357-70-0
| Name | (4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol |
| CAS | 357-70-0 |
| EINECS(EC#) | 609-175-3 |
| Molecular Formula | C17H21NO3 |
| MDL Number | MFCD00867189 |
| Molecular Weight | 287.35 |
| MOL File | 357-70-0.mol |
Synonyms
(4as,6r,8as)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6h-benzofuro[3a,3,2-ef][2]benzazepin-6-ol
GALANTAMINE
GALANTHAMINE
GALANTHAMINE HYDROCHLORIDE
6H-Benzofuro(3a,3,2-ef)(2)benzazepin-6-ol, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-, (4aS-(4aalpha,6beta,8aR*))-
6h-benzofuro(3a,3,2-ef)(2)benzazepin-6-ol,4a,5,9,10,11,12-hexahydro-3-methox
Galantamin
Jilkon
Lycoremin
Lycoremine
y-11-methyl-
Galanthamine base
Galanthamine HBr CP2000
Galanthamine HCl
GalanthamineHydrobromideBase
FumalicAcid
Galantaminehydrochloride
(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofurol[3a,3,2,-ef][2]benzazepin-6-ol
6H-Benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-, (4aS,6R,8aS)-,
DANSHEN P.E.FOR INJECTION
Chemical Properties
| Appearance | Off-White Solid |
| Melting point | 119-1210C |
| alpha | D20 -118.8° (c = 1.378 in ethanol) |
| Boiling point | 429.65°C (rough estimate) |
| density | 1.0662 (rough estimate) |
| refractive index | 1.5022 (estimate) |
| storage temp. | Sealed in dry,Room Temperature |
| solubility | ≥14.37 mg/mL in DMSO; ≥14.43 mg/mL in H2O with gentle warming; ≥45 mg/mL in EtOH with gentle warming |
| form | Powder |
| pka | pKa 8.32 (Uncertain) |
| Usage | A selective acetylcholinesterase inhibitor |
| CAS DataBase Reference | 357-70-0(CAS DataBase Reference) |
| NIST Chemistry Reference | Galantamin(357-70-0) |
Safety Data
| Hazardous Substances Data | 357-70-0(Hazardous Substances Data) |
| Toxicity |
LD50 intraperitoneal in mouse: 10mg/kg
|
Hazard Information
Description
Galantamine is an Amaryllidaceae alkaloid which is first obtained from the plant of
snowdrop (Galanthus nivalis), and nowadays, it’s extracted from the plants of
Narcissus and Galanthus species or obtained from chemosynthesis. In many
areas in Europe such as Bulgaria, eastern Turkey, and the Caucasus, the plants of
Galanthus are native species. But its earliest pharmaceutical applications are seldom known. Plaitakis and Duvoisin hypothesized that “moly” in ancient Homer’s
epic might be snowdrops. In Homer’s epic Odyssey, “moly” was used as an antidote
by Odysseus against Circe’s poisonous drugs. To be used as an antidote may be the
plants of Galanthus’ oldest medicinal records. But there is not much evidence for
that. There is little evidence of the traditional application of the plants of
Galanthus, and it is certain that until the Second World War, the plants of Galanthus
and other genera of Amaryllidaceae were not frequently used in European drugs
Italian scholar Iannello studied Pancratium illyricum L., an Amaryllidaceae species endemic to Sardinia, and isolated a new galantamine-type alkaloid in its leaves. This new galantamine-type compound exhibited a pronounced in?vitro AChE inhibitory activity (IC50? =? 3.5±1.1? μM) in comparison with the reference standard galantamine hydrobromide (IC50?=?1.5±0.2?μM)
Italian scholar Iannello studied Pancratium illyricum L., an Amaryllidaceae species endemic to Sardinia, and isolated a new galantamine-type alkaloid in its leaves. This new galantamine-type compound exhibited a pronounced in?vitro AChE inhibitory activity (IC50? =? 3.5±1.1? μM) in comparison with the reference standard galantamine hydrobromide (IC50?=?1.5±0.2?μM)
Chemical Properties
Off-White Solid
Physical properties
Hydrobromide of galantamine can be used as drug although galantamine can’t be
used as drugs
Appearance: an almost white powder. Solubility: soluble in water; slightly soluble in alcohol; and insoluble in acetone, trichloromethane, and diethyl ether. Melting point: 269–270?°C. Specific optical rotation: ?90 to ?100°.
