CERAMIDE COMPOUND CONTAINING CONJUGATED CARBOXYLIC ACID, PREPARATION METHOD THEREFOR AND APPLICATION

Abstract

The present invention provides A ceramide compound, comprising: a structure of general formula I or an enantiomer or diastereomer of general formula I:

##STR00001## in which: R.sup.1 is selected from the condensation residues of ferulic acid, sinapic acid, abscisic acid, sotretinoin, tretinoin, fusidic acid, royal jelly acid, sorbic acid, caffeic acid or trans-cinnamic acid; R.sup.2 is selected from one of the following structures:C.sub.15H.sub.29, C.sub.15H.sub.31, C.sub.15H.sub.27, CHOHC.sub.14H.sub.27, CHOHC.sub.14H.sub.29.

The present disclosure also provides a ceramide compound containing conjugated carboxylic acid, preparation method therefor and application thereof. The invention reacts functional carboxylic acid with sphingosine base to obtain a class of ceramide compound with novel structure. The introduction of physiologically active molecular fragments of functional carboxylic acids into ceramides will enhance the original efficacy of this type of molecules and also improve the physical and chemical properties of ceramide compound. For example, improving the antioxidant properties of ceramide compound.

Claims

1. A ceramide compound, comprising: a structure of general formula I or an enantiomer or diastereomer of general formula I: ##STR00021## in which: R.sup.1 is selected from the condensation residues of ferulic acid, sinapic acid, abscisic acid, sotretinoin, tretinoin, fusidic acid, royal jelly acid, sorbic acid, caffeic acid or trans-cinnamic acid; R.sup.2 is selected from one of the following structures: C.sub.15H.sub.29, C.sub.15H.sub.31, C.sub.15H.sub.27, CHOHC.sub.14H.sub.27, CHOHC.sub.14H.sub.29.

2. The ceramide compound of claim 1, wherein the R.sup.2 is selected from one of the following structures: ##STR00022##

3. The ceramide compound of claim 2, wherein the R.sup.2 is selected from one of the following structures: ##STR00023##

4. The ceramide compound of claim 1, wherein the R.sup.1 is selected from the condensation residues of ferulic acid, trans-cinnamic acid, royal jelly acid, sorbic acid, caffeic acid, tretinoin or sinapic acid.

5. The ceramide compound of claim 1, wherein it is selected from one of the following compounds: ##STR00024## ##STR00025##

6. The application of the ceramide compound of claim 1 as antioxidants.

7. A preparation method of the ceramide compound, wherein the following steps: ##STR00026## compound S1 reacts with N-hydroxysuccinimide and a condensing agent to obtain compound S2; compound S2 reacts with sphingosine base to obtain compound I; R.sup.1 and R.sup.2 are as defined in claim 1.

8. The preparation method of claim 7, wherein the molar ratio of compound S1, N-hydroxysuccinimide, the condensing agent, and sphingosine base is 1:(12):(12):(0.81); the condensation agent is DCC; the solvent of the reaction is THF.

9. A preparation method of the ceramide compound, wherein the following steps: ##STR00027## compound S1 reacts with sphingosine base and the condensing agent to obtain compound I; R.sup.1 and R.sup.2 are as defined in claim 1.

10. The preparation method of claim 9, wherein the condensing agent includes EDCI and HOBT; the molar ratio of compound S1, EDCI, HOBT, and sphingosine base is 1:(12):(12):(0.81); the condensation agent is DCC; the solvent of the reaction is DCM.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0046] The invention will be further described with reference to the accompanying drawings, from which the object, technical solutions and beneficial effects of the invention will be clearer.

[0047] FIG. 1 is the test results of the antioxidant properties of the ceramide compound in Example 10.

DETAILED DESCRIPTION

[0048] The present disclosure will be described in detail with reference to the following specific embodiments, which are used to help those skilled in the art to further understand the present disclosure, and shall not be construed to limit the present disclosure in any form. It would be appreciated by those skilled in the art that changes and modifications can be made in the embodiments without departing from the spirit of the present disclosure, which also belong to the protection scope of the present disclosure. It should be noted that the drawings provided in the following embodiments are only used to illustrate the basic idea of the present invention in a schematic manner, and the following embodiments and features in the embodiments can be combined with each other without conflict.

