US20030065007A1 - NK1 receptor antagonists - Google Patents

NK1 receptor antagonists Download PDF

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US20030065007A1
US20030065007A1 US10/267,477 US26747702A US2003065007A1 US 20030065007 A1 US20030065007 A1 US 20030065007A1 US 26747702 A US26747702 A US 26747702A US 2003065007 A1 US2003065007 A1 US 2003065007A1
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indol
propionamide
ylmethyl
amino
benzofuran
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Mark Creswell
Michael Higginbottom
David Horwell
Russel Lewthwaite
Martyn Pritchard
Jennifer Raphy
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the neurokinins are a family of mammalian neuropeptides that are involved with numerous biological activities such as pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system, and neurogenic inflammation.
  • One such neuropeptide known as substance P is widely distributed throughout the peripheral and central nervous system of mammals, and is known to mediate a variety of biological actions via interaction with three neurokinin (NK or tachykinin) receptor types known as NK 1 , NK 2 , and NK 3 .
  • Substance P binds with higher affinity to the NK 1 receptor than it does to the other receptors. Accordingly, compounds capable of antagonizing the effects of substance P at the NK 1 receptor are useful for treating and controlling disorders mediated by such interactions, including disorders such as anxiety, pain, depression, schizophrenia, and emesis.
  • substance P mediate various biological actions, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-constriction, activation of the immune system and neurogenic inflammation via an interaction with NK receptors, preferably NK 1 , thus compounds capable of antagonising the effects of substance P at NK 1 receptors will be useful in treating or preventing a variety of: brain disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and addiction disorders; inflammatory diseases such as arthritis, asthma, bronchitis and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis.
  • brain disorders including pain (inflammatory, surgical and neuropathic
  • NK 1 receptor antagonists are useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NK 1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
  • This invention provides NK 1 receptor antagonists characterized as non-peptide acetamide derivatives.
  • the compounds of the invention differ from those of U.S. Pat. Nos. 5,716,979 or 5,594,022 in that the compounds of Formula I below are not (N-substituted aryl-methyl) carbamates, i.e. they do not have a —O—C(O)—N— link in the backbone; certain final products being more stable than known compounds, they should show improved oral bioavailability and improved CNS penetration.
  • the invention compounds are defined by Formula I:
  • R is:
  • benzoxazolyl wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, —CF 3 , carboxy, sulfonamide, or nitro;
  • R can also be:
  • R 1 and R 2 are each independently H or C 1 -C 4 alkyl
  • m is an integer from 0 to 3;
  • X is NHCONH, or NR 8 where R 8 is H or C 1 -C 4 alkyl
  • R 3 is hydrogen or C 1 -C 4 alkyl
  • n is an integer from 1 to 2;
  • R 4 is naphthyl or indolyl, wherein said groups are unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy or formyl;
  • R 9 is hydrogen or C 1 -C 4 alkyl
  • R 5 and R 7 are each independently hydrogen or (CH 2 ) p R 10 where:
  • P is an integer of 1 to 3
  • R 10 is H, CH 3 , CN, OH, OCH 3 , CO 2 CH 3 , NH 2 , NHCH 3 , or N(CH 3 ) 2 ;
  • q is an integer of 0 to 4.
  • R 6 is:
  • cycloalkyl of from 5 to 8 carbons or
  • R 5 and R 6 when joined by a bond, can form a ring
  • R 6 is also
  • Prodrugs of the above are also contemplated such as would occur to one skilled in the art; see Bundgaard, et al, Acta Pharm Suec, 1987; 24: 233-246.
  • a suitable moiety may be attached to a nitrogen of the linker X, to the nitrogen of the NR 9 linker, or that of an indolyl radical of R 4 .
  • Preferred compounds of the invention are those of Formula I above wherein
  • m is an integer from 1 to 3;
  • cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with up to one or two substituents selected from OH,
  • R 5 and R 6 when joined by a bond can form a ring.
  • benzoxazolyl where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or —CF 3 ,
  • R 1 and R 2 are each H;
  • m is an integer from 1 to 3;
  • X is NR 8 or NHCONH, where R 8 is H or methyl;
  • R 9 is hydrogen or alkyl of 1 to 3 carbon atoms
  • benzimidazolyl where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
  • R 5 and R 6 when joined by a bond, can form a ring.
  • R 3 is hydrogen or methyl
  • X is NH or NHCONH
  • R 5 and R 7 independently are hydrogen or CH 2 R 10 , where R 10 is H, CH 3 or OH;
  • the invention additionally provides pharmaceutical formulations comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier, diluent or excipient therefor. Especially preferred formulations comprise a compound of Formula II.
  • the invention also provides a method for antagonizing NK 1 receptors in a mammal comprising administering to a mammal an NK 1 binding amount of a compound of Formula I.
  • the invention further provides a method for treating a CNS disorder including pain, anxiety, depression, obesity, or schizophrenia; an allergic or inflammatory disease; a gastrointestinal disorder; a vascular disorder; or a neuropathological disorder including emesis; comprising administering to a mammal in need of treatment an effective amount of a compound of Formula I.
  • An especially preferred method of treatment utilizes a compound of Formula II.
  • alkyl means a straight or branched hydrocarbon having from one to 12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl, dodecyl, and the like unless stated specifically otherwise.
  • cycloalkyl means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl except as otherwise stated.
  • alkoxy means an alkyl as described above attached through an oxygen atom.
  • halogen is chlorine, bromine, fluorine or iodine.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandalate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like. For example, see Berge S. M., et al., Pharmaceutical Salts
  • the acid addition salts of the compounds of Formula I are prepared by contacting the free base form of the compound with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • a compound of Formula I can be converted to an acidic salt by treating an aqueous solution of the desired acid, such that the resulting pH is less than four.
  • the solution can be passed through a C18 cartridge to absorb the compound, washed with copious amounts of water, the compound eluted with a polar organic solvent such as, for example methanol, acetonitrile, aqueous mixtures thereof, and the like, and isolated by concentrating under reduced pressure followed by lyophilisation.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for the purpose of the present invention.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example intranasally.
  • the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of the compound of Formula I.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, pills, tablets, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances that may also act as diluents, flavouring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid that is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% or 10% to about 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 200 mg, preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the highly selective and competitive antagonists of the NK 1 receptor and compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg/kg to about 500 mg/kg daily.
  • a daily dose range of about 0.01 mg/kg to about 100 mg/kg is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller doses, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • the compounds of Formula I can be prepared by any several synthetic processes well known to those skilled in the art of organic chemistry.
  • the coupling can be achieved by routine acylation, e.g. by converting the acid to an acid halide, followed by reaction with the amine, or by utilizing a common coupling reagent such as 1,3 -dicyclohexylcarbodiimide (DCC) or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ).
  • DCC 1,3 -dicyclohexylcarbodiimide
  • EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
  • the synthesis can be carried out on racemic reactants, to provide invention compounds in racemic form, which can then be resolved by conventional methods, if desired.
  • the invention compounds can be prepared in optically active form by using enantiomeric reactants.
  • an optically active acetic acid is first prepared by conventional methods.
  • Schemes 1-5 illustrate the preparation of intermediates utilized in Examples 1-5, which illustrate the synthesis of specific compounds of Formula I in optically active form.
  • Scheme 1 describes the synthesis of intermediates I and II, which are required for Examples 1 to 5.
  • the N-terminal benzofuran moiety is introduced by the reductive amination of either tryptophan methyl ester or alpha-methyl-tryptophan methyl ester with benzofuran-2-carboxaldehyde and sodium triacetoxy borohydride in DCM.
  • the methyl ester is then hydrolyzed to the corresponding carboxylic acid with lithium hydroxide.
  • Scheme 2 describes the synthesis of intermediate III. 3-Acetyl-l-methyl pyrrole is converted to the corresponding oxime by reaction with hydroxylamine sulfate and potassium hydroxide in water/methanol. The oxime is then reduced on palladium on carbon.
  • Scheme 3 shows the synthesis of intermediate IV.
  • This compound was prepared from (R)-2-phenylglycinol, which was first N-terminal protected as the carbobenzoxy (CBZ) analogue. The alcohol was then treated with triethylamine and methane sulfonylchloride, followed by dimethylamine to introduce the tertiary amine. Removal of the CBZ protection with hydrogen over Pearlman's catalyst gave the required intermediate.
  • Scheme 4 describes the synthesis of Examples 1 to 4. Each was prepared by activation of the acid, intermediate I, with HBTU in the presence of DIPEA and then reacting with the required amine in DMF.
  • Example 5 The synthesis of Example 5 is outlined in scheme 5. Intermediate I was activated with HBTU in DMF and then coupled with methoxybenzylamine. The methyl ether was then reduced with boron tribromide in DCM.
  • Boc-tryptophan was coupled to alpha-methylbenzylamine using HBTU activation.
  • the Boc group was removed using formic acid in DCM to give Intermediate V.
  • Examples 6, 8 and 10 to 21 were prepared by a reductive amination of the relative aldehydes and Intermediate V with sodium triacetoxyborohydride as shown in scheme 7.
  • Example 22 The synthesis of Example 22 is described in scheme 11. 2-benzofurancarboxaldehyde was reacted with hydroxylamine in aqueous potassium hydroxide/EtOH. The oxime was then reduced with lithium aluminum hydride to give the amine. The corresponding isocyanate, prepared by reacting the amine with triphosgene in DCM/pyridine, was reacted with 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide to give Example 22.
  • Scheme 12 shows the synthesis of the key intermediate VII that was used in the synthesis of Examples 192 to 308.
  • This N-carboxyanhydride was prepared by reacting intermediate I with phosgene in toluene.
  • N-methylmorpholine NMM, 5.31 g, 52.5 mmol
  • THF THF
  • 2-benzofuranacetic acid 8.80 g, 50 mmol
  • ethyl chloroformate 5.70 g, 52.5 mmol
  • THF 150 mL, anhydrous
  • the reaction mixture was stirred for 1 h at room temperature before filtering off the precipitate of NMM.HCl.
  • the filtrate was cooled to 0° C. and a solution of lithium borohydride (30 mL, 60 mmol, 2M in THF) was added dropwise over 30 min.
  • reaction was refluxed for 48 h, a further equivalent of NEt 3 was added, and reflux was continued for a further 48 h.
  • the reaction mixture was cooled and washed with 1N NaOH, the organic layer was dried (MgSO 4 ), and solvent removed under reduced pressure.
  • the residue was purified by chromatography on normal phase silica using 20% EtOAc in heptane as eluent and then on reverse phase silica using 70% MeOH in H 2 O as elan.
  • step 2 The product from step 1 (174 mg, 1 mmol) and intermediate V (307 mg, 1 mmol) were dissolved in DMF (10 mL, anhydrous) and stirred at 60° C. for 10 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on reverse phase silica using 60% MeOH in H 2 O as eluent.
  • the aqueous phase was extracted with CH 2 Cl 2 (100 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO 4 ), and the solvent was removed under reduced pressure. The residue was initially purified by chromatography on normal phase silica using 95% EtOAc in heptane as eluent. The solvent was removed under reduced pressure and the residue was dissolved in aqueous acetonitrile and acidified using formic acid. Purification by chromatography on reverse phase silica using 25% CH 3 CN in H 2 O (0.1% formic acid in mobile phases) as eluent gave pure product. The solvent was removed under reduced pressure and the residue was suspended between EtOAc and saturated NaHCO 3 .
  • a 40-well DTI synthesizer rack (U.S. Pat. No. 5,324,483) was loaded with 40 DTI vials (12 mL). To each vial 0.15-0.21 mmol of an amine or amine HCl salt was added. The rack was placed in a Cyberlab Liquid Handling Robot and to each vial 0.10 mmol N-[b]benzofuranylmethyl-R- ⁇ -methyl-tryptophan-N-carboxyanhydride (0.227 M in THF) was added. To those vials that contained amine HCl salts, 0.15 mmol triethylamine (0.254 M in THF) was added, in order to liberate the free amines.
  • THF was then added to each vial to make up the total volume to 3 mL.
  • the vials were placed in a 40-well DTI synthesizer equipped with a heating block, 40 condensers and a nitrogen manifold.
  • the synthesizer was kept under a continuous flow of nitrogen and was shaken at 65° C. on an orbital shaker for 2 days.
  • the reactions were monitored by TLC (10% CH 3 CN in CH 2 Cl 2 ).
  • the vials in which the reaction had gone to completion were taken out.
  • CH 3 CN (2 mL) was added each and these were shaken at 85° C. for 19 h.
  • the vials in which the reaction had gone to completion were taken out.
  • a 40-well DTI synthesizer rack was loaded with 40 Kimble vials (10 mL). To each vial approximately 0.34 g (0.10 mmol) N-[b]benzofuranylmethyl-R-tryptophan was added followed by 1.5 equivalent of an amine or amine HCl salt. The rack was placed in a Cyberlab Liquid Handling Robot and to each vial 1.0 equivalent of HBTU (0.4 M in DMF) was added followed by 1.5 equivalent of diisopropylethylamine (0.5 M in DMF). To those vials, which contained amine HCl salts, an additional equivalent of diisopropylethylamine was added. DMF was added to make the total volume up to 1.5 mL.
  • the vials were capped and the rack was shaken on an orbital shaker at room temperature for 3 h.
  • water (1 mL) was added and the mixtures were purified on 3 mL LC-18 reversed phase SPE cartridges containing 500 mg of sorbent, using an ASPEC XL4 robot.
  • the cartridges were conditioned with methanol (4 mL) followed by methanol/water 1:1 (4 mL).
  • Water (1 mL) was loaded onto the cartridges and the crude reaction mixtures were loaded into the water layer.
  • the cartridges were washed with water (4 mL) and methanol/water 1:1 (4 mL) and were eluted with methanol (4 mL).
  • the methanol fractions were concentrated and the products were subjected to LC-MS. Those products which did contain the desired molecular ion, but were not sufficiently pure (typically ⁇ 90%) were further purified by prep HPLC on a C18 reversed phase preparative column. The HPLC-purified products were re-analyzed by LC-MS to determine the purity. The 40 final products were analyzed by 1 H NMR.
  • the compounds are potent ligands to the NK 1 receptor, they are effective at displacing substance P at that position, and therefore are useful for treating biological conditions otherwise mediated by substance P. Accordingly, compounds capable of antagonising the effects of substance P at NK 1 receptors will be useful in treating or preventing a variety of brain disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, and addiction disorders; inflammatory diseases such as arthritis, asthma, and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis.
  • pain inflammatory, surgical and neuropathic
  • anxiety anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders,
  • NK 1 receptor antagonists are also useful as anti-angiogenic agents, for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NK 1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
  • the compounds of the present invention are highly selective and competitive antagonists of the NK 1 receptor. They have been evaluated in an NK 1 -receptor binding assay which is described below.
  • Human lymphoma IM9 cells were grown in RPMI 1640 culture medium supplemented with 10% fetal calf serum and 2 mM glutamine and maintained under an atmosphere of 5% CO 2 . Cells were passaged every 3-4 days by reseeding to a concentration of 4-8 ⁇ 10 6 /40 ml per 175 cm 2 flask. Cells were harvested for experiments by centrifugation at 1000 g for 3 min.
  • Pelleted cells were washed once by resuspension into assay buffer (50 mM Tris HCl pH 7.4, 3 mM MnCl 2 , 0.02% BSA, 40 mg/mL bacitracin, 2 mg/mL chymostatin, 2 mM phosphoramidon, 4 mg/mL leupeptin) and repeating the centrifugation step before resuspending at a concentration of 2.5 ⁇ 10 6 cells/mL assay buffer.
  • Cells 200 ml
  • Non-specific binding (10% of the total binding observed under these conditions) was defined by 1 mM [Sar 9 , Met(0 2 ) 11 ] substance P. Reactions were terminated by rapid filtration under vacuum onto GF ⁇ C filters presoaked in 0.2% PEI for 1-2 h, using a Brandel cell harvester. Filters were washed with 6 ⁇ 1 ml ice-cold Tris HCl (50 mM, pH 7.4) and radioactivity bound determined using a gamma counter. Results were analyzed using iterative curve fitting procedures in RS1 or Graphpad Inplot.
  • Tablet Formulation Ingredient Amount 3-[(benzofuran-2-ylmethyl)-amino]-3 -(IH-indol-3-yl)-2- 50 mg methyl-N-(1-phenyl-ethyl)-propionamide,[R-(R*, S*)] potato starch 100 mg talc 50 mg magnesium carbonate 20 mg dextrose 20 mg 240 mg
  • the ingredients are blended to uniformity and encapsulated into gelatin telescoping capsules.
  • the capsules are administered to a human at the rate of one to three each day for treatment of rheumatoid arthritis, atheroclerosis, aberrant neovascularization, and for the inhibition of tumor cell growth.

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Abstract

Non-peptide acetamide derivatives of Formula I are specific NK1 antagonists,
Figure US20030065007A1-20030403-C00001
where R is aryl, R1 and R2 are H or alkyl, m, n and q are integers from 0 to 4, X is NR8 or NHCONH, R3 and R9 are H or alkyl, R4 is naphthyl or indolyl, R5 and R2 are H or alkyl, and R6 is aryl.
The compounds are useful agents for treating inflammatory and allergic disorders, pain, anxiety, depression, schizophrenia and emesis.

Description

    BACKGROUND OF THE INVENTION
  • The neurokinins are a family of mammalian neuropeptides that are involved with numerous biological activities such as pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system, and neurogenic inflammation. One such neuropeptide known as substance P is widely distributed throughout the peripheral and central nervous system of mammals, and is known to mediate a variety of biological actions via interaction with three neurokinin (NK or tachykinin) receptor types known as NK[0001] 1, NK2, and NK3.
  • Substance P binds with higher affinity to the NK[0002] 1 receptor than it does to the other receptors. Accordingly, compounds capable of antagonizing the effects of substance P at the NK1 receptor are useful for treating and controlling disorders mediated by such interactions, including disorders such as anxiety, pain, depression, schizophrenia, and emesis.
  • Since 1991, a number of high-affinity nonpeptide tachykinin antagonists have been reported; for a review see Sprecher A, et al ([0003] IDrugs, 1:73-91, 1998).
  • U.S. Pat. Nos. 5,594,022 and 5,716,979 describe nonpeptides that are relatively specific NK[0004] 1 antagonists.
  • Since substance P mediate various biological actions, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-constriction, activation of the immune system and neurogenic inflammation via an interaction with NK receptors, preferably NK[0005] 1, thus compounds capable of antagonising the effects of substance P at NK1 receptors will be useful in treating or preventing a variety of: brain disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity and addiction disorders; inflammatory diseases such as arthritis, asthma, bronchitis and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis.
  • The compounds of the invention, NK[0006] 1 receptor antagonists, are useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NK1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
    • SUMMARY OF THE INVENTION
  • This invention provides NK[0007] 1 receptor antagonists characterized as non-peptide acetamide derivatives. The compounds of the invention differ from those of U.S. Pat. Nos. 5,716,979 or 5,594,022 in that the compounds of Formula I below are not (N-substituted aryl-methyl) carbamates, i.e. they do not have a —O—C(O)—N— link in the backbone; certain final products being more stable than known compounds, they should show improved oral bioavailability and improved CNS penetration. The invention compounds are defined by Formula I:
    Figure US20030065007A1-20030403-C00002
  • and the pharmaceutically acceptable salts thereof, wherein [0008]
  • ▪, , and ▴ indicate all stereoisomers, [0009]
  • R is: [0010]
  • pyridyl, [0011]
  • thienyl, [0012]
  • furyl, [0013]
  • pyrrolyl, [0014]
  • pyrazolyl, [0015]
  • quinolyl, [0016]
  • isoquinolyl, [0017]
  • naphthyl, [0018]
  • indolyl, [0019]
  • benzofuryl, [0020]
  • benzothiophenyl, [0021]
  • benzimidazolyl, and [0022]
  • benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, —CF[0023] 3, carboxy, sulfonamide, or nitro;
  • R can also be: [0024]
    Figure US20030065007A1-20030403-C00003
  • R[0025] 1 and R2 are each independently H or C1-C4 alkyl;
  • m is an integer from 0 to 3; [0026]
  • X is NHCONH, or NR[0027] 8 where R8 is H or C1-C4 alkyl;
  • R[0028] 3 is hydrogen or C1-C4 alkyl;
  • n is an integer from 1 to 2; [0029]
  • R[0030] 4 is naphthyl or indolyl, wherein said groups are unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy or formyl;
  • R[0031] 9 is hydrogen or C1-C4 alkyl;
  • R[0032] 5 and R7 are each independently hydrogen or (CH2)pR10 where:
  • P is an integer of 1 to 3, and [0033]
  • R[0034] 10 is H, CH3, CN, OH, OCH3, CO2CH3, NH2, NHCH3, or N(CH3)2;
  • q is an integer of 0 to 4; [0035]
  • R[0036] 6 is
  • phenyl, [0037]
  • pyridyl, [0038]
  • thienyl, [0039]
  • furyl, [0040]
  • pyrrolyl, [0041]
  • pyrazolyl, [0042]
  • imidazolyl, [0043]
  • quinolyl, [0044]
  • isoquinolyl, [0045]
  • naphthyl, [0046]
  • indolyl, [0047]
  • benzofuryl, [0048]
  • benzothiophenyl, [0049]
  • benzimidazolyl, or [0050]
  • benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or [0051]
  • trisubstituted by [0052]
  • alkyl, [0053]
  • hydroxy, [0054]
  • alkoxy, [0055]
  • halogen, [0056]
  • CF[0057] 3,
  • NO[0058] 2,
  • N(CH[0059] 3)2,
  • OCF[0060] 3,
  • SONH[0061] 2,
  • NH[0062] 2,
  • CONH[0063] 2,
  • CO[0064] 2CH3, or
  • CO[0065] 2H,
  • or R[0066] 6 is:
  • straight alkyl of from 1 to 3 carbons, [0067]
  • branched alkyl of from 3 to 8 carbons, [0068]
  • cycloalkyl of from 5 to 8 carbons or [0069]
  • heterocycloalkyl, [0070]
  • each of which can be substituted with up to one or two substituents selected from [0071]
  • OH, [0072]
  • CO[0073] 2H,
  • N(CH[0074] 3)2,
  • NHCH[0075] 3 and
  • CH[0076] 3; and
  • R[0077] 5 and R6, when joined by a bond, can form a ring;
  • R[0078] 6 is also
    Figure US20030065007A1-20030403-C00004
  • where X[0079] 1 represents the rest of the molecule.
  • Prodrugs of the above are also contemplated such as would occur to one skilled in the art; see Bundgaard, et al, [0080] Acta Pharm Suec, 1987; 24: 233-246. For example, a suitable moiety may be attached to a nitrogen of the linker X, to the nitrogen of the NR9 linker, or that of an indolyl radical of R4.
