US20090305382A1 - Alkoxy indolinone based protein kinase inhibitors - Google Patents

Alkoxy indolinone based protein kinase inhibitors Download PDF

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US20090305382A1
US20090305382A1 US11/991,971 US99197106A US2009305382A1 US 20090305382 A1 US20090305382 A1 US 20090305382A1 US 99197106 A US99197106 A US 99197106A US 2009305382 A1 US2009305382 A1 US 2009305382A1
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Congxin Liang
Yangbo Feng
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Scripps Research Institute
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Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to protein kinase inhibitors and to their use in treating disorders related to abnormal protein kinase activities such as cancer and inflammation. More particularly, the invention relates to alkoxy indolinone based derivatives and their pharmaceutically acceptable salts employable as protein kinase inhibitors.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins. Many aspects of cell life (for example, cell growth, differentiation, proliferation, cell cycle and survival) depend on protein kinase activities. Furthermore, abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, considerable effort has been directed to identifying ways to modulate protein kinase activities. In particular, many attempts have been made to identify small molecules that act as protein kinase inhibitors.
  • the invention is directed to alkoxy indolinone based derivatives and to their use as inhibitors of protein kinases. It is disclosed herein that alkoxy indolinone based derivatives have enhanced and unexpected drug properties that advantageously distinguish this class of compounds over known pyrrolyl-indolinone derivatives having protein kinase inhibition activity. It is also disclosed herein that alkoxy indolinone based derivatives are useful in treating disorders related to abnormal protein kinase activities such as cancer.
  • One aspect of the invention is directed to a compound represented by Formula (I):
  • R 1 is selected from the group consisting of hydrogen, halo, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, hydroxy, (C1-C6) alkoxy, amino, (C1-C6) alkylamino, amide, sulfonamide, cyano, substituted or unsubstituted (C6-C10) aryl;
  • R 2 is selected from the group consisting of hydrogen, halo, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, hydroxy, (C1-C6) alkoxy, (C2-C8) alkoxyalkyl, amino, (C1-C6) alkylamino, (C6-C10) arylamino;
  • R 3 is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C6-C10) aryl, (C5
  • R 12 is selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C8) cycloalkyl. Other groups are as defined in Formula (I).
  • R 1 and R 2 are independently selected from the group consisting of hydrogen and fluoro;
  • R 3 and R 4 are methyl;
  • R 5 , R 6 , R 8 , and R 12 are hydrogen;
  • R 7 is (C1-C6) alkyl; n is 1 or 2; and m is 0 or 1.
  • Preferred species include the following compounds:
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, cyano;
  • R 3 is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C6-C10) aryl, (C5-C10) heteroaryl, and amide;
  • R 4 , R 5 , R 6 and R 8 are independently selected from the group consisting of hydrogen and (C1-C6))alkyl;
  • R 7 is (C1-C6) alkyl; n is 1 or 2; m is 0 or 1;
  • R 10 and R 11 are selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C2-C6) dihydroxyalkyl, (C1-C6) alkoxy, (C2-C6) alkyl carboxylic acid, (C1-C6) alkyl phosphonic acid, (C1-C6) alkyl sulfonic
  • R 9 is selected from the group consisting of radicals represented by the following structures:
  • Another aspect of the invention is directed to a method for the modulation of the catalytic activity of a protein kinase with a compound or salt of any one of the compounds of Formulas (I-III).
  • the protein kinase is selected from the group consisting of VEGF receptors and PDGF receptors.
  • FIG. 1 illustrates a scheme that is used for the synthesis of the 3-alkoxy-4-acylaminoamide derivatives starting from methyl 3-hydroxy-4-aminobutanoate hydrochlorides and the activated acylating agent 1-3.
  • FIG. 2 illustrates a scheme that is used for the synthesis of the 2-alkoxy-3-acylaminoamide derivatives starting from methyl 2-hydroxy-3-aminopropionate hydrochlorides and the activated acylating agent 1-3.
  • FIG. 3 illustrates a scheme that is used for the synthesis of the (2S)-2-alkoxy-4-acylamino-amide derivatives starting from methyl (2S)-2-hydroxy-4-aminobutanoate hydrochloride and the activated acylating agent 1-3.
  • Example 2 A similar route as that for the synthesis of Example 1 was used to prepare the title compound. Iodoethane was used instead of iodomethane to obtain the 3-ethoxy compound (9.7% based on compound 1-3).
  • Example 9 A similar route as that for the synthesis of Example 9 was used to prepare the title compound. Iodoethane was used instead of iodomethane to obtain the 2-ethoxy compound (38% based on compound 1-3).
  • R 9 is selected from the following radicals:
  • Example 316 A similar route as that for the synthesis of Example 316 was used to prepare the title compound. Iodoethane was used instead of iodomethane to obtain the 2-ethoxy compound (84% based on compound 1-3).
  • the compounds were assayed for biochemical activity by Upstate Ltd at Dundee, United Kingdom, according to the following procedure.
  • KDR (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/ml myelin basic protein, 10 mM MgAcetate and [ ⁇ - 33 P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required).
  • the reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 ⁇ l of a 3% phosphoric acid solution. 10 ⁇ l of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
