Use of isopropyl-d-glucopyranoside derivatives on regeneration of injured neurons

Abstract

The isopropyl-D-glucopyranoside derivative of this invention is a novel compound, and its synthetic method was investigated for preparation. Furthermore, the isopropyl-D-glucopyranoside derivative of this invention can effectively promote the regeneration of brain and retinal nerves and repair damage to brain and retinal nerves.

Description

Technical Field

[0001] This invention provides an isopropyl-D-glucopyranoside derivative and its synthesis method, as well as the use of the isopropyl-D-glucopyranoside derivative in promoting nerve repair. Prior Technology

[0002] Currently, neurological injuries, such as traumatic brain injury (TBI), affect approximately 70 million people worldwide each year. Common treatments include physical therapy, hyperbaric oxygen therapy, and non-invasive therapies such as cranial magnetic stimulation and direct current stimulation of the head, which can improve depression and cognitive function after TBI. However, there are currently no effective drugs to promote nerve regeneration after brain injury.

[0003] Traumatic brain injury (TBI) is damage to the brain caused by external force striking it. Globally, there are approximately 70 million confirmed cases each year. TBI damages cranial nerves, leading to functional impairments in movement or cognition. Because the central nervous system is difficult to regenerate after injury, there are currently no effective treatments to promote nerve regeneration in TBI patients. After a period of time, TBI patients often develop brain lesions and later neurodegenerative diseases. Therefore, early use of drugs that promote nerve regeneration after brain injury is a solution for treatment.

[0004] Furthermore, in terms of drug selection, the blood-brain barrier prevents most drugs from easily penetrating it to achieve an effective dose, making the administration of effective drugs a serious problem when treating brain diseases.

[0005] In view of this, there is an urgent need to develop a drug that can treat nerve damage, and there is also an urgent need for a delivery method that can cross the blood-brain barrier. Summary of the Invention

[0006] This summary is intended to provide a simplified overview of the present disclosure to enable the reader to gain a basic understanding of it. It is not a complete summary of the present disclosure and is not intended to identify key / critical elements of the embodiments of the invention or to define the scope of the invention.

[0007] The human nervous system is divided into the central nervous system and the peripheral nervous system, both of which are composed of neurons. The trigeminal nerve is a cranial nerve within the peripheral nervous system and connects to the pons (central nervous system). Therefore, when the compound of this invention passes through the nasal mucosa, penetrates the olfactory epithelial cells, enters the olfactory and trigeminal nerve pathways, and reaches the brain, it can simultaneously achieve a systemic nerve repair effect through the peripheral nerves.

[0008] Therefore, in this invention, brain nerves, which are difficult to repair, are used as experimental subjects. This aims to achieve the effect of repairing both the central and peripheral nerves within the nervous system.

[0009] The "central nervous system" is composed of the brain and spinal cord. The "central nervous system" described in this invention includes, but is not limited to, the olfactory brain, amygdala, hippocampus, neocortex, lateral ventricles, superior thalamus, thalamus, hypothalamus, subthalamus, pituitary gland, pineal gland, third ventricle, midbrain tectum, cerebral peduncle, anterior tegmentum, cerebral aqueduct, pons, cerebellum and medulla oblongata, and spinal cord.

[0010] "Peripheral nerves" consist of the somatic nervous system and the autonomic nervous system. The "peripheral nerves" described in this invention include, but are not limited to, sensory nerves, motor nerves, cranial nerves, spinal nerves, sympathetic nerves, parasympathetic nerves, and the enteric nervous system.

[0011] This invention provides an isopropyl-D-glucopyranoside derivative having the structure of chemical formula (1): Where R1 is the structure of chemical formula (2) or chemical formula (3), which may or may not be substituted; R2 and R3 are structures of chemical formula (4) or chemical formula (5), which may or may not be substituted. R4 is selected from the group consisting of substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, substituted or unsubstituted hydroxyl groups, and substituted or unsubstituted halogens; R5 is selected from the group consisting of substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, substituted or unsubstituted hydroxyl groups, substituted or unsubstituted carbonyl groups, and substituted or unsubstituted halogens; R6 is selected from the group consisting of substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, substituted or unsubstituted hydroxyl groups, substituted or unsubstituted carbonyl groups, and substituted or unsubstituted halogens; R7 is selected from the group consisting of substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, substituted or unsubstituted hydroxyl groups, and substituted or unsubstituted halogens; R1” is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl. R2” is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl. R3” is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4” is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium.

[0012] In some embodiments, the present invention comprises an Isopropyl-D-glucopyranoside derivative, wherein the derivative comprises a compound of the following chemical formula: R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R5 is selected from the group consisting of substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, substituted or unsubstituted hydroxyl groups, substituted or unsubstituted carbonyl groups, and substituted or unsubstituted halogens; R6 is selected from the group consisting of substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, substituted or unsubstituted hydroxyl groups and substituted or unsubstituted halogens.

[0013] This invention uses "Isopropyl-D-glucopyranoside derivatives" for "treatment of nerve damage". To enable those skilled in the art to understand the content of the patented invention, this invention uses "ampelopsisionoside", "Byzantionoside B", and "roseoside" from the "Isopropyl-D-glucopyranoside derivatives" as examples.

