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5-hydroxy-1,7-naphthyridine compound substituted by aryloxy group or hetero-aryloxy group, preparation method and pharmaceutical application thereof

A compound and hydroxyl technology, applied in the field of medicine, can solve problems such as short half-life, low bioavailability, and restrictions on patients' self-medication

Active Publication Date: 2016-11-23
SHENYANG SUNSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as the production and application of EPO have been greatly developed, exogenous EPO still faces several problems: 1. The cost of using EPO is relatively high, especially for patients who need long-term use.
2. As a macromolecular glycoprotein, EPO also has the characteristics of low bioavailability, short half-life in vivo, and easy hydrolysis by enzymes in the gastrointestinal tract. Therefore, EPO must be injected frequently, which limits the patient's self-medication The possibility of this has brought great inconvenience to the patient
3. The industrially synthesized EPO still cannot avoid the problem of immunogenicity, and the product has a certain risk of drug use

Method used

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  • 5-hydroxy-1,7-naphthyridine compound substituted by aryloxy group or hetero-aryloxy group, preparation method and pharmaceutical application thereof
  • 5-hydroxy-1,7-naphthyridine compound substituted by aryloxy group or hetero-aryloxy group, preparation method and pharmaceutical application thereof
  • 5-hydroxy-1,7-naphthyridine compound substituted by aryloxy group or hetero-aryloxy group, preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055]

[0056] Compound No. 1 (2‐(5‐hydroxy‐8‐methyl‐2‐phenoxy‐1,7‐naphthyridine‐6‐carboxamido)acetic acid)

[0057] Step 1: Preparation of methyl 2‐chloro‐6‐phenoxypyridine‐3‐carboxylate

[0058] Add 8.80 g (42.72 mmol) of methyl 2,6-dichloronicotinate and 4.02 g (42.72 mmol) of phenol in sequence in a 250 mL eggplant-shaped bottle, and dissolve them in 45 mL of N,N-dimethylformamide. While stirring, 7.80 mL (55.54 mmol) of triethylamine was added dropwise, and after the dropwise addition, 720 mg (6.41 mmol) of triethylenediamine was added. The reaction was stirred at room temperature for 4-5 hours, and the solution changed from clear to cloudy. TLC analysis [V (petroleum ether) / V (ethyl acetate)=6 / 1] detects that most of the raw materials have reacted. For post-treatment, 1.30 mL of HOAc (21.36 mmol), 25 mL of isopropanol and 15 mL of ice water were sequentially added, the solution changed from turbid to clear, and stirred at room temperature for 0.5 hours. Then, 40 m...

Embodiment 2

[0070]

[0071] Compound No. 2 (2‐(2‐(4‐fluorophenoxy)‐5‐hydroxy‐8‐methyl‐1,7‐naphthyridine‐6‐formylamino)acetic acid)

[0072] Step 1: Preparation of methyl 2‐chloro‐6‐(4‐fluorophenoxy)nicotinate

[0073] Add 2,6-dichloronicotinate methyl ester (2.06 g, 10 mmol) and 4-fluorophenol (1.12 g, 10 mmol) sequentially into a 250 mL eggplant-shaped bottle, 12 ml N,N-dimethylformamide It was dissolved, and triethylamine (1.80ml, 13mmol) was added dropwise under stirring at room temperature. After the dropwise addition, triethylenediamine (168mg, 1.50mmol) was added. The reaction was stirred at room temperature for 4-5 hours, and the solution changed from clear to cloudy. TLC analysis [V (petroleum ether) / V (ethyl acetate)=6 / 1] detects that most of the raw materials have reacted. After treatment, 1.30 mL of HOAc, 25 mL of isopropanol and 15 mL of ice water were added in sequence, the solution changed from turbid to clear, and stirred at room temperature for 0.5 hours. Then, 40 mL...

Embodiment 3

[0086]

[0087] Compound No. 7 (2‐(2‐(4‐chlorophenoxy)‐5‐hydroxy‐8‐methyl‐1,7‐naphthyridine‐6‐formylamino)acetic acid)

[0088] Step 1: Preparation of methyl 2‐chloro‐6‐(4‐chlorophenoxy)nicotinate

[0089] Add 2,6-dichloronicotinate methyl ester (2.06 g, 10 mmol) and 4-chlorophenol (1.57 g, 10 mmol) sequentially into a 250 mL eggplant-shaped bottle, 12 ml N,N-dimethylformamide It was dissolved, and triethylamine (1.80ml, 13mmol) was added dropwise under stirring at room temperature. After the dropwise addition, triethylenediamine (168mg, 1.50mmol) was added. The reaction was stirred at room temperature for 4-5 hours, and the solution changed from clear to cloudy. TLC analysis [V (petroleum ether) / V (ethyl acetate)=6 / 1] detects that most of the raw materials have reacted. After treatment, 1.30 mL of HOAc, 25 mL of isopropanol and 15 mL of ice water were added in sequence, the solution changed from turbid to clear, and stirred at room temperature for 0.5 hours. Then, 40 mL...

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Abstract

The invention relates to a 5-hydroxy-1,7-naphthyridine compound substituted by an aryloxy group or a hetero-aryloxy group, a preparation method and a pharmaceutical application thereof. In particular, the compound is represented as the formula (I), wherein R2, R3 independently are hydrogen; R1 is hydrogen or a C1-C3 alkyl group; Ar is an aromatic ring or a hetero-aromatic ring selected from naphthalene ring, pyridine ring, thiophene ring, furan ring and substituted benzene ring. The invention also relates to the preparation method of the compound, a medicine composition including the compound or a pharmaceutically acceptable salt thereof, and an application of the compound or the pharmaceutically acceptable salt thereof in preparation of a medicine for inhibiting HIF proline hydroxylase or a medicine for promoting generation of endogenous EPO.

Description

technical field [0001] The present invention relates to the field of medicine, in particular, the present invention relates to novel aryloxy or heteroaryloxy substituted 5-hydroxy-1,7-naphthyridine compounds for inhibiting HIF proline hydroxylase, which Preparation method and pharmaceutical use thereof. Background technique [0002] Hypoxia inducible factor (HIF) is a transcriptional activator containing basic helix-loop-helix (bHLH) and PAS (Per / Arnt / Sim), which mediates a series of genes in biological cells Regulation in response to cellular hypoxia. (Chowdhury, R., Hardy, A and Schofield, C.J., The human oxygen sensing machinery and its manipulation, Chem.Soc.Rev., 2008, 37, pp. 1308-1319; Kaelin, W.G., Jr., and Ratcliffe, P.J., Oxygen sensing by metazoans: the central role of the HIFhydroxylase pathway (Oxygen sensing by metazoans: the central role of the HIFhydroxylase pathway) Mol. Cell, 2008, 30, 393-402 pp.; Schofield, C.J., and Ratcliffe, P.J., Oxygen sensing by ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4375A61P43/00A61P7/00A61P7/06A61P19/08
CPCC07D471/04A61K31/4375A61P7/06
Inventor 周云隆蔡遂雄王光凤焦玲玲闵平景羽郭明
Owner SHENYANG SUNSHINE PHARMA CO LTD
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