Isopropyl-D-glucopyranoside derivatives, production method and uses thereof

Abstract

The present invention relates to an isopropyl-D-glucopyranoside derivative and a method for synthesizing the same, and the derivative can effectively promote the regeneration of cranial nerves and retinal nerves and the repair of damage to the cranial nerves and retinal nerves.

Description

[Technical Field]

[0001] The present invention provides isopropyl-D-glucopyranoside derivatives, methods for their synthesis, and the use of isopropyl-D-glucopyranoside derivatives for promoting nerve repair. [Background technology]

[0002] Currently, approximately 70 million people worldwide suffer from neurological injuries such as traumatic brain injury (TBI) each year. Common treatments include physical therapy, hyperbaric oxygen therapy, transcranial magnetic stimulation, and transcranial direct current stimulation (TCS), which are non-invasive treatments that can improve depression and cognitive function after TBI. However, there are currently no effective drugs that can promote neuronal regeneration after brain injury.

[0003] Traumatic brain injury (TBI) is an injury caused by an external force striking the brain, with approximately 70 million diagnosed cases worldwide each year. Traumatic brain injury damages cranial nerves, resulting in deficits in the patient's behavioral or cognitive function. Because the central nervous system is difficult to regenerate or recover from once damaged, current medical science does not offer a treatment that effectively promotes neuronal regeneration after TBI. Furthermore, many patients with brain injury develop brain lesions after a certain period of time, or develop neurodegenerative diseases in the future. Therefore, the use of drugs that promote regeneration of cranial nerves as quickly as possible after brain injury is a therapeutic solution.

[0004] In addition, when selecting therapeutic drugs, because the cerebrum has a blood-brain barrier, common drugs cannot easily pass through the blood-brain barrier to reach an effective dose, so administering effective drugs is an important issue when treating brain diseases. Summary of the Invention [Problem to be solved by the invention]

[0005] In view of the above, there is currently a great need for the development of drugs that can treat neuronal damage, as well as for administration methods that can cross the blood-brain barrier. [Means for solving the problem]

[0006] The purpose of this Summary is to provide an overview of the contents of the present disclosure so that the reader can have a basic understanding of the contents of the present disclosure. This Summary is not a complete summary of the contents of the present disclosure, and is not intended to point out the key / major assemblies of the embodiments of the present invention, nor to define the scope of the present invention.

[0007] The nervous system of the human body is divided into central nervous system and peripheral nervous system, both of which are composed of neurons.The trigeminal nerve is a cranial nerve among peripheral nerves, and is connected to the pons (central nervous system).Therefore, the compound of the present invention can pass through the olfactory epithelium cells through the nasal mucosa, enter the olfactory and trigeminal nerve peripheral pathways, and enter the cerebrum, and at the same time, achieve the effect of repairing the nerves of the whole body through peripheral nerves.

[0008] In view of the above, the present invention focuses on cranial nerves, which are difficult to repair, and thereby achieves the effect of making it possible to repair both central and peripheral nerves within the nervous system.

[0009] The "central nervous system" comprises the brain and spinal cord. The "central nervous system" as used herein includes, but is not limited to, the rhinencephalon, amygdala, hippocampus, neocortex, lateral ventricles, epithalamus, thalamus, hypothalamus, ventral thalamus, pituitary gland, pineal gland, third ventricle, tectum, cerebral peduncle, pretectal area, aqueduct, pons, cerebellum, medulla oblongata, and spinal cord.

[0010] The "peripheral nerves" consist of the somatic nervous system and the autonomic nervous system. As used herein, the "peripheral nerves" include, but are not limited to, sensory nerves, motor nerves, cranial nerves, spinal nerves, sympathetic nerves, parasympathetic nerves, and the enteric nervous system.

[0011] The present invention provides an isopropyl-D-glucopyranoside derivative having a chemical structure represented by chemical formula (1).

[0012] [ka]

[0013] R1 is a substituted or unsubstituted chemical structure represented by chemical formula (2) or chemical formula (3).

[0014] [ka]

[0015] R2 and R3 are substituted or unsubstituted chemical structures represented by chemical formula (4) or chemical formula (5).

[0016] [ka]

[0017] R4 is hydrogen, deuterium, tritium, a hydroxy group or a halogen.

[0018] R5 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen.

[0019] R6 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group or a halogen.

[0020] R7 is hydrogen, deuterium, tritium, a hydroxy group or a halogen.

[0021] R1" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0022] R2" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0023] R3" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0024] R4" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0025] In some embodiments, the isopropyl-D-glucopyranoside derivatives of the present invention include compounds of the following formula:

[0026] [ka]

[0027] [ka]

[0028] The R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0029] R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0030] The R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0031] R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0032] The R5 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen.

[0033] The R6 is hydrogen, deuterium, tritium, a hydroxy group, or a halogen.

[0034] The "isopropyl-D-glucopyranoside derivatives" used in the present invention are used for "treatment of nerve damage." In order to help those skilled in the art understand the contents of the invention of the present patent application, the present invention uses "Ampelopsisionoside," "Byzantionoside B," and "Roseoside" as examples of "isopropyl-D-glucopyranoside derivatives."

[0035] In some embodiments, the compound of the following chemical formula (6) among the isopropyl-D-glucopyranoside derivatives of the present invention can be obtained by the following chemical synthesis steps:

[0036] [ka]

[0037] (A) As shown in Flow 1 below, the compound of formula (7) is converted to the compound of formula (8) by a bis-alkylation reaction, an acylation reaction, and an alkyne nucleophilic addition reaction.

[0038] [ka]

[0039] Regarding the substituents of the compound represented by chemical formula (8), R1 may be a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 may be a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 may be a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; and R4 may be a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0040] The bis-alkylation reaction is carried out using electrophile 1. Electrophile 1 is methyl iodide, ethyl iodide, propyl iodide, MeOTf, EtOTf, PrOTf, propyl bromide / sodium iodide, or dimethyl sulfate. The reagent for the acylation reaction is formaldehyde, acetaldehyde, or propionaldehyde. Compound (8) is obtained by further performing an alkyne nucleophilic addition reaction on this intermediate. The reagent for the alkyne nucleophilic addition includes an alkyne having a functional group R4 and a base. Examples of the base include n-butyllithium (nBuLi), lithium diisopropylamide (LDA), and lithium bis(trimethylsilyl)amide (LHMDS). The functional group R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0041] (B) As shown in Flow 2 below, the compound represented by chemical formula (8) is converted to the compound represented by chemical formula (9) by an olefination reaction, a reduction reaction, and a deprotection reaction.