[0014] In some embodiments, the following chemical formula (6) compounds among the Isopropyl-D-glucopyranoside derivatives of the present invention are obtained by the following chemical synthesis steps: (A) As shown in process 1 below, compound of chemical formula (7) is converted into compound of chemical formula (8) through a dialkylation reaction, a acetylation reaction and an alkynyl nucleophilic addition reaction; In the compound of chemical formula (8), the substituents are respectively possible as follows: R1 may be substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium and substituted or unsubstituted hydroxyl; R2 may be substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium and substituted or unsubstituted hydroxyl; R3 may be substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted The dialkylation reaction is carried out via an electrophilic reagent 1, which includes methyl iodide, ethyl iodide, propyl iodide, MeOTf, EtOTf, PrOTf, propyl bromide / sodium iodide, or dimethyl sulfate. The subsequent alkylating reagent includes formaldehyde, acetaldehyde, or propionaldehyde. This intermediate further undergoes an alkyne nucleophilic addition reaction to give compound (8). The alkyne nucleophilic addition reagent includes an alkyne with an R4 functional group and a base. This base contains nBuLi, lithium diisopropylamino (LDA), lithium di(trimethylsilyl)amino (LHMDS), wherein the functional group of R4 may be substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; (B) As shown in process 2 below, compound (8) is converted into compound (9) through an olefination reaction, a reduction reaction and a deprotection reaction; In this olefination reaction, compound (8) is first reacted with an electrophilic reagent 2 and an amine reagent under low temperature conditions to produce compound (9); the electrophilic reagent 2 includes mesyl chloride, tosyl chloride, acetic anhydride, benzoic anhydride, methyl iodide, or dimethyl sulfate; the amine reagent includes triethylamine, diethylamine, pyridine, pyrrolidine, ethyldisiopropyl amine, 2,6-dimethylpyridine, or 1,4-diazabicyclo[2,2,2]octane, and the low temperature conditions are -30 to 25°C; after completion, a second base is added to complete the olefination, the second base including potassium tertiary butyrate. tert-butoxide), sodium hydroxide, sodium methoxide or 1,8-diazabicyclo[5,4,0]undec-7-ene; after completion, a reduction reaction is carried out, which uses a reducing agent 1 as a reducing agent, which includes lithium aluminum hydride, diisobutyl aluminum hydride (DIBAL)), sodium borohydride, sodium triacetoxyborohydride (NaB(OAc)3H), lithium triethylborohydride (Lithium triethylborohydride) or sodium bis(2-methoxyethoxy)aluminiumhydride, and the reaction temperature of the reduction reaction is -50 to 25°C; after completion, a deprotection step is carried out, which uses a deprotection reagent 1 to carry out a deprotection reaction to obtain the compound of chemical formula (9), wherein the deprotection reagent 1 includes tetrabutylammonium fluoride (tetrabutylammonium fluoride) The deprotection reaction involves the use of fluoride (TBAF), anhydrous pyridine hydrofluoric acid (HF-py), hydrochloric acid, or potassium tert-butyrate. The reaction temperature for this deprotection reaction is -35 to 25°C. (C) As shown in process 3 below, compound of chemical formula (9) is combined with compound of chemical formula (10) through a sugar chain reaction to form compound of chemical formula (11); The compound of chemical formula (9) is reacted with a sugar-linking reagent 1 via the sugar-linking reaction to obtain the compound of chemical formula (10), wherein the sugar-linking reagent 1 comprises nickel sulfide / silver trifluoromethanesulfonate (NIS / AgOTf), sodium tetrabromophenolphthalein sulfonate / tri-tert-butylphenol / trifluoromethanesulfonic anhydride (BSP / TTBP / Tf2O), trimethylsilyl trifluoromethanesulfonate / nickel sulfide (TMSOTf / NIS), trimethylsilyl trifluoromethanesulfonate (TMSOTf), silver trifluoromethanesulfonate (AgOTf), or CuOTf, wherein the reaction temperature of the sugar-linking reaction is -78 to 0°C; (D) The compound of formula (11) is converted into the compound of formula (6) by deketalization, isomerization, debenzoylation and 1,4-reduction; The compound of chemical formula (11) first undergoes deketation and isomerization reactions, which are carried out through a reagent 1, which comprises an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, an aqueous solution of trifluoroacetic acid, a mixture of TsOH and H2O, and HCl dissolved in 1,4-dioxane (HCl in 1,4-dioxane) or an aqueous sulfuric acid solution; then the benzylation reaction is carried out using a benzylation reagent, wherein the benzylation reagent comprises sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, hydrochloric acid methanol solution, hydrochloric acid aqueous solution, trifluoroacetic acid (TFA) and H2O or an aqueous sulfuric acid solution; then the 1,4-reduction reaction is carried out to obtain the target chemical formula (6) compound, the 1,4-reduction reaction is carried out using a 1,4-reduction reaction reagent, wherein the 1,4-reduction reaction reagent comprises sodium borohydride, lithium aluminum hydride, NaB(OAc)3H, NaBCNH3, L-selectride, [CuH(PPh3)]6, diisobutyl aluminum hydride (DIBAL) or H2 / Pd / C, the reaction temperature of the 1,4-reduction reaction is -78 to 25°C; R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium.

[0015] In some embodiments, the following chemical formula (12) compounds among the Isopropyl-D-glucopyranoside derivatives of the present invention are obtained by the following chemical synthesis steps: (A) As shown in process 4 below, the compound of chemical formula (11) is converted into the compound of chemical formula (12); These transformations include the deprotection of an acetal, isomerization, stereoselective deoxidation, and deprotection of a benzoyl group. The deprotection of the acetal and the isomerization are carried out using an acidic reagent comprising an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, trifluoroacetic acid (TFA) with H₂O, TsOH with H₂O, and a mixed solution of HCl dissolved in 1,4-dioxane (HCl in...). The intermediate is subjected to a stereoselective deoxidation reaction with a reducing agent 2 under a first low temperature condition. The reducing agent 2 comprises NaBH4, LiAlH4, NaB(OAc)3H, triacetoxyborohydride (NaBCNH3), Et3SiH / BF3-Et2O, L-selectride, [CuH(PPh3)]6, or diisobutylaluminum hydride (DIBAL), wherein the amount of the reducing agent 2 is 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 equivalents, and the first low temperature condition in the stereoselective deoxidation step is -78 to 25°C. Then, the benzoyl group of the intermediate is removed with a deprotecting agent 2 to produce a compound of formula (11), wherein the deprotecting agent 2 comprises NaOH, NaOMe, NaOEt, KOH, KOMe, KOEt, hydrochloric acid methanol solution, HCl aqueous solution, trifluoroacetic acid (TFA) and H2O or H2SO4 aqueous solution. R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium.

[0016] In some embodiments, the following chemical formula (13) compounds among the Isopropyl-D-glucopyranoside derivatives of the present invention are obtained by the following chemical synthesis steps: (A) As shown in process 5 below, compound of chemical formula (12) is converted into compound of chemical formula (13) through a transformation reaction; The transformation includes a regioselective and a stereoselective 1,4-reduction / carbonyl reduction; the regioselective and stereoselective 1,4-reduction / carbonyl reduction are carried out with a reducing agent 3 under a second low-temperature condition, the reducing agent 3 comprising NaBH4, LiAlH4, NaB(OAc)3H, NaBCNH3, L-selectride, [CuH(PPh3)]6, DIBAL or H2, Pd / C, and the equivalent amount of the reducing agent 3 is 0.5, 1.0, 2.0, 3.0, 4.0 or 5.0 equivalents, wherein the second low-temperature condition in the regioselective and stereoselective 1,4-reduction / carbonyl reduction steps is -78 to 25°C; R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium.

