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Novel application of piperazine acidamide compound in pharmacy

A technology of piperazine amides and compounds, which is applied in the new application field of piperazine amides in pharmaceuticals, and can solve the problems of unapplied rheumatoid arthritis prevention and treatment

Active Publication Date: 2012-06-27
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The applicant of the present invention discloses a new type of piperazine amide compound, its preparation method and its application in the treatment of neurodegenerative diseases or the treatment of diseases such as mental illness, epilepsy, convulsion and stroke in Chinese patent 200910030051.8. Prevention and treatment of rheumatoid arthritis

Method used

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  • Novel application of piperazine acidamide compound in pharmacy
  • Novel application of piperazine acidamide compound in pharmacy
  • Novel application of piperazine acidamide compound in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1 Preparation of 3-cyano-4-methyl-6-phenylpyridazine (compound 2)

[0057]

[0058]Add 1.25g (6.1mol) 3-chloro-4-methyl-6-phenylpyridazine, 0.99g (11.0mol) cuprous cyanide and 20mL pyridine into a 50mL pressure-resistant reaction tube, and react at 130°C for 24 hours , cooled, filtered, the filter cake was washed 3 times with 50 mL of ethyl acetate, and the organic phase was washed twice with 100 mL of 1N HCl, then dried with anhydrous sodium sulfate, and concentrated to obtain the crude product of compound 2 as a brown solid, which can be directly obtained without purification. For the next reaction, MS: 196.0 (M+H + ).

Embodiment 23

[0059] The preparation of embodiment 23-carboxy-4-methyl-6-phenylpyridazine (compound 3)

[0060]

[0061] Compound 2 prepared in Example 1 was added to 20 mL of 8N HCl solution, heated to reflux for 4 hours, neutralized with saturated sodium bicarbonate after cooling to make it a sodium salt, extracted twice with ethyl acetate, and the aqueous phase was Adjust the pH to 2 with dilute hydrochloric acid, then extract 3 times with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain 0.59 g of light yellow solid compound 3, yield 55%, MS: 213.0 (M-H + ).

Embodiment 3

[0062] Example 3 Preparation of (4-(4-fluorophenyl)piperazinyl)(4-methyl-6-phenylpyridazine)methanone (compound 4)

[0063]

[0064] In a 50ml round bottom flask, add 0.40g (1.87mol) of compound 3 and 20ml of dry dichloromethane, then add 0.30g (2.24mol) of HOBt, 0.43g (2.24mol) of EDC hydrochloride, 0.23g of triethyl Amine and 0.34 g (1.87 mol) of 1-(4-fluorophenyl)piperazine. The mixture was stirred at room temperature for 18 h, and then the dichloromethane was removed by rotary evaporation. The obtained oil was extracted with 100 ml of ethyl acetate and 50 ml of saturated sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography. Obtained 40.49 g of white solid compound, 69%.

[0065] 1 H-NMR (400MH, CDCl 3 )δ8.10-8.12 (m, 2H), 7.77 (s, 2H), 7.53-7.57 (m, 3H), 6.97-7.01 (m, 2H), 6.89-6.93 (m, 2H), 4.06 (t, J=4.8Hz, 2H), 3.59(t, J=4.8Hz, 2H), 3.14(t, J=4.8Hz, 2H), 2.49(s, 3H); MS: 3...

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Abstract

The invention discloses an application of a piperazine acidamide compound with a structure as shown in the formula I or its salt in the preparation of medicines for treating rheumatoid arthritis, wherein R1 is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; a substituent is selected from aryl, aryl alkyl, lower alkyl, lower alkyloxy, pseudo-perfluoroalkyl, halogen, hydroxyl, amino or cyan; R2, R3, R4 and R5 are respectively and individually selected from hydrogen, hydroxyl, amino, nitro, cyan, halogen, lower alkyl, lower alkyloxy, cycloalkyl, aryl, aryl alkyl, heteroaryl or heterocyclic radical; Ar is selected from substituted or unsubstituted heteroaryl; and a substituent is selected from lower alkyl, lower alkyloxy, pseudo-perfluoroalkyl, halogen, nitro, hydroxyl, amino, aryl, aryl alkyl or aryloxy. Formula I.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a new application of a piperazine amide compound in medicine. Background technique [0002] Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by joint synovitis and symmetrical and destructive joint lesions. Its typical clinical manifestations are recurrent symmetrical polyarthritis, with the most common involvement of the hand, wrist, foot, knee and other joints. In the early stage, there may be redness, swelling, heat, pain and joint dysfunction. In the late stage, joint stiffness and deformity may appear in different degrees, and bone erosion and skeletal muscle atrophy may occur, which is a disease with a high disability rate. Currently there are three main anti-RA drugs: non-steroidal anti-inflammatory drugs (NSAIDS), slow-acting anti-rheumatic drugs and glucocorticoids. The former such as ampiraxicam, meloxicam, lornoxicam, celecoxib; methotrexat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/501A61K31/506A61K31/517A61K31/50A61P29/00A61P19/02
Inventor 胡文辉钟桂发吴东海
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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