US20030225152A1 - 3-(Arylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors - Google Patents

3-(Arylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors Download PDF

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US20030225152A1
US20030225152A1 US10/259,703 US25970302A US2003225152A1 US 20030225152 A1 US20030225152 A1 US 20030225152A1 US 25970302 A US25970302 A US 25970302A US 2003225152 A1 US2003225152 A1 US 2003225152A1
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dihydro
indol
methylene
phenylamino
fluoro
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Steven Andrews
Julie Wurster
Clarence Hull
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Allergan Inc
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Assigned to ALLERGAN, INC. reassignment ALLERGAN, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HULL III., CLARENCE E., WURSTER, JULIE A., ANDREWS, STEVEN W.
Publication of US20030225152A1 publication Critical patent/US20030225152A1/en
Priority to US10/886,213 priority patent/US7098236B2/en
Priority to US11/396,036 priority patent/US20060194863A1/en
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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Definitions

  • Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • tBu refers to t-butyl
  • Alkoxyl refers to an “O-alkyl” group.
  • the substituent on the aniline moiety is referred to as an o, m or p substituent or a 2, 3 or 4 substituent, respectively.
  • the 5 substituent is also a m substituent and the 6 substituent is an o substituent.
  • the present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction and more particularly receptor and non-receptor tyrosine kinase signal transduction.
  • Tyrosine kinase signal transduction results in, among other responses, cell proliferation, differentiation and metabolism.
  • Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis, e.g. macular degeneration).
  • Examples 242, 243, 244, and 245 are prepared by substituting the appropriate 4′-methyl or 6′-fluoro or 5′-fluoro or 5′-chloro substituted 1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and N-(2-morpholin-4-yl-ethyl)-benzene-1,4-diamine, used for the preparation of Example 235, for aniline in the reaction of Example 1.
  • a room temperature solution of 5.04 gms. 4-nitro-benzoic acid in tetrahydrofuran (10 mL) is treated with 5.14 gms. 1′,1′-carbonyl-diimidizole and immediately immersed in an ice bath.
  • the reaction mixture is stirred in the ice bath for 30 minutes, then it is allowed to warm to room temperature.
  • Once at room temperature the reaction mixture is treated with 3 mL piperidine.
  • the reaction mixture is allowed to stir at room temperature ovenight.
  • the reaction is then made basic with the addition of saturated aqueous sodium bicarbonate solution, and the resulting mixture is extracted with ethyl acetate.
  • the quenched reaction mixture is then extracted with ethyl acetate and water.
  • the organic layer is separated, and concentrated in vacuo, while the aqueous layer is separated and made basic with the addition of aqueous 1 M NaOH.
  • the basic aqueous layer is then extracted with ethyl acetate and the ethyl acetate layer from this extraction is concentrated in vacuo.
  • the solids isolated from both concentrated ethyl acetate layers are combined to yield 92 mg of 1-(4-nitro-benzyl)-piperidine as a white-yellow solid.
  • 6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one (0.2282 gms.) is combined with 0.23 mL of ethylformate in 0.67 mL anhydrous ethanol, and is treated with a solution of 21%, by weight, sodium formate in ethanol (0.40 mL). The resulting solution is allowed to stand at room temperature for 30 minutes, and then is refluxed for 2 h to yield a suspension. Once at room temperature the suspension is acidified to pH 1.0 with 10% HCl(aq), then diluted with 5 mL of H 2 O. The resulting precipitate.
  • the named compound is prepared by refluxing 0.020 gms E & Z 3-Hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (see example 268) with 0.0327 gms 4-(3-diethylamino-propoxy)-phenylamine (used in the preparation of Example 214) in tetrahydrofuran (0.33 mL) for 36 h. Following cooling to room temperature, solvent evaporation in vacuo, trituration with ethyl acetate/(min) hexanes and filtration the reaction yields the named compound as a solid in the amount of 9.0 mg.
  • the named compound is prepared by refluxing 0.0505 gms. E & Z 3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example 1, with 0.085 gms. 4-(2-piperidin-1-yl-ethyl)-phenylamine in tetrahydrofuran (1.0 mL) overnight. Following cooling to room temperature, solvent evaporation in vacuo, trituration with isopropanol and filtration the reaction yields the named compound in the amount of 66 mg.
  • 4-(2-Piperidin-1-yl-ethyl)-phenylamine is prepared from (4-Nitro-phenyl)-acetic acid by the following method:
