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Hydrazine nitrile cathepsin inhibitors with different P<3> structures, and application thereof

A technology of cathepsins and inhibitors, applied in the field of design and synthesis of cathepsins inhibitors, can solve problems such as side effects, and achieve the effects of easy synthesis, convenient synthesis and simple structure

Inactive Publication Date: 2012-10-17
JILIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In view of the complexity of the role of Cats on normal physiological processes, its broad-spectrum inhibition will inevitably lead to unpredictable side effects in clinical trials

Method used

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  • Hydrazine nitrile cathepsin inhibitors with different P&lt;3&gt; structures, and application thereof
  • Hydrazine nitrile cathepsin inhibitors with different P&lt;3&gt; structures, and application thereof
  • Hydrazine nitrile cathepsin inhibitors with different P&lt;3&gt; structures, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] R in this example 1 is isobutyl, R 2 For 4-bromophenyl, the synthetic route is as follows:

[0055]

[0056] (1) Synthesis of Compound A: Put 2.01g of p-bromophenylacetic acid into a 100mL round-bottomed flask filled with a stirring bar, add 20mL of thionyl chloride dropwise, install a spherical condenser, and heat to reflux for 3h. Then change the reflux device to a distillation device, distill off the thionyl chloride, and recrystallize with a small amount of cyclohexane to obtain compound A.

[0057] (2) Synthesis of Compound B: Add 1 mL of thionyl chloride dropwise to 5 mL of anhydrous methanol under stirring in an ice-salt bath. After 10 min, 1 g of L-leucine was added to the system. After 30 minutes, the reaction system was moved to room temperature and stirred. After 2h, the system was heated to reflux in a water bath. After 1 h, the system was removed, and excess methanol was distilled off (so that the amount of methanol was just enough to prevent precip...

Embodiment 2

[0067] In a similar manner to Example 1, compounds 1 and 3 were synthesized with 4-methoxybenzoic acid, 4-trifluoromethylbenzoic acid and 4-nitrobenzoic acid instead of 4-bromobenzoic acid in Example 1, respectively. , 4. The characterization results are as follows:

[0068] Compound 1: 1 H NMR (500MHz, CDCl 3)δ7.77(d,J=8.7Hz,2H),6.94(dd,J=8.9,2.1Hz,2H),6.50(d,J=8.3Hz,1H),5.32(td,J=10.1,3.8 Hz,1H),3.36(s,3H),3.23(s,3H),1.87–1.78(m,1H),1.75–1.55(m,2H),1.09–1.02(dd,J=25.8,6.6Hz, 6H);

[0069] FT-IR (KBr, cm -1 ): 3297, 2960, 2870, 2222, 1694, 1626, 1540, 1503, 1264;

[0070] MS (ESI) m / z: Molecular formula: C 17 h 24 N 4 o 3 ,Theoretical value: 332.18, measured value: 332.9(M+H), 354.8(M+Na), 370.8(M+K);

[0071] Compound 3: 1 H NMR (500MHz, CDCl3) δ7.86(d, J=8.1Hz, 2H), 7.66(d, J=8.2Hz, 2H), 6.86(d, J=7.7Hz, 1H), 5.33–5.25(m ,1H),3.35(s,3H),3.25(s,3H),1.86–1.77(m,1H),1.69(dddd,J=40.1,13.7,9.9,3.8Hz,2H),1.10–0.99(m ,6H);

[0072] FT-IR (KBr, cm -1 ): 3332, 2960, ...

Embodiment 3

[0078] R in this example 1 is isobutyl, R 2 It is 4-(2-thiophene)phenyl, and the synthetic route is as follows:

[0079]

[0080] Add 0.256g (2mmol) 2-thiopheneboronic acid, 0.38g (1mmol) compound 2, 0.058g (0.05mmol) tetrakistriphenylphosphopalladium, 2mL 1M Na to a 100mL round bottom Schlenk flask 2 CO 3 solution and 30 mL THF. The mixture was freeze-thawed and vacuumed three times with nitrogen, then heated at 70°C for 2.5 h with vigorous stirring. Heating was stopped, and the solvent was spin-dried after the solution was cooled to room temperature, and 10 mL of water and 30 mL of ethyl acetate were added to the residue. After the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with water and washed with anhydrous Na 2 SO 4 Dry and rotary evaporate to dryness to obtain the crude product of compound 7. The crude product was purified by column chrom...

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Abstract

The invention which belongs to the field of the design and the synthesis of cathepsin (Cat for short) inhibitors concretely relates to novel and efficient hydrazine nitrile inhibitors with different P<3> structures directed to four Cats (K, B, L and S). The main structure of the hydrazine nitrile inhibitors in the invention is represented by a formula in the specification; and in the formula, R1 is isobutyl, and R2 is alkyl, aryl, or cycloalkyl. The peptidomimetic hydrazine nitrile inhibitors designed and synthesized in the invention have the advantages of relatively simple structure, and easy synthesis; and the design and the synthesis of the maternal structure provide great conveniences for the synthesis of subsequent end products. Synthesized compounds, which can effectively inhibit actives of the Cat K, the Cat B, the Cat S and the Cat L, have an inhibition constant to the Cat K and the Cat L being in a picomole concentration (10<-12>M) level; and the synthesized compounds, which have weak inhibition effects on the Cat B and the Cat S have an inhibition constant being in a nanomole concentration (10<-9>M) level.

Description

technical field [0001] The invention belongs to the field of design and synthesis of cathepsins inhibitors, in particular to four cathepsins (K, B, L and S) with different P 3 A new type of high-efficiency hydrazinonitrile inhibitor with a bit structure. Background technique [0002] Cathepsins (Cats) are the main members of the cysteine ​​protease family, and 11 species have been found in the human body. They are a class of intracellular proteases that mainly exist in lysosomes. They are unstable in neutral solutions and have low activity. They are easily activated and exert their physiological functions only in weakly acidic environments. [1] . Cats in lysosomes generate their active forms by hydrolyzing and cutting off the precursor peptides of some zymogens or prohormones, or activate other proteolytic enzyme systems to make them function. In addition to the main function of degrading proteins, Cats are also considered to be closely related to many important diseases ...

Claims

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Application Information

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IPC IPC(8): C07C261/04C07D213/56C07D333/24A61K31/275A61K31/381A61K31/4409A61P19/02A61P19/10A61P31/14A61P35/00
Inventor 吴玉清任兴凤李洪伟
Owner JILIN UNIV
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