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Heterocyclic compounds and their uses

a technology of heterocyclic compounds and compounds, applied in the field of heterocyclic compounds and their, can solve the problems of limited utility of these compounds in studying the roles of individual class i pi 3-kinases, compounds, and non-specific pi3k inhibitors

Inactive Publication Date: 2011-06-23
CHEN YI +8
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Though a wealth of information has been accumulated in recent past on the cellular functions of PI 3-kinases in general, the roles played by the individual isoforms are not fully understood.
These compounds, however, are nonspecific PI3K inhibitors, as they do not distinguish among the four members of Class I PI 3-kinases.
Hence, the utility of these compounds in studying the roles of individual Class I PI 3-kinases is limited.
However, inasmuch as these compounds do not distinguish among the various isoforms of PI3K, it remains unclear from these studies which particular PI3K isoform or isoforms are involved in these phenomena and what functions the different Class I PI3K enzymes perform in both normal and diseased tissues in general.

Method used

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  • Heterocyclic compounds and their uses
  • Heterocyclic compounds and their uses
  • Heterocyclic compounds and their uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

9-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-9H-purin-6-amine

[0203]

[0204]9-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-9H-purin-6-amine. A mixture of 3-(bromomethyl)-2-(2-chlorophenyl)-8-methylquinoline (66 mg, 0.19 mmol), {prepared in a similar way as 3-(bromomethyl)-8-methyl-2-o-tolyl-quinoline, example 9} adenine (39 mg, 0.29 mmol), and cesium carbonate (124 mg, 0.38 mmol) in DMF (0.7 mL) was stirred at rt for 2 h. The crude mixture was evaporated onto silica gel and purified by flash chromatography (Biotage Si 25+M) eluting with MeOH / CH2Cl2 (5% to 10%). The resulting white solid was further purified by HPLC (Berger SFC) eluting with i-PrOH / CO2 / DEA to provide a white solid [PI3Kδ IC50=2130 nM]. MS (ESI+) m / z=401.1 (M+1).

example 2

Preparation of 4-Amino-8-((2-(2-chlorophenyl)-8-methyl-quinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one

[0205]

[0206]To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616 mmol), Cs2CO3 (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added 3-(chloromethyl)-2-(2-chlorophenyl)-8-methyl-quinoline (0.2049 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at 140° C. for 2.5 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 10 min as eluent to provide 4-amino-8-((2-(2-chlorophenyl)-8-methyl-quinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one as white solid. The white solid was triturated with EtOAc-Hexane (1:1) and filtered to provide 4-amino-8-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=58 nM] a...

example 3

3-Iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

3-(Chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline

[0207]

[0208]Prepared according to Procedure B using 8-methyl-2-(2-(trifluoromethyl)phenyl)-quinoline-3-carbaldehyde (1.6541 g, 5.25 mmol) and solid NaBH4 (0.2977 g, 7.87 mmol, 1.5 eq) in THF (26 mL) followed by Procedure C using the crude (8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol and SOCl2 (1.9 mL, 26.23 mmol, 5 eq) in CHCl3 (26 mL). After purification, 3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline was obtained as as yellow syrup. 1H NMR (DMSO-d6) δ ppm 8.60 (1H, s), 7.92 (2H, dd, J=11.5, 8.0 Hz), 7.72-7.85 (2H, m), 7.67 (2H, dd, J=14.3, 7.2 Hz), 7.54-7.62 (1H, m), 4.71 (2H, dd, J=89.8, 11.9 Hz), 2.62 (3H, s). Mass Spectrum (ESI) m / e=336.1 (M+1).

3-Iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0209]

[0210]Prepared accord...

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Abstract

Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.

Description

[0001]This application is a division and claims the benefit of application Ser. No. 12 / 079,281, filed Mar. 24, 2008 which claims the benefit of U.S. Provisional Application No. 60 / 919,565, filed Mar. 23, 2007, which are hereby incorporated by reference.[0002]The present invention relates generally to phosphatidylinositol 3-kinase (PI3K) enzymes, and more particularly to selective inhibitors of PI3K activity and to methods of using such materials.BACKGROUND OF THE INVENTION[0003]Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity (see Rameh et al., J. Biol Chem, 274:8347-8350 (1999) for a review). The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (PI 3-kinase; PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519C07D473/34A61K31/52A61P19/02A61P17/06A61P29/00A61P35/00C07D471/04C07D487/04
CPCC07D471/04C07D519/00C07D487/04A61P1/00A61P7/04A61P7/06A61P9/00A61P13/10A61P17/00A61P17/06A61P19/02A61P21/04A61P25/00A61P27/02A61P29/00A61P35/00A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08
Inventor CHEN, YICUSHING, TIMOTHY D.HAO, XIAOLINHE, XIAOREICHELT, ANDREASRZASA, ROBERT M.SEGANISH, JENNIFERSHIN, YOUNGSOOKZHANG, DAWEI
Owner CHEN YI
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