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7, 9-nitrogen radical-4-oxo-4h-pyrido[l,2-a]pyrimidine-2-carboxylic acid benzylamide anti-virals

An alkyl and aryl technology, applied in the field of new bicyclic pyrimidinone (pyrimidinone) compounds, can solve problems such as drug resistance

Inactive Publication Date: 2013-05-01
AVEXA LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages of using current inhibitors include the rapid emergence and increased incidence of drug resistance and many side effects, thus requiring new classes of inhibitors that target proteins such as integrase

Method used

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  • 7, 9-nitrogen radical-4-oxo-4h-pyrido[l,2-a]pyrimidine-2-carboxylic acid benzylamide anti-virals
  • 7, 9-nitrogen radical-4-oxo-4h-pyrido[l,2-a]pyrimidine-2-carboxylic acid benzylamide anti-virals
  • 7, 9-nitrogen radical-4-oxo-4h-pyrido[l,2-a]pyrimidine-2-carboxylic acid benzylamide anti-virals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0210] Example 1: N-(4-fluorobenzyl)-3-hydroxyl-7-(4-methylpiperazin-1-yl)-4-oxo-9-(2-oxo-1,3- Preparation of oxazin (oxazinan)-3-yl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[0211]

[0212] [1,3]oxazinyl-2-ones were prepared according to the literature Journal of Heterocyclic Chemistry, 1966, 3(1), 84-89 using the starting materials (raw materials) described in Synthesis Scheme 1 .

Embodiment 11

[0213] Example 1.1: Methyl-3-(benzyloxy)-7-bromo-4-oxo-9-(2-oxo-1,3-oxazin-3-yl)-4H-pyrido[1 ,2-a] the preparation of pyrimidine-2-carboxylate

[0214]

[0215] [1,3]oxazinyl-2-one (235 mg, 2.23 mmol), 3-(benzyloxy)-7-bromo-9-iodo-4-oxo-4H-pyrido[1,2- a] methyl pyrimidine-2-carboxylate (1 g, 1.94 mmol), Pd 2 dba 3 (179mg, 0.19mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (xantphos) (224mg, 0.39mmol) and Cs 2 CO 3 (950mg, 2.9mmol) mixture in dioxane (10ml). in N 2 The mixture was heated at 90° C. for 6 hours under atmosphere. After cooling to room temperature, the dioxane was removed in vacuo. The residue was purified by column chromatography (EA / PE=1 / 1) to yield the desired product (350 mg, 40%).

[0216] 1 H NMR (300M Hz, CDCl 3 )δ9.08(d,J=2.1Hz,1H),7.79(d,J=2.1Hz,1H),7.55-7.45(m,2H),7.44–7.31(m,3H),5.34(s,2H ), 4.53(t, J=5.1Hz, 2H), 3.91(s, 3H), 3.84-3.64(m, 2H), 2.34-2.19(m, 2H).

[0217] MS (ESI + ) m / z488 (M[Br 79 ]+1),490(M[Br 81 ]+1)

Embodiment 12

[0218] Example 1.2: Methyl-3-(benzyloxy)-7-(4-methylpiperazin-1-yl)-4-oxo-9-(2-oxo-1,3-oxazine- Preparation of 3-yl)-4H-pyrido[1,2-a]pyrimidine-2-carboxylate

[0219]

[0220] The product from Example 1.1 (300 mg, 0.61 mmol), 1-methylpiperazine (123 mg, 1.23 mmol), Pd 2 dba 3 (56mg, 0.06mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (69mg, 0.12mmol) and Cs 2 CO 3 (298mg, 0.92mmol) were mixed in dioxane (3ml). in N 2 The mixture was heated at 85° C. for 6 hours under atmosphere. After cooling to room temperature, the dioxane was removed in vacuo. The residue was purified by column chromatography (DCM / MeOH=20 / 1) to give the desired product (120 mg, 33%).

[0221] 1 H NMR (300M Hz, CDCl 3 )δ9.08(d,J=2.1Hz,1H),7.79(d,J=2.1Hz,1H),7.59-7.49(m,2H),7.44-7.31(m,3H),5.30(s,2H ),4.53(t,J=4.8Hz,2H),3.89(s,3H),3.84-3.70(m,2H),3.36-3.20(m,4H),2.67-2.51(m,4H),2.38( s,3H), 2.34-2.18(m,2H).

[0222] MS (ESI + )m / z508(M+1)

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Abstract

The present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. Further provided is a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. A pharmaceutical composition or medicament comprising a compound of Formula I is also provided.

Description

technical field [0001] The present invention relates to novel bicyclic pyrimidinone compounds comprising nitrogen-containing substituents at positions 7 and 9 for use in the treatment of viral infections, especially HIV infections. Background technique [0002] The retrovirus known as "Human Immunodeficiency Virus" or "HIV" is the etiological agent of complex diseases that progressively destroy the immune system. The disease is called Acquired Immunodeficiency Syndrome or AIDS. As of December 2005, an estimated 40 million people worldwide were living with HIV, and more than three million deaths occurred each year. [0003] Features of retroviral replication include the reverse transcription of the viral genome into proviral DNA and its integration into the host cell genome. These steps are essential for HIV replication and are mediated by virally encoded enzymes, reverse transcriptase and integrase, respectively. [0004] HIV infection follows the pathway of viral particl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P31/18
CPCC07D471/04C07D487/04A61P31/12A61P31/14A61P31/18
Inventor 大卫·伊恩·罗兹约翰·约瑟夫·戴德曼黎江成尼古拉斯·安德鲁·范德格拉夫吕龙李新明冯骁于长江
Owner AVEXA LTD