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Rosmarinic acid derivative, its preparation method, and its application in preparation of antitubercular medicines

A technology of rosmarinic acid and its derivatives, which can be used in antibacterial drugs, organic chemistry, etc., and can solve the problem of blood drug concentration reduction

Inactive Publication Date: 2015-06-10
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the mutagenicity of PA-824 is a major obstacle for its use in the fight against tuberculosis; while OPC-67683 has drug interactions with the existing first-line drugs rifampin or pyrazinamide, which will make its blood concentration Its development is limited to a certain extent; although TMC207 has a unique target and a new mechanism of action with Mycobacterium tuberculosis, it can be metabolized by cytochrome P450 isoenzymes, so it has a certain relationship with rifampicin. Drug interactions, when combined with rifampicin, the plasma concentration will be reduced by 50%

Method used

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  • Rosmarinic acid derivative, its preparation method, and its application in preparation of antitubercular medicines
  • Rosmarinic acid derivative, its preparation method, and its application in preparation of antitubercular medicines
  • Rosmarinic acid derivative, its preparation method, and its application in preparation of antitubercular medicines

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Experimental program
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Effect test

Embodiment 1

[0058] Embodiment 1, the synthesis of (Z)-4-(3,4-dimethoxymethylenebenzene)-2-methyloxazolone

[0059]

[0060]Add veratraldehyde (10mmol, 1.66g), acetylglycine (10mmol, 1.17g), anhydrous sodium acetate (20mmol, 1.64g) and 20mL anhydrous acetic anhydride in a 50mL round bottom flask, stir to make it dissolve, and heat up to After reacting at 110°C for 8 hours, cool to room temperature, add 20 mL of ice water, crush the solid in the bottle, filter, wash the filter cake (5×10 mL) with distilled water, and then wash with 50% ethanol (5×10 mL), after drying, Recrystallized with acetone to obtain 2.11 g of yellow crystalline product (Z)-4-(3,4-dimethoxymethylenebenzene)-2-methyloxazolone with a yield of 85%; m.p.166~168°C ; 1 H NMR (DMSO-d 6 , 300MHz): δ2.37(s, 3H, CH 3 ), 3.83 (s, 3H, OCH 3 ), 3.86(s, 3H, OCH 3 ), 7.01(d, J=7.7Hz, 1H, ArH), 7.10(s, 1H, ArH), 7.66(d, J=7.7Hz, 1H, ArH), 7.93(s, 1H, CH); ESI- MS m / z 270.1[M+Na] + , 246.1[M-H] - ;HRMS(ESI):m / z calcd for C ...

Embodiment 2

[0061] The synthesis of embodiment 2,3,4-dimethoxyphenylpyruvate

[0062]

[0063] Add (Z)-4-(3,4-dimethoxymethylenebenzene)-2-methyloxazolone (9mmol, 2.01g) (2), 3M HCl 50mL, 90 Reaction at °C for 10 h. After stopping the reaction, cool to room temperature, filter, wash with water (3×10mL), dry, and wash the crude product with MeOH / H 2 O was recrystallized to obtain 1.80 g of light yellow solid 3,4-dimethoxyphenylpyruvate, with a yield of 89%; m.p.200~203°C; 1 H NMR (DMSO-d 6 , 300MHz): δ3.74(s, 3H, OCH 3 ), 3.75(s, 3H, OCH 3 ), 6.37(s, 1H, CH), 6.94(d, J=8.7Hz, 1H, ArH), 7.30(dd, J=2.1, 1.8Hz, 1H, ArH), 7.42(d, J=1.8Hz, 1H, ArH), 8.99 (brs, 1H, OH), 13.02 (brs, 1H, COOH); ESI-MS m / z 247.0 [M+Na] + , 471.0[2M+Na] + , 222.9[M-H] - ; HRMS (ESI): m / z calcd for C 11 h 12 o 5 Na[M+Na] + : 247.0582, found 247.0598.

Embodiment 3

[0064] The synthesis of embodiment 3,3,4-dimethoxyphenylalanine

[0065]

[0066] Add 3,4-dimethoxyphenylpyruvate (6.7mmol, 1.5g) and 30mL of 25% methanol into a 50mL round-bottomed flask, stir in an ice-water bath until the solid dissolves, adjust the pH to 10 with 10% NaOH solution, Add NaBH in batches 4 (10mmol, 0.54g), after the addition, react at room temperature overnight. 0.1 M HCl to make acidic, extracted with ethyl acetate (4 × 25mL), combined organic phase, anhydrous MgSO 4 Dry, filter, evaporate to dryness, and column chromatography (V (dichloromethane): V (methanol): V (acetic acid) = 90: 9: 1) to obtain light yellow solid 3,4-dimethoxyphenylalanine 1.18g, yield 78%; m.p.124~126℃; 1 H NMR (DMSO-d 6 , 300MHz) δ2.94 (dd, J=14.1, 6.9Hz, 1H, CH 2 ), 3.14 (dd, J=14.1, 14.1Hz, 1H, CH 2 ), 3.85(s, 6H, OCH 3 ), 4.48(dd, J=6.9, 4.2Hz, 1H, CH), 6.82(s, 3H, ArH); ESI-MS m / z 249.1[M+Na] + , 225.1[M-H] - ; HRMS (ESI): m / z calcd for C 11 h 14 o 5 Na[M+Na] + : 24...

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Abstract

The invention provides a rosmarinic acid derivative which comprises compounds 1-47 and their R-isomers or S-isomers. The structural general formula of the derivative is represented by a formula in the specification; and in the formula, R1, R2, R3 and R4 are defined in the specification. According to in-vitro anti-Mycobacterium tuberculosis experiments of the rosmarinic acid derivative of the invention, a medicine to be detected and a positive contrast medicine are respectively added to a small bottle containing a liquid medium in a continuous two-time dilution manner, a certain bacterium amount of Mycobacterium tuberculosis standard strains H37Rv is inoculated and is cultured for 14 days at 37DEG C, and the minimum inhibitory concentration (MIC) of each medicine to the Mycobacterium tuberculosis is observed. And experiment results show that the compounds in the invention have good anti-Mycobacterium tuberculosis activities, so the compounds can be used for preparing medicines for treating tuberculosis infection, and have large clinical application values. The invention provides a preparation method of the rosmarinic acid derivative.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to rosmarinic acid derivatives, their preparation methods and their application in the preparation of anti-tuberculosis drugs. Background technique [0002] Tuberculosis (Tuberculosis) is a common fatal infection caused by Mycobacterium tuberculosis, which usually infects and attacks the human lungs (such as tuberculosis), lymphatic system, circulatory system, urinary system, joints and skin. In 1882, Guo Huoshi first discovered Mycobacterium Tuberculosis, which brought hope for the treatment of tuberculosis in humans. Since the 1950s, due to the continuous discovery of anti-tuberculosis drugs, the prevalence of tuberculosis has been controlled to a certain extent. However, in the past 30 years, due to the neglect of tuberculosis, coupled with factors such as population flow and growth, and the prevalence of AIDS, the epidemic of tuberculosis has resurged, and some countries and regions have ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C59/64C07C69/734C07C69/618C07C69/62C07C233/46C07C235/32C07C259/06C07D307/54C07D213/30A61K31/215A61K31/341A61K31/4406A61P31/06
Inventor 张卫东孙青龑苏娟单磊徐希科柳润辉李慧梁袁虎
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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