[0042] [ka]

[0043] In an olefination reaction, a compound represented by chemical formula (8) is first reacted with an electrophile 2 and an amine-based reagent under low-temperature conditions to produce a compound represented by chemical formula (9). The electrophile 2 is mesyl chloride, tosyl chloride, acetic anhydride, benzoic anhydride, methyl iodide, or dimethyl sulfate. The amine-based reagent is triethylamine, diethylamine, pyridine, pyrrolidine, diisopropyl amine, 2,6-lutidine, or 1,4-diazabicyclo[2.2.2]octane. The low-temperature conditions are at a temperature of -30 to 25°C. Subsequently, after completion, a second base is added to complete the olefination. The second base is potassium tert-butoxide, sodium hydroxide, sodium methoxide, or 1,8-diazabicyclo[5,4,0]undec-7-ene. Subsequently, after completion, a reduction reaction is carried out. In the reduction reaction, reducing agent 1 is used. Reducing agent 1 is lithium aluminum hydride, diisobutyl aluminum hydride (DIBAL), sodium borohydride, sodium triacetoxyborohydride (NaB(OAc)H), lithium triethylborohydride, or sodium bis(2-methoxyethoxy)aluminumhydride. The reaction temperature for the reduction reaction is −50 to 25° C. After completion of the reaction, a deprotection step is carried out, in which a deprotection reaction is carried out using a deprotection reagent 1 to obtain a compound represented by chemical formula (9).The deprotection reagent 1 is tetrabutyl ammonium fluoride (TBAF), anhydrous hydrofluoric acid-pyridine (HF-py), hydrochloric acid, or potassium tert-butoxide. The reaction temperature for the deprotection reaction is −35 to 25° C.

[0044] (C) As shown in Flow 3 below, a glycosylation reaction is performed to link a compound represented by formula (9) to a compound represented by formula (10) to form a compound represented by formula (11).

[0045] [ka]

[0046] The compound represented by the chemical formula (9) reacts with the sugar-binding reagent 1 in the sugar-binding reaction to give the compound represented by the chemical formula ( 11 The sugar-binding reagent 1 can be prepared by a method such as nickel sulfide / silver trifluoromethanesulfonate (NIS / AgOTf), bromosulfophthalein / tri-tert-butylphenol / trifluoromethanesulfonic anhydride (BSP / TTBP / Tf 2 O ), trimethylsilyl trifluoromethanesulfonate / nickel sulfide (TMSOTf / NIS), trimethylsilyl trifluoromethanesulfonate (TMSOTf), silver trifluoromethanesulfonate (AgOTf), or CuOTf. The reaction temperature for the glycosylation reaction is -78 to 0°C.

[0047] (D) The compound of formula (11) is converted to the compound of formula (6) by deketalization, isomerization, debenzoylation and 1,4-reduction.

[0048] The compound represented by chemical formula (11) is first subjected to deketalization and isomerization. The deketalization and isomerization reactions are carried out using Reagent 1. Reagent 1 is an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, an aqueous solution of trifluoroacetic acid, TsOH and HO, a mixed solution of HCl in 1,4-dioxane (HCl in 1,4-dioxane), or an aqueous solution of sulfuric acid. Subsequently, the debenzoylation reaction is carried out. The debenzoylation reaction is carried out using a debenzoylation reagent. The debenzoylation reagent is sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, a hydrogen chloride-methanol solution, an aqueous solution of hydrochloric acid, trifluoroacetic acid (TFA) and HO, or an aqueous solution of sulfuric acid. Subsequently, the 1,4-reduction reaction is carried out to obtain the compound represented by chemical formula (6). The 1,4-reduction reaction is carried out using a 1,4-reduction reaction reagent. The 1,4-reduction reaction reagent is sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride (NaB(OAc)H), NaBCNH, lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh)], diisobutyl aluminum hydride (DIBAL), or H / Pd / C. The reaction temperature for the 1,4-reduction reaction is −78 to 25° C.

[0049] R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0050] R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0051] R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0052] R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0053] In some embodiments, the compound represented by the following chemical formula (12) among the isopropyl-D-glucopyranoside derivatives of the present invention can be obtained by the following chemical synthesis steps.

[0054] [ka]

[0055] (A) As shown in Flow 4 below, the compound represented by chemical formula (11) is converted into the compound represented by chemical formula (12).

[0056] [ka]

[0057] The transformation involves deprotection of the acetal, isomerization, stereoselective deoxidation, and deprotection of the benzoyl group. The deprotection of the acetal and the isomerization are carried out using an acidic reagent. The acidic reagent is an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, trifluoroacetic acid (TFA) and HO, TsOH and HO, a mixed solution of HCl in 1,4-dioxane (HCl in 1,4-dioxane), or an aqueous solution of sulfuric acid. Then, stereoselective deoxidation is carried out using a reducing agent 2 under a first low-temperature condition. The reducing agent 2 is NaBH, LiAlH, sodium triacetoxyborohydride (NaB(OAc)H), NaBCNH, EtSiH / BF-EtO, lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh)], or diisobutylaluminum hydride (DIBAL). The amount of the reducing agent 2 is 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 equivalents. The temperature of the first low-temperature conditions in the stereoselective deoxidation step is −78 to 25° C. Subsequently, the benzoyl group of the intermediate is removed with a deprotection reagent 2 to give a compound of the chemical formula ( 12The deprotection reagent 2 is NaOH, NaOMe, NaOEt, KOH, KOMe, KOEt, a hydrogen chloride-methanol solution, an aqueous HCl solution, trifluoroacetic acid (TFA) and H2O, or an aqueous H2SO4 solution.

[0058] R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0059] R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0060] R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0061] R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0062] In some embodiments, the compound represented by the following chemical formula (13) among the isopropyl-D-glucopyranoside derivatives of the present invention can be obtained by the following chemical synthesis steps.

[0063] [ka]

[0064] (A) As shown in Flow 5 below, the compound represented by chemical formula (12) is converted into the compound represented by chemical formula (13) by a conversion reaction.

[0065] [ka]

[0066] The transformation includes a regioselective and stereoselective 1,4-reduction / carbonyl reduction. The regioselective and stereoselective 1,4-reduction is carried out under second low-temperature conditions using a reducing agent 3. The reducing agent 3 is NaBH4, LiAlH4, sodium triacetoxyborohydride (NaB(OAc)3H), NaBCNH3, lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh3)]6, DIBAL, or H2, Pd / C. The equivalent of the reducing agent 3 is 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 equivalents. The temperature of the second low-temperature conditions in the regioselective and stereoselective 1,4-reduction step is −78 to 25°C.

[0067] R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0068] R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0069] R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0070] R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0071] In some embodiments, the compound represented by the following chemical formula (14) among the isopropyl-D-glucopyranoside derivatives of the present invention can be obtained by the following chemical synthesis steps.

[0072] [ka]

[0073] (A) Compounds of formula (12) are converted to compounds of formula (14) by selective alkene reduction, as shown in Scheme 6 below.