[0049] All reactions were performed under nitrogen atmosphere. Unless otherwise stated, chemicals were purchased commercially and without further purification. The dichloromethane and tetrahydrofuran used in the experiment are anhydrous solvents. Thin layer chromatography (TLC) uses 60F254 silica gel plates. Silica gel column chromatography uses Qingdao marine silica gel (particle size 0.040-0.063 mm). TLC color development uses UV light (254 nm) or iodine. The NMR spectrum was characterized using a Bruker DPX 400 nuclear magnetic resonance instrument. 1H NMR is 400 MHz. The solvent is Methanol-D4, deuterated DMSO or deuterated tetrahydrofuran, with tetramethylsilane (TMS) as the internal standard. The unit of chemical shift is ppm and the unit of coupling constant is Hz. In .sup.1H NMR, 8 represents a chemical shift, s represents a singlet, d represents a doublet, t represents a triplet, q represents a quartet, and m represents a multiplet.

[0050] DCC refers to dicyclohexylcarbodiimide, THF refers to tetrahydrofuran, DCM refers refers to dichloromethane, EDCI to N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide, HOBT Refers to 1-hydroxybenzotriazole.

[0051] General synthesis method of ceramide compound.

Method A

##STR00010##

[0052] Step 1: place compound S1 (50 mmol), N-hydroxysuccinimide (6075 mmol, preferably 60 mmol), and DCC (6075 mmol, preferably 60 mmol) into a 250 ml round-bottomed flask, add 100 mL tetrahydrofuran, then stir at room temperature for 4 to 24 hours, and detect by TLC until compound S1 disappears completely. Post-treatment: filter the reaction system, collect the filtrate and use it directly for the next reaction.

[0053] step 2: add sphingosine base (4050 mmol, preferably 45 mmol) to the filtrate of the previous step, then stir at room temperature for 2472 hours, and detect by TLC until the sphingosine base completely disappears. Post-treatment: add saturated sodium bicarbonate aqueous solution to quench. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column to obtain the product (5070% yield).

Method B

##STR00011##

[0054] Place compound S1 (50 mmol), EDCI (6075 mmol, preferably 60 mmol), and HOBT (6075 mmol, preferably 60 mmol) into a 250 mL round-bottomed flask, add 100 mL DCM, then stir at room temperature for 1 hour, and then sphingosine base (4050 mmol, preferably 45 mmol) is added to the reaction system, and stirred at room temperature for 2472 hours until the sphingosine base disappears completely. Post-treatment: add water to quench. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column to obtain the product (5065% yield).

Example 1

[0055] The product of the condensation of ferulic acid and phytosphingosine by method A.

##STR00012##

[0056] .sup.1H NMR (400 MHZ, Methanol-d.sub.4) 7.45 (d, J=15.6 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.3, 1.9 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H), 6.53 (d, J=15.7 Hz, 1H), 4.23 (q, J=5.3 Hz, 1H), 3.88 (s, 3H), 3.80 (qd, J=11.2, 5.0 Hz, 2H), 3.64 (t, J=5.8 Hz, 1H), 3.56 (ddd, J=8.9, 5.9, 2.5 Hz, 1H), 1.68 (dtd, J=12.9, 7.2, 6.2, 3.5 Hz, 1H), 1.53 (d, J=8.4 Hz, 1H), 1.43 (ddd, J=12.4, 8.1, 3.7 Hz, 1H), 1.36-1.16 (m, 23H), 0.89 (t, J=6.7 Hz, 3H).

Example 2

[0057] The product of the condensation of ferulic acid and sphingosine base by method A.

##STR00013##

[0058] .sup.1H NMR (400 MHZ, Methanol-d.sub.4) 7.43 (d, J=15.7 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.2, 2.0 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H), 6.50 (d, J=15.7 Hz, 1H), 5.75-5.62 (m, 1H), 5.55-5.44 (m, 1H), 4.35 (t, J=7.0 Hz, 1H), 4.12 (t, J=7.4 Hz, 1H), 4.01-3.94 (m, 1H), 3.88 (s, 3H), 3.78-3.68 (m, 1H), 2.54-2.45 (m, 1H), 2.30-2.16 (m, 1H), 2.02 (p, J=7.2 Hz, 2H), 1.37-1.10 (m, 20H), 0.89 (t, J=6.9 Hz, 3H).

