Spermine derivatives and their therapeutic uses in diseases

Abstract

The present invention relates to spermine derivatives and their therapeutic uses in diseases. Specifically, the present invention relates to spermine derivatives shown in formula I, pharmaceutical compositions containing the same, and their uses in treating inflammatory diseases and autoimmune diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of treatment of inflammatory diseases and tumors. Specifically, the present invention relates to spermine derivatives and their therapeutic uses in inflammatory diseases and autoimmune diseases. Background Art

[0002] Spermine is a polyamine substance containing two amino groups and two imino groups. It is produced in the body by putrescine (butanediamine) and S-adenosylmethionine catalyzed by various enzymes. It and spermidine are both present in bacteria and most animal cells and are important substances for promoting cell proliferation. Under acidic conditions, it exhibits the characteristics of polycationic polyamines and can bind to DNA in viruses and bacteria. It makes DNA molecules more stable and flexible, and is also one of the necessary components in cell culture medium.

[0003] Spermine plays a key role in regulating cell growth, division, differentiation and proliferation of animal tissues, and is an important cell growth and proliferation factor. Pharmacological studies have shown that spermine and spermidine also have antioxidant, anti-aging, anti-inflammatory and immunomodulatory effects.

[0004] In addition, dietary intake and intestinal flora production are also important sources of spermidine for the human body. Many foods, such as milk, soy products and cheese, are rich in spermidine. Spermidine ingested through diet will be quickly absorbed and distributed by the intestines without being degraded. The average daily nutritional intake of spermidine is about 7 to 25 mg, or even higher, which is beneficial to human health.

[0005] The therapeutic uses of spermine and spermidine have been reported in the prior art, for example, the therapeutic effect of spermine in periprosthetic osteolysis (CN111096959A); the use of spermidine in weight loss (CN 109820844 A), treatment of nerve cell damage (CN107929270 A), treatment of aneurysms (CN 110548020 A) and treatment of hepatitis B virus (CN111529516A).

[0006] Inflammation or inflammatory diseases are associated with inflammatory cytokines, also known as inflammatory cytokines, which are produced by lymphocytes and macrophages and are involved in inflammatory responses associated with bacterial or viral infections, tumors or tissue damage. Known inflammatory cytokines include interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), type I interferons, tumor necrosis factor (TNF-α) and GM-CSF, etc.

[0007] The development of more spermine derivatives and / or analogs will help promote its therapeutic use in inflammatory diseases and tumors. Summary of the invention

[0008] After unexpectedly discovering that spermine has an immunosuppressive effect, the present invention further optimized and modified the spermine compound based on the spermine molecular structure, and finally obtained a new spermine derivative SD1 with a broad immunosuppressive effect. Compound SD1 can significantly inhibit the immune inflammatory response of body cells to type I interferon (IFN-I) and interleukin (IL)-2; through the systemic lupus erythematosus experimental animal model, we confirmed that the spermine derivative SD1 significantly inhibited the immune inflammatory response in vivo, proving that it has the effect of an immune inflammatory inhibitor.

[0009] Based on the above findings, in the first aspect, the present invention provides a spermine derivative or a pharmaceutically acceptable salt thereof, wherein the spermine derivative has the following structure:

[0010]

[0011] In a second aspect, the present invention provides a pharmaceutical composition comprising the spermine derivative of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0012] In a third aspect, the present invention provides use of a spermine derivative or a pharmaceutically acceptable salt thereof according to the present invention, or a pharmaceutical composition according to the present invention, in the preparation of a medicament for treating a disease selected from an inflammatory disease or an autoimmune disease.

[0013] In a specific embodiment, there is provided a use of a spermine derivative or a pharmaceutically acceptable salt thereof according to the present invention, or a pharmaceutical composition according to the present invention, in the preparation of a pharmaceutical composition for treating a disease selected from acute inflammation, chronic inflammation, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, neurodegenerative diseases associated with inflammation, and tumors.

[0014] In a specific embodiment, the spermine derivative or a pharmaceutically acceptable salt thereof of the present invention exerts an anti-inflammatory effect by inhibiting the effect of inflammatory cytokines. Preferably, the inflammatory cytokines are selected from type I interferon, IFN-β and IL-2.

