Tertiary amine analogical peptide derivative and application of tertiary amine analogical peptide derivative in inhibiting HIV-1 protease

A technology of derivatives and tertiary amines, used in the inhibition of HIV-1 protease, the preparation of tertiary amine derivatives can solve the problems of metabolic inactivation, AIDS, and increased blood drug concentration.

Active Publication Date: 2015-04-01
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, studies have found that taking statins and HIV-1 protease inhibitors at the same time may increase the blood concentration of statins and increase the risk of serious adverse reactions including rhabdomyolysis
3) Low bioavailability, most of the ...

Method used

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  • Tertiary amine analogical peptide derivative and application of tertiary amine analogical peptide derivative in inhibiting HIV-1 protease
  • Tertiary amine analogical peptide derivative and application of tertiary amine analogical peptide derivative in inhibiting HIV-1 protease
  • Tertiary amine analogical peptide derivative and application of tertiary amine analogical peptide derivative in inhibiting HIV-1 protease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0158] "Example 1" Preparation of Compound 1

[0159]

[0160] 2-((2,6-Dimethylphenyl)(2-morpholine-2-oxoethyl)amino)-N-((2S,3R)-3-hydroxy-4-(N-isobutyl Base-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)-acetamide

[0161] Preparation of step A intermediate 2-(2,6-dimethylphenyl)aminoacetate

[0162]

[0163] Add 2,6-dimethylaniline (9.9g, 81.30mmol), ethyl chloroacetate (10.39mL, 97.56mmol), sodium acetate (8.0g, 97.56mmol) into an eggplant-shaped bottle containing 30mL of ethanol, and reflux for 3 Hour. The completion of the reaction was detected by TLC, the ethanol was removed by concentration under reduced pressure, the residue was extracted with ethyl acetate (50×3 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by flash column with ethyl acetate-n-hexane (1:8) to obtain the target product (11.7 g, 69.2%) as brown oil.

[0164] 1 H NMR (400MHz, DMSO) δ6.92 (d, J = 7.4Hz...

Embodiment 2

[0188] "Example 2" Preparation of Compound 5

[0189]

[0190] 2-((2,6-Dimethylphenyl)(2-N,N-Dimethyl-2-oxoethyl)amino)-N-((2S,3R)-3-Hydroxy-4- (N-isobutyl-4-methoxyphenylsulfonamido)-1-phenylbutan-2-yl)-acetamide

[0191] Preparation of intermediate ethyl 2-((2,6-dimethylphenyl)(2-N,N-dimethyl-2-oxoethyl)amino)acetate

[0192]

[0193] According to the synthesis method of Step B in Example 1, react 2-(2,6-dimethylphenyl)aminoacetate and N,N-dimethylbromoacetamide at 100°C in the presence of potassium carbonate 1.5h prepared.

[0194] 1 H NMR (400MHz, CDCl 3 )δ7.01(dd, J=3.8,3.2Hz,3H),6.95(dd,J=8.5,6.2Hz,1H),4.13(q,J=7.1Hz,2H),4.04(s,2H), 4.01(s,2H),3.86(s,1H),3.03(s,1H),2.94(s,1H),2.91(s,3H),2.85(s,3H),2.46(s,6H),2.39 (s, 2H), 1.23 (t, J=7.1Hz, 3H); LC-MS (ESI, M+Na + ) m / z 315.2.

[0195] Preparation of intermediate 2-((2,6-dimethylphenyl)(2-N,N-dimethyl-2-oxoethyl)amino)acetic acid

[0196]

[0197] According to the synthesis method of step C in Example 1,...

Embodiment 3

[0202] 《Example 3》The preparation of compound 6

[0203]

[0204] 2-((2,6-Dimethylphenyl)(2-N,N-Dimethyl-2-oxoethyl)amino)-N-((2S,3R)-3-Hydroxy-4- (N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)-acetamide

[0205] Preparation of intermediate (2S,3R)-1-benzyl-2-hydroxy-3-(N-isobutylamine-4-nitrosulfonamide)carbamate tert-butyl ester

[0206]

[0207] According to the preparation method of step E in Example 1, ((2S,3R))-1-benzyl-2-hydroxyl-3-(isobutylamine) tert-butyl carbamate and 4-nitrobenzenesulfonyl chloride were Prepared by stirring at room temperature for 3.5h under the catalyst of DIEA.

[0208] Melting point 113–115°C. 1 H NMR (400MHz, DMSO) δ8.37 (d, J = 8.8Hz, 2H), 8.06 (d, J = 8.8Hz, 2H), 7.25–7.12 (m, 5H), 6.69 (d, J = 8.9Hz ,1H),4.96(d,J=6.5Hz,1H),3.51–3.43(m,2H),3.38–3.35(m,1H),3.15(dd,J=13.6,8.4Hz,1H),3.08( dd,J=14.9,8.8Hz,1H),2.96–2.92(m,2H),2.03–1.93(m,1H),1.25(s,9H),0.85(d,J=6.7Hz,3H),0.83 (d, J=6.7Hz, 3H); LC-MS (ESI, M+H + ) m / z 521.9....

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Abstract

The invention belongs to the technical field of medicine and relates to a tertiary amine derivative as shown as the general formula I, and pharmaceutically acceptable salt or a prodrug of the tertiary amine derivative. Results of experimental studies show that the tertiary amine derivative has higher capacity of inhibiting the activity of HIV-1 (human immunodeficiency virus-1) protease and is expected to be developed into an effective drug for resisting Aids.

Description

Technical field: [0001] The invention belongs to the field of pharmacy, and specifically relates to the preparation of a group of tertiary amine derivatives and their application in inhibiting HIV-1 protease. Background technique: [0002] AIDS is a syndrome in which human immunodeficiency caused by infection with immunodeficiency virus (HIV) leads to a series of opportunistic infections and tumors. my country as a whole is a country with low prevalence of HIV-1, but some areas show high prevalence. At present, due to reasons such as viral drug resistance and low bioavailability, a large part of AIDS patients cannot receive effective treatment, and serious complications or death occur. [0003] HIV-1 protease inhibitors can prevent infected cells from producing immature, non-infectious viruses by preventing protease from cutting the viral gag or gag-pol gene. [0004] Since the launch of saquinavir, 10 HIV-1 protease inhibitors have been used clinically. According to its ...

Claims

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Application Information

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IPC IPC(8): C07D295/185C07C311/29C07C303/40C07C311/18C07C311/41C07D307/22C07D407/12A61P31/18
CPCC07C303/40C07C311/18C07C311/29C07C311/41C07D295/185C07D307/22C07D407/12
Inventor 白晓光杨志衡王玉成王菊仙周磊李子强董彪岑山王静
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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