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Tetrahydro-1H-pyrrolo fused pyridones

一种化合物、-CR4R5的技术，应用在药物组合、细胞外液疾病、杀生剂等方向，能够解决HIF-α羟基化反应效率低等问题

Inactive Publication Date: 2011-01-19
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under low oxygenation, the HIF-α hydroxylation reaction is less efficient, and HIF-α is used to interact with HIF- dimerization

Method used

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  • Tetrahydro-1H-pyrrolo fused pyridones

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0175] Abbreviations used in describing the preparation of compounds of the invention:

[0176] AcOH acetic acid

[0177] Aq aqueous

[0178] Saline Saturated aqueous sodium chloride

[0179] CH 2 Cl 2 Dichloromethane

[0180] DMF N,N-Dimethylformamide

[0181] Dppf 1,1″-bis(diphenylphosphino)ferrocene

[0182] DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

[0183] DIEA N,N-Diisopropylethylamine

[0184] DMAP 4-N,N-Dimethylaminopyridine

[0185] DMF N,N-Dimethylformamide

[0186] DMSO Dimethyl Sulfoxide

[0187] EtOAc ethyl acetate

[0188] Et(et) ethyl

[0189] EtOH ethanol

[0190] Et 2 O or Ether Ether

[0191] G grams

[0192] h or hr hours

[0193] HCl hydrochloric acid

[0194] HPLC high performance liquid chromatography

[0195] IPA 2-propanol

[0196] i-PrOH Isopropanol

[0197] Mg mg

[0198] mL milliliter

[0199] Mmol millimole

[0200] MeCN acetonitrile

[0201] MeOH Methanol

[0202] Min minutes

[0203] ms or MS mass spectrometry

[0204]...

Embodiment 1

[0297]

[0298] N-({4-hydroxy-2-oxo-6-pent-4-enoyl-1-[4-(trifluoromethyl)benzyl]-2,5,6,7-tetrahydro-1H- Pyrrolo[3,4-b]pyridin-3-yl}carbonyl)glycine (E1-1)

[0299] At room temperature, to CH 2 Cl 2 To the product of intermediate 5 (112 mg, 0.204 mmol) in (0.7 mL) was added TFA (1.5 mL). The reaction was stirred for 25 min and concentrated. Use Et 2 O and hexane solidified the product. The solution was decanted and the solid was washed with hexane to yield the title compound E1-1. HPLC / MS: 494.0 (M+1); R t = 3.29 min.

[0300] Using a synthetic strategy similar to Intermediates 1 to 5 and Example 1, together with the appropriate amines in Step A of the Intermediate 4 process, Examples 2-4 as shown in Table 1 were prepared.

[0301] Table 1

[0302]

[0303]

Embodiment 5

[0305]

[0306] N-{[1-(4-bromobenzyl)-4-hydroxy-7-methyl-2-oxo-6-pent-4-enoyl-2,5,6,7-tetrahydro-1H- Pyrrolo[3,4-b]pyridin-3-yl]carbonyl}glycine (E5-1)

[0307] The title compound was prepared using a procedure analogous to Example 1, starting with Intermediate 2 and substituting 4-bromobenzylamine hydrochloride for 1-[4-(trifluoromethyl)phenyl] in Intermediate 4, Step A methylamine. HPLC / MS: 519.8 (M+1); R t = 3.11 min.

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Abstract

The present invention relates to tetrahydro-1H-pyrrolo fused pyridone 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, defined as insufficient oxygen-carrying capacity of the blood, and ischemia, in which constriction or blockage of blood vessels results in a restriction of the blood supply. Anemia can be caused by loss of red blood cells (hemorrhage), excessive destruction of red blood cells (hemolysis), or insufficient erythropoiesis (production of red blood cells from precursors in the bone marrow). Symptoms of anemia can include weakness, dizziness, fatigue, pallor, impaired cognitive function and a general decrease in quality of life. Chronic and / or severe anemia can lead to myocardial, cerebral or peripheral ischemic deterioration and heart failure. Ischemia is defined as an absolute or relative lack of oxygen to a tissue or organ, which can be caused by conditions such as atherosclerosis, diabetes, thromboembolism, hypotension, and the like. The heart, brain and kidneys are particula...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/90A61K31/519C07C229/00
CPCC07D471/04A61P7/06A61P43/00
Inventor M·J·克莱门茨V·J·科兰德里J·S·德本哈姆J·J·黑尔C·B·马森-杜根T·F·沃尔什
Owner SCHERING AG
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