(R)-3-Hydroxy-1-(1-hydroxy-3-benzyl propyl-2-)2-methyl pyridine-4(1H)-one
CN-128 is potentially for the treatment of thelassemia and iron overload.
|Zhejiang University, 浙江大学|
CAS No. 1335282-04-6
- Molecular Weight, 259.30
Many diseases in humans and animals are caused by excessive accumulated metals, such as iron. Among such diseases, excess iron is accumulated in various tissues, which is called iron overload disorders, formerly known as siderosis Haemorrhagic. Excess iron has the following sources: 1) long-term blood transfusion; 2) the gastrointestinal system absorbing excess iron, because stimulated by diseases such as anemia. It is necessary to repeat transfusion for some patients with severe anemia, for example, β-thalassemia, as well as other anemia requiring transfusion therapy. Excessive iron absorption from the gastrointestinal tract usually occurs in hemochromatosis patients and in anemia patients who do not require blood transfusion, such as thalassemia intermedia. If iron overload disease is not treated, it will result in severe tissue damage, especially the liver, heart and endocrine organs, and ultimately lead to death. Iron chelators can remove and clear excess iron from such organs, relieve symptoms and reduce the corresponding mortality.
Desferrioxamine (DFO) is an effective iron chelator for a long time. However, in the treatment of the diseases mentioned above, the biggest disadvantage regarding DFO and its salts is its poor oral absorption capability. So, administration is achieved with a slow injection method (8∼12h/day), patients need to wear a portable drug delivery device during treatment, such as mounting the syringe on a mechanical pressing device. This method is inconvenient, and also expensive, which largely limits the utilization of DFO, especially for thalassemia-prone areas, such as Mediterranean, Middle East, and India &South East Asia, it plays no role in treatment of malaria in world-wide and sickle cell anemia in some African countries, which is a very serious problem to the populations there.
UK Patent No. 2, 13, 807, US Patent No. 4, 585, 780 and other scientific research have reported the treatment of iron overload symptoms by using 3-hydroxypyridin-4-one derivatives, especially in some pathological symptoms, such as thalassemia, sickle cell anemia, aplastic anemia in children, and idiopathic hemochromatosis, usually, treatment of the first three diseases includes frequent regular blood transfusion. 3-Hydroxypyridin-4-one derivatives, especially CP20 (commercial named Ferriprox) is employed to treat systemic iron overload disorders, and also to treat certain diseases associated with local iron overload distribution, although such patients do not show symptoms of systemic iron overload, i.e. inhibition free radical mediated reactions caused by excess iron ions in certain neurodegenerative diseases and cancer diseases. A serious limitation of CP20 is that the hydroxyl group at 3′ position is vulnerable to glycosylation, which reduces the half-life of this compound (approximately 2∼3 h). So it requires a high dosage, which is associated with obvious side effects.
EP0120669 discloses compounds with a 3-hydroxypyrid-4-one in which the H attached to the N atom is substituted by an aliphatic acyl group, or an aliphatic hydrocarbon group, these groups can be further substituted, but not by aromatic groups and their use against illnesses related to iron overload. Molenda et al. disclose in Journal of Medicinal Chemistry 1994, 37, pages 4363-4370 chiral 3-hydroxy-pyridin-4-one compound 6 as enhancing iron excretion.
US Patent No. 6, 465, 604 described a series of 3,5-diphenyl-1,2,4-triazole compounds, wherein including Exjade (commercial name), which has strong affinity to Fe(III), However, its active groups contain two negatively charged oxygen ions and a carboxyl group; it is a tridentate ligand while chelating Fe(III), which forms a Fe-L2 type complex, possessing three unit negative charges itself, that is bad for their discharge from cells/tissues. Moreover, one of the active groups is a nitrogen atom with a lone pair of electrons, Exjade may have a negative effect on the balance of Zn(II) in vivo, at the same time because it has two phenolic hydroxyl groups in different positions (forming intramolecular hydrogen bonds structure similar to cis/trans isomerization), it can be complexed to several zinc ions to form high molecular weight polymers complexes, which is not conducive to its discharge from the cells either.
