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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 that are non-specific pi3k inhibitors, and unfulfilled understanding of individual isoforms, etc., to achieve low inhibitory potency, promote medical treatment of diseases, and inhibit the biological activity of human pi3k

Inactive Publication Date: 2010-12-30
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

which are useful to inhibit the biological activity of human PI3Kδ. Another aspect of the invention is to provide compounds that inhibit PI3Kδ selectively while having relatively low inhibitory potency against the other PI3K isoforms. Another aspect of the invention is to provide methods of characterizing the function of human PI3Kδ. Another aspect of the invention is to provide methods of selectively modulating human PI3Kδ activity, and thereby promoting medical treatment of diseases mediated by PI3Kδ dysfunction. Other aspects and advantages of the invention will be readily apparent to the artisan having ordinary skill in the art.

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
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specific example

Method A

Synthesis of (2-amino-3-fluorophenyl)methanol

To a round bottomed flask containing 2-amino-3-fluorobenzoic acid (15.7 g, 101 mmol) was added 100 mL of anhydrous THF. The reaction was cooled to 0° C. and lithium aluminum hydride (7.68 g, 202 mmol) was added as a solution in 200 mL of anhydrous Et2O. The reaction was allowed to warm to rt and stirred for 3 h, after which time it was quenched with 7.7 mL water, 7.7 mL of 15% NaOH, and 30 mL of water. The reaction was diluted with 300 mL of Et2O and filtered. The filtrated was dried over MgSO4 and filtered and concd to afford (2-amino-3-fluorophenyl)methanol. 1H NMR (400 MHz, CDCl3) δ 6.91 (ddd, J=10.8, 8.2, 1.2 Hz, 1H), 6.86 (br d, J=7.4 Hz, 1H), 6.64 (td, J=7.6, 5.1 Hz, 1H), 4.69 (s, 1H).

2-Amino-3-fluorobenzaldehyde

(2-Amino-3-fluorophenyl)methanol (13.5 g, 96 mmol) was dissolved in 319 mL of DCM. Manganese dioxide (66.5 g, 765 mmol, 8 eq) was added and the resultant slurry was stirred at rt overnight. The reaction mixture was f...

example 1

Preparation of N-((5-chloro-3-(3-fluorophenyl)quinolin-2-yl)methyl)-9H-purin-6-amine

2,5-Dichloroquinolin-3-ylboronic acid

To a cold solution of diisopropylamine (2.2 mL, 1.1 eq) in THF (33 mL) was added drop-wise a solution of n-BuLi (1.1 eq, 2.5M, 6.2 mL) in hexane at −20° C. The resulted LDA solution was kept in 0° C. for 30 min and cooled to −78° C. before addition of a solution of 2,5-dichloroquinoline (J. Am. Chem. Soc. 2005, 127, 12657) (2.8 g, 14 mmol) in THF (14 mL) drop-wise. The temperature was controlled below −72° C. by adjusting the addition rate (15 min). After another 5 min, trimethyl borate (2.4 mL, 1.5 eq) was added drop-wise. After 30 min, the reaction was quenched with water, acidified to pH 4 and partitioned between EtOAc (50 mL) and water (100 mL). The combined organics were washed with water, brine, dried over Na2SO4. Removal of solvent gave a pale yellow solid which was washed with EtOAc (10 mL×2) followed with hexane (10 mL). A pale yellow solid was obtained. ...

example 2

Preparation of N-((S)-1-(5-chloro-3-(3-fluorophenyl)quinolin-2-yl)ethyl)-9H-purin-6-amine, and

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PUM

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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

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 INVENTIONCell 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 that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol 2:358-60 (1992)).The levels of phosphatidylinositol-3,4,5-triphosphate (PIP3), the primary product of PI 3-k...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/52C07D473/34C07D487/04A61K31/519C07D401/14A61K31/506C07D471/04C07D401/12C07D413/14A61K31/5377C07D417/14A61K31/541A61P35/00A61P29/00A61P37/06A61P17/00
CPCC07D401/12C07D487/04C07D471/04C07D401/14C07D473/34A61P1/00A61P11/00A61P11/06A61P13/10A61P17/00A61P17/06A61P19/00A61P19/02A61P21/04A61P25/00A61P27/02A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/00A61P7/06A61P9/10A61P9/12A61P3/10A61K31/4375A61K31/444
Inventor BUI, MINNACHEN, YICUSHING, TIMOTHY D.DUQUETTE, JASON A.FISHER, BENJAMINGONZALEZ LOPEZ DE TURISO, FELIXHAO, XIAOLINHE, XIAOJOHNSON, MICHAEL G.LUCAS, BRIAN
Owner AMGEN INC
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