KR-102964994-B1 - Novel Baicalein carbamate derivatives and pharmaceutical composition for prevention or treatment of allergic diseases including asthma or atopic dermatitis comprising the same

Abstract

The present invention relates to novel baicalein carbamate derivative compounds. Since the baicalein carbamate derivative compounds according to the present invention exhibit excellent physicochemical properties, metabolic stability, biotransformation, and pharmacokinetic properties as baicalein prodrugs, it is expected that allergic diseases such as asthma or atopy can be fundamentally prevented or treated by using a pharmaceutical composition containing such compounds.

Inventors

• 변영주
• 이기호
• 전영호
• 손상현

Assignees

• 고려대학교 세종산학협력단

Dates

Publication Date

20260513

Application Date

20210901

Claims (7)

1. Baicalein carbamate derivative represented by the following [Chemical Formula 1]: [Chemical Formula 1] In the above [Chemical Formula 1], R is , , , , , and It is one of the selected ones.
2. In claim 1, the baicalein carbamate derivative represented by [Chemical Formula 1] is a baicalein carbamate derivative that is a baicalein prodrug.
3. delete
4. A pharmaceutical composition for the prevention or treatment of allergic diseases comprising, as an active ingredient, a bicalein carbamate derivative represented by [Chemical Formula 1] according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.
5. In claim 4, the baicalein carbamate derivative represented by [Chemical Formula 1] is a baicalein prodrug, a pharmaceutical composition for the prevention or treatment of allergic diseases.
6. delete
7. A pharmaceutical composition for the prevention or treatment of an allergic disease according to claim 4, characterized in that the allergic disease is selected from the group consisting of asthma, atopic dermatitis, urticarial rhinitis, and allergic rhinitis.

Description

Novel Baicalein carbamate derivatives and pharmaceutical composition for prevention or treatment of allergic diseases including asthma or atopic dermatitis comprising the same as an active ingredient The present invention relates to a novel baicalein carbamate derivative, and more specifically, to a baicalein carbamate derivative compound that exhibits efficacy in the prevention or treatment of allergic diseases such as asthma or atopic dermatitis, and to a pharmaceutical composition for the prevention and treatment of allergic diseases such as asthma or atopic dermatitis containing the same as an active ingredient. Baicalein is a flavonoid compound and a major component of * Scutellaria baicalensis *. This substance possesses various pharmacological effects, including antioxidant, angiogenesis inhibition, antiplatelet aggregation, antithrombotic, and free radical scavenging properties. Additionally, baicalein can be used as a drug to treat asthma and atopic dermatitis by inhibiting the TSLP/TSLP receptor (TSLPR) signaling pathway. However, in vivo studies have reported that the systemic bioavailability of baicalein is very low upon oral and intravenous administration. Baicalein undergoes rapid Phase II metabolism primarily in the liver and is metabolized in vivo into baicalin and baicalein-6-O-glucuronide by UDP-glucuronosyltransferase. Both substances are also key components of Scutellaria root that exhibit anti-inflammatory and anti-tumor activities. Baicalin is metabolized in vivo into baicalein by β-glucuronidase. Meanwhile, chemical modification strategies for prodrugs aim to optimize pharmacokinetic (PK) properties. This involves optimizing PK characteristics by controlling physicochemical properties, including solubility, biochemical metabolism, and toxicity. Prodrugs are initially inactive compounds that do not possess pharmacological effects, but they are converted into active compounds through chemical reactions or enzymes. While prodrugs are generally stable in the gastrointestinal tract, they can undergo biotransformation in the liver and blood. Biotransformation primarily occurs via CYP450 in the liver and esterases in the blood. Recently, an amino acid carbamate functional group has been reported as a resveratrol prodrug. Resveratrol, like many other polyphenolic natural products such as baicalein, is known to be rapidly metabolized by phase II biotransformation reactions, exhibiting a wide first-pass effect and low oral absorption rate. Figure 1 is the result of confirming the metabolic stability in mouse plasma of a baicalein carbamate derivative synthesized according to one embodiment of the present invention. Figure 2 is the result of confirming the metabolic stability of a baicalein carbamate derivative synthesized according to one embodiment of the present invention in the mouse liver S9 fraction. The present invention will be described in more detail below through examples. These examples are intended solely to explain the invention more specifically, and it will be obvious to those skilled in the art that the scope of the invention is not limited by these examples according to the gist of the invention. Synthesis Example. Synthesis of a baicalein carbamate derivative according to the present invention. According to the synthesis process flowchart [1] of the compounds described above, derivatives of [Chemical Formula 2] to [Chemical Formula 8] according to the present invention were synthesized by the following method. All chemicals and solvents used in the reaction were purchased from Sigma-Aldrich, TCI, and Acros and used without further purification. Baicalein, trifluoroacetic acid (TFA), glipizide, 7-EC, enalapril maleate, formic acid, MeOH, 1-octanol, UDPGA, NADPH, PAPS, GSH, hydroxypropyl-β-cyclodextrin (HPβCD), MgCl₂ , and alamethicin were purchased from Sigma-Aldrich. Tris-hydrochloride (Tris-HCl) was purchased from Roche Diagnostics GmbH. HPLC-grade water and acetonitrile were purchased from Avantor Performance Materials. Pooled mouse liver S9 fractions were purchased from BD Biosciences. The reaction was monitored by TLC on silica gel plates (60 F 254 ) pre-coated with 0.25 mm Merck. Reaction progress was monitored by TLC analysis using a UV lamp and/or KMnO 4 staining for detection purposes. Column chromatography was performed on silica gel (230-400 mesh, Merck, Germany). 1H and 13C NMR spectra were recorded in CDCl 3 ( 7.26/77.16 ppm) or DMSO-d 6 (2.50/39.50 ppm) using a Bruker Ultrashield 600 MHz Plus spectrometer at room temperature (298 K) and referenced the internal solvent. Chemical shifts were recorded in parts per million (ppm). Coupling constants (J) were provided in Hertz. Splitting patterns for the 1H NMR data were denoted as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. High-resolution mass spectra (HRMS) were recorded on an Agilent 6530 Accurate Mass Q-TOF LC/MS spectrometer. Low-resolution mass spectra (LRMS) analysis was ob