Sphingosine alkali derivative of short-chain fully-saturated esterified carbon chain and synthesis method of spingosine alkali derivative

Abstract

The invention discloses a sphingosine alkali derivative of a short-chain fully saturated esterified carbon chain and a synthesis method thereof, and the sphingosine alkali derivative has a structure of a general formula I or an isomer structure of the general formula I, and comprises an enantiomer and a diastereoisomer. The short-chain fully-saturated esterified carbon chain sphingosine derivative is obtained by carrying out aminolysis reaction on a sphingosine alkali compound and 5-8-membered ring lactone and then carrying out site specific selective esterification reaction with C4-C8 short-chain saturated carboxylic acid, so that not only is the stability of the derivative to illumination and air enhanced, but also the permeability of the derivative is improved. The product has an obvious proliferation effect on keratinocytes and fibroblasts, inhibits inflammatory response caused by external environment pollution, can enhance the toughness of in-vitro hair, and has a wide application prospect in skin care and hair care products, health care products and medicines. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and particularly relates to a sphingoid base derivative with a short-chain fully saturated esterified carbon chain, a synthesis method thereof, and an application thereof. Background Art

[0002] Sphingoid Bases, as a class of important bioactive molecules, exhibit extensive application values in multiple fields. In the pharmaceutical aspect: It has been found that sphingoid bases are involved in various cellular functions, such as signal transduction, cell cycle regulation, and heat stress response; sphingoid bases may play an anti-cancer role by inducing apoptosis or inhibiting cell growth; sphingoid bases have an inhibitory effect on bacteria and may be used to develop new antibacterial drugs. In skin care: Sphingoid bases, as precursors of ceramides, can enhance the skin barrier function, reduce water loss, and relieve dryness and inflammation; compositions containing sphingoid bases can be used to treat skin diseases related to barrier function damage and synergistically promote skin repair with ceramides. In addition, due to the natural properties and biological activities of sphingoid bases, there is a promising future for their application in the field of food additives and becoming ingredients of functional foods or nutritional supplements.

[0003] The application fields of sphingoid bases cover pharmacy, cosmetics, and food, and their core functions are to regulate cell functions, anti-inflammatory, antibacterial, and enhance the skin barrier. In the future, with technological innovation and the growth of market demand, their application scope is expected to be further expanded, especially with great potential in personalized skin care and the development of natural drugs.

[0004] There have been some reports on the research of sphingoid base derivatives in the skin care field. For example, Korean Patent Document KR20170100906A discloses a sphingoid base derivative, which obtains a series of ceramide-like compounds by connecting various alkyl and acyl groups to the hydroxyl side chain of C14-ω-hydroxyceramide, and is used to maintain moisture in the skin, repair skin damage, and prevent skin aging. Chinese Patent Document CN115894270A also discloses a sphingoid base derivative, which connects linoleic acid to the hydroxyl side chain of C10-ω-hydroxyceramide to obtain an ω-hydroxyacylated ceramide product, and studies its application in skin care. However, there are no reports on the synthesis and biological activities of sphingoid base derivatives with short-chain saturated acyl groups connected to the hydroxyl side chain of short-chain ω-hydroxyceramides in these documents.

[0005] In addition, the synthetic routes of ω-hydroxyacylated ceramides in the existing literature are particularly lengthy, involving operations such as protection and deprotection, as well as the use of environmentally unfriendly materials such as acyl chlorides, which pose great challenges to industrial production and green environmental protection processes. On the other hand, commercially available ω-hydroxyacylated ceramides are usually linoleoyl-sphingosine derivatives. Due to the presence of two cis-unsaturated double bonds in these compounds, they are sensitive to light and air and require special storage conditions, which is not conducive to product development and storage.

[0006] Due to the importance of sphingosine derivatives in the fields of medicine, skin care, and food, the wide market demand for different functional products, and the existing problems in industrial production and stability of existing products, in order to solve the deficiencies of existing technical methods, the present invention provides a class of sphingosine derivatives with short-chain fully saturated esterified carbon chains, their synthesis methods, and applications. Summary of the Invention

[0007] The object of the present invention is to provide a sphingosine derivative with a short-chain fully saturated esterified carbon chain and its synthesis method, to synthesize sphingosine compounds through a new green environmental protection technical route, and to solve the problems of scale-up production and environmental pollution; by introducing a side chain of short-chain saturated fatty acid into ω-hydroxyceramide, the sensitivity of the compound to light and air is improved; and its application in hair care is also provided.