[0015] In a fourth aspect, the present invention provides a method for preparing a spermine derivative as shown in formula I or a pharmaceutically acceptable salt thereof, the method comprising the step of reacting 2,2-phenylpropionic acid with spermine.

[0016] In a fifth aspect, the present invention provides a method for treating a disease, the method comprising administering a therapeutically effective amount of a spermine derivative or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition according to the present invention to a subject in need thereof; the disease is selected from an inflammatory disease or an autoimmune disease.

[0017] In a sixth aspect, the present invention provides a method for treating systemic lupus erythematosus, the method comprising administering a therapeutically effective amount of the spermine derivative or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition according to the present invention to a subject suffering from or suspected of suffering from, or at risk of, systemic lupus erythematosus; preferably, the spermine derivative or a pharmaceutically acceptable salt thereof exerts a therapeutic effect by inhibiting type I interferon. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1A It was shown that SD1 inhibited the activity of interferon response elements in mouse macrophages stimulated by IFN-β; Figure 1B It was shown that SD1 inhibited the mRNA expression of interferon-stimulated genes, Ifit1 and Mx1 in mouse macrophages stimulated by IFN-α.

[0019] Figure 2A and Figure 2B It was shown that SD1 (10 μM) inhibited the cell response to type I interferon ( Figure 2A ) and interleukin (IL)-2 ( Figure 2B )'s immune inflammatory response.

[0020] FIG. 3A to FIG. 3C It was shown that SD1 inhibited the expression of ISG genes Ifit1, Isg15 and Rsad2 in peripheral blood cells of SLE modeling mice.

[0021] Figure 4A and Figure 4B It was shown that SD1 (10 μM) inhibited interleukin (IL)-2 expression and NFAT reporter gene activity in human Jurkat T cells.

[0022] Figure 5 Displays the results of H NMR spectrum detection.

[0023] In the figure, "*" indicates P < 0.05, "**" indicates P < 0.01, and "***" indicates P < 0.001. Unpaired two-tailed T test was used for data analysis of the two groups. DETAILED DESCRIPTION

[0024] In the first aspect of the present invention, there is provided a spermine derivative represented by formula I or a pharmaceutically acceptable salt thereof:

[0025]

[0026]

[0027] In a specific embodiment, the compound represented by formula I of the present invention is obtained by the following synthesis steps:

[0028]

[0029] In a specific embodiment, the compound represented by formula I of the present invention is obtained by reacting 2,2-phenylpropionic acid with spermine.

[0030] Salts of the present invention can be synthesized by conventional chemical methods. Acid addition salts (mono or di-salts) can be formed with a wide variety of inorganic and organic acids. Examples of acid addition salts include mono or di-salts formed with acids selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphor, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid).

[0031] A particular group of salts consists of salts formed from acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, methanesulfonic acid (mesylate), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, propionic acid, butyric acid, malonic acid, glucuronic acid and lactobionic acid. One specific salt is the hydrochloride. Another specific salt is the acetate. Another specific salt is the phosphate.

[0032] If the compound is anionic, or has a functional group that can be anionic (e.g., -COOH can be -COO - ), then it can form a salt with an organic or inorganic base to generate a suitable cation. Examples of suitable inorganic cations include, but are not limited to: alkali metal ions (such as Li + 、Na + and K + ), alkaline earth metal cations (such as Ca 2+ and Mg 2+ ) and other cations (such as Al 3+ or Zn + Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4 + ) and substituted ammonium ions (e.g., NH3R + NH2R2 + 、NHR3 + NR4 +). Some examples of suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + .

[0033] In a specific embodiment of the present invention, the spermine derivative or its pharmaceutically acceptable salt can be formulated into a pharmaceutical composition with one or more conventional carriers and / or excipients according to techniques well known in the art. Generally, the pharmaceutical composition of the present invention is suitable for oral or parenteral administration, for example, by intradermal, subcutaneous, intraperitoneal or intravenous injection. Therefore, suitable pharmaceutical dosage forms include plain tablets or coated tablets, capsules, suspensions and solutions, which contain active ingredients and optionally contain one or more conventional inert carriers and / or diluents, such as corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, octadecyl alcohol, carboxymethyl cellulose or fatty substances (such as stearin) or any suitable mixture of these substances.

[0034] In a specific embodiment, the pharmaceutical composition is formulated as tablets, capsules, granules, oral liquids, granules, dropping pills or micropills.

