KR20080065086A - Ceramide derivatives, pharmaceutically acceptable salts thereof, preparation method and pharmaceutical composition for the prevention and treatment of cancers containing the same as an active ingredient - Google Patents

Abstract

A ceramide derivative is provided to change equilibrium of sphingolipid metabolites by mimicking the activity of ceramide and controlling related enzymes, thereby being developed as a controlling agent of apoptosis induction or a prophylactic and therapeutic agent of cancer. A ceramide derivative is represented by a formula(1) and is prepared by reacting a compound represented by a formula(2) with an alkyne compound, wherein R1 is C1-35 alkyl which may be substituted or unsubstituted with at least one substitutent selected from the group consisting of halogen, hydroxy, amino, amino substituted with at least one C1-20 alkyl, thiol, cyano, nitro, sulfonyl, phenyl, C1-30 alkoxy, C1-30 alkyl, C1-30 haloalkyl, C1-30 hydroxyalkyl, C1-30 alkoxyalkyl, C5-10 aryl, C5-10 heteroaryl, C5-10 arylalkyl and C5-10 heteroarylalkyl; a bond is a single bond or a double bond; and R2 is hydroxy when the bond is the single bond, and R2 is H when the bond is the double bond. A controlling agent for inducing apoptosis or a pharmaceutical composition for preventing and treating cancer comprises the ceramide derivative or a pharmaceutically acceptable salt thereof as an effective ingredient.

Description

Ceramide derivatives, pharmaceutically acceptable salts thereof, preparation method and pharmaceutical composition for the prevention and treatment of cancers containing the same as an active ingredient}

1 shows the results of DNA analysis of cancer cells killed by C-2 ceramide and the derivative of Formula 1 of the present invention,

2 shows the metabolism of spinolipids.

The present invention relates to a ceramide derivative, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing and treating cancer containing the same as an active ingredient, in particular, changing the balance of spinolipide metabolites and abnormally. Various diseases caused by damaged cells, in particular, ceramide derivatives that can be developed as cancer prevention and treatment, pharmaceutically acceptable salts thereof, preparation methods thereof, and pharmaceutical compositions for preventing and treating cancer containing the same as active ingredients It is about.

Apoptosis refers to the destruction or suicide of cells in eukaryotic cells (Kerr, et al., British Journal of Cancer, 26, 239-257, 1972), regulating the normal development of animals and unnecessary or abnormal In addition to requiring energy to maintain homeostasis of individuals, such as the removal of damaged cells, they have characteristic cell types (Thompson, C. B, Science, 267, 1456-1462, 1995; and Raff. M, Nature, 396, 119-122, 1998). This apoptosis causes the cells to contract with the surrounding cells, which are in contact with the cells, and into blebbing of the cell membrane, further condensation of the nucleus and small oligonucleotides of DNA in the nucleus. It is cut into sections to form an apoptotic body. The apoptosis thus formed undergoes a series of processes such as phagocytosis by macrophages, resulting in cell death. Most morphological changes are caused by aspartic acid-specific cysteine protease (caspase), an activating enzyme during cell death (Hengartner, MO, Nature, 407, 770-776, 2000; Nicholson, DW). And Thornberry.NA, Trends.Biochem.Sci., 22, 290-306, 1997; Budihardjo. I., et al., Annu. Rev. Cell Dev. Biol., 15, 269-290, 1999; and Degterev. A., et al., Oncogene, 22, 8543-8567, 2003).

Apoptosis and proliferation are opposite intracellular processes that maintain the homeostasis of multicellular organisms. In recent years, a number of common regulators, such as p53, p21, retinoblastoma (Rb) proteins, protein dephosphorylation enzymes, which regulate cell division, are in opposing systems of apoptosis and cell proliferation. cdc25, c-Myc, a tumor protein, E2F-1, a transcriptional regulator, and E1A, a viral tumor protein, have been reported to control apoptosis. In addition, cyclin-dependent kinase-2, an important protein that regulates cell division, is required for its activation not only in cell division but also in apoptosis process. When selectively inhibiting the activity of these enzymes, the progression of apoptosis is blocked. In addition, there is a series of reports (Ying Hua Jin, et. Al., J. Biol. Chem., 276, 30256-30263, 2000) that cell growth returns to normal levels.

