C-] -Cs alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl;
  • R5 is selected from the group consisting of 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-i-C ⁇ alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phen
  • R6 is selected from the group consisting of C-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkyl lower alkyl;
  • G is selected from the group consisting of pyrrolidinyl, piperdinyl, dihydroindolyl, tetrohydroquinolinyl, morpholino, azetidinyl, hexahydroazepinyl, and 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-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C-i -C ⁇ lower alkyl, or C3-C8 alkenyl
  • the preferred compounds are selected from the group consisting of:
  • 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 , 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 nosyl- 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, which were treated with 50% trifluoroacetic acid in 1 ,2-dichloroethane to afford targeted compounds 6.
  • DMHB resin 2,6- dimethoxy-4-polystyrenebenzyloxy-benzaldehyde
  • PhSH 1-methyl-2-pyrrolidinone, rt; h) R2CHO, Na(OAc ⁇ BH, 10% acetic acid in 1-methyl-2-pyrrolidinone, rt; i) 50% trifluoroacetic acid in 1 ,2-dichloroethane, rt.
  • 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). The resulting resin was dried in vacuum oven at 35 0 C for 24 h.
  • the above dry resin (1 b, 0.192 mmol) was treated with 4 ml_ of 50% trifluoroacetic acid in dichloroethane at rt for 2h. After the cleavage solution was collected, the resin was treated with another 4 ml_ of 50% trifluoroacetic acid in dichloroethane at rt for 10 min. The combined cleavage solutions were concentrated in vacuo.
  • Tables 1 - 10 were prepared.
  • 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 7. Reactions of 7 with ethyl 4-isocyanatobenzoate afforded the corresponding resin-bound ureas, which were subsequently treated with potassium carbonate and thiophenol to give secondary amines 8. Reductive alkylation of 8 with appropriate aldehydes produced resin-bound tertiary amines, which were treated with potassium trimethylsilanolate (KOTMS) in tetrahydrofuran (THF) to give the corresponding carboxylic acids 9.
  • KTMS potassium trimethylsilanolate
  • THF tetrahydrofuran
  • Resin-bound acids 9 were prepared in the same way as described in preparation 2. Reactions of acids 9 with appropriate amines in presence of PyBOP and diisopropylethyl amine (DIEA) afforded the corresponding amides, which were treated with 50% trifluoroacetic acid in 1 ,2-dichloroethane to afford targeted compounds 11 (Scheme 3).
  • DIEA diisopropylethyl amine
  • example 135a (0.04 mmol) in 1-methyl-2-pyrrolidinone (2 ml_) was added PyBOP (0.31 g, 0.3 M in 1-methyl-2-pyrrolidinone), followed by 1- propylamine (0.2 mL, 1.2 M in 1-methyl-2-pyrrolidinone) and diisopropylethyl amine (0.21 mL, 0.6 M in 1-methyl-2-pyrrolidinone). After the resulting mixture was shaken at rt for 24 h, the resin was washed with DCM (3 x 5 mL), CH2Cl2/MeOH (1 :1 , 3 x 5 mL) and MeOH (3 x 5 mL).
  • the resulting 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 dichloroethane at rt for 2 h.
  • the resin was treated with another 2 mL of 50% trifluoroacetic acid in dichloroethane at rt for 10 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 an acid chloride, which reacted with a series of cycloalkyl alcohols to provide corresponding esters 12.
  • the nitro group in 12 was converted to amine by hydrogenation using 10% palladium on carbon.
  • the amines 13 were coupled with resin-bound intermediate 4 to afford the corresponding resin-bound ureas 14.
  • 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 15.
  • the resin was then cleaved by 50% trifluoroacetic acid in dichloromethane to afford targeted compounds 16 (Scheme 4).
  • N, N'-Dimethylaminopyridine 236 mg, 1.44 mmol
  • triethyl amine 1.61 ml_, 11.56mmol
  • cyclooctanol 1.11 g, 8.67 mmol
  • the reaction mixture was filtered through a pad of silica gel (100g), eluting with methylene chloride. Cyclooctanol 5-nitro-2-thiophenecarboxylate was obtained after concentration.
  • 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.
  • mAChRs expressed on CHO cells were analyzed by monitoring receptor-activated calcium mobilization as previously described .
  • 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 PO4, 25 mM NaH CO3, 1.0 mM CaCI 2 , 1.1 mM
  • mice (0.003-10 ⁇ g/mouse) in 50 ⁇ l of vehicle (10% DMSO) intranasally, and were then placed in the plethysmography chamber. Once in the chamber, the mice were allowed to equilibrate for 10 min before taking a baseline Penh measurement for 5 minutes. 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.
  • 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), 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
  • 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).
  • RDPI reservoir dry powder inhaler
  • MDPI multi-dose dry powder inhaler
  • MDI metered dose inhaler
  • 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 MDPI
  • 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. More preferably, 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 lid 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 nanomilling
  • 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 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.
  • 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

Muscarinic Acetylcholine receptor antagonists and methods of using them are provided.

Description

Novel M3 Muscarinic Acetylcholine Receptor Antagonists
FIELD OF THE INVENTION
This invention relates to novel derivatives of cyclic amines, pharmaceutical compositions, processes for their preparation, and use thereof in treating M3 muscarinic acetylcholine receptor mediated diseases.
BACKGROUND OF THE INVENTION
Acetylcholine released from cholinergic neurons in the peripheral and central nervous systems affects many different biological processes through interaction with two major classes of acetylcholine receptors - the nicotinic and the muscarinic acetylcholine receptors. Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily of G-protein coupled receptors that have seven transmembrane domains. There are five subtypes of mAChRs, termed M-|-
M5, and each is the product of a distinct gene. Each of these five subtypes displays unique pharmacological properties. 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,
Evans, et al. 1999 72 /id}{Minette, Lammers, et al. 1989 248 /id}. Similarly, inflammation of the gastrointestinal tract in inflammatory bowel disease (IBD) results in M3 mAChR-mediated hypermotility {Oprins, Meijer, et al. 2000 245 /id}.
Incontinence due to bladder hypercontractility has also been demonstrated to be mediated through increased stimulation of M3 mAChRs {Hegde & Eglen 1999 251 /id}. Thus the identification of subtytpe-selective mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.
Despite the large body of evidence supporting the use of anti-muscarinic receptor therapy for treatment of a variety of disease states, relatively few anti- muscarinic compounds are in use in the clinic. Thus, there remains a need for novel compounds that are capable of causing blockade at M3 mAChRs.
Conditions associated with an increase in stimulation of M3 mAChRs, such as asthma, COPD, IBD and urinary incontinence would benefit by compounds that are inhibitors of mAChR binding. SUMMARY OF THE INVENTION
This invention relates to compounds of Formula I
Figure imgf000003_0001
wherein When X and Y are carbons, n is 1 , 2, or 3; m is 1 , 2, or 3; p is 0, 1 , or 2;
When X is oxygen and Y is carbon, n is 1 ; m is 2; p is 1 ;
When X is carbon and Y is nitrogen, n is 2; m is 1 ; p is 2;
W is O, S, or NH;
U is NR3, O, or bond; R3 is selected from the group consisting of hydrogen, C-] -Cs branched or unbranched alkyl, C3-C-8 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 C1-C8 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-i-Cs branched or unbranched alkyl, C3-C8 cycloalkyl and C3-C8 cycloalkyl lower alkyl; q is an integer from 0 to 7; h is O, 1 , or 2; g is 1 , 2, or 3;
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, Ci-Cs alkoxy, C-|-C8 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, COR6,
COOR6, CONHR6, CON(R6)2, NHR6, N(R6)2, and G; k is an integer from 0 to 5; 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-|-C-8 alkoxy, halo, hydroxy, amino, trifluoromethyl, Ci -Cs branched or unbranched alkyl, C3-C-8 cycloalkyl, C3-C3 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl;
R5 is selected from the group consisting of COOR6, CONHR6, 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-|-C-8 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl, C-j-Cs alkoxy, halo, hydroxy, amino, cyano and trifluoromethyl; R6 is selected from the group consisting of C-|-Cs branched or unbranched alkyl, C3-C-8 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-|-C8 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-|-C-8 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, tetrohydroquinolinyl, morpholino, azetidinyl, hexahydroazepinyl, or octahydroazocinyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-i-Cs alkoxy, hydroxy, amino, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C-8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl; R1 is selected from the group consisting of an unsubstituted or substituted following group: hydrogen, phenyl, phenyl C1-C6 lower alkyl, thiophenyl, thiophenyl C1-C6 lower alkyl, furanyl, furanyl C1-C6 lower alkyl, pyridinyl, pyridinyl C1-C6 lower alkyl, imidazolyl, imidazolyl C1-C6 lower alkyl, naphthyl, naphthyl C1- C6 lower alkyl, quinolinyl, quinolinyl C1-C6 lower alkyl, indolyl, indolyl C1-C6 lower alkyl, benzothiophenyl, benzothiophenyl C1 -C6 lower alkyl, benzofuranyl, benzofuranyl C1-C6 lower alkyl, benzoimidazolyl, benzoimidazolyl C1-C6 lower alkyl, C-| -C-8 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C-i-Cg lower alkyl, or C3-C8 alkenyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-] -Cs alkoxy, phenoxy, phenyl C1-C3 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, C-|-C8 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, thiophenyl, thiophenyl C1-C3 lower alkyl, furanyl, furanyl C1-C3 lower alkyl, pyridinyl, pyridinyl C1-C3 lower alkyl, naphthyl, naphthyl C1-C3 lower alkyl, quinolinyl, quinolinyl C1 -C3 lower alkyl, indolyl, indolyl C1-C3 lower alkyl, benzothiophenyl, benzothiophenyl C1 -C3 lower alkyl, benzofuranyl, benzofuranyl C1-C3 lower alkyl, COOH, COR6, COOR6, CONHR6, CON(R6)2, COG, NHR6, N(R6)2, G, OCOR6, OCONHR6, NHCOR6, N(R6)COR6, NHCOOR6 and NHCONHR6; or a pharmaceutically acceptable salt. SUMMARY OF THE INVENTION
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. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
The meaning of 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.