[0017] In some embodiments, the following chemical formula (14) compounds in the Isopropyl-D-glucopyranoside derivatives of the present invention are obtained by the following chemical synthesis steps: (A) As shown in process 6 below, compound of chemical formula (12) is converted into compound of chemical formula (14) by selective alkene reduction; The selective alkene reduction is carried out using a reducing agent 4, which includes sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride (NaB(OAc)3H), NaBCNH3, L-selectride, [CuH(PPh3)]6, diisobutyl aluminum hydride (DIBAL), H2 / Pd / C, or RhCl(PPH3)3 / H2. The reaction temperature for this selective alkene reduction reaction is -78 to 25°C. R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium.

[0018] In some embodiments, the following chemical formula (15) compounds in the Isopropyl-D-glucopyranoside derivatives of the present invention are obtained by the following chemical synthesis steps: As shown in process 7 below, the compound of chemical formula (9) is converted into the compound of chemical formula (15) through a deketalization, isomerization, and debenzoyl protection. The compound of chemical formula (9) first undergoes the deketation and isomerization reactions, which are carried out using a deketation and isomerization reagent comprising aqueous acetic acid, aqueous hydrochloric acid, aqueous trifluoroacetic acid, a mixed solution of TsOH and H2O, HCl dissolved in 1,4-dioxane (HCl in 1,4-dioxane), or aqueous sulfuric acid. The subsequent debenzoylation protection reaction is carried out using a debenzoylation protecting reagent comprising sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, methanol hydrochloric acid, aqueous hydrochloric acid, trifluoroacetic acid (TFA) and H2O, or aqueous sulfuric acid. R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium.

[0019] In some embodiments, the following compounds of chemical formula (16) and chemical formula (17) in the Isopropyl-D-glucopyranoside derivatives of the present invention are obtained by the following chemical synthesis steps: As shown in process 8 below, compound (15) is converted into compound (16) and compound (17) through a selective reduction reaction; The selective reduction reaction of compound (15) yields compounds (16) and (17) through a selective reduction reagent, which includes sodium borohydride, lithium aluminum hydride, NaB(OAc)3H, NaBCNH3, L-selectride, [CuH(PPh3)]6, diisobutyl aluminum hydride (DIBAL), or H2 / Pd / C. The reaction temperature of the selective reduction reaction is from -78°C to 25°C. R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium.

[0020] In some embodiments, the Isopropyl-D-glucopyranoside derivative of the present invention exhibits relatively low cytotoxicity to Neuro2a cells.

[0021] The present invention also provides the use of an Isopropyl-D-glucopyranoside derivative for promoting nerve repair.

[0022] In some embodiments, the Isopropyl-D-glucopyranoside derivative, when used alone, can promote the regeneration of injured hippocampal neurons and promote neural regeneration in 3D brain tissue slices, demonstrating that the compound can effectively promote neuronal regeneration and can be used to repair nerve damage.

[0023] In some embodiments, the Isopropyl-D-glucopyranoside derivative of the present invention can promote the repair of retinal nerves.

[0024] In some embodiments, the Isopropyl-D-glucopyranoside derivative of the present invention, when administered nasally, can cross the blood-brain barrier of the user and enter the brain to promote the repair of the damaged neurons.

[0025] In some embodiments, the Isopropyl-D-glucopyranoside derivative can penetrate the blood-brain barrier to enter the brain, thereby promoting the repair, regeneration, or increase in the number of neurons.

[0026] In some embodiments, the Isopropyl-D-glucopyranoside derivative can promote the regeneration of cortical neurons after traumatic brain injury.

[0027] In some embodiments, the effective dose concentration of the Isopropyl-D-glucopyranoside derivative used in this invention is from 9.674 nM to 1342 μM.

[0028] In some embodiments, the Isopropyl-D-glucopyranoside derivative of the present invention has a significant effect on nerve repair, wherein the nasal administration of the compound can penetrate the blood-brain barrier and enter the brain to promote the repair of damaged neurons; promote the repair, regeneration or increase in the number of brain nerves; and promote the regeneration of the neural axons of cortical neurons and hippocampal neurons after brain injury.

[0029] After reading the following embodiments, those skilled in the art will easily understand the basic spirit and other inventive objectives of the present invention, as well as the technical means and implementation methods adopted by the present invention. Simple Explanation of the Diagram

[0030] Figures 1A-1C show the cytotoxicity test results of the Isopropyl-D-glucopyranoside derivative of this invention. Figure 2 is a flowchart of the in vitro nerve repair experiment of the present invention. Figure 3 is a schematic diagram of the gap closure rate calculation of the present invention, used to quantify relative neural axis regeneration. Figures 4A-4B show the results of in vitro experiments on the neural repair of hippocampal nerve cells using Ampelopsisoside, the Isopropyl-D-glucopyranoside derivative of this invention. Figure 5 shows the results of an in vitro experiment on cortical nerve cell repair using Ampelopsisoside, the Isopropyl-D-glucopyranoside derivative of this invention. Figure 6 shows the results of an in vitro experiment on the neural repair of hippocampal nerve cells using Byzantionoside B, an Isopropyl-D-glucopyranoside derivative of this invention. Figure 7 shows the results of an in vitro experiment on cortical nerve cell repair using Byzantionoside B, an Isopropyl-D-glucopyranoside derivative of this invention. Figure 8 shows the results of an in vitro experiment on the neural repair of hippocampal nerve cells using Roseoside, the Isopropyl-D-glucopyranoside derivative of this invention. Figure 9 shows the results of the in vitro cortical nerve cell repair and regeneration experiment of Roseoside, the Isopropyl-D-glucopyranoside derivative of this invention. Figure 10 is a flowchart of the ex vivo brain tissue section experiment of the present invention. Figure 11 shows the experimental results of three-dimensional brain tissue sections of Ampelopsisoside, the Isopropyl-D-glucopyranoside derivative of this invention, in vitro. Figure 12 shows the experimental results of three-dimensional brain tissue sections of Byzantionoside B, the Isopropyl-D-glucopyranoside derivative of this invention, in vitro. Figure 13 shows the experimental results of three-dimensional brain tissue sections of Roseoside, the Isopropyl-D-glucopyranoside derivative of this invention, in vitro. Figure 14 shows the experimental flowchart of the controlled cortical impact brain injury model of the present invention and the experimental results of the Isopropyl-D-glucopyranoside derivative Ampelopsisoside promoting the recovery of motor function in mice after brain injury. Figure 15 shows the experimental flowchart of the controlled cortical impact brain injury model of the present invention and the experimental results of the Isopropyl-D-glucopyranoside derivative Ampelopsisoside promoting the recovery of environmental exploration ability in mice after brain injury (stress test). Figure 16 is an experimental flowchart of the Isopropyl-D-glucopyranoside derivative Ampelopsisoside controlled cortical impact brain injury model of the present invention. Figure 17 shows the results of the horizontal bar test in the experimental model of cortical impact brain injury controlled by the amplepsisionoside derivative of the Isopropyl-D-glucopyranoside of this invention. Figure 18 is a flowchart illustrating the process by which the Isopropyl-D-glucopyranoside derivative Byzantionoside B promotes the repair of ex vivo retinal nerves. Figure 19 shows the experimental results of the Isopropyl-D-glucopyranoside derivative Byzantionoside B promoting the repair of ex vivo retinal nerves. Figure 20 is a flowchart illustrating the process by which Roseoside, an Isopropyl-D-glucopyranoside derivative of the present invention, promotes the repair of ex vivo retinal nerves. Figure 21 shows the experimental results of Roseoside, the Isopropyl-D-glucopyranoside derivative of this invention, promoting the repair of nerves in ex vivo retina. Figure 22 is a flowchart of the synthesis of various derivatives of Isopropyl-D-glucopyranoside in this invention. Implementation