Cell Survival-Death Reversible Controlling Technology is a next-generation key technology for developing apoptosis modulating therapy. Recent studies have shown that the pathogenesis of a variety of diseases is primarily caused by abnormal functioning of apoptosis signaling machinery (Nicholson, DW, Nature , 407, 810-816, 2000). Apoptosis therapy is useful for treating diseases by blocking or progressing the disease by abnormal cell death by inducing or inhibiting apoptosis and converting abnormal cells into normal cells.

Diseases applied to apoptosis control therapy that are competitively developed around the world include leukemia, cancer, dementia, Parkinson's disease, various senile and degenerative diseases such as AIDS and aging. In addition, recent studies have shown that the onset of death in most diseases is ultimately due to abnormal functioning of the apoptosis signaling machinery, and thus, apoptosis control therapy has been spotlighted as a useful technology for treating a wider range of diseases. I am getting it.

Meanwhile, spiningolipid is a lipid (lipid) having a spingosine or a similar long-chain aminoalcohol. (Glycerol phospholipid). Spinolipids are degraded by hydrolytic enzymes in the lysosomes in the cytoplasm, which accumulate in the lysosomes when one of these enzymes is inherently deleted due to genetic abnormalities. Its metabolites, ceramide, spingosine-1-phosphate (S1P), and spingosine-1-phosphocoline are secondary to regulate various intracellular delivery processes. It acts as a second messenger. In addition, ceramide has pro-apoptotic and anti-proliferative activity, while its metabolite, spinocin 1-phosphate, has the opposite effect. Therefore, it is possible to regulate intracellular delivery processes that regulate the balance of spinoid metabolism through regulation of enzymes involved in spinlipid metabolism or local delivery of spinoids.

Ceramides play a central role in spinolipid metabolism and as pre-differentiation of all major spinolipids (see FIG. 2 ). The amide bonds of ceramides are broken down into fatty acids and spinosine by ceramide degrading enzymes. The resulting spinosine is itself bioactive and can act as a substrate capable of forming spinosine 1-phosphate by spinosine kinase.

Currently, 1,2,3-triazole is attracting attention in drug development among bioisosteres of various amide moieties. Triazoles can transform into the topological and electronic properties of amide bonds and are actively involved in hydrogen bonding and dipole-dipole interactions.

Accordingly, the present inventors have synthesized hydrolytically stable ceramide derivatives by introducing 1,2,3-triazole into spinolipid, thereby mimicking the activity of ceramide, as well as modulating related enzymes, The present invention has been completed by finding a change in balance and finding that the ceramide derivative of the present invention can be developed as a prophylactic and therapeutic agent for various diseases caused by abnormally damaged cells, especially cancer.

It is an object of the present invention to provide a ceramide derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing and treating cancer containing the same as an active ingredient.

In order to achieve the above object, the present invention provides a ceramide derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for preventing and treating cancer containing the same as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel ceramide derivative represented by the following formula (1).

In the above formula

R ₁ is an C ₁ to C ₃₅ alkyl group which is unsubstituted or substituted with 1 or 2 or more substituents,

When the alkyl group is substituted, the substituent is halogen, hydroxy group, amino group, amino group substituted with 1 or 2 or more C ₁ ~ C ₂₀ alkyl group, thiol group, cyano, nitro group, sulfonyl group, phenyl group, C ₁ ~ C ₃₀ Alkoxy group, C ₁ to C ₃₀ alkyl group, C ₁ to C ₃₀ haloalkyl group, C ₁ to C ₃₀ hydroxyalkyl group, C ₁ to C ₃₀ alkoxyalkyl group, C ₅ to C ₁₀ aryl group, C ₅ to C ₁₀ heteroaryl group, C ₅ ~ C ₁₀ arylalkyl group or C ₅ ~ C ₁₀ heteroarylalkyl group,

는 단일결합 또는 이중결합이고,

Is a single bond or a double bond,

R ₂ is a hydroxy group when the bond is a single bond,

When the bond is a double bond, it is hydrogen.