Appearance: an almost white powder. Solubility: soluble in water; slightly soluble in alcohol; and insoluble in acetone, trichloromethane, and diethyl ether. Melting point: 269–270?°C. Specific optical rotation: ?90 to ?100°.
Originator
Reminyl,Janssen Pharmaceutica Inc.
Occurrence
Galanthamine is a bulb plant found throughout the world.
History
In the early 1950s, Soviet Union’s scientists started modern medicine research of
galantamine. In 1951, the Soviet Union’s pharmacologist Mashkovsky and
Kruglikova-Lvova firstly proved its AChE-inhibiting properties, which was published in the paper. In 1957, the Bulgarian pharmacologist Paskov et?al. found that
the plants of Galanthus were the richest sources of galantamine, which opened a
way for its commercial development by the company Sopharma in Bulgaria.
Galantamine hydrobromide was launched into market under the trade name Nivalin.
Initially, Nivalin was used in anesthesia to antagonize the effects of non-depolarizing
muscle relaxants, and since then, it was rapidly introduced in other areas of
medicine
Galantamine hydrobromide was launched into market for the indication of mild to moderate Alzheimer’s disease firstly in 1995, developed by Sanochemia Pharmaceuticals. In the United States, galantamine hydrobromide was developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, and was listed under the trade name Razadyne in 2001. So far, galantamine hydrobromide has been marketed in more than 20 countries and regions, such as the United States, Europe, and Japan.
Galantamine hydrobromide was launched into market for the indication of mild to moderate Alzheimer’s disease firstly in 1995, developed by Sanochemia Pharmaceuticals. In the United States, galantamine hydrobromide was developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, and was listed under the trade name Razadyne in 2001. So far, galantamine hydrobromide has been marketed in more than 20 countries and regions, such as the United States, Europe, and Japan.
Definition
ChEBI: A natural product found in Crinum asiaticum var. sinicum.
Indications
Its formulation includes capsule, tablet, and oral solution. It is used in the symptomatic treatment of mild to moderately severe dementia in Alzheimer’s disease.
Manufacturing Process
2 Methods of isolation of galantamine from Narcissus pseudonarcissus bulbs
1. 10 kg air-dried, comminuted bulbs of Narcissus pseudonarcissus "Carlton" is carefully mixed with 400 g sodium carbonate. 23 L dichloroethane is added.
The mixture is allowed to stand for 10 h; then the solvent is decanted. The
bulbs are once again doused with 23 L dichloroethane which is decanted after
2 to 3 hs. After that, 17 L dichloroethane is added to the bulbs for the third
time; however, this is decanted immediately. The mixed dichloroethane
extracts are extracted by means of 10% sulfuric acid (2 times 600 ml each; 2
times 300 ml each).
The acidic extracts are mixed and purified from traces of dichloroethane by means of shaking out with diethyl ether. Under stirring and cooling to 15° to 20°C, about 200 ml of a 25% aqueous ammonia solution is then added up to alkaline litmus reaction (the pH is in the range of 7 to 8). Different from the indications in the art, the companion alkaloids do not precipitate. The alkaline solution is saturated with salt and extracted with diethyl ether.
After evaporation of the ether, a negligible residue remains, which is also different from the indications in the art. The pH-value of the aqueous phase is set to about 14 by saturating it with potash. The aqueous phase is repeatedly extracted with diethyl ether. The mixed ether extracts are evaporated to dryness, the remaining galanthamine-containing residue is dissolved in acetone (50 ml). In contrast to the art, there is no precipitate. 350 ml acetone is replenished, 200 g aluminum oxide is added, and stirring is effected for 45 min. The aluminum oxide is filtered off and washed twice with 100 ml acetone each time. The mixed acetone solutions are evaporated to dryness. 1.3 g of an oily residue is obtained which is examined by means of HPLC.
2. 100 kg air-dried, comminuted bulbs of Narcissus pseudonarcissus "Carlton" is carefully mixed with 4 kg of sodium carbonate. The mixture is divided into three equal parts, and each is doused with 15 L special boiling-point gasoline 80/110. The mixtures are allowed to stand for 24 hs. The solvents are each renewed twice, collected, and evaporated to dryness in low vacuum. The extracts are placed in 2% aqueous sulfuric acid and adjusted to a pH of 4 with concentrated aqueous ammonia solution. Five extractions with diethyl ether follow. The aqueous phase is set to a pH of 9 with concentrated ammonia and extracted five times with diethyl ether. These ether fractions are collected, dried with sodium sulfate, and evaporated. 20 g of a slightly yellow, oily residue is obtained, which is recrystallized from hot isopropanol. 10 g of white galanthamine base having a melting point of 129°-130°C is obtained.
