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Pyrrolidine inhibitors of IAP

Inactive Publication Date: 2006-07-27
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0473] The reactions were read after an incubation time of 10 minutes at room temperature with standard cut-off filters for the fluorescein fluorophore (λex=485 nm; λem=530 nm) in 96-well black HE96 plates (Molecular Devices Corp.). Fluorescence values were plotted as a function of the protein concentration, and the IC50s were obtained by fitting the data to a 4-parameter equation using Kaleidograph software (Synergy software, Reading, Pa.). Competition experiments were performed by addition of the MLXBIR3SG at 30 nM to wells containing 5 nM of the AVP-diPhe-FAM probe as well as 1:3 serial dilutions of antagonist compounds starting at a concentration of 300 μM in the polarization buffer. Samples were read after a 10-minute incubation. Fluorescence polarization values were plotted as a function of the antagonist concentration, and the IC50 values were obtained by fitting the data to a 4-parameter equation using Kaleidograph software (Synergy software, Reading, Pa.). Inhibition constants (Ki) for the antagonists were determined from the IC50 values. Compounds of the invention that were tested in this assay exhibited a Ki or less than 100 μM.

Problems solved by technology

Agents such as adriamycin and 4-tertiary butylphenol (4-TBP) were tested in a cell culture system of melanomas overexpressing ML-IAP and the chemotherapeutic agents were significantly less effective in killing the cells when compared to a normal melanocyte control.

Method used

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  • Pyrrolidine inhibitors of IAP
  • Pyrrolidine inhibitors of IAP
  • Pyrrolidine inhibitors of IAP

Examples

Experimental program
Comparison scheme
Effect test

example 1

2-[tert-Butoxycarbonyl-(1H-pyrrol-2-ylmethyl)-amino]-propionic acid

[0109]

[0110] Alanine ethyl ester b (5 g, 32.5 mmol), pyrrole-2-carboxaldehyde a (3.1 g, 32.5 mmol), sodium cyanoborohydride (2.04 g, 32.5 mmol) and AcOH (1%) were mixed in DMF and stirred overnight. The reaction was quenched with H2O, and DMF was evaporated. The mixture was diluted with EtOAc, washed by 0.1N NaOH, dried and concentrated to yield product c 2.5 g. The resulting ester c (2.5 g, 12.8 mmol), di-tert-butyldicarbonate (3.06 g, 14 mmol) were mixed in THF, H2O with NaHCO3 and stirred overnight. THF was evaporated, and the mixture was diluted with EtOAc, washed by 1N NaOH, sat. NH4Cl and brine. After dried, the mixture was concentrated to yield the Boc-protected ester d 3.3 g. The Boc-protected ester d (1.67 g, 5.6 mol), lithium hydroxide mono hydrate (284 mg, 6.77 mmol) were mixed in THF and H2O at 0° C. THF was vacuumed off, and the solution was acidified by dilute H2SO4, extracted by EtOAc twice. Organic l...

example 2

Thiazole Substituted Pyrrolidine

[0111]

[0112] Following the general procedure of Williams (Williams, D. R. et al, M. J. Org. Chem. 2001, 66, 8463), a mixture of N-Cbz-proline amide a (500 mg, 2.0 mmol) Lawesson's reagent (420 mg, 1.05 mmol) and toluene (5 mL) was heated at reflux for 2 h. The solution was concentrated, adsorbed onto Celite, and purified by flash chromatography (SiO2, 40% ethyl acetate-hexanes) to afford 393 mg (74%) of compound b as a colorless solid.

[0113] Following the general procedure of Ciufolini (Ciufolini, M. A. et al, J. Org. Chem. 1997, 62, 3804), ethyl bromopyruvate (200 μl, 1.43 mmol) was added to a suspension of thioamide b (378 mg, 1.43 mmol) in ethanol (5 mL), and the mixture heated at 80° C. for 5 min. The solvent was evaporated under reduced pressure, and the residue purified by flash chromatography (SiO2, gradient elution, 30-40-50% ethyl acetate-hexanes) to afford 393 mg (74%) of thiazole c as a colorless solid.

[0114] Phenyl magnesium bromide (...

example 3

Oxazole Substituted Pyrrolidine

[0117]

[0118] A mixture of N-Boc-proline a (5.35 g, 24.9 mmol) serine methyl ester hydrochloride b (3.50 g, 22.5 mmol), EDC (4.76 g, 24.85 mmol), DIPEA (4.0 mL, 22.5 mmol) and CH2Cl2 (90 mL) was maintained overnight. The mixture was diluted with CH2Cl2 (200 mL) and washed with 1 N HCl (3×100 mL), 0.1 N NaOH (3×100 mL) and brine (1×100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford 5.2 g (73%) of dipeptide c as a colorless foam.

[0119] To a cool (0° C.) solution of dipeptide c (4.57 g, 14.4 mmol) and THF (100 mL) was added Burgess Reagent (Pihko, P. M.; Koskinen, A. M. P.; Nissinen, M. J.; Rissanen, K. J. Org. Chem. 1999, 64, 652, and references therein) (3.77 g, 15.8 mmol) in 3 portions over 30 min. The cooling bath was removed and the reaction allowed to reach rt, then heated at reflux for 1 h. After cooling to rt, the THF was removed under reduced pressure and the residue was partitioned between EtOAc (200 mL) and sa...

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Abstract

The invention provides novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies where the compounds have the general formula I: wherein A, Q, X1, X2, Y, R1, R2, R3, R4, R4′, R5, R6′ and R6′ are as described herein.

Description

[0001] This application claims priority under 35 U.S.C. § 119(e)(1) to United States provisional application 60 / 638,202 filed on Dec. 20, 2004 which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002] The present invention relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular to inhibitors of IAP proteins useful for treating cancers. BACKGROUND OF THE INVENTION [0003] Apoptosis or programmed cell death is a genetically and biochemically regulated mechanism that plays an important role in development and homeostasis in invertebrates as well as vertebrates. Aberrancies in apoptosis that lead to premature cell death have been linked to a variety of developmental disorders. Deficiencies in apoptosis that result in the lack of cell death have been linked to cancer and chronic viral infections (Thompson et al., (1995) Science 267, 1456-1462). [0004] One of the key effector molecules in apoptosis are the caspases (cy...

Claims

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Application Information

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IPC IPC(8): A61K31/427A61K31/422C07D417/02C07D413/02
CPCC07D417/04C07D417/14C07D471/04A61P35/00A61P43/00A61K31/427
Inventor COHEN, FREDERICKTSUI, VICKIELY, CUONGFLYGARE, JOHN
Owner GENENTECH INC
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