Preferably,

R ₁ is a C ₁ to C ₃₀ alkyl group which is unsubstituted or substituted with 1 or 2 or more substituents, and when the alkyl group is substituted, the substituent is a halogen, a hydroxy group, an amino group, 1 or 2 or more C ₁ to C ₁₅ alkyl group Amino group, thiol group, cyano group, nitro group, sulfonyl group, phenyl group, C ₁ ~ C ₂₀ alkoxy group, C ₁ ~ C ₂₀ alkyl group, C ₁ ~ C ₂₀ haloalkyl group, C ₁ ~ C ₂₀ substituted with Hydroxyalkyl group, C ₁ to C ₂₀ alkoxyalkyl group, C ₅ to C ₈ aryl group, C ₅ to C ₈ heteroaryl group, C ₅ to C ₈ arylalkyl group or C ₅ to C ₈ heteroaryl An alkyl group,

는 단일결합 또는 이중결합이고,

Is a single bond or a double bond,

R ₂ is a hydroxy group when the bond is a single bond,

When the bond is a double bond, it is hydrogen.

More preferably,

R ₁ is a C ₁ to C ₂₅ alkyl group which is unsubstituted or substituted with 1 or 2 or more substituents, and when the alkyl group is substituted, the substituent is a halogen, a hydroxy group, an amino group, 1 or 2 or more C ₁ to C ₁₀ alkyl group An amino group substituted with a thiol group, a phenyl group, a C ₁ to C ₂₀ alkyl group, a C ₁ to C ₂₀ haloalkyl group or a C ₁ to C ₂₀ hydroxyalkyl group,

는 단일결합 또는 이중결합이고,

Is a single bond or a double bond,

R ₂ is a hydroxy group when the bond is a single bond,

When the bond is a double bond, it is hydrogen.

Most preferably,

R ₁ is an C ₁ ~ C ₂₅ alkyl group which is unsubstituted or substituted with 1 or 2 or more substituents, and when the alkyl group is substituted, the substituent is a hydroxy group,

는 단일결합 또는 이중결합이고,

Is a single bond or a double bond,

R ₂ is a hydroxy group when the bond is a single bond,

When the bond is a double bond, it is hydrogen.

In the derivative of Formula 1 according to the present invention, the alkyl group is meant to include a linear or branched alkyl group.

Preferred examples of the ceramide derivative of the novel structure represented by Formula 1 according to the present invention are as follows:

1) (2S, 3S, 4R) -2- (4-propyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

2) (2S, 3S, 4R) -2- (4-butyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

3) (2S, 3S, 4R) -2- (4-pentyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

4) (2S, 3S, 4R) -2- (4-hexyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

5) (2S, 3S, 4R) -2- (4-heptyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

6) (2S, 3S, 4R) -2- (4-decyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

7) (2S, 3S, 4R) -2- (4-tridecyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

8) (2S, 3S, 4R) -2- (4-hexadecyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

9) (2S, 3S, 4R) -2- (4-tricosyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

10) (2S, 3S, 4R) -2- (4-tetracosyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

11) (2S, 3S, 4R) -2- (4-pentacosyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

12) (2S, 3S, 4R) -2- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

13) (2S, 3S, 4R) -2- (4- (hydroxyethyl) -1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

14) (2S, 3S, 4R) -2- (4- (hydroxypropyl) -1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

15) (2S, 3S, 4R) -2- (4- (hydroxybutyl) -1H-1,2,3-triazol-1-yl) octane-1,3,4-triol;

16) (2S, 3R, E) -2- (4-propyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

17) (2S, 3R, E) -2- (4-butyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

18) (2S, 3R, E) -2- (4-pentyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

19) (2S, 3R, E) -2- (4-hexyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

20) (2S, 3R, E) -2- (4-heptyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

21) (2S, 3R, E) -2- (4-decyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

22) (2S, 3R, E) -2- (4-tridecyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

23) (2S, 3R, E) -2- (4-hexadecyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

24) (2S, 3R, E) -2- (4-tricosyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

25) (2S, 3R, E) -2- (4-tetracosyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

26) (2S, 3R, E) -2- (4-pentacosyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

27) (2S, 3R, E) -2- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

28) (2S, 3R, E) -2- (4- (2-hydroxyethyl) -1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol;

29) (2S, 3R, E) -2- (4- (3-hydroxypropofyl) -1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol ; And

30) (2S, 3R, E) -2- (4- (4-hydroxybutyl) -1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol.

The novel ceramide derivative represented by Formula 1 according to the present invention can be used in the form of a pharmaceutically acceptable salt. As the salts, acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful. Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid, male Acids, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid, and the like can be used. Examples of suitable inorganic acids include halogen acids such as hydrochloric acid and sulfuric acid; Phosphoric acid and the like can be used.

The ceramide derivative represented by Chemical Formula 1 according to the present invention may include all salts, hydrates, and solvates that can be prepared by conventional methods, as well as pharmaceutically acceptable salts.