[0074] [ka]

[0075] The selective alkene reduction is carried out using a reducing agent 4. The reducing agent 4 is sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride (NaB(OAc)H), NaBCNH, lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh)], diisobutyl aluminum hydride (DIBAL), H / Pd / C, or RhCl(PPH) / H. The reaction temperature for the selective alkene reduction reaction is −78 to 25° C.

[0076] R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0077] R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0078] R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0079] R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0080] In some embodiments, the compound represented by the following chemical formula (15) among the isopropyl-D-glucopyranoside derivatives of the present invention can be obtained by the following chemical synthesis steps.

[0081] [ka]

[0082] (A) As shown in Flow 7 below, deketalization, isomerization, and debenzoylation afford the compound of formula ( 11) is converted into a compound represented by chemical formula (15).

[0083] [ka]

[0084] The chemical formula ( 11 The compound represented by the formula (I) is first subjected to the deketalization and isomerization reactions. The deketalization and isomerization reactions are carried out using a deketalization and isomerization reaction reagent. The deketalization and isomerization reaction reagent is an aqueous acetic acid solution, an aqueous hydrochloric acid solution, an aqueous trifluoroacetic acid solution, TsOH and HO, a mixed solution of HCl in 1,4-dioxane (HCl in 1,4-dioxane), or an aqueous sulfuric acid solution. The subsequent debenzoyl-protection reaction is carried out using a debenzoyl-protection reagent. The debenzoyl-protection reagent is sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, a hydrogen chloride-methanol solution, an aqueous hydrochloric acid solution, trifluoroacetic acid (TFA) and HO, or an aqueous sulfuric acid solution.

[0085] R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0086] R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0087] R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0088] R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0089] In some embodiments, the compounds represented by the following chemical formula (16) and the compounds represented by the following chemical formula (17) among the isopropyl-D-glucopyranoside derivatives of the present invention can be obtained by the following chemical synthesis steps.

[0090] As shown in Flow 8 below, the compound represented by chemical formula (15) is converted into a compound represented by chemical formula (16) and a compound represented by chemical formula (17) by a selective reduction reaction.

[0091] [ka]

[0092] The compound represented by chemical formula (15) is subjected to the selective reduction reaction, and a compound represented by chemical formula (16) and a compound represented by chemical formula (17) are obtained using a selective reduction reaction reagent. The selective reduction reaction reagent is sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride (NaB(OAc)H), NaBCNH, lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh)], diisobutyl aluminum hydride (DIBAL), or H / Pd / C. The reaction temperature for the selective reduction reaction is −78 to 25°C.

[0093] R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0094] R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group.

[0095] R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0096] R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

[0097] In some embodiments, the isopropyl-D-glucopyranoside derivatives of the present invention have very low toxicity to Neuro2a cells. [Effects of the Invention]

[0098] The present invention further comprises: A pharmaceutical composition for use in treating nerve damage is provided, which comprises an isopropyl-D-glucopyranoside derivative.

[0099] In some examples, when isopropyl-D-glucopyranoside derivatives were used alone, they were able to promote the regeneration of injured hippocampal neurons and promote nerve regeneration in three-dimensional brain tissue slices, demonstrating that the compounds can effectively promote neuronal regeneration and can be used to repair nerve injuries.

[0100] In some embodiments, the isopropyl-D-glucopyranoside derivatives of the present invention can promote neural retinal repair.

[0101] In some embodiments, the isopropyl-D-glucopyranoside derivatives of the present invention, when administered intranasally, can cross the blood-brain barrier of the user and enter the cerebrum, thereby promoting the repair of damaged neurons.

[0102] In some embodiments, the isopropyl-D-glucopyranoside derivatives of the present invention can cross the blood-brain barrier and enter the cerebrum, thereby promoting the repair, regeneration, or increase in the number of cranial nerves.

[0103] In some embodiments, the isopropyl-D-glucopyranoside derivatives of the present invention can promote the regeneration of cortical neurons after brain trauma.

[0104] In some embodiments, the effective dose / concentration of the isopropyl-D-glucopyranoside derivative used in the present invention is 9.674 nM to 1342 μM. The pharmaceutical composition can be administered to a subject.

[0105] In some embodiments, the isopropyl-D-glucopyranoside derivatives of the present invention have significant effects on nerve repair: when administered intranasally, the compounds penetrate the blood-brain barrier and enter the cerebrum, promoting the repair of damaged neurons, promoting the repair, regeneration, or increase in the number of cranial nerves, and promoting the regeneration of axons of cortical and hippocampal neurons after brain trauma.

[0106] In some embodiments, the pharmaceutical composition is administrable to a subject.

[0107] In some embodiments, the pharmaceutical composition can be administered to a subject by injection, infusion, intravenous, nasal, or oral administration.

[0108] By referring to the following embodiments, those skilled in the art can easily understand the basic spirit and other objects of the present invention, as well as the technical means and embodiments used in the present invention. [Brief explanation of the drawings]

[0109] [Figure 1A] FIG. 1A shows the results of a cytotoxicity experiment using the isopropyl-D-glucopyranoside derivative of the present invention. [Figure 1B] FIG. 1B shows the results of a cytotoxicity experiment using the isopropyl-D-glucopyranoside derivative of the present invention. [Figure 1C] FIG. 1C shows the results of a cytotoxicity experiment using the isopropyl-D-glucopyranoside derivative of the present invention. [Figure 2] FIG. 2 is a flow chart of an in vitro nerve repair test according to the present invention. [Figure 3] FIG. 3 is a schematic diagram of the calculation of gap closure rate to quantify relative axonal regeneration in the present invention. [Figure 4A] FIG. 4A shows the results of an in vitro neuronal repair experiment on hippocampal neurons using ampelopsicionoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 4B] FIG. 4B shows the results of an in vitro neuronal repair experiment on hippocampal neurons using ampelopsicionoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 5] FIG. 5 shows the results of an in vitro neuronal repair experiment on cortical neurons using ampelopsicionoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 6] FIG. 6 shows the results of an in vitro neuronal repair experiment on hippocampal neurons using bizanthione B, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 7] FIG. 7 shows the results of an in vitro neuronal repair experiment on cortical neurons using bizanthione B, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 8] FIG. 8 shows the results of an in vitro neuronal repair experiment on hippocampal neurons using roseoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 9] FIG. 9 shows the results of an in vitro neuronal repair experiment on cortical neurons using roseoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 10] FIG. 10 is a flow chart of an ex vivo brain tissue slice experiment in the present invention. [Figure 11] FIG. 11 shows the results of an ex vivo three-dimensional brain tissue slice experiment using ampelopsicionoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 12] FIG. 12 shows the results of an ex vivo three-dimensional brain tissue slice experiment using bizanthione B, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 13] FIG. 13 shows the results of an ex vivo three-dimensional brain tissue slice experiment using roseoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 14] FIG. 14 shows a flow chart of the controlled cortical impact brain injury model experiment of the present invention and the results of an experiment on the promotion of motor recovery in rats after brain injury using ampelopsicionoside, an isopropyl-D-glucopyranoside derivative. [Figure 15] FIG. 15 shows a flow chart of the controlled cortical impact brain injury model experiment of the present invention and the results of an experiment on the promotion of recovery of environmental exploration ability in rats after brain injury (pressure measurement) using ampelopsicionoside, an isopropyl-D-glucopyranoside derivative. [Figure 16] FIG. 16 is a flow chart of an experiment on a controlled cortical impact brain injury model using ampelopsicionoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 17] FIG. 17 shows the results of a horizontal bar test in a controlled cortical impact brain injury model experiment using ampelopsicionoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 18] FIG. 18 is a flow chart showing the promotion of ex vivo retinal neural repair by bizanthione B, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 19] FIG. 19 shows the results of an ex vivo experiment on the promotion of retinal neural repair by bizanthione B, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 20] FIG. 20 is a flow chart showing the promotion of ex vivo retinal neural repair by roseoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 21] FIG. 21 shows the results of an ex vivo experiment on the promotion of retinal neural repair by roseoside, an isopropyl-D-glucopyranoside derivative of the present invention. [Figure 22] FIG. 22 is a flowchart showing the synthesis of each derivative of isopropyl-D-glucopyranoside according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0110] In order to provide a more detailed and complete description of the contents of the present disclosure, the following describes illustrative embodiments and specific examples of the present invention. However, these are not the only ways to implement or operate the specific examples of the present invention. Although the embodiments cover the features of multiple specific examples and the methods and applications for operating these specific examples, other specific examples may achieve the same or equivalent effects. It should be understood that these examples are intended to illustrate the present invention and do not limit the scope of the present invention. [Example]

