1-Amino-3-ethyl-5-nitratemethyladamantane hydrochloride (MN-05)
Cas 1835197-63-1
C13 H22 N2 O3, 254.33
Tricyclo[3.3.1.13,7]decane-1-methanol, 3-amino-5-ethyl-, 1-nitrate
Amantadine and its derivatives have a variety of biological activity, in the field of medicine has a wide range of applications. Rimantine (1-aminoethyl adamantane, Rimantadine) is currently widely used in clinical prevention and treatment of influenza drugs. Amantadine is widely used in the treatment of influenza and Parkinson & apos; s Disease (PD) (Schwab et al., J. Am. Med. Asos. 1669, 208: 1168). Memantine is the only NMDA receptor antagonist approved by the US FDA for the treatment of moderate to severe Alzheimer’s disease (AD). NMDA receptors are a subtype of the important excitatory amino acid ionotropic glutamate receptors in the central nervous system and are important receptors in the learning and memory process. NMDA receptor pathway is opened after the non-selective allow some cations, such as Ca 2+ , K + and Na + into the cells, these ions, especially calcium ions can cause a series of biochemical reactions, and ultimately lead to neurotoxicity , Causing neuronal apoptosis. Memantine is a noncompetitive antagonist of the NMDA receptor open channel, which binds to binding sites within the ion channel and blocks the intramolecular flow and acts as a neuroprotective effect. The combination of memantine to NMDA receptors is reversible and has a moderate dissociation rate that ensures both pharmacological effects and ensures that it does not accumulate in the channel and affects normal physiological functions (Lipton et al. Journal of neurochemistry. 2006, 97: 1611-1626). At the same time, the antagonism of memantine to NMDA receptor has a strong voltage dependence, only in the neuronal depolarization can be combined with the receptor, which can block the pathological conditions of neurons continue to depolarize the NMDA receptor Activation, without blocking NMDA receptor activation under normal physiological conditions (Wenk et al., CNS drug reviews. 2003, 9 (3): 275-308; McKeage., Drugs & aging.2010,27 (2): 177-179 ). This protection mechanism is also important for the treatment of other central nervous system diseases such as stroke, PD, ALS and so on, and therefore it has a good prospect for the treatment of these diseases.
Nitric oxide (NO) also has a variety of biological activities in the body, it plays the role of signal molecules. Nitric oxide molecules can penetrate the cell wall into the smooth muscle cells, so that relaxation, expansion of blood vessels, lower blood pressure. But also into the platelet cells, reduce its activity, thereby inhibiting its agglutination and adhesion to the vascular endothelium to prevent thrombosis, prevent atherosclerosis. NO is a free radical gas, with an unpaired electron, the body is very unstable, very easy to react with free radicals, which can reduce the number of free radicals. The accumulation of free radicals can cause nucleic acid cleavage, enzyme passivation, polysaccharide depolymerization, and lipid peroxidation eventually leads to neuronal death (Yan et al. Free Radic. Biol. Med. 2013, 62: 90-101). NO has a strong ability to react with various free radicals, which can effectively reduce the number of free radicals, but its synthesis in vivo requires the participation of nitric oxide synthase (NOS). Under normal circumstances, NOS activity is relatively low, the need for nitro-like molecules or saponins substances activated. The introduction of NO-releasing groups on small molecule drugs can increase NO content in the body and have significant efficacy, such as nitroglycerin.
Because of the complex pathogenesis of AD, at present, the clinical treatment of AD is limited, only four acetylcholinesterase inhibitors and an NMDA receptor inhibitor. These drugs for the role of a single target molecules, can only alleviate some aspects of clinical symptoms of AD can not fundamentally cure the disease, blocking the process of neurodegeneration.