  • Preferred compounds of the invention are those of Formula I above wherein [0081]
  • R is [0082]
  • pyridyl, [0083]
  • thienyl, [0084]
  • furyl, [0085]
  • quinolyl [0086]
  • isoquinolyl [0087]
  • naphthyl, [0088]
  • indolyl, [0089]
  • benzofuryl, [0090]
  • benzothiophenyl, [0091]
  • benzimidazolyl, [0092]
  • benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or [0093]
  • trisubstituted by alkyl, hydroxy, alkoxy, halogen, or CF[0094] 3,
    Figure US20030065007A1-20030403-C00005
  • m is an integer from 1 to 3; [0095]
  • R[0096] 6 is
  • phenyl [0097]
  • pyridyl, [0098]
  • thienyl, [0099]
  • furyl, [0100]
  • pyrrolyl, [0101]
  • quinolyl, [0102]
  • isoquinolyl, [0103]
  • naphthyl, [0104]
  • indolyl, [0105]
  • benzofuryl, [0106]
  • benzothiophenyl, [0107]
  • benzimidazolyl, or [0108]
  • benzoxazolyl, [0109]
  • wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by [0110]
  • alkyl, [0111]
  • hydroxy, [0112]
  • alkoxy, [0113]
  • halogen, [0114]
  • CF[0115] 3,
  • NO[0116] 2
  • N(CH[0117] 3)2,
  • OCF[0118] 3,
  • SONH[0119] 2,
  • NH[0120] 2,
  • CONH[0121] 2,
  • CO[0122] 2CH3, or
  • CO[0123] 2H,
  • cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with up to one or two substituents selected from OH, [0124]
  • CO[0125] 2H,
  • N(CH[0126] 3)2,
  • NHCH[0127] 3 and
  • CH[0128] 3; and
  • R[0129] 5 and R6 when joined by a bond can form a ring.
  • More preferred compounds of the invention are those of Formula I above wherein [0130]
  • R is [0131]
  • pyridyl, [0132]
  • thienyl, [0133]
  • furyl, [0134]
  • quinolyl, [0135]
  • naphthyl, [0136]
  • benzofuryl, [0137]
  • benzothiophenyl, [0138]
  • benzimidazolyl, or [0139]
  • benzoxazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or —CF[0140] 3,
    Figure US20030065007A1-20030403-C00006
  • R[0141] 1 and R2 are each H;
  • m is an integer from 1 to 3; [0142]
  • X is NR[0143] 8 or NHCONH, where R8 is H or methyl;
  • R[0144] 9 is hydrogen or alkyl of 1 to 3 carbon atoms;
  • R[0145] 6 is
  • phenyl, [0146]
  • pyridyl, [0147]
  • thienyl, [0148]
  • furyl, [0149]
  • pyrrolyl, [0150]
  • benzimidazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by [0151]
  • alkyl, [0152]
  • hydroxy, [0153]
  • alkoxy, [0154]
  • halogen, [0155]
  • CF[0156] 3,
  • NO[0157] 2,
  • N(CH[0158] 3)2;
  • cyclohexyl or heterocycloalkyl, with up to one or two substituents selected from [0159]
  • OH, [0160]
  • CO[0161] 2H,
  • N(CH[0162] 3)2,
  • NHCH[0163] 3 and
  • CH[0164] 3; and
  • R[0165] 5 and R6, when joined by a bond, can form a ring.
  • The most preferred compounds of the invention have Formula II: [0166]
    Figure US20030065007A1-20030403-C00007
  • wherein: [0167]
  • R is [0168]
  • benzofuryl, [0169]
  • benzoxazolyl, [0170]
  • 3-cyanophenyl, [0171]
  • 3-nitrophenyl, or [0172]
  • 3-trifluoromethylphenyl; [0173]
  • R[0174] 3 is hydrogen or methyl;
  • X is NH or NHCONH; [0175]
  • R[0176] 5 and R7 independently are hydrogen or CH2R10, where R10 is H, CH3 or OH;
  • R[0177] 6 is
  • phenyl, [0178]
  • substituted phenyl, [0179]
  • pyridyl, or, [0180]
  • cyclohexyl; [0181]
  • and the pharmaceutically acceptable salts thereof [0182]
  • Most preferred compounds of the invention are: [0183]
  • 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)][0184]
  • 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)][0185]
  • 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3 -yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide, [R—(R*,R*)][0186]
  • 2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, [R—(R*,R*)][0187]
  • [R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide [0188]
  • [R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide [0189]
  • 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-ethyl)-propionamide, [R—(R*,S*)][0190]
  • 2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)][0191]
  • 3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)][0192]
  • 3-(1 H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R—(R*,S*)][0193]
  • 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)][0194]
  • 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)][0195]
  • 2-[(Benzoxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide [0196]
  • 2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)], and [0197]
  • 2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]. [0198]
  • The invention additionally provides pharmaceutical formulations comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier, diluent or excipient therefor. Especially preferred formulations comprise a compound of Formula II. The invention also provides a method for antagonizing NK[0199] 1 receptors in a mammal comprising administering to a mammal an NK1 binding amount of a compound of Formula I. The invention further provides a method for treating a CNS disorder including pain, anxiety, depression, obesity, or schizophrenia; an allergic or inflammatory disease; a gastrointestinal disorder; a vascular disorder; or a neuropathological disorder including emesis; comprising administering to a mammal in need of treatment an effective amount of a compound of Formula I. An especially preferred method of treatment utilizes a compound of Formula II.
    • DETAILED DESCRIPTION OF THE INVENTION
  • Throughout this application, the following abbreviations have the meanings listed below: [0200]
    Boc tertiary butyloxycarbonyl
    DCE dichloroethane
    DCM dichloromethane
    HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium
    hexafluorophosphate
    DIPEA N,N-diisopropylethylamine
    DMF N,N-dimethylformamide
    DCC 1,3-dicyclohexylcarbodiimide
    EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
    EtOAc ethyl acetate
    EtOH ethanol
    MeOH methanol
    KOH potassium hydroxide
    DIBAL Diisobutylaluminium hydride
    NMM N-methyl-morpholine
    NMR nuclear magnetic resonance
    Trp Tryptophan
  • The term “alkyl” means a straight or branched hydrocarbon having from one to 12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, undecyl, dodecyl, and the like unless stated specifically otherwise. [0201]
  • The term “cycloalkyl” means a saturated hydrocarbon ring which contains from 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl except as otherwise stated. [0202]
  • The term “alkoxy” means an alkyl as described above attached through an oxygen atom. [0203]
  • The term “halogen” is chlorine, bromine, fluorine or iodine. [0204]
  • The ring formed by joining R[0205] 5 and R6 is from 4 to 6 atoms total and is unsubstituted.
  • The compounds of Formula I are capable of forming pharmaceutically acceptable acid addition salts. All of these forms are within the scope of the present invention. [0206]
  • Pharmaceutically acceptable acid addition salts of the compound of Formula I include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like as well as the salts derived from nontoxic organic acids, such as the aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandalate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like. For example, see Berge S. M., et al., Pharmaceutical Salts, [0207] J. Pharm. Sci., 66:1-19 (1977) incorporated herein by reference.
  • The acid addition salts of the compounds of Formula I are prepared by contacting the free base form of the compound with a sufficient amount of the desired acid to produce the salt in the conventional manner. Preferably, a compound of Formula I can be converted to an acidic salt by treating an aqueous solution of the desired acid, such that the resulting pH is less than four. The solution can be passed through a C18 cartridge to absorb the compound, washed with copious amounts of water, the compound eluted with a polar organic solvent such as, for example methanol, acetonitrile, aqueous mixtures thereof, and the like, and isolated by concentrating under reduced pressure followed by lyophilisation. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for the purpose of the present invention. [0208]
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. [0209]
  • Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R([0210] D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate mixtures thereof
  • The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. In addition, the compounds of the present invention can be administered by inhalation, for example intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of the compound of Formula I. [0211]
  • For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, pills, tablets, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavouring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. [0212]
  • In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component. [0213]
  • In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. [0214]
  • The powders and tablets preferably contain from 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0215]
  • For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify. [0216]
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. [0217]
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents as desired. [0218]
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose sodium carboxymethylcellulose, and other well-known suspending agents. [0219]
  • Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents and the like. [0220]
  • The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or it can be the appropriate number of any of these in packaged form. [0221]
  • The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 200 mg, preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. [0222]
  • In therapeutic use, the highly selective and competitive antagonists of the NK[0223] 1 receptor and compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg/kg to about 500 mg/kg daily. A daily dose range of about 0.01 mg/kg to about 100 mg/kg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller doses, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • The compounds of Formula I can be prepared by any several synthetic processes well known to those skilled in the art of organic chemistry. [0224]
    Figure US20030065007A1-20030403-C00008
  • In a typical synthesis, a carboxylic acid of the formula [0225]
  • is coupled to an amine of the formula [0226]
    Figure US20030065007A1-20030403-C00009
  • The coupling can be achieved by routine acylation, e.g. by converting the acid to an acid halide, followed by reaction with the amine, or by utilizing a common coupling reagent such as 1,3 -dicyclohexylcarbodiimide (DCC) or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ). The synthesis can be carried out on racemic reactants, to provide invention compounds in racemic form, which can then be resolved by conventional methods, if desired. Alternatively, the invention compounds can be prepared in optically active form by using enantiomeric reactants. [0227]
  • In a typical synthesis, an optically active acetic acid is first prepared by conventional methods. Schemes 1-5 illustrate the preparation of intermediates utilized in Examples 1-5, which illustrate the synthesis of specific compounds of Formula I in optically active form. Scheme 1 describes the synthesis of intermediates I and II, which are required for Examples 1 to 5. The N-terminal benzofuran moiety is introduced by the reductive amination of either tryptophan methyl ester or alpha-methyl-tryptophan methyl ester with benzofuran-2-carboxaldehyde and sodium triacetoxy borohydride in DCM. The methyl ester is then hydrolyzed to the corresponding carboxylic acid with lithium hydroxide. [0228]
  • Scheme 2 describes the synthesis of intermediate III. 3-Acetyl-l-methyl pyrrole is converted to the corresponding oxime by reaction with hydroxylamine sulfate and potassium hydroxide in water/methanol. The oxime is then reduced on palladium on carbon. [0229]
  • Scheme 3 shows the synthesis of intermediate IV. This compound was prepared from (R)-2-phenylglycinol, which was first N-terminal protected as the carbobenzoxy (CBZ) analogue. The alcohol was then treated with triethylamine and methane sulfonylchloride, followed by dimethylamine to introduce the tertiary amine. Removal of the CBZ protection with hydrogen over Pearlman's catalyst gave the required intermediate. [0230]
  • Scheme 4 describes the synthesis of Examples 1 to 4. Each was prepared by activation of the acid, intermediate I, with HBTU in the presence of DIPEA and then reacting with the required amine in DMF. [0231]
  • The synthesis of Example 5 is outlined in scheme 5. Intermediate I was activated with HBTU in DMF and then coupled with methoxybenzylamine. The methyl ether was then reduced with boron tribromide in DCM. [0232]
    Figure US20030065007A1-20030403-C00010
    Figure US20030065007A1-20030403-C00011
    Figure US20030065007A1-20030403-C00012
    Figure US20030065007A1-20030403-C00013
    Figure US20030065007A1-20030403-C00014
    • EXAMPLE 1 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-methyl-1-phenyl-ethyl)-propionamide, (R)
  • Step 1 [0233]
  • Alpha methyl tryptophan methyl ester (26.8 g, 0.115 mol) and benzofuran-2-carboxaldehyde (17.57 g, 0.115 mol) were dissolved in DCM (400 mL) under an atmosphere of nitrogen and sodium triacetoxyborohydride (34.12 g, 0.161 mol) was added portionwise over 20 min at 0° C. The mixture was stirred at room temperature for 2 h and then quenched by the addition of sat. NaHCO[0234] 3 (500 mL). The organic layer was collected and the aqueous layer was extracted three times with EtOAc. The organics were combined, dried (MgSO4), filtered, and evaporated to dryness. The residue was crystallized from ether/heptane to give the product (34.13 g, 82%); IR (film): 3410, 2948, 1724, 1455, 1253, 1104, 742cm−1; NMR (CDCl3)δ1.48 (3H, s); 3.18 (1H, d, J=14 Hz); 3.21 (1H, d, J=14 Hz); 3.53 (3H, s); 3.85 (1H, d, J=Hz); 3.92 (1H, d, J=14 Hz); 6.55 (1H, s); 7.04-7.59 (9H, m); 8.07 (1H, s); MS; ES+ 363, ES− 361.
  • Step 2. Intermediate I [0235]
  • The methyl ester from step one (24.94 g, 68.8 mmol) was dissolved in dioxan (800 mL) and aq. LiOH (8.66 g, 206 mmol in 400 mL) was added. The reaction mixture was stirred overnight at room temperature and then heated to 60° C. for 5 h. The mixture was reduced in vacuo to a volume of approximately 200 ml. Water (1200 mL) was added and the reaction was stirred vigorously while it was neutralized with 1N HCl. Ether (1200 mL) was added and the mixture was stirred for two h, the precipitate was filtered off, washed with water, ether and dried to give a white solid; (24.5 g, 100%); NMR (Dmso-d[0236] 6) 1.28 (3H, s); 3.05 (1H, d, J=14 Hz); 3.07 (1H, d, J=14 Hz); 3.33 (2H, br s); 3.87 (2H, s); 6.72 (1H, s); 6.97-7.07 (3H, m); 7.14 (1H, d, J=2 Hz); 7.18-7.33 (3H, m); 7.50-7.58 (3H, m); 10.89 (1H, s); MS; ES+ 349, ES− 347.
  • Step 3 [0237]
  • Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol), DIPEA (0.35 mL, 2 mmol) and cumylamine (0.20 g, 1.48 mmol) were stirred in DMF (25 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10% Na[0238] 2CO3, and brine. Drying and purification by column chromatography using 20% EtOAc/Heptane gave a white solid (0.285 g, 61%). mp=57-62° C.; NMR (CDCl3): δ1.40 (3H, s); 1.70 (6H, s); 1.92 (1H, b s); 3.17 and 3.22 (2H, 2×d, J=14.4,14.6); 3.82 and 3.89 (2H, 2×d, J=14.6, 14.1); 6.46 (1H, s); 7.02-7.68 (15H, m); 8.10 (1H, s); IR (film): 3317, 2987, 1661, 1506, 1455 cm−1; [α]D 23=26.1° (c=1, MeOH); MS(ES+) 466 (M+1); Analysis calculated for C30H31N3O2. 0.25H2O: C, 76.65; H, 6.75; N, 8.94%. Found: C, 76.73; H, 6.54; N, 8.80%.
    • EXAMPLE 2 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(1-methyl- 1H-pyrrol-3-yl)-ethyl]-propionamide, [R—(R*,R*)] and [R—(R*,S*)]
  • [0239]
    Figure US20030065007A1-20030403-C00015
  • Step 1 [0240]
  • 3-Acetyl-1-methyl pyrrole (2.00 g, 16.2 mmol) was dissolved in MeOH (60 mL) and treated with potassium hydroxide (4.10 g, 73 mmol) in water (10 mL) and hydroxylamine sulfate (4.00 g, 24.3 mmol) in water (10 mL) and stirred for 18 h. The methanol was removed in vacuo and the residue was diluted with water and extracted with EtOAc. Drying (MgSO[0241] 4) and evaporation gave an off-white solid (1.82 g, 81%). (E:Z=9:1); NMR (CDCl3): δ2.17 (3H, s); 3.65 (3H, s); 3.69 (3H, s); 6.39 (1H, m); 6.46 (1H, m); 6.56 (1H, m); 6.58 (1H, m); 6.85 (1H, m); 7.59 (1H, m); 8.10 (1H, bs); IR(film): 3240, 2916, 1644, 1554, 1422, 1257, 892cm−1;
  • Step 2 Intermediate III [0242]
  • The oxime from step one (0.25 g, 1.8 mmol) was dissolved in methanol and 10% Palladium on carbon (50 mg) was added. The mixture was shaken under an atmosphere of hydrogen at 35 psi and at 30° C. for 5 h. Filtering through Kieselguhr and evaporation gave a colorless oil (220 mg) which was a mixture of starting material and product ˜1:1. The crude, intermediate III was used in step 3. [0243]
  • Step 3 [0244]
  • Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol), DIPEA (0.35 mL, 2 mmol) and the amine (Intermediate III) (220 mg, 1.8 mmol) were stirred in DMF (13 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10%Na[0245] 2CO3, and brine. Drying and purification by column chromatography using 20% EtOAc/Heptane followed by reverse phase chromatography using 50-100% MeOH/H2O gave a white solid (0.205 g, 45%); mp=53-57° C.; NMR (CDCL3): δ1.35 and 1.43 (3H, 2×d, J=6.6 and 6.6 Hz); 1.45 (obs H2O) and 1.5 (3H, 2×s); 1.89 (1H, bs); 3.21 and 3.22 (2H, 2×s,); 3.49 and 3.54 (3H, 2×s); 3.72-3.86 (2H, 2×AB, J=14.4,14.4); 5.05 (1H, m); 6.00 (1H, m); 6.34-7.72 (13H, m); IR (film): 3278, 2969, 1648, 1507, 1455 cm−1; MS(ES+): 455(M+H) Analysis calculated for C28H30N4O4; C, 73.98; H, 6.65; N,12.32%. Found: C, 73.69; H, 6.44; N, 12.12%.
    • EXAMPLE 3 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl) -propionamide, [R—(R*,S*)]
  • [0246]
    Figure US20030065007A1-20030403-C00016
  • Intermediate I (0.174 g, 0.5 mmol), HBTU (0.190 g, 0.5 mmol), DIPEA (0.348 mL, 2 mmol) and the amine (prepared as described in U.S. Pat. No. 5,594,022) (252 mg, 0.6 mmol) were stirred in DMF (25 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10%Na[0247] 2CO3, and brine. Drying and purification by column chromatography using 3%MeOH/DCM gave a white solid (0.14 g, 62%). mp=66-69° C.; NMR (CDCl3): δ1.44(3H,d, J=7.2 Hz); 1.50 (3H, s); 1.96 (1H, bs) 3.12 (1H, d, J=14.4 Hz) and 3.23 (1H, d, J=14.4 Hz); 3.80 (1H, d, J=14.2 Hz) and 3.92(1H, d, J=14.2 Hz); 5.02 (1H, m); 6.48 (1H, s); 6.89-8.00 (12H, m); 8.03 (1H, s); 8.46(2H, m); IR (film) 3326, 2978, 1660, 1602, 1505, 1455 cm−1; MS(ES+) 453 (M+1); [α]D 23=−29.0° (c=0.39, MeOH); Analysis calculated for C28H28N4O2. 0.2H2O: C, 73.73; H, 6.28; N, 12.28% Found: C, 73.76; H, 6.2; N, 12.08%.
    • EXAMPLE 4 2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-dimethylamino-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, (R,R)
  • [0248]
    Figure US20030065007A1-20030403-C00017
  • Step 1 [0249]
  • To a solution of (R)-2-phenyl glycinol (2.11 g, 15 mmol) and benzyl chloroformate (2.35 mL, 16.5 mmol) in THF (30 mL) at 0° C. was added triethylamine (2.30 mL, 16.5 mmol) in THF (5 mL). After stirring for 18 h at room temperature, the mixture was filtered and evaporated to a white solid which was purified by column chromatography on silica using 50% EtOAc/heptane, giving a white solid (4.00 g, 98%); NMR (CDCl[0250] 3): δ3.88 (2H, m); 4.85 (1H, m); 5.10 (2H, m); 5.48 (1H, m); 7.23-7.40 (10H, m); IR (film): 3324, 2950, 1687, 1540, 1259 cm−1;
  • Step 2 [0251]
  • To a solution of the alcohol from step one (1.00 g, 3.68 mmol) and triethylamine (1.16 mL, 8 mmol) in THF (20mL) was added a solution of methane sulphonylchloride (0.31 mL, 4.0 mmol) in THF (3 mL). The mixture was stirred for 1 h. 2M dimethylamine in THF solution. (1 7 mL, 34 mmol) was added and the sealed mixture was stirred for 12 days. Evaporation of the solvent and purification by column chromatography using 2% MeOH/DCM gave a yellow oil (0.399 g, 36%); NMR (CDCl[0252] 3): δ2.23 (6H, s); 2.35-2.58 (2H, m); 4.64 (1H, bs); 5.06 (2H, m); 5.77 (1H, bs); 7.20-7.40 (10 H, m); IR (film): 3330, 2945, 1716, 1538, 1246, 1050 cm−1.
  • Step 3 Intermediate IV [0253]
  • The protected amine from step one (0.226 g, 0.75 mmol) was dissolved in methanol (30 mL) and Pearlman's catalyst (30 mg) was added. The mixture was shaken for 2 h at 50 psi and then filtered through kieselguhr. Evaporation gave a yellow syrup (0.127 g, 100%); NMR (CDCl[0254] 3): δ2.22-2.51 (8H, m); 4.07 (1H, m); 7.22-7.39 (5H, m).
  • Step 4 [0255]
  • Intermediate I (0.174 g, 0.5 mmol), HBTU (0.19 g, 0.5 mmol), DIPEA (0.174 mL, 1.0 mmol) and the amine (Intermediate IV) (0.12 mg, 0.73 mmol) were stirred in DMF (15 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10% Na[0256] 2CO3, and brine. Drying and purification by column chromatography using 1% MeOH/DCM and reverse phase chromatography using 40-100% MeOH/H2O gave a white solid (0.10 g, 40%). mp=130-134° C.; NMR (CDCl3) δ1.44 (3H, s); 2.16 (6H, s); 2.41 (1H, dd, J=5.6, 12.4 Hz) and 2.59 (1H, dd, H=10.0, 12.4); 3.17 (2H, s); 3.86 (1H, d, 14.4 Hz) and 3.92 (1H, d, J=14.6 Hz); 4.95 (1H, m); 6.55 (1H, s); 6.90 (1H, s); 7.09-7.67 (13H, m); 8.01 (1H, s); 8.18, d, J=6.6 Hz); IR (film) 3317, 2934, 1658, 1496, 1455 cm−1; MS(ES+) 482 (M+1); [α]D 23=31.9 (c=0.72, MeOH); Analysis calculated for C31H34N4O2: C, 75.28; H, 6.93; N, 11.33% Found: C, 75.24; H, 6.92; N, 11.15%.