[0111] Cytotoxicity experiments of isopropyl-D-glucopyranoside derivatives

[0112] The toxicity of the isopropyl-D-glucopyranoside derivatives of the present invention, Ampelopsisionoside, Byzantionoside B, and Roseoside, to Neuro2a cells was examined using the CellTiter-Glo cell viability assay. By measuring the ATP content in the cells using the CellTiter-Glo cell viability assay, cell viability after compound addition could be quantified.

[0113] As shown in Figures 1A to 1C, the experimental results clearly showed that the IC50 values ​​of ampelopsicionoside, byzantionoside B, and roseoside for Neuro2a cells ranged from approximately 4.175 mM to 32.658 mM. This indicates that the isopropyl-D-glucopyranoside derivatives have very low toxicity to the cells. [Example]

[0114] In vitro neuronal repair of hippocampal neurons by ampelopsicionoside, an isopropyl-D-glucopyranoside derivative

[0115] As shown in Figure 2, in this experimental procedure, rat fetuses were removed on day 18 of pregnancy and the fetal cerebrum was divided into the cerebral cortex and hippocampus. Next, the cerebral cortex and hippocampus were separated into cortical neurons and hippocampal neurons, and the hippocampal neurons were transferred to a 48-well plate. This day was designated Day In Vitro 0 (DIV 0). At DIV 2, cytosine arabinoside (Cβ-D-arabinoside, AraC) was added to inhibit glial cell proliferation. At DIV 8, neurons were injured using a micropipette tip and ampelopsicionoside (concentrations 9.674 nM–967.4 μM) was added. 0.1% dimethyl sulfoxide (DMSO) was used as the solvent for ampelopsicionoside. Seventy-two hours after the addition of ampelopsicionoside, the neuronal regeneration was observed using immunofluorescence staining with TUJ1 antibody. Images of the experiment were taken with a Zeiss Observer Z1 microscope.

[0116] As shown in Figure 3, the degree of axon regeneration was quantified from the gap closure rate. The white dotted line represents the boundary created when neurons were injured by rubbing with the micropipette tip, and the black area in the center represents the area scraped by the micropipette tip. Regenerated neurites grew from both sides of the dotted line toward the center. A line was drawn every 50 μm of the injury area to calculate the gap width. After drawing a total of 10 lines, the average gap length (Lg) between injured borders was calculated. After a certain period of time, a line was drawn every 50 μm of the same injury area to connect the regenerated axons and calculate their length. The average gap length (Ln) between regenerated neurons was calculated, and the gap closure rate was calculated as (Lg - Ln) / Lg. The scale is 100 μm. This experiment was photographed with a Zeiss Observer Z1 microscope.

[0117] The degree of axon regeneration was quantified from the gap closure rate, as shown in Figure 4A-B. The experimental results indicated that ampelopsicionoside could effectively promote the growth of hippocampal neurites. [Example]

[0118] Ampelopsicionoside, an isopropyl-D-glucopyranoside derivative, promotes regeneration of injured cortical neurons in vitro

[0119] In this experiment, rat fetuses were removed on day 18 of pregnancy. The fetal cerebrum was divided into the cerebral cortex and hippocampus, and then cortical and hippocampal neurons were isolated. The cortical neurons were transferred to a 48-well plate. This day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were injured using a micropipette tip and ampelopsicionoside (9.674 nM–96.74 μM) was added. 0.1% DMSO served as the solvent control. Results are normalized to the DMSO group. Seventy-two hours after ampelopsicionoside addition, neurons were labeled with TUJ1 antibody using immunofluorescence staining to observe the status of neuronal regeneration. Images were taken with a Zeiss Observer Z1 microscope. The scale is 100 μm.

[0120] The degree of axon regeneration was quantified by calculating the gap closure rate relative to 0.1% DMSO, as shown in Figure 5. The area between the two dotted lines in the immunofluorescence image represents the damaged area. These experimental results indicated that ampelopsicionoside could effectively promote the growth of cortical neurites. [Example]

[0121] In vitro neuronal repair of hippocampal neurons by isopropyl-D-glucopyranoside derivative, bisantianoside B

[0122] In this experiment, rat fetuses were removed on day 18 of pregnancy. The fetal cerebrum was divided into the cerebral cortex and hippocampus, and then the cortical and hippocampal neurons were separated. The hippocampal neurons were transferred to a 48-well plate. This day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were injured using a micropipette tip, and bisantigen B (0.13 μM–1342 μM) was added. ddH2O was used as the solvent control. Results shown in the figures are normalized to the ddH2O control. Seventy-two hours after the addition of bisantigen B, neurons were labeled with TUJ1 antibody using immunofluorescence staining to observe the status of neuronal regeneration. Images were taken with a Zeiss Observer Z1 microscope. The scale is 100 μm.