[0008] To achieve the above-mentioned invention object, the technical solution of the present invention is as follows:

[0009] A sphingosine derivative with a short-chain fully saturated esterified carbon chain of the present invention has the structure of general formula I or the structure of an isomer of general formula I:

[0010]

[0011] Among them, n = 1-4, m = 1-5; R is a substituted or unsubstituted alkyl group;

[0012] The isomers include enantiomers and diastereomers.

[0013] Preferably, R is selected from one of the following structures:

[0014]

[0015] Among them, the -C 15 H 31 , -C 14 H 29 , -C 13 H 27 is a straight-chain saturated alkyl group or a branched-chain saturated alkyl group.

[0016] More preferably, R is selected from one of the following structures:

[0017]

[0018] Preferably, the sphingosine base derivative is one of the structures of the following formula (1) to formula (7):

[0019]

[0020]

[0021] On the other hand, a method for synthesizing a sphingosine base derivative with a short-chain fully saturated esterified carbon chain according to the present invention includes the following steps:

[0022] (1) React a lithium salt catalyst, a medium-ring lactone compound (S1) and a sphingosine base (S2) in a solvent, remove the solvent from the reaction solution to obtain an intermediate (I-1);

[0023] The temperature of the reaction is 60-70 °C, and the reaction time is 4-6 h;

[0024] (2) Under the action of a boron salt, the intermediate (I-1) and a short-chain saturated fatty acid (S3) carry out a specific esterification reaction in a solvent to obtain a compound (I), which is the sphingosine base derivative; the overall reaction equation is shown in formula (8):

[0025]

[0026] Among them, R in the sphingosine base (S2) is a substituted or unsubstituted alkyl group, and R in the short-chain saturated fatty acid (S3) 1 is a saturated straight-chain alkyl group with 3-7 carbon atoms.

[0027] Both step (1) and step (2) are carried out under an inert gas atmosphere, and the inert gas is preferably argon.

[0028] Preferably, in step (1), the lithium salt is lithium chloride; the medium-ring lactone compound (S1) is at least one of a five-membered ring lactone, a six-membered ring lactone, a seven-membered ring lactone, and an eight-membered ring lactone; the molar ratio of the medium-ring lactone compound (S1), the lithium salt, and the sphingosine base (S2) is (1-2):(0.1-1.0):1; the lithium salt activates the medium-ring lactone substrate, and the sphingosine base acts as a strong nucleophile to attack the carbonyl carbon of the medium-ring lactone, and after ring opening, the intermediate (I-1) is generated.

[0029] Preferably, in step (2), the boron salt is borax; the short-chain saturated fatty acid (S3) is at least one of butyric acid, valeric acid, caproic acid, enanthic acid, and caprylic acid; the molar ratio of the intermediate (I-1), boron salt, and short-chain saturated fatty acid (S3) is (1 to 1.5):(1 to 1.5):1.

[0030] Preferably, the solvent in step (1) is ethanol, and the solvent in step (2) is tetrahydrofuran.

[0031] Preferably, in step (2), the short-chain saturated fatty acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, and the solvent are stirred and mixed under argon protection to obtain reaction mixture A; the intermediate (I-1) obtained in step (1) and borax are previously stirred and mixed in the solvent, and then added to reaction mixture A, and stirring is continued at room temperature for 12 to 18 h until it is monitored that the intermediate (I-1) has completely reacted.

[0032] Preferably, the reaction solution of the esterification reaction is extracted with deionized water and saturated brine respectively, the organic layer is separated, dried, filtered, and concentrated in vacuo; the residue thus obtained is purified by a silica gel column to obtain sphingosine base derivatives with short-chain fully saturated esterified carbon chains, and the yield is 60% to 75%.

