Lenalidomide derivative and preparation method and pharmaceutical application thereof

A drug and pharmaceutical technology, applied in the direction of preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve problems such as long-term use restrictions

Inactive Publication Date: 2013-12-04
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its long-term use is limited due to the plethora of side effects of thalidomide, especially peripheral neuropathy

Method used

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  • Lenalidomide derivative and preparation method and pharmaceutical application thereof
  • Lenalidomide derivative and preparation method and pharmaceutical application thereof
  • Lenalidomide derivative and preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157]N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-glucopyranosyl)-4-(2-(2,6-dioxopiperidine-3- Preparation of -1-oxoisoindoline-4-amino)-4-oxobutyramide 1.5 hydrate (I-2)

[0158] N-Benzyloxycarbonyl-L-glutamine (1)

[0159] Dissolve L-glutamine (58.4g, 0.4mol) in K 2 CO 3 (82.8g, 0.6mol) in water (400ml). Benzyl chloroformate (85ml, 0.5mol) was added dropwise in an ice-water bath, and after the addition was complete, the mixture was stirred at room temperature for 3h. The reaction solution was extracted with ethyl acetate (300ml×3), the aqueous layer was acidified with concentrated HCl until the pH value was 2-3 (no more white turbidity), and placed in the refrigerator overnight for crystallization. Suction filtration, grind the filter cake with a mortar, wash the obtained white solid with water, and dry under an infrared lamp to obtain 82.0 g of a white solid, with a yield of 73.1%, m.p.132~133 (literature value: m.p.133~135°C [Justus Liebigs Annalen der Chemie,1961,640,145-1...

Embodiment 2

[0201] N-(2,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl)-5-(2-(2,6-dioxopiperidine-3- Preparation of -1-oxoisoindoline-4-amino)-5-oxopentamide dihydrate (I-3)

[0202] 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-amino)-5-oxopentanoic acid (7-3)

[0203] Lenalidomide (3.93g, 15mmol) was dissolved in DMF (30ml), glutaric anhydride (2.58g, 22.5mmol) was added, heated to 60°C for 48h. Pour the reaction solution into ether, stir to precipitate a large amount of solids, place in the refrigerator overnight to continue crystallization, and filter. After washing with ether, 5.15 g of light yellow solid was obtained, with a yield of 93.0%, m.p.150-152°C;

[0204] 1 H-NMR (300MHz, DMSO-d 6 )δ (ppm): 12.08 (1H, brs, COOH), 11.03 (1H, s, CONHCO), 9.82 (1H, s, CONH), 7.82 (1H, s, aromatic), 7.50 (2H, s, aromatic) ,5.15(1H,d,J=11.7Hz,NCHCO),4.34(2H,s,PhCH 2 ),2.92~2.87(2H,m,CONHCH 2 CH 2 C H 2 COOH), 2.63~2.53 (2H, mCONHC H 2 CH 2 CH 2 COOH),2.40(2H,s,CH 2 C H 2 CO...

Embodiment 3

[0216] N-(2,3,4,6-tetra-O-acetyl-1-deoxy-β-D-galactopyranosyl)-4-(2-(2,6-dioxopiperidine-3 Preparation of -yl)-1-oxoisoindoline-4-amino)-4-oxobutyramide (I-5)

[0217] 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranose (8-2)

[0218] Anhydrous NaOAc (2.5 g, 30.4 mmol) was suspended in Ac 2O (35ml), heated to reflux. Control the reflux speed, add D-galactopyranose (5.0 g, 0.029 mol) in batches, and continue to reflux for 1 hour. After cooling, the reaction solution was poured into crushed ice (about 250 ml), stirred for 4 hours, and a solid was precipitated. Filter and wash with cold water to obtain 6.5 g of off-white solid, recrystallize from absolute ethanol (50 ml) to obtain 5 g of white crystal, yield 44.2%. m.p.147-149°C. (Literature value mp.144-146°C [CN1594342A])

[0219] 1-bromo-2,3,4,6-tetra-O-acetyl-1-deoxy-α-D-galactopyranose (9-2)

[0220] In a three-necked flask, suspend red phosphorus (0.7g, 5.6mmol) in acetic acid (7.7ml), stir well, and slowly add liquid bromi...

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Abstract

The invention relates to the field of pharmaceutical chemistry, and in particular to a lenalidomide derivative (I). G and n are defined in a direction book. Pharmacological tests show that the lenalidomide derivative plays an inhibiting role in vascular endothelial cell proliferation and can be used for clinical treatment of tumors or chronic inflammations.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of lenalidomide derivatives, their preparation method and their inhibitory effect on the proliferation of vascular endothelial cells. Background technique [0002] Abnormal growth of blood vessels is closely related to the occurrence and development of various diseases including tumors and age-related macular degeneration. The growth of blood vessels depends on the interaction of promoting and inhibiting factors. Under physiological conditions, the two types of factors, pro-angiogenic growth factors and angiogenesis inhibitory factors, maintain a dynamic balance; however, in pathological tissues, the dynamic balance of these two types of factors is broken. Promote the synthesis and release of angiogenesis factors, such as vascular endothelial growth factor (VEGF), angiopoietin (Ang) and fibroblast growth factor (FGF), while the growth factors that inhibit angiogenesis ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/26C07H13/06C07H7/02C07H5/06C07H1/00A61K31/706A61K31/7024A61K31/70A61K31/7008A61P35/00A61P29/00A61P9/00
Inventor 徐云根董缙刘坤楼影涵庄毅超
Owner CHINA PHARM UNIV
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