In addition, the present invention provides a method for preparing a ceramide derivative represented by the formula (1).

In Scheme 1,

R ₁ is any one selected from various substituents R ₁ defined in Formula 1,

는 단일결합 또는 이중결합이고,

Is a single bond or a double bond,

R ₂ is a hydroxy group when the bond is a single bond,

When the bond is a double bond, it is hydrogen.

Hereinafter, a method for preparing a derivative of Chemical Formula 1 according to the present invention will be described in detail.

Derivatives of formula (1) according to the present invention can be prepared by reacting a compound of formula (2) as a starting material with a terminal alkyne compound having various substituents R ₁ . The preparation method may provide a ceramide derivative having various substituents according to the substituent R ₁ of another starting material, as a single step reaction.

Specifically, the compound of Formula 2 is mixed with the alkane, 0.5 M copper sulfide and 1 M sodium ascorbate at room temperature with 0.2 to 0.5 M t-butyl alcohol / water (1: 1, v / v) mixed solvent. After mixing, the target compound of Chemical Formula 1 may be synthesized by reacting at 50 ° C. The reaction product obtained after synthesis is extracted with ethyl acetate and concentrated to perform silica gel column chromatography using a mixed solvent of hexane / ethyl acetate or methylene chloride / methyl alcohol as a developing solvent to obtain the target compound of formula (1).

Furthermore, the present invention provides a spinolipide metabolism modulator containing the ceramide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for preventing and treating cancer, which contains the ceramide derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Spinolipide metabolites such as ceramide, spingosine-1-phosphate (S1P) and spingosine 1-phosphocoline regulate various intracellular delivery processes. Act as a second messenger. In addition, ceramide has pro-apoptotic and anti-proliferative activity, while its metabolite, spinocin 1-phosphate, has the opposite effect. Therefore, it is possible to regulate intracellular delivery processes that regulate the balance of spinoid metabolism through regulation of enzymes involved in spinlipid metabolism or local delivery of spinoids.

Cytotoxicity of the derivatives of formula 1 of the present invention has a high impact along the length of the chain. The compounds of Examples 1 to 30 have cytotoxicity against the cancer cell line and have been shown to have a great effect on cancer cell growth disorders, of which Example compounds having shorter alkyl chains are more than those of Comparative Example 1 compounds. It showed a good effect (see Experimental Example 1).

In experiments conducted to determine whether the cytotoxicity against the cancer cells was by regulation of apoptosis induction, as shown in FIG . 1 , the derivatives of Formula 1 of the present invention affect DNA cleavage of apoptosis. Could know. Through DNA cleavage analysis, it can be seen that the derivatives of formula 1 of the present invention induce cell death in cancer cells.

Therefore, the ceramide derivatives of Formula 1 according to the present invention can be used as a useful prophylactic and therapeutic pharmaceutical composition for treating apoptosis or cancer treatment for various diseases caused by abnormally damaged cells.

Therefore, the ceramide derivatives according to the present invention can be used as a regulator of cell death induction or a pharmaceutical composition for preventing and treating cancer against various diseases caused by abnormally damaged cells such as cancer.

The ceramide derivative of Formula 1 according to the present invention can be administered parenterally, including oral or mucosal, intravenous, intramuscular injection during clinical administration and can be provided in the form of a general pharmaceutical formulation. When formulating galactosyl ceramide derivatives of the present invention, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid form preparations include at least one excipient such as starch, calcium carbonate, It is prepared by mixing sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrene talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for oral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers, suppositories, and the like. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, ester which can be injected by injection such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Formula 1 ceramide derivatives according to the present invention may be administered in an amount effective to modulate spinolipid metabolism. For example, the ceramide derivative of Formula 1 may be administered to humans once to several times, with a dosage of 1 to 250 μg, more preferably 2 to 50 μg.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples.