[0035] In a specific embodiment, the pharmaceutical composition comprises a spermine derivative or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable carriers selected from the following: for example, diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes and combinations thereof.

[0036] In a specific embodiment, the pharmaceutical composition comprises a tablet or gelatin capsule of a spermine derivative or a pharmaceutically acceptable salt thereof as an active ingredient and one or more of the following pharmaceutically acceptable carriers:

[0037] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0038] b) lubricants, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0039] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary

[0040] d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and

[0041] e) Absorbents, colorants, flavorings and sweeteners.

[0042] The spermine derivative or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same according to the present invention can treat inflammatory diseases or autoimmune diseases by inhibiting the immune inflammatory response in a subject.

[0043] As used herein, the term "treating" includes treating a disease or condition described herein in a subject, such as a human, and includes: (i) inhibiting the disease or condition, i.e., preventing its occurrence; (ii) relieving the disease or condition, i.e., causing regression of the condition; (iii) slowing the progression of the disease; and / or (iv) inhibiting, relieving or slowing the progression of one or more symptoms of the disease or condition.

[0044] As used herein, the term "treatment" includes prophylactic administration of a drug or composition described herein to a subject to inhibit or hinder the occurrence of a disease or condition in a subject in need thereof.

[0045] The terms "patient", "subject", "individual" and the like are used interchangeably herein and refer to any animal or its cells suitable for the methods described herein, whether in vitro or in situ. In certain non-limiting embodiments, the patient, subject or individual is a human.

[0046] As used herein, "inflammatory diseases" or "autoimmune diseases" include, but are not limited to, acute and chronic inflammatory diseases, such as inflammatory bowel disease (Crohn's disease, ulcerative colitis), rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis and / or neurodegenerative diseases associated with inflammation.

[0047] In a specific embodiment, the spermine derivatives or pharmaceutically acceptable salts thereof as described herein, or pharmaceutical compositions comprising the same, for treating diseases can be used for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, instillation, transdermal or topical administration) and rectal administration. Topical administration also includes inhalation or intranasal administration. The spermine derivatives or pharmaceutically acceptable salts thereof of the present invention, or pharmaceutical compositions comprising the same, can be prepared in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). Tablets can be added with film coatings or enteric coatings according to methods known in the art.

[0048] The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention. Experimental methods in the examples of the present invention that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or commodity manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0049] Example 1. Preparation and confirmation of arginine derivatives

[0050] Preparation and confirmation of SD1

[0051] preparation:

[0052] 2,2-phenylpropionic acid (565 mg, 2.5 mM), CDI (412 mg, 2.6 mM), and DCM (10 mL) were added to a 25 mL reaction bottle in sequence. After reacting for 30 min in an ice bath, spermine (202 mg, 1 mM) was slowly added and reacted at room temperature overnight. TLC monitoring showed that the reaction was not complete. After heating to 40°C and continuing the reaction for 1 h, TLC monitoring showed no change. Saturated 20 mL NaHCO3 and DCM (20 mL x 3) were added for extraction three times. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by a 200-300 mesh alkaline silica gel column to give 220 mg of the target compound JA-1-29. The yield was 40%. MS: [M+H] 619.55. 1H NMR (400 MHz, CD3OD) δ7.36-7.31 (m, 8H), 7.29-7.24 (m, 12H), 3.29 (t, J = 6.6 Hz, 4H), 2.57-2.45 (m, 8H), 1.94 (s, 6H), 1.72-1.63 (m, 4H), 1.53-1.42 (m 4H).

[0053] Confirmation: After the compound is synthesized, the product is verified by H NMR. The results are shown in Figure 5 .

[0054] Example 2. SD1 (10 μM) inhibits the response of mouse macrophages to interferon stimulation.

[0055] (A) RAW264.7 reporter cell line pretreated with SD1

[0056] The RAW264.7 cell line with the ISG promoter reporter gene was purchased from Invivogen and cultured in DMEM containing 10% fetal bovine serum (FBS). The cells were pretreated with 10 μM SD1 for 3 hours. The SD1 needed to be prepared into a fresh concentrate with a concentration of 20 mM using DMSO before each use and diluted as needed. The cells were then stimulated with recombinant mouse interferon-β (mIFN-β) at a dose of 1 ng / ml for 7 hours, and the cell culture supernatant was obtained. At the same time, the luciferase substrate was prepared, and the substrate powder was dissolved in 25 ml of deionized water under light-proof conditions, and stored at -80°C after aliquoting. Transfer 20 μl of the culture supernatant to a 96-well ELISA plate dedicated to Luciferase, and detect it using Thermo's VARIOSKAN FLASH ELISA reader ( Figure 1A ).