Galantamine may be isolated from Galanthus nivalis or G. woronowi bulbs too.
The acidic extracts are mixed and purified from traces of dichloroethane by means of shaking out with diethyl ether. Under stirring and cooling to 15° to 20°C, about 200 ml of a 25% aqueous ammonia solution is then added up to alkaline litmus reaction (the pH is in the range of 7 to 8). Different from the indications in the art, the companion alkaloids do not precipitate. The alkaline solution is saturated with salt and extracted with diethyl ether.
After evaporation of the ether, a negligible residue remains, which is also different from the indications in the art. The pH-value of the aqueous phase is set to about 14 by saturating it with potash. The aqueous phase is repeatedly extracted with diethyl ether. The mixed ether extracts are evaporated to dryness, the remaining galanthamine-containing residue is dissolved in acetone (50 ml). In contrast to the art, there is no precipitate. 350 ml acetone is replenished, 200 g aluminum oxide is added, and stirring is effected for 45 min. The aluminum oxide is filtered off and washed twice with 100 ml acetone each time. The mixed acetone solutions are evaporated to dryness. 1.3 g of an oily residue is obtained which is examined by means of HPLC.
2. 100 kg air-dried, comminuted bulbs of Narcissus pseudonarcissus "Carlton" is carefully mixed with 4 kg of sodium carbonate. The mixture is divided into three equal parts, and each is doused with 15 L special boiling-point gasoline 80/110. The mixtures are allowed to stand for 24 hs. The solvents are each renewed twice, collected, and evaporated to dryness in low vacuum. The extracts are placed in 2% aqueous sulfuric acid and adjusted to a pH of 4 with concentrated aqueous ammonia solution. Five extractions with diethyl ether follow. The aqueous phase is set to a pH of 9 with concentrated ammonia and extracted five times with diethyl ether. These ether fractions are collected, dried with sodium sulfate, and evaporated. 20 g of a slightly yellow, oily residue is obtained, which is recrystallized from hot isopropanol. 10 g of white galanthamine base having a melting point of 129°-130°C is obtained.
Galantamine may be isolated from Galanthus nivalis or G. woronowi bulbs too.
Therapeutic Function
Cholinesterase inhibitor
General Description
Galantamine, 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro-[3a,3,2,ef][2]-benzazepin-6-ol (Nivalin, Reminyl), is an alkaloid extractedfrom the tuberous plant Leucojum aestivum (L.) belongingto the Amaryllidaceae family and from the bulbs of thedaffodil, Narcissus pseudonarcissus. It is a reversiblecholinesterase inhibitor that appears to have no effect on butyrylcholinesterase.In addition, it acts at allosteric nicotinicsites, further enhancing its cholinergic activity. Galantamineundergoes slow and minor biotransformation with approximately5% to 6% undergoing demethylation. It is primarilyexcreted in the urine.
Pharmacology
hydrolyzed and metabolized by AChE.?When AD occurs, neurons in the basal forebrain region of the brain are lost, resulting in the reduction of synthesis, storage and
release of ACh, which leads to a variety of clinical manifestations especially memory and recognition dysfunction. Galantamine is a reversible AChE inhibitor, which
is highly selective and competitive. It competitively binds to AChE in a synaptic gap
with Ach, blocks the degradation of Ach by AChE, and thus achieves efficacy.
Besides, it has the activity as an allosteric modulator of nicotinic acetylcholine
receptor (nAChR). nAChR is mainly located in the muscarinic choline receptor’s
presynaptic structure. It can promote the release of Ach, which is critical to maintain
the survival and function of cholinergic neurons. The study found that in cerebral cortex of the patients of AD, nAChR was significantly reduced. Galantamine binds
to AChR’s allosteric site to increase the transmission of acetylcholine signaling.
Galantamine has a 53-fold greater inhibitory activity in?vitro for AChE than for butyrylcholinesterase (BChE). The low affinity of galantamine for BChE may be responsible for a tolerability advantage. BChE, which is primarily found in plasma, is not thought to be directly involved in the cholinergic disruption seen in early AD, and its inhibition may contribute to peripheral side effects.