  • NIH3T3 cells are plated in a 96 well plate in DMEM+10% FBS. Following cell attachment the cells are serum starved overnight before adding the chemical test compounds to a final concentration of 0.1% DMSO. Following a 1 hour incubation at 37° C. cells are removed from the incubator and allowed to cool to RT for 20 min before stimulation with PDGF-BB for 15 min at RT. Cells are placed on ice for 5 min, the media removed and the cells are lysed with 100 ⁇ L/well lysis buffer for 1 hour at 4° C. Plates are spun at 2000 rpm for 30 min at 4° C. and solubilized phosphorylated PDGFR is quantitated by ELISA.
  • High binding microplates are incubated overnight at RT with anti-mouse PDGFR-b capture-antibody in PBS, washed with PBS+0.05% Tween20 and blocked for 4 h at RT with PBS+1% BSA and washed again. 100 ⁇ L lysate/well is incubated overnight at 4° C. Plates are washed and wells are incubated with 100 ⁇ L/well of mouse anti-phosphotyrosine-HRP antibody for 2 h at 37° C. Plates are washed again and colorimetric detection is performed using TMB as substrate.
  • NIHT3T cells overexpressing mouse VEGFR-2 (FLK-1) are plated in a 96 well plate in DMEM+10% FBS. Following cell attachment for 4 hours the cells are serum starved overnight before adding the chemical test compounds to a final concentration of 0.1% DMSO. Following a 1 hour incubation at 37° C. cells are stimulated for 15 min at 37° C. with VEGF165. Cells are placed on ice for 5 min, the media removed, washed once with ice cold PBS and the cells are lysed with 50 ⁇ L/well lysis buffer for 1 hour at 4° C. Plates are spun for 10 min at 2000 rpm at 4° C. and solubilized phosphorylated VEGFR is quantitated by ELISA.
  • High binding microplates are incubated overnight at room temperature with VEGFR antibody in 50 ⁇ L PBS, washed with PBS+0.05% Tween20 and blocked for 4 h at RT with PBS+1% BSA and washed again. 50 ⁇ L lysate/well is incubated overnight at 4° C. Plates are washed and wells are incubated with 50 ⁇ L/well of mouse anti-phosphotyrosine-HRP antibody for 2 h at 37° C. Plates are washed again and colorimetric detection is performed using TMB as substrate.
  • HUVEC VEGF Induced Proliferation
  • HUVEC cells (Cambrex, CC-2517) were maintained in EGM (Cambrex, CC-3124) at 37° C. and 5% CO 2 . HUVEC cells were plated at a density 5000 cells/well (96 well plate) in EGM. Following cell attachment (1 hour) the EGM-medium was replaced by EBM (Cambrex, CC-3129)+0.1% FBS (ATTC, 30-2020) and the cells were incubated for 20 hours at 37° C.
  • the medium was replaced by EBM+1% FBS, the compounds were serial diluted in DMSO and added to the cells to a final concentration of 0-5,000 nM and 1% DMSO.
  • cells were stimulated with 10 ng/ml VEGF (Sigma, V7259) and incubated for 45 hours at 37° C.
  • Cell proliferation was measured by BrdU DNA incorporation for 4 hours and BrdU label was quantitated by ELISA (Roche kit, 16472229) using 1M H 2 SO 4 to stop the reaction. Absorbance was measured at 450 nm using a reference wavelength at 690 nm.
  • FIG. 1 shows a scheme that is used for the synthesis of the 3-alkoxy-4-acylaminoamide derivatives starting from methyl 3-hydroxy-4-aminobutanoate hydrochlorides and the activated acylating agent 1-3.
  • the amino ester hydrochloride starting material was prepared by refluxing the free amino acid in anhydrous methanol in the presence of 1.2 eq of HCl.
  • the amino group was protected as its monomethoxytrityl derivative in the presence of the secondary hydroxyl group to give the neutral hydroxy ester 1-1.
  • the hydroxyl group was alkylated using methyl- or ethyl iodide to form the protected amino alkoxy ester.
  • the Mmt group was removed in 1% trifluoroacetic acid leaving the amino hydrochloride or trifluoracetate compound 1-2.
  • This compound was quickly acylated with the preformed acylating agent 1-3 and the methyl ester was hydrolyzed by potassium hydroxide in water/DMF to give 1-4.
  • the free acid was then exposed to HATU, amine and diisopropylethyl amine in DMF to give the alkoxy amide 1-5.
  • FIG. 2 shows a scheme that is used for the synthesis of the 2-alkoxy-3-acylaminoamide derivatives starting from methyl 2-hydroxy-3-aminopropionate hydrochlorides and the activated acylating agent 1-3.
  • the amino ester hydrochloride starting material was prepared by refluxing the free amino acid in anhydrous methanol in the presence of 1.2 eq of HCl.
  • the amino group was protected as its monomethoxytrityl derivative in the presence of the secondary hydroxyl group to give 2-1.
  • the hydroxyl group was alkylated using methyl- or ethyl iodide to form the protected amino alkoxy ester.
  • the Mmt group was removed in 1% trifluoroacetic acid leaving the amino hydrochloride or trifluoracetate compound 2-2.
  • This compound was quickly acylated with the preformed acylating agent 1-3 and the methyl ester was hydrolyzed by potassium hydroxide in water/DMF to give 2-4.
  • the free acid was then exposed to HATU, amine and diisopropylethyl amine in DMF to give the alkoxy amide 2-5.
  • FIG. 3 shows a scheme that is used for the synthesis of the (2S)-2-alkoxy-4-acylamino-amide derivatives starting from methyl (2S)-2-hydroxy-4-aminobutanoate hydrochloride and the activated acylating agent 1-3.
  • the amino ester hydrochloride starting material was prepared by refluxing the free amino acid in anhydrous methanol in the presence of 1.2 eq of HCl.
  • the amino group was protected as its monomethoxytrityl derivative in the presence of the secondary hydroxyl group to give the neutral hydroxy ester 3-1.
  • the hydroxyl group was alkylated using methyl- or ethyl iodide to form the protected amino alkoxy ester.
  • the Mmt group was removed in 1% trifluoroacetic acid leaving the amino hydrochloride or trifluoracetate compound 3-2.
  • This compound was quickly acylated with the preformed acylating agent 1-3 and the methyl ester was hydrolyzed by potassium hydroxide in water/DMF to give 3-4.
  • the free acid was then exposed to HATU, amine and diisopropylethyl amine in DMF to give the alkoxy amide 3-5.