. The term "C-i-Cβ alky'" and "C-) .CQ 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, tert-butyl, pentyl, hexyl, heptyl, octyl and the like. "Lower alkyl" has the same meaning as C-i-Cβ alkyl.
The term "C-1-C3 lower alkyl" is used herein includes methyl, ethyl, n- propyl, and isopropyl. Herein "C-). Cg 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, fert-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-methyl-1-propenyl,
1-butenyl, 2-butenyl and the like. "Halogen" or "halo" means F, Cl, Br, and I.
The preferred compounds of Formula I include those compounds wherein: When X and Y are carbons, n is 1 , or 2; m is 1 , 2, or 3; p is 0, or 1 ; When X is oxygen and Y is carbon, n is 1 ; m is 2; p is 1 ; When X is carbon and Y is nitrogen, n is 2; m is 1 ; p is 2;
W is O; U is NR3; R3 is selected from the group consisting of hydrogen, C-j-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, and phenyl C1- C3 lower alkyl; q is O; h is O; g is 1 ;
V is selected from the group consisting of phenyl, thiophenyl, furanyl, naphthyl, benzothiophenyl and benzofuranyl; R4 is selected from the group consisting of hydrogen, hydroxy, amino, halo, cyano, trifluoromethyl, Ci-Cs alkoxy, Ci-Ce alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, phenylcarbonyl; k is an integer from 1 to 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 Ci-Cs alkoxy, halo, hydroxy, amino, trifluoromethyl, Ci-Cs alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1 -C3 lower alkyl;
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, and 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, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C-\ -CQ lower alkyl, or C3-C8 alkenyl;wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of Ci-Cs alkoxy, phenoxy, phenyl C1-C3 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, thiophenyl, thiophenyl C1-C3 lower alkyl, furanyl, furanyl C1-C3 lower alkyl, pyridinyl, pyridinyl C1-C3 lower alkyl, naphthyl, naphthyl C1 -C3 lower alkyl, quinolinyl, quinolinyl C1-C3 lower alkyl, indolyl, indolyl C1-C3 lower alkyl, benzothiophenyl, benzothiophenyl C1-C3 lower alkyl, benzofuranyl, benzofuranyl C1-C3 lower alkyl, COOH, COR6, COOR6, CONHR6, CON(R6)2, COG, NHR6, N(R6)2, G, OCOR6, OCONHR6, NHCOR6, N(R6)COR6, NHCOOR6 and NHCONHR6; or a pharmaceutically acceptable salt.
Even more preferred are those compounds where:
X and Y are carbons; n is 1 , or 2; m is 1 , 2, or 3; p is 0, or 1 ;
W is O;
U is NR3;
R3 is hydrogen; q is 0; h is O; g is 1 ;
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-|-C-8 alkoxy, C-1-C3 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, phenylcarbonyl; k is 1 , 2, or 3;
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 Ci-Cs alkoxy, halo, hydroxy, amino, trifluoromethyl, C-] -Cs alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl; R5 is selected from the group consisting of 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-i-Cβ 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-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkyl lower alkyl;
G is selected from the group consisting of pyrrolidinyl, piperdinyl, dihydroindolyl, tetrohydroquinolinyl, morpholino, azetidinyl, hexahydroazepinyl, and 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-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C-i -Cβ lower alkyl, or C3-C8 alkenyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-| -C8 alkoxy, phenoxy, phenyl C1-C3 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, C-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, thiophenyl, thiophenyl C1-C3 lower alkyl, furanyl, furanyl C1-C3 lower alkyl, pyridinyl, pyridinyl C1-C3 lower alkyl, naphthyl, naphthyl C1-C3 lower alkyl, quinolinyl, quinolinyl C1-C3 lower alkyl, indolyl, indolyl C1-C3 lower alkyl, benzothiophenyl, benzothiophenyl C1-C3 lower alkyl, benzofuranyl, benzofuranyl C1-C3 lower alkyl, COOH, COR6, COOR6, CONHR6, CON(R6)2, COG, NHR6, N(R6)2, G, OCOR6 and NHCOR6; or a pharmaceutically acceptable salt.
The preferred compounds are selected from the group consisting of:
Ethyl 4-{[({(1 S)-2-{[1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-fluorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({(3S)-1 -[(4-hydroxyphenyl)methyl]-
3-pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate ;
Ethyl 4-{[({(1 S)-2-({(3S)-1 -[(4-fluorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[1 -(cyclopropylmethyO-S-pyrrolidiny^aminoJ-i -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-({[((1 S)-1 -[(4-hydroxyphenyl)methyl]-2-oxo-2-{[1 -(phenylmethyl)-3- pyrrolidinyl]amino}ethyl)amino]carbonyl}amino)benzoate;
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(3-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(3-cyanophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbon'yl]amino}benzoate;
Ethyl 4-{[({(1 S)-1-[(4-hydroxyphenyl)methyl]-2-oxo-2-[(1-{[4-
(trifluoromethyl)phenyl]methyl}-3- pyrrolidinyl)amino]ethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(3-chlorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-[(1 -{[3,4-bis(methyloxy)phenyl]methyl}-3-pyrrolidinyl)amino]-1 -
[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-1-[(4-hydroxyphenyl)methyl]-2-[(1 -{[4-(methyloxy)phenyl]methyl}-3- pyrrolidinyl)amino]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-[(1 -{[3-(methyloxy)phenyl]methyl}-3- pyrrolidinyl)amino]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-({1 -[(4-chlorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxθθthyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-oxo-2-[(1 -{[3-
(trifluoromethyl)phenyl]methyl}-3- pyrrolidinyl)amino]ethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Propyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; 1 -methylethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate; Λ/-[({4-[(ethylamino)carbonyl]phenyl}amino)carbonyl]-Λ/-{1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}-L-tyrosinamide; Λ/-{1 -[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}-Λ/-[({4-
[(propylamino)carbonyl]phenyl}amino)carbonyl]-L-tyrosinamide; Λ/-{1 -[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}-Λ/-{[(4-{[(1 - methylethyl)amino]carbonyl}phenyl)amino]carbonyl}-L-tyrosinamide; Λ/-[({4-[(cyclopropylamino)carbonyl]phenyl}amino)carbonyl]-Λ/-{1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}-L-tyrosinamide;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- chlorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-[({[(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-(2- naphthalenylmethyl)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-({[((1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-2- oxo-1 -{[4-(phenylcarbonyl)phenyl]methyl}ethyl)amino]carbonyl}amino)benzoate; Ethyl 4-({[((1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-{[4- (methyloxy)phenyl]methyl}-2-oxoethyl)amino]carbonyl}amino)benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- fluorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-({[((1 S)-1-[(4-aminophenyl)methyl]-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-
3-pyrrolidinyl]amino}-2-oxoethyl)amino]carbonyl}amino)benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- methylphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(4- bromophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(3- chlorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- cyanophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(3-cyanophenyl)methyl]-2-({(3S)-1 -[(4-f luorophenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({(3S)-1 -[(4-cyanophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-[((3S)-1 -{[3,4-bis(methyloxy)phenyl]methyl}-3- pyrrolidinyl)amino]-1 -[(4-hydroxyphenyl)methyl]-2- oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(cyclopropylmethyl)-3-pyrrolidinyl]amino}-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-{[({(1 S)-2-({1 -[(4-fluorophenyl)methyl]-3-piperidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-cyanophenyl)methyl]-3-piperidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[1 -(1 ,3:benzodioxol-5-ylmethyl)-3-piperidinyl]amino}-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-[(1 -{[3,4-bis(methyloxy)phenyl]methyl}-3-piperidinyl)amino]-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[1 -(cyclopropylmethylJ-S-piperidinyllaminoJ-i -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-4- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-{[({(1 S)-2-{[1-(cyclopropylmethyl)hexahydro-1 H-azepin-3-yl]amino}-1-[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4- hydroxyphenyl)methyl]hexahydro-1 H-azepin-3-yl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({[1 -(cyclopropylmethyl^-piperidinyllmethylJaminoH -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Cyclooctyl 5-[({[(1 S)-1 -[(3-hydroxyphenyl)methyl]-2-({(3S)-1 -[(3- hydroxyphenyl)methyl]-3-piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]-2- thiophenecarboxylate;
Cyclooctyl 5-[({[(1 S)-1 -[(4-chlorophenyl)methyl]-2-({(3S)-1 -[(3- hydroxyphenyl)methyl]-3-piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]-2- thiophenecarboxylate;
Phenylmethyl 5-{[({(1 S)-2-({(3S)-1 -[(3-hydroxyphenyl)methyl]-3-piperidinyl}amino)- 1-[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate;
Phenylmethyl 5-{[({(1 S)-2-({(3S)-1 -[(4-chlorophenyl)methyl]-3-piperidinyl}amino)-1 -
[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate; and Cycloheptyl 5-{[({(1 S)-2-({(3S)-1 -[(4-chlorophenyl)methyl]-3-piperidinyl}amino)-1 -
[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate; or a pharmaceutically acceptable salt.
