1953-04-4 Usage
Outline
Galantamine hydrobromide also called as 11-methyl-3-methoxy-4a, 5, 9, 10, 11, 12-hexahydro-6H-benzene and furan [3a, 3, 2-ef] [2] benzazepine-6-ol hydrobromide, is an alkaloid isolated from Lycoris plants. In the 1960 s, China had first successfully isolated it from domestic Medicago Lycoris and Lycoris radiata, and had recorded into the Chinese Pharmacopoeia in 1977. The hydrobromide salt is white crystalline powder and is odorless with bitter taste. It is soluble in water, slightly soluble in ethanol but insoluble in chloroform, acetone, and ether. The absorption coefficient (50 ug in 1 ml of water): at 289nm wavelength, it has an absorption coefficient of 79.6~86.2. It is mainly applied to myasthenia gravis, poliomyelitis sequelae and resting stage as well as being used for the treatment of children with cerebral paralysis, polyneuritis, radiculitis and sensory motor disorders caused by nerve disorders or trauma. It is clinically also used for the treatment of Alzheimer's disease as well as treatment of dementia and memory disorders caused by the organic disease of the brain with significant therapeutic effect.
Galantamine is a kind of phenanthridine alkaloids discovered by the Soviet scholars 50 years ago. It is the inhibitor of the reversible cholinesterase (ChE) and can selectively inhibit the real cholinesterase (AChE). Galantamine belongs to the second generation of acetylcholinesterase inhibitor drugs with its pharmaceutical composition being same as the extracted alkaloids of the European Mountain narcissus bulb. This kind of herbal medicine has already had a history of 30 years of clinical application in some countries and regions for the treatment of reversal neuromuscular blockade, myasthenia gravis, and children with cerebral palsy psychosis.
Cholinesterase inhibitors
Galantamine Hydrobromide is the hydrobromide salt form of galantamine, a tertiary alkaloid obtained synthetically or naturally from the bulbs and flowers of Narcissus and several other genera of the Amaryllidaceae family with anticholinesterase and neurocognitive-enhancing activities.It can improve the cognitive abilities of Alzheimer's patients and has been already applied as the drug of the treatment of mild to severe Alzheimer's disease (AD) drugs and has entered into market in EC countries. "Chinese Pharmacopoeia" has included the both the raw material and injection of galantamine hydrobromide. It is clinically mainly used for the treatment of poliomyelitis (polio) sequelae, muscular dystrophy and myasthenia gravis. It can be used to substitute neostigmine methyl-sulfate for antagonism of tubocurarine but with weak performance with the usage amount being ten times as high as the usage amount of neostigmine methyl-sulfate. Intravenous injection of 0.5 mg/kg of galantamine hydrobromide can quickly reverse the central anticholinergic effects caused through injection of scopolamine hydrobromide. It can also be used for treating children cerebral palsy, traumatic sensorimotor disorders, multiple neuritis and radiculitis.The above information is edited by the lookchem of Dai Xiongfeng.
Physical and Chemical Properties
It is white crystalline powder and is odorless with bitter taste. It is soluble in water, slightly soluble in ethanol and insoluble in acetone, chloroform, ether and benzene.
Extracting Lycoris galantamine hydrobromide
Galantamine hydrobromide can be extracted from Amaryllidaceae plant Lycoris radiata with the process of extraction, separation and preparation as below:
The first step: the extract of total alkaloids
Step two: The separation of galantamine
Step three: Preparation of galanthamine hydrobromide
Pharmacological effects
Galantamine hydrobromide is a kind of tertiary amino alkaloid and is a reversible competitive inhibitor of cholinesterase. With the deepened understanding of the Alzheimer’s disease (AD) pathogenesis, people have started the study of using this product for treating AD in the early 1980s. In 1987, the United States scholars Bonnie had first successfully receive a patent of applying galantamine hydrobromide for treatment of AD. After this, many countries, one after another, have carried out related pharmacological, pharmacodynamic and pharmacokinetic studies related to it. This result had showed that galantamine hydrobromide, as the second-generation cholinesterase inhibitors, targeted on nerve synapses by competing with acetylcholine for binding to the cholinesterase and further blocking this enzymatic degradation of acetylcholine and therefore increasing the acetyl choline concentration inside the brain.
