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Aryl nitrogen mustard-domide conjugate and preparation method and pharmaceutical application thereof

A kind of aromatic nitrogen mustard and conjugate technology, applied in the field of biomedicine

Inactive Publication Date: 2018-08-17
NANTONG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The invention discloses a class of aromatic nitrogen mustard-mildamine conjugates with medicinal value and pharmaceutically acceptable salts thereof. There is no report on this type of compound so far

Method used

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  • Aryl nitrogen mustard-domide conjugate and preparation method and pharmaceutical application thereof
  • Aryl nitrogen mustard-domide conjugate and preparation method and pharmaceutical application thereof
  • Aryl nitrogen mustard-domide conjugate and preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 4-(4-(bis(2-chloroethyl)amino)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline- 4-yl) butanamide (I 1 ) preparation

[0048] Lenalidomide (1a, 259mg, 1.0mmol) was dissolved in 10ml of anhydrous CH 2 Cl 2 , then sequentially added chlorambucil (2a, 333mg, 1.1mmol), EDCI (384mg, 2.0mmol) and DMAP (25.9mg, 10%), and heated to 40°C for reflux reaction after all of them were dissolved. After the reaction was detected by TLC, the solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (mobile phase ethyl acetate:petroleum ether=2:1-4:1) to obtain 338mg of white solid, yield 62%.ESI-MS (m / z):545[M+H] + . 1 H NMR (DMSO-d 6 ,400MHz): δ11.04(s,1H,NH),9.79(s,1H,NH),7.81(d,1H,J=8.0Hz,Ar-H),7.52(d,1H,J=8.0Hz ,Ar-H),7.49(m,1H,Ar-H),7.06(d,2H,J=8.0Hz,Ar-H),6.68(d,2H,J=8.0Hz,Ar-H),5.15 (m,1H,CH),4.37(m,2H,CH 2 ),3.70(m,8H,CH 2 ),2.59(m,2H,CH 2 ),2.51(m,2H,CH 2 ),2.36(m,2H,CH 2 ),2.03(m,2H,CH 2 ),1.87(m,2H,CH 2 ...

Embodiment 2

[0050] 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-(2-(2,6-dioxopiper Pyridin-3-yl)-1-oxoisoindoline-4-yl)butanamide (I 2 ) preparation

[0051] Lenalidomide (1a, 259mg, 1.0mmol) was dissolved in 10ml of anhydrous CH 2 Cl 2 , and then sequentially added bendamustine hydrochloride hydrate (2b, 454mg, 1.1mmol), HATU (2.0mmol), DMAP (130mg, 50%) and triethylamine (404mg, 4.0mmol), until it was completely dissolved After heating to 40 ° C reflux reaction. After the reaction was detected by TLC, the solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (mobile phase methanol: dichloromethane = 1:30-1:15) to obtain 305 mg of a light yellow solid with a yield of 51%. ESI-MS (m / z):599[M+H] + . 1 H NMR (DMSO-d 6 ,400MHz):δ11.03(s,1H,NH),9.87(s,1H,NH),7.81(m,1H,Ar-H),7.50(m,1H,Ar-H),7.34(d, 1H,J=8.0Hz,Ar-H),6.93(m,1H,Ar-H),6.79(m,1H,Ar-H),5.15(m,1H,CH),4.37(m,2H,CH 2 ),3.71(s,8H,CH 2 ),3.69(s,3H,CH...

Embodiment 3

[0053] 4-(4-(bis(2-chloroethyl)amino)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol Indoline-4-yl)butanamide (I 3 ) preparation

[0054] Referring to compound (I) in Example 1 1 ) preparation method, pomalidomide (1b, 273mg, 1.0mmol) was substituted for lenalidomide and chlorambucil to react to obtain light yellow solid 301mg, yield 54%, ESI-MS (m / z): 559[M+H] + . 1 HNMR (DMSO-d 6 ,400MHz):δ11.15(s,1H,NH),9.69(s,1H,NH),8.45(d,1H,J=8.0Hz,Ar-H),7.82(t,1H,J=8.0Hz ,Ar-H),7.61(d,1H,J=8.0Hz,Ar-H),7.05(d,2H,J=8.0Hz,Ar-H),6.67(d,2H,J=8.0Hz,Ar -H),5.15(m,1H,CH),3.69(s,8H,CH 2 ),2.90(m,2H,CH 2 ),2.62(m,2H,CH 2 ),2.46(t,2H,J=8.0Hz,CH 2 ),2.05(m,2H,CH 2 ),1.89(m,2H,CH 2 ).

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Abstract

The invention discloses an aryl nitrogen mustard-domide conjugate and a preparation method and pharmaceutical application thereof. Compound (1) is subjected to reaction with compound (2) in the presence of polypeptide condensing agents EDCI and DMAP, or HATU and DIPEA to obtain compound I that is used to prepare antitumor drugs. The two drugs of different target types are combined herein to form aprodrug; multi-action synergic antitumor effect is achieved; antitumor activity and tolerance are improved; drug resistance of tumors is decreased. The domide drugs are linked via amido bonds, so that chances for amino groups on domide benzene rings to be degraded by in-vivo enzymes can be slimmed, and in-vivo bioavailability of the drugs is improved.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to a class of aromatic nitrogen mustard-mildamine conjugates and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and their medical applications, Especially the application in the preparation of antitumor drugs. Background technique [0002] The chemical name of Lenalidomide is 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione, which is An important derivative of thalidomide is the second-generation oral immunomodulatory drug developed by Celgene Corporation of the United States. It has dual mechanisms of inhibiting tumor necrosis factor and inhibiting tumor angiogenesis. On the one hand, it can directly The anti-cancer effect can effectively inhibit the development of cancer cells and induce the death of cancer cells. On the other hand, it can regulate the immune function of patients a...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/04A61K31/454A61K45/06A61K31/196A61K31/4184A61P35/00A61P35/02
CPCC07D401/14A61K31/196A61K31/4184A61K31/454A61K45/06A61P35/00A61P35/02C07D401/04A61K2300/00
Inventor 凌勇吴彩霞刘功清熊彪彭炎福刘季高伟杰许庭青张婷
Owner NANTONG UNIVERSITY
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