The most preferred compounds are selected from the group consisting of:
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({(3S)-1 -[(4-hydroxyphenyl)methyl]- 3-pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({(3S)-1 -[(4-fluorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(3-cyanophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(3-chlorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-chlorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Propyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; 1-methylethyl 4-[({[(1 S)-1-[(4-hydroxyphenyl)methyl]-2-({1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate;
Λ/-{1 -[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}-Λ/-{[(4-{[(1 - methylethylJaminofcarbonylJphenyOaminolcarbonylJ-L-tyrosinamide;
Λ/-[({4-[(cyclopropylamino)carbonyl]phenyl}amino)carbonyl]-Λ/-{1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}-L-tyrosinamide;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- chlorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Cyclooctyl 5-[({[(1 S)-1 -[(3-hydroxyphenyl)methyl]-2-({(3S)-1 -[(3- hydroxyphenyl)methyl]-3-piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]-2- thiophenecarboxylate;
Cyclooctyl 5-[({[(1 S)-1-[(4-chlorophenyl)methyl]-2-({(3S)-1-[(3- hydroxyphenyl)methyl]-3-piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]-2- thiophenecarboxylate;
Phenylmethyl 5-{[({(1 S)-2-({(3S)-1 -[(3-hydroxyphenyl)methyl]-3-piperidinyl}amino)-
1-[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate;
Phenylmethyl 5-{[({(1 S)-2-({(3S)-1 -[(4-chlorophenyl)methyl]-3-piperidinyl}amino)-1 - [(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- fluorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-({[((1 S)-1-[(4-aminophenyl)methyl]-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)- 3-pyrrolidinyl]amino}-2-oxoethyl)amino]carbonyl}amino)benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(4- methylphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- bromophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(3- chlorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- cyanophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(3-cyanophenyl)methyl]-2-({(3S)-1 -[(4-fluorophenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({(3S)-1 -[(4-cyanophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-[((3S)-1 -{[3,4-bis(methyloxy)phenyl]methyl}-3- pyrrolidinyl)amino]-1-[(4-hydroxyphenyl)methyl]-2- oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(cyclopropylmethyO-S-pyrrolidinyllaminoJ-i -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-fluorophenyl)methyl]-3-piperidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-({1 -[(4-cyanophenyl)methyl]-3-piperidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[1 -(1 ,3-benzodioxol-5-ylmethyl)-3-piperidinyl]amino}-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-[(1 -{[3,4-bis(methyloxy)phenyl]methyl}-3-piperidinyl)amino]-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[1 -(cyclopropylmethyl)-3-piperidinyl]amino}-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-4- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-{[({(1 S)-2-({[1 -(cyclopropylmethyl)-4-piperidinyl]methyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; and Cycloheptyl 5-{[({(1 S)-2-({(3S)-1 -[(4-chlorophenyl)methyl]-3-piperidinyl}amino)-1 - [(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate; or a pharmaceutically acceptable salt. Methods of Preparation
Preparation
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 , 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.
Preparation 1
Resin-bound amines 3 were prepared by reductive alkylation of 2,6- dimethoxy-4-polystyrenebenzyloxy-benzaldehyde (DMHB resin) with nosyl- 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, which were treated with 50% trifluoroacetic acid in 1 ,2-dichloroethane to afford targeted compounds 6.
Scheme 1
Figure imgf000018_0001
Conditions: a) 2-nitrobenzenesulfonyl chloride (Nosyl-CI), pyridine, CH2CI2, 0 °C
- rt; b) 4 M HCI in1 ,4-dioxane, MeOH, rt; c) 2,6-dimethoxy-4- polystyrenebenzyloxy-benzaldehyde (DMHB resin), Na(OAc)3BH, diisopropylethylamine, 10% acetic acid in 1 -methyl-2-pyrrolidinone, rt; d) Fmoc- protected amino acids, 1 ,3-diisopropylcarbodiimide, 1-hydroxy-7- azabenzotriazole, 1-methyl-2-pyrrolidinone, rt; e) 20% piperidine in 1-methyl-2- pyrrolidinone, rt; f) ethyl 4-isocyanatobenzoate, 1 ,2-dichloroethane, rt; g) K2CO3,
PhSH, 1-methyl-2-pyrrolidinone, rt; h) R2CHO, Na(OAc^BH, 10% acetic acid in 1-methyl-2-pyrrolidinone, rt; i) 50% trifluoroacetic acid in 1 ,2-dichloroethane, rt.
SYNTHETIC EXAMPLES
The following examples are provided as illustrative of the present invention but not limiting in any way:
Example 1 Preparation of Ethyl 4-r((r(1 S)-1-r(4-hvdroxyphenyl)methyll-2-((1-r(4- hvdroxyphenyl)methyll-3-pyrrolidinyl|amino)-2- oxoethvnaminolcarbonvDaminolbenzoate a) 3-Amino-N-(2-nitrobenzenesulfonyl)pyrrolidine HCI salt
To a solution of 3-(te/ϊ-butoxycarbonyl-amino)pyrrolidine (20.12 g, 108 mmol) in 250 mL of anhydrous methylene chloride at 0 0C was added 13.1 mL (162 mmol) of anhydrous pyridine, followed by slow addition of 25.2 g (113.4 mmol) of 2-nitrobenzenesulfonyl chloride. The mixture was warmed to rt over 1 h and stirred at rt for 16 h. The mixture was poured into 300 mL of 1 M aqueous NaHCθ3 solution. After the resulting mixture was stirred at rt for 30 min, the organic layer was separated and washed with 500 mL of 1 N aqueous HCI solution twice. The resulting organic layer was dried over MgSO4 and concentrated in vacuo. The residue was used for the next step without further purification.