[0031] To make the description of this disclosure more detailed and complete, illustrative descriptions of embodiments and specific examples of the present invention are provided below; however, these are not the only forms of implementing or utilizing the specific examples of the present invention. The embodiments cover features of multiple specific embodiments and methods and uses for operating these specific embodiments; however, other specific embodiments may also be used to achieve the same or equivalent effects. It should be understood that these embodiments are for illustrative purposes only and not for limiting the scope of the present invention.

[0032] [Example 1: Cytotoxicity assay of isopropyl-D-glucopyranoside derivative]

[0033] The CellTiter-Glo cell viability assay was used to detect the toxicity of stem-derived ampelopsisoside, byzantionoside B, and roseoside to Neuro2a cells. The CellTiter-Glo cell viability assay measures the ATP content in cells, thereby quantifying cell survival after the addition of these compounds.

[0034] As shown in Figures 1A-1C, the experimental results show that the IC50 values ​​of amplepsisionoside, byzantionoside B, and roseoside for Neuro2a cells range from approximately 4.175 mM to 32.658 mM, indicating that the Isopropyl-D-glucopyranoside derivatives have relatively low cytotoxicity.

[0035] [Example 2: In vitro analysis of the Isopropyl-D-glucopyranoside derivative Ampelopsisoside (, in vitro [Hippocampal gyrus nerve cell neural repair experiment]

[0036] The experimental procedure is shown in Figure 2. The fetus of a rat at 18 days of gestation was removed, and the fetal brain was divided into the cortex and hippocampus. The cortex and hippocampus were then separated into cortical neurons and hippocampal neurons. The hippocampal neurons were seeded in 48-well plates; this day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine beta-D-arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, the neurons were scratched with a micropipette tip, and amplepsisionoside (concentrations ranging from 9.674 nM to 967.4 μM) was added. 0.1% dimethyl sulfoxide (DMSO) was used as the solvent for amplepsisionoside. 72 hours after the addition of amplepsisionoside, nerve cells were labeled with TUJ1 antibody using immunofluorescence staining to observe nerve regeneration. This experiment was conducted using a Zeiss Observer Z1 microscope.

[0037] As shown in Figure 3, the degree of neural axon regeneration is quantified by the gap closure rate. The white dashed line represents the boundary created by the micropipette tip scratching the nerve cells, and the black part in the middle is the area scratched by the micropipette tip. The regenerated neurites grow from both sides of the dashed line towards the middle. The calculation method is to draw a line every 50 μm between the gaps in the injured area and calculate the width of the gap. After drawing ten lines, the average value is taken: the length of gap between injured borders (Lg). After a period of time, a line is drawn every 50 μm in the same injured area to connect the regenerated neural axons and the length is calculated. After drawing ten lines, the average value is taken: the length of gap between regenerated neurons (Ln). The gap closure rate is calculated by dividing (Lg-Ln) / Lg. The scale bar is 100 μm. This experiment was photographed using a Zeiss Observer Z1 microscope.

[0038] As shown in Figures 4A-4B, the degree of neural axon regeneration is quantified by the gap closure rate. The results of this experiment indicate that amplepsisionoside can effectively promote the proliferation of hippocampal neurites.

[0039] [Example 3: In vitro analysis of the Isopropyl-D-glucopyranoside derivative Ampelopsisoside (, in vitro Experiments to promote nerve regeneration of injured cortical nerve cells]

[0040] In this experiment, fetal rats at 18 days of gestation were removed, and their brains were divided into the cerebral cortex and hippocampus. Cortical neurons and hippocampal neurons were then separated, and the cortical neurons were seeded in 48-well plates. This day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine beta-D-arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were scratched with a micropipette tip, and amplepsisionoside (9.674 nM to 96.74 μM) was added, with 0.1% DMSO as a solvent control group. Results in the figure have been standardized to the DMSO group. 72 hours after the addition of amplepsisionoside, TUJ1 antibody was used to label neurons using immunofluorescence staining to observe neurogenesis. This experiment was photographed using a Zeiss Observer Z1 microscope, scale bar 100 μm.

[0041] As shown in Figure 5, the gap closure rate relative to 0.1% DMSO was calculated to quantify the degree of neural axon regeneration. The area between the two dashed lines in the immunofluorescence image represents the injury zone. These experimental results indicate that amplepsisionoside can effectively promote cortical neurite proliferation.

[0042] [Example 4: In vitro analysis of Isopropyl-D-glucopyranoside derivative Byzantionoside B (, in vitro [Hippocampal gyrus nerve cell neural repair experiment]

[0043] In this experiment, fetal rats at 18 days of gestation were removed, and their brains were divided into the cerebral cortex and hippocampus. Cortical neurons and hippocampal neurons were then separated. The hippocampal neurons were seeded in 48-well plates; this day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine beta-D-arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were scratched with a micropipette tip, and Byzantionoside B (0.13 μM to 1342 μM) was added to each group, with ddH2O as the solvent control. Results in the figures have been standardized to the ddH2O group. 72 hours after the addition of Byzantionoside B, TUJ1 antibody was used to label neurons using immunofluorescence staining to observe neurogenesis. This experiment was photographed using a Zeiss Observer Z1 microscope; the scale bar is 100 μm.