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US11/991,971 2005-09-22 2006-09-21 Alkoxy indolinone based protein kinase inhibitors Abandoned US20090305382A1 (en)

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EP (1) EP1926725A4 (enrdf_load_stackoverflow)
JP (1) JP2009508971A (enrdf_load_stackoverflow)
KR (1) KR20080046701A (enrdf_load_stackoverflow)
CN (1) CN101282965A (enrdf_load_stackoverflow)
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CA2621809A1 (en) * 2005-09-22 2007-04-05 The Scripps Research Institute Alkoxy indolinone based protein kinase inhibitors
US7928136B2 (en) * 2006-09-11 2011-04-19 Curis, Inc. Substituted 2-indolinone as PTK inhibitors containing a zinc binding moiety
CA2662902C (en) 2006-09-15 2015-11-24 Xcovery, Inc. Kinase inhibitor compounds
CN104394868A (zh) 2012-04-20 2015-03-04 安基生技制药股份有限公司 嘌呤类似物的环丙烷羧酸酯
RS58384B1 (sr) 2014-03-07 2019-04-30 Hoffmann La Roche Novi 6-fuzionisani heteroarildihidropirimidini za lečenje i profilaksu infekcije virusom hepatitisa b
PL3270915T3 (pl) 2015-03-16 2020-08-24 F. Hoffmann-La Roche Ag Leczenie skojarzone z zastosowaniem agonisty tlr7 i inhibitora składania kapsydu hbv
MX388408B (es) 2016-09-13 2025-03-19 Hoffmann La Roche Tratamiento combinado con un agonista de tlr7 y un inhibidor de montaje de capsida de hbv
CN110016052B (zh) * 2018-01-08 2021-09-28 四川海思科制药有限公司 N-去乙基舒尼替尼的磷酰胺衍生物及其制备方法
AU2020249331A1 (en) 2019-03-25 2021-09-23 F. Hoffmann-La Roche Ag Solid forms of a compound of HBV core protein allosteric modifier

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US72934A (en) * 1867-12-31 Improvement in marking-gauge fob sswim-mgohines
US6653308B2 (en) * 2001-02-15 2003-11-25 Sugen, Inc. 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors
US7629339B2 (en) * 2005-09-22 2009-12-08 The Scripps Research Institute Alkoxy indolinone based protein kinase inhibitors

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Publication number Priority date Publication date Assignee Title
TWI259081B (en) * 2001-10-26 2006-08-01 Sugen Inc Treatment of acute myeloid leukemia with indolinone compounds
AU2004294981A1 (en) * 2003-11-26 2005-06-16 The Scripps Research Institute Advanced indolinone based protein kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US72934A (en) * 1867-12-31 Improvement in marking-gauge fob sswim-mgohines
US6653308B2 (en) * 2001-02-15 2003-11-25 Sugen, Inc. 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors
US7629339B2 (en) * 2005-09-22 2009-12-08 The Scripps Research Institute Alkoxy indolinone based protein kinase inhibitors

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AU2006294600A1 (en) 2007-04-05
CN101282965A (zh) 2008-10-08
BRPI0616378A2 (pt) 2011-06-21
US20070072934A1 (en) 2007-03-29
US7629339B2 (en) 2009-12-08
EP1926725A4 (en) 2010-10-06
JP2009508971A (ja) 2009-03-05
EP1926725A1 (en) 2008-06-04
WO2007038251A1 (en) 2007-04-05
KR20080046701A (ko) 2008-05-27
CA2621809A1 (en) 2007-04-05

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