To a mixture of the above residue in 140 mL of anhydrous MeOH was added 136 mL (544 mmol) of 4 M HCI in 1 ,4-dioxane solution. The mixture was stirred at rt for 16 h, concentrated in vacuo and further dried in vaccum oven at 35
0C for 24 h to yield 3-amino-N-(2-nitrobenzenesulfonyl)pyrrolidine HCI salt as a yellow solid (30.5 g, 92% over the two steps): 1 H NMR (400 MHz, dø-DMSO) δ
8.63 (s, 3 H), 8.08-7.98 (m, 2 H), 7.96-7.83 (m, 2 H), 3.88-3.77 (m, 1 H), 3.66-3.56 (m, 2 H), 3.46-3.35 (m, 2 H), 2.28-2.16 (m, 1 H), 2.07-1.96 (m, 1 H).
b) DMHB resin-bound ethyl 4-[({[(1 S)-1-({4-[(1 ,1-dimethylethyl)oxy]phenyl}methyl)- 2-({1 -[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate
To a mixture of 7.20 g (10.37 mmol, 1.44 mmol/g) of 2,6-dimethoxy-4- polystyrenebenzyloxy-benzaldehyde (DMHB resin) in 156 mL of 10% acetic acid in anhydrous 1-methyl-2-pyrrolidinone was added 9.56 g (31.1 mmol) of example 1a and 9.03 mL (51.84 mmol) of diisopropylethyl amine, followed by addition of 11.0 g (51.84 mmol) of sodium triacetoxyborohydride. After the resulting mixture was shaken at rt for 72 h, the resin was washed with DMF (3 x 250 mL), CH2Cl2/MeOH (1 :1 , 3 x 250 mL) and MeOH (3 x 250 mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. Elemental analysis N: 4.16, S: 3.12. To a mixture of 800 mg (0.860 mmol, 1.075 mmol/g) of the above resin in
15 mL of anhydrous 1-methyl-2-pyrrolidinone was added 1.98 g (4.30 mmol) of
Fmoc-Try(tBu)-OH and 117 mg (0.86 mmol) of 1-hydroxy-7-azabenzotriazole, followed by addition of 0.82 ml_ (5.16 mmol) of 1 ,3-diisopropylcarbodiimide. After the resulting mixture was shaken at rt for 24 h, the resin was washed with DMF (3 x 25 mL), CH2CI2/Me0H (1 :1 , 3 x 25 ml_) and MeOH (3 x 25 ml_). The resulting resin was dried in vacuum oven at 35 0C for 24 h. An analytical amount of resin was cleaved with 50% trifluoroacetic acid in dichloroethane for 2 h at rt. The resulting solution was concentrated in vacuo: MS (ESI) 657 [M+H-tBu]+.
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), CH2CI2/MeOH (1 :1 , 3 x 25 mL) and MeOH (3 x 25 mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. An analytical amount of resin was cleaved with 50% trifluoroacetic acid in dichloroethane for 2 h at rt. The resulting solution was concentrated in vacuo: MS (ESI) 435 [M+H-tBu]+.
To a mixture of 200 mg (0.192 mmol, 0.959 mmol/g) of the above dry resin in 5 mL of anhydrous 1 ,2-dichloroethane was added 183.4 mg (0.959 mmol) of ethyl 4-isocyanatobenzoate. After the resulting mixture was shaken at rt for 24 h, the resin was washed with DMF (3 x 10 mL), CH2CI2/MeOH (1 :1 , 3 x 10 mL) and MeOH (3 x 10 mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. An analytical amount of resin was cleaved with 50% trifluoroacetic acid in dichloroethane for 2 h at rt. The resulting solution was concentrated in vacuo: MS
(ESI) 626 [M+H-tBu]+.
To a mixture of the above dry resin (0.192 mmol) in 6.4 mL of 1-methyl-2- pyrrolidinone was added 265 mg (1.92 mmol) of K2CO3 and 0.0985 mL (0.96 mmol) of PhSH. After the resulting mixture was shaken at rt for 2 h, the resin was washed with DMF (3 x 10 mL), H2O (3 x 10 mL), DMF (3 x 10 mL),
CH2CI2/MeOH (1 :1 , 3 x 10 mL) and MeOH (3 x 10 mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. An analytical amount of resin was cleaved with 50% trifluoroacetic acid in dichloroethane for 2 h at rt. The resulting solution was concentrated in vacuo: MS (ESI) 441 [M+H-tBu]+. To a mixture of the above dry resin (0.192 mmol) in 6.4 ml_ of 10% HOAc in anhydrous 1-methyl-2-pyrrolidinone solution was added 234 mg (1.918 mmol) of 4-hydroxybenzaldehyde and 407 mg (1.918 mmol) of sodium triacetoxyborohydride. After the resulting mixture was shaken at rt for 72 h, the resin was washed with DMF (3 x 10 ml_), CH2Cl2/MeOH (1 :1 , 3 x 10 ml_) and
MeOH (3 x 10 ml_). The resulting resin was dried in vacuum oven at 35 0C for 24 h to yield DMHB resin-bound ethyl 4-[({[(1 S)-1-({4-[(1 ,1- dimethylethyl)oxy]phenyl}methyl)-2-({1-[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate (0.192 mmol).
c) Ethyl 4-[({[(1 S)-1-[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate
The above dry resin (1 b, 0.192 mmol) was treated with 4 ml_ of 50% trifluoroacetic acid in dichloroethane at rt for 2h. After the cleavage solution was collected, the resin was treated with another 4 ml_ of 50% trifluoroacetic acid in dichloroethane at rt for 10 min. The combined cleavage solutions were concentrated in vacuo. The residue was purified using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 3.2 min, hold for 1 min where A = H2O (0.1% trifluoroacetic acid) and B = CH3CN (0.1% trifluoroacetic acid) pumped at 25 ml_/min, to produce ethyl 4-[({[(1 S)-1-[(4-hydroxyphenyl)methyl]-2-({1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate (white powder, 63 mg, 60% over 9 steps): MS (ESI) 547 [M+H]+.
Proceeding in a similar manner, but replacing 3-(terf-butoxycarbonyl- amino)pyrrolidine with the appropriate Boc-protected diamines and/or replacing 4- hydroxybenzaldehyde with the appropriate aldehydes, the compounds listed in
Tables 1 - 10 were prepared.
Figure imgf000022_0001
Table 1
Figure imgf000022_0002
Figure imgf000023_0002
Figure imgf000023_0001
Table 2
Figure imgf000023_0003
Figure imgf000024_0003
Figure imgf000024_0001
Table 3
Figure imgf000024_0004
Figure imgf000024_0002
Table 4
Figure imgf000024_0005
Figure imgf000025_0001
Table 5
Figure imgf000025_0004
Figure imgf000025_0002
Table 6
Figure imgf000025_0005
Figure imgf000025_0003
Table 7
Figure imgf000026_0003
Figure imgf000026_0001
Table 8
Figure imgf000026_0004
Figure imgf000026_0002
Table 9
Figure imgf000026_0005
Figure imgf000027_0003
Table 10
Figure imgf000027_0001
Proceeding in a similar manner as described in example 1 , but replacing 3- (terf-butoxycarbonyl-amino)pyrrolidine with 3S-(-)-(te/t-butoxycarbonyl- amino)pyrrolidine or 3/:?-(+)-(tø/t-butoxycarbonyl-amino)pyrrolidine, replacing Fmoc-Try(tBu)-OH with other Fmoc protected amino acids and/or replacing 4- hydroxybenzaldehyde with the appropriate aldehydes, the compounds listed in Tables 11 - 14 were prepared.
Table 11
Figure imgf000027_0002
Figure imgf000028_0001
Table 12
Figure imgf000028_0002
Figure imgf000029_0001
Table 13
Figure imgf000029_0004
Figure imgf000029_0002
Table 14
Figure imgf000029_0005
Proceeding in a similar manner as described in example 1 , but replacing ethyl 4-isocyanatobenzoate with the appropriate isocyanates and/or replacing 4- hydroxybenzaldehyde with the appropriate aldehydes, the compounds listed in Tables 15 and 16 were prepared.
Figure imgf000029_0003
Table 15
Figure imgf000029_0006
Table 16
Figure imgf000030_0001
Preparation 2
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 7. Reactions of 7 with ethyl 4-isocyanatobenzoate afforded the corresponding resin-bound ureas, which were subsequently treated with potassium carbonate and thiophenol to give secondary amines 8. Reductive alkylation of 8 with appropriate aldehydes produced resin-bound tertiary amines, which were treated with potassium trimethylsilanolate (KOTMS) in tetrahydrofuran (THF) to give the corresponding carboxylic acids 9. Acids 9 reacted with appropriate alcohols in presence of 1- (mesitylene-2-sulfonyl)-3-nitro-1 ,2,4-triazole (MSNT) and 1-methylimidazole (MeIm) to afford the corresponding esters, which were treated with 50% trifluoroacetic acid in 1 ,2-dichloroethane to yield targeted compounds 10 (Scheme 2).
Scheme 2
Figure imgf000031_0001
Conditions: a) Fmoc-Try(tBu)-OH, 1 ,3-diisopropylcarbodiimide, 1-hydroxy-7- azabenzotriazole, i-methyl-2-pyrrolidinone, rt; b) 20% piperidine in 1 -methyl-2- pyrrolidinone, rt; c) ethyl 4-isocyanatobenzoate, 1 ,2-dichloroethane, rt; d) K2CO3,
PhSH, 1-methyl-2-pyrrolidinone, rt; e) R2CHO, Na(OAc)3BH, 10% acetic acid in
1-methyl-2-pyrrolidinone, rt; f) KOTMS, THF, rt; g) R1OH, MSNT, MeIm, dichloromethane, rt; h) 50% trifluoroacetic acid in 1 ,2-dichloroethane, rt.
