Prolyl hydroxylase small molecule photosensitive prodrug and its preparation method and application

A prolyl hydroxylase and small molecule technology, applied in the field of chemical biology, can solve the problems of complexity and poor bioavailability, and achieve the effects of improved selectivity, reasonable design and novel structure

Active Publication Date: 2021-09-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most current PHD2 inhibitors lack tissue-specific selectivity and have broad-spectrum HIF-stabilizing activity in vivo, which complicates their use in the treatment of ischemic diseases with poor bioavailability

Method used

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  • Prolyl hydroxylase small molecule photosensitive prodrug and its preparation method and application
  • Prolyl hydroxylase small molecule photosensitive prodrug and its preparation method and application
  • Prolyl hydroxylase small molecule photosensitive prodrug and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of fluorescent probe Ⅰ-1

[0038] N-(5-(1-(2-(4-chlorophenoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-hydroxypicolinate)glycine (0.834 g, 2.0mmol), 4-(bromomethyl)-7-(diethylamino)-2H-pyran-2-one (0.494g, 2.0mmol), and potassium fluoride (0.174g, 3.0mmol) Dissolved in DMF (6mL), under N 2 The mixture was stirred at 45 °C for 2.0 h under protection and washed with CH 2 Cl 2 (3 x 5 mL) extraction. The combined organic phases were washed twice with saturated NaCl water (5 mL), anhydrous NaCl2 SO 4 Dry, filter, concentrate in vacuo, and purify the crude product by column chromatography (CH 2 Cl 2 : EtOAc=3:8), the target product probe Ⅰ-1 0.641g was obtained, the yield was 49.7%, R f : 0.31 (methanol:ethyl acetate=2:5), m.p.250.7-253.1°C, the compound 1 H-NMR (300MHz, DMSO-d 6 )δ12.29(s,1H),9.62(s,1H),8.92(s,1H),8.70(s,1H),7.83(s,1H),7.43(d,J=7.9Hz,1H), 7.31(d, J=7.1Hz, 2H), 6.98(d, J=7.0Hz, 2H), 6.58(d, J=7.8Hz, 1H), 6.50(s, 1H), 6.06(s, 1H), 5.36(s,2H),4.84...

Embodiment 2

[0040] Preparation of fluorescent probe Ⅰ-2

[0041] The preparation method is the same as in Example 1, replacing (4-(bromomethyl) with 4-(hydroxymethyl)-7-(piperidin-1-yl)-2H-chromen-2-one (0.518g, 2.0mmol) )-7-(diethylamino)-2H-pyran-2-one, to obtain yellow solid 0.716g, yield 54.4%, R f : 0.32 (methanol:ethyl acetate=2:5), m.p.253.1-255.6°C, the compound 1 H NMR (500MHz, DMSO-d 6 )δ8.73(d, J=1.6Hz, 1H), 8.41–8.34(m, 1H), 8.12(s, 1H), 7.86(d, J=1.5Hz, 1H), 7.52(d, J=7.5 Hz,1H),7.29–7.23(m,2H),6.98–6.93(m,2H),6.76(dd,J=7.4,1.6Hz,1H),6.59(d,J=1.5Hz,1H),6.14 (t,J=1.0Hz,1H),5.28(d,J=1.1Hz,2H),4.54–4.48(m,2H),4.46–4.31(m,2H),4.17(d,J=9.7Hz, 2H), 3.42(t, J=6.9Hz, 4H), 1.72–1.56(m, 6H)., HRMS(ESI):found659.1949(C 33 h 31 ClN 6 o 7 ,[M+H]+,requires 659.1943).

Embodiment 3

[0043] Preparation of fluorescent probe Ⅰ-3

[0044] The preparation method is the same as in Example 1, replacing N-(5-(1-(2-(4-chloro Phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-hydroxypyridinecarboyl)glycine, with 2,2'-((4-(bromomethyl)- 2-Oxo-2H-chromen-7-yl)azadiyl)diacetic acid (0.742 g, 2.0 mmol) in place of 4-(bromomethyl)-7-(diethylamino)-2H-pyran -2-ketone, 0.790g of yellow solid was obtained, the yield was 66.7%, m.p.260.1-263.6°C, the compound 1 H NMR (500MHz, DMSO-d 6 )δ8.45(d, J=1.6Hz, 1H), 8.37(t, J=9.6Hz, 1H), 7.67(d, J=1.4Hz, 1H), 7.64–7.58(m, 2H), 7.50( d,J=7.5Hz,1H),7.39–7.36(m,1H),7.35(dt,J=7.5,1.7Hz,1H),6.88(dd,J=7.5,1.5Hz,1H),6.64(d , J=1.4Hz, 1H), 6.14(t, J=0.9Hz, 1H), 5.28(d, J=1.1Hz, 2H), 4.19–4.13(m, 6H)., HRMS(ESI): found 595.1004 (C 28 h 22 ClN 3 o 10 ,[M+H] + ,requires 596.0994).

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Abstract

The invention discloses the design, synthesis and pharmaceutical application of a photosensitive prodrug based on prolyl hydroxylase. The structural modules of this type of photosensitive prodrug include a prolyl hydroxylase binding group and a coumarin photosensitive group. This kind of photosensitive small molecule causes the photosensitive group to leave under specific laser irradiation, releasing active molecules, which can be used for proline Photomodulation of the activity of acyl hydroxylase inhibitors, based on light-controlled photosensitive molecules, can selectively activate prolyl hydroxylase inhibitors in time and space. The prolyl hydroxylase photosensitive prodrug of the present invention has a novel structure and reasonable design, and uses such structural molecules as tool molecules to efficiently and accurately realize the activation of light-controlled prolyl hydroxylase inhibitors and realize the light-regulated HIF. Stability and expression of downstream gene EPO. The photosensitive prodrug can be used to prepare medicine for treating anemia and ischemic disease.

Description

technical field [0001] The invention relates to chemical biology, in particular to a class of small-molecule photosensitive prodrugs designed based on prolyl hydroxylase, a preparation method thereof, and an application in stabilizing hypoxia-inducible factor (HIF). Background technique [0002] Hypoxia-inducible factor (HIF) can regulate a variety of signaling transcriptional programs, such as erythropoiesis, mitochondrial metabolism, and angiogenesis, which are often associated with stroke, chronic renal anemia, neurodegenerative diseases, and acute renal failure. Injuries and other ischemic diseases are closely related, seriously affecting the normal life of patients. The main cause of ischemic diseases is the decreased expression of hypoxia-inducible factor (HIF), which leads to insufficient production and secretion of erythropoietin (EPO) in related organs (Clin.Sci.2018,132(7),825-838 ). The current standard of care in ischemic diseases aims to restore red blood cell...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14C07D405/12A61P7/02A61P7/06A61P9/10A61K31/4439A61K31/4545A61K31/4709A61K31/4433A61K41/00
CPCA61K41/0057A61P7/02A61P7/06A61P9/10C07D405/12C07D405/14
Inventor 张晓进李治红
Owner CHINA PHARM UNIV
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