Thiazine amide derivative and application thereof in preparation of medicines for preventing and controlling neurodegenerative diseases

A technology of thiazinamide and derivatives, applied in the field of compounds of formula I, can solve the problems of unsuitability for prevention and treatment of neurodegenerative diseases, low melting point, poor blood-brain barrier passing ability, etc., and achieves excellent processability and good fluidity. , the effect of high bioavailability

Active Publication Date: 2012-09-19
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have found that its ability to pass through the blood-brain barrier is poor, and because of its low melting point, it is o

Method used

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  • Thiazine amide derivative and application thereof in preparation of medicines for preventing and controlling neurodegenerative diseases
  • Thiazine amide derivative and application thereof in preparation of medicines for preventing and controlling neurodegenerative diseases
  • Thiazine amide derivative and application thereof in preparation of medicines for preventing and controlling neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0025] Example 1 2-Hydroxyethylcysteine

[0026] Add 109 g (0.9 mol) of cysteine ​​to a 2000 ml round bottom flask, dissolve it with 1000 ml of distilled water, cool to 10°C in an ice bath, and add 24 ml of 1M NaOH aqueous solution to neutralize to pH-7. Pipette 100 ml of ethylene oxide cooled in advance at 10°C. After the addition, react at a constant temperature at 10°C for 1 hour, then rise to room temperature and react for 1.5 hours.

[0027] Extract with ether 400ml×4 to remove unreacted ethylene oxide. The water layer in the system was evaporated under the condition of less than 60℃ to obtain a yellow solid, which was recrystallized with water:ethanol=85ml:350ml, filtered and washed thoroughly with 95% ethanol to obtain the target compound, a white scaly solid, mp195 -196°C, about 100 grams, yield 67.5%. 1 H-NMR (400MHz, D 2 O)δ: 3.96131(dd, 1H, J 1 =4.272Hz, J 2 =7.816Hz), 3.80680-3.77293(m, 2H), 3.17887(dd, 1H, J 1 =4.268Hz, J 2 = 14.814Hz), 3.08224 (dd, 1H, J 1 =7.480Hz,...

Example Embodiment

[0028] Example 2 2-Chloroethylcysteine ​​hydrochloride

[0029] Add 44 g of 2-hydroxyethylcysteine ​​to a 1000 ml round bottom flask, dissolve it in 600 ml of concentrated hydrochloric acid, and heat to an external temperature of 90-95° C. and stir to react for 7 hours. After the reaction was completed, let it stand overnight in a refrigerator, and a large amount of needle-like solids precipitated in the system. The solvent was removed by suction filtration, and the obtained solid was naturally dried to obtain an off-white solid, mp185-186°C. About 40 grams, yield>70%. 1 H-NMR (400MHz, D 2 O) δ: 4.30477-4.26952 (m, 1H), 3.81913-3.78409 (m, 2H), 3.25903 (dd, 1H, J 1 =4.444Hz, J 2 = 14.984 Hz), 3.18877 (dd, 1H, J 1 = 7.352 Hz, J 2 =15.072 Hz), 3.04410-3.00625 (m, 2H).

Example Embodiment

[0030] Example 3 L-1,4-thiazine-3-carboxylic acid hydrochloride

[0031] Take 20 grams of 2-chloroethylcysteine ​​hydrochloride, dissolve it in water, add 7.2 grams of NaHCO dropwise under ice bath 3 After the addition, stir thoroughly to neutralize, extract 3 times with ethyl acetate, combine the organic phases, and Na 2 SO 4 dry.

[0032] The solvent was evaporated under reduced pressure, 400 ml of anhydrous methanol was added, and the reaction was stirred at room temperature for 5 days. The solvent was distilled off under reduced pressure and recrystallized with methanol: ether to obtain about 6 g of a white solid. mp160-161°C. 1 H-NMR(400M Hz, DMSO-d 6 )δ: 10.0898 (brs, 2H), 4.4214 (dd, 1H, J 1 =3.52Hz, J 2 =8.56Hz), 3.7833 (s, 3H), 3.4986-3.4766 (m, 1H), 3.2246-3.0606 (m, 3H), 2.9897-2.9593 (m, 1H), 2.8763-2.8622 (m, 1H); MS ( FAB) m / z: 162.0 (M-35.5), 102.0, 74.0.

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Abstract

The invention relates to a compound shown as the formula I, pharmaceutically acceptable salts of the compound, and/ or solvates and/ or hydrates of the compound. The invention also relates to a preparation method of the compound, a medicinal composition containing the compound, and application of the compound in preparation of medicines for preventing and controlling neurodegenerative diseases. In the formula I, R1 is hydrogen or linear-chain or branched paraffin containing 1-4 carbon atoms, and R2 is linear-chain or branched paraffin containing 1-4 carbon atoms, or linear-chain or branched paraffin which contain 1-4 carbon atoms and is substituted by benzene ring.

Description

Invention field [0001] The present invention relates to a compound of formula I, its pharmaceutically acceptable salt and / or its solvate and / or its hydrate. The preparation method of the compound, the pharmaceutical composition containing the compound and its use for preparing drugs for preventing and treating neurodegenerative diseases. [0002] [0003] Wherein R1 is hydrogen, or a straight or branched chain alkane of 1-4 carbon atoms, R2 is a straight or branched chain alkane of 1-4 carbon atoms, or a straight chain of 1-4 carbon atoms substituted by a benzene ring Chain or branched alkanes. Background technique [0004] Neurodegenerative diseases are a class of diseases caused by progressive diseases of the nervous system, including Alzheimer's disease, Parkinson's disease, Huntington's disease and muscular atrophy Lateral sclerosis (ALS) is ischemic or hemorrhagic stroke. Due to the complex causes of this type of disease, the pathogenic mechanism is not very clear, and no ef...

Claims

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Application Information

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IPC IPC(8): C07D279/12A61K31/54A61P25/28A61P25/16A61P37/02A61P25/00A61P25/14
Inventor 李松肖军海韩丹王莉莉姜丹钟武郑志兵王晓奎谢云德赵国明李行舟
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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