Example 1 Preparation of Ceramide Derivative 1

(2S, 3S, 4R) -2- (4-propyl-1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

Azidophytospingosin (1.0 equiv) and 1-pentine (1-alkaine, 1.5 equiv) were mixed in a t-butyl alcohol / water (1: 1, 0.2-0.5 M) mixed solution, and then 0.5 M copper sulfide (II) (10 mol% of 1-alkaine) and 1 M sodium ascorbate (40 mol% of 1-alkaine) were added at room temperature. The reaction mixture was stirred at 50 ° C. for one day, diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography (developing solvent = hexane / ethyl acetate, 1: 2 or methylene chloride / methyl alcohol, 10: 1) to obtain a white solid target compound ( 130 mg, 88%, 1) was obtained.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.7 Hz, 3H), 0.97 (t, J = 7.2 Hz 3H), 1.15-1.62 (m, 26H), 1.70 (qt J = 7.3 , 7.3 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H), 3.40-3.27 (m, 1H), 3.76 (dd, J = 5.4, 6.9 Hz, 1H), 4.11 (d, J = 6.6 Hz , 2H), 4.91 (td, J = 5.8, 5.8 Hz, 1H), 7.81 (s, 1H).

Example 2 Ceramide Derivative 2

(2S, 3S, 4R) -2- (4-butyl-1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (150 mg, 90%, 2) as a white solid using 1- hexine as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.8 Hz, 3H), 0.95 (t, J = 7.1 Hz 3H), 1.20-1.71 (m, 30H), 2.70 (t, J = 7.5 Hz, 2H), 3.40-3.27 (m, 1H), 3.77 (dd, J = 5.1, 6.5 Hz, 1H), 4.11 (d, J = 6.3 Hz, 2H), 4.90 (td, J = 5.8, 5.8 Hz, 1H), 7.80 (s, 1H).

Example 3 Ceramide Derivative 3

(2S, 3S, 4R) -2- (4- Pentyl -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (168 mg, 89%, 3) as a white solid using 1-heptin as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.3 Hz, 3H), 0.91 (t, J = 6.3 Hz 3H), 1.20-1.73 (m, 32H), 2.69 (t, J = 7.7 Hz, 2H), 3.29-3.34 (m, 1H), 3.77 (dd, J = 5.1, 6.3 Hz, 1H), 4.11 (d, J = 6.6 Hz, 2H), 4.89 (td, J = 5.8, 5.8 Hz, 1H), 7.80 (s, 1H).

Example 4 Ceramide Derivative 4

(2S, 3S, 4R) -2- (4-1H- Hexyl -1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (220 mg, 94%, 4) as a white solid using 1-octin as 1-alkaine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.6 Hz, 3H), 0.90 (t, J = 6.7 Hz 3H), 1.20-1.72 (m, 34H), 2.69 (t, J = 7.7 Hz, 2H), 3.27-3.31 (m, 1H), 3.78 (dd, J = 5.1, 6.3 Hz, 1H), 4.11 (d, J = 6.3 Hz, 2H), 4.89 (td, J = 5.8, 5.8 Hz, 1H), 7.80 (s, 1H).

Example 5 Ceramide Derivatives 5

(2S, 3S, 4R) -2- (4- Heptyl -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (180 mg, 95%, 5) as a white solid using 1-nonine as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.891 (t, J = 6.6 Hz, 3H), 0.893 (t, J = 6.7 Hz 3H), 1.20-1.70 (m, 36H), 2.69 (t, J = 7.7 Hz, 2H), 3.29-3.31 (m, 1H), 3.78 (dd, J = 5.1, 6.0 Hz, 1H), 4.11 (d, J = 6.3 Hz, 2H), 4.89 (td, J = 5.8, 5.8 Hz, 1H), 7.80 (s, 1H).

Example 6 Ceramide Derivative 6

(2S, 3S, 4R) -2- (4-decyl-1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (80 mg, 82%, 6) as a white solid using 1-dodecine as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.891 (t, J = 6.6 Hz, 6H), 1.20-1.70 (m, 39H), 2.69 (t, J = 7.7 Hz, 2H), 3.29-3.40 (m , 1H), 3.79 (app.t, J = 5.9 Hz, 1H), 4.11 (d, J = 6.3 Hz, 2H), 4.89 (td, J = 5.8, 5.8 Hz, 1H), 7.80 (s, 1H) .

Example 7 Ceramide Derivative 7

(2S, 3S, 4R) -2- (4- Tridecyl -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (192 mg, 93%, 7) as a white solid using 1-pentadecin as 1-alkine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (t, J = 6.6 Hz, 6H), 1.20-1.40 (m, 42H), 1.68 (m 3H), 1.85 (m, 2H), 2.16 ( m, 1H), 2.81 (t, J = 7.8 Hz, 2H), 4.09 (m, 1H), 4.56 (m, 1H), 4.86 (m 2H), 5.88 (m, 1H), 8.27 (s, 1H) .

