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Aminopropanediol compound containing five-membered aromatic heterocycle, its preparation method and its medical application

A compound, amino technology, applied in the field of medicinal chemistry, can solve problems such as blood pressure lowering, bradycardia, etc., and achieve the effect of high immunosuppressive activity in the body

Active Publication Date: 2019-04-09
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, FTY720-P for S1P 3 , S1P 4 , S1P 5 Receptor agonism generates complex physiological and biochemical responses in vivo through cellular signaling cascades, especially for S1P 3 The agonistic effect of the receptor, it was found in the course of clinical research that it is easy to induce toxic side effects such as bradycardia and blood pressure reduction

Method used

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  • Aminopropanediol compound containing five-membered aromatic heterocycle, its preparation method and its medical application
  • Aminopropanediol compound containing five-membered aromatic heterocycle, its preparation method and its medical application
  • Aminopropanediol compound containing five-membered aromatic heterocycle, its preparation method and its medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] 2-Amino-2-(4-(2-pentyloxazol-4-yl)phenethyl)propane-1,3-diol hydrochloride

[0128]

[0129] (1) Preparation of 2-acetylamino-2-phenylethylmalonate

[0130]

[0131] Sodium metal (4.1g, 178.3mmol) was dissolved in 250mL of absolute ethanol, diethyl acetamidomalonate (38.7g, 178.3mmol) was added in batches under ice cooling, and stirred at room temperature for 2 hours. Add 2-bromophenylethane (30g, 162.1mmol) in anhydrous ethanol solution dropwise under ice bath, reflux at 80°C for 18 hours, filter, concentrate the filtrate, dissolve the residue in 200ml of ethyl acetate, wash with saturated ammonium chloride solution 1 time, washed 2 times with water, 1 time with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrate and separate by column chromatography, the eluent is petroleum ether: ethyl acetate = 3:1, to obtain 23 g of white solid, the yield is 44.2%. The melting point is 112-115°C.

[0132] 1HNMR (300MHz, CDCl 3 )δ7.29-7...

Embodiment 2

[0159] 2-amino-2-(4-(1-pentyl-1H-1,2,3-triazol-4-yl)phenethyl)propane-1,3-diol hydrochloride

[0160]

[0161] (1) Preparation of 2-acetylamino-2-(4-bromophenethyl)diethyl malonate

[0162]

[0163]Sodium metal (3.66g, 159.1mmol) was dissolved in 250mL of absolute ethanol, and diethyl acetamidomalonate (36.2g, 166.7mmol) was added in batches under ice-cooling, and stirred at room temperature for 2 hours. Add 1-bromo-4-(2-bromoethyl)benzene (40g, 151.5mmol) in anhydrous ethanol solution dropwise under ice bath, reflux at 80°C for 18 hours, filter, concentrate the filtrate, add 300ml ethyl acetate to the residue dissolved, washed once with saturated ammonium chloride solution, twice with water, once with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrate and separate by column chromatography, the eluent is petroleum ether: ethyl acetate = 3:1, to obtain 20 g of a yellow solid, with a yield of 32.8%. The melting point is 35-38°C.

[...

Embodiment 3

[0191] 2-Amino-2-[4-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenethyl]propane-1,3-diolate salt

[0192]

[0193] (1) 2-Acetamido-2-[4-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenethyl]propane-1,3 -diol

[0194]

[0195] Prepared according to the method of step (5) in Example 2, substituting p-methylbenzyl bromide for 1-bromo-n-pentane to obtain 187 mg of light yellow solid with a yield of 75%. Melting point 100-103°C.

[0196] 1HNMR (400MHz, CD 3 OD)δ8.15(s,1H),7.63(d,J=7.6Hz,2H),7.22-7.19(m,4H),7.14(d,J=7.6Hz,2H),5.50(s,2H) ,3.73(d,J=11.2Hz,2H),3.64(d,J=11.2Hz,2H),2.57(t,J=8.4Hz,2H),2.27(s,3H),1.98-1.92(m, 5H)

[0197] MS(ESI)m / z409.2314(M+H) +

[0198] (2) Preparation of title compound

[0199] It was prepared according to the method of step (6) in Example 1 to obtain 157 mg of a tan solid with a yield of 85.0%. The melting point is 163-167°C.

[0200] 1HNMR (400MHz, CD 3 OD)δ8.21(s,1H),7.65(d,J=8Hz,2H),7.24(d,J=8Hz,2H),7.19(d,J=7.6Hz,2H),7.13(d,J =8Hz...

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Abstract

The present invention relates to a class of five-membered aromatic heterocycle-containing amino propanediol compounds, a preparation method, drug compositions containing the compounds, and pharmaceutical preparations thereof, and uses of the compounds as drugs, particularly as immunoloregulation drugs, wherein the five-membered aromatic heterocycle-containing amino propanediol compound is represented by a general formula I. Pharmacological test results show that the five-membered aromatic heterocycle-containing amino propanediol compounds can be sued for treatment of organ transplantation rejection and autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis vulgaris, psoriasis and the like. The formula I is defined in the instruction.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a class of aminopropanediol compounds containing five-membered aromatic heterocycles, their preparation methods, pharmaceutical compositions containing them, pharmaceutical preparations thereof, and their use as medicines, especially as immunomodulatory medicines . Background technique [0002] In recent years, organ transplantation technology has achieved remarkable development, and the number of organ transplant recipients continues to increase. After the human body receives a heterologous organ transplant, the autoimmune system will have a rejection reaction, which can be life-threatening in severe cases. Therefore, patients must take immunosuppressive drugs for life after organ transplantation to ensure safety. At the same time, autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, psoriasis, etc., are majo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/32C07D249/06C07D413/04C07D413/06A61K31/421A61K31/4192A61K31/4439A61K31/422A61P37/06A61P37/02A61P29/00A61P19/02A61P17/06
CPCC07D249/06C07D263/32C07D413/04C07D413/06
Inventor 田育林汪小涧金晶齐建国周琬琪陈晓光尹大力
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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