Pharmacokinetics
In 1989, Miliailova et al reported the pharmacokinetic studies of galantamine hydrobromide on humans. Studies have shown that, subcutaneous injection and oral administration can give similar excellent bioavailability. When being administered with 8-32 mg per day, the pharmacokinetics of this product exhibits a linear correlation. Oral administration of this tablets for 4 mg per time, 2 times per day has the serum half-life (t1/2) being 5-7 h, the average time for reaching peak (Tmax) being 0.5-1 h, and the protein binding rate being 20%. Nearly 50% of the drugs are excreted through urine in which 25% is proto-drug, 20% has been metabolized into O-demethylated galantamine-glucuronic acid, and 5% is the N-demethylated galantamine while those drugs which has been metabolized into galantamine or galantamine ketone only accounting for less than 2%. The ratios of the distribution level of this product in mouse tissue and its plasma levels were: erythrocytes 1.3, brain 2.1, liver 5.0, and the kidney concentration is 10 times as high as plasma concentration.
Indications
It is suitable for treatment of benign memory disorders, improving the directed memory, associative learning, image memory, nonsense figure recognition and also portraits recalling capability of the patients. It can also alleviate the symptom of dementia patients and also memory impairment caused by organic brain lesions.
Drug Interactions
Galantamine hydrobromide can play a potential role on weakening the treatment efficacy of the anti-cholinergic drug.
It has synergistic effect in combination with cholinomimetic effectors and other kinds of cholinesterase inhibitors.
Combined with cimetidine ketoconazole may increase the bioavailability of the product.
Combination with erythromycin can reduce the efficacy of this product.
It has been reported that the combination between galantamine hydrobromide with digoxin can cause atrioventricular block
Side effects
Nervous System: Common symptoms include fatigue, dizziness, headache, trembling, insomnia, dreaminess; and hypertonia, rate aphasia, hyperactivity, etc in some rare cases.
Gastrointestinal system: nausea, vomiting, abdominal distension, abdominal pain and diarrhea, anorexia and weight loss as well as indigestion.
Cardiovascular system: commonly bradycardia, arrhythmia; rarely hypotension.
Blood system: commonly anemia; occasionally thrombocytopenia .
Endocrine and metabolic systems: occasionally increased blood sugar; hypokalemia had also reported.
Contraindications
Patients being allergic to galantamine hydrobromide are prohibited
Galantamine, as a kind of cholinesterase inhibitors is prohibited during the process of anesthesia
Patients with angina and bradycardia are disabled
Patients with severe asthma or pulmonary dysfunction are disabled
Patients of severe liver damage were banned
Patients of severe kidney damage were disabled
Patients with mechanical obstruction are disabled
Uses
Different sources of media describe the Uses of 1953-04-4 differently. You can refer to the following data:
1. It can be used for the treatment of neurological diseases and trauma-induced movement disorders, multiple neuritis, and radiculitis.
Cholinesterase inhibitors can reverse the process of scopolamine-induced amnesia.
2. Galantamine hydrobromide (marketed as Reminyl) is one of a group of three drugs for people with Alzheimer's disease called cholinesterase inhibitors. The other two are called donepezil hydrochloride (common brand name Aricept) and rivastigmine (common brand name Exelon). It is a selective acetylcholinesterase inhibitor that for the treatment and prevention of Alzheimer's disease and other diseases resulting from reduced neuronal metabolism.
Chemical Properties
Galantamine hydrobromide is a white to almost white powder and is sparingly soluble in water.
General Description
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.Galantamine Hydrobromide, a reversible, competitive acetyl cholinesterase inhibitor, is suggested for the remedy of mild to moderate dementia of the Alzheimer′s type.
Biological Activity
Long-acting, centrally active acetylcholinesterase inhibitor (IC 50 = 410 nM) and allosteric potentiator at neuronal nicotinic ACh receptors. Prevents β -amyloid-induced apoptosis in SH-SY5Y and bovine chromaffin cells. Long-term administration reduces amyloid precursor protein deposition and neurodegeneration in a mouse model of Alzheimer's disease.
Check Digit Verification of cas no
The CAS Registry Mumber 1953-04-4 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 1,9,5 and 3 respectively; the second part has 2 digits, 0 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 1953-04:
(6*1)+(5*9)+(4*5)+(3*3)+(2*0)+(1*4)=84
84 % 10 = 4
So 1953-04-4 is a valid CAS Registry Number.
