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2-amino-7,8-dihydro-6h-pyrido[4,3-d]pyrimidin-5-ones

A pyridine and pyrimidine technology applied in the field of 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one

Inactive Publication Date: 2011-07-20
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, most forms of cancer are polygenic and harbor multiple signaling aberrations

Method used

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  • 2-amino-7,8-dihydro-6h-pyrido[4,3-d]pyrimidin-5-ones
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  • 2-amino-7,8-dihydro-6h-pyrido[4,3-d]pyrimidin-5-ones

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[0413] Referring to the examples below, the compounds of the invention can be synthesized using the methods described herein or other methods well known in the art.

[0414] The compounds and / or intermediates were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium Chromatography System (Milford, MA) with a 2690 Separation Module. The analytical column was an Alltima C-18 reverse phase, 4.6 x 250 mm, purchased from Alltech (Deerfield, IL). Gradient elution was used, typically starting with 5% acetonitrile / 95% water and proceeding to 100% acetonitrile over 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet (UV) absorption at 220 or 254 nm. HPLC solvents were purchased from Burdick and Jackson (Muskegan, MI) or Fisher Scientific (Pittsburgh, PA). In some cases, purity is assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates (eg, Baker-Flex Silica G...

example 1

[0456] Representative Procedures for Compounds of the Invention

[0457] Step A: α,β-Unsaturated Esters

[0458]

[0459] at -78°C, N 2 Next, to a stirred solution of triethylphosphonoacetate (88 mmol) in dry THF (176 mL) was added n-butyllithium (84 mmol) dropwise. The solution was stirred for 30 min keeping the internal temperature below -70 °C. at -78°C and N 2 Next, the phosphate ester solution was transferred via cannula to a solution of 2-bromo-4-fluorobenzaldehyde 1-1 (80 mmol) in THF (160 mL). The resulting solution was warmed to room temperature for 2 hours. By adding aqueous NH 4 The reaction mixture was quenched with Cl and then extracted with EtOAc (x3). The organic fractions were combined and washed with H 2 O (×3), washed with saturated brine (×3), then dried (Na 2 SO 4 ), filtered and evaporated under low pressure to yield a pale yellow oil. White crystals formed after cooling in the refrigerator. The crystals were filtered and washed with methanol...

example 2

[0479] Synthesis of Representative N-Alkylated Compounds of the Invention

[0480] Step A: Reductive Amination Reaction

[0481]

[0482] To a stirred solution of the free amine 1-5 (1 eq.), aldehyde 2-1 (1 eq.) in DCM was added sodium triacetoxyborohydride (1.1 eq.) at room temperature. The reaction was stirred at room temperature until complete as judged by LCMS. The mixture was subsequently made in DCM with aqueous NaHCO 3 The layers were separated, extracted with DCM (×3) and the combined organic fractions were subsequently washed with H 2 O (×3), washed with saturated brine (×3), then dried (Na 2 SO 4 ), filtered and evaporated under low pressure to give crude product compound 2-2, which was directly used in the next reaction.

[0483] Steps B-E: Acylation reaction, cyclization reaction, amino-pyrimidine-lactam formation reaction, Suzuki coupling reaction

[0484]

[0485] Steps B to E are the same as Steps E to G in Example 1.

[0486] Step F: Deprotect

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Abstract

Disclosed are 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, either alone or in combination with at least one additional therapeutic agent. Disclosed also are methods of using the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of cellular proliferative, viral, autoimmune, cardiovascular, and central nevous system diseases.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. 119(e), this application claims U.S. Provisional Patent Application No. 60 / 722,796, filed September 30, 2005, and U.S. Patent No. 60 / 836,886, filed August 9, 2006 No., each of which is incorporated herein by reference in its entirety. technical field [0003] The present invention relates to novel 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof; compositions of the novel compounds (alone or in combination with at least one additional therapeutic agent) and pharmaceutically acceptable carriers; and the novel compounds and compositions—alone or in combination with at least A combination of additional therapeutic agents - use in the prevention or treatment of cellular proliferation, viral, autoimmune, cardiovascular and central nervous system diseases. Background technique [0004] Heat shock or h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61P35/00A61K31/519C07D211/86
Inventor 蒂莫西・D・马哈约夫斯基辛西娅・M・谢弗克里斯托弗・麦克布赖德威廉・安东尼-麦克雷布兰登・M・多甘巴里・H・莱文夏奕莫琳・麦克纳X・迈克尔・王克里斯・门登霍尔周亚新龚宝清古丹约翰・多兰约翰・图林斯基克里斯廷・布林纳高振海丹尼尔・彭保罗・A・巴尔桑迪林晓东阿布兰・科斯塔莱斯艾丽斯・里克纳坦・布拉梅尔特雷莎・皮科保罗・A・雷恩霍韦
Owner NOVARTIS AG