[0123] As shown in Figure 6, the gap closure rate relative to ddH2O was calculated to quantify the degree of axon regeneration. The area between the two dotted lines in the immunofluorescence images represents the damaged area. The dotted line in the lower panel represents the ddH2O group. These experimental results demonstrated that bizanthione B can effectively promote the growth of hippocampal neurites. [Example]

[0124] Neuronal repair in cortical neurons in vitro using isopropyl-D-glucopyranoside derivative, bisantianoside B

[0125] In this experiment, rat fetuses were removed on day 18 of pregnancy and the fetal cerebrum was divided into the cerebral cortex and hippocampus. The cerebral cortex and hippocampus were then dissociated into cortical neurons and hippocampal neurons, and the cortical neurons were transferred to a 48-well plate. This day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were injured with a micropipette tip and bisthionoside B (1.34 μM–26.84 μM) was added. Bisthionoside B was used as a solvent in double-distilled water (ddH2O). Seventy-two hours after the addition of bisthionoside B, neurons were labeled with TUJ1 antibody using immunofluorescence staining to observe the status of neural regeneration. This experiment was photographed with a Zeiss Observer Z1 microscope. The area between the two dotted lines represents the damaged area.

[0126] The degree of axon regeneration was quantified from the gap closure rate, as shown in Figure 7. The experimental results indicated that bizanthione B could effectively promote the growth of cortical neurites. [Example]

[0127] In vitro neuronal repair of hippocampal neurons using roseoside, an isopropyl-D-glucopyranoside derivative

[0128] In this experiment, rat fetuses were removed on day 18 of pregnancy. The fetal cerebrum was divided into the cerebral cortex and hippocampus, and then cortical and hippocampal neurons were isolated. The hippocampal neurons were transferred to a 48-well plate. This day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were injured using a micropipette tip, and roseoside (0.013 μM to 1294 μM) was added. ddH2O was used as the solvent control. Results shown in the figures are normalized to the ddH2O control. 72 hours after roseoside addition, neurons were labeled with TUJ1 antibody using immunofluorescence staining to observe the status of neuronal regeneration. Images were taken with a Zeiss Observer Z1 microscope. The scale is 100 μm.

[0129] As shown in Figure 8, the gap closure rate relative to ddH2O was calculated to quantify the degree of axon regeneration. The area between the two dotted lines in the immunofluorescence images represents the damaged area. The dotted line in the lower panel represents the ddH2O group. These experimental results demonstrated that roseoside can effectively promote the growth of hippocampal neurites. [Example]

[0130] In vitro neuronal repair studies of cortical neurons using roseoside, an isopropyl-D-glucopyranoside derivative

[0131] In this experiment, rat fetuses were removed on day 18 of pregnancy. The fetal cerebrum was divided into the cerebral cortex and hippocampus, and then the cortical and hippocampal neurons were separated. The cortical neurons were transferred to a 48-well plate. This day was designated Day In Vitro 0 (DIV0). At DIV2, cytosine arabinoside (AraC) was added to inhibit glial cell proliferation. At DIV8, neurons were injured using a micropipette tip, and roseoside (1.29 μM–25.88 μM) was added. ddH2O was used as the roseoside solvent. 72 hours after roseoside addition, neurons were labeled with the TUJ1 antibody using immunofluorescence staining to observe the status of neuronal regeneration. This experiment was photographed using a Zeiss Observer Z1 microscope.

[0132] The degree of axon regeneration was quantified from the gap closure rate, as shown in Figure 9. The experimental results indicated that roseoside can effectively promote cortical axon regeneration. [Example]

[0133] Ex vivo 3D brain tissue slice experiments with ampelopsicionoside, an isopropyl-D-glucopyranoside derivative

[0134] As shown in Figure 10, the experimental flow was as follows: first, fetal rat brains were removed, embedded in low-melting-point agarose gel, and sliced ​​into 350 μm-thick tissue sections using a Leica microtome VT100. The brain sections were then incised with a scalpel and cultured, with daily addition of ddH2O or ampelopsicionoside. After 96 hours of culture, neurons were labeled with TUJ1 antibody, glial cells with GFAP antibody, and cell nuclei with DAPI reagent using immunofluorescence staining. The scale of this experiment was 100 μm. Images were taken using a Zeiss LSM800 confocal microscope.

[0135] As shown in Figure 11, the white dotted line indicates the incision made with a scalpel, and the area to the right of the dotted line is the newly generated axon. This experiment demonstrated that ampelopsicionoside has the effect of promoting nerve regeneration. [Example]

[0136] Ex vivo brain tissue slice experiments with isopropyl-D-glucopyranoside derivative, bisantianoside B

[0137] As shown in Figure 10, the experimental flow was as follows: first, fetal rat brains were removed, embedded in low-melting-point agarose gel, and sliced ​​into 350 μm-thick tissue sections using a Leica VT100 microtome. The brain sections were then incised with a scalpel and cultured, with daily addition of ddH2O or bisantigen B. After 96 hours of culture, the neurons were labeled with TUJ1 antibody, glial cells with GFAP antibody, and cell nuclei with DAPI reagent using immunofluorescence staining. The scale for this experiment was 100 μm. Images were taken using a Zeiss LSM800 confocal microscope.

[0138] As shown in Figure 12, the white dotted line indicates the incision made with a scalpel, and the newly generated neurites are to the right of the dotted line. This experiment demonstrated that byzantionoside B has the effect of promoting nerve regeneration. [Example]

[0139] Ex vivo brain tissue slice experiments with roseoside, an isopropyl-D-glucopyranoside derivative

[0140] As shown in Figure 10, the experimental flow was as follows: first, fetal rat brains were removed, embedded in low-melting-point agarose gel, and sliced ​​into 350 μm-thick tissue sections using a Leica VT100 microtome. The brain sections were then incised with a scalpel and cultured, with daily addition of ddH2O or roseoside. After 96 hours of culture, neurons were labeled with TUJ1 antibody, glial cells with GFAP antibody, and cell nuclei with DAPI reagent using immunofluorescence staining. The scale for this experiment was 100 μm. Images were taken using a Zeiss LSM800 confocal microscope.

[0141] As shown in Figure 13, the white dotted line indicates the incision made with a scalpel, and the newly generated neurites are to the right of the dotted line. This experiment demonstrated that roseoside has the effect of promoting nerve regeneration. [Example]

[0142] Ampelopsicionoside, an isopropyl-D-glucopyranoside derivative, enhances motor recovery after brain trauma in rats

[0143] In this experiment, mice underwent craniotomy without brain injury, brain injury, and daily administration of 14 μg / kg ampelopsicionoside after brain injury. The open field test was used to measure motor performance at 1 day post-injury (1 dpi) and 5 days post-injury (5 dpi). The experimental model used in this experiment is shown in Figure 14. At 0 dpi, mice were brain-injured using a controlled cortical impact brain injury model, and at 0, 2, 4, 6, 8, 10, and 12 dpi (days post-injury), 14 μg / kg ampelopsicionoside was administered intranasally.

