Serine derivative compound for preventing or treating central nervous system diseases
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A technology of central nervous system and compound, applied in nervous system diseases, neuromuscular system diseases, muscular system diseases, etc., can solve problems such as low permeability, and achieve the effect of improving blood-brain barrier permeability
Pending Publication Date: 2021-03-30
アストロゲン カンパニーリミティド
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However, when L-serine passes through the blood-brain barrier, it exhibits low permeability, so the biosynthesis defect in the brain is considered to be the cause of neurodevelopmental disorders such as cerebellar disease, epilepsy, and mental retardation.
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preparation example Construction
[0059] Therefore, the present invention provides the preparation method of the compound of above-mentioned chemical formula (I), comprises introducing H-Ser(Trt)-OH to 2-chlorotrityl chloride resin (2-Chlorotrityl chloride resin) continuously 3 times, and introducing H - A step to cleave the resin after Lys(Boc)-OH.
[0060] Referring to the synthesis scheme (scheme), the specific preparation method of the serine derivative compound of chemical formula (I) is described as follows:
[0061] [Scheme]
[0062]
[0063] (1) CLTR Swelling and H-Ser(Trt)-OH introduction
[0064] 1) Add 2-chlorotrityl chloride resin (2-Chlorotrityl chloride resin) (0.1 mmol) and MC (0.4 L) to a 4 L reactor, and expand (swelling) for 2 hours.
[0065] 2) Add dimethylformamide (DMF) containing Fmoc-Ser(trt)-OH (1.5eq) and diisopropylethylamine (DIPEA) (3eq) to the resin (resin) of Swelling ( 0.2L), and reacted at room temperature for 6 hours.
[0066] 3) After the reaction, wash with DMF (0.2 L)...
Embodiment
[0135] 1. Materials and methods
[0136] 1.1. Medium and reagents
[0137] Dulbecco's Modified Eagle Medium (DMEM), fetal bovine serum (FBS), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES, 4 Reagents for cell culture such as -(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid) and streptomycin-penicillin were purchased from Gibco BRL (Grand Island, USA).
[0138] 1.2. Preparation of a novel serine derivative compound (AST-009)
[0139]2-Chlorotrityl chloride resin (2-Chlorotrityl chloride resin) (0.1 mmol) and MC (0.4 L) were added to a 4 L reactor, and swelling (swelling) was carried out for 2 hours. Add Fmoc-Ser(trt)-OH (1.5eq) and DIPEA (3eq) in DMF (0.2L) to the resin (resin) of swelling (resin), and react at room temperature (RT) for 6 hours, and the reaction ends Thereafter, washing was performed with DMF (0.2 L). A mixed solution of MC / MeOH / DIPEA (255:30:15) was added, followed by capping shaking reaction at room temperature for 2 hours, followed by washin...
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Abstract
The present invention relates to a novel serine derivative compound having improved blood-brain barrier (BBB) permeability, and a use of same, and more specifically, to a novel serine derivative compound having further improved BBB permeability compared to L-serine, and a pharmaceutical composition comprising the compound as an effective compound for preventing or treating / alleviating central nervous system diseases, such as cognitive disorders, intellectual disabilities, microcephaly, epilepsy, neurodevelopmental disorders, dementia, autism spectrum disorders, Down syndrome, Rett syndrome, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A compound of chemical formula (I) or a pharmaceutically acceptable salt thereof asan effective component for the pharmaceutical composition of the present invention for preventing or treating central nervous system diseases exhibits significantly improved BBB permeability comparedto L-serine, and activates the propagation of neurons, and through the neuroprotective effect that inhibits oxidative stress-induced mitochondrial membrane potential disruption and / or endoplasmic reticulum stress-induced apoptotic neuronal cell death, exhibits desirable effects in the prevention, treatment, and alleviation of central nervous system diseases, such as cognitive disorders, intellectual disabilities, microcephaly, epilepsy, neurodevelopmental disorders, dementia, autism spectrum disorders, Down syndrome, Rett syndrome, fragile X syndrome, Alzheimer's disease, Parkinson's disease,Huntington's disease, and amyotrophic lateral sclerosis. Thus, the compound is an extremely useful invention in the drug industry, food industry, and livestock industry.
Description
technical field [0001] The present invention relates to a novel serine derivative compound (serine derivative compound) with improved permeability of the blood-brain barrier (BBB) and its application, and more specifically, relates to A novel serine derivative compound having improved blood-brain barrier permeability and a compound containing the above-mentioned compound as an active ingredient for preventing or treating / improving cognitive impairment, mental retardation, cerebellar disease, epilepsy, neurodevelopmental disorder, dementia, autonomic Central nervous system diseases such as autism spectrum disorder, Down syndrome, Ritter syndrome, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis pharmaceutical compositions, etc. Background technique [0002] L-serine is not only a component of protein in the body, but also in the biosynthesis of purine, pyrimidine, glycine, cysteine, etc. and sphingomyeline...
Claims
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