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N-benzyl-substituted amide derivatives of amino salicylic acid and 4-aminobutyric acid and drug application of N-benzyl-substituted amide derivatives

A technology of aminosalicylic acid and amide derivatives, which can be used in the preparation of carboxylic acid amides, drug combinations, medical preparations containing active ingredients, etc., can solve problems such as unsatisfactory distribution of the central nervous system, and achieve good neuropathic pain relief. effect of pain

Inactive Publication Date: 2014-12-24
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high hydrophilicity of ZL006, the distribution in the central nervous system is not ideal, and it is ineffective when taken orally

Method used

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  • N-benzyl-substituted amide derivatives of amino salicylic acid and 4-aminobutyric acid and drug application of N-benzyl-substituted amide derivatives
  • N-benzyl-substituted amide derivatives of amino salicylic acid and 4-aminobutyric acid and drug application of N-benzyl-substituted amide derivatives
  • N-benzyl-substituted amide derivatives of amino salicylic acid and 4-aminobutyric acid and drug application of N-benzyl-substituted amide derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 11-(2-Hydroxy-4-nitrobenzamidomethyl)-cyclohexylacetic acid (2-a)

[0022] Add 2g of 4-nitrosalicylic acid, 4g of thionyl chloride, 1-2 drops of pyridine, 20mL of dichloromethane into a 100mL eggplant-shaped bottle, react at 40°C for 12h, stop the reaction, and remove the solvent by rotary evaporation to obtain paranitrate Base salicyloyl chloride, add 15mL of dichloromethane for later use. Take another 100mL eggplant-shaped bottle, add 1.87g of gabapentin and 0.44g of sodium hydroxide, and dissolve with 15mL of water. At -5°C, add the freshly prepared p-nitrosalicyloyl chloride solution dropwise, the dropwise addition is completed in about 1 hour, react at 0°C for 2 hours, and react at 25°C for 12 hours, filter with suction, transfer the filtrate to a 50mL eggplant-shaped bottle, add concentrated hydrochloric acid Adjust the pH to 4-5, a large amount of white solid precipitated, filtered with suction, and dried. Silica gel column purification, eluent (petrole...

Embodiment 2

[0023] Example 23-(2-Hydroxy-4-nitrobenzoyl)aminomethyl-5-methylhexanoic acid (2-b)

[0024] Using 4-nitrosalicylic acid and pregabalin as raw materials, the rest of the steps are the same as compound 2-a. White solid, 38% yield. 1 HNMR 500MHz, DMSO-d 6 ,δ(ppm): 0.83(d,3H,J=8.6Hz); 0.86(d,3H,J=8.6Hz); 1.10-1.25(m,2H); 1.65-1.73(m,1H); 2.12- 2.19(m,2H); 2.26-2.30(m,1H); 3.19-3.24(m,1H); 3.35-3.41(m,1H); 7.68(d,,1H J=2.3Hz); 7.72(dd, 1H, J=8.6Hz, J=2.3Hz); 8.04(d, 1H, J=8.6Hz); 8.88(t, 1H, J=5.5Hz); 12.08(s, 1H); 12.58(s, 1H)

Embodiment 3

[0025] Example 36-(2-Hydroxy-4-nitrobenzoyl)aminocaproic acid (2-c)

[0026] Using 4-nitrosalicylic acid and 6-aminocaproic acid as raw materials, the rest of the steps are the same as compound 2-a. White solid, 40% yield. 1 HNMR 500MHz, DMSO-d 6 ,δ(ppm):1.30-1.37(m,2H); 1.51-1.59(m,4H); 2.22(t,2H,J=7.3Hz); 3.31(dd,2H,J=12.9Hz,J=6.8 Hz); 7.67(d,1H,J=2.3Hz); 7.71(dd,1H,J=8.7Hz,J=2.3Hz); 8.05(d,1H,J=8.7Hz); 8.92(t,1H, J=5.5Hz); 12.35(s,1H)

[0027] Example 41-{[2-hydroxyl-4-(2-hydroxyl-3,5-dichlorobenzyl)aminobenzoyl]aminomethyl}-cyclohexylacetic acid (6-a)

[0028] In a 500mL autoclave, add 150mL of methanol, 1g of 1-(2-hydroxy-4-nitrobenzamidomethyl)-cyclohexylacetic acid, 1g of Raney nickel, 3 times of hydrogen gas exchange, and react at 38°C for 12 Hour. The reaction was stopped, and the reaction liquid was rotary evaporated to 15 mL. A solution of 3,5-dichlorosalicylaldehyde (0.57 g) in methanol (5 mL) was added to the reaction liquid, and a large amount of solids wer...

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Abstract

The invention relates to N-benzyl-substituted amide derivatives of amino salicylic acid and 4-aminobutyric acid and a drug application of the N-benzyl-substituted amide derivatives. The N-benzyl-substituted amide derivatives have the structures which are in line with the general formula shown in the specification. The drug is a multi-target twin drug of a nNOS-PSD-95 decoupling agent, gabapentin and pregabalin and has better analgesic effect on the neuropathic pain than the single-target drugs such as nNOS-PSD-95 decoupling agent, gabapentin and pregabalin, and the N-benzyl-substituted amide derivatives can be used for preparing drugs for treatment of neuropathic pain diseases.

Description

technical field [0001] The invention belongs to the field of pharmacy, and provides a kind of N-benzyl substituted aminosalicylic acid and 4-aminobutyric acid amide derivatives and their medicinal application. Background technique [0002] Neuropathic pain is "pain that results directly from damage or disease affecting the somatosensory system." Epidemiological surveys show that 7%-8% of people have experienced neuropathic pain in their lifetime (Pain, 2008, 136:380-387). It is a disease that is difficult to treat and has great harm to humans (Physical Medicine and Rehabilitation Clinics of North America 2013, 24, 507-520). Neuropathic pain is a continuous process that may recur and requires long-term treatment. Gabapentin (gabapentin) and its analog pregabalin (pregebalin) are commonly used oral neuropathic pain drugs, but there are many adverse reactions such as drowsiness and sedation (Clin Ther., 2007, 29:26-48). At present, there is a lack of satisfactory safe and eff...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/44C07C231/12A61K31/197A61K31/195A61P25/00
Inventor 朱东亚李飞戴鹏陈云陈明路赵婷李婷沈盈盈李俊
Owner NANJING MEDICAL UNIV
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