[0033] The sphingosine base derivatives with short-chain fully saturated esterified carbon chains according to the present invention are used for the maintenance, repair, and anti-inflammation of the skin and / or hair, for example, as one of the components of skin care products, shampoos, hair conditioners, anti-inflammatory external ointments, etc.

[0034] The present invention also provides a composition for the repair and anti-inflammation of the skin and / or hair, and the composition includes the sphingosine base derivatives with short-chain fully saturated esterified carbon chains, or pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof.

[0035] The "pharmaceutically acceptable salts" used in the present invention mean salts that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound; such salts include: (1) acid addition salts formed with organic acids or inorganic acids, organic acids such as lactic acid, acetic acid, cinnamic acid, mandelic acid, azelaic acid, succinic acid, tartaric acid, citric acid, benzoic acid, benzenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 3-phenylpropionic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, palmitic acid, and oleic acid; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, etc.; or (2) salts formed when the acidic protons in the amide bonds present in the parent compound are substituted.

[0036] The "hydrate" used in the present invention means a compound that is non-covalently bound to water.

[0037] As used herein, "solvate" means a complex formed by solute molecules / ions and solvent molecules / ions.

[0038] Finally, the present invention provides the use of the sphingoid base derivatives in skin care products, hair care products, health products or medicines.

[0039] The beneficial effects of the present invention are:

[0040] (1) The present invention conducts an aminolysis reaction of a sphingosine base compound with a 5-8-membered ring lactone, and then conducts a site-specific selective esterification reaction with a C4-C8 short-chain saturated carboxylic acid to obtain a class of short-chain fully saturated esterified carbon chain sphingosine derivatives with novel structures.

[0041] (2) Compared with the previously reported synthetic methods of ω-hydroxy acylated ceramides, which have lengthy steps and are environmentally unfriendly, the present invention firstly reacts a medium-ring lactone compound with a sphingoid base under the catalysis of a lithium salt to obtain an ω-hydroxy ceramide, and then, under the action of a boron salt, passesivates it by complexing with the polyhydroxyl groups of the sphingoid base fragment, so that the ω-hydroxyl groups selectively react with short-chain saturated fatty acids to efficiently prepare the target product. This process not only eliminates the lengthy steps of protection and deprotection, but also develops a highly selective esterification reaction, greatly improving the atom economy of the process.

[0042] (3) The present invention not only improves the sensitivity of the compound to light and air, but also improves the permeability of the compound by introducing short-chain saturated fatty acid fragments.

[0043] (4) The product of the present invention has a significant proliferation effect on keratinocytes and fibroblasts, thus having a good repair effect; it has a good inhibitory effect on inflammatory reactions caused by external environmental pollution (such as PM2.5). When the concentration is 31.25 mg / L, the inhibition rate of the example sample group is as high as 66.65%, thus having a good anti-inflammatory effect; it can also enhance the toughness of isolated hair. Compared with the control group, the hair breaking strength of the example sample group can be increased by 19.67%, thus having a good prospect for hair care application. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is the H NMR spectrum of the sphingoid base derivative of formula (1) obtained in Example 1.

[0045] Figure 2 This is the carbon NMR spectrum of the sphingoid base derivative of formula (1) obtained in Example 1.

[0046] Figure 3 The figure shows the effect of 1% of the sphingoid base derivative samples obtained in Examples 1-1 and 2-1 on the strength of isolated hair.

[0047] Figure 4 The contents of sphingosine base derivatives obtained in Examples 1-1, 2-1, and 3-1 under light conditions vary with time.

[0048] Figure 5 The contents of sphingosine base derivatives obtained in Examples 1-1, 2-1, and 3-1 under air conditions vary with time. Detailed implementation mode

[0049] The following non-limiting examples can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary illustration of the scope claimed by the present invention. Those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and it should also fall within the scope claimed by the present invention.

[0050] The present invention will be further described below by way of specific examples. Unless otherwise specified, the chemical products are purchased from commercial products and are not further purified. Ethanol and tetrahydrofuran used in the experiments are anhydrous solvents; EDCI refers to 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and DMAP refers to 4-dimethylaminopyridine. All reactions in the examples of the present invention are carried out under an argon atmosphere.