[0144] As shown in Figure 14, part A shows the test in which a mouse was placed in a large white acrylic box divided into four equal parts and allowed to move freely for 5 minutes. The mouse's movement was recorded for 5 minutes using a Microsoft LifeCam Cinema camera and analyzed using Anubis track software.

[0145] As shown in Figure 14, part B shows that the path lengths of the ampelopsicionoside group and the uninjured group were almost the same, while the untreated brain-injured group had only half the path length. This demonstrates that ampelopsicionoside, an isopropyl-D-glucopyranoside derivative of the present invention, has the effect of promoting the recovery of motor ability in rats after brain trauma. [Example]

[0146] Ampelopsicionoside, an isopropyl-D-glucopyranoside derivative, promotes recovery of exploratory ability after brain trauma in rats

[0147] In this experiment, mice were subjected to craniotomy without brain injury, brain injury, and administration of 14 μg / kg of ampelopsicionoside after brain injury. Five days after injury (5 dpi), their exploration ability in the area and the time spent in the central open area were measured using an open field test. The experimental model for this experiment is shown in Figure 1. 15 At 0 dpi, mice were brain injured using a controlled cortical impact brain injury model, and 14 μg / kg of ampelopsicionoside was administered intranasally at 0, 2, 4, 6, 8, 10, and 12 dpi (days post injury).

[0148] As shown in Figure 15, part A shows the test in which a mouse was placed in a large white acrylic box divided into four equal parts and allowed to move freely for 5 minutes. The mouse's movement was recorded for 5 minutes using a Microsoft LifeCam Cinema camera and analyzed using Anubis track software.

[0149] As shown in Figure 15, part B shows that the ampelopsicionoside group and the uninjured group spent more time in the central region, while the uninjured group barely moved to the center. The combined results of Figure 15 demonstrate that ampelopsicionoside, an isopropyl-D-glucopyranoside derivative of the present invention, can promote the recovery of exploratory ability in rats after brain trauma. [Example]

[0150] Ampelopsicionoside, an isopropyl-D-glucopyranoside derivative, promotes recovery of motor coordination after brain trauma in rats

[0151] In the horizontal bar experiment, mice were placed on a 38 cm long brass bar, 2 mm, 4 mm, or 6 mm in diameter, located 49 cm above the ground, and asked to grasp the bar with their forepaws. The time the mouse spent on the bar was calculated, and the mouse's motor coordination ability was evaluated based on whether or not it reached the platform at the end of the bar. The evaluation criteria were as follows: 1 point for 1-5 seconds, 2 points for 5-10 seconds, 3 points for 10-20 seconds, 4 points for 20-30 seconds, and 5 points for 30 seconds or more or reaching the platform.

[0152] As shown in Figure 16, pre-training was performed on days -5, -3, and -1 dpi (days post-injury) (5, 3, and 1 days before brain injury). At 0 dpi, mice were brain-injured using a controlled cortical impact model. Ampelopsicionoside was administered intranasally at 14 μg / kg or 140 μg / kg at 0, 2, 4, 6, 8, 10, and 12 dpi. A horizontal bar test was also performed at 1, 3, 6, 10, and 13 dpi.

[0153] As shown in Figure 17, the group that received only water (ddH2O) after brain injury showed a loss of motor coordination, but the group that received ampelopsicionoside showed motor coordination similar to that of the sham group, demonstrating that recovery of motor coordination was clearly promoted. [Example]

[0154] Bizanthionoside B, an isopropyl-D-glucopyranoside derivative, promotes ex vivo retinal neural repair

[0155] The experimental design and flow are shown in Figure 18. Retinal explants were isolated from 8-day-old C57BL / 6 mice. After sacrifice, the eyes were removed, and the retina was separated from the globe using tweezers and microscissors, and the vitreous was removed. Finally, the isolated retina was divided into four pieces, and the tissue edges were trimmed and scratched using microscissors. Each piece was cultured on an 18-mm circular glass plate and then placed in a 12-well plate. The plate was then placed in an incubator at 5% CO2 and 35°C for 5 days. Fresh culture medium was replaced daily, and 13.5 μM or 135 μM bisantithionoside B was added to each retinal tissue. After 5 days of culture, the retinal tissue was fixed in a mixture of 0.1% glutaraldehyde and 4% paraformaldehyde for 1 hour at room temperature. The sections were then stained with the primary antibody axonal marker beta-III-tubulin (TUJ1) and DAPI to label neurons and cell nuclei, and then photographed using a super-resolution upright confocal microscope (LSM-800, Carl Zeiss). The tissue boundary was selected and the perimeter and extracellular nerve fiber area were calculated using the image analysis program ImageJ. The nerve fiber area was then divided by the perimeter of the tissue boundary to calculate the nerve fiber length per perimeter.

[0156] As shown in FIG. 19, the group to which bizanthione B was administered after retinal tissue injury had a clear post-injury recovery effect compared to the group to which only water (ddH2O) was administered. [Example]

[0157] Roseoside, an isopropyl-D-glucopyranoside derivative, promotes ex vivo retinal neural repair

[0158] The experimental design and flow are shown in Figure 20. Retinal explants were isolated from 8-day-old C57BL / 6 mice. After sacrifice, the eyes were removed, and the retina was separated from the eyeball using tweezers and microscissors, and the vitreous was removed. Finally, the isolated retina was divided into four pieces, and the tissue edges were trimmed and scratched using microscissors. Each piece was cultured on an 18-mm circular glass plate and then placed in a 12-well plate. The plate was then placed in an incubator at 5% CO2 and 35°C for 5 days. Fresh culture medium was replaced daily, and 13 μM or 130 μM roseoside was added to each retinal tissue. After 5 days of culture, the retinal tissue was fixed in a 0.1% glutaraldehyde and 4% paraformaldehyde solution at room temperature for 1 hour. The sections were then stained with the primary antibody axonal marker beta-III-tubulin (TUJ1) and DAPI to label neurons and cell nuclei, and then photographed using a super-resolution upright confocal microscope (LSM-800, Carl Zeiss). The tissue boundary was selected and the perimeter and extracellular nerve fiber area were calculated using the image analysis program ImageJ. The nerve fiber area was then divided by the perimeter of the tissue boundary to calculate the nerve fiber length per perimeter.

[0159] As shown in FIG. 21, after retinal tissue injury, the group administered with roseoside had a clear post-injury recovery effect compared to the group administered with water (ddH2O) alone. [Example]

[0160] Sequential synthesis of isopropyl-D-glucopyranoside derivatives

[0161] The sequential steps for synthesizing the isopropyl-D-glucopyranoside derivative in the present invention were as follows:

[0162] [ka]

[0163] The above experimental data are preliminary experimental results obtained under specific conditions, and are only intended to facilitate understanding or reference of the technical content of the present invention, and further related experiments need to be conducted. The experimental data and results are not intended to limit the scope of the present invention.

