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Heteronuclear compound with dicyandiamide connection and its medicinal use

A technology of heterocyclic compounds and cyanoguanidine, which is applied in the field of heterocyclic compounds composed of cyanoguanidine links and its pharmaceutical applications, can solve the problems of unsatisfactory preparation stability, unsatisfactory physical and chemical properties, and poor water solubility.

Inactive Publication Date: 2006-11-01
李伟章
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But unfortunately, the physical and chemical properties of levosimendan are not ideal, the water solubility is poor, the stability is poor in aqueous solution, especially alkaline aqueous solution, and the stability of preparation is not ideal either, J.Pharm.Biomed.Anal., 2003, 31( 1): 125-31 reported the dimerization of levosimendan in ethanol solution to generate OR-1746 compound

Method used

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  • Heteronuclear compound with dicyandiamide connection and its medicinal use
  • Heteronuclear compound with dicyandiamide connection and its medicinal use
  • Heteronuclear compound with dicyandiamide connection and its medicinal use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1: (3S, 4R, 4'R)-N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl] -N'-cyano-N"-(6-acetyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)guanidine

[0219] 1.1 Synthesis of (4R)-4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenylthioisocyanate

[0220] 3.45g (0.017mol) (5R)-(-)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (2-1b) Soluble in 200ml 75% acetic acid and 100ml 2mol.L -1 In the mixed solvent of hydrochloric acid, under ice-water cooling, 500 ml of chloroform solution in which 2 ml (0.026 mol) of thiophosgene was dissolved was added dropwise thereto. The reaction was stirred at room temperature until the orange color of the chloroform layer disappeared, and the conversion of the raw material was detected by TLC. The organic layer was separated and washed with dilute NaHCO 3 aqueous solution and distilled water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (4R...

Embodiment 2

[0225] Example 2: (3R, 4S, 4'R)-N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl] -N'-cyano-N"-(6-acetyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)guanidine

[0226] The compound was prepared according to the method of 1.3 in Example 1, and the optically active 6-substituted benzopyran chiral amino alcohol was (3R, 4S)-4-amino-6-acetyl-3,4-dihydro-2 , 2-Dimethyl-2H-1-benzopyran-3-ol (1-3h'). 1 HNMR (600MHz, DMSO-d 6 , δ / ppm): 10.92(s, 1H), 9.48(s, 1H), 7.85-7.75(m, 5H), 7.38(d, J=7.8Hz, 2H), 6.85(d, J=8.4Hz, 1H), 5.89(broad peak, 1H), 4.96(m, 1H), 3.73(m, 1H), 3.39(m, 1H), 2.67(m, 1H), 2.50(s, 3H), 2.24(d, J=16.2Hz, 1H), 1.42(s, 3H), 1.19(s, 3H), 1.07(d, J=6.6Hz, 3H).

Embodiment 3

[0227] Example 3: (3S, 4R, 4'R)-N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl] -N'-cyano-N"-{6-[(N,N-diisobutylamino)sulfonyl]-3,4-dihydro-3-hydroxyl-2,2-dimethyl-2H- 1-benzopyran-4-yl}guanidine

[0228] The compound was prepared according to the method of 1.3 in Example 1, and the optically active 6-substituted benzopyran chiral amino alcohol was (3S, 4R)-4-amino-6-[(N, N-diisobutylamino )sulfonyl]-3,4-dihydro-2,2-dimethyl-2H-1-chromen-3-ol (1-3a). 1 HNMR (600MHz, DMSO-d 6 , δ / ppm): 10.92(s, 1H), 9.55(s, 1H), 7.86(d, J=8.4Hz, 1H), 7.76(d, J=9.0Hz, 2H), 7.60(m, 1H) , 7.53(m, 1H), 7.37(m, 2H), 6.92(d, J=8.4Hz, 1H), 5.90(broad peak, 1H), 4.92(m, 1H), 3.78(m, 1H), 3.38 (m, 1H), 2.77(d, J=7.8Hz, 4H), 2.67(m, 1H), 2.24(d, J=16.2Hz, 1H), 1.85(m, 2H), 1.43(s, 3H) , 1.17 (s, 3H), 1.07 (d, J=7.2Hz, 3H), 0.84 (d, J=7.2Hz, 12H). MS (m / z, FAB): 638 (M+1) + .

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Abstract

A heterocyclic compound with ethyl guanidine connection and its medicinal use are disclosed. The compound contains optical isomer or diastereomeric mixture, their medicinal salt, group and potassium channel developer and calcium spiking agent. It can be used to treat and prevent cardiac lassitude and cardiovascular diseases.

Description

technical field [0001] The present invention relates to heterocyclic compounds composed of cyanoguanidine linkages, or their optical isomers, or their diastereoisomer mixtures, their preparation methods, pharmaceutical compositions containing them and as calcium sensitizers Potassium channel openers with cardioprotective effects are used to prepare and / or prevent coronary heart disease, myocardial ischemia, atherosclerosis, hypertension, pulmonary hypertension, rheumatic valvular disease, dilated cardiomyopathy, etc. Acute or chronic heart failure during the development of the disease; and the use of drugs for acute or chronic heart failure caused by diabetes, nephritis, endotoxin and agrochemical or other chemical substance poisoning. Background technique [0002] Acute and chronic heart failure has become one of the high-mortality diseases that seriously endanger human health. It is a common symptom of various heart diseases such as coronary heart disease, myocardial isch...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61K31/4155A61K31/433A61K31/501A61P9/04A61P9/10A61P9/12C07D413/14C07D417/12
Inventor 李伟章
Owner 李伟章
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