Application of compound in preparation of medicine for preventing and / or treating skin light injury

Abstract

The invention discloses application of a compound in preparation of a medicine for preventing and / or treating skin light injury, and belongs to the field of biological medicine. It is found for the first time that the compound shown in the formula I can be used for local treatment of acute skin light injury and has wide application prospects in preparation of drugs for preventing and / or treating acute skin light injury. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to the use of a compound in preparing a drug for preventing and / or treating skin photodamage. Background Art

[0002] Ultraviolet (UV) radiation is one of the main factors causing skin damage. Studies have shown that excessive UV stimulation can cause a series of damage reactions including tanning, cell DNA damage and photocarcinogenesis. In recent years, visible light (400-700nm) and ozone have also been found to cause skin damage. Chromophores in the skin absorb UV radiation and produce harmful reactive oxygen species, which attack cellular components such as cell membranes, proteins, lipids and DNA. In addition, skin damage caused by environmental exposure is mainly caused by the production of reactive oxygen species, which cause oxidative damage to cellular components such as proteins, lipids and nucleic acids, and then trigger a complex series of reactions inside the skin.

[0003] Skin photodamage includes two types: acute skin photodamage and chronic skin photodamage. Acute skin photodamage mainly refers to the damage to the skin caused by a large amount of ultraviolet rays irradiating the skin in a short period of time. This damage is usually caused by a one-time, strong light exposure, such as long-term exposure to ultraviolet light or electric welding. Chronic skin photodamage refers to the damage caused by long-term exposure to ultraviolet rays to the skin, such as photoaging and photocancer. Photodamage skin diseases include photoaging, photosensitive skin diseases, photoinduced skin tumors, etc. Treatment methods include local treatment, systemic treatment and photoprotection.

[0004] Research on skin photodamage has made certain progress in many fields, but there are still many shortcomings and challenges, and more effective prevention and treatment methods need to be developed. Summary of the invention

[0005] To solve the above problems, the present invention aims to provide a compound for use in preparing a drug for preventing and / or treating skin photodamage.

[0006] The present invention also provides the use of the compound represented by Formula I, its pharmaceutically acceptable salt or its stereoisomer in the preparation of a pharmaceutical preparation for preventing and / or treating skin photodamage;

[0007]

[0008] Wherein, R1 is selected from C 1-4 Alkyl; R2 is selected from C 1-4 Alkyl; p is selected from 1, 2 or 3; q is selected from 1, 2 or 3.

[0009] Furthermore, the structure of the compound is:

[0010]

[0011] Furthermore, the skin photodamage is acute skin photodamage.

[0012] Furthermore, the acute skin photodamage is acute skin photodamage caused by ultraviolet radiation.

[0013] Furthermore, the drug is a drug for improving skin erythema, edema and erosion, and / or the drug is a drug for reducing skin thickness.

[0014] Furthermore, the pharmaceutical preparation is a preparation prepared with the compound, its pharmaceutically acceptable salt or its stereoisomer as an active ingredient and pharmaceutically acceptable excipients.

[0015] Furthermore, the pharmaceutical preparation is an external preparation.

[0016] Furthermore, the external preparation is a cream, a liquid preparation or a gel.

[0017] Furthermore, in the liquid preparation, the concentration of the active ingredient is 2.5-10 μM, preferably 5 μM.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The present invention discovers for the first time that compound SZ-15 can be used for local treatment of acute skin photodamage and has broad application prospects in the preparation of drugs for preventing and / or treating skin photodamage.

[0020] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0021] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 These are the skin photographs, HE staining and Masson staining results of mice with acute skin photodamage model in the blank control group, modeling group, GSK-2982772 group and SZ-15 treatment group.

[0023] Figure 2 Comparison of skin thickness in mice with acute skin photodamage model among blank control group, modeling group, GSK-2982772 group and SZ-15 treatment group. DETAILED DESCRIPTION

[0024] The reagents and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0025] SZ-15 is a known compound with the structure It can be prepared according to the method described in paragraph 0423 of the patent application specification with publication number CN 114989156A.

[0026] Example 1 Inhibitory effect of SZ-15 on HaCaT cell death

[0027] 1. Experimental Methods

[0028] It is well known to those skilled in the art that TNF-α+Smac Mimetics+Z-VAD-fmk can induce cell necrosis.

[0029] In a 96-well plate with HaCaT cells (human immortalized epidermal cells) in the logarithmic growth phase, Z-VAD-fmk and SZ-15 were added to the plate to the target concentrations: 20μM Z-VAD-fmk and 2.5μM to 40μM gradient concentrations of SZ-15, and cultured for 2h. Then TNF-α was added to 100ng / mL and Smac Mimetics (birinapant) to 100nM. After incubation in a cell culture incubator for 24h, CCK-8 determination was completed. The group without SZ-15 was used as the model group and named TSZ group.

[0030] 2. Experimental results

[0031] Statistical analysis was performed using GraphPad (results in Table 1), and the cell survival rate of the normal control group was recorded as 100%. The analysis showed that the cell survival rate of the TSZ group was 56.56%, and the cell survival rate of the TSZ group to which 2.5 to 10 μM of SZ-15 prepared by the present invention was added was 84.47% to 100.6%.

[0032] Table 1 Inhibitory effect of SZ-15 on TNF-α-induced HaCaT cell death

[0033]

[0034] The above experimental results show that SZ-15 can effectively inhibit HaCaT cell death, among which 2.5 to 10 μM SZ-15 has an inhibitory effect of up to 87.47% to 100.6%, and 5 μM SZ-15 has the best inhibitory effect.