It was recorded in Martindale: The Complete Drug Reference that an initial oral dose of 4?mg is given twice daily with food for 4?weeks and then increased to 8?mg twice daily. This dose should be maintained for at least 4?weeks; thereafter, the dose may be further increased to 12?mg twice daily according to response and tolerance. The clinical benefit of galantamine should be reassessed, preferably within the first 3?months and thereafter on a regular basis
Galantamine is metabolized by hepatic cytochrome P450 enzymes CYP3A4 and CYP2D6, glucuronidated, and excreted unchanged in the urine. After intravenous injection or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine, and the other was metabolized by the hepar.
Galantamine has a 53-fold greater inhibitory activity in?vitro for AChE than for butyrylcholinesterase (BChE). The low affinity of galantamine for BChE may be responsible for a tolerability advantage. BChE, which is primarily found in plasma, is not thought to be directly involved in the cholinergic disruption seen in early AD, and its inhibition may contribute to peripheral side effects.
It was recorded in Martindale: The Complete Drug Reference that an initial oral dose of 4?mg is given twice daily with food for 4?weeks and then increased to 8?mg twice daily. This dose should be maintained for at least 4?weeks; thereafter, the dose may be further increased to 12?mg twice daily according to response and tolerance. The clinical benefit of galantamine should be reassessed, preferably within the first 3?months and thereafter on a regular basis
Galantamine is metabolized by hepatic cytochrome P450 enzymes CYP3A4 and CYP2D6, glucuronidated, and excreted unchanged in the urine. After intravenous injection or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine, and the other was metabolized by the hepar.
Clinical Use
Before the 1990s, galantamine was mainly used to treat poliomyelitis sequelae,
muscle atrophy, postoperative intestinal muscle paralysis, urinary retention, and
myasthenia gravis. In the 1990s, it was found that galantamine had improved memory impairment in mice, suggesting that it might be effective for central cholinergic
disorders in Alzheimer’s disease
In a 3–6?months’ well-designed clinical trial, recipients of galantamine achieved significant improvements in cognitive symptoms compared to placebo recipients. Galantamine also improved activities of daily living in these patients and significantly reduced the requirement for caregiver assistance with activities of daily living. Clinical development of new indications of galanthamine is currently underway, such as smoking cessation and improving cognitive impairment in schizophrenia and mania.
In a 3–6?months’ well-designed clinical trial, recipients of galantamine achieved significant improvements in cognitive symptoms compared to placebo recipients. Galantamine also improved activities of daily living in these patients and significantly reduced the requirement for caregiver assistance with activities of daily living. Clinical development of new indications of galanthamine is currently underway, such as smoking cessation and improving cognitive impairment in schizophrenia and mania.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: erythromycin increases concentration of galantamine.
Antibacterials: erythromycin increases concentration of galantamine.
Metabolism
Galantamine is partially (up to 75%) metabolised by the
cytochrome P450 isoenzymes CYP2D6 and CYP3A4; a
number of active metabolites are formed.
After 7 days, 90-97% of a single oral dose is recovered in the urine with up to about 6% detected in the faeces; about 20-30% of the dose is excreted in the urine as unchanged galantamine. Clearance is reported to be 20% lower in females than in males and 25% lower in poor metabolisers than in extensive metabolisers.
After 7 days, 90-97% of a single oral dose is recovered in the urine with up to about 6% detected in the faeces; about 20-30% of the dose is excreted in the urine as unchanged galantamine. Clearance is reported to be 20% lower in females than in males and 25% lower in poor metabolisers than in extensive metabolisers.
Questions And Answer
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Physical and Chemical Properties
Galanthamine，White or slightly yellow crystalline powder. Odorless, bitter taste. Melting point 127~129 ℃, [α] D20-118.8 ° (ethanol). Soluble in ethanol, acetone, chloroform, insoluble in benzene, ether and water. After reaction with ammonium molybdate solution, water bath, evaporate, sulfuric acid is added ，it turns to blue-green. Use bulbs of Lycoris squamigera Maxim as raw material, under different acidity ， extract and refine repeatedly with ethanol and chloroform to obtain the product . It belongs to anti-cholinesterase drugs.It is used for sequelae of infantile paralysis and myasthenia gravis. Medicinal use is its hydrobromide. ; -
Alkaloids
Galanthamine is alkaloid which is extracted from Amaryllidaceae plants Lycoris squamigera Maxim or Lycoris aurea,it is a reversible anti-cholinesterase drug, it is easy for it to go through the blood brain barrier into the brain tissue ,its effect on central nervous system is stronger, it can improve neuromuscular conduction , compared with physostigmine, neostigmine , pyridostigmine , it has wide range of treatment, and low toxicity, muscarinic effects are weak and short-lived. Clinically Galanthamine is used not only for the treatment of myasthenia gravis, polio sequelae resting, but also for children with cerebral palsy, multiple neuritis, radiculitis and sensorimotor disorders caused by nervous system disease or trauma . ; -
Alzheimer's disease drugs
Alzheimer's disease (AD) is a primary degenerative disease of the central nervous system, and it is more common in the elderly or pre-senile dementia ,it has a latent onset, course of disease is progressive. AD patients account for 55% of patients with dementia. The prevalence rate is 5% to 8%, the prevalence increases with the increase of age . Cause is unknown.
