Novel 1,8-naphthyridine compounds

A compound and solvate technology, applied in the field of new 1,8-naphthyridine compounds, can solve problems such as low efficiency

Inactive Publication Date: 2010-03-03
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under low oxidation, the HIF-α hydroxylation reaction is less efficient, and HIF-α will interact with Dimerization HIF dimers are transported into the nucleus to bind hypoxia-responsive enhancer elements of HIF target genes

Method used

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  • Novel 1,8-naphthyridine compounds
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  • Novel 1,8-naphthyridine compounds

Examples

Experimental program
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preparation example Construction

[0166] The preparation of the compounds of the present invention is illustrated in the following schemes. Other synthetic methods are well known to those skilled in the art. The examples describing the preparation of compounds represented by formula I and similar compounds are not to be considered as limiting the invention set forth in the appended claim description. Unless otherwise stated, all variants are as previously defined.

[0167]Intermediates useful in the preparation of compounds of the invention are materials known in the art or can be prepared using chemistry known to those skilled in the art. Examples of reported intermediates and methods for their preparation include ethyl 1-benzyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (IIa) and related substituted analogs (IIb) (see WO 2005 / 021546); 1-alkyl-4-hydroxy-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine - 3-ethyl carboxylate analog (IIc) (see Kuroda et al., "Journal of Medicinal Chemistry", 1992...

Embodiment 1

[0185] N-({4-Hydroxy-2-oxo-1-[4-(trifluoromethyl)benzyl]-1,2-dihydro-1,8-naphthyridine-3-yl}carbonyl) Glycine

[0186]

[0187] Step A: 2H-Pyrido[2,3-d][1,3]oxazine-2,4(1H)-dione

[0188]

[0189] 2-(Carbamoyl)nicotinic acid (3.2 g, 19.26 mmol) was dissolved in DMF (30 mL), and lead tetraacetate (8.5 g, 19.26 mmol) was added to the solution in small portions at 0°C. The resulting solution was stirred and allowed to come to room temperature. The reaction mixture was heated at 55°C for one hour, then quenched with water (30 mL). The precipitate formed was filtered off, washed with water and dried to give 2.72 g of the title compound as a solid. 1 H NMR (500MHz, DMSO-d 6 ) δ 12.27 (s), 8.65 (d, 1H, J=4.3Hz), 8.29 (d, 1H, J=7.5Hz), 7.31 (d, 1H, J=7.3Hz).

[0190] Step B: 1-[4-(Trifluoromethyl)benzyl]-2H-pyrido[2,3-d][1,3]oxazine-2,4(1H)-dione

[0191]

[0192] 5.0 g (30.5 mmol) of the compound obtained in step A was dissolved in 50 mL of dimethylacetamide, and 1.46 ...

Embodiment 2

[0201] N-{[1-(4-Chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthalene-3-yl]carbonyl}glycine

[0202]

[0203] The title compound was prepared in a similar manner to Example 1, substituting 4-(chloro)benzyl bromide for 4-(trifluoromethyl)benzyl bromide in step B: MS: m / z 388 (M+H).

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Abstract

The present invention relates to naphthyridine compounds useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.

Description

Background technique [0001] Insufficient oxygen supply to cells and tissues is associated with anemia, which is defined as a lack of oxygen-carrying capacity of the blood, and isemia, which is a restriction of blood supply due to constriction or blockage of blood vessels. Causes of anemia include reduced red blood cells (bleeding), excessive destruction of red blood cells (hemolysis), or defective erythropoiesis (production of red blood cells from precursor cells in the bone marrow). Symptoms of anemia include weakness, dizziness, fatigue, pallor, cognitive impairment, and an overall decrease in quality of life. Chronic and / or severe anemia can lead to worsening heart muscle weakness, cerebral or peripheral vascular ischaemia, and heart failure. Ischemia is defined as the absolute or relative hypoxia of a tissue or organ. The causes of ischaemia include arteriosclerosis, diabetes, thromboembolism, hypotension and other diseases. The heart, brain, and kidneys are particularly...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/535
CPCC07D471/04A61P7/06A61P43/00
Inventor D·圭亚迪恩J·J·黑尔S·科坦达拉曼
Owner MERCK & CO INC
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