Example 3

[0059] The product of the condensation of ferulic acid and D-sphinganine base by method A.

##STR00014##

[0060] .sup.1H NMR (400 MHZ, Methanol-d.sub.4) 7.48 (d, J=15.7 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.06 (dd, J=8.2, 1.9 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.55 (d, J=15.7 Hz, 1H), 4.01-3.93 (m, 1H), 3.91 (s, 3H), 3.79 (d, J=5.0 Hz, 2H), 3.77-3.71 (m, 1H), 1.92-1.85 (m, 2H), 1.38-1.23 (m, 26H), 0.96-0.87 (m, 3H).

Example 4

[0061] The product of the condensation of trans-cinnamic acid and phytosphingosine by method A.

##STR00015##

[0062] .sup.1H NMR (400 MHZ, Methanol-d.sub.4) 7.60-7.50 (m, 3H), 7.42-7.31 (m, 3H), 6.71 (d, J=15.8 Hz, 1H), 4.25 (td, J=5.7, 4.2 Hz, 1H), 3.83 (dd, J=11.3, 4.3 Hz, 1H), 3.77 (dd, J=11.3, 5.8 Hz, 1H), 3.64 (t, J=5.8 Hz, 1H), 3.56 (ddd, J=9.1, 5.9, 2.5 Hz, 1H), 1.75-1.61 (m, 1H), 1.53 (d, J=9.1 Hz, 1H), 1.48-1.16 (m, 24H), 0.90 (t, J=6.8 Hz, 3H).

Example 5

[0063] The product of the condensation of royal jelly acid and phytosphingosine by method A.

##STR00016##

[0064] .sup.1H NMR (600 MHZ, Methanol-d.sub.4) 6.81 (dt, J=15.3, 7.0 Hz, 1H), 6.02 (dt, J=15.3, 1.5 Hz, 1H), 4.19 (td, J=5.8, 4.3 Hz, 1H), 3.81 (dd, J=11.3, 4.4 Hz, 1H), 3.76 (dd, J=11.2, 5.8 Hz, 1H), 3.62 (t, J=5.8 Hz, 1H), 3.58-3.53 (m, 3H), 2.23 (qd, J=7.2, 1.6 Hz, 2H), 1.57-1.49 (m, 5H), 1.39-1.29 (m, 32H), 0.92 (t, J=7.0 Hz, 3H).

Example 6

[0065] The product of the condensation of tretinoin and phytosphingosine by method B.

##STR00017##

[0066] .sup.1H NMR (400 MHZ, Methanol-d.sub.4) 7.01 (dd, J=15.0, 11.4 Hz, 1H), 6.32 (dd, J=23.7, 15.6 Hz, 2H), 6.21-6.09 (m, 2H), 5.93 (s, 1H), 4.17 (td, J=5.7, 4.4 Hz, 1H), 3.86-3.72 (m, 2H), 3.64 (t, J=5.8 Hz, 1H), 3.61-3.53 (m, 1H), 2.33 (d, J=1.1 Hz, 3H), 2.06 (t, J=6.5 Hz, 2H), 2.01 (d, J=1.1 Hz, 3H), 1.73 (d, J=1.0 Hz, 3H), 1.66 (ddp, J=8.8, 5.6, 2.9 Hz, 3H), 1.54-1.47 (m, 3H), 1.30 (d, J=4.9 Hz, 25H), 1.05 (s, 6H), 0.92 (t, J=6.8 Hz, 3H).

Example 7

[0067] The product of the condensation of sinapic acid and phytosphingosine by method B.

##STR00018##

[0068] .sup.1H NMR (400 MHZ, Methanol-d.sub.4) 7.47 (d, J=15.6 Hz, 1H), 6.88 (s, 2H), 6.58 (d, J=15.6 Hz, 1H), 4.26 (td, J=5.6, 4.3 Hz, 1H), 3.89 (s, 6H), 3.85-3.78 (m, 2H), 3.67 (t, J=5.8 Hz, 1H), 3.59 (ddd, J=9.0, 5.9, 2.6 Hz, 1H), 1.77-1.61 (m, 2H), 1.61-1.43 (m, 2H), 1.29 (dd, J=11.8, 5.4 Hz, 22H), 0.92 (t, J=6.8 Hz, 3H).