[0057] (B) Mouse primary cells pretreated with SD1

[0058] Mouse primary peritoneal macrophages (PMs) were isolated from C57BL / 6 mice (6-8 weeks old, male) 3 days after intraperitoneal injection of 2 ml of 3% thioglycolate (dissolved in double distilled water at a ratio of % m / v and then sterilized by high pressure), and cultured in endotoxin-free high-glucose DMEM medium containing 10% FBS.

[0059] The next day, fresh complete medium was replaced and cells were pretreated with 10 μM SD1 for 3 hours. An equal volume of DMSO was added to the culture medium for cells in the control group (dose 0). After that, mIFN-β (dose 500 pg / ml) was used to stimulate the cells for 3 hours, and RNA was subsequently extracted for reverse transcription. Using commercially available primers and conditions recommended by the manufacturer, the mRNA content of interferon-stimulated genes (ISGs) (including Ifit1 and Mx1) was detected and analyzed by fluorescence quantitative PCR (qPCR) ( Figure 1B ).

[0060] Experimental results and discussion:

[0061] SD1 pretreatment can effectively inhibit the ISG promoter activity in RAW264.7 cells (see Figure 1A ), and at the same time, it was verified by primary cells that pretreatment with SD1 could also reduce the expression of Ifit1 and MX1, which are downstream of type I interferon.

[0062] The results suggest that SD1 has a significant inhibitory effect on the effects of inflammatory factors (such as type I interferon), indicating that SD1 has an anti-inflammatory function.

[0063] Example 3. SD1 (10 μM) inhibits the body's immune inflammatory response.

[0064] (A) Mouse primary cells pretreated with SD1

[0065] PM were obtained using the method in Example 2 and cultured in endotoxin-free high-glucose DMEM medium containing 10% FBS. Cells were pretreated with 10 μM SD1 for 3 hours, and an equal volume of DMSO was added to the culture medium for cells in the control group (dose 0). Afterwards, cells were stimulated with mIFN-β (dose 500 pg / ml) for different periods of time. Subsequently, total cell protein was extracted, and Western blot was used to detect the activation of type I interferon signaling pathway ( Figure 2A ).

[0066] (B) Mouse spleen cells pretreated with SD1

[0067] Mouse spleen single cells were isolated from the spleen of male mice aged 6-8 weeks. Freshly obtained cells were cultured in RPMI1640 containing 10% FBS, non-essential amino acids and β-mercaptoethanol. Cells were pretreated with 10 μM SD1 for 3 hours, and an equal volume of DMSO was added to the culture medium for cells in the control group (dose 0). Subsequently, cells were stimulated with 10 ng / ml recombinant mouse interleukin (IL)-2 for different periods of time, and cells were collected to extract total cell protein. Western blot was used to detect the activation of type I interferon signaling pathway ( Figure 2B ).

[0068] Experimental results and discussion:

[0069] The experimental results showed that SD1 can effectively inhibit the activation of the JAK-STAT signaling pathway mediated by cytokines (such as IFN-β and IL-2) in different cells, such as the levels of p-JAK1, p-TYK2 and p-STAT1 / 2 were inhibited ( Figure 2A , Figure 2B ). This suggests that SD1 effectively inhibits the body's immune response.

[0070] Example 4. SD1 inhibits ISG gene expression in peripheral blood cells of SLE modeling mice.

[0071] The hydrocarbon compound pristane (also known as pristane, 2,6,10,14-tetramethylpentadecane) can be used to induce lupus-like symptoms in mice, which are the same as those in human patients (Zhuang, H et al. Animal Models of Interferon Signature Positive Lupus. Front Immunol. 2015. 6: p. 291; Nacionales, DC et al. (2006). Type I interferon production by tertiary lymphoid tissue developing inresponse to 2, 6, 10, 14-tetramethyl-pentadecane (pristane). The American journal of pathology 168, 1227-1240; Reeves, WH et al. (2009). Induction of autoimmunity by pristane and other naturally occurring hydrocarbons. Trends Immunol. 30, 455-464). The type I interferon in the pristane-induced SLE mouse model appears overactivated and exhibits a strong "interferon signature". It is a recognized model that can be used to simulate the overexpression of type I interferon in SLE patients, and can help clarify the pathogenesis of SLE and find therapeutic targets.