    • EXAMPLE 5 2-[(Benzofuran-2-ylmethyl)-amino]-N-(3-hydroxy-benzyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, R
  • [0257]
    Figure US20030065007A1-20030403-C00018
  • Step 1 [0258]
  • Intermediate I (0.348 g, 1 mmol), HBTU (0.379 g, 1 mmol), DIPEA (0.35 mL, 2 mmol) and 3-methoxybenzylamine (0.206 g, 1.5 mmol) were stirred in DMF (17 mL) for 18 h. The reaction mixture was evaporated and the residue taken up in EtOAc and washed with 10%Na[0259] 2CO3, and brine. Drying and purification by column chromatography using 40% EtOAc/Heptane gave a white solid (0.190 g; 41%). mp=42-47° C.; NMR (CDCl3): δ1.50 (3H, s); 1.90 (1H, bs); 3.20 (1H, d, J=14.4 Hz) and 3.28 (1H, d, J=14.4 Hz); 3.72-3.82 (4H, m); 3.88 (1H, d, J=14.0 Hz); 4.37 (2H, d, J=6.0 Hz); 6.37 (1H, s); 6.75-7.70 (14H, m); 8.12 (1H, s); IR (film): 3322, 2920, 1654, 1602, 1455, 1256 cm−1; MS(ES+) 468 (M+1); [α]D 23.5=−31.3° (c=1.01, MeOH); Analysis calculated for C29H29N3O3: C, 74.50; H, 6.25; N, 8.99%; Found: C, 74.20; H, 6.24; N, 8.78%
  • Step 2 [0260]
  • 1.0M Boron tribromide in dichloromethane (0.62 mL; 0.62 mmol) was added dropwise to a solution of the methoxy compound from step one (0.146 g; 0.31 mmol) in dichloromethane at −70° C. under N[0261] 2, warmed slowly to room temperature and stirred for 18 h. The mixture was poured onto 10 g crushed ice/2M HCl (15 mL) and stirred for 10 min. Neutralizing with Na2CO3, extraction with EtOAc and purification by column chromatography using 40% EtOAc/heptane gave a white solid (0.115 g; 82%). mp=60-69° C.; NMR (CDCl3): δ1.53 (3H, s); 1.96 (1H, bs); 3.14 (1H, d, J=14.4 Hz) and 3.37 (1H, d, J=14.4 Hz); 3.81 (1H, d, J=14.0 Hz) and 3.93 (1H, d, J=14.0 Hz); 4.14-4.50 (2H, m); 5.23 (1H, bs); 6.32-7.82 (15H, m); 8.14 (1H, s); IR (film): 3333, 2907, 1645, 1599, 1520, 1455, 1254 cm−1; MS(ES+): 454 (M+1); [α]D 23.5=−25.9° (c=0.73, MeOH); Analysis calculated for C28H27N3O3. 0.5 H2O: C, 72.71; H, 6.10; N, 9.08% Found: C, 72.83, 72.86; H, 6.03, 5.96; N, 8.81, 8.83%.
  • Scheme 6 describes the synthesis of intermediate V, which is required for Examples 6to 17. [0262]
  • Boc-tryptophan was coupled to alpha-methylbenzylamine using HBTU activation. The Boc group was removed using formic acid in DCM to give Intermediate V. [0263]
  • Examples 6, 8 and 10 to 21 were prepared by a reductive amination of the relative aldehydes and Intermediate V with sodium triacetoxyborohydride as shown in scheme 7. [0264]
  • Scheme 8 outlines the synthesis of Example 7. 2-Benzofuranacetic acid was reacted with ethyl chloroformate in THF and then reduced with lithium borohydride. The alcohol was then converted to the corresponding mesylate and reacted with Intermediate V to give Example7. [0265]
  • Scheme 9 describes the synthesis of Example 9. 2-Hydroxymethyl benzimidazole was reacted with bis(4-nitrophenyl)carbonate in DMF to form the cyclic carbamate. This compound was then reacted with intermediate V to give Example 9. [0266]
  • The synthesis of Intermediate VI is shown in scheme 10; the intermediate was used to prepare Example 10. Benzo[b]thiophene-2-carboxylic acid was activated with ethyl chloroformate and then coupled with N,O-dimethylhydroxylamine. The Weinreb amide was then reduced to the corresponding aldehyde with DIBAL. [0267]
  • The synthesis of Example 22 is described in scheme 11. 2-benzofurancarboxaldehyde was reacted with hydroxylamine in aqueous potassium hydroxide/EtOH. The oxime was then reduced with lithium aluminum hydride to give the amine. The corresponding isocyanate, prepared by reacting the amine with triphosgene in DCM/pyridine, was reacted with 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide to give Example 22. [0268]
  • Scheme 12 shows the synthesis of the key intermediate VII that was used in the synthesis of Examples 192 to 308. This N-carboxyanhydride was prepared by reacting intermediate I with phosgene in toluene. [0269]
    Figure US20030065007A1-20030403-C00019
    Figure US20030065007A1-20030403-C00020
    Example R1 R2
    6 H 2-Benzofuran-CH2
    8 H 2-(4,5-Dimethylfuran)-CH2
    10 H 2-Benzothiophene-CH2
    11 H 3-quinoline-CH2
    12 H 2-(5-Cl-thiophene)-CH2
    13 H (3-SCF3—Ph)—CH2
    14 H (3-CN—Ph)—CH2
    15 H (3-NO2—Ph)—CH2
    16 H (3-OCF3—Ph)—CH2
    17 H (3-OH—Ph)—CH2
    18 CH3 2-Benzofuran-CH2
    19 CH3 3-Benzofuran-CH2
    20 CH3 2-pyrrole-CH2
    21 CH3 3-pyrazole-CH2
  • [0270]
    Figure US20030065007A1-20030403-C00021
    Figure US20030065007A1-20030403-C00022
    Figure US20030065007A1-20030403-C00023
    Figure US20030065007A1-20030403-C00024
    Figure US20030065007A1-20030403-C00025
    • EXAMPLE 6 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0271]
    Figure US20030065007A1-20030403-C00026
  • Step 1. Intermediate V [0272]
  • To a stirred solution of Boc-(R)-Trp-OH (6.08 g, 0.02mol) in DMF (50 mL) was added HBTU (7.59, 0.02 mol) and DIPEA (3.57 mL, 0.02 mol). After 5 min DIPEA (3.57 mL, 0.02 mol) and (S)-(−)-α-methylbenzylamine in DMF (10 mL) was added. After a further 60 min, the solvent was removed under reduced pressure. The residue was taken up in EtOAc (250 mL) and washed with brine (50 mL), 1N HCl (100 mL), saturated NaHCO[0273] 3 (3×100 mL), brine (50 mL), dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and formic acid (30 mL). The reaction was stirred over night at room temperature before refluxing for 4 h. The solvent was removed under reduced pressure and the product was crystallized from ether. Stirring in EtOAc (100 mL) for 4 h and filtration gave pure product (4.17 g, 68%). The filtrate was purified by chromatography using EtOAc and then EtOAc/MeOH/NH3(aq) (95:5:0.5) as eluent. Crystallization from ether gave white crystalline solid (0.98 g , 16%); mp 142-144° C.; [αD 19=−83.9° (c=1, MeOH); IR (film): 3338, 3295, 3059, 2975, 2928, 1649, 1518, 1494, 1455, 1342, 1104, 894, 740 cm−1; NMR (CDCl3): δ1.44 (3H, d, J=7.1 Hz); 1.51 (2H, s); 2.95 (1H, d.d, J=14.4 and 8.5 Hz); 3.36 (1H, d,d, J=14.4 and 4.4 Hz); 3.74 (1H, d.d, J=8.5 and 4.4 Hz); 5.05-5.15 (1H, m); 6.95 (1H, d, J=2.2 Hz); 7.10-7.38 (8H, m); 7.48-7.52 (1H, m); 7.66-7.69 (1H, m); 7.98 (1H, s); MS m/e (APCI+): 309.1 (20%), 308.1 (100%, M++H); Analysis calculated for C19H21N3O: C, 74.24; H, 6.89; N, 13.66%. Found: C, 74.07; H, 6.87; N, 13.70%.
  • Step 2 [0274]
  • To a stirred solution of 2-benzofurancarboxaldehyde (0.73 g, 5 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (1.54 g, 5 mmol) followed by sodium triacetoxyborohydride (1.48 g, 7 mmol). After stirring for 3 h the reaction was cautiously quenched with saturated NaHCO[0275] 3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography using 30% EtOAc in heptane as eluent to give pure product as a glass (2.0 g, 91%); [αD]20=+34.0° (c=0.5, MeOH); IR (film): 3316, 3059, 2973, 2925, 1653, 1517, 1455, 1341, 1254, 1104, 1010, 909, 741 cm−1; NMR (CDCl3): δ1.38 (3H, d, J=7.1 Hz); 1.93 (1H, s); 2.92 (1H, d.d, J=14.6 and 9.3 Hz); 3.29-3.35 (1H, m); 3.58 (1H, d.d, J=9.3 and 4.2 Hz); 3.75 (1H, d, J=14.9 Hz); 3.82 (1H, d, J=14.9 Hz); 5.07-5.15 (1H, m); 6.36 (1H, s); 6.87 (1H, d, J=2.2 Hz); 7.04-7.08 (1H, m); 7.15-7.35 (10H, m); 7.43-7.45 (1H, m); 7.58-7.64 (2H, m); 7.92 (1H, s); MS m/e (APCI+): 439.9 (5%), 438.9 (34%), 437.9 (100%, M++H), 307.0 (9%); Analysis calculated for C28H27N3O2: C, 76.86; H, 6.22; N, 9.60%. Found: C, 77.11; H, 6.31; N, 9.67%.
    • EXAMPLE 7 2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0276]
    Figure US20030065007A1-20030403-C00027
  • Step 1 [0277]
  • A solution of N-methylmorpholine (NMM, 5.31 g, 52.5 mmol) in THF (30 mL) was added dropwise over 15 min to a stirred solution of 2-benzofuranacetic acid (8.80 g, 50 mmol) and ethyl chloroformate (5.70 g, 52.5 mmol) in THF (150 mL, anhydrous) at 0° C. The reaction mixture was stirred for 1 h at room temperature before filtering off the precipitate of NMM.HCl. The filtrate was cooled to 0° C. and a solution of lithium borohydride (30 mL, 60 mmol, 2M in THF) was added dropwise over 30 min. The reaction was allowed to reach room temperature and stirred over night before being cautiously quenched with 1N HCl (100 mL)—vigorous effervescence. The THF was removed under reduced pressure and the aqueous phase was extracted with EtOAc (200 mL). The organic phase was washed with 1N HCl, H[0278] 2O, saturated NaHCO3 (×2), brine, and dried (MgSO4). Removal of solvent under reduced pressure gave intermediate VI (7.74 g, 93%). Used in the next step without further purification. IR (film): 3347, 2957, 2887, 1603, 1587, 1455, 1422, 1317, 1252, 1167, 1105, 1049, 945, 926, 881, 854, 807, 751 cm−1; NMR (CDCl3): δ1.64 (1H, t, J=6.0 Hz); 3.05 (2H, t, J=6.2 Hz); 4.00 (2H, q, J=6.1 Hz); 6.51 (1H, d, J=1.0 Hz); 7.17-7.25 (2H, m); 7.41-7.44 (1H, m); 7.49-7.52 (1H, m).
  • Step 2 [0279]
  • To an ice-cold solution of alcohol VI (1.62 g, 10 mmol) and NEt[0280] 3 (1.01 g, 10 mmol) in ether (50 mL, anhydrous) was added a solution of methanesulphonyl chloride (1.20 g, 10.5 mmol) dropwise over 5 min. The ice bath was removed and the reaction was stirred at room temperature for 30 min before filtering off the NEt3.HCl. The ether was removed under reduced pressure. To a portion of the mesylate (240 mg, 1 mmol) dissolved in toluene (50 mL, anhydrous) was added amine V. The reaction was refluxed for 48 h, a further equivalent of NEt3 was added, and reflux was continued for a further 48 h. The reaction mixture was cooled and washed with 1N NaOH, the organic layer was dried (MgSO4), and solvent removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 20% EtOAc in heptane as eluent and then on reverse phase silica using 70% MeOH in H2O as elan. Product crystallized on drying in vacuum oven to give pure product (82 mg, 18%); mp 105-107° C.; [α]D 22=−1.2° (c=0.25, MeOH); IR (film): 3305, 3058, 2924, 2851, 1651, 1515, 1455, 1356, 1342, 1252, 1166, 1105,742 cm−1;NMR (CDCl3): δ1.37 (3H, d, J=7.1 Hz); 1.57 (1H, s); 2.72-2.97 (5H, m); 3.28-3.34 (1H, m); 3.44-3.48 (1H, m); 5.07-5.15 (1H, m); 6.06 (1H, s); 6.75 (1H, d, J=2.2 Hz); 7.06-7.33 (11H, m); 7.40-7.44 (1H, m); 7.51 (1H, d, J=8.5 Hz); 7.62-7.65 (2H, m); MS m/e (ES+): 453.1 (33%), 452.2 (100%, M++H); Analysis calculated for C29H29N3O2: C, 77.14; H, 6.47; N, 9.31%. Found: C, 77.06; H, 6.48; N, 9.30%.
    • EXAMPLE 8 2-[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0281]
    Figure US20030065007A1-20030403-C00028
  • To a stirred solution of the 4,5-dimethyl-2-furaldehyde (124 mg, 1 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (307 mg, 1 mmol) followed by sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over night the reaction was cautiously quenched with saturated NaHCO[0282] 3 (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 25% EtOAc in heptane as eluent to give pure product as a glass (196 mg, 47%); [α]D 21=+18.6° (c=0.5, MeOH); IR (film): 3312, 3059, 2971, 2922, 1651, 1516, 1455, 1342, 1220, 1106, 741 cm−1; NMR (CDCl3): δ1.44 (3H, d, J=6.8 Hz); 1.60-1.90 (1H, br.s); 1.83 and 2.06 (each 3H, s); 2.89 (1H, d,d, J=14.6 and 9.3 Hz); 3.26-3.32 (1H, m); 3.49 (1H, d, J=14.4 Hz); 3.50-3.54 (1H, m); 3.58(1H, d, J=14.4 Hz); 5.08-5.16 (1H, m); 5.76 (1H, s); 6.89 (1H, d, J=2.2 Hz); 7.01-7.11 (1H, m); 7.17-7.36 (7H, m); 7.62-7.65 (2H, m); 7.95 (1H, s); MS m/e (ES+): 417.3 (31%), 416.3 (100%, M++H), 308.3 (34%); Analysis calculated for C26H29N3O2.0.2H2O: C, 74.51; H, 7.07; N, 10.03%. Found: C, 74.43; H, 6.82; N, 10.03%.
    • EXAMPLE 9 2-[(1H-Benzoimidazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0283]
    Figure US20030065007A1-20030403-C00029
  • Step 1 [0284]
  • A solution of 2-hydroxymethyl benzimidazole (1.19 g, 8 mmol) and bis(4-nitrophenyl)carbonate (2.43 g, 8 mmol) in DMF (20 mL, anhydrous) was stirred for 12 h at room temperature. The DMF was removed under reduced pressure and the residue stirred in ether (50 mL) for 2 h. Filtration and washing with ether (50 mL) gave crystalline intermediate VII (1.04 g, 74%); IR (film): 1819, 1623, 1592, 1568, 1486, 1445, 1411, 1369, 1359, 1147, 1106, 1076, 1009, 997, 941, 862, 847, 765, 750, 741 cm[0285] −1; NMR (CDCl3): δ5.49 (2H, s); 7.42-7.50 (2H, m); 7.79-7.84 (1H, m); 7.88-7.93 (1H, m).
  • Step 2 [0286]
  • The product from step 1 (174 mg, 1 mmol) and intermediate V (307 mg, 1 mmol) were dissolved in DMF (10 mL, anhydrous) and stirred at 60° C. for 10 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on reverse phase silica using 60% MeOH in H[0287] 2O as eluent. The solvent was removed under reduced pressure and the residue was crystallized from EtOAc to give pure product (396 mg, 91%); mp 148-152.5° C.; [α]D 21=+24.2° (c=0.5, MeOH); IR (film): 3300, 3058, 2923, 1651, 1520, 1455, 1340, 1271, 1235, 1218, 1109, 1013, 909, 739 cm−1; NMR (CDCl3): δ1.31 (3H, d, J=7.1 Hz); 2.00-2.50 (1H, br.s); 3.04 (1H, d.d, J=14.4 and 8.8 Hz); 3.29 (1H, d.d, J=14.4 and 5.2 Hz); 3.50 (1H, d.d, J=8.8 and 5.2 Hz); 3.94 (1H, d, J=15.9 Hz); 4.04 (1H, d, J=15.9 Hz); 5.03-5.10 (1H, m); 6.85 (1H, d, J=7.8 Hz); 6.99 (1H, d, J=2.2 Hz); 7.10-7.30 (10H, m); 7.20-7.70 (1H, br.s); 7.42 (1H, d, J=8.1 Hz); 7.66 (1H, d, J=7.8 Hz); 8.06 (1H, s); 8.80-9.20 (1H, br.s); MS m/e (ES+): 439.3 (28%), 438.3 (100%, M++H); Analysis calculated for C27H27N5O: C, 74.12; H, 6.22; N, 16.01%. Found: C, 74.04; H, 6.19; N, 15.95%.
    • EXAMPLE 10 2-[(Benzo[b]thiophen-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide
  • [0288]
    Figure US20030065007A1-20030403-C00030
  • Step 1 [0289]
  • A solution of NMM (2.309 mL, 21 mmol) in THF (10 mL) was added dropwise to a stirred ice cooled solution of benzo[b]thiophene-2-carboxylic acid (3.56 g, 20 mmol) and ethyl chloroformate (2.008 mL, 21 mmol) in THF (150 mL) over 15 mins. The reaction mixture was stirred at room temperature for 1 h before adding N,O-dimethylhydroxylamine hydrochloride (2.146 g, 22 mmol) and NMM (2.419 mL, 22 mmol). The reaction was stirred at room temperature over night. The solvent was removed under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with 2N HCl (3×100 mL), 2N NaOH (100 mL), H[0290] 2O, brine, dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 30% EtOAc in heptane as eluent. Crystallization from ether/heptane gave pure product (3.24 g, 73%).
  • To a stirred solution of the Weinreb amide (2.06 g, 9.3 mmol) in THF (100 mL, anhydrous) under nitrogen at 0° C. was added diisobutylaluminum hydride (11 mL, 11 mmol, 1M in CH[0291] 2Cl2) dropwise. After 20 min the reaction mixture was poured onto ice cold 2N HCl and extracted with ether. The organic phase was washed with brine, dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 5% EtOAc in heptane as eluent to give solid benzo[b]thiophene-2-carboxaldehyde (Intermediate VI) (665 mg, 44%). IR (film): 1669, 1592, 1516, 1431, 1255, 1224, 1135, 840, 747, 725 cm−1; NMR (CDCl3): δ7.42-7.54 (2H, m); 7.91 (1H, d, J=8.1 Hz); 7.95(1H, d, J=7.8 Hz); 8.04 (1H, s); 10.12 (1H, s).
  • Step 2 [0292]
  • To a stirred solution of the benzo[b]thiophene-2-carboxaldehyde (Intermediate VI) (162 mg, 1 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (307 mg, 1 mmol) followed by sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over night the reaction was cautiously quenched with saturated NaHCO[0293] 3 (20 mL) and extracted with CH2Cl2 (2×20 mL).
  • The combined organic phases were dried (MgSO[0294] 4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 20% EtOAc in heptane as eluent. Crystallization from ether/heptane gave pure product (305 mg, 67%); mp 102-108° C.; [α]D 21=+51.4° (c=0.5, MeOH); IR (film): 3311, 3059, 2925, 1651, 1515, 1456, 743 cm−1; NMR (CDCl3): δ1.40 (3H, d, J=7.1 Hz); 1.97 (1H, s); 2.99 (1H, d.d, J=14.7 and 8.8 Hz); 3.35 (1H, d.d, J=14.4 and 4.2 Hz); 3.59 (1H, d.d, J=8.5 and 4.4 Hz); 3.94 (2H, m); 5.07-5.16 (1H, m); 6.91-6.93 (2H, m); 7.06-7.11 (1H, m); 7.17-7.37 (9H, m); 7.50 (1H, d, J=8.5 Hz); 7.60 (1H, d.d, J=7.0 and 1.6 Hz); 7.65 (1H, d, J=8.1 Hz); 7.72-7.76 (1H, m); 7.95 (1H, s); MS m/e (ES+): 476.1 (60%, M++Na), 454.1 (100%, M++H), 402.2 (25%); (ES−): 453.2 (25%), 452.1 (100%, M−−H); Analysis calculated for C28H27N3OS: C, 74.14; H, 6.00; N, 9.26; S, 7.07%. Found: C, 74.27; H, 6.16; N, 9.31; S, 7.11%.
    • EXAMPLE 11 3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-[(quinolin-3-ylmethyl)-amino]-propionamide, [R—(R*,S*)]
  • [0295]
    Figure US20030065007A1-20030403-C00031
  • Method as for Example 10, step 2. The residue was purified by chromatography on normal phase silica using 2% MeOH in CH[0296] 2Cl2 as eluent. Crystallization from EtOAc/heptane gave pure product (340 mg, 76%); mp 161-163° C.; [α]D 22=+40° (c=0.5, MeOH); IR (film): 3280, 3055, 2972, 2926, 1655, 1515, 1497, 1456, 1342, 1127, 742 cm−; NMR (CDCl3): δ1.40 (3H, d, J=7.1 Hz); 1.90 (1H, s); 2.96 (1H, d.d, J=14.7 and 9.0 Hz); 3.36 (1H, d.d, J=14.5 and 4.5 Hz); 3.53-3.56 (1H, m); 3.78 (1H, d, J=13.7 Hz); 3.92 (1H, d, J=13.7 Hz); 5.08-5.16 (1H, m); 6.90 (1H, d, J=2.2 Hz); 7.03-7.08 (1H, m); 7.15-7.20 (1H, m); 7.23-7.37 (6H, m); 7.43 (1H,d J=8.3 Hz); 7.49-7.51 (1H, m); 7.59-7.72 (4H, m); 8.02 (1H, s); 8.04 (1H, d, J=8.3 Hz); 8.66 (1H, d, J=2.2 Hz); MS m/e (ES+): 471.1 (31%, M++Na), 449.1 (100%, M++H); Analysis calculated for C29H28N4O: C, 77.65; H, 6.29; N, 12.49%. Found: C, 78.02; H, 6.30; N, 12.48%.