[0044] As shown in Figure 6, the gap closure rate relative to ddH2O was calculated to quantify the degree of neural axon regeneration. The area between the two dashed lines in the immunofluorescence spectrum represents the injury zone. The dashed lines in the figure below represent the ddH2O group. This experimental result indicates that Byzantionoside B can effectively promote the proliferation of hippocampal neurites.

[0045] [Example 5: In vitro analysis of Isopropyl-D-glucopyranoside derivative Byzantionoside B (, in vitro Cortical nerve cell repair experiment]

[0046] In this experiment, fetuses of rats at 18 days of gestation were removed, and the fetal brains were divided into the cortex and hippocampus. The cortex and hippocampus were then separated into cortical neurons and hippocampal neurons. The cortical neurons were seeded in 48-well plates; this day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine beta-D-arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, the neurons were scratched with a micropipette tip, and Byzantionoside B (1.34 μM to 26.84 μM) was added, with double-distilled water (ddH2O) as the solvent. 72 hours after the addition of Byzantionoside B, the neurons were labeled with TUJ1 antibody using immunofluorescence staining to observe neurogenesis. This experiment was conducted using a Zeiss Observer Z1 microscope. The area between the two dashed lines represents the wound area.

[0047] As shown in Figure 7, the degree of neural axon regeneration is quantified by the gap closure rate. This experimental result indicates that Byzantionoside B can effectively promote cortical neurite proliferation.

[0048] [Example 6: In vitro analysis of Roseoside, an Isopropyl-D-glucopyranoside derivative (, in vitro [Hippocampal gyrus nerve cell neural repair experiment]

[0049] In this experiment, fetal rats at 18 days of gestation were removed, and their brains were divided into the cerebral cortex and hippocampus. Cortical neurons and hippocampal neurons were then separated, and the hippocampal neurons were seeded in 48-well plates. This day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine beta-D-arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were scratched with a micropipette tip, and roseoside (0.013 μM to 1294 μM) was added to each group, with ddH2O as the solvent control. Results in the figures have been standardized to the ddH2O group. 72 hours after the addition of roseoside, TUJ1 antibody was used to label neurons using immunofluorescence staining to observe neurogenesis. This experiment was photographed using a Zeiss Observer Z1 microscope, scale bar 100 μm.

[0050] As shown in Figure 8, the gap closure rate relative to ddH2O was calculated to quantify the degree of neural axon regeneration. The area between the two dashed lines in the immunofluorescence spectrum represents the injury zone. The dashed lines in the lower figure represent the ddH2O group. This experimental result indicates that Roseoside can effectively promote the proliferation of hippocampal neurites.

[0051] [Example 7: In vitro analysis of Roseoside, an Isopropyl-D-glucopyranoside derivative (, in vitro Cortical nerve cell repair experiment]

[0052] In this experiment, fetal rats at 18 days of gestation were removed, and their brains were divided into the cerebral cortex and hippocampus. Cortical neurons and hippocampal neurons were then separated and seeded in 48-well plates; this day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine beta-D-arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were scratched with a micropipette tip, and roseoside (1.29 μM to 25.88 μM) was added, with ddH2O as the solvent for roseoside. 72 hours after the addition of roseoside, the neurons were labeled with TUJ1 antibody using immunofluorescence staining to observe neurogenesis. This experiment was photographed using a Zeiss Observer Z1 microscope.

[0053] As shown in Figure 9, the degree of neural axon regeneration is quantified by the gap closure rate. This experimental result indicates that Roseoside can effectively promote cortical neural axon regeneration.

[0054] [Example 8: In vitro analysis of the Isopropyl-D-glucopyranoside derivative Ampelopsisoside (, ex vivo Three-dimensional brain tissue slice experiment]

[0055] The experimental procedure is shown in Figure 10. First, the brain of a fetal rat was removed and embedded in low-melting-point agarose gel. Using a Leicamicrotome VT100, the brain was sliced ​​into 350 μm thick sections. After surgically incising the brain sections, they were cultured, with ddH2O or amplepsisionside added daily. After 96 hours of culture, TUJ1 antibody was used to label nerve cells, GFAP antibody to label glial cells, and DAPI reagent to label cell nuclei using fluorescence immunoassay. The scale bar for this experiment was 100 μm. This experiment was photographed using a Zeiss LSM800 confocal microscope.

[0056] As shown in Figure 11, the white dashed line represents the surgical incision, and the newly formed nerve axis is to the right of the dashed line. This experiment demonstrates that amplepsisionside promotes nerve regeneration.

[0057] [Example 9: Isopropyl-D-glucopyranoside derivative Byzantionoside B in vitro (, ex vivo Brain tissue slice experiment]

[0058] The experimental procedure is shown in Figure 10. First, the brain of a fetal rat was removed and embedded in low-melting-point agarose gel. Using a Leica microtome VT100, the brain was sliced ​​into 350 μm thick sections. After surgically incising the brain sections, they were cultured, with ddH2O or Byzantionoside B added daily. After 96 hours of culture, TUJ1 antibody was used to label nerve cells, GFAP antibody to label glial cells, and DAPI reagent to label cell nuclei using fluorescence immunoassay. The scale bar for this experiment was 100 μm. This experiment was photographed using a Zeiss LSM800 confocal microscope.

[0059] As shown in Figure 12, the white dashed line represents the notch created by the scalpel, and the newly formed neural process is located to the right of the dashed line. This experiment demonstrates that Byzantionoside B has a promoting effect on nerve regeneration.

[0060] [Example 10: In vitro analysis of Roseoside, an Isopropyl-D-glucopyranoside derivative (, ex vivo Brain tissue slice experiment]

[0061] The experimental procedure is shown in Figure 10. First, the brain of a fetal rat was removed and embedded in low-melting-point agarose gel. Using a Leica microtome VT100, the brain was sliced ​​into 350 μm thick sections. After surgically incising the brain sections, they were cultured, with ddH2O or Roseoside added daily. After 96 hours of culture, TUJ1 antibody was used to label nerve cells, GFAP antibody to label glial cells, and DAPI reagent to label cell nuclei using fluorescence immunoassay. The scale bar for this experiment was 100 μm. This experiment was photographed using a Zeiss LSM800 confocal microscope.

[0062] As shown in Figure 13, the white dashed line represents the notch created by the scalpel, and the newly formed nerve spur is to the right of the dashed line. This experiment demonstrates that Roseoside promotes nerve regeneration.