Example 3, Synthesis of compound NM-004a
A 50 mL round bottom flask was cooled in an ice-water bath and 20 mL of concentrated sulfuric acid, 2 mL of n-hexane and 970 mg (4 mmol) of compound NM-003a were added to the round bottom flask. To maintain the ice bath, slowly add formic acid (1.8mL). After dripping, continue the ice bath reaction for 3 hours. The reaction solution was poured into 100 mL of ice water to precipitate a solid. The mixture was allowed to stand and filtered to give a pale yellow solid. After drying in solid, it is dissolved in ethyl acetate and the aqueous solution of sodium hydroxide is basified to pH to about 9-10. The aqueous layer is separated. The organic layer was extracted with an aqueous solution of sodium hydroxide (30 mL x 3) and the aqueous solution was combined with a dilute hydrochloric acid solution to acidify the aqueous layer to a pH of about 3. Filtered and dried to give the pure compound NM-004a 640 mg (77%). ESI-MS: m / z 207 ([MH] – ). 1 H-NMR (DMSO-d6, ppm): 0.76 (t, 3H, J = 7.5Hz), 1.11 (q, 2H, J = 7.5Hz) (M, 2H), 1.47 (s, 2H), 1.51-1.64 (m, 2H), 1.66-1.81 (m, 4H), 2.01 (m, 2H), 11.99 (s, 1H).
Example 4, Synthesis of compound NM-004b
To a 50 mL round bottom flask, 624 mg (3 mmol) of compound NM-004a was added and the mixture was cooled in an ice bath. Add 0.55mL concentrated nitric acid, stir well. To the mixture was added 3.5 mL of concentrated sulfuric acid, and the reaction was carried out in an ice bath for 1 hour. After which 2.5 mL of acetonitrile (4.8 mmol) was added dropwise and the reaction was continued for 1 hour in an ice bath. The reaction solution was poured into 20 mL of ice water and vigorously stirred for 30 minutes and allowed to stand overnight. The precipitate was removed by filtration, and the solid was washed with the appropriate amount of water and dried to obtain the compound NM-004b (580 g, 73%) without further purification. ESI-MS: m / z 266 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.74 (t, 3H, J = 7.5Hz), 1.15 (q, 2H, J = 7.5 Hz, 1.26-1.35 (m, 2H), 1.36-1.47 (m, 2H), 1.52-1.70 (m, 4H), 1.72-1.86 (m, 5H), 1.88-1.98 (m, 2H) M, 1H), 7.43 (s, 1H).
Example 5, Synthesis of compound NM-004c
The compound NM-004b 878 mg (3.3 mmol) was dissolved in 10 mL of dry tetrahydrofuran and cooled in an ice-water bath. 0.5 mL of triethylamine and 0.5 mL of ethyl chloroformate were added to the mixture, followed by an ice bath for 30 minutes. The ice bath was removed and reacted at room temperature for 4 hours. The filtrate was filtered and the filtrate was washed with an appropriate amount of tetrahydrofuran. To the filtrate by adding sodium borohydride 1.5g, dropping funnel slowly dropping 1mL water, 1 hour drop finished. After dripping at room temperature, the reaction was continued for 1 hour. TLC monitoring, the reaction is completed, the reaction system to add water 30mL, dry spin dry tetrahydrofuran. The aqueous layer was extracted with ethyl acetate (20 mL x 4), combined with ethyl acetate, 25 mL of 0.5 N hydrochloric acid, saturated aqueous sodium chloride solution and water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude oil. Silica gel column (petroleum ether: ethyl acetate = 1: 1), and finally a white solid, NM-004c, 348 mg (42%) was obtained. ESI-MS: m / z 252.2 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.76 (t, 3H, J = 7.5Hz), 1.03-1.20 (m, 4H) 1.28 (m, 4H), 1.58 (m, 4H), 1.75 (m, 5H), 2.09 (s, 1H), 3.02 (d, 2H, J = 5.5 Hz), 4.38 (t, 1H, J = ), 7.33 (s, 1H).