    • EXAMPLE 12 2-[(5-Chloro-thiophen-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0297]
    Figure US20030065007A1-20030403-C00032
  • Method as for Example 10, step 2. The residue was dissolved in aqueous acetonitrile and acidified using formic acid before being purified by chromatography on reverse phase silica using 40% CH[0298] 3CN in H2O (0.1% formic acid in mobile phases) as eluent. The solvent was removed under reduced pressure and the residue was suspended between EtOAc and saturated NaHCO3. The EtOAc was dried (MgSO4) and the solvent was removed under reduced pressure to give pure product as a glass (245 mg, 56%); [α]D 22=+26.2° (c=0.5, MeOH); IR (film): 3307, 3059, 2973, 2925, 1652, 1515, 1455, 1342, 1230, 1105, 1061, 1000, 796, 742 cm−1; NMR (CDCl3): δ1.43 (3H, d, J=6.8 Hz); 1.85 (1H, s); 2.96 (1H, d.d, J=14.7 and 8.5 Hz); 3.31 (1H, d.d, J=14.5 and 4.5 Hz); 3.49-3.53 (1H, m); 3.71-3.79 (2H, m); 5.07-5.15 (1H, m); 6.50 (1H, d, J=3.7 Hz); 6.65 (1H, d, J=3.9 Hz); 6.91 (1H, d, J=2.4 Hz); 7.09-7.14 (1H, m); 7.18-7.39 (8H, m); 7.63 (1H, d, J=7.6 Hz); 7.98 (1H, s); MS m/e (ES+): 437.9 (100%, M++H); Analysis calculated for C24H24N3OSCl: C, 65.81; H, 5.52; N, 9.59; Cl, 8.09; S, 7.32%. Found: C, 65.54; H, 5.45; N, 9.40; Cl, 7.85; S, 7.42%.
    • EXAMPLE 13 3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethylsulfanyl-benzylamino)-propionamide, [R—(R*,S*)]
  • [0299]
    Figure US20030065007A1-20030403-C00033
  • To a stirred solution of 3-(trifluoromethylthio)benzaldehyde (72 mg, 0.55 mmol) in 1,2-dichloroethane (20 mL) was added intermediate V (154 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (148 mg, 0.7 mmol). After stirring over night the reaction was cautiously quenched with saturated NaHCO[0300] 3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 30% EtOAc in heptane as eluent. The solvent was removed under reduced pressure to give pure product as a glass (193 mg, 77%); IR (film): 3306, 3058, 2972, 2923, 1651, 1516, 1456, 1342, 1114, 743 cm−1; NMR (CDCl3): δ1.41 (3H, d, J=6.8 Hz); 1.60-1.90 (1H, br.s); 2.96 (1H, d.d, J=14.5 and 8.9 Hz); 3.32 (1H, d.d, J=14.4 and 4.4 Hz); 3.48 (1H, d.d, J=8.9 and 4.5 Hz); 3.62 (1H, d, J=13.9 Hz); 3.76 (1H, d, J=13.7 Hz); 5.08-5.16 (1H, m); 6.91 (1H, d, J=2.2 Hz); 7.07-7.48 (13H, m); 7.60 (1H, d, J=7.8 Hz); 7.97 (1H, s); MS m/e (ES+): 499.4 (32%), 498.4 (100%, M++H); Analysis calculated for C27H26N3OSF3.0.25H2O: C, 64.59; H, 5.32; N, 8.37; S, 6.39%. Found: C, 64.69; H, 5.34; N, 8.30; S, 6.27%.
    • EXAMPLE 14 2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0301]
    Figure US20030065007A1-20030403-C00034
  • Method as for Example 13. Chromatography on normal phase silica using 45% EtOAc in heptane as the eluent and subsequent removal of the solvent under reduced pressure gave pure product as a glass (130 mg, 62%); IR (film): 3312, 3059, 2973, 2924, 2229, 1652, 1516, 1456, 1342, 1231, 1101, 743 cm[0302] −1; NMR (CDCl3): δ1.42 (3H, d, J=6.8 Hz); 1.87 (1H, s); 2.91 (1H, d.d, J=14.5 and 9.2 Hz); 3.32 (1H, d.d, J=14.5 and 4.0 Hz); 3.41 (1H, d.d, J=9.0 and 4.4 Hz); 3.58 (1H, d, J=14.2 Hz); 3.76 (1H, d, J=14.2 Hz); 5.08-5.17 (1H, m); 6.94 (1H, d, J=2.2 Hz); 7.07-7.12 (1H, m); 7.19-7.45 (12H, m); 7.58 (1H, d, J=8.1 Hz); 8.05 (1H, s); MS m/e (ES+): 424.4 (30%), 423.4 (100%, M++H); (ES−): 422.3 (30%, M−), 421.3 (100%, M−−H); Analysis calculated for C27H26N4O: C, 76.75; H, 6.20; N, 13.26%. Found: C, 76.58; H, 6.14; N, 13.24%.
    • EXAMPLE 15 3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0303]
    Figure US20030065007A1-20030403-C00035
  • To a stirred solution of 3-nitrobenzaldehyde (332 g, 2.2 mmol) in 1,2-dichloroethane (60 mL) was added intermediate V (614 mg, 2 mmol) followed by sodium triacetoxyborohydride (594 mg, 2.8 mmol). After stirring over night the reaction was cautiously quenched with saturated NaHCO[0304] 3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 45% EtOAc in heptane as eluent. The solvent was removed under reduced pressure to give pure product as a glass (648 mg, 73%); IR (film): 3317, 2925, 1652, 1526, 1456, 1349, 733 cm−1;NMR (CDCl3): δ1.43 (3H, d, J=6.8 Hz); 1.85-1.95 (1H, br.s); 2.90 (1H, d.d, J=14.5 and 9.1 Hz); 3.33 (1H, d.d, J=14.4 and 4.4 Hz); 3.43 (1H, d.d, J=9.0 and 4.5 Hz); 3.65 (1H, d, J=14.2 Hz); 3.83 (1H, d, J=14.2 Hz); 5.09-5.17 (1H, m); 6.94 (1H, d, J=2.4 Hz); 7.06 (1H, t, J=7.5 Hz); 7.18 (1H, t, J=7.5 Hz); 7.22-7.40 (10H, m); 7.87 (1H, m); 7.97-8.10 (2H, m); MS m/e (ES+): 444.4 (30%), 443.4 (100%, M++H); Analysis calculated for C26H26N4O3: C, 70.57; H, 5.92; N, 12.66%. Found: C, 70.55; H, 5.88; N, 12.67%.
    • EXAMPLE 16 3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R—(R*,S*)]
  • [0305]
    Figure US20030065007A1-20030403-C00036
  • Method as for Example 13. Chromatography on normal phase silica using 35% EtOAc in heptane as the eluent and subsequent removal of the solvent under reduced pressure gave pure product as a glass (130 mg, 54%); IR (film): 3307, 3060, 2974, 2925, 1652, 1589, 1516, 1495, 1456, 1260, 1217, 1164, 1012, 743 cm[0306] −1; NMR (CDCl3): δ1.40 (3H, d, J=6.8 Hz); 1.60-2.00 (1H, br.s); 2.97 (1H, d.d, J=14.7 and 8.8 Hz); 3.29-3.35 (1H, m); 3.48 (1H, d.d, J=8.8 and 4.6 Hz); 3.62 (1H, d, J=13.9 Hz); 3.74 (1H, d, J=13.9 Hz); 5.07-5.15 (1H, m); 6.91 (1H, d, J=2.2 Hz); 6.96-7.39 (13H, m); 7.63 (1H, d, J=7.8 Hz); 7.97 (1H, m); MS m/e (ES+): 483.4 (30%), 482.4 (100%, M++H); Analysis calculated for C27H26N3O2F3: C, 67.35; H, 5.44; N, 8.73%. Found: C, 67.31; H, 5.43; N, 8.67%.
    • EXAMPLE 17 2-(3-Hydroxy-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0307]
    Figure US20030065007A1-20030403-C00037
  • Method as for Example 13. Chromatography on normal phase silica using 40% EtOAc in heptane as the eluent and subsequent removal of the solvent under reduced pressure gave pure product as a glass (94 mg, 45%); IR (film): 3317, 3059, 2975, 2926, 1645, 1589, 1520, 1456, 1266, 1159, 743 cm[0308] −1; NMR (CDCl3): δ1.40 (3H, d, J=7.1 Hz); 1.70-1.90 (1H, br.s); 2.89 (1H, d.d, J=14.5 and 9.4 Hz); 3.33 (1H, d.d, J=14.7 and 4.2 Hz); 3.49-3.54 (1H, m); 3.53 (1H, d, J=13.9 Hz); 3.69 (1H, d, J=13.9 Hz); 5.00-5.20 (2H, m); 6.28 (1H, d, J=1.7 Hz); 6.60 (1H, d, J=7.6 Hz); 6.65 (1H, d.d, J=7.9 and 2.0 Hz); 6.89 (1H, d, J=2.2 Hz); 7.06 (1H, t, J=7.8 Hz); 7.09-7.13 (1H, m); 7.19-7.52 (7H, m); 7.54 (1H, d, J=8.5 Hz); 7.64 (1H, d, J=8.5 Hz); 8.05 (1H, m); MS m/e (ES+): 415.4 (30%), 414.4 (100%, M++H); Analysis calculated for C26H27N3O2: C,75.52; H, 6.58; N, 10.16%. Found: C, 75.28; H, 6.61; N, 10.03%.
    • EXAMPLE 18 2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0309]
    Figure US20030065007A1-20030403-C00038
  • To a stirred solution of 2-benzofurancarboxaldehyde (3.19 g, 21.8 mmol) in 1,2-dichloroethane (150 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (prepared as described by Boyle S. et al., [0310] Bioorg. Med. Chem. 2:357, 1994) (5 g, 15.6 mmol), followed by sodium triacetoxyborohydride (6.6 mg, 31.2 mmol). After stirring over night the reaction was cautiously quenched with 2N NaOH (150 mL) and extracted with CH2Cl2 (3×200 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 30% EtOAc in heptane as eluent and then on reverse phase silica using 70% MeOH in H2O as eluent. Crystallization from ether gave pure product (5.55 g, 79%); mp 118-121° C.: [α)D 20=+12.5° (c=1, MeOH); IR (film): 3329, 3059, 2975, 2926, 1652, 1506, 1455, 1371, 1354, 1342, 1255, 1170, 1105, 1010, 938, 743 cm−1; NMR (CDCl3): δ1.47 (3H, s); 1.47 (3H, d, J=6.8 Hz); 1.89 (1H, s); 3.16 (2H, s); 3.78 (1H, br.d, J=12.9 Hz); 3.86 (1H, d, J=14.4 Hz); 5.05-5.13 (1H, m); 6.43 (1H, s); 6.87 (1H, d, J=2.2 Hz); 7.09-7.40 (11H, m); 7.47-7.50 (1H, m); 7.65 (1H, d, J=7.8 Hz); 7.92 (1H, d, J=7.8 Hz); 7.96 (1H, s); MS m/e (ES+): 453.1 (30%), 452.1 (100%, M++H), 393.2 (15%); Analysis calculated for C29H29N3O2: C, 77.14; H, 6.47; N, 9.30%. Found: C, 77.14; H, 6.42; N, 9.36%.
    • EXAMPLE 19 2-[(Benzofuran-3-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0311]
    Figure US20030065007A1-20030403-C00039
  • To a stirred solution of 3-benzofurancarboxaldehyde (146 mg, 1 mmol) (Ind. J. Chem., Vol. 31B, 1992, 526) in 1,2-dichloroethane (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (321 mg, 1 mmol) followed by sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over night at room temperature another portion of sodium triacetoxyborohydride (424 mg, 2 mmol) was added. The reaction was heated to reflux for 4 h. Cooled to room temperature and cautiously quenched with saturated NaHCO[0312] 3 (100 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 25% EtOAc in heptane as eluent. Crystallization from ether/heptane gave pure product (232 mg, 51%); mp 104-106° C.: [α]D 23=−13.4° (c=1, MeOH); IR (film): 3418, 3314, 3058, 2976, 2927, 1652, 1505, 1452, 1371, 1354, 1341, 1279, 1266, 1186, 1095, 1010, 858, 743 cm−1; NMR (CDCl3): δ1.40 (3H, d, J=6.8 Hz); 1.52 (3H, s); 1.71 (1H, s); 3.15 (1H, d, J=14.4 Hz); 3.27 (1H, d, J=14.4 Hz); 3.80 (1H, d, J=13.2 Hz); 3.88 (1H, d, J=13.2 Hz); 5.01-5.09 (1H, m); 6.79 (1H, d, J=2.2 Hz); 7.07-7.40 (12H, m); 7.44 (1H d,d, J=8.3 and 0.7 Hz); 7.65 (1H, d, J=7.8 Hz); 7.68 (1H, d, J=8.1 Hz); 7.93 (1H, s); MS m/e (ES+): 452.1 (100%, M++H); Analysis calculated for C29H29N3O2: C, 77.14; H, 6.47; N, 9.30%. Found: C, 76.91; H, 6.39; N, 9.26%.
    • EXAMPLE 20 3-(1H-Indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-2-[(1H-pyrrol-2-ylmethyl)-amino]-propionamide, [R—(R*,S*)]
  • [0313]
    Figure US20030065007A1-20030403-C00040
  • To a stirred solution of 2-pyrrolecarboxaldehyde (71 mg, 0.75 mmol) in 1,2-dichloroethane (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (424 mg, 2 mmol). After stirring over night at room temperature the reaction was cautiously quenched with saturated NaHCO[0314] 3 (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using 40% EtOAc in heptane as eluent. Crystallization from ether/heptane gave pure product (50 mg, 25%); mp 123-133° C.; [α]D 23=(c=1, MeOH); IR (film): 3314, 2976, 2926, 2852, 1651, 1511, 1455, 909, 736 cm−1; NMR (CDCl3): δ1.41 (3H, d, J=6.8 Hz); 1.45 (3H, s); 3.14 (1H, d, J=14.4 Hz); 3.29 (1H, d, J=14.4 Hz); 3.70 (1H, d, J=13.1 Hz); 3.76 (1H, d, J=12.9 Hz); 5.02-5.10 (1H, m); 5.97 (1H, s); 6.07-6.09 (1H, m); 6.58-6.60 (1H, m); 6.74 (1H, d, J=2.2 Hz); 7.10-7.35 (8H, m); 7.41 (1H d, J=7.6 Hz); 7.65 (1H, d, J=7.8 Hz); 7.89 (2H, s); MS m/e (ES+): 423.2 (20%, M++Na); 402.2 (30%); 401.2 (100%, M++H); 322.2 (40%); Analysis calculated for C25H28N4O: C, 74.97; H, 7.05; N, 13.99%. Found: C, 74.83; H, 7.05; N, 13.95%.
    • EXAMPLE 21 3-(1H-Indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-2-[(2H-pyrazol-3-ylmethyl)-amino]-propionamide, [R—(R*,S*)]
  • [0315]
    Figure US20030065007A1-20030403-C00041
  • To a stirred solution of pyrazole-3-carboxaldehyde (96 mg, 1 mmol, supplied as dimer) in pyridine (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (848 mg, 4 mmol). After stirring over night at room temperature another portion of sodium triacetoxyborohydride (424 mg, 2 mmol) was added. After stirring over night at room temperature the pyridine was removed under reduced pressure. The residue was taken up in CH[0316] 2Cl2 (100 mL) and saturated NaHCO3. The aqueous phase was extracted with CH2Cl2 (100 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was initially purified by chromatography on normal phase silica using 95% EtOAc in heptane as eluent. The solvent was removed under reduced pressure and the residue was dissolved in aqueous acetonitrile and acidified using formic acid. Purification by chromatography on reverse phase silica using 25% CH3CN in H2O (0.1% formic acid in mobile phases) as eluent gave pure product. The solvent was removed under reduced pressure and the residue was suspended between EtOAc and saturated NaHCO3. The EtOAc was dried (MgSO4) and the solvent was removed under reduced pressure to give pure product as a glass (20 mg, 10%); IR (film): 3260, 3059, 2979, 2927, 1651, 1515, 1456, 1374, 1266, 1105, 1048, 1011, 932, 741 cm−1; NMR (DMSO-d6): δ1.22 (3H, s); 1.35 (3H, d, J=6.8 Hz); 2.26 (1H, s); 2.96-3.05 (2H, m); 3.50-3.75 (2H, m); 4.93 (1H, s); 6.10 (1H, s); 6.89-6.93 (2H, m); 7.00-7.04 (1H, m); 7.18-7.32 (6H, m); 7.35 (0.5H, s); 7.52 (1H, d, J=7.8 Hz); 7.60 (0.5H, s); 8.05-8.20 (1H, m); 10.82 (1H, s); 12.52 (0.5H, s); 12.73 (0.5H, s); MS m/e (ES+): 424.1 (27%); 402.1 (100%, M++H).
    • EXAMPLE 22 2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
  • [0317]
    Figure US20030065007A1-20030403-C00042
  • Step 1 [0318]
  • To a stirred solution of potassium hydroxide (6.6 g, 100 mmol, 85%) and hydroxylamine (3.66, 52.5 mmol) in EtOH (100 mL, 95%) and water (100 mL) was added 2-benzofurancarboxaldehyde (7.34 g, 50 mmol). Stirred for 48 h before removing the EtOH under reduced pressure. The aqueous phase was saturated with NaCl and then extracted with EtOAc (2×300 mL). The combined organic phases were dried (MgSO[0319] 4) and the solvent removed under reduced pressure. Crystallization from ether gave pure oxime (7.2 g, 89%). To an ice-cold solution of the oxime (3.22 g, 20 mmol) in THF (150 mL, anhydrous) was added dropwise a solution of lithium aluminum hydride (20 mL, 20 mmol, 1M in THF) under an atmosphere of nitrogen. Reaction mixture allowed to reach room temperature and stirred over night. Reaction mixture cautiously quenched using water. Added 5N NaOH, and aqueous phase extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried (MgSO4), and the solvent was removed under reduced pressure. The residue was purified by chromatography on normal phase silica using EtOAc as eluent to give intermediate IX (1.75 g, 59%).
  • Step 2 [0320]
  • A solution of the amine prepared in step 1 (1.358 g, 9.23 mmol) and pyridine (1.46, 18.5 mmol) in CH[0321] 2Cl2 (20 mL, anhydrous) was added dropwise over 20 min to an ice cooled solution of triphosgene (0.96, 3.23 mmol). Reaction mixture allowed to reach room temperature. After 30 min, solvent removed under reduced pressure. The residue was taken up in EtOAc, filtered, and solvent removed under reduced pressure to give isocyanate (1.60 g, 100%). IR (film): 2256 cm−1. A solution of the isocyanate (1.038 g, 6 mmol) and 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (1.926 g, 6 mmol) in THF (50 mL, anhydrous) was stirred at room temperature for 5 min. The solvent was removed under reduced pressure. The residue was taken up in EtOAc and washed with 1N HCl (3×20 mL), saturated Na2CO3 (30 mL), brine (30 mL), dried MgSO4, and the solvent removed under reduced pressure. The residue was purified by chromatography on reverse phase silica using 65% MeOH in H2O as eluent. Crystallization from MeOH/H2O gave pure product (1.35 g, 45%). mp 176-178° C.; [α]D 22=+30.420 (c=1, MeOH); IR (film): 3321, 3058, 2978, 2932, 1645, 1558, 1506, 1495, 1445, 1253, 741 cm−1; NMR (CDCl3): δ1.35 (3H, d, J=6.8 Hz); 1.61 (3H, s); 3.20 (1H, d, J=14.6 Hz); 3.54 (1H, d, J=14.6 Hz); 4.38 (1H, d.d, J=16.0 and 6.0 Hz); 4.45 (1H, d.d, J=15.9 and 6.1 Hz); 4.78 (1H, t, J=6.0 Hz); 4.97 (1H, s); 4.95-5.05 (1H, m); 6.49 (1H, s); 6.76 (1H, d, J=2.4 Hz); 7.00 (1H, d, J=7.6 Hz); 7.05-7.10 (1H, m); 7.13-7.28 (9H, m); 7.38 (1H, d, J=8.1 Hz); 7.48-7.50 (1H, m); 7.57 (1H, d, J=7.8 Hz); 7.74 (1H, s); MS m/e (APCI+): 496.3 (30%); 495.2 (100%, M++H); 477.2 (7%); 374.2 (7%); 322.3 (17%); Analysis calculated for C30H30N4O3: C, 72.85; H, 6.11; N, 11.32%. Found: C, 73.09; H, 6.08; N, 11.35%.
    • EXAMPLES 23 TO 191
  • (See Table 2 Below) [0322]
    • Intermediate VII, N-[b]benzofuranylmethyl-R-α-methyl-tryptophan-N-carboxyanhydride
  • Intermediate I (5.23 g, 15 mmol) was stirred in toluene (50 mL) under nitrogen and heated to 55° C. Phosgene in toluene (37 mL, 75 mmol) was added in one portion and as soon as the temperature had returned to 55° C. dry THF (150 mL) was added rapidly dropwise. Stirring was continued for 30 min and the reaction was then cooled, the solvent removed in vacuo. The residue taken up in ether (50 mL) and filtered and evaporated to dryness several times until a solid was obtained; (6.15 g, 100%); IR (film): 3418, 1844, 1771, 1455, 1397, 1251, 986, 746 cm[0323] −1; NMR (CDCl3) 1.64 (3H, s); 3.31 (1H, d, J=15 Hz); 3.44 (1H, d, J=15 Hz); 4.45 (1H, d J=16Hz); 4.81 (1H, d, J=16 Hz); 6.77 (1H, s); 6.94 (1H, d J=2.8 Hz); 7.14-7.58 (8H, m); 8.16 (1H, s).
  • General Procedure for Array Synthesis of Examples 23 to 191 [0324]
  • A 40-well DTI synthesizer rack (U.S. Pat. No. 5,324,483) was loaded with 40 DTI vials (12 mL). To each vial 0.15-0.21 mmol of an amine or amine HCl salt was added. The rack was placed in a Cyberlab Liquid Handling Robot and to each vial 0.10 mmol N-[b]benzofuranylmethyl-R-α-methyl-tryptophan-N-carboxyanhydride (0.227 M in THF) was added. To those vials that contained amine HCl salts, 0.15 mmol triethylamine (0.254 M in THF) was added, in order to liberate the free amines. THF was then added to each vial to make up the total volume to 3 mL. The vials were placed in a 40-well DTI synthesizer equipped with a heating block, 40 condensers and a nitrogen manifold. The synthesizer was kept under a continuous flow of nitrogen and was shaken at 65° C. on an orbital shaker for 2 days. The reactions were monitored by TLC (10% CH[0325] 3CN in CH2Cl2). The vials in which the reaction had gone to completion were taken out. To the remaining vials CH3CN (2 mL) was added each and these were shaken at 85° C. for 19 h. The vials in which the reaction had gone to completion were taken out. To the remaining vials pyridine (1 mL) was added each and these were shaken at 105° C. for 6 h followed by 15 h at 65° C. The vials were then concentrated at reduced pressure in a Speedvac and were purified by chromatography over a 12 mL LC-Si SPE cartridge containing 2 g silica (elution with 10% CH3CN in CH2Cl2 followed by 20% CH3CN in CH2Cl2, 5% methanol in CH2Cl2, 10% methanol in CH2Cl2, 20% methanol in CH2Cl2 and 50% methanol in CH2Cl2, depending on the polarity of the products). The products were subjected to LC-MS. Those products which did contain the desired molecular ion, but were not sufficiently pure (typically<85%) were further purified by prep HPLC on a C18 reversed phase preparative column. The HPLC-purified products were re-analyzed by LC-MS to determine the purity. The 40 final products were analyzed by 1H NMR.