InChI:InChI=1/C17H21NO3/c1-18-8-7-17-6-5-12(19)9-14(17)21-16-13(20-2)4-3-11(10-18)15(16)17/h3-6,12,14,19H,7-10H2,1-2H3/p+1/t12-,14-,17-/m0/s1
1953-04-4Relevant articles and documents
METHOD FOR PREPARATION OF PURIFIED GALANTAMINE HYDROBROMIDE
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Page/Page column 5-9, (2019/12/15)
The invention concerns a method for preparation of purified galantamine hydrobromide, i.e. extraction of galantamine from plant raw material, its conversion into hydrobromide and its purification. The method consists of extraction from Leucojum aestivum or Narcissus Carlon cv in aqueous medium or in medium of low alcohol, alkalized with calcium hydroxide to pH 9 - 12 at a temperature of 30 - 40°C of galantamine base, after filtration and concentration it is extracted 2 to 4 times with methyl isobutyl ketone, ethyl acetate or butyl acetate or with n-butanol in a ratio of extract/extractant of 8:1 during the extractions in water medium, and respectively 2:1 during the extractions in the presence of simple alcohol. Concentration of the collected organic extracts from 1/20 to 1/30 of the initial volume and replacement of the solvent with ethanol. Conversion of the obtained galantamine base during treatment with hydrobromic acid to galantamine hydrobromide which at a temperature of 80 - 85°C in aqueous medium is purified with activated carbon. Filtration of the purified solution, cooling down to 20-25°C and alkalization with ammonium hydroxide to pH 9-12. Extraction of the obtained galantamine base 2-4 times with methyl isobutyl ketone, ethyl acetate or butyl acetate in a ratio of alkaline water solution/organic solvent of 2:1 to 3:1 and after concentration from 1/5 to 1/10 of the initial volume, cooling and treating with selective reagent for N-desmethyl galantamine under stirring for 7-10 hours, followed by extraction with mineral acid to pH 2-3 in aqueous medium, alkalization of the acid water extract of the galantamine salt at pH 9-12, extraction of the released galantamine base with methyl isobutyl ketone, ethyl acetate or butyl acetate in a ratio of aqueous solution/organic solvent of 2:1 to 3:1, replacement of the solvent with ethanol and processing with hydrobromic acid and obtaining galantamine hydrobromide with HPLC grade more than 99% and high yield of about 90 - 92% of the content of Galantamine hydrobromide in the technical product.
Stereoselective syntheses of galanthamine and its stereoisomers by complementary Luche and L-selectride reductions
Trinadhachari, Ganala Naga,Kamat, Anand Gopalkrishna,Raghu Babu, Korupolu,Sanasi, Paul Douglas,Prabahar, Koilpillai Joseph
, p. 117 - 124 (2014/02/14)
A diastereodivergent approach for the stereoselective syntheses of all four stereoisomers of galanthamine, (-)-galanthamine 1, (+)-galanthamine 2, (-)-epigalanthamine 3, and (+)-epigalanthamine 4, from (±)-narwedine 5 is reported. Thus (±)-narwedine 5 was resolved by dynamic kinetic resolution to obtain enantiomerically pure (-)-narwedine 6 and (+)-narwedine 7. Each enantiomerically pure isomer of narwedine was subjected to Luche and L-selectride reactions to obtain all four isomers of galanthamine. In these reactions, the (-)-galanthamine 1 and (+)-galanthamine 2 isomers were obtained with an enantiomeric purity of >99.5%, whereas (-)-epigalanthamine 3 and (+)-epigalanthamine 4 are obtained with a chiral purity of >97%. The axial hydride attack by the Luche reduction and the equatorial hydride attack by the L-selectride reduction on the cyclic enone system are explored in the stereoselective synthesis of the galanthamine isomers and thus it was demonstrated that the stereoselective synthesis involving the Luche and L-selectride reductions are complementary in yielding enantiomeric stereogenic centers from a prochiral carbonyl group on the cyclic enone system.
An improved process for the preparation of galantamine hydrobromide
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Page/Page column 11, (2009/01/24)
The present invention relates to an improved process for the preparation of [4aS,6R,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol of Formula I
