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Substituted L-cysteine compound, as well as preparation method and use thereof

A compound and substituent technology, applied in the field of substituted L-cysteine ​​compounds, can solve the problems of no oral activity, large toxic adverse reactions, poor drugability and the like

Inactive Publication Date: 2014-05-07
INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are many drugs used to prevent radiation clinically, mainly sulfur-containing compounds, estrogens, cytokines, etc., but most of them have certain side effects, and their druggability is poor, and administration is inconvenient. Except for amifostine, No other chemical radioprotectors have been approved for clinical use, and in addition, no drugs have been approved for the prevention of acute radiation syndrome
The practical application of amifostine is limited due to its low drug protective potency, short effective time, high toxicity and adverse reactions, and no oral activity.
[0003] Since the discovery that cysteine ​​has an obvious radiation protection effect on mammals, many scholars at home and abroad have screened and studied various types of compounds such as cysteamine, cystamine, and aminoethyl phosphorothioate. However, these compounds All have certain toxic and side effects at effective doses

Method used

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  • Substituted L-cysteine compound, as well as preparation method and use thereof
  • Substituted L-cysteine compound, as well as preparation method and use thereof
  • Substituted L-cysteine compound, as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: 2-amino-3-allylmercaptopropionic acid

[0066] Add 10mmol of L-cysteine ​​to a 100ml reaction bottle, and add 3mol / L NH 4 After dissolving in 25ml OH, use saturated Na 2 CO 3 After cooling in an ice-salt bath to below 3°C, 15 mmol of allyl bromide was added dropwise with vigorous stirring, and the reaction was continued for 4 h while maintaining the reaction temperature. After the reaction, the solvent was evaporated to dryness under reduced pressure (2 O / C 2 h 5 OH recrystallized to obtain white needle crystals with a yield of 75.8%. mp 218~220℃. MS: Calculated value [C 6 h 11 NO 2 S+H] + : 162.0583, test value [C 6 h 11 NO 2 S+H] + : is 162.0582. 1 H-NMR (300MHz, DMSO-d 6 ) δppm: 7.57 (br, 3H), 5.76 (m, 1H), 5.10 (m, 2H), 3.27 (m, 1H), 3.10 (d, 2H), 2.64-2.95 (m, 2H). IR: 3086, 1583, 990, 910 (v -C-H , v C＝C , γ= C-H CH 2 =CH-), 1617 (v as C=O), 3438, 964 (v, γ-OH), 3438, 1500 (v, δ-NH 2 ).

Embodiment 2

[0067] Example 2: 2-amino-3-(3-methylbut-2-enylmercapto)propionic acid

[0068] Add 10mmol of L-cysteine ​​to a 100ml reaction bottle, and add 3mol / LNH 4 After dissolving in 25ml OH, use saturated Na 2 CO 3 After cooling in an ice-salt bath to below 3°C, 15 mmol of bromoisoamylene was added dropwise with vigorous stirring, and the reaction was continued for 4 h while maintaining the reaction temperature. After the reaction, the solvent was evaporated to dryness under reduced pressure (2 O was recrystallized to obtain white flaky crystals with a yield of 82.6%. mp 191-193°C. MS: Calculated value [C 8 h 15 NO 2 S+H] + : 190.0896, test value [C 8 h 15 NO 2 S+H] + : 190.0899. 1 H-NMR (300MHz, D 2 O) δppm: 5.08 (t, 1H), 3.68 (m, 1H), 3.05 (d, 2H), 2.74-2.89 (m, 2H), 1.52 (d, 6H). IR: 2971(v as -CH 3 ), 1580, 836 (v C＝C , γ = C-H -C=CH-), 1618 (v as C=O), 3134, 961 (v, γ-OH), 3246, 1480 (v, δ-NH 2 ).

Embodiment 3

[0069] Example 3: Synthesis of N-acetyl-L-cysteine

[0070] Add 7.9g (0.05mol) L-cysteine ​​hydrochloride to a mixed solvent of 20ml THF and 2ml water, add 13.6g (0.1mol) sodium acetate trihydrate under nitrogen protection, stir for 20min, and cool to 3 ~6°C. Then add 5ml (5.2g, 0.05mol) acetic anhydride, react at room temperature for 5h, reflux at 72°C for 3h, then add 4.3ml (0.05mol) hydrochloric acid and 5ml THF for acidification, filter, concentrate the filtrate to about 15ml, filter, and the filtrate at low temperature Under crystallization, the yield was 78.4%. mp 105-106°C. 1 H-NMR (300MHz, D 2 O) δppm: 4.44 (t, 1H), 2.78 (t, 2H), 1.89 (s, 3H).

[0071] Example 4: 2-acetylamino-3-allyl mercaptopropionic acid

[0072] Add 10mmol of N-acetyl-L-cysteine ​​to a 100ml reaction bottle, add 3mol / L NH 4 After dissolving in 25ml OH, use saturated Na 2 CO 3 Cool in an ice-salt bath to below 3°C, add 15 mmol of allyl bromide dropwise under vigorous stirring, maintain the r...

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Abstract

The invention relates to a substituted L-cysteine compound, as well as a preparation method and use thereof, and particularly discloses a compound with a general formula (I), pharmaceutically acceptable salts of the compound, a medicinal composition comprising the compound and the effects of the compound in radiation damage resisting, radiation protection and protection of the hematopoietic and immune system. In the general formula (I), R1 is selected from C1 to C6 linear and branched unsaturated substituents and aromatic substituents, preferably an allyl group, an isopentene group, a benzyl group and 2-butenyl; R2 is selected from H atoms and linear and branched C1 to C6 carbonyl substituents.

Description

technical field [0001] The present invention relates to a novel substituted L-cysteine ​​compound, its preparation method and its use in protecting hematopoiesis, immune system and radiation protection. Background technique [0002] Ionizing radiation (X or gamma rays, neutrons, and alpha particles with sufficient energy) produces reactive free radicals in biological tissues, and these free radicals interact with key macromolecules such as DNA, proteins, or biomembranes, resulting in cell damage and even May cause cellular dysfunction and apoptosis. In recent years, with the tense nuclear safety situation in the world and the rapid development of radiotherapy, especially after the nuclear leakage accident at Fukushima Nuclear Power Plant in Japan, the research on radiation protective agents has once again aroused people's attention. The application of radioprotectants can effectively reduce the morbidity or mortality caused by ionizing radiation. At present, there are many...

Claims

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Application Information

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IPC IPC(8): C07C323/58C07C323/59C07C319/14A61K31/198A61P7/00A61P37/02A61P17/16
Inventor 刘培勋于光允赵斌张浩姜明龙伟
Owner INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI