138112-76-2

Usage

Uses

Used in Pharmaceutical Industry:
Agomelatine is used as an antidepressant drug for treating major depressive disorder. It works by modulating the activity of melatonin receptors and serotonin receptors, leading to an improvement in mood and a reduction in depressive symptoms.
Used in Neuroprotection Research:
Agomelatine is used as a research compound to study its effects on adult neurogenesis, hippocampus apoptosis, tau protein phosphorylation, and its neuroprotective mechanism. These studies aim to understand the potential therapeutic applications of Agomelatine in various neurological conditions.
Used in Neuroendocrine Model of Depression:
Agomelatine is used as a compound to study its effects on intracellular calcium ([Ca2+]i) signaling in peripheral neurons of rat dorsal root ganglion (DRG) neurons. This helps researchers explore the compound's potential role in modulating neurotransmission and its implications in the treatment of depression.
Chemical Properties:
Agomelatine is a white solid with the following properties:
Acts as an agonist of melatonin (MT) receptors, binding to MT1 and MT2 receptors with Kis of 0.14 and 0.41 nM, respectively.
Acts as an antagonist of serotonin (5-HT) receptor subtypes 5-HT2B and 5-HT2C, with Kis of 0.26 and 0.71 nM, respectively, for the human receptors.
Increases extracellular levels of noradrenaline and dopamine in the frontal cortex of freely moving rats when administered at doses ranging from 20 to 80 mg/kg.
Reduces immobility time in the forced swim test and increases the amount of time spent in the open arms of the elevated plus maze in mice, indicating antidepressant-like and anxiolytic-like activity.

Antidepressants

Agomelatine, which is developed by the French Servier company, is the world's first melatonin receptors MT1 and MT2 agonist class of antidepressants. It applies to the treatment of adult patients with severe depressive. We know that melatonin is an endogenous neural hormones. It is only produced by the pineal gland anterior pituitary at night, and acts on the melatonin receptor that focuses on the presence of hypothalamic suprachiasmatic nucleus (SCN). It is involved in mediating the circadian rhythms in mammals. It is the well-known time guardian in the body, which can regulate the biological clock that is modulated by external circadian cycle. However, since that melatonin has high catabolism rate in vivo which mikes its half-life shorter and the selectivity of its receptor located in the SCN poorer, the treatment of circadian rhythms disorders is limited. Therefore, in order to overcome these drawbacks of melatonin, the researchers designed a series of melatonin analogues. Molecular modeling studies have shown that indole ring of melatonin is the structure sites of catabolic inactivation. Indole ring is an ideal site of isosteric modifications. Agomelatine developed by Servier company is melatonin’s naphthalene biological (electronic) isostere analogs. Indole ring is substituted by naphthalene nucleus, which leads it have more metabolic stability than melatonin.

Pharmacological effects

The listing of agomelatine is a new breakthrough in the field of the treatment of depression. It is melatonin MT1/MT2 receptor agonist and serotonin 2c (5-HT2C) receptor antagonist. It can make depressed patients’ biological rhythm disorders return to normal through the synergy between the two and then result in antidepressant efficacy. Its unique mechanism of action has opened up an innovative way to treat depression. Agomelatine’s mechanism of drug action is completely different with antidepressants that are commonly used today, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI). SSRI and SNRI antidepressants achieve antidepressant efficacy by increasing concentration of serotonin. But it also brings a lot of side effects, such as weight changes, sexual dysfunction, withdrawal syndrome and the like. The molecular structure of agomelatine directly combines with serotonin 2c (5HT2c) receptor of post-synaptic membrane so as to exert its antidepressant efficacy without increasing serotonin concentration in the synaptic cleft. This unique mechanism of action makes agomelatine quickly and effectively exert its antidepressant efficacy at the same time, and avoid the occurrence of adverse drug reactions to an extreme. Another unique targets of agomelatine is in melatonin receptors. MT1 and MT2 receptors densely distribute in the human suprachiasmatic nucleus. The nucleus mainly control human sleep rhythm. Agomelatine can well improve the quality of patients’ sleep by agonism on MT1 MT2 receptors, and improve patients’ wakefulness during the day. The quality of sleep has both cause and effect relationship with depression outcomes state. It is reported that 80% of patients with depression have the problems of sleep disorders at different levels. The improvement of sleep quality can directly contribute to the improvement of the overall clinical condition of patients with depression. The above information is edited by the lookchem of Ge Qian.

Health risk

October 30, 2012, the British Medicines and Healthcare Products Agency (MHRA) released agomelatine (agomelatine, Valdoxan/Thymanax) security information. MHRA found that several cases appears serious reports of liver toxicity with agomelatine, including six cases of liver failure patients within worldwide report. Agomelatine's drug information already includes in the recommendations that all patients need liver function tests at the start of treatment and during treatment. Now liver function tests should also be recommended when the drug dose is increased. MHRA recommends that if the patients have potential liver damage symptoms or signs, or that the increases of serum transaminase beyond the upper limit of normal (ULN) three times is found in the function tests, it should be immediately suspended.

Patent cases

The earliest agomelatine compound patent is French Patent FR902393, which is applied in February 27, 1990. This patent has the same patent family in Europe, USA, Canada, Japan and Australia. But there is no Chinese patent. The above patents were all authorized after January 1, 1993. Therefore China is also ineligible for administrative protection. Agomelatine has both technology patent and polymorph patent in China. But it also can be avoided.

Biochem/physiol Actions

Agomelatine is an extremely potent agonist at both melatonin receptors (MT1 and MT2), with additional antagonism at 5HT2C. It is a novel antidepressant with many desired in vivo properties, including neuroprotection and neurogenesis in depression-sensitive brain areas. Agomelatine′s efficacy appears to be due to both melatonergic and serotonergic properties. In neurogenesis assays, both in vitro and in vivo, the compound effects were differentially affected by antagonists for MT1/MT2 and 5HT2C, demonstrating actions through all three receptors.

Clinical Use

Antidepressant

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: avoid with ciprofloxacin. Antidepressants: metabolism inhibited by fluvoxamine. Antimalarials: avoid with artemether with lumefantrine and artenimol with piperaquine.

Metabolism

Agomelatine is rapidly metabolised, mainly by the hepatic cytochrome P450 isoenzyme CYP1A2; the isoenzymes CYP2C9 and CYP2C19 also make a minor contribution. The major metabolites, hydroxylated and demethylated agomelatine, are not active and are rapidly conjugated and eliminated in the urine.

references

[1] zupancic m, guilleminault c. agomelatine. cns drugs, 2006, 20(12): 981-992.

InChI:InChI=1/C11H14N4O2.CH4O3S/c1-5-2-9(16)7-3-8(14-15-11(12)13)10(17)4-6(5)7;1-5(2,3)4/h3-5,9,16H,2H2,1H3,(H4,12,13,15);1H3,(H,2,3,4)/b14-8-;

Synthetic route

2-(7-methoxynaphthalen-1-yl)ethanamine hydrochloride (139525-77-2) + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
With sodium acetate In ethanol for 1h; Reflux;	99.5%
With sodium acetate In Isopropyl acetate	99%
With sodium acetate In ethanol for 1h; Reflux;	95%

2-(2-methoxynaphthalen-8-yl)acetaldehyde oxime (1331869-01-2) → agomelatine (138112-76-2)

Conditions	Yield
With hydrogen; acetic anhydride In tetrahydrofuran at 50℃; under 7500.75 Torr; for 6h; Autoclave; Inert atmosphere;	98%

N,N-dibenzyl-2-(7-methoxynaphthalen-1-yl)ethanamine + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
Stage #1: N,N-dibenzyl-2-(7-methoxynaphthalen-1-yl)ethanamine With 20% palladium hydroxide-activated charcoal; hydrogen In ethanol; water; ethyl acetate under 3750.38 Torr; for 30h; Autoclave; Stage #2: acetic anhydride With sodium acetate for 4h;	98%

2-(7-methoxynaphth-1-yl)ethylamine (138113-09-4) + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
In tetrahydrofuran at 0 - 20℃; for 6h; Concentration; Temperature;	97.5%
With sodium acetate In ethanol at 65℃; Green chemistry;	92%
With triethylamine In toluene at 20 - 30℃;	90%

2-(7-methoxynaphth-1-yl)ethylamine (138113-09-4) + acetyl chloride (75-36-5) → agomelatine (138112-76-2)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 5℃;	95%
In pyridine	92%
With pyridine for 0.5h; Product distribution / selectivity; Cooling with ice;	92%

dimethyl sulfate (77-78-1) + N-[2-(7-Hydroxy-1-naphthyl)ethyl]-acetamide (152302-45-9) → agomelatine (138112-76-2)

Conditions	Yield
With potassium carbonate In acetone for 5h; Reflux;	94.5%

1-(2-nitroethyl)-7-methoxynaphthalene (1424944-40-0) + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In water; ethyl acetate at 20℃;	92%

1-[2-(7-methoxynahthalen-1-yl)-ethyl]-2λ5-triaz-1-en-2-yne (1384536-35-9) + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In water; ethyl acetate at 20℃;	92%

N-[2-(7-methoxy-3,4-dihydro-naphthalen-1-yl)ethyl]acetamide (1352139-51-5) → agomelatine (138112-76-2)

Conditions	Yield
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane at 20℃;	91.8%
With 2,3-dicyano-5,6-dichloro-p-benzoquinone for 4h; Product distribution / selectivity; Reflux;	90%
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran at 20℃; Product distribution / selectivity;	80%

2-(7-methoxynaphthalen-1-yl)ethanamine hydrochloride (139525-77-2) + acetyl chloride (75-36-5) → agomelatine (138112-76-2)

Conditions	Yield
With potassium carbonate In dichloromethane; water at 0 - 20℃; for 2h;	91%
Stage #1: 2-(7-methoxynaphthalen-1-yl)ethanamine hydrochloride With triethylamine In dichloromethane at 25 - 35℃; for 0.5h; Stage #2: acetyl chloride In dichloromethane at 10 - 20℃; for 1h;	90%
With potassium carbonate In chloroform; water for 0.5h; Ambient temperature;	89%
With potassium carbonate In chloroform; water at 0℃;
Stage #1: 2-(7-methoxynaphthalen-1-yl)ethanamine hydrochloride With potassium carbonate In water; ethyl acetate at 20℃; Schotten-Baumann reaction; Stage #2: acetyl chloride In water; ethyl acetate at 0 - 20℃; for 1h; Schotten-Baumann reaction;

2-(7-methoxynaphthalen-1-yl)ethanamine carbon dioxide adduct + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
With sodium acetate In methanol Reflux;	91%
With sodium acetate In methanol Reflux;	91%
With sodium acetate In methanol Reflux;	91%

acetic anhydride (108-24-7) + (7-methoxy-1-naphthyl)acetonitrile (138113-08-3) → agomelatine (138112-76-2)

Conditions	Yield
With hydrogen; Raney nickel In ethanol; water at 70℃; under 22502.3 Torr;	89%
With hydrogen In ethanol; water at 70℃; under 22502.3 Torr;	89%
With hydrogen In ethanol; water at 70℃; under 22502.3 Torr; for 1h;	89%
With hydrogen In ethanol at 60℃; under 37503.8 Torr; for 4h;
Stage #1: (7-methoxy-1-naphthyl)acetonitrile With hydrogen; sodium hydroxide In methanol; water at 30℃; under 3000.3 Torr; Stage #2: acetic anhydride In methanol at 15 - 25℃;

2-(7-methoxynaphthalen-1-yl)ethen-1-amine + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
With sodium acetate In ethanol; acetic anhydride at 25℃; for 1h; Temperature;	88.1%

1-[2-(acetylamino)ethyl]-7-methoxynaphthalen-2-yl propane-1-sulphonate → agomelatine (138112-76-2)

Conditions	Yield
With palladium 10% on activated carbon; ammonium acetate; magnesium In ethanol for 16h;	87%

N-[2-(1-hydroxyl-7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)ethyl]-acetamide (1352139-49-1) → agomelatine (138112-76-2)

Conditions	Yield
With acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone In toluene at 40℃; for 5h;	85%
With acetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone In toluene at 40℃; for 5h;
Multi-step reaction with 2 steps 1: hydrogenchloride / ethyl acetate; water / 2 h / 20 °C 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone / dichloromethane / 20 °C View Scheme

2-(2-(7-methoxynaphthalen-1-yl)ethyl) isoindoline-1,3-dione (1206788-15-9) + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
Stage #1: 2-(2-(7-methoxynaphthalen-1-yl)ethyl) isoindoline-1,3-dione With hydrazine hydrate In methanol; dichloromethane at 30℃; for 14h; Stage #2: acetic anhydride With triethylamine In methanol; dichloromethane; toluene at 25℃; for 0.333333h;	85%

1-[2-(acetylamino)ethyl]-7-methoxynaphthalen-2-yl-4-methylbenzenesulphonate → agomelatine (138112-76-2)

Conditions	Yield
With methanol; sodium tetrahydroborate; nickel dichloride at 20℃; for 0.5h; Sealed tube; Inert atmosphere;	80%

2-(2-methoxynaphthalen-8-yl)acetamide (138113-07-2) + acetic acid (64-19-7) → agomelatine (138112-76-2)

Conditions	Yield
With sodium tetrahydroborate In 1,4-dioxane at 95 - 98℃; for 22h;	76.3%

acetic anhydride (108-24-7) + 2-(7-methoxynaphthalen-1-yl)ethyl methanesulphonate (185336-04-3) → agomelatine (138112-76-2)

Conditions	Yield
Stage #1: 2-(7-methoxynaphthalen-1-yl)ethyl methanesulphonate With ammonia In water; acetonitrile at 110℃; for 3h; Stage #2: acetic anhydride With sodium acetate for 1h;	74%

N-[2-(4-chloro-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide (1384261-25-9) → agomelatine (138112-76-2)

Conditions	Yield
With potassium tert-butylate In tert-butyl alcohol for 3h; Reflux;	68%

N-[2-(4-bromo-7-methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide (1384261-27-1) → agomelatine (138112-76-2)

Conditions	Yield
With potassium tert-butylate In tert-butyl alcohol for 3h; Reflux;	68%

(E)-7-methoxy-1-(2-nitrovinyl)naphthalene (1415243-95-6) + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
With palladium 10% on activated carbon; acetic acid	65%

2-(7-methoxynaphth-1-yl)ethylamine (138113-09-4) + sodium acetate (127-09-3) → agomelatine (138112-76-2)

Conditions	Yield
With acetic anhydride In ethanol at 20℃; for 1h;	61%

N-[2-(7-methoxy-1,2-dihydro-1-naphthyl)ethyl]acetamide (1384261-23-7) → agomelatine (138112-76-2)

Conditions	Yield
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane for 48h;	48%

1-[2-(2,5-dioxopyrrolidin-1-yl)ethyl]-7-methoxynaphthalen-2-yl propane-1-sulphonate + acetic anhydride (108-24-7) → agomelatine (138112-76-2)

Conditions	Yield
Stage #1: 1-[2-(2,5-dioxopyrrolidin-1-yl)ethyl]-7-methoxynaphthalen-2-yl propane-1-sulphonate With palladium 10% on activated carbon; ammonium acetate; magnesium In methanol at 30℃; for 12h; Stage #2: acetic anhydride With sodium acetate; sodium hydroxide In ethanol; water for 1h; Sealed tube;	37%

2-(7-methoxynaphth-1-yl)ethylamine (138113-09-4) + [14C]acetyl-CoA → agomelatine (138112-76-2)

Conditions	Yield
With sheep pineal supernatant (serotonin-N-acetyl transferase); Pargyline In phosphate buffer at 37℃; for 0.166667h; pH=6.8; Enzyme kinetics;

2-(7-methoxynaphthalen-1-yl)acetic acid (6836-22-2) → agomelatine (138112-76-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / CHCl3 2: aq. NH4OH / diethyl ether / 0 °C 3: AlH4 / diethyl ether 4: K2CO3 / H2O; CHCl3 / 0 °C View Scheme
Multi-step reaction with 5 steps 1: thionyl chloride / CHCl3 2: aq. NH4OH / diethyl ether / 0 °C 3: (CF3CO)2O / tetrahydrofuran / 0 °C 4: H2, HCl / Ni Raney / diethyl ether 5: K2CO3 / H2O; CHCl3 / 0 °C View Scheme
Multi-step reaction with 5 steps 1.1: thionyl chloride / dichloromethane / 2 h / Reflux 2.1: ammonia / ethyl acetate; water / Cooling with ice 3.1: triethylamine; trifluoroacetic anhydride / tetrahydrofuran / 20 °C / Cooling with ice 4.1: hydrogen; ammonia / ethanol; water / 12 h / 60 °C / 228015 Torr / Autoclave 5.1: pyridine / 40 °C 5.2: 20 °C / Cooling with ice View Scheme

2-(2-methoxynaphthalen-8-yl)acetamide (138113-07-2) → agomelatine (138112-76-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: AlH4 / diethyl ether 2: K2CO3 / H2O; CHCl3 / 0 °C View Scheme
Multi-step reaction with 3 steps 1: (CF3CO)2O / tetrahydrofuran / 0 °C 2: H2, HCl / Ni Raney / diethyl ether 3: K2CO3 / H2O; CHCl3 / 0 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine; trifluoroacetic anhydride / tetrahydrofuran / 20 °C / Cooling with ice 2.1: hydrogen; ammonia / ethanol; water / 12 h / 60 °C / 228015 Torr / Autoclave 3.1: pyridine / 40 °C 3.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 3 steps 1.1: trichlorophosphate / dichloromethane; N,N-dimethyl-formamide / 2 h / 85 °C 2.1: sodium hydroxide; hydrogen / water; methanol; isopropyl alcohol / 25 - 30 °C / 7500.75 Torr 2.2: 1 h / 50 - 55 °C 3.1: sodium hydroxide / water; toluene / 0.25 h / 20 - 25 °C 3.2: 35 - 40 °C View Scheme

(7-methoxy-1-naphthyl)acetonitrile (138113-08-3) → agomelatine (138112-76-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2, HCl / Ni Raney / diethyl ether 2: K2CO3 / H2O; CHCl3 / 0 °C View Scheme
Multi-step reaction with 2 steps 1.1: hydrogen; ammonia / ethanol; water / 12 h / 60 °C / 228015 Torr / Autoclave 2.1: pyridine / 40 °C 2.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydroxide; hydrogen / water; methanol; isopropyl alcohol / 25 - 30 °C / 7500.75 Torr 1.2: 1 h / 50 - 55 °C 2.1: sodium hydroxide / water; toluene / 0.25 h / 20 - 25 °C 2.2: 35 - 40 °C View Scheme
Multi-step reaction with 2 steps 1.1: ammonia; hydrogen / methanol / 15 - 55 °C / 3750.38 Torr / Autoclave 1.2: 1 h / 0 - 5 °C 2.1: triethylamine / dichloromethane / 0.5 h / 25 - 35 °C 2.2: 1 h / 10 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: ammonia; hydrogen / ethanol / 24 h / 30 - 40 °C / 2250.23 - 3000.3 Torr / Autoclave 2: triethylamine / toluene / 0.5 h / 0 - 30 °C View Scheme

(7-methoxy-1-naphthyl)acetic acid chloride (6836-23-3) → agomelatine (138112-76-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: aq. NH4OH / diethyl ether / 0 °C 2: AlH4 / diethyl ether 3: K2CO3 / H2O; CHCl3 / 0 °C View Scheme
Multi-step reaction with 4 steps 1: aq. NH4OH / diethyl ether / 0 °C 2: (CF3CO)2O / tetrahydrofuran / 0 °C 3: H2, HCl / Ni Raney / diethyl ether 4: K2CO3 / H2O; CHCl3 / 0 °C View Scheme
Multi-step reaction with 4 steps 1.1: ammonia / ethyl acetate; water / Cooling with ice 2.1: triethylamine; trifluoroacetic anhydride / tetrahydrofuran / 20 °C / Cooling with ice 3.1: hydrogen; ammonia / ethanol; water / 12 h / 60 °C / 228015 Torr / Autoclave 4.1: pyridine / 40 °C 4.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 4 steps 1.1: ammonia / toluene / 0 - 5 °C / pH 10 - 11 2.1: trichlorophosphate / dichloromethane; N,N-dimethyl-formamide / 2 h / 85 °C 3.1: sodium hydroxide; hydrogen / water; methanol; isopropyl alcohol / 25 - 30 °C / 7500.75 Torr 3.2: 1 h / 50 - 55 °C 4.1: sodium hydroxide / water; toluene / 0.25 h / 20 - 25 °C 4.2: 35 - 40 °C View Scheme

agomelatine (138112-76-2) + maleic acid (110-16-7) → agomelatine maleic acid (1403960-82-6)

Conditions	Yield
In ethanol for 0.75h;	100%
In methanol; ethyl acetate at 20℃; for 168h; Product distribution / selectivity;
for 1h;

agomelatine (138112-76-2) + citric acid (77-92-9) → agomelatine citric acid (1403960-81-5)

Conditions	Yield
In acetone at 20℃;	100%
In methanol; ethyl acetate at 2 - 5℃; Product distribution / selectivity; Reflux;
In methanol at 20℃; for 20h; Product distribution / selectivity;

2,5-dihydroxybenzoic acid. (490-79-9) + agomelatine (138112-76-2) → agomelatine gentisic acid (1419379-42-2)

Conditions	Yield
In toluene for 0.75h;	100%

ethylene glycol (107-21-1) + agomelatine (138112-76-2) → C2H6O2*C15H17NO2 (1259393-47-9)

Conditions	Yield
at 110 - 130℃; for 5h;	98%

isonicotinamide (1453-82-3) + agomelatine (138112-76-2) → agomelatine isonicotinamide adduct (1366181-84-1)

Conditions	Yield
at 135℃; Neat (no solvent);	98%

methyl 4-hydroxylbenzoate (99-76-3) + agomelatine (138112-76-2) → agomelatine methyl 4-hydroxybenzoate adduct (1366181-85-2)

Conditions	Yield
at 110℃; Neat (no solvent);	98%

agomelatine (138112-76-2) → N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide hydrogen sulfate

Conditions	Yield
With sulfuric acid In acetone at 10 - 20℃; Solvent; Temperature;	96.9%
With sulfuric acid In acetone at 10 - 20℃; Solvent; Temperature;	13.6 g
With sulfuric acid In ethyl acetate at 20℃;

acetic acid (64-19-7) + agomelatine (138112-76-2) → agomelatine 1:1 cocrystal with acetic acid (1259393-46-8)

