DaMocles- Presentation Group H Julia Kredel, Jasmin Milzetti, Stephan Klose, Viktor Koch

Transcription

1 Galanthamine DaMocles- Presentation Group H Julia Kredel, Jasmin Milzetti, Stephan Klose, Viktor Koch 1. Introduction: Snowdrops, daffodils and some other tubers contain Galanthamin. All these plants are considered poisonous and may cause vomitus, diarrhea, constricted pupils, sweating, and dizziness. With strong poisoning, paralyzes and throat paralyzes can occur. Nevertheless, it is known in naturopathy in the Caucasus. Worth mentioning is, that particularly the Caucasian snowdrop contains a high amount of Galanthamine. Since a few years ago, it has been used in academic medicine in the treatment of dementia. 2. General information: IUPAC name: (4aS, 6R, 8aS)-3-Methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzofuro [3a,3,2-e, f] benzazepine-6-ol GHS Hazard Statements: H 301: Toxic if swallowed P: If swallowed, call a poison center or doctor 1 Physical properties: Boiling point: ± 45.0 C (1 atm) Melting point: about 128 C Density: 1.28 ± 0.1 g/cm3 (20 C, 1 atm) 2 pka: Patent was granted to the synthesis process in Market Launch: Trade name Reminyl by Janssen-Cilag Chemical properties: stereogenic centers Galanthamine is an alkaloid. There are disputes about the definition of the term alkaloid. Generally Galanthamine is considered an alkaloid due to it being a cyclic tertiary amine. DaMocles Präsentation 2013 Gruppe H Galantamin 1/5

2 3. Synthesis: The industrial production of Galanthamine was developed by the Austrian company Sanochemia Parmazeutika. There are three synthetic routes: Sanochemia Industrial Production Trost Galanthamine synthesis Eli Lilly / U. of Southampton Galanthamine synthesis In the following, we will elaborate on the industrial process because the laboratory methods are hardly used anymore. This process is started from 3,4-Dimethoxy-benzaldehyde. In the first step, the aldehyde is brominated. The solvent is acetic acid. After that, an Acidic ether cleavage takes place. Only the ethergroup para-positioned to the bromine is regioselectivel y splitted. In the next step, an imine is formed with Tyramine (= 4 - (2-aminoethyl)-phenol). It will be reduced with Sodium-borohydride. This process is called reductive amination. The product reacts with ethyl-methyl ester (solvent: Dioxane). The ester is attacked by the nucleophilic Nitrogene, ethanol reacts as the leaving group. The reaction should be conducted in Dioxane in order to avoid side reactions with the solvent. Then using Potassium-hexacyanoferrate and Potassium-carbonate, an oxidative Phenol coupling in Toluene and a Michael reaction, takes place. This creates two stereogenic centers and therefore four products, the main product formed the enantiomers R / R and S / S and as a by-product R / S and S / R. The diastereomers are now separated. DaMocles Präsentation 2013 Gruppe H Galantamin 2/5

3 In the next step, the ketone group reacts with 1,2-Propylene-glycol, so that a acetal is introduced as a protecting Then, two Carbon atoms in the molecule will be reduced with Lithium-aluminum-hydride. This happens to the brominated Carbon and the aldehyde group. Now, the protecting group is removed with Hydrochloric acid. So far, all enantiomers and diastereomers are build they are: Now the enantiomers R/R can be converted to S / S using ethanol. The ketone is then selectively reduced to a hydroxide-group with L-selectride, so that the new stereogenic center will be in the R configuration. The product is Galanthamine. Source for this section: 6 DaMocles Präsentation 2013 Gruppe H Galantamin 3/5

4 4. Pharmaceutical Effect: 4.1. Development: Galanthamine was first isolated in 1953 from the bulb of the Caucasian snowdrop. Initially it was used to reverse the muscle relaxations induced by curare compounds in anasthtics. It was also used in the 60s as a drug against polio. The trade name was Nivalin Biochemical and physiological effects/ Benefits: Galanthamine-hydrobromide is used as a drug for mild to moderate dementia. The trade name is Reminyl. Since last year there has been a generic drug. It is sold under the name of Galnora. In dementia patients some specific brain cells are dying slowly. These cells produce the neurotransmitter Achetylcholine (Ach), resulting in a lack of it. ACh is responsible for the transmission of nervous impulses between two neurons in the Central Nervous System (CNS). With dementia, the orientation and the concentration of the patients get worse due to a shortage of ACh and thus reduced transmission of nerve impulses. There are two ways in which Galanthamine affect the nervous system. - Galanthamine inhibits the enzyme Acetylcholinesterase, which hydrolizes ACh. Thus, the concentration of ACh in the synapse increases again and the brain performance is improved by increasing the transmission of nervous impulses. - There are two types of ACh receptors: nicotinic and muscarinic. The nicotinic receptors are found in brain and muscles, especially the muscarinic the sympathetic nervous system. Galanthamine acts allosterically on the nicotinic ACh receptors, i.e. it increases the affinity of the receptor for ACh, thereby improving the transmission of impulses. When treated with Galanthamine, the patients are more receptive. The way in which Galanthamine manipulates the transmission of stimuli in the synapses may also work for other diseases in which Acetylcholine is involved. There are studies conducted on the use of Galanthamine in personality disorders after stroke, postoperative delirium and traumatic brain trauma, as well as during hypoxia (reduction of oxygen supply to tissues, for example within the brain). 7 Studies have shown that patients treated with Galanthamine have a 38% lower risk of heart attacks. 8 The exact effect of Galanthamine on the heart is not known yet. However, researchers suggest that the increased vagal tone has a favorable effect on cardiac function. A vagal tone is an imbalance in the autonomic nervous system between the sympathetic and parasympathetic nervous systems. As mentioned above, Galanthamine affects the parasympathetic nervous system. The equilibrium is shifted towards the parasympathetic nervous system. This results in low blood pressure and slow pulse Restrictions / side effects: Additional information: The CNS includes brain and spinal cord, in contrast to the peripheral nervous system Looking at the CNS, one can distinguish between the vegetative and somatic nervous system. The vegetative system controls the unconscious functions of the body. It is divided into the sympathetic and parasympathetic nervous system. However, Galanthamine is effective only for mild to moderate age-related brain disorders because it cannot stop the death of the cells, but only improves the function of the remaining nerve cells. Therefore, the precondition for the effectiveness is a sufficient residual function of the brain. The side effects are consistent with the symptoms of poisoning that have been described previously. Galanthamine also damages the kidneys and liver function, so it cannot be used in hypersensitive patients and patients with pre-existing conditions to kidney or liver. In most cases, drugs with Galanthamine as an ingredient will be taken only for a limited period in time, usually no longer than one year. The effectiveness wears off quickly because the body gets used to the increased neurotransmitter concentration (such as in addiction to coffee, nicotine, heroin...). With prolonged intake, the risk for a damage of liver and kidney as side effects becomes higher. DaMocles Präsentation 2013 Gruppe H Galantamin 4/5

5 Further Sources: Molecules designed with ChemDraw and ChemSketch DaMocles Präsentation 2013 Gruppe H Galantamin 5/5