Example 8

[0069] The product of the condensation of caffeic acid and phytosphingosine by method B.

##STR00019##

[0070] .sup.1H NMR (400 MHZ, Methanol-d.sub.4) 7.53 (d, J=15.9 Hz, 1H), 7.02 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.2, 2.1 Hz, 1H), 6.76 (d, J=8.2 Hz, 1H), 6.24 (d, J=15.9 Hz, 1H), 4.20 (q, J=5.3 Hz, 1H), 3.78 (qd, J=11.2, 5.0 Hz, 2H), 3.62 (t, J=6.0 Hz, 1H), 3.50 (ddd, J=8.9, 6.0, 2.4 Hz, 1H), 1.64 (dtd, J=12.9, 7.2, 6.2, 3.5 Hz, 1H), 1.51 (d, J=8.4 Hz, 1H), 1.43 (ddd, J=12.4, 8.1, 3.7 Hz, 1H), 1.36-1.16 (m, 23H), 0.89 (t, J=6.7 Hz, 3H).

Example 9

[0071] The product of the condensation of sorbic acid and phytosphingosine by method B.

##STR00020##

[0072] .sup.1H NMR (400 MHZ, Methanol-d.sub.4) 7.70 (td, J=6.8, 3.8 Hz, 1H), 7.32-7.23 (m, 1H), 7.14 (dd, J=15.1, 10.6 Hz, 1H), 6.25 (ddd, J=15.1, 10.6, 1.7 Hz, 1H), 6.13 (dq, J=15.2, 6.5 Hz, 1H), 6.00 (d, J=15.1 Hz, 1H), 4.20 (td, J=5.7, 4.3 Hz, 1H), 3.79 (qd, J=11.2, 5.1 Hz, 2H), 3.62 (t, J=5.8 Hz, 1H), 3.55 (ddd, J=8.9, 5.9, 2.5 Hz, 1H), 1.86 (dd, J=6.6, 1.4 Hz, 3H), 1.74-1.61 (m, 1H), 1.54 (d, J=9.0 Hz, 1H), 1.39-1.30 (m, 24H), 0.95-0.86 (m, 3H).

Example 10

[0073] The antioxidant-ABTS method was used to test the antioxidant properties of the ceramide compound prepared in Examples 1, 2, 3, and 5.

[0074] Experimental principle: The use of ABTS to evaluate the antioxidant capacity of samples was first proposed by Miller et al. (1993). The method currently used is generally the method improved by Re et al. (1999). This method utilizes the fact that ABTS can be oxidized by a series of compounds such as potassium persulfate, hydrogen peroxide, and manganese dioxide to generate blue-green ABTS+ cationic free radicals with a maximum absorption peak at 734 nm. Under the action of antioxidants, ABTS+ is reduced to colorless ABTS. By measuring the absorbance value at 734 nm, the antioxidant capacity of the reactant can be determined.

[0075] ABTS free radical scavenging test antioxidant performance: Mix 3 mL ABTS aqueous solution (12 mmol/L) and 3 mL potassium persulfate solution (2.45 mmol/L) evenly, and keep it stable for 12 to 16 hours at room temperature in the dark. Use DMSO as the dilution medium, select an appropriate dilution ratio, and adjust the absorbance of the potassium persulfate solution at a wavelength of 734 nm to 0.7000.025. Add samples of different concentrations and shake well, place in the dark for 10 minutes, and measure the absorbance value at 734 nm.

[0076] The results are shown in FIG. 1. Control 1 is Ceramide 3B, and Control 2 is Ceramide 3.

[0077] It can be seen that the compound of the present invention has a better antioxidant effect than the existing ceramide compound, and its free radical scavenging rate is generally 15 to 75% higher.

[0078] Above are only preferred embodiments of the present disclosure and are not intended to limit the present disclosure. Any modification, equivalent replacement and improvement made within spirit and principle of the present disclosure should be included in protective scope of the present disclosure.