Example 8 Ceramide Derivative 8

(2S, 3S, 4R) -2- (4- Hexadecyl -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (163 mg, 87%, 8) as a white solid using 1-octadecine as 1-alkine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.85 (t, J = 6.3 Hz, 6H), 1.20-1.40 (m, 48H), 1.68 (m 3H), 1.84 (m, 2H), 2.15 ( m, 1H), 2.80 (t, J = 7.7 Hz, 2H), 4.09 (m, 1H), 4.54 (m, 1H), 4.86 (m 2H), 5.87 (m, 1H), 8.26 (s, 1H) .

Example 9 Ceramide Derivative 9

(2S, 3S, 4R) -2- (4- Tricosyl -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (140 mg, 89%, 9) as a white solid using 1-pentacin as 1-alkaine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (t, J = 6.5 Hz, 6H), 1.20-1.40 (m, 62H), 1.69 (m 3H), 1.85 (m, 2H), 2.17 ( m, 1H), 2.81 (t, J = 7.7 Hz, 2H), 4.10 (m, 1H), 4.56 (m, 1H), 4.88 (m 2H), 5.87 (m, 1H), 8.27 (s, 1H) .

Example 10 Ceramide Derivative 10

(2S, 3S, 4R) -2- (4- Tetracosyl -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (136 mg, 85%, 10) as a white solid using 1-hexacosine as 1-alkine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (t, J = 6.5 Hz, 6H), 1.20-1.40 (m, 64H), 1.68 (m 3H), 1.85 (m, 2H), 2.17 ( m, 1H), 2.81 (t, J = 7.7 Hz, 2H), 4.09 (m, 1H), 4.55 (m, 1H), 4.88 (m 2H), 5.87 (m, 1H), 8.27 (s, 1H) .

Example 11 Ceramide Derivative 11

(2S, 3S, 4R) -2- (4- Pentacosyl -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (114 mg, 86%, 11) as a white solid using 1-heptacosine as 1-alkine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (t, J = 6.5 Hz, 6H), 1.15-1.40 (m, 66H), 1.69 (m 3H), 1.86 (m, 2H), 2.17 ( m, 1H), 2.81 (t, J = 7.7 Hz, 2H), 4.10 (m, 1H), 4.55 (m, 1H), 4.88 (m 2H), 5.87 (m, 1H), 8.27 (s, 1H) .

Example 12 Ceramide Derivatives 12

(2S, 3S, 4R) -2- (4- ( Hydroxymethyl ) -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (168 mg, 93%, 12) as a white solid using 1-propyn-1-ol as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.8 Hz, 3H), 1.24-1.35 (m, 24H), 1.52 (m, 1H), 1.67 (m, 1H), 3.34 (m , 1H), 3.73 (dd, J = 4.1, 6.9 Hz, 1H), 4.13 (d, J = 6.0 Hz, 2H), 4.68 (s, 2H), 4.99 (m, 1H), 8.00 (s, 1H) .

Example 13 Ceramide Derivative 13

(2S, 3S, 4R) -2- (4- ( Hydroxyethyl ) -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol Manufacture

According to the preparation method of Example 1 to obtain the target compound (98 mg, 90%, 13) as a white solid using 1-butyn-1-ol as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.9 Hz, 3H), 1.24-1.35 (m, 24H), 1.52 (m, 1H), 1.64 (m, 1H), 2.91 (t , J = 6.6 Hz, 2H), 3.34 (m, 1H), 3.73 (dd, J = 4.5, 6.3 Hz, 1H), 3.81 (t, J = 6.8 2H), 4.12 (d, J = 6.3 Hz, 2H ), 4.95 (m, 1 H), 7.88 (s, 1 H).

Example 14 Ceramide Derivative 14

(2S, 3S, 4R) -2- (4- (hydroxypropyl) -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (136 mg, 87%, 14) as a white solid using 1-pentin-1-ol as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.9 Hz, 3H), 1.20-1.34 (m, 24H), 1.52 (m, 1H), 1.62 (m, 1H), 1.89 (m , 2H), 2.78 (t, J = 7.7 Hz, 2H), 3.32 (m, 1H), 3.60 (t, J = 6.3 Hz, 2H), 3.74 (dd, J = 4.5, 6.6 Hz, 1H), 4.11 (d, J = 6.3 Hz, 2H), 4.93 (m, 1H), 7.84 (s, 1H).