[0063] [Example 11: An experiment on the effect of the Isopropyl-D-glucopyranoside derivative Ampelopsisoside on the recovery of motor function in mice after brain injury]

[0064] This experiment used an open-field test to measure the motor function of mice after craniotomy without brain injury, after brain injury, and after brain injury, with daily administration of 14 μg / kg Ampelopsisionoside for one or five days (1 day post injury, 1 dpi; 5 days post injury, 5 dpi). The experimental model is shown in Figure 14. At 0 dpi, mice were subjected to brain injury using a controlled cortical impact model, and 14 μg / kg Ampelopsisionoside was administered intranasally at 0, 2, 4, 6, 8, 10, and 12 dpi (day post injury).

[0065] As shown in Figure 14, Part A describes the test procedure. Mice are placed in a large white acrylic box that is divided into four equal compartments, and allowed to move freely for five minutes. During these five minutes, the mice's movements are recorded by a Microsoft LifeCam Cinema camera and analyzed by Anubis Track tracking software.

[0066] As shown in Figure 14, Part B of this experiment shows that the movement path length of the Amplepsisionoside group and the uninjured group is almost the same, while the path length of the brain injury group without drug administration is only half that of the group. This demonstrates that the Isopropyl-D-glucopyranoside derivative Amplepsisionoside of this invention has the effect of promoting the recovery of motor function in mice after brain injury.

[0067] [Example 12: Ampelopsisoside, an Isopropyl-D-glucopyranoside derivative, promotes the recovery of exploratory abilities in mice after brain injury]

[0068] This experiment used an open field test to measure the ability of mice to explore the brain region and the time spent in the open field after craniotomy without brain injury, after brain injury, and after brain injury, when administered 14 μg / kg of Ampelopsisionoside five days later (5 days post-injury, 5 dpi). The experimental model is shown in Figure 17. At 0 dpi, mice were subjected to brain injury using a controlled cortical impact model, and 14 μg / kg of Ampelopsisionoside was administered intranasally at 0, 2, 4, 6, 8, 10, and 12 dpi (day post-injury).

[0069] As shown in Figure 15, Part A describes the test procedure. Mice are placed in a large white acrylic box that is divided into four equal compartments, and allowed to move freely for five minutes. During these five minutes, the mice's movements are recorded by a Microsoft LifeCam Cinema camera and analyzed by Anubis Track tracking software.

[0070] As shown in Figure 15, Part B of this experiment revealed that the Amplepsisionoside group and the uninjured group spent a longer time in the central region, while the untreated brain-injured group showed almost no activity in the central region. Combined with Figure 15, it can be seen that the Isopropyl-D-glucopyranoside derivative Amplepsisionoside of this invention has the effect of promoting the recovery of exploratory abilities in mice after brain injury.

[0071] [Example 13: Isopropyl-D-glucopyranoside derivative Ampelopsisoside promotes the recovery of motor coordination in mice after brain injury]

[0072] The horizontal bar test was used to assess the motor coordination of mice. Mice were placed on brass bars 49 cm above the ground, 38 cm long, and with diameters of 2 mm, 4 mm, and 6 mm. The mice were instructed to grasp the bars with their forepaws. The time the mice spent on the bars and whether they reached the platform at the end of the bars were recorded to evaluate their motor coordination. The evaluation criteria were as follows: 1-5 seconds = 1 point, 5-10 seconds = 2 points, 10-20 seconds = 3 points, 20-30 seconds = 4 points, and more than 30 seconds or reaching the platform = 5 points.

[0073] The experimental model is shown in Figure 16. Pre-training was conducted at -5, -3, and -1 dpi (day post-injury). At 0 dpi, mice were subjected to brain injury using a controlled cortical impact model. Ampelopsisoside at 14 or 140 μg / kg was administered intranasally at 0, 2, 4, 6, 8, 10, and 12 dpi. Horizontal bar experiments were conducted at 1, 3, 6, 10, and 13 dpi.

[0074] As shown in Figure 17, it can be seen that the group that received only water (ddH2O) after brain injury experienced a loss of motor coordination, while the group that received amplepsisionoside showed similar motor coordination to the Sham group, significantly promoting the recovery of motor coordination.

[0075] [Example 14: Isopropyl-D-glucopyranoside derivative Byzantionoside B promotes the repair of ex vivo retinal nerves]

[0076] The experimental design and procedure are shown in Figure 18. Retinal explants were obtained from 8-day-old C57BL / 6 mice. After sacrifice, their eyes were removed. The eyeball and retina were then separated using forceps and microscissors, and the vitreous humor was removed. Finally, the separated retina was cut into four segments, and the edges of the tissue were trimmed and scratched with microscissors. Each segment was cultured on an 18mm circular glass slide and placed in a 12-well dish. The slides were then placed in an incubator and cultured at 5% CO2 and 35°C for five days. Fresh culture medium was added to each retinal explant daily, along with 13.5μM or 135μM Byzantionoside B. On day 5 of retinal tissue culture, the tissue was fixed at room temperature for one hour with a mixture of 0.1% Glutaraldehyde solution and 4% paraformaldehyde solution. The tissue was then stained with primary antibodies axonal marker beta-III-tubulin (TUJ1) and DAPI to label nerve cells and nuclei. The tissue was then photographed using an ultra-resolution upright conjugate microscope (LSM-800, Carl Zeiss). The perimeter of the tissue and the area of ​​nerve fibers outside the tissue were calculated using the ImageJ image analysis program. The nerve fiber area was divided by the perimeter of the tissue boundary to obtain the nerve fiber length per unit perimeter.

[0077] As shown in Figure 19, after retinal tissue injury, the group given Byzantionoside B showed a significantly better recovery effect compared to the group given only water (ddH2O).

[0078] [Example 15: Roseoside, an Isopropyl-D-glucopyranoside derivative, promotes the repair of ex vivo retinal nerves]

[0079] The experimental design and procedure are shown in Figure 20. Retinal explants were obtained from 8-day-old C57BL / 6 mice. After sacrifice, their eyes were removed. The eyeball and retina were then separated using forceps and microscissors, and the vitreous humor was removed. Finally, the separated retina was cut into four pieces, and the edges of the tissue were trimmed and scratched with microscissors. Each piece was cultured on an 18mm circular glass slide and placed in a 12-well dish. The slides were then placed in an incubator and cultured at 5% CO2 and 35°C for five days. Fresh culture medium was added to each retinal explant daily, along with 13μM or 130μM Roseoside. On the fifth day of retinal tissue culture, the tissue was fixed at room temperature for one hour with a mixture of 0.1% Glutaraldehyde solution and 4% paraformaldehyde solution. The tissue was then stained with the primary antibody axonal marker beta-III-tubulin (TUJ1) and DAPI to label nerve cells and cell nuclei. The tissue was then photographed using a super-resolution upright conjugate microscope (LSM-800, Carl Zeiss). The perimeter of the tissue and the area of ​​nerve fibers outside the tissue were calculated using the ImageJ image analysis program. The nerve fiber area was divided by the perimeter of the tissue boundary to obtain the nerve fiber length per unit perimeter.