[0051] Example 1

[0052] According to the following reaction equation, the synthesis steps of short-chain fully saturated esterified carbon chain phytosphingosine derivatives are as follows:

[0053]

[0054] (1) Add 60 mmol of medium-ring lactone compound (S1), 6 mmol of lithium chloride, 55 mmol of phytosphingosine base (S2), and 180 mL of ethanol to a 500 mL round-bottom flask, heat to 60 °C and stir for 4 h until the phytosphingosine base reaction is complete as monitored by TLC. The reaction solution is concentrated under vacuum to dry the ethanol to obtain intermediate I-1;

[0055] (2) Add 60 mmol of short-chain saturated fatty acid (S3), 66 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 75 mmol of 4-dimethylaminopyridine (DMAP), and 150 mL of tetrahydrofuran to a 500 mL round-bottom flask, and stir at room temperature for 1 h under argon protection to obtain reaction mixture A;

[0056] Pre-stir the intermediate (I-1) obtained in step (1) and 60 mmol of borax in 100 mL of tetrahydrofuran solution at room temperature for 30 min, then add it to the reaction mixture A, and continue to stir at room temperature for the specific esterification reaction for 12 - 18 h until the reaction of the intermediate (I-1) is complete as monitored by thin layer chromatography (TLC);

[0057] (3) Quench the reaction with dilute hydrochloric acid, and then extract the reaction twice with deionized water and saturated brine respectively; separate the organic layer, dry, filter and concentrate under vacuum; the residue thus obtained is purified by silica gel column to obtain the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain.

[0058] According to the change of R1 in the short-chain saturated fatty acid (S3), the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (1), formula (3) or formula (5) can be obtained.

[0059] The yield of the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (1) is 65%; its 1H NMR spectrum is shown in Figure 1 and the 1H NMR data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.8 Hz, 1H), 4.58 (d, J = 5.3 Hz, 1H), 4.49 (t, J = 5.4 Hz, 1H), 4.27 (d, J = 6.5 Hz, 1H), 3.98 (t, J = 6.6 Hz, 2H), 3.86 (dq, J = 10.2, 5.4 Hz, 1H), 3.50 (dq, J = 18.7, 5.6 Hz, 2H), 3.41 - 3.33 (m, 2H), 2.27 (t, J = 7.4 Hz, 2H), 2.12 - 2.05 (m, 2H), 1.61 - 1.35 (m, 8H), 1.34 - 1.14 (m, 32H), 0.86 (t, J = 6.9 Hz, 6H).

[0060] The 13C NMR spectrum of the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (1) is shown in Figure 2 and the 13C NMR data are as follows: 13 C NMR (101 MHz, CDCl3) δ 174.19, 173.91, 76.20, 72.78, 64.04, 61.55, 52.58, 36.36, 34.32, 33.31, 31.92, 31.31, 29.72, 29.66, 29.36, 28.38, 25.84, 25.51, 25.21, 24.65, 22.67, 22.29, 14.09, 13.89.

[0061] The yield of the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (3) is 60%, and its 1H NMR data are as follows:1 H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 8.6 Hz, 1H), 4.55 (d, J = 5.1 Hz, 1H), 4.43 (t, J = 5.2 Hz, 1H), 4.19 (d, J = 6.3 Hz, 1H), 3.88 (t, J = 6.8 Hz, 2H), 3.82 - 3.77 (m, 1H), 3.53 (dq, J = 18.2, 5.4 Hz, 2H), 3.44 - 3.36 (m, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.14 - 2.07 (m, 2H), 1.64 - 1.33 (m, 10H), 1.31 - 1.10 (m, 34H), 0.82 (t, J = 6.7 Hz, 6H).

[0062] The yield of the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (5) is 75%, and its 1H NMR data are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (d, J = 8.6 Hz, 1H), 4.53 (d, J = 5.4 Hz, 1H), 4.44 (t, J = 5.3 Hz, 1H), 4.21 (d, J = 6.4 Hz, 1H), 3.88 (t, J = 6.8 Hz, 2H), 3.76 (dq, J = 10.0, 5.6 Hz, 1H), 3.54 (dq, J = 18.4, 5.6 Hz, 2H), 3.46 - 3.36 (m, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.10 - 2.01 (m, 4H), 1.62 - 1.38 (m, 8H), 1.33 - 1.18 (m, 32H), 0.83 (t, J = 7.2 Hz, 6H).