    • EXAMPLES 192 TO 308
  • (See Table 3 Below) [0326]
  • Intermediate II [0327]
  • Step 1 [0328]
  • The compound was prepared as described for Intermediate I, step 1; (20.5 g, 59%); NMR (CDCl[0329] 3) 2.10 (1H, s); 3.18 (2H, m); 3.60 (3H, s); 3.80-4.00 (2H, m); 6.43 (1H, s); 7.03-7.60 (9H, m); 8.00 (1H, s).
  • Step 2 [0330]
  • The compound was prepared as described for Intermediate I; (7.02 g, 85%); NMR (DMSO-D[0331] 6) 3.01-3.12 (2H, m); 3.52 (1H, m); 3.80 (1H, d, J=15 Hz); 3.80 (1H, d, J=14.8 Hz); 6.61 (1H, s); 6.93-7.54 (9H, m); 10.82 (1H, s).
  • General Procedure for Array Synthesis of Examples 192 to 308 (See Table 4 Below) [0332]
  • A 40-well DTI synthesizer rack was loaded with 40 Kimble vials (10 mL). To each vial approximately 0.34 g (0.10 mmol) N-[b]benzofuranylmethyl-R-tryptophan was added followed by 1.5 equivalent of an amine or amine HCl salt. The rack was placed in a Cyberlab Liquid Handling Robot and to each vial 1.0 equivalent of HBTU (0.4 M in DMF) was added followed by 1.5 equivalent of diisopropylethylamine (0.5 M in DMF). To those vials, which contained amine HCl salts, an additional equivalent of diisopropylethylamine was added. DMF was added to make the total volume up to 1.5 mL. The vials were capped and the rack was shaken on an orbital shaker at room temperature for 3 h. To each vial, water (1 mL) was added and the mixtures were purified on 3 mL LC-18 reversed phase SPE cartridges containing 500 mg of sorbent, using an ASPEC XL4 robot. The cartridges were conditioned with methanol (4 mL) followed by methanol/water 1:1 (4 mL). Water (1 mL) was loaded onto the cartridges and the crude reaction mixtures were loaded into the water layer. The cartridges were washed with water (4 mL) and methanol/water 1:1 (4 mL) and were eluted with methanol (4 mL). The methanol fractions were concentrated and the products were subjected to LC-MS. Those products which did contain the desired molecular ion, but were not sufficiently pure (typically<90%) were further purified by prep HPLC on a C18 reversed phase preparative column. The HPLC-purified products were re-analyzed by LC-MS to determine the purity. The 40 final products were analyzed by [0333] 1H NMR.
    • EXAMPLES 309 TO 405
  • (See Table 5 Below) [0334]
  • General Procedure for Array Synthesis of Examples 309 to 405 [0335]
  • The N-terminal derivatives where prepared from 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, prepared as described by Boyle S., et al., [0336] Bioorg. Med. Chem. 2:357 (1994), or from 2-amino-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide (Intermediate V), using the procedure of Siegel M. G., et al., Tet. Lett. 38: 3357, (1997).
  • Because the compounds are potent ligands to the NK[0337] 1 receptor, they are effective at displacing substance P at that position, and therefore are useful for treating biological conditions otherwise mediated by substance P. Accordingly, compounds capable of antagonising the effects of substance P at NK1 receptors will be useful in treating or preventing a variety of brain disorders including pain (inflammatory, surgical and neuropathic), anxiety, panic, depression, schizophrenia, neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, and addiction disorders; inflammatory diseases such as arthritis, asthma, and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including scleroderma and emesis. The compounds of the invention, NK1 receptor antagonists, are also useful as anti-angiogenic agents, for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis and tumour cell growth. They will also be useful as agents for imaging NK1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
  • The compounds of the present invention are highly selective and competitive antagonists of the NK[0338] 1 receptor. They have been evaluated in an NK1-receptor binding assay which is described below.
  • Human lymphoma IM9 cells were grown in RPMI 1640 culture medium supplemented with 10% fetal calf serum and 2 mM glutamine and maintained under an atmosphere of 5% CO[0339] 2. Cells were passaged every 3-4 days by reseeding to a concentration of 4-8×106/40 ml per 175 cm2 flask. Cells were harvested for experiments by centrifugation at 1000 g for 3 min. Pelleted cells were washed once by resuspension into assay buffer (50 mM Tris HCl pH 7.4, 3 mM MnCl2, 0.02% BSA, 40 mg/mL bacitracin, 2 mg/mL chymostatin, 2 mM phosphoramidon, 4 mg/mL leupeptin) and repeating the centrifugation step before resuspending at a concentration of 2.5×106 cells/mL assay buffer. Cells (200 ml) were incubated with [125I]Bolton-Hunter substance P (0.05-0.1 nM) in the presence and absence of varying concentrations of test compounds for 50 min at 21° C. Non-specific binding (10% of the total binding observed under these conditions) was defined by 1 mM [Sar9, Met(02)11] substance P. Reactions were terminated by rapid filtration under vacuum onto GF\C filters presoaked in 0.2% PEI for 1-2 h, using a Brandel cell harvester. Filters were washed with 6×1 ml ice-cold Tris HCl (50 mM, pH 7.4) and radioactivity bound determined using a gamma counter. Results were analyzed using iterative curve fitting procedures in RS1 or Graphpad Inplot.
    TABLE 1
    In Vitro Human NK1 Receptor Binding Assay
    NK1 binding
    Example No IC50 (nM)
    1 591
    2 23
    3 6
    4 1213
    5 295
    6 0.7
    7 3.3
    8 27
    9 112
    10 51
    11 46
    12 14
    13 35
    14 4.7
    15 >10,000
    16 9.1
    17 344
    18 4.4
    19 58
    20 815
    21 1808
    22 2.9
  • Similiar binding data are presented in Tables 2-5 for specific invention compounds. [0340]
    TABLE 2
    Examples 23-191
    Yield Mol. Icms % Icms Rt IC50 (nM)
    Ex. Name (mg) ion purity (min) hNK1
    23 2-[(Benzofuran-2-ylmethyl)-amino]-3 19.7 439 100 3.07 1284
    (1H-indol-3-yl)-2-methyl-N-pyridin-2
    ylmethyl-propionamide
    24 2-[(Benzofuran-2-ylmethyl)-amino]- 23.5 439 100 2.6 547
    3-(1H-indol-3-yl)-2-methyl-N-
    pyridin-3-ylmethyl-propionamide
    25 2-[(Benzofuran-2-ylmethyl)-amino]- 41.9 439 100 2.6 131
    3-(1H-indol-3-yl)-2-methyl-N-
    pyridin-4-ylmethyl-propionamide
    26 2-[(Benzofuran-2-ylmethyl)-amino]- 18.4 430 100 5.2 1011
    N-cyclohexyl-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    27 2-[(Benzofuran-2-ylmethyl)-amino]- 24.6 444 100 5.81 311
    N-cyclohexylmethyl-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    28 2-[(Benzofuran-2-ylmethyl)-amino]- 26.5 438 97 4.6 44
    N-benzyl-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    29 2-[(Benzofuran-2-ylmethyl)-amino]- 43.1 468 82 3.22 7
    N-(2-hydroxy-1-phenyl-ethyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    30 2-[(Benzofuran-2-ylmethyl)-amino ]- 43.3 486 74 5.81 17
    N-[1-(4-chloro-phenyl)-ethyl]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    31 2-((Benzofuran-2-ylmethyl)-amino]- 29.4 502 100 6.05 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    naphthalen-1-yl-ethyl)-propionamide
    32 2-[(Benzofuran-2-ylmethyl)-amino]- 40.1 502 100 5.96 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    naphthalen-1-yl-ethyl)-propionamide
    33 2-[(Benzofuran-2-ylmethyl)-amino]- 44.4 470 100 5.11 9
    N-[1-(4-fluoro-phenyl)-ethyl]-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    34 2-[(Benzofuran-2-ylmethyl)-amino]- 23.8 497 100 5.07 14
    3-(1H-indol-3-yl)-2-methyl-N-[1-(4-
    nitro-phenyl)-ethyl]-propionamide
    35 2-[(Benzofuran-2-ylmethyl)-amino]- 27.8 482 100 4.86 31
    3-(1H-indol-3-yl)-N-[1-(4-methoxy-
    phenyl)-ethyl]-2-methyl-
    propionamide
    36 N-[1-(2-Amino-phenyl)-ethyl]-2- 25.8 467 100 4.45 1620
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    37 N-[1-(3-Amino-phenyl)-ethyl]-2- 25.5 467 100 3.7 364
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    38 N-[1-(4-Amino-phenyl)-ethyl]-2- 22.5 467 100 3.2 141
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    39 2-[(Benzofuran-2-ylmethyl)-amino]- 48.3 495 100 5.26 863
    N-[1-(4-dimethylamino-phenyl)-
    ethyl]-3-(1H-indol-3-yl)-2-methyl-
    propionamide
    40 2-[(Benzofuran-2-ylmethyl)-amino]- 25.3 495 100 5.18 1065
    N-[1-(3-dimethylamino-phenyl)-
    ethyl]-3-(1H-indol-3-yl)-2-methyl-
    propionamide
    41 2-[(Benzofuran-2-ylmethyl)-amino]- 17 458 100 4.89 19
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    thiophen-3-yl-ethyl)-propionamide
    42 2-[(Benzofuran-2-ylmethyl)-amino]- 34.5 452 100 5.06 261
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    43 2-{[2-[(Benzofuran-2-ylmethyl)- 28.5 500 10 9.4 3613
    amino]-3-(1H-indol-3-yl)-2-methyl-
    propionylamino]-methyl }-4-
    hydroxy-pyrimidine-5-carboxylic
    acid
    44 2-[(Benzofuran-2-ylmethyl)-amino]- 43.9 453 90 6.85 151
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    pyridin-3-yl-ethyl)-propionamide
    45 2-[((Benzofuran-2-ylmethyl)-amino]- 43 453 95 7.15 913
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    pyridin-2-yl-ethyl)-propionamide
    46 2-[(Benzofuran-2-ylmethyl)-amino]- 49.5 506 95 10.2 1560
    N-(2,4-dichloro-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    47 2-[(Benzofuran-2-ylmethyl)-amino]- 52.6 531 95 6.66 7616
    3-(1H-indol-3-yl)-2-methyl-N-[2-(4-
    sulfamoyl-phenyl)-ethyl]-
    propionamide
    48 N-(2-Amino-6-fluoro-benzyl)-2- 49.3 471 95 8.68 6423
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    49 2-[(Benzofuran-2-ylmethyl)-amino]- 4.9 460 95 8.22 1550
    N-(2-hydroxy-cyclohexylmethyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    50 2-[(Benzofuran-2-ylmethyl)-amino]- 44.4 468 95 7.6 1333
    N-(2-hydroxy-2-phenyl-ethyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    51 2-[(Benzofuran-2-ylmethyl)-amino]- 31.1 574 95 10.32 179
    N-(3,5-bis-trifluoromethyl-benzyl)-
    3-(1H-indol-3-yl)-2-methyl-
    propionamide
    52 2-[(Benzofuran-2-ylmethyl)-amino]- 39.3 459 95 9.16 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[2-(1-
    methyl-pyrrolidin-2-yl)-ethyl]-
    propionamide
    53 2-[(Benzofuran-2-ylmethyl)-amino]- 42 452 90 8.9 262
    3-(1H-indol-3-yl)-2-methyl-N-
    phenethyl-propionamide
    54 2-[(Benzofuran-2-ylmethyl)-amino]- 23.2 466 90 9.95 834
    N-(2,3-dimethyl-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    55 2-[(Benzofuran-2-ylmethyl)-amino]- 49 468 95 8.95 643
    3-(1H-indol-3-yl)-N-(3-methoxy-
    benzyl)-2-methyl-propionamide
    56 N-[2-(4-Amino-phenyl)-ethyl]-2- 49 467 90 7.31 3228
    [(benzofuran-2-ylmethyl)-amino ]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    57 2-[(Benzofuran-2-ylmethyl)-amino] 7 458 95 10.73 290
    N-(1-cyclohexyl-ethyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    58 2-[(Benzofuran-2-ylmethyl)-amino]- 27 466 90 9.95 624
    3-(1H-indol-3-yl)-2-methyl-N-(1-p-
    tolyl-ethyl)-propionamide
    59 2-[(Benzofuran-2-ylmethyl)-amino]- 46 522 90 9.61 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(3-
    trifluoromethoxy-benzyl)-
    propionamide
    60 2-[(Benzofuran-2-ylmethyl)-amino]- 10 481 90 9.16 964
    N-(4-dimethylamino-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    61 2-[(Benzofuran-2-ylmethyl)-amino ]- 48.4 456 90 8.74 61
    N-(4-fluoro-benzyl)-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    62 N-(4-Amino-benzyl)-2- 32.3 453 90 7.29 837
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    63 2-[(Benzofuran-2-ylmethyl)-amino]- 21.6 466 75 9.95 58
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-propyl)-propionamide
    64 2-[(Benzofuran-2-ylmethyl)-amino]- 50.2 472 90 9.3 76
    N-(4-chloro-benzyl)-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    65 2-[(Benzofuran-2-ylmethyl)-amino]- 43.9 516 90 9.43 700
    N-(2-bromo-benzyl)-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    66 2-[(Benzofuran-2-ylmethyl)-amino]- 40.9 522 90 9.69 3444
    3-(1H-indol-3-yl)-2-methyl-N-(4-
    trifluoromethoxy-benzyl)-
    propionamide
    67 2-[(Benzofuran-2-ylmethyl)-amino]- 18.8 466 92 9.94 3
    3-(1H-indol-3-yl)-2-methyl-N-(1-p-
    tolyl-ethyl)-propionamide
    68 2-[(Benzofuran-2-ylmethyl)-amino]- 48.9 468 90 8.41 312
    3-(1H-indol-3-yl)-N-(4-methoxy-
    benzyl)-2-methyl-propionamide
    69 2-[(Benzofuran-2-ylmethyl)-amino]- 44.7 453 95 7.68 112
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    pyridin-2-yl-ethyl)-propionamide
    70 2-[(Benzofuran-2-ylmethyl)-amino]- 38.1 458 90 10.45 216
    N-(2-cyclohexyl-ethyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    71 2-[(Benzofuran-2-ylmethyl)-amino]- 40 452 90 9.13 144
    3-(1H-indol-3-yl)-2-methyl-N-(4-
    methyl-benzyl)-propionamide
    72 2-[(Benzofuran-2-ylmethyl)-amino]- 43.2 516 90 9.43 18
    N-(3-bromo-benzyl)-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    73 2-[(Benzofuran-2-ylmethyl)-amino]- 35.2 468 90 7.56 1229
    N-(2-hydroxy-2-phenyl-ethyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    74 2-[(Benzofuran-2-ylmethyl)-amino]- 16 506 90 9.51 12
    3-(1H-indol-3-yl)-2-methyl-N-(3-
    trifluoromethyl-benzyl)-
    propionamide
    75 2-[(Benzofuran-2-ylmethyl)-amino]- 48.1 528 100 7.06 >10,000
    N-(1,2-diphenyl-ethyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    76 2-[(Benzofuran-2-ylmethyl)-amino]- 28 405 50 2.01 3696
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    methylamino-ethyl)-propionamide
    77 2-[(Benzofuran-2-ylmethyl)-amino ]- 20 472 100 6.19 17
    N-(3-chloro-benzyl)-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    78 2-[(Benzofuran-2-ylmethyl)-amino ]- 9.2 485 50 1.93 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-
    (1,3,5-triaza-tricyclo[3.3.1.1 > 3,7]-
    dec-7-yl)-propionamide
    79 2-[(Benzofuran-2-ylmethyl)-amino]- 30.1 534 100 6.84 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[1-
    methyl-2-(3-trifluoromethyl-phenyl)-
    ethyl]-propionamide
    80 2-[(Benzofuran-2-ylmethyl)-amino]- 22.4 529 100 5.9 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    phenyl-2-pyridin-2-yl-ethyl)-
    propionamide
    81 4-{[2-[(Benzofuran-2-ylmethyl)- 37.4 526 100 5.59 >10,000
    amino]-3-(1H-indol-3-yl)-2-methyl-
    propionylamino]-methyl}-3-
    methoxy-benzoic acid methyl ester
    82 2-[(Benzofuran-2-ylmethyl)-amino]- 8.5 432 100 6.51 1144
    3-(1H-indol-3-yl)-2-methyl-N-
    (1,2,2-trimethyl-propyl)-
    propionamide
    83 2-[(Benzofuran-2-ylmethyl)-amino]- 27.5 419 100 3.61 3519
    N-(2-dimethylamino-ethyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    84 4-[2-[(Benzofuran-2-ylmethyl)- 5 544 100 1.62 >10,000
    amino]-3-(1H-indol-3-yl)-2-methyl-
    propionylamino]-3-(4-chloro-
    phenyl)-butyric acid
    85 2-[(Benzofuran-2-ylmethyl)-amino]- 11.3 479 100 3.73 2443
    3-(1H-indol-3-yl)-2-methyl-N-(3-
    oxo-2,3-dihydro-1H-isoindol-1-yl)-
    propionamide
    86 2-[(Benzofuran-2-ylmethyl)-amino]- 24.7 460 100 2.58 >10,000
    oxo-imidazolidin-1-yl)-ethyl]-
    propionamide
    87 2-[(Benzofuran-2-ylmethyl)-amino]- 38.9 551 100 4.63 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[3-(4-
    pyridin-2-yl-piperazin-1-yl)-propyl]-
    propionamide
    88 2-[(Benzofuran-2-ylmethyl)-amino]- 33.4 515 100 4.58 >10,000
    N-[4-(2.6-dimethyl-piperidin-1-yl)-
    butyl]-3-(1H-indol-3-yl)-2-methyl-
    propionamide
    89 2-[(Benzofuran-2-ylmethyl)-amino]- 21.2 527 100 8.88 6735
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    piperidin-1-ylmethyl-cyclohexyl)-
    propionamide
    90 2-[(Benzofuran-2-ylmethyl)-amino]- 8.2 456 100 3.07 >10,000
    N-[2-(1H-imidazol-4-yl)-1-methyl-
    ethyl]-3-(1H-indol-3-yl)-2-methyl-
    propionamide
    91 2-[(Benzofuran-2-ylmethyl)-amino]- 28.1 473 100 3.07 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[3-(2-
    oxo-pyrrolidin-1-yl)-propyl]-
    propionamide
    92 2-[(Benzofuran-2-ylmethyl)-amino]- 17.6 390 100 4.96 2285
    3-(1H-indol-3-yl)-N-isopropyl-2-
    methyl-propionamide
    93 2-[(Benzofuran-2-ylmethyl)-amino]- 17.6 473 100 3.29 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[1-
    methyl-2-(2-oxo-pyrrolidin-1-yl)-
    ethyl]-propionamide
    94 2-[(Benzofuran-2-ylmethyl)-amino]- 30.6 501 100 3.27 >10,000
    N-[4-(2,5-dimethyl-pyrrolidin-1-yl)-
    butyl]-3-(1H-indol-3-yl)-2-methyl-
    propionamide
    95 N-[2-(5-Amino-1H-imidazol-4-yl)- 19.2 471 100 3.5 >10,000
    2-oxo-ethyl]-2-[(benzofuran-2-
    ylmethyl)-amino]-3-(1H-indol-3-yl)-
    2-methyl-propionamide
    96 2-[(Benzofuran-2-ylmethyl)-amino]- 4.6 461 100 2.26 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[2-(2-
    oxo-oxazolidin-3-yl)-ethyl]-
    propionamide
    97 2-[(Benzofuran-2-ylmethyl)-amino]- 30 442 100 2.26 >10,000
    N-[2-(1H-imidazol-4-yl)-ethyl]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    98 2-[(Benzofuran-2-ylmethyl)-amino]- 34.5 528 100 2.26 >10,000
    N-(2,2-diphenyl-ethyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    99 2-[(Benzofuran-2-ylmethyl)-amino]- 17.9 459 100 2.26 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[2-(2-
    oxo-pyrrolidin-1-yl)-ethyl]-
    propionamide
    100 2-[(Benzofuran-2-ylmethyl)-amino]- 7.2 473 100 2.26 390
    3-(1H-indol-3-yl)-2-methyl-N-(5-
    nitro-furan-2-ylmethyl)-
    propionamide
    101 2-[(Benzofuran-2-ylmethyl)-amino]- 19.4 456 100 2.27 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[2-(5-
    methyl-1H-imidazol-4-yl)-ethyl]-
    propionamide