Conditions	Yield
In diethyl ether for 48h;	96%
at 20 - 45℃; for 480h; Sealed tube;

agomelatine (138112-76-2) + urea (57-13-6) → agomelatine urea adduct (1366181-82-9)

Conditions	Yield
at 120℃; for 0.333333h; Neat (no solvent);	96%
In ethanol at 20℃; for 2h; Time;	70%
In isopropyl alcohol at 20℃; for 20h;	41%

agomelatine (138112-76-2) + benzenesulfonic acid (98-11-3) → N-[2-(7-methoxyl-1-naphthyl)ethyl]acetamide benzenesulfonic acid (1402317-73-0)

Conditions	Yield
In acetone at 25℃; Solvent; Temperature;	95.8%
In methanol; ethyl acetate at 2 - 20℃; Product distribution / selectivity;
In dichloromethane at 10 - 20℃; Solvent; Temperature;	15.6 g
In methanol; ethyl acetate Heating;

toluene-4-sulfonic acid (104-15-4) + agomelatine (138112-76-2) → agomelatine p-toluenesulfonic acid monohydrate

Conditions	Yield
In tetrahydrofuran; hexane for 0.5h; Solvent; Temperature; Reflux;	95.8%

agomelatine (138112-76-2) → N-[2-(7-Hydroxy-1-naphthyl)ethyl]-acetamide (152302-45-9)

Conditions	Yield
With boron tribromide In dichloromethane at -10 - 20℃; for 2h;	93.3%
Stage #1: agomelatine With boron tribromide In dichloromethane at 0℃; for 2h; Stage #2: With water In dichloromethane at 0℃;	80%
With hydrogenchloride In water at 80℃;	74.8%

glycolic Acid (79-14-1) + agomelatine (138112-76-2) → agomelatine glycolic acid adduct (1366181-83-0)

Conditions	Yield
In acetonitrile for 2h; Reflux;	93%
for 0.25h;

agomelatine (138112-76-2) → N [2-(7-methoxynaphthalen-1-yl)ethyl]acetamide hydrochloride (1176316-99-6)

Conditions	Yield
With hydrogenchloride In water; ethyl acetate at 10℃; Product distribution / selectivity;	88.7%
With hydrogenchloride In water; ethyl acetate at 10℃; for 1h;	88.7%
With hydrogenchloride In water; ethyl acetate at 10℃; for 1h;	88.7%

toluene-4-sulfonic acid (104-15-4) + agomelatine (138112-76-2) → agomelatine p-toluenesulfonic acid

Conditions	Yield
In acetone at 0 - 10℃;	88.2%
In acetone at 0 - 10℃;	1.5 g

agomelatine (138112-76-2) → N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide hydrobromide (1176317-02-4)

Conditions	Yield
With hydrogen bromide In water; ethyl acetate at 20℃; for 1h; Product distribution / selectivity;	85.3%
With hydrogen bromide In water; ethyl acetate at 20℃; for 1h; Temperature;	85.3%
With hydrogen bromide In water; ethyl acetate for 1h;	85.3%

Upstream product

• 139525-77-2 2-(7-methoxynaphthalen-1-yl)ethanamine hydrochloride 
• 75-36-5 acetyl chloride 
• 6836-22-2 2-(7-methoxynaphthalen-1-yl)acetic acid 
• 138113-07-2 2-(2-methoxynaphthalen-8-yl)acetamide 
• 108-24-7 acetic anhydride 
• 138113-09-4 2-(7-methoxynaphth-1-yl)ethylamine 
• 138113-08-3 (7-methoxy-1-naphthyl)acetonitrile 
• 1331869-01-2 2-(2-methoxynaphthalen-8-yl)acetaldehyde oxime 
• 178677-49-1 (R,S) 2-(7-methoxy-1,2,3,4-tetrahydronaphth-1-yl)ethylacetamide 
• 59081-66-2 1-(2-aminoethyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene 
• 127299-26-7 (7-methoxy-3,4-dihydro-2H-naphthalene-1-ylidene)acetonitrile 
• 1424944-38-6 8-(2-chloroethyl)naphthalen-2-yl acetate 
• 1206788-15-9 2-(2-(7-methoxynaphthalen-1-yl)ethyl) isoindoline-1,3-dione 
• 127-09-3 sodium acetate 