Example 135
Preparation of Propyl 4-r((lϊ1 S)-I-Ff 4-hvdroχyphenyl)methvπ-2-((1-r(4- hvdroxyphenyl)methyll-3-pyrrolidinyllamino)-2- oxoethyllaminolcarbonvDaminolbenzoate
a) DMHB resin-bound 4-[({[(1 S)-1-({4-[(1 ,1-dimethylethyl)oxy]phenyl}methyl)-2-({1- [(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoic acid
To a mixture of 50 mg (0.04 mmol, 0.809 mmol/g) of example 1b in THF (3 mL) was added potassium trimethylsilanolate (KOTMS) (0.27 g, 0.7 M in THF). The mixture was shaken at rt for 2 days and then the resin was washed with THF (1 x 2 mL), CH2CI2 (3 x 2 mL), MeOH (3 x 2 mL) and CH2CI2 (3 x 2 mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. An analytical amount of resin was cleaved with 50% trifluoroacetic acid in dichloroethane for 1 h at rt. The resulting solution was concentrated in vacuo: MS (ESI) 519 [M+H-tBu]+.
b) Propyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1-[(4-hydroxyphenyl)methyl]- 3-pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate
To a mixture of the above dry resin (135a, 0.04 mmol) in dichloromethane (2 ml_) was added 1 -methylimidazole (0.043 ml_, 0.27 M in DCM), followed by 1- (mesitylene-2-sulfonyl)-3-nitro-1 ,2,4-triazole (MSNT) (119 mg, 0.2 M in DCM) and 1-propanol (0.06 ml_, 0.4 M in DCM). After the resulting mixture was shaken at rt for 24 h, the resin was washed with DCM (3 x 5 ml_), Ch^C^/MeOH (1 :1 , 3 x 5 ml_) and MeOH (3 x 5 ml_). The resulting resin was dried in vacuum oven at 35
0C for 24 h. The dry resin was treated with 2 ml_ of 50% trifluoroacetic acid in dichloroethane at rt for 2h. After the cleavage solution was collected, the resin was treated with another 2 ml_ of 50% trifluoroacetic acid in dichloroethane at rt foMOmin. The combined cleavage solutions were concentrated in vacuo. The residue was purified using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 3.2 min, hold for 1 min where A = H2O (0.1 % trifluoroacetic acid) and B = CH3CN
(0.1 % trifluoroacetic acid) pumped at 25 mUmin, to produce propyl 4-[({[(1 S)-1- [(4-hydroxyphenyl)methyl]-2-({1-[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate (white powder, 6 mg, 27% over 11 steps): MS (ESI) 561 [M+H]+.
Proceeding in a similar manner as described in example 135, but replacing 1 -propanol with the appropriate alcohols and/or replacing 4-hydroxybenzaldehyde with the appropriate aldehydes, the compounds listed in Table 17 were prepared.
Figure imgf000032_0001
Table 17
Figure imgf000033_0001
Preparation 3
Resin-bound acids 9 were prepared in the same way as described in preparation 2. Reactions of acids 9 with appropriate amines in presence of PyBOP and diisopropylethyl amine (DIEA) afforded the corresponding amides, which were treated with 50% trifluoroacetic acid in 1 ,2-dichloroethane to afford targeted compounds 11 (Scheme 3).
Scheme 3
Figure imgf000034_0001
Conditions: a) (R1)(R3)NH, PyBOP, diisopropylethyl amine, 1-methyl-2- pyrrolidinone, rt; b) 50% trifluoroacetic acid in 1 ,2-dichloroethane, rt.
Example 163
Preparation of ΛK1 -r(4-hvdroxyphenvπmethvπ-3-pyrrolidinyl)-ΛH({4- r(propylamino)carbonyllphenyl)amino)carbonvn-L-tyrosinamide
To a mixture of example 135a (0.04 mmol) in 1-methyl-2-pyrrolidinone (2 ml_) was added PyBOP (0.31 g, 0.3 M in 1-methyl-2-pyrrolidinone), followed by 1- propylamine (0.2 mL, 1.2 M in 1-methyl-2-pyrrolidinone) and diisopropylethyl amine (0.21 mL, 0.6 M in 1-methyl-2-pyrrolidinone). After the resulting mixture was shaken at rt for 24 h, the resin was washed with DCM (3 x 5 mL), CH2Cl2/MeOH (1 :1 , 3 x 5 mL) and MeOH (3 x 5 mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. The dry resin was treated with 2 mL of 50% trifluoroacetic acid in dichloroethane at rt for 2 h. After the cleavage solution was collected, the resin was treated with another 2 mL of 50% trifluoroacetic acid in dichloroethane at rt for 10 min. The combined cleavage solutions were concentrated in vacuo. The residue was purified using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 3.2 min, hold for 1 min where A = H2O (0.1% trifluoroacetic acid) and B = CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min, to produce Λ/-{1 -[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}-Λ/-[({4- [(propylamino)carbonyl]phenyl}amino)carbonyl]-L-tyrosinamide (white powder, 12 mg, 54% over 11 steps): MS (ESI) 560 [M+H]+.
Proceeding in a similar manner as described in example 163, but replacing 1 -propylamine with the appropriate amines and/or replacing 4- hydroxybenzaldehyde with the appropriate aldehydes, the compounds listed in Table 18 were prepared.
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000036_0001
Figure imgf000037_0001
Preparation 4
Using the methodology described above, thiophene ester and amide antagonist compounds were prepared. 5-Nitro-2-thiophenecarboxylic acid was treated with oxalyl chloride to form an acid chloride, which reacted with a series of cycloalkyl alcohols to provide corresponding esters 12. The nitro group in 12 was converted to amine by hydrogenation using 10% palladium on carbon. The amines 13 were coupled with resin-bound intermediate 4 to afford the corresponding resin-bound ureas 14. 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 15. The resin was then cleaved by 50% trifluoroacetic acid in dichloromethane to afford targeted compounds 16 (Scheme 4).
Scheme 4
Figure imgf000038_0001
Figure imgf000038_0002
Conditions: a) oxalyl chloride, R-|OH or R-| NH2, rt b) 10% palladium on carbon, rt c) 4-nitrobenzene chloroformate, diisopropylethylamine, N,N-dimethyl formamide, dichloromethane, rt; d) K2CO3, PhSH, 1 -methyl-2-pyrrolidinone, rt; e) R2CHO,
Na(OAc)3BH, 10% acetic acid in 1 -methyl-2-pyrrolidinone, rt; f) 50% trifluoroacetic acid in dichloromethane, rt.
Example 208 Preparation of cvclooctyl 5-r((r(1 S)-1-r(4-hvdroxyphenyl)methvn-2-(((3S)-1- r(3-hvdroχyphenv0methvπ-3-piper8dinyl}amino)-2- oxoethvnamino)carbonvhamino1-2-thiophenecarboxylate
5-Nitro-2-thiophenecarboxylic acid (1.0 g, 5.7 mmol) was suspended in methylene chloride (10 ml_). Oxalyl chloride in methylene chloride (2.0 M, 6.0 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 (20 ml_) was added, concentrated again and redissolved in methylene chloride (10 ml_). N, N'-Dimethylaminopyridine ( 236 mg, 1.44 mmol) , triethyl amine( 1.61 ml_, 11.56mmol) and cyclooctanol (1.11 g, 8.67 mmol) were added to reaction mixture and stirred at room temperature overnight. The reaction mixture was filtered through a pad of silica gel (100g), eluting with methylene chloride. Cyclooctanol 5-nitro-2-thiophenecarboxylate was obtained after concentration. To cyclooctanol 5-nitro-2-thiophenecarboxylate in ethyl alcohol (20 ml_) was added palladium on carbon (10%, 2 g). The reaction mixture was hydrogenated at 15 psi overnight. Cyclooctanol 5-amino-2-thiophenecarboxylate (1.3 g, 89.7%) was obtained after filtration and concentration. LCMS (ESI) 254.2 [M+H]+.