Cholinergic deficiency plays an important role in the pathogenesis of Alzheimer's disease. Cholinergic system is necessary to maintain the human short-term memory and attention, the cholinergic system dysfunction is associated with certain neuropsychiatric symptoms and behaviors occurring in patients . Cholinesterase inhibitors by inhibiting the degradation of acetylcholine increase the amount of acetylcholine. New evidence suggests that long-term use of cholinesterase inhibitors not only improves cognitive and behavioral disorders, but also may affect the function and survival of neurons. In the current treatment of Alzheimer's disease, cholinesterase inhibitor occupies an important position. Cholinesterase inhibitors have been approved for the treatment of mild to moderate Alzheimer's, such as tetrahydro-amino acridine (tacrine), donepezil (trade name: Aricept), rivaroxaban neostigmine (trade name: Exelon), galanthamine, huperzine.
Galanthamine is the second generation of AchE inhibitors. It sas a dual mechanism of action, which can better stimulate and inhibit AchE, it can increase brain levels of acetylcholine, slow brain cell function loss process. It can significantly improve mild to moderate AD patients' cognitive function, maintain their daily living skills. After oral ,plasma peak time is 2h, T1/2 is 5~6h. It has quick absorption and well tolerance, its improving cognitive effects are stronger than Brooklyn . Oral doses of each 10mg, 3 times a day.
The above information is edited by the chemicalbook of Tian Ye. ; -
Clinical application
Galanthamine hydrobromide is used for myasthenia gravis, muscular dystrophy, polio sequelae, children cerebral palsy, sensory or motor disorders caused by neurological disorders , multiple neuritis. The oral dosage form of the drug can be used for memory impairment, mild to moderate Alzheimer's disease.
Oral: it is used for myasthenia gravis, muscular dystrophy, multiple peripheral neuropathy treatment: 1 10mg per time, tid. Children 0.5~1mg/(kg · d), 3 times.
It is used for Alzheimer's disease: initial dose of 1 4mg, bid, for four weeks; maintenance dose of 8mg per time, bid, at least for four weeks; maximum maintenance dose of 1 times 12mg, bid.
Intramuscular or subcutaneous injection: 2.5~10mg/d, children each 0.05~0.1mg/kg, qd, 1 course is 2 to 6 weeks. Poliomyelitis continuous medication 40~50d, the general course of treatment is 20~40d, the start of the second compartment is 30~45d after treatment. After 1 to 2 courses ,if the condition has not been improved, patients should stop the medication. If it is effective ,3 courses can be used. Application of the dose should be small to large, in order to reduce adverse reactions. ; -
Adverse reactions
Overdose can lead to bradycardia, dizziness, salivation, and abdominal pain. Atropine confrontation can be used. ; -
Precautions
1. epilepsy, mechanical obstruction, angina pectoris, bradycardia and bronchial asthma patients are disabled.
2. Applications should start from small dose, then it is gradually increased, generally 20 to 40 days for treatment is a course,according to the condition . If one or two courses of treatment are ineffective, it should be suspended.
3. patients with a history of peptic ulcer or using with non-steroidal anti-inflammatory drugs, moderate liver and kidney damage patients, severe heart disease patients should use with caution. ; -
Hazardous characteristics
Galanthamine has a reversible effect on cholinesterase , its pharmacological and toxicological effects are similar to physostigmine and neostigmine , but it has less effect, and its toxicity is also low. Mouse oral LD50 18.7mg/kg; intraperitoneal injection LD506.42mg/kg; intravenous LD505.2mg/kg~8.0mg/kg. ; -
Uses
It is used for neurological diseases and trauma-induced movement disorders, multiple neuritis, ramitis and so on. ;
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