Downstream Products

• 138113-09-4 2-(7-methoxynaphth-1-yl)ethylamine 
• 152302-45-9 N-[2-(7-Hydroxy-1-naphthyl)ethyl]-acetamide 
• 1379005-34-1 C₁₇H₁₉NO₃ 
• 1418372-35-6 C₂₁H₂₁NO₄S 
• 1402317-73-0 N-[2-(7-methoxyl-1-naphthyl)ethyl]acetamide benzenesulfonic acid 
• 1366181-85-2 agomelatine methyl 4-hydroxybenzoate adduct 
• 1363155-79-6 N-(2-[7-methoxy-3-(4-methoxy-benzylamino)-naphthalen-1-yl]ethyl)acetamide 
• 1363156-07-3 N-[2-(3-cyclohexylmethyl-7-methoxy-naphthalen-1-yl)ethyl]acetamide 
• 1096252-78-6 N-(2-{7-[(4-methoxybenzyl)amino]naphth-1-yl}ethyl)acetamide 
• 1176316-99-6 Agomelatine hydrochloride 
• 166526-99-4 N-[2-(7-methoxy-3-hydroxynaphth-1-yl)ethyl]-acetamide 

Related news

AGOMELATINE (cas 138112-76-2) treatment corrects symptoms of depression and anxiety by restoring the disrupted melatonin circadian rhythms of rats exposed to chronic constant light08/25/2019

Desynchronization of circadian rhythms is a hallmark of depression. The antidepressant agomelatine, which is an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist has advantages compared to the selective serotonin reuptake inhibitors as a circadian phase-shifting agent. The ...detailed

Mucoadhesive olaminosomes: A novel prolonged release nanocarrier of AGOMELATINE (cas 138112-76-2) for the treatment of ocular hypertension08/24/2019

Mucoadhesive olaminosomes are novel nanocarriers designed to control agomelatine release and enhance its bioavailability. Olaminosomes were prepared using oleic acid, oleylamine and sorbitan monooleate adopting thin film hydration technique. Chitosan HCl was added to impart the mucoadhesive prop...detailed

Behavioural pharmacologyStudies on the reproductive effects of chronic treatment with AGOMELATINE (cas 138112-76-2) in the rat08/23/2019

Agomelatine is an antidepressant with a novel mechanism of action. It is a melatonergic agonist for MT1 and MT2 receptors and a serotonin (5-HT2C) receptor antagonist. Agomelatine has been suggested not to have adverse effects on sexual functions. However, the effects of chronic agomelatine admi...detailed

Research paperEffect of AGOMELATINE (cas 138112-76-2) 25–50 mg on functional outcomes in patients with major depressive disorder08/22/2019

PurposeThe purpose of this work is to investigate the effect of agomelatine on functioning compared with placebo in patients suffering from Major Depressive Disorder (MDD).detailed

Spike–Wave Discharges and Sleep–Wake States during Circadian Desynchronization: No Effects of AGOMELATINE (cas 138112-76-2) upon Re-Entrainment08/21/2019

Rapid changes in the light–dark cycle cause circadian desynchronization between rhythms of spike–wave discharges (SWDs) and motor activity in genetic epileptic rats, and this is accompanied by an increase in epileptic activity. Given the close relationship between absence seizures and sleep–w...detailed

Effects of AGOMELATINE (cas 138112-76-2) on electrocorticogram activity on penicillin-induced seizure model of rats08/18/2019

Agomelatine is a new antidepressant drug acting as an antagonist of 5-hydroxytryptamine receptor 2C (5-HTR2C) and agonist of melatonergic receptors 1 and 2 (MT1 and MT2). Because of this dual action, it is an atypical antidepressant. The aim of this study was to investigate chronic anticonvulsan...detailed

Selective crystallization of AGOMELATINE (cas 138112-76-2) from molten state induced by polymer08/17/2019

In this study, agomelatine Form I was selectively recrystallized from molten state induced by ethyl cellulose (EC). It was found EC could effectively inhibit the transformation process of Form I to Form II. The effect of EC on the recrystallization of agomelatine from molten state was studied in...detailed

Research articleEffects of AGOMELATINE (cas 138112-76-2) in rotenone-induced Parkinson’s disease in rats08/16/2019

The effects of melatonin and melatonin analogs in experimental Parkinson’s disease (PD) models remain controversial. Agomelatine, a novel analog of melatonin, is both agonists for melatonin-1 and melatonin-2 receptors and antagonist of 5-HT2C receptors. While agomelatine has been commonly used ...detailed

Relevant academic research and scientific papers

Simple and Efficient Process for the Large-Scale Preparation of Agomelatine: An Antidepressant Drug

A simple and efficient process for the large-scale preparation of agomelatine (1), an antidepressant drug is, described. Agomelatine was prepared in a linear manner starting from readily available, inexpensive 2-naphthol. Key steps in the synthesis are Friedel-Crafts acylation of 2-naphthyl acetate with chloroacetyl chloride, reduction of keto intermediate, and nucleophilic displacement of chloro intermediate with sodium diformylamide. A systemic approach was described to streamline the process into a robust scalable process by controlling the impurities.