To a mixture of 381 mg (1.5 mmol) cyclooctanol 5-amino-2-thiophenecarboxylate in 2OmL of anhydrous dichloromethane was added 301.5 mg (1.5 mmol) A- nitrobezenechloroformate. The reaction mixture was stirred at room temperature for half an hour and concentrated. Diisopropylethylamine (0.8 mL, 4.56 mmol), DMHB resin bound O-(1 ,1-dimethylethyl)-Λ/-{(3S)-1-[(2-nitrophenyl)sulfonyl]-3- pyrrolidinyl}-L-tyrosinamide 4 (400 mg, 0.32 mmol)and dimethyl formamide (20 mL) were added to reaction mixture and shaked overnight.. The resin was washed with CH2CI2 (3 x 1 mL), CH2CI2/Me0H (1 :1 , 3 x 1 mL), MeOH (3 x 1 mL) and
CH2CI2 (3 x 10mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. An analytical amount of resin was cleaved with 50% trifluoroacetic acid in dichloroethane for 2 h at rt. The resulting solution was concentrated in vacuo: MS
(ESI) 728 [M+H-tBu]+. To a mixture of the above dry resin (0.04 mmol) in 1 mL of 1-methyl-2- pyrrolidinone was added 41.5 mg (0.3 mmol) of K2(X>3 and 15.4 μL (0.15 mmol) of PhSH. After the resulting mixture was shaken at rt for 2 h, the resin was washed with DMF (3 x 10 mL), H2O (3 x 10 mL), DMF (3 x 10 mL),
CH2CI2/MeOH (1 :1 , 3 x 10 mL) and MeOH (3 x 10 mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. An analytical amount of resin was cleaved with 50% trifluoroacetic acid in dichloroethane for 2 h at rt. The resulting solution was concentrated in vacuo: MS (ESI) 543 [M+H-tBu]+.
To a mixture of the above dry resin (50mg, 0.04 mmol) in 3 ml_ of 10% HOAc in anhydrous 1-methyl-2-pyrrolidinone solution was added 147mg (1.2 mmol) of 3-hydroxylbenzaldehyde and 254.4 mg (1.2 mmol) of sodium triacetoxyborohydride. After the resulting mixture was shaken at rt for 24 h, the resin was washed with DMF (3 x 10 mL), CH2Cl2/MeOH (1 :1 , 3 x 10 ml_) and
MeOH (3 x 10 mL). The resulting resin was dried in vacuum oven at 35 0C for 24 h. The dry resin was treated with 2 mL of 50% trifluoroacetic acid in dichloromethane at rt for 2h. After the cleavage solution was collected, the resin was treated with another 2 mL of 50% trifluoroacetic acid in dichloromethane at rt for 10min. The combined cleavage solutions were concentrated in vacuo. The residue was purified using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 3.2 min, hold for 1 min where A = H2O (0.1 % trifluoroacetic acid) and B = CH3CN (0.1 % trifluoroacetic acid) pumped at 25 mL/min, to produce cyclooctyl 5-[({[(1 S)- 1-[(4-hydroxyphenyl)methyl]-2-({(3S)-1-[(3-hydroxyphenyl)methyl]-3- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]-2-thiophenecarboxylate
(white powder, 21 mg, 40% over 4 steps): MS (ESI) 650[M]+. Proceeding in a similar manner as described in example 208, but replacing cyclooctyl alcohol with the appropriate alkyl alcohols, and/or replacing 3- hydroxylbenzaldehyde with the appropriate aldehydes, the compounds listed in Tables 19- 21 were prepared.
Figure imgf000040_0001
Table 19
Figure imgf000041_0003
Figure imgf000041_0001
Table 20
Figure imgf000041_0004
Figure imgf000041_0002
Table 21
Figure imgf000041_0005
BIOLOGICAL EXAMPLES
The inhibitory effects of compounds at the M3 mAChR of the present invention are determined by the following in vitro and in vivo assays:
Analysis of Inhibition of Receptor Activation by Calcium Mobilization:
1) 384-well FLIPR assay
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. After overnight incubation of plated cells at 37 degrees C in a tissue culture incubator, the assay is run the next day. To run the assay, media are aspirated, and cells are washed with 1x assay buffer (145mM NaCI, 2.5mM KCI, 1OmM glucose, 1OmM HEPES, 1.2 mM MgCI2, 2.5mM CaCI2, 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. Cells are washed with assay buffer, and then resuspended in 5OuI assay buffer prior to use for experiments. 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. To measure the activity of inhibitors / antagonists, acetylcholine ligand is added at an ECso concentration, and the antagonist IC50 can then be determined using dose response dilution curves. The control antagonist used with M3 is atropine. 2) 96-well FLIPR assay
Stimulation of mAChRs expressed on CHO cells were analyzed by monitoring receptor-activated calcium mobilization as previously described . 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 μl of load media (EMEM with Earl's salts, 0.1% RIA-grade BSA (Sigma, St. Louis MO), and 4 μM Fluo-3-acetoxymethyl ester fluorescent indicator dye (Fluo-3 AM, Molecular Probes, Eugene, OR) and incubated 1 hr at 37° C. 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 μl of assay buffer (0.1% gelatin (Sigma), 120 mM NaCI, 4.6 mM KCI, 1 mM KH2 PO4, 25 mM NaH CO3, 1.0 mM CaCI2, 1.1 mM
MgCI2, 11 mM glucose, 2OmM HEPES (pH 7.4)). 50 μl of compound (1x10"1 1 -
1x10"5 M final in the assay) was added and the plates were incubated for 10 min. at 37° C. Plates were then placed into a fluorescent light intensity plate reader (FLIPR, Molecular Probes) where the dye loaded cells were exposed to excitation light (488 nm) from a 6 watt argon laser. Cells were activated by adding 50 μl of acetylcholine (0.1 -10 nM final), prepared in buffer containing 0.1% BSA, at a rate of 50 μl/sec. Calcium mobilization, monitored as change in cytosolic calcium concentration, was measured as change in 566 nm emission intensity. The change in emission intensity is directly related to cytosolic calcium levels . The emitted fluorescence from all 96 wells is measured simultaneously using a cooled CCD camera. Data points are collected every second. This data was then plotting and analyzed using GraphPad PRISM software.
Methacholine-induced bronchoconstriction
Airway responsiveness to methacholine was determined in awake, unrestrained BaIbC mice (n = 6 each group). Barometric plethysmography was used to measure enhanced pause (Penh), a unitless measure that has been shown to correlate with the changes in airway resistance that occur during bronchial challenge with methacholine . Mice were pretreated with 50 μl of compound
(0.003-10 μg/mouse) in 50 μl of vehicle (10% DMSO) intranasally, and were then placed in the plethysmography chamber. Once in the chamber, the mice were allowed to equilibrate for 10 min before taking a baseline Penh measurement for 5 minutes. 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.
FORMULATION-ADMINISTRATION
Accordingly, 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. Hereinafter, the term "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. Use of lactose is preferred. Each capsule or cartridge may generally contain between 20μg-10mg of the compound of formula (I) optionally in combination with another therapeutically active ingredient. Alternatively, 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.
Suitably, 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).
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. By multi-dose dry powder inhaler (MDPI) 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. In a preferred aspect, 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. Preferably, 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.
In one aspect, 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. In one aspect, the multi-dose blister pack comprises plural blisters arranged in generally circular fashion on a disk-form blister pack. In another aspect, the multi-dose blister pack is elongate in form, for example comprising a strip or a tape. Preferably, 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. In this aspect, the device is usually provided with an opening station comprising peeling means for peeling the members apart to access each medicament dose. Suitably, 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. More preferably, 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 lid 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.
By metered dose inhaler (MDI) 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. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxide or other suitable gas may also be used as propellant. 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.
