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Pyridinum derivatives for management of aging-related and diabetic vascular complications, process for their prepn. and therepeutic uses thereof

A technology for diabetes and complications, applied in the field of new pyridinium series compounds, which can solve problems such as unclear mechanisms

Inactive Publication Date: 2001-10-17
TORRENT PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Diabetes with symptoms of capillary disease and macrovascular disease have also been reported to exhibit oxidative stress, the mechanism of which is unclear

Method used

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  • Pyridinum derivatives for management of aging-related and diabetic vascular complications, process for their prepn. and therepeutic uses thereof
  • Pyridinum derivatives for management of aging-related and diabetic vascular complications, process for their prepn. and therepeutic uses thereof
  • Pyridinum derivatives for management of aging-related and diabetic vascular complications, process for their prepn. and therepeutic uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 The following screening methods confirm the AGE destroyer activity:

[0056] Materials: Bovine Serum Albumin (Fraction V) (BSA) Ribose, Analytical Grade Phosphate Buffered Saline (PBS)

[0057] Equipment: Microplate ELISA Reader-Spectramax Plus (Molecular Devices, USA) Microplate Washer (Bio-Tec Instruments, USA) pH Meter

[0058] method:

[0059] 160 mg / ml of protein bovine serum albumin (BSA) and 1.6M glucose were dissolved in phosphate buffered saline (PBS). Add 0.02% sodium azide as a preservative. The solution was sterile-filtered with a 0.02 μm filter membrane and aged at 37° C. for 16 weeks. After 16 weeks, the solution was dialyzed against PBS, aliquoted and stored at -20°C.

[0060] In order to measure the AGE destroying activity, 10 μg / ml and 100 μg / ml AGE-BSA of 16 weeks were co-cultured with different concentrations of test compounds at 37°C for 24 hours, and the AGE destroying activity was measured by ELISA.

[0061] ELISA was performed as fo...

Embodiment 2

[0081] Example 2 Preparation of N,N'-bis[3-carbonyl-1-(2-phenyl-2-oxyethyl)-3-pyridinium]hydrazine dibromide (compound 1):

[0082] Add a solution of phenacyl bromide (1.99g, 0.01mol) in isopropanol (10ml) to boiling N,N'-bis-(nicotinoyl)hydrazine (1.21g, 0.005mol) in methanol (20ml) , and the reaction mixture was refluxed for 6 hours. The reaction mixture was concentrated in vacuo to about 10 ml and filtered. The resulting residue was washed with hot ethyl acetate, and the isolated solid was crushed. It was recrystallized from a mixture of methanol:ethyl acetate (3:1, 20ml) to obtain a pale yellow solid. Yield: 60% m.p.: 260-262°C (decomposition) IR (KBr, cm -1 ):1696 and 1680 1 H NMR (DMSOd 6 ,400MHz)δ:11.65(2H,s),9.56(2H,s),9.21-9.16(4H,m),8.49-8.45(2H,m),8.08-8.05(4H,d),7.81-7.77( 2H,m),7.68-7.64(4H,m),6.58(4H,s) mass spectrum (m / z):479,480

[0083] According to the above method, the corresponding pyridine derivative is reacted with a suitable reagent, and the follo...

Embodiment 4

[0084] Example 4 N,N'-bis[3-carbonyl-1-(2-(2,4-dichlorophenyl)-2-oxyethyl)pyridinium]hydrazine dibromide (compound 3): Yield : 24% m.p.: 225-227 ℃ (decomposition) IR (KBr, cm -1):1702,1666 1 H NMR (DMSOd 6 ,400MHz)δ:11.69(2H,s),9.58(2H,bs),9.20-9.18(4H,m),8.49-8.47(2H,m),8.17-8.15(2H,d),7.92(2H, bs), 7.78-7.76 (2H, d), 6.50 (4H, s) mass spectrum (m / z): 615, 617, 618, 620. Example 5 brominated 1-(2-ethoxy-2-oxyethyl)-3- (2-(2-pyridyl)hydrazinocarbonyl)pyridinium (compound 4): Yield: 16% m.p.: 210-212°C IR (KBr, cm -1 ): 3140, 3005, 1732 and 1690 1 H NMR (DMSOd 6 ,400MHz) δ: 9.63(1H,s),9.27(2H,d),8.49-8.45(1H,m),8.13-8.07(2H,m),7.32-7.30(1H,m),7.12-7.11(1H ,m),5.77(2H,s),4.23(2H,q),1.25(3H,t) mass spectrum (m / z): 301,302

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Abstract

The invention discloses novel compounds of the pyridinium series useful for the management of diabetes and aging-related vascular complications, including kidney disease, nerve damage, atherosclerosis, retinopathy, dermatological disorders and discoloration of teeth, by breaking preformed AGE, of general formula (I), or pharmaceutically acceptable salts thereof, wherein, R1, R2, R3, X and m are as defined in the specification. The invention also discloses, method for preparation of the novel compounds of the series and pharmaceutical composition having one or more compounds as defined above as active ingredients. The invention further discloses a method of treatment of a diabetic patient by administering the compounds as defined above, either singly or in combination with drugs for antidiabetic therapy.

Description

field of invention [0001] The invention relates to a new class of pyridinium series compounds and their application in treating diabetes and related diseases. More specifically, the present invention relates to this series of compounds, processes for their preparation, pharmaceutical compositions containing such compounds and their use in the treatment of diabetic complications. These compounds exhibit AGE-disrupting activity, which is important for the treatment of complications associated with diabetes and aging, including kidney disease, nerve damage, atherosclerosis, retinopathy and skin diseases. The invention also relates to a method for reversing the yellowing of teeth caused by non-enzymatic oral browning, which comprises administering an effective dose of medicine to reverse the formed advanced glycation cross-links. Background of the invention [0002] In 1912, Maillard discovered that reducing sugars such as glucose and ribose react with proteins to form brown pi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/79A61K8/00A61K8/49A61K9/08A61K9/20A61K31/4425A61K31/4427A61K31/4436A61K31/444A61K31/455A61K45/06A61K47/02A61K47/12A61K47/26A61K47/32A61K47/34A61K47/36A61P1/02A61P3/10A61P9/00A61P9/10A61P13/12A61P17/00A61P27/02A61P37/00A61P43/00A61Q11/00A61Q19/08C07D207/00C07D213/00C07D213/77C07D213/80C07D213/81C07D213/82C07D213/87C07D333/00C07D401/06C07D405/12C07D409/06C07D409/14
CPCA61K31/4425A61K31/4436A61K31/444C07D409/14C07D213/87C07D213/77C07D213/82A61K45/06A61P1/02A61P13/12A61P17/00A61P27/02A61P37/00A61P43/00A61P9/00A61P9/10A61P3/10A61K2300/00
Inventor A·桑卡兰拉亚安
Owner TORRENT PHARMA LTD
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