  • a room temperature solution of 2.53 gms. (4-Nitro-phenyl)-acetic acid in tetrahydrofuran (10 mL) is treated with 2.44 gms. 1′,1′-carbonyl-diimidizole and immediately immersed in an ice bath.
  • the reaction mixture is stirred in the ice bath for 30 minutes then it is allowed to warm to room temperature.
  • Once at room temperature the reaction mixture is treated with 1.21 mL piperidine, and then is stirred overnight at room temperature.
  • the reaction is then made basic with the addition of saturated aqueous sodium bicarbonate, and the resulting mixture is extracted with ethyl acetate.
  • the named compound is prepared by refluxing 0.051 gms. E & Z 3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one, as prepared in Example 1, with 0.085 gms. 4-morpholin-4-ylmethyl-phenylamine in tetrahydrofuran (2.0 mL) overnight. Following cooling to room temperature, solvent evaporation in vacuo, trituration with isopropanol and filtration the reaction yields the named compound as a solid in the amount of 0.070 gms.
  • N-(3-Morpholin-4-yl-propyl)-benzene-1,4-diamine (4.39 gms.) is isolated upon evaporation of the filtrate, and is subsequently used without purification in the reaction of Example 297.
  • a suspension of 0.1385 gms. of [3-(4-methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine in 3 mL of ethanol is heated to 50° C. Once dissolution is achieved 0.144 mL hydrazine monohydrate is added to the solution.
  • a Raney nickel slurry in water is added to the 50° C. solution dropwise, waiting after each addition for the gas evolution to cease. Sufficient quantities of Raney nickel have been added when continued addition of Raney nickel causes no further gas evolution. The reaction is then maintained at 50° C. for an additional hour, and subsequently is cooled to room temperature.
  • the named compound is prepared by substituting 4-methyl-1,3-dihydro-indol-2-one for the 1,3-dihydro-indol-2-one and N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (used for the preparation of Example 302) for aniline in the reaction of Example 1.
  • 4-(2-Morpholin-4-yl-ethyl)-phenylamine is prepared from (4-nitro-phenyl)-acetic acid by the following method:
  • reaction mixture is maintained at refluxing temperature overnight, then cooled to 0° C., and quenched with the addition of concentrated HCl (added until fizzing stops).
  • the quenched reaction mixture is then warmed to room temperature, and extracted with ethyl acetate and water.
  • the organic layer is then separated, dried over sodium sulfate and concentrated in vacuo.
  • the solid isolated is then chromatographed by flash silica gel chromatography using 30% ethyl acetate in hexanes as the eluant to yield 0.7993 gms. of 4-[2-(4-nitro-phenyl)-ethyl]-morpholine as a white solid.
  • the named compound is prepared by refluxing 0.0707 gms. E & Z-3-Hydroxymethylene-4-methyl-1,3-dihydro-indol-2-one, as prepared in the reaction of Example 1, with 0.1088 gms. 4-(2-morpholin-4-yl-ethyl)-phenylamine (used in the preparation of Example 306) in tetrahydrofuran (1.5 mL) overnight. Following cooling to room temperature, solvent evaporation in vacuo, trituration with isopropanol and filtration the reaction yields the named compound as a solid in the amount of 77 mg.
  • 4-(4-Morpholin-4-yl-butyl)-phenylamine is prepared from 4-(4-nitro-phenyl)-butyric acid by the following method:
  • a room temperature solution of 1.1180 gms. 4-(4-nitro-phenyl)-butyric acid in tetrahydrofuran (3 mL) is treated with 0.9052 gms. 1′,1′-carbonyl-diimidizole using an ice bath to attenuate the intensity of the reaction.
  • the reaction mixture is stirred for 1 h.
  • the reaction mixture is then treated with 0.5 mL morpholine.
  • the reaction is heated overnight at 35° C.
  • the reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate.
  • the resulting mixture is extracted with ethyl acetate.
  • the named compound is prepared by refluxing 0.131 gms. E & Z-3-hydroxymethylene-4-methyl-1,3-dihydro-indol-2-one, as prepared in the reaction of Example 1, with 0.0759 gms. 4-(4-morpholin-4-yl-butyl)-phenylamine (used in the preparation of Example 312) in tetrahydrofuran (1.5 mL) overnight. Following cooling to room temperature, solvent evaporation in vacuo, trituration with isopropanol and filtration the reaction yields the named compound as a solid in the amount of 98.0 mg.
  • a room temperature solution of 1.1220 gms. 4-(4-nitro-phenyl)-butyric acid in tetrahydrofuran (3 mL) is treated with 0.8978 gms. 1′,1′-carbonyl-diimidizole using an ice bath to attenuate the intensity of the reaction.
  • the reaction mixture is stirred for 30 minutes in the ice bath and 30 minutes at room temperature.
  • the reaction mixture is then treated with 0.5 mL morpholine.
  • the reaction was heated overnight at 35° C.
  • the reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate.
  • the resulting mixture is extracted with ethyl acetate.