A facile synthesis of melatonergic antidepressant agomelatine

Agomelatine was synthesized from 8-aminonaphthalen-2-ol by diazotization-iodination, formylation, C-C bond formation by nitroaldol and Pd/C hydrogenation of β-nitrovinylnaphthalene followed by N-acetylation. The route reported employs readily and commercially viable starting materials and reagents, and can potentially be utilized for process synthesis of agomelatine.

A simple and efficient procedure for synthesis of agomelatine

A simple and efficient process for the large scale preparation of agomelatine, an antidepressant drug is described. Agomelatine was synthesized from 7-methoxy-1-tetralone in five steps. The route reported employs readily, commercially viable starting materials, reagents and potentially be utilized for the process of synthesis of agomelatine.

Novel conformationally constrained analogues of agomelatine as new melatoninergic ligands

Novel conformationally restricted analogues of agomelatine were synthesized and pharmacologically evaluated at MT1 and MT2 melatoninergic receptors. Replacement of the N-Acetyl side chain of agomelatine by oxathiadiazole-2-oxide (compound 3), oxadiazole-5(4H)-one (compound 4), tetrazole (compound 5), oxazolidinone (compound 7a), pyrrolidinone (compound 7b), imidazolidinedione (compound 12), thiazole (compounds 13 and 14) and isoxazole moieties (compound 15) led to a decrease of the melatoninergic binding affinities, particularly at MT1. Compounds 7a and 7b exhibiting nanomolar affinity towards the MT2 receptors subtypes have shown the most interesting pharmacological results of this series with the appearance of a weak MT2-selectivity.

A novel synthesis of the antidepressant agomelatine

Agomelatine was synthesized from (2-methoxynaphthalene-8-yl)oxoacetic acid in a four-step approach involving borane reduction, semipinacol rearrangement of the resulting diol, ald-oxime formation, and Ra-Ni hydrogenation/acetylation in 51% overall yield. The reaction sequence includes a novel one-pot conversion of an aldoxime into an N-acetylamine. The synthetic route could be useful as a new approach towards N-acetylarylethyl-amines. Georg Thieme Verlag Stuttgart · New York.

Total synthesis of agomelatine via Friedel-Crafts acylation followed by Willgerodt-Kindler reaction

Total synthesis of antidepressant drug, agomelatine is reported. Regio selective Friedel-Crafts acylation followed by Willgerodt-Kindler reactions is used as the key steps for the synthesis of agomelatine.

Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands

A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the melatonin receptor was determined by binding studies using [2- 125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent of the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analogue was a poor ligand. Compound 7, the naphthalenic analogue of melatonin, a selective ligand of the melatonin receptor and an agonist derivative, has been selected for clinical development.

PROCESS FOR THE PREPARATION OF AGOMELATINE IN CRYSTALLINE FORM

The present invention pertains to a process for the preparation of polymorph form X of agomelatine, which comprises providing agomelatine, and crystallizing agomelatine in the presence of at least one of an acid and a salt thereof, and to a polymorph form of agomelatine.

Preparation method of agomelatine

The invention provides a preparation method of agomelatine. According to the preparation method, 7-methoxy-1-naphthaldehyde is taken as a substrate, and three reaction steps including a condensation dehydration reaction, a reduction reaction and a acetylation reaction are respectively carried out. The preparation method disclosed by the invention has the beneficial effects that the process is simple and only comprises three reaction steps, the operation is convenient, and the industrial production is easily realized; secondly, synthetic raw materials are easily available and cheap, and the cost of the whole process is very low; thirdly, the agomelatine product prepared by virtue of the preparation method reaches up to 99.9%, and the quality of the agomelatine product meets the requirementsof European and the United States Pharmacopoeias; and finally, the agomelatine product prepared by virtue of the preparation method is high in yield, and the total yield reaches 64%.

Preparation method of agomelatine

The invention discloses a preparation method of agomelatine. In the method, 1-methyl-7-methoxynaphthalene is used as an initial raw material and is successively subjected to a bromination reaction with N-bromosuccinimide, a substitution reaction with nitromethane, a nitro-reduction reaction, and an acetylation reaction to produce a final product of agomelatine. The preparation method has fewer steps and employs low-cost and easy-to-obtained raw materials. During the reactions, high-risk and high-cost hydrogenation catalysts, such as palladium-carbon and Raney nickel, are not employed, so that the reactions are more reliable and require lower energy. The method can reduce transfer loss of intermediates, is simpler in operation, occupies fewer operators, is stable in product quality and high in yield and is suitable for large-scale industrial stable production.