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Lenalidomide derivative and use thereof as medicine

A pharmacy and compound technology, applied in the field of long-acting lenalidomide derivatives, the preparation of prevention or treatment of malignant tumors, the preparation of lenalidomide derivatives, the field of malignant tumors of the blood and lymphatic system, can solve long-term medication difficulties, give Problems such as increased frequency of medication and impact on drug efficacy

Inactive Publication Date: 2013-11-20
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, lenalidomide has been widely used in the treatment of various malignant tumor diseases. However, it still has some defects, such as certain toxic and side effects, and short half-life of the drug, among which the short half-life is the biggest obstacle for long-term medication.
[0010] The biological half-life of a drug is an important indicator to measure the speed of drug metabolism and excretion in the body. If the half-life of a drug is too short, rapid elimination in the body will directly affect the efficacy of the drug and increase the frequency of administration, which may lead to poor patient compliance. Long-term medication brings certain difficulties

Method used

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  • Lenalidomide derivative and use thereof as medicine
  • Lenalidomide derivative and use thereof as medicine
  • Lenalidomide derivative and use thereof as medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Example 1 N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)-hexadecanoylamide

[0139]

[0140] Dissolve 0.29g (1.14mmol) hexadecylcarboxylic acid, 0.20g (0.76mmol) lenalidomide, 0.103g (0.76mmol) HOBT, 0.093g (0.76mmol) DMAP in 30mL DMF, add 0.17mL ( 1.5mmol) NMM, stirred at room temperature, 0.22g (1.14mmol) EDCI was added after 15min, and reacted at 50°C for 72h, the reaction solution gradually turned into a yellow suspension, and TLC detection did not continue the reaction. 50 mL of water was added and extracted with ethyl acetate (100 mL×3), the organic layer was washed with water (100 mL×3) and saturated sodium chloride solution 100 mL in turn, and the organic layer was dried over anhydrous sodium sulfate. Vacuum filtration and spin-drying of the filtrate gave a light yellow solid, which was recrystallized from ethyl acetate to give 0.11 g of a white solid powder, yield: 29%. m.p.215.6-217.5°C. 1 H-NMR (400MHz, DMSO-d 6 )δppm: 11.048(s,1H),9.776(s,1H),7....

Embodiment 2

[0141] Example 2 N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)-decylamide

[0142]

[0143] The method is the same as in Example 1, the raw materials are capric acid and lenalidomide, and a white solid powder is obtained, and the yield is 32%. m.p.217.5-217.7℃.1H-NMR: 1 H-NMR (400MHz, DMSO-d 6 )δppm: 11.045(s,1H),9.775(s,1H),7.820-7.798(dd,1H,J=6.72,J=1.96),7.504-7.501(m,2H),5.176-5.130(dd,1H ,J=13.16,J=5.04),4.409-4.365(d,1H,J=17.36),4.342-4.299(d,1H,J=17.64),2.957-2.893(m,1H),2.585-2.508(m ,1H),2.499-2.318(m,3H),2.039-2.025(m,1H),1.617-1.600(t,2H,J=6.88),1.290-1.253(m,12H),0.869-0.835(t, 3H,J=6.72).ESI-MS m / z:414.5[M+H] +

Embodiment 3

[0144]Example 3 N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)-tetradecamide

[0145]

[0146] The method is the same as in Example 1, the raw materials are myristic acid and lenalidomide, and a white solid powder is obtained, and the yield is 27%. m.p.212.7-213.0℃. 1 H-NMR(400MHz,DMSO-d6)δppm:11.052(s,1H),9.784(s,1H),7.804-7.799(dd,1H,J=7.00,J=1.96),7.502-7.499(m,2H ), 5.177-5.131 (dd, 1H, J=13.16, J=5.04), 4.409-4.365 (d, 1H, J=17.64), 4.342-4.299 (d, 1H, J=17.40), 2.957-2.880 (m ,1H),2.624-2.512(m,1H),2.499-2.327(m,3H),2.041-2.004(m,1H),1.613-1.578(t,2H,J=6.72),1.285-1.233(m, 20H),0.867-0.833(t,3H,J=6.76).ESI-MS m / z:470.4[M+H] +

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Abstract

The invention relates to a lenalidomide derivative and a use thereof as a medicine, and in particular relates to a compound shown as a formula (I), a solvate, a hydrate, a stereoisomer or pharmaceutically acceptable salt thereof. The invention further relates to a pharmaceutical composition comprising the compound, and the use of the compound in preparing medicines for preventing or treating malignant tumors, in particular malignant tumors in the blood-lymphatic system. Compared with lenalidomide, the compound provided by the invention has a longer half-life period and can be used for preparing long-acting preparations.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to long-acting lenalidomide derivatives. The present invention also relates to a preparation method of lenalidomide derivatives, a pharmaceutical composition containing lenalidomide derivatives, and the preparation of said lenalidomide derivatives for the prevention or treatment of malignant tumors, especially blood and lymphatic system The use of drugs for malignant tumors (such as multiple myeloma and myelodysplastic syndrome, etc.). Background technique [0002] Multiple myeloma (MM) is a malignant tumor caused by abnormal proliferation of monoclonal plasma cells. Current drugs for the treatment of MM mainly include: proteasome inhibitors, immunomodulatory drugs (IMiDs), monoclonal antibodies, histone deacetylase (HDAC) inhibitors, and cell cycle-specific drugs. Among them, the immunomodulatory drug lenalidomide is the focus of current research. [0003] Myelodysplastic syndrom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C08G65/333A61K31/454A61K47/48A61P35/00A61K47/60
Inventor 李松郑志兵胡坤周辛波钟武肖军海谢云德李行舟王晓奎
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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