[0063] Example 2

[0064] According to the following reaction equation, the synthesis steps of the dihydrosphingosine derivative with a short-chain fully saturated esterified carbon chain are as follows:

[0065]

[0066] (1) Add 60 mmol of the medium-ring lactone compound (S1), 8 mmol of lithium chloride, 55 mmol of dihydrosphingosine base (S2), and 200 mL of ethanol to a 500 mL round-bottom flask, heat to 70 °C and stir for 6 h until the reaction of the dihydrosphingosine base is complete as monitored by TLC. The reaction solution is concentrated in vacuo to rotary dry the ethanol to obtain the intermediate (I-1);

[0067] (2) Add 60 mmol of short-chain saturated fatty acid (S3), 70 mmol of EDCI, 80 mmol of DMAP, and 200 mL of tetrahydrofuran to a 500 mL round-bottom flask. Under argon protection, stir at room temperature for 1 h to obtain reaction mixture A;

[0068] Pre-stir the intermediate (I-1) obtained in step (1) and 65 mmol of borax in 100 mL of tetrahydrofuran solution at room temperature for 30 min, then add it to reaction mixture A, and continue to stir at room temperature for the specific esterification reaction for 14 - 20 h until the reaction of intermediate (I-1) is complete as monitored by thin-layer chromatography (TLC);

[0069] (3) Add dilute hydrochloric acid to quench the reaction, and then extract the reaction twice with deionized water and saturated brine respectively; separate the organic layer, dry, filter, and concentrate under vacuum; the residue thus obtained is purified by silica gel column to obtain the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain.

[0070] According to the change of R1 in short-chain saturated fatty acid (S3) and the change of the size of the middle-ring lactone ring, the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (2), formula (4), or formula (6) can be obtained.

[0071] The yield of the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (2) is 78%, and its 1H NMR data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 6.43 (d, J = 7.8 Hz, 1H), 4.11 - 3.99 (m, 3H), 3.90 - 3.72 (m, 3H), 2.27 (t, J = 7.4 Hz, 2H), 2.12 - 2.05 (m, 2H), 1.64 - 1.35 (m, 8H), 1.43 - 1.25 (m, 32H), 0.90 (t, J = 7.2 Hz, 6H).

[0072] The yield of the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (4) is 70%, and its 1H NMR data are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 6.48 (d, J = 7.8 Hz, 1H), 4.14 - 4.02 (m, 3H), 3.96 - 3.84 (m, 1H), 3.81 - 3.74 (m, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.14 - 2.07 (m, 2H), 1.68 - 1.41 (m, 8H), 1.48 - 1.27 (m, 36H), 0.89 (t, J = 7.5 Hz, 6H).

[0073] The yield of the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (6) is 62%, and its 1H NMR data are as follows: 1 H NMR(400MHz,Chloroform-d)δ6.53(d,J=7.6Hz,1H),4.14-4.08(m,1H),4.04-3.92(m,2H),3.89-3.74(m,3H),2.23(t,J=7.6Hz,2H),2.15-2.09(m,2H),1.72-1.45(m,8H),1.43-1.28(m,34H),0.87(t,J=7.1Hz,6H).

[0074] Example 3

[0075] The phytosphingosine derivative with a short-chain fully saturated esterified carbon chain was prepared according to the following steps:

[0076]

[0077] (1) 60 mmol of the medium-ring lactone compound (S1), 6.6 mmol of lithium chloride, 60 mmol of sphingosine base (S2) and 160 mL of ethanol were added to a 500 mL round-bottom flask, heated to 65 °C and stirred for 5 h until the sphingosine base reaction was complete monitored by TLC. The reaction solution was concentrated in vacuo to remove ethanol, and the intermediate (I-1) was obtained.

[0078] (2) 60 mmol of the short-chain saturated fatty acid (S3), 72 mmol of EDCI, 80 mmol of DMAP and 200 mL of tetrahydrofuran were added to a 500 mL round-bottom flask, and stirred at room temperature for 1 h under argon protection to obtain the reaction mixture A.