[0080] As shown in Figure 21, after retinal tissue injury, the group given Roseoside showed a significantly better recovery effect compared to the group given only water (ddH2O).

[0081] [Example 16: Sequential Synthesis of Isopropyl-D-glucopyranoside Derivative]

[0082] The sequential synthesis steps of the Isopropyl-D-glucopyranoside derivative of this invention are as follows:

[0083] The above experimental data are preliminary results obtained under specific conditions and are only used to facilitate understanding or reference of the technical content of this invention. Further related experiments are required. This experimental data and its results are not intended to limit the scope of this invention.

[0084] The foregoing preferred embodiments are merely illustrative of the present invention and its technical features. The technology of these embodiments can still be implemented by various substantially equivalent modifications and / or substitutions. Therefore, the scope of the present invention shall be determined by the scope defined in the appended claims.

Claims

1. An isopropyl-D-glucopyranoside derivative, selected from the group consisting of , , , , , and .

2. A method for preparing an isopropyl-D-glucopyranoside derivative of the following chemical formula (6), comprising the following synthetic steps: Chemical formula (6) (A) Converting a compound of chemical formula (7) into a compound of chemical formula (8) through a dialkylation reaction, a ylated reaction and an alkynyl nucleophilic addition reaction; wherein, R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium groups; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted hydroxyl groups. The group consisting of substituted tritium, wherein the dialkylation reaction is carried out by an electrophilic reagent 1, which includes methyl iodine, ethyl iodine, propyl iodine, MeOTf, EtOTf, PrOTf, propyl bromide / sodium iodide or dimethyl sulfate, and the subsequent alkylating reagent includes formaldehyde, acetaldehyde or propionaldehyde, and the intermediate further undergoes an alkyne nucleophilic addition reaction to give a compound of formula (8); the alkyne nucleophilic addition reagent includes an alkyne having an R4 functional group and a base; the base includes nBuLi, lithium diisopropylamino (LDA), lithium di(trimethylsilyl)amino (LHMDS), wherein the R4 functional group is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium; (B) The compound of formula (8) is converted into a compound of formula (9) through an olefination reaction, a reduction reaction and a deprotection reaction; wherein the compound of formula (8) is first reacted with an electrophilic reagent 2 and an amine reagent under low temperature conditions in the olefination reaction to produce the compound of formula (9); the electrophilic reagent 2 includes mesyl chloride, tosyl chloride, acetic anhydride, benzoic anhydride, methyl iodide or dimethyl sulfate; the amine reagent includes triethylamine, diethylamine, pyrrolidine, ethyldisiopropyl amine, 2,6-lutidine or 1,4-diazabicyclo[2,2,2]octane, the low temperature conditions being -30 to 25°C; after completion, a second base is added to complete the olefination, the second base including potassium tert-butyrate, sodium hydroxide, sodium methoxide or 1,8-diazabicyclo[5,4,0]undec-7-ene;After completion, a reduction reaction is carried out, which uses a reducing agent 1 as a reducing agent. The reducing agent 1 includes lithium aluminum hydride, diisobutyl aluminum hydride (DIBAL), sodium borohydride, NaB(OAc)3H, Lithium triethylborohydride or sodium bis(2-methoxyethoxy)aluminiumhydride. The reaction temperature of the reduction reaction is -50 to 25°C. After completion, a deprotection step is carried out, which uses a deprotection reagent 1 to carry out a deprotection reaction to obtain compound of formula (9). The deprotection reagent 1 includes tetrabutyl ammonium fluoride (TBAF), HF-py, hydrochloric acid or potassium tributate. The reaction temperature of the deprotection reaction is -35 to 25°C. (C) The compound of formula (9) is combined with a compound of formula (10) through a sugar chain reaction to form a compound of formula (11). The compound of chemical formula (9) is reacted with a sugar-linking reagent 1 via the sugar-linking reaction to obtain the compound of chemical formula (11), wherein the sugar-linking reagent 1 comprises NIS / AgOTf, BSP / TTBP / Tf2O, TMSOTf / NIS, TMSOTf, AgOTf or CuOTf, wherein the reaction temperature of the sugar-linking reaction is -78 to 0℃; (D) The compound of chemical formula (11) is converted into the compound of chemical formula (6) by a deketalization, an isomerization, a debenzoylation and a 1,4-reduction; wherein the compound of chemical formula (11) first undergoes a deketalization and isomerization reaction, the deketalization and isomerization reaction is carried out with a reagent 1, wherein the reagent 1 comprises an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, an aqueous solution of trifluoroacetic acid, a mixed solution of TsOH and H2O, and HCl dissolved in 1,4-dioxane (HCl in 1,4-dioxane) or an aqueous solution of sulfuric acid; then the deprotection reaction is carried out using a deprotection reagent 2, wherein the deprotection reagent 2 comprises sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, hydrochloric acid methanol solution, hydrochloric acid aqueous solution, trifluoroacetic acid (TFA) and H2O or an aqueous solution of sulfuric acid; then the 1,4-reduction reaction is carried out to obtain the target chemical formula (6) compound, the 1,4-reduction reaction is carried out through a 1,4-reduction reaction reagent, the 1,4-reduction reaction reagent comprises sodium borohydride, lithium aluminum hydride, NaB(OAc)3H, NaBCNH3, L-selectride, [CuH(PPh3)]6, diisobutyl aluminum hydride (DIBAL) or H2 / Pd / C, the reaction temperature of the 1,4-reduction reaction is -78 to 25°C;R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium.

3. A method for preparing the isopropyl-D-glucopyranoside derivative of the following chemical formula (6) as described in claim 2, wherein step (B) may further include the following synthetic steps: Chemical formula (6) subjecting a chemical formula (11) to a deketalization, isomerization, and debenzoylation reaction to convert it into the following chemical formula (15); wherein the chemical formula (11) first undergoes the deketalization and isomerization reactions, the deketalization and isomerization reactions being carried out using a deketalization and isomerization reaction reagent comprising an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, an aqueous solution of trifluoroacetic acid, a mixture of TsOH and H2O, and HCl dissolved in 1,4-dioxane (HCl in The following benzylation protection reaction is carried out using a benzylation protecting agent comprising sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, methanol hydrochloric acid solution, aqueous hydrochloric acid solution, trifluoroacetic acid (TFA) and H2O or aqueous hydrochloric acid solution, wherein R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium and substituted or unsubstituted hydroxyl; wherein R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium and substituted or unsubstituted hydroxyl. R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium and substituted or unsubstituted tritium.