    102 2-[(Benzofuran-2-ylmethyl)-amino]- 18.9 549 90 8.66 >10,000
    N-[1-(3-dimethylamino-phenyl)-
    cyclopentylmethyl]-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    103 2-[(Benzofuran-2-ylmethyl)-amino]- 0.4 478 77 0.05 74
    N-(1H-benzoimidazol-2-ylmethyl)-
    3-(1H-indol-3-yl)-2-methyl-
    propionamide
    104 2-[(Benzofuran-2-ylmethyl)-amino]- 8.3 458 100 0.06 8
    N-(1-cyclohexyl-ethyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    105 2-[(Benzofuran-2-ylniethyl)-amino]- 13.2 510 69 0.05 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    phenyl-[1,3]dioxolan-2-ylmethyl)-
    propionamide
    106 2-[(Benzofuran-2-ylmethyl)-amino]- 5.7 507 100 0.06 4630
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    methyl-1,2,3,4-tetrahydro-
    isoquinolin-3-ylmethyl)-
    propionamide
    107 2-[(Benzofuran-2-ylmethyl)-amino]- 14 464 100 0.05 4145
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    phenyl-cyclopropyl)-propionamide
    108 2-[(Benzofuran-2-ylmethyl)-amino]- 0.6 493 100 0.05 4566
    3-(1H-indol-3-yl)-2-methyl-N-
    (1,2,3,4-tetrahydro-isoquinolin-3-
    ylmethyl)-propionamide
    109 2-[(Benzofuran-2-ylmethyl)-amino]- 30.3 512 100 0.06 279
    N-(2,5-dichloro-thiophen-3-
    ylmethyl)-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    110 2-[(Benzofuran-2-ylmethyl)-amino]- 19.7 478 100 0.05 1141
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-cyclopropylmethyl)-
    propionamide
    111 2-[(Benzofuran-2-ylmethyl)-amino]- 1 478 100 0.08 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-
    (1,2,3,4-tetrahydro-naphthalen-2-yl)-
    propionamide
    112 2-[(Benzofuran-2-ylmethyl)-amino]- 3 483 100 0.06 12
    3-(1H-indol-3-yl)-2-methyl-N-(3-
    nitro-benzyl)-propionamide
    113 2-[(Benzofuran-2-ylmethyl)-amino]- 10.1 464 100 0.05 463
    N-indan-2-yl-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    114 2-[(Benzofuran-2-ylmethyl)-amino]- 2.5 472 90 0.05 128
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    thiophen-2-yl-propyl)-propionamide
    115 2-[(Benzofuran-2-ylmethyl)-amino ]- 11.5 442 95 0.05 154
    N-(2-furan-2-yl-ethyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    116 2-[(Benzofuran-2-ylmethyl)-amino]- 5.6 460 100 0.05 >10,000
    N-(1-hydroxy-cyclohexylmethyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    117 2-[(Benzofuran-2-ylmethyl)-amino]- 14.2 482 100 0.06 >10,000
    N-(1-furan-2-yl-cyclobutylmethyl)-
    3-(1H-indol-3-yl)-2-methyl-
    propionamide
    118 2-[(Benzofuran-2-ylmethyl)-amino]- 15 492 100 0.06 45
    N-[1-(5-chloro-thiophen-2-yl)-
    ethyl]-3-(1H-indol-3-yl)-2-methyl-
    propionamide
    119 2-[(Benzofuran-2-ylmethyl)-amino ]- 4.1 483 100 0.07 89
    3-(1H-indol-3-yl)-2-methyl-N-(4-
    nitro-benzyl)-propionamide
    120 2-[(Benzofuran-2-ylmethyl)-amino]- 0.7 506 94 0.06 2652
    N-[2-(1H-indazol-3-yl)-1-methyl-
    ethyl]-3-(1H-indol-3-yl)-2-methyl-
    propionamide
    121 2-[(Benzofuran-2-ylmethyl)-amino]- 15 441 100 0.05 654
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    pyrrol-1-yl-ethyl)-propionamide
    122 2-[(Benzofuran-2-ylmethyl)-amino]- 8.7 526 100 0.08 442
    N-[1-(2,5-dichloro-thiophen-3-yl)-
    ethyl]-3-(1H-indol-3-yl)-2-methyl-
    propionamide
    123 2-[(Benzofuran-2-ylmethyl)-amino]- 7.3 499 63 0.04 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-[2-
    (octahydro-indol-1-yl)-ethyl]-
    propionamide
    124 2-[(Benzofuran-2-ylmethyl)-amino]- 2.6 497 100 0.07 92
    3-(1H-indol-3-yl)-2-methyl-N-[1-(4-
    nitro-phenyl)-ethyl]-propionamide
    125 2-[(Benzofuran-2-ylmethyl)-amino]- 29.5 459 97 0.04 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    piperidin-1-yl-ethyl)-propionamide
    126 2-[(Benzofuran-2-ylmethyl)-amino]- 28 448 95 0.07 6794
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    methyl-[1,3]dioxolan-2-ylmethyl)-
    propionamide
    127 2-[(Benzofuran-2-ylmethyl)-amino]- 23.9 427 100 0.05 191
    N-furan-2-ylmethyl-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    128 2-[(Benzofuran-2-ylmethyl)-amino ]- 31.7 461 95 0.03 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    morpholin-4-yl-ethyl)-propionamide
    129 2-[(Benzofuran-2-ylmethyl)-amino]- 37.7 452 100 0.06 43
    3-(1H-indol-3-yl)-2-methyl-N-(3-
    methyl-benzyl)-propionamide
    130 2-[(Benzofuran-2-ylmethyl)-amino]- 37.8 464 100 0.05 163
    N-indan-1-yl-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    131 2-[(Benzofuran-2-ylmethyl)-amino]- 31.6 487 100 0.08 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    methyl-2-piperidin-1-yl-propyl)-
    propionamide
    132 2-[(Benzofuran-2-ylmethyl)-amino]- 24.6 476 97 0.02 6035
    3-(1H-indol-3-yl)-2-methyl-N-[2-(2-
    thioxo-imidazolidin-1-yl)-ethyl]-
    propionamide
    133 2-[(Benzofuran-2-ylmethyl)-amino]- 5 480 87 0.06 4479
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    methyl-2-phenyl-propyl)-
    propionamide
    134 2-[(Benzofuran-2-ylmethyl)-amino]- 27.3 456 100 0.02 5368
    N-(3-imidazol-1-yl-propyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    135 2-[(Benzofuran-2-ylmethyl)-amino]- 13.5 432 100 0.03 1205
    3-(1H-indol-3-yl)-2-methyl-N-
    (tetrahydro-furan-2-ylmethyl)-
    propionamide
    136 2-[(Benzofuran-2-ylmethyl)-amino]- 26.6 446 95 0.02 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    methyl-tetrahydro-furan-2-
    ylmethyl)-propionamide
    137 2-[(Benzofuran-2-ylmethyl)-amino]- 33.6 444 96 0.03 100
    3-(1H-indol-3-yl)-2-methyl-N-
    thiophen-2-ylmethyl-propionamide
    138 2-[(Benzofuran-2-ylmethyl)-amino]- 25.4 432 96 0.02 4867
    3-(1H-indol-3-yl)-2-methyl-N-
    (tetrahydro-furan-2-ylmethyl)-
    propionamide
    139 2-[(Benzofuran-2-ylmethyl)-amino]- 41.7 474 93 0.05 99
    N-(2,5-difluoro-benzyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    140 2-[(Benzofuran-2-ylmethyl)-amino]- 31.8 466 100 0.05 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    phenyl-propyl)-propionamide
    141 N-(4-Amino-naphthalen-1- 11.6 503 95 0.03 2337
    ylmethyl)-2-[(benzofuran-2-
    ylmethyl)-amino]-3-(1H-indol-3-yl)-
    2-methyl-propionamide
    142 2-[(Benzofuran-2-ylmethyl)-amino]- 19.3 498 96 0.03 1961
    N-(2,3-dimethoxy-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    143 2-[(Benzofuran-2-ylmethyl)-amino]- 32.9 468 96 0.02 >10,000
    N-[2-(4-hydroxy-phenyl)-ethyl]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    144 2-[(Benzofuran-2-ylmethyl)-amino]- 16.4 446 94 0.02 >10,000
    N-(1-hydroxymethyl-cyclopentyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    145 2-[(Benzofuran-2-ylmethyl)-amino]- 35.9 453 97 0.01 1301
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    pyridin-3-yl-ethyl)-propionamide
    146 2-[(Benzofuran-2-ylmethyl)-amino]- 0.8 444 90 0.02 3587
    N-[1-(4,5-dihydro-furan-2-yl)-ethyl]-
    3-(1H-indol-3-yl)-2-methyl-
    propionamide
    147 2-[(Benzofuran-2-ylmethyl)-amino]- 18.5 460 98 0.02 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    piperazin-1-yl-ethyl)-propionamide
    148 2-[(Benzofuran-2-ylmethyl)-amino]- 34.7 478 93 0.03 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-
    (1,2,3,4-tetrahydro-naphthalen-1-yl)-
    propionamide
    149 2-[(Benzofuran-2-ylmethyl)-amino]- 31.8 490 75 0.02 >10,000
    N-(2,5-dimethoxy-2,5-dihydro-
    furan-2-ylmethyl)-3-(1H-indol-3-yl)-
    2-methyl-propionamide
    150 2-[(Benzofuran-2-ylmethyl)-amino]- 32.4 466 95 0.04 2621
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    phenyl-propyl)-propionamide
    151 2-[(Benzofuran-2-ylmethyl)-amino]- 2.4 489 100 0.02 1213
    3-(1H-indol-3-yl)-2-methyl-N-
    quinolin-3-ylmethyl-propionamide
    152 4-[2-[(Benzofuran-2-ylmethyl)- 9 510 94 0.01 >10,000
    amino]-3-(1H-indol-3-yl)-2-methyl-
    propionylamino]-3-phenyl-butyric
    acid
    153 2-[(Benzofuran-2-ylmethyl)-amino]- 6.9 514 100 0.01 3555
    N-[2-hydroxy-2-(4-hydroxy-3-
    methoxy-phenyl)-ethyl]-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    154 2-[(Benzofuran-2-ylmethyl)-amino]- 6.1 431 5 0.04 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-
    pyrrolidin-3-ylmethyl-propionamide
    155 2-[(Benzofuran-2-ylmethyl)-amino]- 25.2 445 93 0.02 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    pyrrolidin-1-yl-ethyl)-propionamide
    156 2-[(Benzofuran-2-ylmethyl)-amino]- 1.4 445 3 0.05 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-
    piperidin-4-ylmethyl-propionamide
    157 2-[(Benzofuran-2-ylmethyl)-amino]- 38.2 452 95 0.02 455
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    methyl-benzyl)-propionamide
    158 2-[(Benzofuran-2-ylmethyl)-amino]- 21.4 464 96 0.02 2567
    N-indan-1-yl-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    159 2-[(Benzofuran-2-ylmethyl)-amino]- 7 492 92 0.01 3757
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    pyridin-3-yl-cyclobutylmethyl)
    propionamide
    160 2-[(Benzofuran-2-ylmethyl)-amino]- 6.1 511 100 0.03 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    thiophen-2-yl-cyclohexyl)-
    propionamide
    161 2-[Benzofuran-2-ylmethyl)amino]- 12.3 484 100 0.01 >10,000
    N-[2-(3,4-dihydroxy-phenyl)-ethyl]-
    3-(1H-indol-3-yl)-2-methyl-
    propionamide
    162 2-[(Benzofuran-2-ylmethyl)-amino]- 8.7 466 95 0.02 42
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-propyl)-propionamide
    163 2-[(Benzofuran-2-ylmethyl)-amino]- 16.9 466 80 0.07 166
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    oxo-2-phenyl-ethyl)-propionamide
    164 2-[(Benzofuran-2-ylmethyl)-amino]- 5.5 542 10 0.06 >10,000
    N-(5-hydroxy-4-oxo-4H-pyran-2-
    ylmethyl)-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    165 2-[(Benzofuran-2-ylmethyl)-amino]- 38.1 456 100 0.08 >10,000
    N-bicyclo[2.2.1]hept-2-ylmethyl-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    166 2-[Benzofuran-2-ylmethyl)-amino]- 41.9 456 95 0.07 37
    N-(3-fluoro-benzyl)-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    167 2-[(Benzofuran-2-ylmethyl)-amino]- 23.2 474 100 0.07 29
    N-(3,4-difluoro-benzyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    168 2-[(Benzofuran-2-ylmethyl)-amino]- 42.8 490 95 0.08 230
    N-(2-chloro-4-fluoro-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    169 2-[(Benzofuran-2-ylmethyl)-amino]- 11.2 467 100 0.06 6016
    N-(4,6-dimethyl-pyridin-3-
    ylmethyl)-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    170 2-[(Benzofuran-2-ylmethyl)-amino]- 49.6 533 100 0.08 2384
    N-(5-bromo-2-hydroxy-benzyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    171 4-{[2-[(Benzofuran-2-ylmethyl)- 28.7 482 95 0.06 >10,000
    amino]-3-(1H-indol-3-yl)-2-methyl-
    propionylamino]-methyl}-benzoic
    acid
    172 2-[(Benzofuran-2-ylmethyl)-amino]- 36.8 458 100 0.07 153
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    thiophen-2-yl-ethyl)-propionamide
    173 2-[(Benzofuran-2-ylmethyl)-amino]- 36.3 475 90 0.06 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(2-
    morpholin-4-yl-2-oxo-ethyl)-
    propionamide
    174 N-Benzo[1,3 ]dioxol-5-ylmethyl-2- 45.7 482 100 0.07 94
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    175 2-[(Benzofuran-2-ylmethyl)-amino]- 21.4 507 90 0.08 96
    N-(3,4-dichloro-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    176 2-[2-[(Benzofuran-2-ylmethyl)- 44.3 453 100 0.07 1763
    amino]-3-(1H-indol-3-yl)-2-methyl-
    propionylamino]-3-(1H-imidazol-4-
    yl)-propionic acid methyl ester
    177 2-[(Benzofuran-2-ylmethyl)-amino]- 24.6 490 100 0.08 444
    N-(4-chloro-2-fluoro-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    178 N-(3-Amino-benzyl)-2- 36.2 453 100 0.06 1373
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    179 2-[(Benzofuran-2-ylmethyl)-amino]- 3.1 470 56 0.06 5917
    N-(2,4-diamino-pyrimidin-5-
    ylmethyl)-3-(1H-indol-3-yl)-2-
    methyl-propionamide
    180 2-[Benzofuran-2-ylmethyl)-amino]- 42 456 95 0.07 266
    N-(2-fluoro-benzyl)-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    181 2-[(Benzofuran-2-ylmethyl)-amino]- 23.4 474 100 0.07 269
    N-(2,4-difluoro-benzyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    182 2-[(Benzofuran-2-ylmethyl)amino]- 4.1 470 90 0.06 >10,000
    N-(3,4-dihydroxy-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
    183 2-[(Benzofuran-2-ylmethyl)-amino]- 1.7 472 33 0.05 >10,000
    N-[1-hydroxymethyl-2-(1H-
    imidazol-4-yl)-ethyl]-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    184 2-[(Benzofuran-2-ylmethyl)-amino]- 36.4 460 100 0.07 >10,000
    N-(2-hydroxy-cyclohexylmethyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    185 2-[(Benzofuran-2-ylmethyl)-amino]- 28.5 475 100 0.06 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(3-
    morpholin-4-yl-propyl)-
    propionamide
    186 2-[Benzofuran-2-ylmethyl)-amino]- 8.5 454 81 0.07 84
    N-(2-hydroxy-benzyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    187 2-[(Benzofuran-2-ylmethyl)-amino]- 42.2 486 100 0.07 131
    N-(3-fluoro-4-methoxy-benzyl)-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    188 N-(2-Amino-methoxy-benzyl)-2- 10 483 96 0.06 2282
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-2-methyl-
    propionamide
    189 2-[(Benzofuran-2-ylmethyl)-amino]- 47 472 94 0.07 1129
    N-(2-chloro-benzyl)-3-(1H-indol-3-
    yl)-2-methyl-propionamide
    190 2-[(Benzofuran-2-ylmethyl)-amino]- 41.6 474 97 0.07 3537
    N-(2,6-difluoro-benzyl)-3-(1H-indol-
    3-yl)-2-methyl-propionamide
    191 2-[(Benzofuran-2-ylmethyl)-amino]- 24.4 490 99 0.07 55
    N-(3-chloro-4-fluoro-benzyl)-3-(1H-
    indol-3-yl)-2-methyl-propionamide
  • [0341]
    TABLE 3
    Examples 192-308
    Yield Mol. Icms % Icms Rt IC50 (nM)
    Ex. Name (mg) ion purity (min) hNK1
    192 2-[(Benzofuran-2-ylmethyl)-amino]- 26 425 100 3.94 1981
    3-(1H-indol-3-yl)-N-pyridin-2-
    ylmethyl-propionamide
    193 2-[(Benzofuran-2-ylmethyl)-amino]- 27 446 94 1.04 >10,000
    3-(1H-indol-3-yl)-N-(2-piperazin-1-
    yl-ethyl)-propionamide
    194 2-[(Benzofuran-2-ylmethyl)-amino]- 41 464 100 5.63, 703
    3-(1H-indol-3-yl)-N-(1,2,3,4- 5.80
    tetrahydro-naphthalen-1-yl)-
    propionamide
    195 2[(Benzofuran-2-ylmethyl)-amino]- 23 450 100 5.39 1750
    N-indan-1-yl-3-(1H-indol-3-yl)-
    propionamide
    196 2-[(Benzofuran-2-ylmethyl)-amino]- 36 458 100 5.67 92
    3-(1H-indol-3-yl)-N-(1-thiophen-2-
    yl-propyl)-propionamide
    197 2-[(Benzofuran-2-ylmethyl)-amino]- 44 488 99 6.77 933
    3-(1H-indol-3-yl)-N-(1-naphthalen-
    1-yl-ethyl)-propionamide
    198 2-[(Benzofuran-2-ylmethyl)-amino]- 31 445 99 2.27 >10,000
    3-(1H-indol-3-yl)-N-[2-(1-methyl-
    pyrrolidin-2-yl)-ethyl]-propionamide
    199 2-[(Benzofuran-2-ylmethyl)-amino]- 39 454 100 5.11 130
    3-(1H-indol-3-yl)-N-(4-methoxy-
    benzyl)-propionamide
    200 2-[(Benzofuran-2-ylmethyl)-amino]- 34 508 96 6.19 355
    3-(1H-indol-3-yl)-N-(3-
    trifluoromethoxy-benzyl)-
    propionamide
    201 2-[(Benzofuran-2-ylmethyl)-amino]- 21 442 100 1.22 >10,000
    N-(3-imidazol-1-yl-propyl)-3-(1H-
    indol-3-yl)-propionamide
    202 2-[(Benzofuran-2-ylmethyl)-amino]- 6 417 98 4.3 2184
    3-(1H-indol-3-yl)-N-pyrrolidin-3-
    ylmethyl-propionamide
    203 2-[(Benzofuran-2-ylmethyl)-amino]- 22 431 96 1.26 >10,000
    3-(1H-indol-3-yl)-N-piperidin-4-
    ylmethyl-propionamide
    204 2-[(Benzofuran-2-ylmethyl)-amino]- 18 460 100 5.53 68
    N-(2,5-difluoro-benzyl)-3-(1H-indol-
    3-yl)-propionamide
    205 2-[(Benzofuran-2-ylmethyl)-amino]- 10 475 97 4.27 2315
    3-(1H-indol-3-yl)-N-quinolin-3-
    ylmethyl-propionamide
    206 2-[(Benzofuran-2-ylmethyl)-amino]- 16 428 98 2.31 6681
    N-[2-(1H-imidazol-4-yl)-ethyl]-3-
    (1H-indol-3-yl)-propionamide
    207 2-[(Benzofuran-2-ylmethyl)-amino]- 43 489 98 6.76 591
    3-(1H-indol-3-yl)-N-(1-naphthalen-
    1-yl-ethyl)-propionamide
    208 2-[(Benzofuran-2-ylmethyl)-amino]- 31 458 100 5.94 15
    3-(1H-indol-3-yl)-N-[1-(5-methyl-
    thiophen-2-yl)-ethyl]-propionalnide
    209 2-[(Benzofuran-2-ylmethyl)-amino]- 35 438 100 5.74 82
    3-(1H-indol-3-yl)-N-(4-methyl-
    benzyl)-propionamide
    210 2-[(Benzofuran-2-ylmethyl)-amino]- 36 452 100 5.98 337
    3-(1H-indol-3-yl)-N-(1-p-tolyl-
    ethyl)-propionamide
    211 2-[(Benzofuran-2-ylmethyl)-amino]- 21 432 100 5 >10,000
    N-(1-hydroxymethyl-cyclopentyl)-3-
    (1H-indol-3-yl)-propionamide
    212 2-[(Benzofuran-2-ylmethyl)-amino]- 18 427 96 5.21 658
    3-(1H-indol-3-yl)-N-(2-pyrrol-1-yl-
    ethyl)-propionamide
    213 2-[(Benzofuran-2-ylmethyl)-amino]- 28 447 100 1.39 1256
    3-(1H-indol-3-yl)-N-(2-morpholin-4-
    yl-ethyl)-propionamide
    214 2-[(Benzofuran-2-ylmethyl)-amino]- 39 467 99 4.3 4015
    N-(4-dimethylamino-benzyl)-3-(1H-
    indol-3-yl)-propionamide
    215 2-[(Benzofuran-2-ylmethyl)-amino]- 9 498 97 6.61 70
    N-(2,5-dichloro-thiophen-3-
    ylmethyl)-3-(1H-indol-3-yl)-
    propionamide
    216 2-[(Benzofuran-2-ylmethyl)-amino]- 2 459 11 5.07 >10,000
    3-(1H-indol-3-yl)-N-(5-nitro-furan-
    2-ylmethyl)-propionamide
    217 2-[(Benzofuran-2-ylmethyl)-amino]- 44 481 99 4.46, 819
    N-[1-(4-dimethylamino-phenyl)- 4.78
    ethyl]-3-(1H-indol-3-yl)-
    propionamide
    218 2-[(Benzofuran-2-ylmethyl)-amino]- 20 560 85 7.14 294
    N-(3,5-bis-trifluoromethyl-benzyl)-
    3-(1H-indol-3-yl)-propionamide
    219 2-[(Benzofuran-2-ylmethyl)-amino]- 17 502 96 6.96 31