[0079] The intermediate (I-1) obtained in step (1) and 62 mmol of borax were pre-stirred in 100 mL of tetrahydrofuran solution at room temperature for 30 min, and then added to the reaction mixture A, and the reaction was continued to stir at room temperature for the regioselective esterification reaction for 14 - 20 h until the intermediate (I-1) reaction was complete monitored by thin layer chromatography (TLC).

[0080] (3) The reaction was quenched by adding dilute hydrochloric acid, and then extracted twice with deionized water and saturated brine respectively; the organic layer was separated, dried, filtered and concentrated in vacuo; the residue thus obtained was purified by silica gel column to obtain the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (7), and the yield was 72%.

[0081] The yield of the phytosphingosine derivative with a short-chain fully saturated esterified carbon chain of formula (7) is 72%, and its 1H NMR data are as follows: 11H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J = 8.6 Hz, 1H), 5.75 (dt, J = 14.0, 6.6 Hz, 1H), 5.42 - 5.31 (m, 1H), 4.52 (d, J = 5.2 Hz, 1H), 4.39 (t, J = 5.2 Hz, 1H), 4.22 (d, J = 6.6 Hz, 1H), 3.92 (t, J = 6.6 Hz, 2H), 3.76 (dq, J = 10.4, 5.2 Hz, 1H), 3.50 (dq, J = 18.7, 5.6 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 2.15 - 2.07 (m, 4H), 1.66 - 1.45 (m, 8H), 1.31 - 1.18 (m, 26H), 0.91 (t, J = 7.0 Hz, 6H).

[0082] Test Experimental Example 1

[0083] The MTT colorimetric method was used to detect the proliferation viability of sphingosine base derivatives obtained in Examples 1-1, 2-1, and 3-1 on cells respectively:

[0084] Human keratinocyte HaCaT cells and fibroblast L929 cells were seeded in 96-well plates at a density of 1×10 4 cells / well and incubated overnight in an incubator; after 24 h, the supernatant was discarded, 100 μL of medium containing different concentrations of samples (compounds of Examples 1-1, 2-1, and 3-1) or blank was added (three groups were set in parallel for each concentration), and after continuing to incubate for 24 h, the medium was removed. 100 μL of thiazolyl blue (MTT) was added to each well, and the absorbance at 450 nm was measured. The cell survival rate was calculated as A 给药孔 / A 空白孔 ×100%.

[0085] Table 1 Test results of the proliferation viability of sphingosine base derivatives on HaCaT cells

[0086]

[0087] Table 2 Test results of the proliferation viability of sphingosine base derivatives on L929 cells

[0088]

[0089] It can be seen from Table 1 and Table 2 that for HaCaT cells and L929 cells, the compounds of Examples 1-3 have very obvious proliferation effects at low concentrations; when the compounds of Examples 1-3 are at a concentration of 250 mg / L, the HaCaT cell viability is 100.8%, 97.85%, and 100.52%, respectively; the L929 cell viability is 96.5%, 102.7%, and 113.6%, respectively, with no toxic side effects on cells, showing good biosafety.

[0090] Test Example 2

[0091] The inhibition experiment of TSLP (allergic factor) by the sphingosine base derivatives obtained in Examples 1-1, 2-1 and 3-1 was tested:

[0092] TSLP and inflammation: TSLP is an upstream regulatory factor of the inflammatory cascade, and therapeutic strategies targeting TSLP have an inhibitory effect on the inflammatory cascade.

[0093] Experimental operation process: RAW cells were seeded in 6-well plates and the cells were allowed to fuse to about 80%; 1000 μL of DMEM medium was added to the control group, 900 μL of DMEM medium was added to the model group, and 900 μL of DMEM-diluted samples of different concentrations were added to each well of the experimental group; 1-2 hours after pre-protection, 100 μL of 100 μg / ml LPS was added to each well except the control group (the final concentration of LPS was 10 μg / ml); 24 hours later, cell RNA was extracted, and the relative expression of TSLP m-RNA was detected by real-time fluorescence quantitative PCR after reverse transcription.