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 Oμm, preferably 2- 5μm. The optimum aerodynamic particle size for inhalation into the alveolar region for achieving systemic delivery to the lung is approximately .5-3 μm, preferably 1 - 3 μm. Particles having an aerodynamic size above 20μm 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. To achieve a desired particle size, the particles of the active ingredient as produced may be size reduced by conventional means eg by controlled crystallization, micronisation or nanomilling The desired fraction may be separated out by air classification. Alternatively, 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. Preferably, the particles will be crystalline, although amorphous material may also be employed where desirable. When 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. 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 60-90μm and not less than 15% will have a MMD of less than 15μm. 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) may also be employed on 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. 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.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is:
1. A compound according to Formula I herein below:
Figure imgf000050_0001
wherein
When X and Y are carbons, n is 1 , 2, or 3; m is 1 , 2, or 3; p is 0, 1 , or 2; When X is oxygen and Y is carbon, n is 1 ; m is 2; p is 1 ; When X is carbon and Y is nitrogen, n is 2; m is 1 ; p is 2; W is O, S, or NH;
U is NR3, O, or bond;
R3 is selected from the group consisting of hydrogen, Ci-Cs 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 Ci-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 integer from 0 to 7; h is 0, 1 , or 2; g is 1 , 2, or 3;
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, Ci-Cs alkoxy, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, COR6, COOR6, CONHR6, CON(R6)2, NHR6, N(R6)2, and G; k is an integer from 0 to 5;
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-|-Cs alkoxy, halo, hydroxy, amino, trifluoromethyl, C-| -C8 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1 -C3 lower alkyl;
R5 is selected from the group consisting of COOR6, CONHR6, 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-| -C-8 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1 -C3 lower alkyl, C-) -Ce alkoxy, halo, hydroxy, amino, cyano and trifluoromethyl;
R6 is selected from the group consisting of Ci -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-| -C8 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-| -C-8 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, tetrohydroquinolinyl, morpholino, azetidinyl, hexahydroazepinyl, or octahydroazocinyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-i -Cs alkoxy, hydroxy, amino, C-| -C-8 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1 -C3 lower alkyl; R1 is selected from the group consisting of an unsubstituted or substituted following group: hydrogen, phenyl, phenyl C1-C6 lower alkyl, thiophenyl, thiophenyl C1-C6 lower alkyl, furanyl, furanyl C1-C6 lower alkyl, pyridinyl, pyridinyl C1-C6 lower alkyl, imidazolyl, imidazolyl C1 -C6 lower alkyl, naphthyl, naphthyl C1- C6 lower alkyl, quinolinyl, quinolinyl C1-C6 lower alkyl, indolyl, indolyl C1 -C6 lower alkyl, benzothiophenyl, benzothiophenyl C1-C6 lower alkyl, benzofuranyl, benzofuranyl C1-C6 lower alkyl, benzoimidazolyl, benzoimidazolyl C1-C6 lower alkyl, C-) -Ce branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C-\ -CQ lower alkyl, or C3-C8 alkenyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-|-C-8 alkoxy, phenoxy, phenyl C1-C3 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, C-1-C8 branched or unbranched alkyl, C3-C-8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, thiophenyl, thiophenyl C1-C3 lower alkyl, furanyl, furanyl C1-C3 lower alkyl, pyridinyl, pyridinyl C1-C3 lower alkyl, naphthyl, naphthyl C1-C3 lower alkyl, quinolinyl, quinolinyl C1-C3 lower alkyl, indolyl, indolyl C1-C3 lower alkyl, benzothiophenyl, benzothiophenyl C1-C3 lower alkyl, benzofuranyl, benzofuranyl C1-C3 lower alkyl, COOH, COR6, COOR6, CONHR6, CON(R6)2, COG, NHR6, N(R6)2, G, OCOR6, OCONHR6, NHCOR6, N(R6)COR6, NHCOOR6 and NHCONHR6; or a pharmaceutically acceptable salt.
2. A compound according to claim 1 consisting of the group selected from:
When X and Y are carbons, n is 1 , or 2; m is 1 , 2, or 3; p is 0, or 1 ; When X is oxygen and Y is carbon, n is 1 ; m is 2; p is 1 ;
When X is carbon and Y is nitrogen, n is 2; m is 1 ; p is 2; W is O; U is NR3; R3 is selected from the group consisting of hydrogen, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, or phenyl C1 -C3 lower alkyl; q is O; h is O; g is 1 ;
V is selected from the group consisting of phenyl, thiophenyl, furanyl, naphthyl, benzothiophenyl and benzofuranyl; R4 is selected from the group consisting of hydrogen, hydroxy, amino, halo, cyano, trifluoromethyl, C-|-C8 alkoxy, C-|-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, phenylcarbonyl; k is an integer from 1 to 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-|-C-8 alkoxy, halo, hydroxy, amino, trifluoromethyl, C-1-C3 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1 -C3 lower alkyl; 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, and 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, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C-i-Cβ lower alkyl, or C3-C8 alkenyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-|-C-8 alkoxy, phenoxy, phenyl C1-C3 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, C-i-Cβ branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, thiophenyl, thiophenyl C1-C3 lower alkyl, furanyl, furanyl C1-C3 lower alkyl, pyridinyl, pyridinyl C1-C3 lower alkyl, naphthyl, naphthyl C1-C3 lower alkyl, quinolinyl, quinolinyl C1-C3 lower alkyl, indolyl, indolyl C1-C3 lower alkyl, benzothiophenyl, benzothiophenyl C1 -C3 lower alkyl, benzofuranyl, benzofuranyl C1 -C3 lower alkyl, COOH, COR6, COOR6, CONHR6, CON(R6)2, COG, NHR6, N(R6)2, G, OCOR6, OCONHR6, NHCOR6, N(R6)COR6, NHCOOR6 and NHCONHR6; or a pharmaceutically acceptable salt.
3. A compound according to claim 1 consisting of the group selected from:
X and Y are carbons; n is 1 , or 2; m is 1 , 2, or 3; p is 0, or 1 ; W is O;
U is NR3;
R3 is hydrogen; q is 0; h is O; g is 1 ;
V is selected from the group consisting of phenyl, or naphthyl;
R4 is selected from the group consisting of hydroxy, amino, halo, cyano, trifluoromethyl, Ci-Cs alkoxy, C-|-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, phenylcarbonyl; k is 1 , 2, or 3;
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-|-C8 alkoxy, halo, hydroxy, amino, trifluoromethyl, C-|-C-8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl;
R5 is selected from the group consisting of 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-|-C-8 alkyl, C3-C-8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl C1-C3 lower alkyl;
R6 is selected from the group consisting of Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, or C3-C8 cycloalkyl lower alkyl;
G is selected from the group consisting of pyrrolidinyl, piperdinyl, dihydroindolyl, tetrohydroquinolinyl, morpholino, azetidinyl, hexahydroazepinyl, and 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, Ci-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C-j-Cs lower alkyl, or C3-C8 alkenyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of Ci-Cs alkoxy, phenoxy, phenyl C1-C3 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, methylenedioxy, ethylenedioxy, propylenedioxy, butylenedioxy, C-|-Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl, phenyl C1-C3 lower alkyl, thiophenyl, thiophenyl C1-C3 lower alkyl, furanyl, furanyl C1 -C3 lower alkyl, pyridinyl, pyridinyl C1-C3 lower alkyl, naphthyl, naphthyl C1-C3 lower alkyl, quinolinyl, quinolinyl C1-C3 lower alkyl, indolyl, indolyl C1-C3 lower alkyl, benzothiophenyl, benzothiophenyl C1-C3 lower alkyl, benzofuranyl, benzofuranyl C1-C3 lower alkyl, COOH, COR6, COOR6, CONHR6, CON(R6)2, COG, NHR6, N(R6)2, G, OCOR6 and NHCOR6; or a pharmaceutically acceptable salt.