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US10/259,703 2001-09-27 2002-09-27 3-(Arylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors Abandoned US20030225152A1 (en)

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US10/259,703 US20030225152A1 (en) 2001-09-27 2002-09-27 3-(Arylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors
US10/886,213 US7098236B2 (en) 2001-09-27 2004-07-06 3-(arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors
US11/396,036 US20060194863A1 (en) 2001-09-27 2006-03-31 3-(Arylamino)methylene-1, 3-dihydro-2H-indol-2-ones as kinase inhibitors

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US10/259,703 Abandoned US20030225152A1 (en) 2001-09-27 2002-09-27 3-(Arylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors
US10/256,879 Expired - Fee Related US6765012B2 (en) 2001-09-27 2002-09-27 3-(Arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors
US10/783,325 Expired - Lifetime US7015220B2 (en) 2001-09-27 2004-02-20 3-(arylamino)methylene-1, 3-dihydro-2H-indol-2-ones as kinase inhibitors
US10/886,213 Expired - Lifetime US7098236B2 (en) 2001-09-27 2004-07-06 3-(arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors
US11/228,780 Abandoned US20060025413A1 (en) 2001-09-27 2005-09-16 3-(arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors
US11/274,681 Expired - Lifetime US7414054B2 (en) 2001-09-27 2005-11-15 3-(arylamino)methylene-1, 3-dihydro-2H-indol-2-ones as kinase inhibitors
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AU2002341881B2 (en) 2008-05-08
US20060063940A1 (en) 2006-03-23
US20050228036A1 (en) 2005-10-13
WO2003027102A1 (en) 2003-04-03
US7414054B2 (en) 2008-08-19
US20060194863A1 (en) 2006-08-31
JP2010116411A (ja) 2010-05-27
CA2461812A1 (en) 2003-04-03
US20030199478A1 (en) 2003-10-23
JP2005508336A (ja) 2005-03-31
US7015220B2 (en) 2006-03-21
US7098236B2 (en) 2006-08-29
EP1430048A1 (en) 2004-06-23
US20060025413A1 (en) 2006-02-02
CA2461812C (en) 2011-09-20
US20040198720A1 (en) 2004-10-07
US6765012B2 (en) 2004-07-20

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