[0094] Table 3 Relative expression of TSLP m-RNA

[0095]

[0096] The experimental results are shown in Table 3: Compared with the model group, the co-incubation of Examples 1-1, 2-1, and 3-1 with cells can reduce the expression of TSLP inflammatory factors in cells, and the inhibition rates can reach 64.86%, 61.15%, and 66.65% respectively at a concentration of 31.25 mg / L, indicating that the sphingoid base derivatives described in the examples have a good inhibitory effect on the inflammatory response caused by external environmental pollution (such as PM2.5).

[0097] Test Example 3

[0098] The effects of the hair creams containing 1% of the sphingoid base derivatives obtained in Examples 1-1 and 2-1 on the strength of isolated hair were tested respectively:

[0099] Three identical flat hair bundles were selected and randomly divided into three groups, 2 bundles in the sample group and 1 bundle in the control group;

[0100] Sample treatment process: Apply evenly to the hair bundle at a dosage of 0.15 g / g of hair, rub for 45 s, and rinse with water at a water temperature of 35 °C and a flow rate of 2 L / min for 45 s. Repeat the above steps once, for a total of two treatments, and finally wring dry.

[0101] After the test samples (hair creams containing 1% of the sphingosine base derivatives obtained from Examples 1-1 and 2-1 respectively) and the control (clear water) are treated, hang the hair bundles in a constant temperature and humidity chamber at 24 ± 1 °C and RH 50 ± 5% to dry and equilibrate for 24 hours.

[0102] Select 40 hairs from the treated sample group and the control group hair bundles for sample preparation, measure the cross-sectional thickness at the center of each hair and its diameter d, and calculate the cross-sectional area of a single hair: S = 1 / 4πd 2 . After the diameter test, place the 40 hair specimens of the sample group and the control group in an environment of 24 ± 1 °C and RH 50 ± 5% to equilibrate for 24 h, and test the tensile fracture load and total tensile fracture work of the hair; finally, 30 hair fracture strengths are completed for the hair bundles of the sample group and the control group respectively; calculate the fracture strength of each hair (fracture strength = fracture load / cross-sectional area); the test results are as Figure 3 shown.

[0103] From Figure 3 it can be seen that the fracture strength of the hair bundles treated with the sphingosine base derivatives containing 1% of Examples 1-1 and 2-1 respectively is significantly higher than that of the control group hair bundles. Among them, the sample group of Example 1-1 is 12.49% higher than the control group, and the sample group of Example 2-1 is 19.67% higher than the control group, indicating that the sphingosine base derivatives with short-chain fully saturated esterified carbon chains have the effect of improving hair toughness and have good application prospects in the field of hair care.

[0104] Test Experimental Example 4 Light Stability Test

[0105] Dissolve the commercially available ω-hydroxyacyl ceramide, the sphingosine base derivatives obtained from Examples 1-1, 2-1 and 3-1 respectively in chloroform to prepare a solution with a mass concentration of 2%, and place it under sunlight irradiation; at day 0, week 1, week 2, week 3 and week 4, test the content with the control respectively, and the change trend of the content results is shown in Figure 4 .

[0106] From Figure 4 it can be seen that after 4 weeks of sunlight irradiation, the content of the commercially available ω-hydroxyacyl ceramide sample decreased by 40.6%, while the content of the short-chain fully saturated esterified carbon chain sphingosine base derivatives of the present invention hardly changed. It shows that the short-chain fully saturated esterified carbon chain sphingosine base derivatives of the present invention have higher stability to light and are more suitable for application in skin care products.

[0107] Test Experimental Example 5 Air Stability Test

[0108] Place commercially available ω-hydroxyacyl ceramides and the sphingosine base derivatives obtained in Example 1-1, Example 2-1, and Example 3-1 in the air respectively, and use the reference substance to test the content on the 0th day, 1st week, 2nd week, 3rd week, and 4th week respectively. The change trend of the content results is shown in Figure 5 .