[0164] The above preferred embodiments are merely illustrative of the present invention and its technical features, and the technology of the embodiments may be implemented by appropriately making various substantially equivalent modifications and / or substitutions. Therefore, the scope of the present invention is limited to the scope defined in the claims.

Claims

1. The chemical structural formula is as shown in chemical formula (1), 【Chemistry 1】 R1 is a substituted or unsubstituted structure of chemical formula (2) or chemical formula (3), 【Chemistry 2】 R2 and R3 are substituted or unsubstituted structures of chemical formula (4) or chemical formula (5), 【Transformation 3】 R4 is hydrogen, deuterium, tritium, a hydroxy group, or a halogen; R5 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen; R6 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen; R7 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen; R1" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; An isopropyl-D-glucopyranoside derivative, wherein R4" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

2. When R1 is represented by chemical formula (2), 【Chemistry 4】 R2 is a substituted or unsubstituted structure of chemical formula (4) or chemical formula (5), 【Transformation 5】 R4 is hydrogen, deuterium, tritium, a hydroxyl group, or a halogen; R5 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen; R6 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen; R7 is hydrogen, deuterium, tritium, a hydroxyl group, or a halogen; R1" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; The isopropyl-D-glucopyranoside derivative according to claim 1, wherein R4″ is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

3. When R1 is represented by chemical formula (3), 【Transformation 6】 R3 is a substituted or unsubstituted structure of chemical formula (4) or chemical formula (5), 【Transformation 7】 R4 is hydrogen, deuterium, tritium, a hydroxyl group, or a halogen; R5 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen; R6 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen; R7 is hydrogen, deuterium, tritium, a hydroxyl group, or a halogen; R1" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3" is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; The isopropyl-D-glucopyranoside derivative according to claim 1, wherein R4″ is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium.

4. The derivatives include compounds of the formula: 【Transformation 8】 【Chemistry 9】 R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R5 is hydrogen, deuterium, tritium, a hydroxy group, a carbonyl group, or a halogen; 2. The isopropyl-D-glucopyranoside derivative according to claim 1, wherein R6 is hydrogen, deuterium, tritium, a hydroxyl group, or a halogen.

5. A method for producing an isopropyl-D-glucopyranoside derivative, a compound represented by chemical formula (6), 【Chemistry 10】 (A) converting a compound represented by chemical formula (7) into a compound represented by chemical formula (8) by a bis-alkylation reaction, an acylation reaction, and an alkyne nucleophilic addition reaction; 【Chemistry 11】 R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; the bis-alkylation reaction is carried out with an electrophile 1; the electrophile 1 is methyl iodide, ethyl iodide, propyl iodide, MeOTf, EtOTf, PrOTf, propyl bromide / iodide the reagent for the acylation reaction includes formaldehyde, acetaldehyde, or propionaldehyde, and this intermediate is further subjected to an alkyne nucleophilic addition reaction to obtain compound (8), the reagent for the alkyne nucleophilic addition includes an alkyne having a functional group R4 and a base, and this base includes n-butyllithium (nBuLi), lithium diisopropylamide (LDA), or lithium bis(trimethylsilyl)amide (LHMDS), and the functional group R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; (B) converting the compound represented by chemical formula (8) to a compound represented by chemical formula (9) by an olefination reaction, a reduction reaction, and a deprotection reaction; 【Chemistry 12】 In the olefination reaction, the compound represented by the chemical formula (8) is first reacted with an electrophile 2 and an amine-based reagent under low-temperature conditions to produce a compound represented by the chemical formula (9). The electrophile 2 is selected from mesyl chloride, tosyl chloride, acetic anhydride, benzoic anhydride, methyl iodide, and dimethyl sulfate, and the amine-based reagent is selected from triethylamine, diethylamine, pyridine, pyrrolidine, diisopropyl ethylamine, and the like. The low temperature condition is −30 to 25° C., and then, after completion, a second base is added to complete the olefination, and the second base is potassium tert-butoxide, sodium hydroxide, sodium methoxide, or 1,8-diazabicyclo[5,4,0]undec-7-ene. Then, after completion, a reduction reaction is carried out, and in the reduction reaction, a reducing agent 1 is used as a reducing agent, and the reducing agent 1 is lithium aluminum hydride, diisobutyl aluminum hydride, or the like. hydride (DIBAL)), sodium borohydride, sodium triacetoxyborohydride (NaB(OAc) ３ H), lithium triethylborohydride, or sodium bis(2-methoxyethoxy)aluminumhydride, the reaction temperature of the reduction reaction is −50 to 25° C., and subsequently, after completion, a deprotection step is performed, in which a deprotection reaction is performed using a deprotection reagent 1 to obtain a compound represented by chemical formula (9), the deprotection reagent 1 being tetrabutylammonium fluoride (TBAF), anhydrous hydrofluoric acid-pyridine (HF-py), hydrochloric acid, or potassium tert-butoxide, the reaction temperature of the deprotection reaction is −35 to 25° C., (C) coupling the compound represented by formula (9) to the compound represented by formula (10) via a glycosylation reaction to form a compound represented by formula (11); 【Chemistry 13】 The compound represented by chemical formula (9) is subjected to the glycosylation reaction using glycosylation reagent 1 to obtain a compound represented by chemical formula (11), wherein the glycosylation reagent 1 is nickel sulfide / silver trifluoromethanesulfonate (NIS / AgOTf), bromosulfophthalein / tri-tert-butylphenol / trifluoromethanesulfonic anhydride (BSP / TTBP / Tf 2 O), trimethylsilyl trifluoromethanesulfonate / nickel sulfide (TMSOTf / NIS), trimethylsilyl trifluoromethanesulfonate (TMSOTf), silver trifluoromethanesulfonate (AgOTf), or CuOTf, and the glycosylation reaction is carried out at a temperature of −78 to 0° C. (D) converting the compound represented by the chemical formula (11) into a compound represented by the chemical formula (6) by deketalization, isomerization, debenzoylation, and 1,4-reduction; The compound represented by chemical formula (11) is first subjected to deketalization and isomerization reactions. The deketalization and isomerization reactions are carried out using Reagent 1, which is a mixture of an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, an aqueous solution of trifluoroacetic acid, TsOH and H ２ The debenzoylation is carried out using a debenzoylation reagent, which may be sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, hydrogen chloride-methanol solution, aqueous hydrochloric acid, trifluoroacetic acid (TFA) and H ２ 0 or sulfuric acid aqueous solution, followed by 1,4-reduction reaction to obtain the target compound of chemical formula (6), the 1,4-reduction reaction is carried out with a 1,4-reduction reaction reagent, the 1,4-reduction reaction reagent being sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride (NaB(OAc) ３ H), NaBCNH ３ , L-selectride (lithium tri-sec-butylborohydride), [CuH(PPh ３ )] ６ , diisobutyl aluminum hydride (DIBAL) or H ２ / Pd / C, and the reaction temperature of the 1,4-reduction reaction is −78 to 25° C.; R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; A method for producing the compound according to claim 1, comprising the step of synthesizing