[0072] First, C57 female mice were pretreated by intraperitoneal injection of PBS and SD1 (10 mg / kg, once a day, for 5 consecutive days). Then, SLE mice were induced by intraperitoneal injection of pristane (500 μl / mouse). On the fourth and sixth days after the injection of pristane, blood was collected from the fundus vascular plexus, and total RNA from peripheral blood was obtained using Trizol to detect the effect of spermine on the early type I interferon effect of pristane-induced mice.

[0073] Experimental results and discussion:

[0074] SD1 pretreatment can inhibit the expression of ISG in peripheral blood cells of SLE model mice ( FIG. 3A to FIG. 3C ).

[0075] Example 5. SD1 (10 μM) inhibits interleukin (IL)-2 expression and NFAT reporter gene activity in human Jurkat T cells.

[0076] (A) SD1 treatment of Jurkat cells

[0077] Human T lymphocyte leukemia Jurkat cells were cultured in RPMI1640 medium containing 10% FBS. Cells were pretreated with 10 μM SD1 for 3 hours, and an equal volume of DMSO was added to the culture medium for the cells in the control group (dose 0). Phorbol ester (PMA, 50 ng / ml) and ionomycin (1 μg / μ) were then used to stimulate for 24 hours, and the cell culture supernatant was collected to detect IL-2 levels using enzyme-linked immunosorbent assay (ELISA) ( Figure 4A ).

[0078] (B) SD1 treatment of Jurkat-Lucia NFAT reporter gene cell line

[0079] The Jurkat-Lucia NFAT reporter gene cell line was purchased from invivogen and cultured in RPMI1640 medium containing 10% FBS. The cells were pretreated with 10μM SD1 for 3 hours, and the cells in the control group (dose 0) had an equal volume of DMSO added to the culture medium. Subsequently, PMA (50ng / ml) and ionomycin (300ng / ml) were used to stimulate for 24 hours, and the cell culture supernatant was obtained. At the same time, the luciferase substrate was prepared, and the substrate powder was dissolved in 25ml of deionized water under light-proof conditions, and stored at -80°C after aliquoting. Transfer 20μl of the culture supernatant to a 96-well ELISA plate dedicated to Luciferase, and use Thermo's VARIOSKAN FLASH ELISA reader for detection ( Figure 4B ).

[0080] Experimental results and discussion:

[0081] The experimental results showed that SD1 can effectively inhibit the IL-2 secretion level of activated Jurkat cells, and also confirmed that SD1 effectively inhibits the transcriptional activity of NFAT, a key transcription factor for T cell activation. The above results indicate that SD1 has a significant immunosuppressive function in T cells ( Figure 4A , Figure 4B ).

Claims

1. A spermine derivative or a pharmaceutically acceptable salt thereof, wherein the spermine derivative has a structure shown in Formula I:

2. The spermine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is selected from acetate, hydrochloride, phosphate, sulfate, citrate, lactate, succinate, maleate, malate, isethionate, fumarate, benzenesulfonate and toluenesulfonate.

3. A pharmaceutical composition comprising the spermine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, and one or more pharmaceutically acceptable carriers.

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is formulated for oral or parenteral administration.

5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is formulated into tablets, capsules, granules, oral liquids, granules, dropping pills or micropills for oral administration.

6. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is formulated as a solution or a lyophilized preparation for intradermal, subcutaneous, intratumoral or intramuscular injection administration.

7. Use of the spermine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, or the pharmaceutical composition according to any one of claims 3 to 6, in the preparation of a medicament for treating a disease, wherein the disease is selected from an inflammatory disease or an autoimmune disease.

8. The use according to claim 7, wherein the disease is selected from acute inflammation and chronic inflammation.

9. The use according to claim 7, wherein the disease is selected from Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and neurodegenerative diseases associated with inflammation.

10. A method for preparing a spermine derivative represented by formula I, the method comprising: 1) reacting 2,2-phenylpropionic acid, CDI and DCM; and 2) Add spermine and react at room temperature overnight;

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