Absorption, distribution, metabolism and excretion of chiral medicines are largely related to the 3D structures of their chiral centers. For drug absorption, chiral compounds entering cells via active transport mechanism are usually carried by special transport proteins, their recognition of enantiomers can be different, resulting in different absorption of enantiomers. For drug distribution, the binding effects of plasma protein and tissues are also somewhat stereoselective, leading to different in vivo distribution of enantiomers; for stereoselective of drug metabolism refers to when the substrate is biotransformated, the pathway and speed of enantiomer metabolism by biological systems can be different. One enantiomer may show ascendant metabolism, and therefore it is of great significance to the indicators including drug transformation and in vivo half-life. Glomerular filtration, tubular secretion and reabsorption of chiral drugs to clear the chiral drugs, having stereoselectivity, while the glomerular filtration rate is closely related to drug’s selectivity to binding plasma protein, so discharge style of enantiomers (urine / feces percentage) and the rate is also different.
Therefore, the qualitative difference of the interactions of a pair of enantiomers with various binding sites may exist or not, and the quantitive difference may exist (strong or weak), which results in the different activities between enantiomers. Thus the selection of optical enantiomers for medical use, requires a comprehensive study of metabolic activity, toxicology and pharmacokinetic properties etc. Thus the chiral nature of the 3-hydroxypyridin-4-one derivatives described in this patent has an important role on in vivo iron chelation.
The effectiveness of many oral 3-hydroxy-4-one derivatives drugs are subject to metabolic reaction of the 3-hydroxy moiety, which may be quickly glycosylated (see Reaction I). The hydroxypyridone after glycosylation loses the ability to chelate Fe(III). We can effectively inhibit glycosylation reaction by introducing hydroxyl groups to alkyl substituted residues on the pyridine ring. In addition, the partition coefficient of 3-hydroxy-pyridin-4-one derivatives has a great impact on the in vivo distribution and toxic effects. We have introduced various alkyl groups to the chiral point of the compound, in order to modify their lipophilicity, i.e. a phenyl group connected to the chiral point in compound IV-b while in IV-a it is a methyl group, and thus compound IV-b is relatively more lipophilic, and easier to penetrate through cell membranes of various tissues and critical barriers such as the blood-brain barrier and the placental barrier, thus affecting its in vivo distribution. Thus increase of hydroxyl groups can affect the intestinal absorption capacity, by introducing a large alkyl group, intestinal absorption of 3-hydroxy-pyridin-4-one derivatives can be enhanced.
Example7. (R)-3-Hydroxy-1-(1-hydroxy-3-benzyl propyl-2-)2-methyl pyridine-4(1H)-one, Number: CN128.
60 g 3-phenyloxy-2-methyl-4H-pyran-one(Example 1) was dissolved in 150 mL n-butanol, then 83.7 g D-phenylalaninol was added in. After thoroughly mixing, the solution was refluxed at 118°C for 36 h. After cooling and filtration, products were purified by silica gel column chromatography with Eluent ethanol: acetic ester=1:40. After Elution, light brown solid was obtained after rotary evaporation, which was then dissolved into 150 mL ethanol and 15 mL water, then it was hydrogenated and debenzylated with 5% Pd/C as catalyst, the solvent was removed under rotary evaporation, the remaining solid was recrystallized with methanol and ether, leading to 25.25 g light yellow solid. The yield was 35.1%. The free alkali’s 1HNMR (DMSO-d6): δ 2.00 (s, 3H), 2.98 (dd, J1=14, J2=5.5, 1H), 3.11 (dd, J1=14, J2=5, 1H), 3.73 (m, 2H), 4.54 (m, 1H), 6.21 (d, J=7, 1H), 7.17 (m, 5H), 7.87 (d, J=7.5, 1H).