    N-(3-bromo-benzyl)-3-(1H-indol-3-
    yl)-propionamide
    220 2-[(Benzofuran-2-ylmethyl)-amino]- 38 452 100 6.16 2
    3-(1H-indol-3-yl)-N-(1-p-tolyl-
    ethyl)-propionamide
    221 2-[(Benzofuran-2-ylmethyl)-amino]- 37 469 100 5.67 23
    3-(1H-indol-3-yl)-N-(4-nitro-
    benzyl)-propionamide
    222 2-[(Benzofuran-2-ylmethyl)-amino]- 30 431 100 1.64 >10,000
    3-(1H-indol-3-yl)-N-(2-pyrrolidin-1-
    yl-ethyl)-propionamide
    223 2-[(Benzofuran-2-ylmethyl)-amino]- 36 418 100 4.65 >10,000
    3-(1H-indol-3-yl)-N-(tetrahydro-
    furan-2-ylmethyl)-propionamide
    224 2-[(Benzofuran-2-ylmethyl)-amino]- 9 450 100 6.05 2902
    3-(1H-indol-3-yl)-N-(2-phenyl-
    cyclopropyl)-propionamide
    225 2-[(Benzofuran-2-ylmethyl)-amino]- 32 458 97 7.07 1341
    N-(1-cyclohexyl-1-methyl-ethyl)-3-
    (1H-indol-3-yl)-propionamide
    226 2-[(Benzofuran-2-ylmethyl)-amino]- 33 430 100 6.23 54
    N-cyclohexylmethyl-3-(1H-indol-3-
    yl)-propionamide
    227 2-[(Benzofuran-2-ylmethyl)-amino]- 41 481 96 5.05, 182
    N-[1-(3-dimethylamino-phenyl)- 5.36
    ethyl]-3-(1H-indol-3-yl)-
    propionamide
    228 2-[(Benzofuran-2-ylmethyl)-amino]- 31 492 100 6.63 82
    3-(1H-indol-3-yl)-N-(3-
    trifluoromethyl-benzyl)-
    propionamide
    229 2-[(Benzofuran-2-ylmethyl)-amino]- 39 476 98 6.4 33
    N-(3-chloro-4-fluoro-benzyl)-3-(1H-
    indol-3-yl)-propionamide
    230 2-[(Benzofuran-2-ylmethyl)-amino]- 38 441 100 5.54 21
    3-(1H-indol-3-yl)-N-[1-(1-methyl-
    1H-pyrrol-3-yl)-ethyl]-propionamide
    231 2-[(Benzofuran-2-ylmethyl)-amino]- 35 425 100 0.04 790
    3-(1H-indol-3-yl)-N-pyridin-3-
    ylmethyl-propionamide
    232 2-[(Benzofuran-2-ylmethyl)-amino]- 30 430 100 0.06 63
    3-(1H-indol-3-yl)-N-thiophen-2-
    ylmethyl-propionamide
    233 2-[(Benzofuran-2-ylmethyl)-amino]- 37 452 100 0.07 1998
    3-(1H-indol-3-yl)-N-(2-phenyl-
    propyl)-propionamide
    234 2-[(Benzofuran-2-ylmethyl)-amino]- 37 438 100 0.07 75
    3-(1H-indol-3-yl)-N-(1-phenyl-
    ethyl)-propionamide
    235 2-[(Benzofuran-2-ylmethyl)-amino]- 40 456 100 0.07 3
    N-[1-(4-fluoro-phenyl)-ethyl]-3-(1H-
    indol-3-yl)-propionamide
    236 2-[(Benzofuran-2-ylmethyl)-amino]- 41 444 100 0.07 7
    3-(1H-indol-3-yl)-N-(1-thiophen-3-
    yl-ethyl)-propionamide
    237 2-[(Benzofuran-2-ylmethyl)-amino]- 38 435 0 0.10 5341
    3-(1H-indol-3-yl)-N-(2-oxo-2-
    phenyl-ethyl)-propionamide
    238 2-[(Benzofuran-2-ylmethyl)-amino]- 34 442 100 0.07 89
    N-(2-fluoro-benzyl)-3-(1H-indol-3-
    yl)-propionamide
    239 2-[(Benzofuran-2-ylmethyl)-amino]- 36 450 100 0.07 243
    N-indan-2-yl-3-(1H-indol-3-yl)-
    propionamide
    240 2-[(Benzofuran-2-ylmethyl)-amino]- 33 425 100 0.04 196
    3-(1H-indol-3-yl)-N-pyridin-4-
    ylmethyl-propionamide
    241 2-[(Benzofuran-2-ylmethyl)-amino]- 29 444 100 0.07 2
    N-(1-cyclohexyl-ethyl)-3-(1H-indol-
    3-yl)-propionamide
    242 2-[(Benzofuran-2-ylmethyl)-amino]- 39 438 100 0.07 170
    3-(1H-indol-3-yl)-N-(2-methyl-
    benzyl)-propionamide
    243 2-[(Benzofuran-2-ylmethyl)-amino]- 44 478 100 0.07 15
    N-[1-(5-chloro-thiophen-2-yl)-
    ethyl]-3-(1H-indol-3-yl)-
    propionamide
    244 2-[(Benzofuran-2-ylmethyl)-amino]- 38 442 100 0.07 12
    N-(4-fluoro-benzyl)-3-(1H-indol-3-
    yl)-propionamide
    245 2-[(Benzofuran-2-ylmethyl)-amino]- 32 483 100 0.07 3
    3-(1H-indol-3-yl)-N-[1-(4-nitro-
    phenyl)-ethyl]-propionamide
    246 2-[(Benzofuran-2-ylmethyl)-amino]- 39 438 100 0.07 77
    3-(1H-indol-3-yl)-N-phenethyl-
    propionamide
    247 2-[(Benzofuran-2-ylmethyl)-amino]- 33 444 100 0.07 56
    3-(1H-indol-3-yl)-N-(2-thiophen-2-
    yl-ethyl)-propionamide
    248 2-[(Benzofuran-2-ylmethyl)-amino]- 37 442 100 0.07 6
    N-(3-fluoro-benzyl)-3-(1H-indol-3-
    yl)-propionamide
    249 2-[(Benzofuran-2-ylmethyl)-amino]- 43 454 100 0.06 607
    N-(2-hydroxy-1-phenyl-ethyl)-3-
    (1H-indol-3-yl)-propionamide
    250 2-[(Benzofuran-2-ylmethyl)-amino]- 36 464 100 0.05 3413
    N-(1H-benzoimidazol-2-ylmethyl)-
    3-(1H-indol-3-yl)-propionamide
    251 2-[(Benzofuran-2-ylmethyl)-amino]- 4 428 95 0.06 129
    N-(2-furan-2-yl-ethyl)-3-(1H-indol-
    3-yl)-propionamide
    252 2-[(Benzofuran-2-ylmethyl)-amino]- 37 438 100 0.07 33
    3-(1H-indol-3-yl)-N-(3-methyl-
    benzyl)-propionamide
    253 2-[(Benzofuran-2-ylmethyl)-amino]- 25 464 81 0.07 3327
    3-(1H-indol-3-yl)-N-(1,2,3,4-
    tetrahydro-naphthalen-2-yl)-
    propionamide
    254 2-[(Benzofuran-2-ylmethyl)-amino]- 37 424 100 0.06 22
    N-benzyl-3-(1H-indol-3-yl)-
    propionamide
    255 2-[(Benzofuran-2-ylmethyl)-amino]- 41 468 100 0.07 9
    3-(1H-indol-3-yl)-N-[1-(4-methoxy-
    phenyl)-ethyl]-propionamide
    256 2-[(Benzofuran-2-ylmethyl)-amino]- 5 440 68 0.05 >10,000
    N-(2-hydroxy-benzyl)-3-(1H-indol-
    3-yl)-propionamide
    257 2-[(Benzofuran-2-ylmethyl)-amino]- 35 466 100 0.07 >10,000
    3-(1H-indol-3-yl)-N-(2-methyl-2-
    phenyl-propyl)-propionamide
    258 2-[(Benzofuran-2-ylmethyl)-amino]- 38 458 100 0.07 46
    N-(4-chloro-benzyl)-3-(1H-indol-3-
    yl)-propionamide
    259 2-[(Benzofuran-2-ylmethyl)-amino]- 39 452 100 0.07 21
    3-(1H-indol-3-yl)-N-(1-phenyl-
    propyl)-propionamide
    260 2-[(Benzofuran-2-ylmethyl)-amino]- 32 469 100 0.06 14
    3-(1H-indol-3-yl)-N-(3-nitro-
    benzyl)-propionamide
    261 2-[(Benzofuran-2-ylmethyl)-amino]- 31 414 100 0.06 406
    N-furan-2-ylmethyl-3-(1H-indol-3-
    yl)-propionamide
    262 2-[(Benzofuran-2-ylmethyl)-amino]- 41 450 100 0.07 86
    N-indan-1-yl-13-(1H-indol-3-yl)-
    propionamide
    263 2-[(Benzofuran-2-ylmethyl)-amino]- 36 458 100 0.07 9
    N-(3-chloro-benzyl)-3-(1H-indol-3-
    yl)-propionamide
    264 2-((Benzofuran-2-ylmethyl)-amino]- 44 472 100 0.07 7
    N-[1-(4-chloro-phenyl)-ethyl]-3-
    (1H-indol-3-yl)-propionamide
    265 2-[(Benzofuran-2-ylmethyl)-amino]- 41 452 96 0.07 328
    3-(1H-indol-3-yl)-N-(1-methyl-1-
    phenyl-ethyl)-propionamide
    266 2-[(Benzofuran-2-ylmethyl)-amino]- 39 442 100 0.07 633
    N-bicyclo[2.2.1]hept-2-ylmethyl-3-
    (1H-indol-3-yl)-propionamide
    267 N-Benzo[1,3]dioxol-5-ylmethyl-2- 40 468 100 0.06 55
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-propionamide
    268 2-[(Benzofuran-2-ylmethyl)-amino]- 39 460 91 0.07 10
    N-(3,4-difluoro-benzyl)-3-(1H-indol-
    3-yl)-propionamide
    269 2-[(Benzofuran-2-ylmethyl)-amino]- 9 439 92 0.04 9
    3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-
    ethyl)-propionamide
    270 2-[(Benzofuran-2-ylmethyl)-amino]- 19 432 100 0.04 >10,000
    N-(2-hydroxy-cyclohexyl)-3-(1H-
    indol-3-yl)-propionamide
    271 2-[(Benzofuran-2-ylmethyl)-amino]- 33 468 98 0.05 196
    3-(1H-indol-3-yl)-N-[2-(4-methoxy-
    phenyl)-ethyl]-propionamide
    272 2-[(Benzofuran-2-ylmethyl)-amino]- 42 468 99 0.05 336
    N-(1-hydroxymethyl-2-phenyl-
    ethyl)-3-(1H-indol-3-yl)-
    propionamide
    273 2-[(Benzofuran-2-ylmethyl)-amino]- 15 432 99 0.04 >10,000
    N-(4-hydroxy-cyclohexyl)-3-(1H-
    indol-3-yl)-propionamide
    274 2-[(Benzofuran-2-ylmethyl)-amino]- 21 456 97 0.05 264
    N-[2-(2-fluoro-phenyl)-ethyl]-3-(1H-
    indol-3-yl)-propionamide
    275 2-[(Benzofuran-2-ylmethyl)-amino]- 38 514 100 0.05 2157
    N-(2-benzylsulfanyl-1-
    hydroxymethyl-ethyl)-3-(1H-indol-
    3-yl)-propionamide
    276 2-[(Benzofuran-2-ylmethyl)-amino]- 10 416 84 0.05 655
    N-cyclohexyl-3-(1H-indol-3-yl)-
    propionamide
    277 2-[(Benzofuran-2-ylmethyl)-amino]- 17 474 96 0.05 2198
    N-(2-cyclohexyl-1-hydroxymethyl-
    ethyl)-3-(1H-indol-3-yl)-
    propionamide
    278 2-[(Benzofuran-2-ylmethyl)-amino]- 33 452 88 0.05 2379
    3-(1H-indol-3-yl)-N-(3-phenyl-
    propyl)-propionamide
    279 2-[(Benzofuran-2-ylmethyl)-amino]- 8 493 86 0.06 30
    N-(3,4-dichloro-benzyl)-3-(1H-
    indol-3-yl)-propionamide
    280 2-[(Benzofuran-2-ylmethyl)-amino]- 25 477 97 0.05 2540
    3-(1H-indol-3-yl)-N-[2-(1H-indol-3-
    yl)-ethyl]-propionamide
    281 2-[(Benzofuran-2-ylmethyl)-amino]- 28 483 93 0.05 51
    3-(1H-indol-3-yl)-N-[2-(4-nitro-
    phenyl)-ethyl]-propionamide
    282 2-[(Benzofuran-2-ylmethyl)-amino]- 30 487 98 0.06 833
    N-[2-(4-chloro-phenyl)-1-methyl-
    ethyl]-3-(1H-indol-3-yl)-
    propionamide
    283 2-[(Benzofuran-2-ylmethyl)-amino]- 9 492 91 0.06 420
    3-(1H-indol-3-yl)-N-(4-
    trifluoromethyl-benzyl)-
    propionamide
    284 2-[(Benzofuran-2-ylmethyl)-amino]- 33 456 98 0.05 62
    N-[2-(4-fluoro-phenyl)-ethyl]-3-(1H-
    indol-3-yl)-propionamide
    285 2-[(Benzofuran-2-ylmethyl)-amino]- 32 483 99 0.05 246
    3-(1H-indol-3-yl)-N-[1-(4-nitro-
    phenyl)-ethyl]-propionamide
    286 4-{[2-[(Benzofuran-2-ylmethyl)-6 474 62 005 >10,000
    amino]-3-(1H-indol-3-yl)-
    propionylamino]-methyl}-
    cyclohexanecarboxylic acid
    287 2-[(Benzofuran-2-ylmethyl)-amino]- 36 449 99 0.06 35
    N-(cyano-phenyl-methyl)-3-(1H-
    indol-3-yl)-propionamide
    288 2-[(Benzofuran-2-ylmethyl)-amino]- 32 472 99 0.06 136
    N-[2-(4-chloro-phenyl)-ethyl]-3-
    (1H-indol-3-yl)-propionamide
    289 2-[(Benzofuran-2-ylmethyl)-amino]- 35 468 99 0.05 209
    N-(1-hydroxymethyl-2-phenyl-
    ethyl)-3-(1H-indol-3-yl)-
    propionamide
    290 2-[(Benzofuran-2-ylmethyl)-amino]- 37 517 100 0.06 8
    N-[1-(4-bromo-phenyl)-ethyl]-3-
    (1H-indol-3-yl)-propionamide
    291 2-[(Benzofuran-2-ylmethyl)-amino]- 29 468 96 0.05 1337
    3-(1H-indol-3-yl)-N-[2-(3-methoxy-
    phenyl)-ethyl]-propionamide
    292 2-[(Benzofuran-2-ylmethyl)-amino]- 3 492 90 0.06 1126
    3-(1H-indol-3-yl)-N-(2-
    trifluoromethyl-benzyl)-
    propionamide
    293 2-[(Benzofuran-2-ylmethyl)-amino]- 33 456 96 0.05 55
    N-[2-(3-fluoro-phenyl)-ethyl]-3-(1H-
    indol-3-yl)-propionamide
    294 2-[(Benzofuran-2-ylmethyl)-amino]- 15 444 86 0.06 58
    N-(1-cyclohexyl-ethyl)-3-(1H-indol-
    3-yl)-propionamide
    295 2-[(Benzofuran-2-ylmethyl)-amino]- 34 482 99 0.06 3531
    3-(1H-indol-3-yl)-N-(1-
    methoxymethyl-2-phenyl-ethyl)-
    propionamide
    296 2-[(Benzofuran-2-ylmethyl)-amino]- 16 484 98 0.06 1338
    N-(2-benzylsulfanyl-ethyl)-3-(1H-
    indol-3-yl)-propionamide
    297 2-[(Benzofuran-2-ylmethyl)-amino]- 36 491 100 0.05 3612
    3-(1H-indol-3-yl)-N-[2-(1H-indol-3-
    yl)-1-methyl-ethyl]-propionamide
    298 2-[(Benzofuran-2-ylmethyl)-amino]- 22 458 99 0.06 221
    N-(2-chloro-benzyl)-3-(1H-indol-3-
    yl)-propionamide
    299 2-[(Benzofuran-2-ylmethyl)-amino]- 28 454 93 0.05 4
    N-(2-hydroxy-1-phenyl-ethyl)-3-
    (1H-indol-3-yl)-propionamide
    300 2-[(Benzofuran-2-ylmethyl)-amino]- 10 452 98 0.06 256
    3-(1H-indol-3-yl)-N-(2-p-tolyl-
    ethyl)-propionamide
    301 2-[(Benzofuran-2-ylmethyl)-amino]- 12 460 98 0.06 53
    N-(2,4-difluoro-benzyl)-3-(1H-indol-
    3-yl)-propionamide
    302 2-[(Benzofuran-2-ylmethyl)-amino]- 25 503 98 0.06 174
    N-(2-bromo-benzyl)-3-(1H-indol-3-
    yl)-propionamide
    303 2-[(Benzofuran-2-ylmethyl)-amino]- 7 510 88 0.06 17
    N-(3-fluoro-5-trifluoromethyl-
    benzyl)-3-(1H-indol-3-yl)-
    propionamide
    304 [2-[(Benzofuran-2-ylmethyl)- 36 482 100 0.06 43
    amino]-3-(1H-indol-3-yl)-
    propionylamino]-phenyl-acetic acid
    methyl ester
    305 2-[(Benzofuran-2-ylmethyl)-amino]- 30 454 99 0.06 400
    3-(1H-indol-3-yl)-N-(2-phenoxy-
    ethyl)-propionamide
    306 N-(4-Amino-benzyl)-2- 32 439 99 0.04 639
    [(benzofuran-2-ylmethyl)-amino]-3-
    (1H-indol-3-yl)-propionamide
    307 2-[(Benzofuran-2-ylmethyl)-amino]- 36 466 99 0.06 392
    3-(1H-indol-3-yl)-N-(1-methyl-3-
    phenyl-propyl)-propionamide
    308 2-[(Benzofuran-2-ylmethyl)-amino]- 6 440 94 0.05 731
    N-(3-hydroxy-benzyl)-3-(1H-indol-
    3-yl)-propionamide
  • [0342]
    TABLE 4
    Examples 309-359
    Yield Mol. Icms % Icms Rt IC50 (nM)
    Ex. Name (mg) ion purity (min) hNK1
    309 3-(1H-Indol-3-yl)-2-methyl-2- 30.51 462 50 6.44 169
    [(naphthalen-2-ylmethyl)-amino]-N-
    (1-phenyl-ethyl)-propionamide
    310 3-(1H-Indol-3-yl)-2-methyl-N-(1- 37.02 413 83 4.74 3325
    phenyl-ethyl)-2-[(pyridin-2-
    ylmethyl)-amino]-propionamide
    311 3-(1H-Indol-3-yl)-2-methyl-N-(1- 31.53 463 84 5.96 88
    phenyl-ethyl)-2-[(quinolin-2-
    ylmethyl)-amino]-propionamide
    312 2-[(Furan-3-ylmethyl)-amino]-3- 28 402 78 4.9 1820
    (1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    313 3-(1H-Indol-3-yl)-2-methyl-N-(1- 41.02 452 8 6.02 50
    phenyl-ethyl)-2-[(pyridin-4-
    ylmethyl)-amino]-propionamide
    314 2-[(Furan-2-ylmethyl)-amino]-3- 27.6 402 74 4.82 141
    (1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    315 3-(1H-Indol-3-yl)-2-methyl-N-(1- 3.13 463 12 3.78 1068
    phenyl-ethyl)-2-[(quinolin-3-
    ylmethyl)-amino]-propionamide
    316 2-[(1H-Benzoimidazol-2-ylmethyl)- 58.59 452 16 4.63 >10,000
    amino]-3-(1H-indol-3-yl)-2-methyl-
    N-(1-phenyl-ethyl)-propionamide
    317 3-(1H-Indo1-3-yl)-2-[(5-methoxy- 33.16 482 75 7.29 >10,000
    benzofuran-2-ylmethyl)-amino]-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    318 3-(1H-Indol-3-yl)-2-](isoquinolin-4- 8.84 463 55 3.28 1596
    ylmethyl)-amino]-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    319 3-(1H-Indol-3-yl)-2-](6-methoxy- 5.15 482 65 7.22 2098
    benzofuran-2-ylmethyl)-amino]-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    320 3-(1H-Indol-3-yl)-2-methyl-N-(1- 20.2 413 72 2.51 5972
    phenyl-ethyl)-2-[(pyridin-3-
    ylmethyl)-amino]-propionamide
    321 2-{2-[2-(1,3-Dioxo-1,3-dihydro- 20.67 552 96 0.05 3040
    isoindol-2-yl)-acetylamino]-
    ethylamino}-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    322 2-(3-Furan-2-yl-allylamino)-3-(1H- 2.88 428 47 0.05 91
    indol-3-yl)-2-methyl-N-(1-phenyl-
    ethyl)-propionamide
    323 3-(1H-Indol-3-yl)-2-methyl-N-(1- 28.74 519 69 0.05 3183
    phenyl-ethyl)-2-[2-(pyridin-2-
    ylmethoxy)-benzylamino]-
    propionamide
    324 3-(1H-Indol-3-yl)-2-methyl-N-(1- 32.96 519 88 0.04 2971
    phenyl-ethyl)-2-[2-(pyridin-3-
    ylmethoxy)-benzylamino]-
    propionamide
    325 3-(1H-Indol-3-yl)-2-methyl-N-(1- 42.66 504 77 0.06 72
    phenyl-ethyl)-2-[(5-styryl-furan-2-
    ylmethyl)-amino]-propionamide
    326 2-(4-Chloro-3-methylsulfamoyl- 8.05 539 83 0.05 4827
    benzylamino)-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    327 5-(4-{[2-(1H-Indol-3-yl)-1-methyl- 7.02 556 92 0.05 >10,000
    1-(1-phenyl-ethylcarbamoyl)-
    ethylamino]-methyl}-phenoxy)-2,2-
    dimethyl-pentanoic acid
    328 3-(1H-Indol-3-yl)-2-methyl-2-{[4- 17.49 498 86 0.07 >10,000
    (4-methyl-pent-2-enyl)-cyclohex-3-
    enylmethyl]-amino}-N-(1-phenyl-
    ethyl)-propionamide
    329 (2-{[2-(1H-Indol-3-yl)-1-methyl-1- 16.92 499 95 0.05 4188
    (1-phenyl-ethylcarbamoyl)-
    ethylamino]-methyl}-phenyl)-
    carbamic acid ethyl ester
    330 2-(4-Chloro-2-methylsulfamoyl- 7.56 539 89 0.05 1100
    benzylamino)-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    331 2-[4-(2-Dimethylamino-ethoxy)- 24.9 499 65 0.03 >10,000
    benzylamino]-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    332 2-(2,3-Diphenyl-propylamino)-3- 10.84 516 98 0.06 4944
    (1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    333 3-(1H-Indol-3-yl)-2-methyl-N-(1- 16.98 516 98 0.06 3606
    phenyl-ethyl)-2-[(1-phenyl-1H-
    indol-2-ylmethyl)-amino]-
    propionamide
    334 3-(1H-Indol-3-yl)-2-methyl-N-(1- 19.88 527 74 0.06 >10,000
    phenyl-ethyl)-2-[4-(4-phenyl-
    piperidin-1-yl)-benzylamino]-
    propionamide
    335 3-(1H-Indol-3-yl)-2-methyl-N-(1- 38.16 571 65 0.06 >10,000
    phenyl-ethyl)-2-[4-(2-pyrrolidin-1-
    yl-ethoxy)-benzylamino]-
    propionamide
    336 2-(4-Chloro-3-sulfamoyl- 5.2 525 79 0.03 4229
    benzylamino)-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    337 4-{[2-(1H-Indol-3-yl)-1-methy1-1- 20.24 525 81 0.04 1920
    (1-phenyl-ethylcarbamoyl)-
    ethylamino]-methyl}-benzoic acid
    methyl ester
    338 2-(2,3-Diphenyl-allylamino)-3-(1H- 20.13 470 99 0.05 >10,000
    indol-3-yl)-2-methyl-N-(1-phenyl-
    ethyl)-propionamide
    339 2-(3-Benzo[1,3]dioxol-5-yl- 24.74 514 54 0.06 343
    allylamino)-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    340 2-[3-(4-Benzyloxy-phenyl)- 24.64 482 72 0.05 4912
    allylamino]-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    341 2-(4-Benzyloxy-benzylamino)-3- 32.02 544 62 0.06 >10,000
    (1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    342 Toluene-4-sulfonic acid 3-{[2-(1H- 20.65 518 96 0.06 5091
    indol-3-yl)-1-methyl-1-(1-phenyl-
    ethylcarbamoyl)-ethylamino]-
    methyl}-phenyl ester
    343 2-[(Benzofuran-2-ylmethyl)-amino]- 23.9 582 93 0.06 13
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    344 2-(3-Benzyloxy-benzylamino)-3- 33.15 518 89 0.06 185
    (1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    345 3-(1H-Indol-3-yl)-2-methyl-2-(4- 31.61 458 90 0.06 609
    methylsulfanyl-benzylamino)-N-(1-
    phenyl-ethyl)-propionamide
    346 2-[(Anthracen-9-ylmethyl)-amino]- 17.46 512 73 0.07 >10,000
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    347 3-(1H-Indol-3-yl)-2-methyl-2-(4- 36.52 504 95 0.06 3382
    phenoxy-benzylamino)-N-(1-phenyl-
    ethyl)-propionamide
    348 2-[(Biphenyl-4-ylmethyl)-amino]-3- 30.82 488 93 0.06 5562
    (1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    349 2-[(Benzo[1,3]dioxol-5-y1methyl)- 33.19 456 94 0.06 356
    amino]-3-(1H-indol-3-yl)-2-methyl-
    N-(1-phenyl-ethyl)-propionamide
    350 2-[2-(4-Chloro-phenylsulfanyl)- 21.92 554 90 0.07 >10,000