Example 6, Synthesis of compound NM-004d
To a 250 mL round bottom flask was added 1.26 g (5 mmol) of compound NM-004c, 3 g of solid sodium hydroxide, 20 mL of diethylene glycol and refluxed at 170 ° C for 15 hours. After cooling to room temperature, the reaction solution was poured into 40 g of crushed ice and the mixture was stirred. The mixture was extracted with ethyl acetate (20 mL x 4). The combined ethyl acetate layer, 30 mL of water and 30 mL of saturated sodium chloride solution were washed and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to give a crude product as a pale yellow oil. The crude product was dissolved in 50 mL of dry ethyl acetate and the resulting dry HCl was passed under stirring to precipitate a large amount of white solid. The solid was washed with an appropriate amount of dry ethyl acetate and dried to give 850 mg (69.4%) of white solid NM-004d. ESI-MS: m / z 210.3 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.74 (t, 3H, J = 7.6 Hz), 1.15 (q, 2H, J = 7.6 Hz, 1.26-1.35 (m, 2H), 1.36-1.47 (m, 2H), 1.53-1.68 (m, 4H), 1.74-1.85 (m, 3H), 1.88-1.96 (m, 2H) M, 1H), 7.43 (s, 3H).
Example 7, Synthesis of compound NM-004e
Take the compound NM-004d 2.45 g, (10 mmol) in 20 mL of water, basify the sodium hydroxide solution to pH 10, and extract with ethyl acetate (30 mL x 4). The combined ethyl acetate was washed with 30 mL of water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1.57 g (7.5 mmol) of free amine as a colorless oil. (15.6 mmol) of triethamine, 2.55 g (11.7 mmol) of Boc anhydride and 10 mg of DMAP were added to 50 mL of distilled steam in tetrahydrofuran, and the reaction was monitored by TLC at room temperature for 5 hours. After completion of the reaction, the reaction solution was quenched by adding 30 mL of saturated ammonium chloride solution to the reaction solution. The solvent was evaporated under reduced pressure and extracted with ethyl acetate (50 mL x 4). The combined ethyl acetate was washed with 30 mL of 0.1 N hydrochloric acid and 30 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product as a colorless oil. The crude product was separated on a silica gel column (petroleum ether: ethyl acetate = 1: 1) and 1.58 g (68%) of the white solid NM-004e was obtained. ESI-MS: m / z 310.3 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.75 (t, 3H, J = 7.5Hz), 1.03-1.19 (m, 4H) 1.24 (m, 4H), 1.36 (s, 9H), 1.44-1.58 (m, 4H), 1.52-1.73 (m, 2H), 2.08 (s, 1H), 3.02 (d, 2H, J = 5.5 Hz) , 4.38 (t, 1H, J = 5.5 Hz), 6.36 (s, 1H).
Example 8, Synthesis of compound NM-004f
The compound NM-004e (620 mg, 2 mmol) was dissolved in 10 mL of dry water, dichloromethane and cooled in an ice-water bath. Add acetic anhydride and fuming nitric acid mixture (acetic anhydride and fuming nitric acid volume ratio equal to 3: 2) 2mL. Ice bath reaction 10-15 minutes. The reaction solution was poured into 10 mL of 1N sodium bicarbonate solution, and the dichloromethane was separated. The aqueous layer was extracted with dichloromethane (10 mL x 3), combined with dichloromethane and washed with 10 mL of water. Dried over anhydrous sodium sulfate, filtered and the dichloromethane was distilled off under reduced pressure to give the crude product as a colorless oil. Silica gel column separation (petroleum ether: dichloromethane = 10: 1) was obtained as a colorless oil NM-004 f 505 mg (73.4%). ESI-MS: m / z 377.2 ([M + Na] + ). 1 H-NMR (DMSO-d6, ppm): 0.76 (t, 3H, J = 7.5Hz), 1.08-1.23 (m, 4H) 1.26-1.49 (m, 14H), 1.56-1.82 (m, 5H), 2.12 (m, 1H), 4.23 (s, 2H), 6.50 (s, 1H).