4. A compound according to claim 1 selected from the group consisting of: Ethyl 4-{[({(1 S)-2-{[1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-fluorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({(3S)-1 -[(4-hydroxyphenyl)methyl]-
3-pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate ; Ethyl 4-{[({(1 S)-2-({(3S)-1 -[(4-fluorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[1 -(cyclopropylmethyO-S-pyrrolidiny^aminoJ-i -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-({[((1 S)-1 -[(4-hydroxyphenyl)methyl]-2-oxo-2-{[1 -(phenylmethyl)-3- pyrrolidinyl]amino}ethyl)amino]carbonyl}amino)benzoate;
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(3-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-{[({(1 S)-2-({1 -[(3-cyanophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-oxo-2-[(1 -{[4- (trifluoromethyl)phenyl]methyl}-3- pyrrolidinyl)amino]ethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(3-chlorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-[(1 -{[3,4-bis(methyloxy)phenyl]methyl}-3-pyrrolidinyl)amino]-1 - [(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-: -[(4-hydroxyphenyl)methyl]-2-[(1 -{[4-(methyloxy)phenyl]methyl}-3- pyrrolidinyl)amino]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-[(1 -{[3-(methyloxy)phenyl]methyl}-3- pyrrolidinyl)amino]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-({1 -[(4-chlorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-1-[(4-hydroxyphenyl)methyl]-2-oxo-2-[(1-{[3-
(trifluoromethyl)phenyl]methyl}-3- pyrrolidinyl)amino]ethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Propyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoθthyl]amino}carbonyl)amino]benzoate;
1-methylethyl 4-[({[(1 S)-1-[(4-hydroxyphenyl)methyl]-2-({1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate;
Λ/-[({4-[(ethylamino)carbonyl]phenyl}amino)carbonyl]-Λ/-{1 -[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}-L-tyrosinamide;
Λ/-{1-[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}-Λ/-[({4-
[(propylamino)carbonyl]phenyl}amino)carbonyl]-L-tyrosinamide; Λ/-{1 -[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}-Λ/-{[(4-{[(1 - methylethyl)amino]carbonyl}phenyl)amino]carbonyl}-L-tyrosinamide;
Λ/-[({4-[(cyclopropylamino)carbonyl]phθnyl}amino)carbonyl]-Λ/-{1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}-L-tyrosinamide;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- chlorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-[({[(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-(2- naphthalenylmethyl)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-({[((1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-2- oxo-1 -{[4-(phenylcarbonyl)phenyl]mΘthyl}ethyl)amino]carbonyl}amino)benzoate; Ethyl 4-({[((1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -{[4-
(methyloxy)phenyl]methyl}-2-oxoethyl)amino]carbonyl}amino)benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- fluorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-({[((1 S)-1-[(4-aminophenyl)methyl]-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)- 3-pyrrolidinyl]amino}-2-oxoethyl)amino]carbonyl}amino)benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- methylphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- bromophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(3- chlorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(4- cyanophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(3-cyanophenyl)methyl]-2-({(3S)-1 -[(4-fluorophenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({(3S)-1 -[(4-cyanophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-[((3S)-1 -{[3,4-bis(methyloxy)phenyl]methyl}-3- pyrrolidinyl)amino]-1-[(4-hydroxyphenyl)methyl]-2- oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(cyclopropylmethyl)-3-pyrrolidinyl]amino}-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-f luorophenyl)methyl]-3-piperidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-cyanophenyl)methyl]-3-piperidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[1 -(1 ,3-benzodioxol-5-ylmethyl)-3-piperidinyl]amino}-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-[(1 -{[3,4-bis(methyloxy)phenyl]methyl}-3-piperidinyl)amino]-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[1 -(cyclopropylmethyO-S-piperidiny^aminoJ-i -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-4- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-{[1-(cyclopropylmethyl)hexahydro-1 H-azepin-3-yl]amino}-1-[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1-[(4-hydroxyphenyl)methyl]-2-({1-[(4- hydroxyphenyl)methyl]hexahydro-1 H-azepin-3-yl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-{[({(1 S)-2-({[1 -(cyclopropylmethyl)-4-piperidinyl]methyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Cyclooctyl 5-[({[(1 S)-1 -[(3-hydroxyphenyl)methyl]-2-({(3S)-1 -[(3- hydroxyphenyl)methyl]-3-piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]-2- thiophenecarboxylate;
Cyclooctyl 5-[({[(1 S)-1 -[(4-chlorophenyl)methyl]-2-({(3S)-1 -[(3- hydroxyphenyl)methyl]-3-piperidinyl}amino)-2-oxoethyl]amino}carbonyl)annino]-2- thiophenecarboxylate;
Phenylmethyl 5-{[({(1 S)-2-({(3S)-1 -[(3-hydroxyphenyl)methyl]-3-piperidinyl}amino)-
1-[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate; Phenylmethyl 5-{[({(1 S)-2-({(3S)-1 -[(4-chlorophenyl)methyl]-3-piperidinyl}amino)-1 -
[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate; and
Cycloheptyl 5-{[({(1 S)-2-({(3S)-1 -[(4-chlorophenyl)methyl]-3-piperidinyl}amino)-1 -
[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate; or a pharmaceutically acceptable salt.
5. A compound according to claim 1 selected from the group consisting of: Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({(3S)-1 -[(4-hydroxyphenyl)methyl]- 3-pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-{[({(1 S)-2-({(3S)-1 -[(4-fluorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(3-cyanophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(3-chlorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-chlorophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Propyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
1 -methylθthyl 4-[({[(1 S)-1-[(4-hydroxyphenyl)methyl]-2-({1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}amino)-2- oxoethyl]amino}carbonyl)amino]benzoate;
Λ/-{1 -[(4-hydroxyphenyl)methyl]-3-pyrrolidinyl}-Λ/-{[(4-{[(1 - methylethyOaminolcarbonylJphenylJaminolcarbonylJ-L-tyrosinamide;
Λ/-[({4-[(cyclopropylamino)carbonyl]phenyl}amino)carbonyl]-Λ/-{1-[(4- hydroxyphenyl)methyl]-3-pyrrolidinyl}-L-tyrosinamide; Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(4- chlorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- fluorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-({[((1 S)-1-[(4-aminophenyl)methyl]-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)- 3-pyrrolidinyl]amino}-2-oxoethyl)amino]carbonyl}amino)benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- methylphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- bromophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1 -[(3- chlorophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- cyanophenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-[({[(1 S)-1 -[(3-cyanophenyl)methyl]-2-({(3S)-1 -[(4-fluorophenyl)methyl]-3- pyrrolidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate;
Ethyl 4-{[({(1 S)-2-({(3S)-1 -[(4-cyanophenyl)methyl]-3-pyrrolidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-{[(3S)-1-(1 ,3-benzodioxol-5-ylmethyl)-3-pyrrolidinyl]amino}-1-[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-[((3S)-1 -{[3,4-bis(methyloxy)phenyl]methyl}-3- pyrrolidinyl)amino]-1-[(4-hydroxyphenyl)methyl]-2- oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[(3S)-1 -(cyclopropylmethyO-S-pyrrolidiny^aminoJ-i -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-3- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-f luorophenyl)methyl]-3-piperidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-({1 -[(4-cyanophenyl)methyl]-3-piperidinyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[1-(1 ,3-benzodioxol-5-ylmethyl)-3-piperidinyl]amino}-1-[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate;
Ethyl 4-{[({(1 S)-2-[(1 -{[3,4-bis(methyloxy)phenyl]methyl}-3-piperidinyl)amino]-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-{[({(1 S)-2-{[1 -(cyclopropylmethyO-S-piperidinyllaminoJ-i -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Ethyl 4-[({[(1 S)-1 -[(4-hydroxyphenyl)methyl]-2-({1 -[(4-hydroxyphenyl)methyl]-4- piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]benzoate; and Ethyl 4-{[({(1 S)-2-({[1 -(cyclopropylmethyl)-4-piperidinyl]methyl}amino)-1 -[(4- hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}benzoate; Cyclooctyl 5-[({[(1 S)-1 -[(3-hydroxyphenyl)methyl]-2-({(3S)-1 -[(3- hydroxyphΘnyl)methyl]-3-piperidinyl}annino)-2-oxoethyl]amino}carbonyl)amino]-2- thiophenecarboxylate;
Cyclooctyl 5-[({[(1 S)-1-[(4-chlorophenyl)methyl]-2-({(3S)-1-[(3- hydroxyphenyl)methyl]-3-piperidinyl}amino)-2-oxoethyl]amino}carbonyl)amino]-2- thiophenecarboxylate; Phenylmethyl 5-{[({(1 S)-2-({(3^-1 -[(3-hydroxyphenyl)methyl]-3-piperidinyl}amino)- 1-[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate;
Phenylmethyl 5-{[({(1 S)-2-({(3^-1 -[(4-chlorophenyl)methyl]-3-piperidinyl}amino)-1 - [(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate; and
Cycloheptyl 5-{[({(1 ^-2-({(3S)-1 -[(4-chlorophenyl)methyl]-3-piperidinyl}amino)-1 -
[(4-hydroxyphenyl)methyl]-2-oxoethyl}amino)carbonyl]amino}-2- thiophenecarboxylate; or a pharmaceutically acceptable salt.
6. A pharmaceutical composition for the treatment of muscarinic acetylcholine receptor mediated diseases comprising a compound according to claim 1 and a pharmaceutically acceptable carrier thereof.
7. A method of inhibiting the binding of acetylcholine to its receptors in a mammal in need thereof comprising administering a safe and effective amount of a compound according to claim 1.
8. A method of treating a muscarinic acetylcholine receptor mediated disease, wherein acetylcholine binds to said receptor, comprising administering a safe and effective amount of a compound according to claim 1.
9. A method according to claim 8 wherein the disease is selected from the group consisting of chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis.
10. A method according to claim 9 wherein administration is via inhalation via the mouth or nose.
11. A method according to claim 10 wherein administration is via a medicament dispenser selected from a reservoir dry powder inhaler, a multi-dose dry powder inhaler or a metered dose inhaler.
12. A method according to claim 11 wherein the compound is administered to a human and has a duration of action of 12 hours or more for a 1 mg dose.
13. A method according to claim 12 wherein the compound has a duration of action of 24 hours or more.
14. A method according to claim 13 wherein the compound has a duration of action of 36 hours or more.
PCT/US2005/026877 2005-07-28 2005-07-28 Novel m3 muscarinic acetylcholine receptor antagonists WO2007018514A1 (en)

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