    benzylamino]-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    351 3-(1H-Indol-3-yl)-2-methyl-N-(1- 22.24 514 88 0.07 >10,000
    phenyl-ethyl)-2-(4-styryl-
    benzylamino)-propionamide
    352 2-(2,6-Dimethyl-octa-2,6- 30.03 458 44 0.07 2212
    dienylamino)-3-(1H-indol-3-yl)-2-
    methyl-N-(1-phenyl-ethyl)-
    propionamide
    353 3-(1H-Indol-3-yl)-2-methyl-2-{[5- 38.51 523 82 0.06 13
    (4-nitro-phenyl)-furan-2-ylmethyl]-
    amino}-N-(1-phenyl-ethyl)-
    propionamide
    354 2-[(9H-Fluoren-2-ylmethyl)-amino]- 27.91 500 92 0.06 1731
    3-(1H-indol-3-yl)-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    355 3-(1H-Indol-3-yl)-2-[(1H-indol-3- 9.83 451 69 0.06 1047
    ylmethyl)-amino]-2-methyl-N-(1-
    phenyl-ethyl)-propionamide
    356 3-(1H-Indol-3-yl)-2-methyl-2-(2- 33.02 508 86 0.07 >10,000
    pentyl-3-phenyl-allylamino)-N-(1-
    phenyl-ethyl)-propionamide
    357 3-(1H-Indol-3-yl)-2-methyl-N-(1- 18.91 418 97 0.05 548
    phenyl-ethyl)-2-[(thiophen-2-
    ylmethyl)-amino]-propionamide
    358 3-(1H-Indol-3-yl)-2-methyl-N-(1- 18.79 418 99 0.05 598
    phenyl-ethyl)-2-[(thiophen-3-
    ylmethyl)-amino]-propionamide
    359 3-(1H-Indol-3-yl)-2-methyl-N-(1- 7.47 413 79 0.04 3712
    phenyl-ethyl)-2-[(pyridin-4-
    ylmethyl)-amino]-propionamide
  • [0343]
    TABLE 5
    Examples 360-405
    Yield Mol. Icms % Icms Rt IC50 (nM)
    Ex. (mg) ion purity (min) hNK1
    360 2-(3-Furan-2-yl-allylamino)-3-(1H- 12.16 414 59 0.06 >10,000
    indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    361 3-(1H-Indol-3-yl)-N-(1-phenyl- 14.01 505 79 0.04 729
    ethyl)-2-[2-(pyridin-3-ylmethoxy)-
    benzylamino]-propionamide
    362 3-(1H-Indol-3-yl)-N-(1-phenyl- 39.92 490 36 0.08 >10,000
    ethyl)-2-[(5-styryl-furan-2-
    ylmethyl)-amino]-propionamide
    363 2-(4-Chloro-3-methylsulfamoyl- 18.8 526 86 0.06 490
    benzylamino)-3-(1H-indol-3-yl)-N-
    (1-phenyl-ethyl)-propionamide
    364 5-(4-{[2-(1H-Indol-3-yl)-1-(1- 12.49 543 79 0.07 1247
    phenyl-ethylcarbamoyl)-
    ethylamino]-methyl}-phenoxy)-2,2-
    dimethyl-pentanoic acid
    365 2-{[4-(4-Hydroxy-4-methyl-pentyl)- 31.21 503 42 0.07 5278
    cyclohex-3-enylmethyl]-amino}-3-
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    366 3-(1H-Indol-3-yl)-2-{[4-(4-methyl- 38.13 484 65 0.09 4046
    pent-2-enyl)-cyclohex-3-
    enylmethyl]-amino}-N-(1-phenyl-
    ethyl)-propionamide
    367 (2-{[2-(1H-Indol-3-yl)-1-(1-phenyl- 4.86 485 82 0.07 236
    ethylcarbamoyl)-ethylamino]-
    methyl}-phenyl)-carbamic acid ethyl
    ester
    368 2-(2-Chloro-4-morpholin-4-yl- 14.38 518 84 0.07 2239
    benzylamino)-3-(1H-indol-3-yl)-N-
    (1-phenyl-ethyl)-propionamide
    369 2-(4-Chloro-2-methylsulfamoyl- 53.07 526 83 0.06 450
    benzylamino)-3-(1H-indol-3-yl)-N-
    (1-phenyl-ethyl)-propionamide
    370 2-(2,3-Diphenyl-propylamino)-3- 11.18 502 73 0.08 534
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    371 3-(1H-Indol-3-yl)-2-[(4-oxo-4H- 16.18 466 66 0.07 >10,000
    chromen-3-ylmethyl)-amino]-N-( 1-
    phenyl-ethyl)-propionamide
    372 3-(1H-Indol-3-yl)-2-[(1-oxo-1,2,3,9- 9 523 26 0.08 >10,000
    tetrahydro-4-thia-9-aza-fluoren-2-
    ylmethyl)-amino]-N-(1-phenyl-
    ethyl)-propionamide
    373 3-(1H-Indol-3-yl)-2-[(5-methyl-4- 17.38 506 2 0.07 507
    oxo-6-phenyl-4H-pyran-3-ylmethyl)-
    amino]-N-(1-phenyl-ethyl)-
    propionamide
    374 4-{[2-(1H-Indol-3-yl)-1-(1-phenyl- 33.82 456 95 0.06 1914
    ethylcarbamoyl)-ethylamino]-
    methyl}-benzoic acid methyl ester
    375 3-(1H-Indol-3-yl)-N-(1-phenyl- 28.55 495 76 0.05 165
    ethyl)-2-[(2-propyl-5-pyrrol-1-yl-
    3H-imidazol-4-ylmethyl)-amino]-
    propionamide
    376 2-(2,3-Diphenyl-allylamino)-3-(1H- 14.27 500 76 0.08 >10,000
    indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    377 2-(3-Benzo[1,3]dioxol-5-yl- 14.52 468 57 0.07 593
    allylamino)-3-(1H-indol-3-yl)-N-(1-
    phenyl-ethyl)-propionamide
    378 2-[3-(4-Benzyloxy-phenyl)- 8.68 530 64 0.09 932
    allylamino]-3-(1H-indol-3-yl)-N-(1-
    phenyl-ethyl)-propionamide
    379 2-(4-Benzyloxy-benzylamino)-3- 15.05 504 80 0.08 587
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    380 3-(1H-Indol-3-yl)-2-(3-naphthalen- 11.18 476 46 0.08 500
    1-yl-propylamino)-N-(1-phenyl-
    ethyl)-propionamide
    381 Toluene-4-sulfonic acid 3-{[2-(1H- 24.84 568 92 0.08 >10,000
    indol-3-yl)-1-(1-phenyl-
    ethylcarbamoyl)-ethylamino]-
    methyl}-phenyl ester
    382 2-(3-Benzyloxy-benzylamino)-3- 44.62 504 91 0.08 >10,000
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    383 3-(1H-Indol-3-yl)-2-(4- 39.33 444 69 0.07 252
    methylsulfanyl-benzylamino)-N-(1-
    phenyl-ethyl)-propionamide
    384 3-(1H-Indol-3-yl)-2-(4-phenoxy- 32.52 490 83 0.08 2350
    benzylamino)-N-(1-phenyl-ethyl)-
    propionamide
    385 2-[(Biphenyl-4-ylmethyl)-amino]-3- 24.28 474 90 0.08 1463
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    386 2.-[(Benzo[1,3]dioxol-5-ylmethyl)- 41.91 442 78 0.06 240
    amino]-3-(1H-indol-3-yl)-N-(1-
    phenyl-ethyl)-propionamide
    387 2-[2-(4-Chloro-phenylsulfanyl)- 48.88 541 96 0.09 201
    benzylamino]-3-(1H-indol-3-yl)-N-
    (1-phenyl-ethyl)-propionamide
    338 3-(1H-Indol-3-yl)-N-(1-phenyl- 12.14 500 66 0.09 >10,000
    ethyl)-2-(4-styryl-benzylamino)-
    propionamide
    389 2-(2,6-Dimethyl-octa-2,6- 50.41 444 5 0.08 2573
    dienylamino)-3-(1H-indol-3-yl)-N-
    (1-phenyl-ethyl)-propionamide
    390 3-(1H-Indol-3-yl)-2-{[5-(4-nitro- 7.86 509 44 0.07 50
    phenyl)-furan-2-ylmethyl]-amino}-
    N-(1-phenyl-ethyl)-propionamide
    391 2-[(9H-Fluoren-2-ylmethyl)-amino]- 37.84 486 85 0.08 846
    3-(1H-indol-3-yl)-N-(1-phenyl-
    ethyl)-propionamide
    392 2-[(2,5-Dimethyl-1-phenyl-1H- 5.27 491 3 0.08 >10,000
    pyrrol-3-ylmethyl)-amino]-3-(1H-.
    indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    393 3-(1H-Indol-3-yl)-N-(1-phenyl- 03.2 399 71 0.04 802
    ethyl)-2-[(pyridin-3-ylmethyl)-
    amino]-propionamide
    394 3-(1H-Indol-3-yl)-2-[(naphthalen-2- 03.7 448 88 0.06 158
    ylmethyl)-amino]-N-(1-phenyl-
    ethyl)-propionamide
    395 3-(1H-Indol-3-yl)-N-(1-phenyl- 02.9 399 74 0.05 >10,000
    ethyl)-2-[(pyridin-2-ylmethyl)-
    amino]-propionamide
    396 3-(1H-Indol-3-yl)-N-(1-phenyl- 04.3 404 98 0.05 1073
    ethyl)-2-[(thiophen-2-ylmethyl)-
    amino]-propionamide
    397 2-(3,4-Dimethoxy-benzylamino)-3- 03.3 458 65 0.05 >10,000
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    398 2-(3,5-Bis-trifluoromethyl- 04.3 534 94 0.07 >10,000
    benzylamino)-3-(1H-indol-3-yl)-N-
    (1-phenyl-ethyl)-propionamide
    399 2-(3,5-Difluoro-benzylamino)-3- 03.5 434 92 0.06 140
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    400 2-(3-Chloro-benzylamino)-3-(1H- 03.4 432 86 0.06 13
    indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    401 2-(3-Fluoro-benzylamino)-3-(1H- 03.4 416 87 0.06 39
    indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    402 2-[(Furan-3-ylmethyl)-amino]-3- 03.0 388 84 0.05 881
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
    403 3-(1H-Indol-3-yl)-N-(1-phenyl- 0.07 426 85 0.06 3907
    ethyl)-2-(3-phenyl-propylamino)-
    propionamide
    404 3-(1H-Indol-3-yl)-N-(1-phenyl- 03.2 404 81 0.05 2390
    ethyl)-2-[(thiophen-3-ylmethyl)-
    amino]-propionamide
    405 2-[(Furan-2-ylmethyl)-amino]-3- 03.2 388 86 0.06 429
    (1H-indol-3-yl)-N-(1-phenyl-ethyl)-
    propionamide
  • As noted above, the compounds of formula I will be best utilized in the form of pharmaceutical formulations. The following examples further illustrate specific formulations that are provided by the invention. [0344]
    • EXAMPLE 406
  • [0345]
    Tablet Formulation
    Ingredient Amount
    3-[(benzofuran-2-ylmethyl)-amino]-3 -(IH-indol-3-yl)-2- 50 mg
    methyl-N-(1-phenyl-ethyl)-propionamide,[R-(R*, S*)]
    potato starch 100 mg 
    talc 50 mg
    magnesium carbonate 20 mg
    dextrose 20 mg
    240 mg 
  • The above ingredients are blended to uniformity and pressed into a tablet. Such tablets are administered to human subjects from one to four times a day for treatment of pain, depression and schizophrenia. [0346]
    • EXAMPLE 407
  • [0347]
    Capsules
    Ingredient Amount
    The compound of Example 5 200 mg
    Corn starch 100 mg
    Sodium benzoate  10 mg
    talc  50 mg
    360 mg
  • The ingredients are blended to uniformity and encapsulated into gelatin telescoping capsules. The capsules are administered to a human at the rate of one to three each day for treatment of rheumatoid arthritis, atheroclerosis, aberrant neovascularization, and for the inhibition of tumor cell growth. [0348]

Claims (18)

We claim:
1. A compound of Formula I
Figure US20030065007A1-20030403-C00043
or a pharmaceutically acceptable salt thereof, wherein
▪, , and and ▴ indicate all stereoisomers,
R is:
pyridyl,
thienyl,
furyl,
pyrrolyl,
pyrazolyl,
quinolyl,
isoquinolyl,
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, and
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
—CF3,
carboxy,
sulfonamide, or
nitro;
R can also be:
Figure US20030065007A1-20030403-C00044
R1 and R2 are each independently H or C1-C4 alkyl;
m is an integer from 0 to 3;
X is NHCONH, or NR8 where R8 is H or C1-C4 alkyl;
R3 is hydrogen or C1-C4 alkyl;
n is an integer from 1 to 2;
R4 is naphthyl or indolyl, wherein said groups are unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy or formyl;
R9 is hydrogen or C1-C4 alkyl;
R5 and R7 are each independently hydrogen or (CH2)pR10 where:
p is an integer of 1 to 3, and
R10 is H, CH3, CN, OH, OCH3, CO2CH3, NH2, NHCH3, or N(CH3)2;
q is an integer of 0 to 4;
R6 is
phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
pyrazolyl,
imidazolyl,
quinolyl,
isoquinolyl,
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3,
NO2,
N(CH3)2,
OCF3,
SONH2,
NH2,
CONH2,
CO2CH3, or
CO2H,
or R6 is:
straight alkyl of from 1 to 3 carbons,
branched alkyl of from 3 to 8 carbons,
cycloalkyl of from 5 to 8 carbons, or
heterocycloalkyl,
each of which can be substituted with up to one or two substituents selected from
OH,
CO2H,
N(CH3)2,
NHCH3 and
CH3; and
R5 and R6, when joined by a bond, can form a ring;
R6 is also
Figure US20030065007A1-20030403-C00045
where X1 represents the rest of the molecule.
2. A compound of claim I wherein R is selected from:
pyridyl,
thienyl,
furyl,
quinolyl
isoquinolyl
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl,
benzoxazolyl, wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or CF3,
Figure US20030065007A1-20030403-C00046
m is an integer from 1 to 3;
R6 is
phenyl
pyridyl,
thienyl,
furyl,
pyrrolyl,
quinolyl,
isoquinolyl,
naphthyl,
indolyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl,
wherein each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3,
NO2
N(CH3)2,
OCF3,
SONH2,
NH2,
CONH2,
CO2CH3, or
CO2H,
cycloalkyl of from 5 to 6 carbons or heterocycloalkyl, with up to one or two substituents selected from
OH,
CO2H,
N(CH3)2,
NHCH3 and
CH3; and
R5 and R6 when joined by a bond can form a ring.
3. A compound according to claim 2 wherein R1 and R2 each are hydrogen.
4. A compound according to claim 3 wherein X is NR8.
5. A compound according to claim 4 wherein
R is
pyridyl,
thienyl,
furyl,
quinolyl,
naphthyl,
benzofuryl,
benzothiophenyl,
benzimidazolyl, or
benzoxazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by alkyl, hydroxy, alkoxy, halogen, or —CF3,
Figure US20030065007A1-20030403-C00047
R1 and R2 are each H;
m is an integer from 1 to 3;
X is NR8 or NHCONH, where R8 is H or methyl;
R9 is hydrogen or alkyl of 1 to 3 carbon atoms;
R6 is
phenyl,
pyridyl,
thienyl,
furyl,
pyrrolyl,
benzimidazolyl, where each of the foregoing is unsubstituted, mono-, di- or trisubstituted by
alkyl,
hydroxy,
alkoxy,
halogen,
CF3,
NO2, or
N(CH3)2;
cyclohexyl or heterocycloalkyl, with up to one or two substituents selected from
OH,
CO2H,
N(CH3)2,
NHCH3 and
CH3; and
R5 and R6, when joined by a bond, can form a ring.
6. A compound of the Formula II
Figure US20030065007A1-20030403-C00048
wherein:
R is
benzofuryl,
benzoxazolyl,
3-cyanophenyl,
3-nitrophenyl, or
3-trifluoromethylphenyl;
R3 is hydrogen or methyl;
X is NH or NHCONH;
R5 and R7 independently are hydrogen or CH2R10, where R10 is H, CH3 or OH;
R6 is
phenyl,
substituted phenyl,
pyridyl, or,
cyclohexyl;
and the pharmaceutically acceptable salts thereof.
7. A compound of claim 6 selected from:
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide, [R—(R*,R*)]
2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, [R—(R*,R*)]
[R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide
[R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-ethyl)-propionamide, [R—(R*,S*)]
2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R—(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
2-[(Benzooxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide
2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] and
2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)].
8. A pharmaceutical formulation comprising a compound of claim I admixed with a pharmaceutically acceptable diluent, carrier or excipient.
9. A formulation according to claim 8 employing a compound of Formula II
Figure US20030065007A1-20030403-C00049
wherein:
R is
benzofuryl,
benzoxazolyl,
3-cyanophenyl,
3-nitrophenyl, or
3-trifluoromethylphenyl;
R3 is hydrogen or methyl;
X is NH or NHCONH;
R5 and R7 independently are hydrogen or CH2R10, where R10 is H, CH3 or OH;
R6 is
phenyl,
substituted phenyl,
pyridyl, or,
cyclohexyl;
or a pharmaceutically acceptable salts thereof.
10. A formulation according to claim 9 employing a compound selected from:
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-[1-(4-nitro-phenyl)-ethyl]-propionamide, [R—(R*,R*)]
2-[(Benzofuran-2-ylmethyl)-amino]-N-(2-hydroxy-1-phenyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide, [R—(R*,R*)]
[R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-N-(1-cyclohexyl-ethyl)-3-(1H-indol-3-yl)-2-methyl-propionamide
[R—(R*,S*)]2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-2-methyl-N-(1-p-tolyl-ethyl)-propionamide
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-p-tolyl-ethyl)-propionamide, [R—(R*,S*)]
2-(3-Cyano-benzylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
3-(1H-Indol-3-yl)-2-(3-nitro-benzylamino)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
3-(1H-Indol-3-yl)-N-(1-phenyl-ethyl)-2-(3-trifluoromethoxy-benzylamino)-propionamide, [R—(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-pyridin-4-yl-ethyl)-propionamide, [R—(R*,S*)]
2-[(Benzofuran-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)]
2-[(Benzooxazol-2-ylmethyl)-amino]-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide
2-(2-Benzofuran-2-yl-ethylamino)-3-(1H-indol-3-yl)-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)] and
2-(3-Benzofuran-2-ylmethyl-ureido)-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide, [R—(R*,S*)].
11. A method for antagonizing the NK1 receptor in a mammal comprising administering a compound of claim 1.
12. A method for treating a CNS disorder in a mammal in need of treatment comprising administering an effective amount of a compound of claim 1.
13. A method according to claim 12 wherein the CNS disorder is selected from pain, anxiety, depression or schizophrenia.
14. A method according to claim 12 wherein the CNS disorder is selected from neuralgia, stress, sexual dysfunction, bipolar disorders, movement disorders, cognitive disorders, obesity, and addiction disorders.
15. A method for treating an allergic or inflammatory disorder in a mammal in need of treatment comprising administering an effective amount of a compound of claim 1.
16. A method according to claim 15 wherein the allergic or inflammatory disorder is selected from arthritis, asthma, bronchitis, psoriasis, eczema, rhinitis, colitis or Crohn's disease.
17. A method for treating a neuropathological disorder in a mammal in need of treatment comprising administering an effective amount of a compound of claim 1.
18. A method according to claim 17 wherein the neuropathological disorder is selected from scleroderma or emesis.
US10/267,477 1998-12-18 2002-10-09 NK1 receptor antagonists Abandoned US20030065007A1 (en)

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* Cited by examiner, † Cited by third party
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Families Citing this family (10)

* Cited by examiner, † Cited by third party
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ATE303804T1 (en) * 2000-11-17 2005-09-15 Warner Lambert Co TREATMENT OF SEXUAL DYSFUNCTION WITH BOMBESIN RECEPTOR ANTAGONISTS
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NZ534757A (en) 2002-03-12 2006-07-28 Merck & Co Inc Substituted amides
WO2006101454A1 (en) * 2005-03-21 2006-09-28 S*Bio Pte Ltd Benzothiophene derivatives: preparation and pharmaceutical applications
WO2006113097A2 (en) * 2005-04-15 2006-10-26 The University Of North Carolina At Chapel Hill Methods of facilitating cell survival using neurotrophin mimetics
EP3470402B1 (en) 2009-11-12 2021-01-06 Pharmatrophix Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
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US6403577B1 (en) 1993-11-17 2002-06-11 Eli Lilly And Company Hexamethyleneiminyl tachykinin receptor antagonists
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