Example 9, Synthesis of compound NM-004
To the compound NM-004f710 mg (2 mmol) was added 5 mL of a saturated solution of hydrogen chloride and reacted at room temperature. At the end of the reaction, a white solid precipitates. Filtration, anhydrous ether washing white solid, you can get NM-004 pure. After drying, NM-004380 mg (65.5%) was obtained. ESI-MS: m / z 255.1 ([M + H] + ). 1 H-NMR (DMSO-d6, ppm): 0.78 (t, 3H, J = 7.5Hz), 1.15-1.28 (m, 4H) (M, 2H), 1.40-1.55 (m, 4H), 1.57-1.67 (m, 2H), 1.71 (s, 2H), 2.23 (m, 1H), 4.30 (s, 2H) S, 3H).
PATENT
CN 105294450
PATENT
CN 106344551
Paper
Med. Chem. Commun., 2017, 8,135-147
DOI: 10.1039/C6MD00509H, Research Article
Zheng Liu, Si Yang, Xiaoyong Jin, Gaoxiao Zhang, Baojian Guo, Haiyun Chen, Pei Yu, Yewei Sun, Zaijun Zhang, Yuqiang Wang
A series of memantine nitrate derivatives, as dual functional compounds with neuroprotective and vasodilatory activity for neurodegenerative diseases, was designed and synthesized
A series of memantine nitrate derivatives, as dual functional compounds with neuroprotective and vasodilatory activity for neurodegenerative diseases, was designed and synthesized
Synthesis and biological evaluation of memantine nitrates as a potential treatment for neurodegenerative diseases
*Corresponding authors
aInstitute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China
E-mail: yxy0723@163.com, zaijunzhang@163.com
Fax: +86 20 8522 4766
Tel: +86 20 8522 5030
E-mail: yxy0723@163.com, zaijunzhang@163.com
Fax: +86 20 8522 4766
Tel: +86 20 8522 5030
Med. Chem. Commun., 2017,8, 135-147
A series of memantine nitrate derivatives, as dual functional compounds with neuroprotective and vasodilatory activity for neurodegenerative diseases, was designed and synthesized. These compounds combined the memantine skeleton and a nitrate moiety, and thus inhibited the N-methyl-D-aspartic acid receptor and released NO in the central nervous system. The biological evaluation results revealed that the new memantine nitrates were effective in protecting neurons against glutamate-induced injury in vitro. Moreover, memantine nitrates dilated aortic rings against phenylephrine-induced contraction. The structure–activity relationships of neuroprotection and vasodilation were both analyzed. In further studies, compound MN-05 significantly protected cortical neurons by inhibiting Ca2+ influx, reducing free radical production and maintaining the mitochondrial membrane potential. Further research on MN-05 is warranted.
1-Amino-3-ethyl-5-nitratemethyladamantane hydrochloride (MN-05).
Compound MN- 05 was synthesized using a similar method to that as described for synthesis of compound MN-01 from compound 16. White solid, 65.5% yield. ESI-MS: m/z 255.1 [M + H]+ .
1H NMR (300 MHz, DMSO-d6) δ 0.75-0.80 (t, J = 7.5 Hz, 3H, CH3), 1.16-1.24 (q, J = 7.5 Hz, 2H, CH2), 1.24-1.25 (m, 2H), 1.30-1.39 (m, 2H), 1.43 (s, 2H), 1.45-1.57 (dd, J = 12 Hz, 6 Hz, 2H), 1.57-1.63 (dd, J = 12 Hz, 6 Hz, 2H), 1.71 (s, 2H), 2.23 (m, 1H, CH), 4.30 (s, 2H, CH2O), 8.21 (s, 3H, NH2HCl).
13C NMR (75 MHz, DMSO-d6) δ 7.4, 28.6, 34.5, 35.0, 36.8, 40.3, 41.6, 43.9, 52.3, 80.9. Anal. Calcd for C13H23N2O3Cl·0.3 H2O: C, 52.72%; H, 8.03%; N, 9.46%. Found: C, 52.72%; H, 7.92%; N, 9.51%
//////// memantine nitrates , neurodegenerative diseases, MN 05
[O-][N+](=O)OCC12CC3(CC(N)(C1)CC(C2)C3)CC
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