4. A method for preparing the isopropyl-D-glucopyranoside derivative shown in the following chemical formula (6) as described in claim 2, wherein the method may further include the following synthetic steps after synthesizing chemical formula (15): Chemical formula (6) converting a compound of chemical formula (15) into the following chemical formula (16) and chemical formula (17) through a selective reduction reaction; wherein the compound of chemical formula (15) is used in the selective reduction reaction through a selective reducing reagent to obtain the compound of chemical formula (16) and chemical formula (17), the selective reducing reagent comprising sodium borohydride, lithium aluminum hydride, NaB(OAc)3H, NaBCNH3, L-selectride, [CuH(PPh3)]6, diisobutyl aluminum hydride (DIBAL), or H2 / Pd / C, the reaction temperature of the selective reduction reaction being -78 to 25°C. R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium.

5. A method for preparing an isopropyl-D-glucopyranoside derivative of the following chemical formula (12), comprising the following synthetic steps: Chemical formula (12) converting a compound of chemical formula (11) into a compound of chemical formula (12) via a conversion reaction; wherein the conversion reaction comprises deprotection of an acetal, isomerization, stereoselective deoxidation, and deprotection of a benzoyl group, wherein the deprotection of the acetal and the isomerization are carried out with an acidic reagent comprising an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, TFA and H2O, TsOH and H2O, and a mixed solution of HCl dissolved in 1,4-dioxane (HCl in... The intermediate is subjected to stereoselective deoxidation with a reducing agent 2 under a first low temperature condition. The reducing agent 2 comprises NaBH4, LiAlH4, NaB(OAc)3H, NaBCNH3, Et3SiH / BF3-Et2O, L-selectride, [CuH(PPh3)]6 or diisobutylaluminum hydride (DIBAL) in an amount of 0.5, 1.0, 2.0, 3.0, 4.0 or 5.0 equivalents. The first low temperature condition in the stereoselective deoxidation step is -78 to 25°C. The intermediate is then removed with a deprotecting agent 2 to produce a compound of formula (11). The deprotecting agent 2 comprises NaOH, NaOMe, NaOEt, KOH, KOMe, KOEt, hydrochloric acid methanol solution, HCl aqueous solution, trifluoroacetic acid (TFA) and H2O or H2SO4 aqueous solution. R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium.

6. A method for preparing the isopropyl-D-glucopyranoside derivative of the following chemical formula (12) compound as described in claim 5, the method further comprising the following synthetic steps: Chemical formula (12) converting a chemical formula (12) compound into a chemical formula (13) compound through a conversion reaction; The conversion reaction includes a regioselective and a stereoselective 1,4-reduction / carbonyl reduction step; the regioselective and stereoselective 1,4-reduction / carbonyl reduction steps are carried out with a reducing agent 3 under a second low temperature condition, the reducing agent 3 comprising NaBH4, LiAlH4, NaB(OAc)3H, NaBCNH3, L-selectride, [CuH(PPh3)]6, DIBAL, or H2 / Pd / C, and the equivalent of the reducing agent 3 is 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 equivalents, wherein the second low temperature condition in the regioselective and stereoselective 1,4-reduction / carbonyl reduction steps is -78 to 25°C; wherein R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl groups; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium.

7. A method for preparing the isopropyl-D-glucopyranoside derivative of the following chemical formula (12) as described in claim 5, the method further comprising the following synthetic steps: Chemical formula (12) converting a chemical formula (12) compound into a chemical formula (14) compound through a selective olefin reduction reaction; wherein the selective olefin reduction reaction is carried out using a reducing agent 4 comprising sodium borohydride, lithium aluminum hydride, NaB(OAc)3H, NaBCNH3, L-selectride, [CuH(PPh3)]6, diisobutyl aluminum hydride (DIBAL), H2 / Pd / C or RhCl(PPH3)3 / H2, wherein the reaction temperature of the selective olefin reduction reaction is -78 to 25°C; R1 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl; R2 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, substituted or unsubstituted tritium, and substituted or unsubstituted hydroxyl; R3 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium; R4 is selected from the group consisting of substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted hydrogen, substituted or unsubstituted deuterium, and substituted or unsubstituted tritium.

8. The use of an isopropyl-D-glucopyranoside derivative in the preparation of a pharmaceutical product for treating nerve injury, wherein the isopropyl-D-glucopyranoside derivative comprises a compound of the following chemical formula: ; wherein R1, R2, R3, and R4 are selected from the group consisting of methyl, ethyl, propyl, hydrogen, deuterium, tritium, and hydroxyl; wherein R5 is selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, and carbonyl; and R6 is selected from the group consisting of hydrogen, deuterium, tritium, and hydroxyl.

9. Use of the isopropyl-D-glucopyranoside derivative as described in claim 8 for the preparation of a pharmaceutical product for treating nerve injury, wherein the nerve injury is central or peripheral.

10. Use of the isopropyl-D-glucopyranoside derivative as described in claim 8 for the preparation of a pharmaceutical product for treating nerve injury, wherein the nerve injury refers to neuronal damage.

11. Use of the isopropyl-D-glucopyranoside derivative as described in claim 8 for the preparation of a pharmaceutical product for treating nerve injury, wherein the nerve injury comprises cortical neurons, hippocampal neurons, or retinal neurons.

12. Use of the isopropyl-D-glucopyranoside derivative as described in claim 8 for the preparation of a pharmaceutical product for the treatment of nerve injury, wherein the treatment refers to nerve regeneration, nerve number increase or nerve repair.

13. The use of the isopropyl-D-glucopyranoside derivative as described in claim 8 in the preparation of a pharmaceutical product for treating nerve injury, wherein the isopropyl-D-glucopyranoside derivative can cross the blood-brain barrier and enter the brain.

14. Use of the isopropyl-D-glucopyranoside derivative as claimed in claim 8 for the preparation of a pharmaceutical product for treating nerve injury, wherein the effective dose of the isopropyl-D-glucopyranoside derivative is from 9.674 nM to 1342 μM.

Images