[0035] Example 2 Effect of SZ-15 on the skin of mice with acute skin photodamage model

[0036] 1. Experimental Methods

[0037] 48 SPF SKH-1 mice aged 6-8 weeks were selected and housed in an SPF animal breeding barrier system. They were randomly divided into 8 groups, with 6 mice in each group. The NC group (also known as the Control group) was a blank control group without UVB irradiation, and the other groups (UVB group, G1, G2, G3 group, S1, S2, S3 group) were all irradiated with UVB. Before irradiation, the ultraviolet light therapy device was preheated for 20 minutes, and the irradiation intensity at 20 cm from the light source was measured using an irradiation meter to be 0.7 mW / cm 2 Each group received the same UVB light dose, about 300mJ / cm 2 , irradiation continued for 3 days. Irradiation dose (mJ / cm 2 ) = irradiance (mW / cm 2 )× irradiation time (s). The total irradiation dose is the irradiation dose per time (mJ / cm 2 )×days (times). Before each UVB irradiation, 100 mg of homemade blank cream without inhibitor was evenly applied on the right side of the back of mice in the blank control group (NC group) and the modeling group (UVB group) with the midline of the back as the boundary (the left side was not treated). 100 mg of cream containing different concentrations of GSK-2982772 (G1: cream containing 0.03% GSK-2982772; G2: cream containing 0.3% GSK-2982772; G3: cream containing 3% GSK-2982772) was evenly applied on the right side of the back of mice in the GSK-2982772 treatment groups (G1, G2, G3 groups) with the midline of the back as the boundary (the left side was not treated). After the cream was completely absorbed (about 30 minutes), UVB irradiation was performed. The back of the mice in the SZ-15 treatment group (S1, S2, S3 group) was evenly smeared with 100 mg of cream containing different concentrations of SZ-15 (S1: cream containing 0.03% SZ-15; S2: cream containing 0.3% SZ-15; S3: cream containing 3% SZ-15) on the right side (left side was not treated) along the midline of the back. After the cream was completely absorbed (about 30 minutes), UVB irradiation was performed. The blank cream matrix ingredients are: A165 PEG-100 stearate, glyceryl stearate, cetyl alcohol, stearyl alcohol, white petrolatum, 2EHP ethylhexyl palmitate, methylparaben, propylparaben, vegetable glycerin, and reverse osmosis purified water. GSK-2982772 is a known RIPK1 inhibitor, CAS number: 1622848-92-3. The structure is:

[0038]

[0039] Comparison of skin thickness: HE sections of 3-5 mice were selected from each group. Five non-repetitive and overlapping fields of view were randomly selected from each HE section. Five epidermal thickness measurement points were taken from each field of view, and the average value was taken as the average epidermal thickness of one mouse.

[0040] 2. Experimental results

[0041] Skin treatment conditions such as Figure 1 Compared with the blank control group, the modeling group mice showed mild erythema after irradiation, and obvious erythema, edema, and mild erosion appeared in the irradiated area of ​​the back the next day. Erythema and more scales were seen on the back of the mice in the GSK-2982772 treatment group, while only mild erythema and scales were seen on the back of the mice in the SZ-15 treatment group (right back), without edema or erosion, and the erythema became less obvious as the concentration of SZ-15 increased.

[0042] The average skin thickness in the NC group was 41.73 μm, the average thickness in the UVB group was 83.49 μm, and in the SZ-15 treatment group, the average thickness in the S1, S2, and S3 groups was 50, 54.5, and 69.36 μm, respectively (see Figure 2 ), which were significantly better than those in the GSK-2982772 treatment group.

[0043] HE staining: Compared with the blank control group, the skin sections of mice in the modeling group showed that the integrity of the epidermis was destroyed, the stratum corneum was significantly thickened, and some cells in the stratum corneum contained concentrated, non-disappeared nuclei. The dermis showed disordered and coarse collagen structure and dilated capillaries. Masson staining: Compared with the control group, the epidermis in the modeling group was thickened, hyperkeratotic, and the collagen was disordered, coarsened, and tangled. Compared with the modeling group, the collagen tangles in the SZ-15 treatment group were reduced, and some collagens were arranged more neatly; compared with the GSK-2982772 treatment group, the collagen tangles in the SZ-15 treatment group were reduced, and some collagens were arranged more neatly.

Claims

1. Use of the compound of formula I, its pharmaceutically acceptable salt or its stereoisomer in the preparation of a pharmaceutical preparation for preventing and / or treating skin photodamage; in, R1 is selected from C 1-4 Alkyl; R2 is selected from C 1-4 Alkyl; p is selected from 1, 2 or 3; q is selected from 1, 2 or 3.

2. The use according to claim 1, characterized in that The structure of the compound is:

3. The use according to claim 1 or 2, characterized in that: The skin photodamage is acute skin photodamage.

4. The use according to claim 4, characterized in that: The acute skin photodamage is acute skin photodamage caused by ultraviolet irradiation.

5. The use according to claim 4, characterized in that: The drug is a drug for improving skin erythema, edema and erosion, and / or the drug is a drug for reducing skin thickness.

6. The use according to claim 1 or 2, characterized in that: The pharmaceutical preparation is a preparation prepared by taking the compound, its pharmaceutically acceptable salt or its stereoisomer as active ingredient and adding pharmaceutically acceptable auxiliary materials.

7. The use according to claim 6, characterized in that: The pharmaceutical preparation is an external preparation.

8. The use according to claim 7, characterized in that: The external preparation is a cream, a liquid preparation or a gel.

9. The use according to claim 8, characterized in that: In the liquid preparation, the concentration of the active ingredient is 2.5-10 μM.

10. The use according to claim 9, characterized in that: The concentration of the active ingredient in the liquid preparation is 5 μM.

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