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Hydrophobic label-containing oxygen-bridged bicyclo-heptylene sulfonamide compound and application thereof

A cycloheptene sulfonamide and compound technology, applied in the field of medicine, can solve the problems of unsatisfactory molecular rigidity and water solubility, difficult to obtain a patterned design strategy, poor oral absorption and membrane permeability, etc., and achieve good estrogen Effects of receptor down-regulation activity

Active Publication Date: 2021-12-10
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, each method has its limitations, such as the first SERDs compounds, which usually need to enter the active pocket of the compound, require a certain binding affinity and occupy the binding pocket of the estrogen receptor molecule to change it so that Only when the hydrophobic pocket is exposed can it be effective, so the requirements for the rational design of the structure are very high, and it is difficult to obtain a patterned design strategy
For PROTAC technology, it has high molecular weight, unsatisfactory molecular rigidity and water solubility, and poor oral absorption and membrane permeability
Therefore, its poor pharmacokinetic properties are the main obstacle to its drugability.

Method used

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  • Hydrophobic label-containing oxygen-bridged bicyclo-heptylene sulfonamide compound and application thereof
  • Hydrophobic label-containing oxygen-bridged bicyclo-heptylene sulfonamide compound and application thereof
  • Hydrophobic label-containing oxygen-bridged bicyclo-heptylene sulfonamide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: (2S)-2-amino-N-(3-(4-((5,6-bis(4-hydroxyphenyl)-N-(2,2,2-trifluoroethyl)- 7) Preparation of -[2.2.1]hept-5-ene)-2-sulfonamide (phenoxy)propyl)-5-guanidine pentaneamide derivative (30a):

[0071]

[0072] Compound 29 (74.62mg, 0.126mmol) and compound 28a (85.95mg, 0.15mmol) were placed in a 25mL single-necked bottle, dissolved in 2mL of THF, triethylamine (15.21mg, 0.15mmol) was added, and reacted for 2h, After TLC confirms that the reaction is complete, it is extracted with ethyl acetate. After the organic phase is concentrated and spin-dried, it is dried with anhydrous sodium sulfate, and is separated and purified by silica gel column chromatography (the eluent ratio is v 二氯甲烷 / v 甲醇 =120:1-30:1), to obtain 108 mg of yellow solid compound 30a, with a yield of 77%. 1 HNMR (400MHz, MeOD-d 6)δ7.19(d, J=8.8Hz, 2H), 7.12(t, J=8.4Hz, 4H), 6.78(t, J=9.1Hz, 4H), 6.69(d, J=8.7Hz, 2H) ,5.45(s,1H),5.29(d,J=4.2Hz,1H),4.40(q,J=8.4Hz,2H),3.97(t,J=6.1Hz,3H),3.84(td,J...

Embodiment 2

[0073] Example 2: (2R)-2-amino-N-(6-(4-((5,6-bis(4-hydroxyphenyl)-N-(2,2,2-trifluoroethyl)- 7) Preparation of -[2.2.1]hept-5-ene)-2-sulfonamide (phenoxy)hexyl)-5-guanidine pentaneamide derivative (30b):

[0074]

[0075] Compound 29 (40mg, 0.068mmol) and compound 28b (57.3mg, 0.10mmol) were placed in a 25mL single-necked bottle, dissolved in 2mL of THF, added triethylamine (8.2mg, 0.08mmol), reacted for 2h, TLC After confirming that the reaction was complete, it was extracted with ethyl acetate, the organic phase was concentrated and spin-dried, dried with anhydrous sodium sulfate, separated and purified by silica gel column chromatography (the eluent ratio was v 二氯甲烷 / v 甲醇 =100:1-15:1), 47 mg of light yellow solid compound 30b was obtained, and the yield was 50%. The H NMR spectrum of point 1: 1 H NMR (400MHz, Acetone-d 6 )δ7.55(s,1H),7.33(d,J=2.2Hz,1H),7.30(d,J=2.2Hz,1H),7.26(d,J=4.3Hz,4H),7.20(dd, J=8.5,4.3Hz,5H),6.88(d,J=1.2Hz,1H),6.86(d,J=1.2Hz,1H),6.83(d,J=2.7Hz,...

Embodiment 3

[0076] Example 3: tert-butyl ((2S)-1-((3-(4-((1R,4R)-5,6-bis(4-hydroxyphenyl)-N-(2,2,2- Trifluoroethyl)-7-oxabicyclo[2.2.1]hept-5-ene)-2-sulfonyl)phenoxy)propyl)amino)-1-oxo-3-phenylpropan-2- base) carbamate (30c):

[0077]

[0078] Compound 29 (40mg, 0.068mmol) and compound 28c (32mg, 0.10mmol) were placed in a 25mL single-necked bottle, dissolved in 2mL of THF, triethylamine (8.2mg, 0.08mmol) was added, reacted for 2h, and confirmed by TLC After the reaction was complete, it was extracted with ethyl acetate, the organic phase was concentrated and spin-dried, dried with anhydrous sodium sulfate, separated and purified by silica gel column chromatography (the eluent ratio was v 二氯甲烷 / v 甲醇 =100:1-15:1), 47 mg of light yellow solid compound 30c was obtained with a yield of 86%. The H NMR spectrum of point 1: 1 H NMR (400MHz, Acetone-d 6 )δ7.55(s,1H),7.33(d,J=2.2Hz,1H),7.30(d,J=2.2Hz,1H),7.26(d,J=4.3Hz,4H),7.20(dd, J=8.5,4.3Hz,5H),6.88(d,J=1.2Hz,1H),6.86(d,J=1.2Hz,1H),6....

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Abstract

The invention discloses a hydrophobic label-containing oxygen-bridged bicyclo-heptylene sulfonamide compound containing and application thereof, and belongs to the technical field of medicines. The compound comprises an OBHSA compound which has a structure shown in a general formula I and contains an adamantane label and an OBHSA compound which has a structure shown in a general formula II and contains a hydrophobic amino acid label; in the general formulas, n1 and n2 are natural numbers from 1 to 60, and R is hydrophobic amino acid. The compound provided by the invention can degrade estrogen receptors and inhibit human breast cancer cells, and can be used for preparing drugs for targeted degradation of estrogen receptors and anti-breast cancer drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a synthesis method of an oxygen bridged bicyclo-heptenesulfonamide (OBHSA) compound containing amantadine and a hydrophobic amino acid label and its application in anti-breast cancer drugs application. Background technique [0002] Targeted protein degradation strategy, as an effective means to overcome drug resistance, has received more and more attention when drug resistance has become a key factor affecting the treatment of many diseases. For the important target of breast cancer, estrogen receptor (ER), whether drug resistance can be overcome has also become a key criterion for judging the therapeutic effect of this target drug. There are two main strategies for targeting ER targets for degradation. One is that the compound displaces the protein helix to expose the hydrophobic pocket to be recognized and degraded by the ubiquitin-protease system, such as RAD1901. And PROTAC...

Claims

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Application Information

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IPC IPC(8): C07D307/00C07D405/12A61K31/343A61K31/405A61P35/00
CPCC07D307/00C07D405/12A61P35/00Y02P20/55
Inventor 周海兵董春娥辛丽兰胡志烨
Owner WUHAN UNIV
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