[0109] From Figure 5 It can be seen that after being placed in the air for 4 weeks, the content of the commercially available ω-hydroxyacyl ceramide sample decreased by 30%, while the content of the sphingosine base derivatives with short-chain fully saturated esterified carbon chains of the present invention hardly changed. It shows that the sphingosine base derivatives obtained in Example 1-1, Example 2-1, and Example 3-1 of the present invention have higher stability to air and are more suitable for application in skin care products.

[0110] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A sphingosine base derivative with a short-chain fully saturated esterified carbon chain, characterized in that, Having the structure of general formula I or the structure of an isomer of general formula I: Wherein, n = 1 to 4, m = 1 to 5; R is a substituted or unsubstituted alkyl group; The isomers include enantiomers and diastereomers.

2. The sphingosine base derivative of a short-chain fully saturated esterified carbon chain according to claim 1, characterized in that, R is selected from one of the following structures: Among them, the -C 15 H 31 , -C 14 H 29 , -C 13 H 27 is a straight-chain saturated alkyl group or a branched-chain saturated alkyl group.

3. The sphingosine base derivative of a short-chain fully saturated esterified carbon chain according to claim 1, characterized in that, The R is selected from one of the following structures:

4. The sphingosine base derivative of a short-chain fully saturated esterified carbon chain according to claim 1, wherein The sphingosine base derivatives are one of the structures of the following formula (1) to formula (7): or / and 5. The synthesis method of the sphingosine base derivative of a short-chain fully saturated esterified carbon chain according to any one of claims 1 to 4, characterized in that, Including the following steps: (1) React a lithium salt catalyst, a medium-ring lactone compound (S1) and a sphingosine base (S2) in a solvent, remove the solvent from the reaction solution to obtain an intermediate (I-1); The temperature of the reaction is 60 to 70 °C, and the reaction time is 4 to 6 h; (2) Under the action of a boron salt, the intermediate (I-1) and a short-chain saturated fatty acid (S3) carry out a specific esterification reaction in a solvent to obtain a compound (I), which is the sphingosine base derivative described; Among them, R in sphingosine base (S2) is a substituted or unsubstituted alkyl group, and R in short-chain saturated fatty acid (S3) 1 is a saturated straight-chain alkyl group with 3 to 7 carbon atoms.

6. The synthesis method of the sphingosine base derivative with a short-chain fully saturated esterified carbon chain according to claim 5, characterized in that, Both step (1) and step (2) are carried out under an inert gas atmosphere; the solvent in step (1) is ethanol, and the solvent in step (2) is tetrahydrofuran.

7. The synthesis method of the sphingosine base derivative with a short-chain fully saturated esterified carbon chain according to claim 5, characterized in that, In step (1), the lithium salt is lithium chloride; the medium-ring lactone compound (S1) is at least one of a five-membered ring lactone, a six-membered ring lactone, a seven-membered ring lactone, and an eight-membered ring lactone; the molar ratio of the medium-ring lactone compound (S1), the lithium salt, and the sphingosine base (S2) is (1 to 2): (0.1 to 1.0): 1; In step (2), the boron salt is borax; the short-chain saturated fatty acid (S3) is at least one of butyric acid, valeric acid, hexanoic acid, heptanoic acid, and octanoic acid; the molar ratio of the intermediate (I-1), the boron salt, and the short-chain saturated fatty acid (S3) is (1 to 1.5): (1 to 1.5):

1.

8. The method for synthesizing sphingosine base derivatives with short-chain fully saturated esterified carbon chains according to claim 5, characterized in that, In step (2), the short-chain saturated fatty acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, and a solvent are stirred and mixed under argon protection to obtain a reaction mixture A; the intermediate (I-1) obtained in step (1) and borax are stirred and mixed in a solvent in advance, and then added to the reaction mixture A, and stirring is continued at room temperature for 12 to 18 h until it is monitored that the intermediate (I-1) has completely reacted.

9. Use of the sphingosine base derivative of a short-chain fully saturated esterified carbon chain according to any one of claims 1 to 4, characterized in that, For skin and / or hair repair and anti-inflammatory.

10. A composition for repairing and anti - inflammatory of skin and / or hair, characterized in that, The composition includes the sphingosine base derivatives of short-chain fully saturated esterified carbon chains as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

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