6. After the step (B), 【Chemistry 14】 (B1) converting the compound represented by the chemical formula (11) into a compound represented by the chemical formula (15) by deketalization, isomerization, and debenzoyl-protection reactions; 【Chemistry 15】 The compound represented by the chemical formula (11) is first subjected to a deketalization and isomerization reaction, and the deketalization and isomerization reactions are carried out using a deketalization and isomerization reaction reagent, and the deketalization and isomerization reaction reagent is an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, an aqueous solution of trifluoroacetic acid, TsOH and H ２ The debenzoylation reaction is carried out using a debenzoylation reagent, which may be sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, hydrogen chloride-methanol solution, aqueous hydrochloric acid, trifluoroacetic acid (TFA) and H ２ O, or an aqueous solution of sulfuric acid; R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; The method for producing the isopropyl-D-glucopyranoside derivative, a compound represented by chemical formula (6), according to claim 5, which may comprise a synthesis step of:

7. After the manufacturing method, 【Chemistry 16】 (B2) converting the compound represented by chemical formula (15) into a compound represented by chemical formula (16) and a compound represented by chemical formula (17) by a selective reduction reaction; 【Chemistry 17】 The compound represented by the chemical formula (15) is selectively reduced using a selective reduction reagent to obtain a compound represented by the chemical formula (16) and a compound represented by the chemical formula (17). The selective reduction reagent is sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride (NaB(OAc) ３ H), NaBCNH ３ , lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh ３ )] ６ , diisobutyl aluminum hydride (DIBAL) or H ２ / Pd / C, and the reaction temperature of the selective reduction reaction is −78 to 25° C.; R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; 7. A method for producing an isopropyl-D-glucopyranoside derivative, which is a compound represented by chemical formula (6) according to claim 6, comprising the step of:

8. A method for producing an isopropyl-D-glucopyranoside derivative, which is a compound represented by chemical formula (12), comprising the steps of: [Chemistry 18] (A) converting a compound represented by chemical formula (11) into a compound represented by chemical formula (12) by a conversion reaction; 【Chemistry 19】 The conversion reaction includes deprotection of the acetal, isomerization, stereoselective deoxidation, and deprotection of the benzoyl group. The deprotection of the acetal and the isomerization are carried out using an acidic reagent, such as an aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, or trifluoroacetic acid (TFA) and H ２ O, TsOH and H ２ The reaction mixture is a mixed solution of 1,4-dioxane, HCl, and 1,4-dioxane (HCl in 1,4-dioxane) or an aqueous sulfuric acid solution. Then, a stereoselective deoxidation reaction is carried out using a reducing agent 2 under a first low-temperature condition. The reducing agent 2 is NaBH ４ , LiAlH ４ , sodium triacetoxyborohydride (NaB(OAc) ３ H), NaBCNH ３ , Et ３ SiH / BF ３ -Et ２ O, lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh ３ )] ６ or diisobutylaluminum hydride (DIBAL), the amount of the reducing agent 2 is 0.5, 1.0, 2.0, 3.0, 4.0 or 5.0 equivalents, the temperature of the first low-temperature condition in the stereoselective deoxidation step is −78 to 25° C., and subsequently, the benzoyl group of the intermediate is removed with a deprotecting reagent 2 to produce a compound represented by chemical formula (11), the deprotecting reagent 2 being NaOH, NaOMe, NaOEt, KOH, KOMe, KOEt, hydrogen chloride-methanol solution, aqueous HCl solution, trifluoroacetic acid (TFA) and H ２ O or H ２ SO ４ It is an aqueous solution, R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; A method for producing the compound according to claim 1, comprising the step of synthesizing

9. Furthermore, 【Chemistry 20】 (B) converting the compound represented by chemical formula (12) into a compound represented by chemical formula (13) by a conversion reaction; 【Chemistry 21】 The conversion reaction includes a regioselective and stereoselective 1,4-reduction / carbonyl reduction step, and the regioselective and stereoselective 1,4-reduction / carbonyl reduction step is carried out under a second low-temperature condition using a reducing agent 3, and the reducing agent 3 is NaBH ４ , LiAlH ４ , sodium triacetoxyborohydride (NaB(OAc) ３ H), NaBCNH ３ , lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh ３ )] ６ , DIBAL or H ２ / 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, and the temperature of the second low-temperature conditions in the regioselective and stereoselective 1,4-reduction / carbonyl reduction step is −78 to 25° C.; R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; The method for producing the isopropyl-D-glucopyranoside derivative represented by the chemical formula (12) according to claim 8, characterized in that it comprises a synthesis step of:

10. Furthermore, 【Chemistry 22】 (A) converting a compound represented by formula (12) to a compound represented by formula (14) by selective alkene reduction; 【Chemistry 23】 The selective alkene reduction reaction is carried out using a reducing agent 4, which is selected from the group consisting of sodium borohydride, lithium aluminum hydride, and sodium triacetoxyborohydride (NaB(OAc)). ３ H), NaBCNH ３ , lithium tri-sec-butylborohydride (L-selectride), [CuH(PPh ３ )] ６ , diisobutyl aluminum hydride (DIBAL), H ２ / Pd / C or RhCl(PPH ３ ) ３ / H ２ the reaction temperature of the selective alkene reduction reaction is −78 to 25° C.; R1 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R2 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, tritium, or a hydroxy group; R3 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; R4 is a methyl group, an ethyl group, a propyl group, hydrogen, deuterium, or tritium; A method for producing an isopropyl-D-glucopyranoside derivative, which is a compound represented by chemical formula (12) according to claim 8, comprising the synthesis step of:

11. A pharmaceutical composition for use in treating nerve damage, comprising: A pharmaceutical composition comprising the isopropyl-D-glucopyranoside derivative of claim 1.

12. The pharmaceutical composition for use in treating nerve damage according to claim 11, characterized in that the nerve damage is damage to the central nervous system or peripheral nerves.

13. The pharmaceutical composition for use in treating nerve damage according to claim 11, characterized in that the nerve damage is neuronal damage.

14. The pharmaceutical composition for treating nerve damage according to claim 11, wherein the nerve damage is damage to cortical neurons or hippocampal neurons.

15. The pharmaceutical composition for use in treating nerve damage according to claim 11, characterized in that the treatment is nerve regeneration, nerve number increase, or nerve repair.

16. The pharmaceutical composition for treating nerve damage according to claim 11, wherein the isopropyl-D-glucopyranoside derivative penetrates the blood-brain barrier and enters the cerebrum.

17. The pharmaceutical composition for treating nerve injury according to claim 11, wherein the effective dose of the isopropyl-D-glucopyranoside derivative is 9.674 nM to 1342 μM.

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