Example 15 Ceramide Derivatives 15

(2S, 3S, 4R) -2- (4- ( Hydroxybutyl ) -1H-1,2,3- Triazole -1-yl) octane-1,3,4- Triol  Produce

According to the preparation method of Example 1 to obtain the target compound (159 mg, 91%, 15) as a white solid using 1-hexyn-1-ol as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.9 Hz, 3H), 1.20-1.34 (m, 24H), 1.50-1.80 (m 6H), 2.73 (t, J = 7.5 Hz, 2H), 3.33 (m, 1H), 3.57 (t, J = 6.5 Hz, 2H), 3.75 (dd, J = 4.8, 6.9 Hz, 1H), 4.11 (d, J = 6.3 Hz, 2H), 4.92 ( m, 1 H), 7.83 (s, 1 H).

Example 16 Ceramide Derivative 16

(2S, 3R, E) -2- (4-propyl-1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

Azido spinosine (1.0 equiv) and 1-pentine (1-alkaine, 1.5 equiv) were mixed in a t-butyl alcohol / water (1: 1, 0.2-0.5 M) mixed solution, followed by 0.5 M copper sulfide ( II) (10 mol% of 1-alkaine) and 1 M sodium ascorbate (40 mol% of 1-alkaine) were added at room temperature. The reaction mixture was stirred at 50 ° C. for one day, diluted with ethyl acetate and washed with brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated, and subjected to silica gel column chromatography (developing solvent = hexane / ethyl acetate, 1: 2 or methylene chloride / methyl alcohol, 10: 1) to obtain a white solid target compound ( 49 mg, 90%, 16).

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.9 Hz, 3H), 0.96 (t, J = 7.4 Hz 3H), 1.20-1.33 (m, 27H), 1.70 (qt J = 7.2 , 7.2 Hz, 2H), 1.88 (m, 2H), 2.65 (t, J = 7.7 Hz, 2H), 4.10 (m, 2H), 4.36 (t, J = 7.7 Hz 1H), 4.47 (qt, J = 4.3, 7.3 Hz, 1H), 5.28 (dd, J = 7.7, 15.5 Hz, 1H), 5.51 (dt, J = 6.9, 15.0 Hz, 1H), 7.73 (s, 1H).

Example 17 Ceramide Derivatives 17

(2S, 3R, E) -2- (4-butyl-1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (72 mg, 86%, 17) as a white solid using 1- hexine as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.9 Hz, 3H), 0.96 (t, J = 7.3 Hz 3H), 1.20-1.34 (m, 24H), 1.71 (qt J = 7.2 , 7.2 Hz, 2H), 1.88 (m, 2H), 2.64 (t, J = 7.7 Hz, 2H), 4.11 (m, 2H), 4.34 (t, J = 7.7 Hz 1H), 4.47 (qt, J = 4.4, 7.5 Hz, 1H), 5.28 dd, J = 7.7, 15.5 Hz, 1H), 5.51 (dt, J = 6.9, 15.0 Hz, 1H), 7.70 (s, 1H).

Example 18 Ceramide Derivative 18

(2S, 3R, E) -2- (4- Pentyl -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (70 mg, 88%, 18) as a white solid using 1-heptin as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.9 Hz, 3H), 0.91 (t, J = 6.8 Hz 3H), 1.20-1.35 (m, 24H), 1.66 (m, 2H) , 1.88 (m, 2H), 2.67 (t, J = 7.1 Hz, 2H), 4.10 (m, 2H), 4.35 (t, J = 7.8 Hz 1H), 4.47 (m, 1H), 5.27 (dd, J = 7.5, 15.3 Hz, 1H), 5.50 (dt, J = 6.3, 15.3 Hz, 1H), 7.76 (s, 1H).

Example 19 Ceramide Derivative 19

(2S, 3R, E) -2- (4- Hexyl -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (74 mg, 92%, 19) as a white solid using 1-octin as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.7 Hz, 3H), 0.90 (t, J = 6.3 Hz 3H), 1.20-1.35 (m, 26H), 1.67 (m, 2H) , 1.87 (m, 2H), 2.68 (t, J = 7.1 Hz, 2H), 4.10 (m, 2H), 4.35 (t, J = 7.8 Hz 1H), 4.47 (m, 1H), 5.26 (dd, J = 7.5, 15.3 Hz, 1H), 5.50 (dt, J = 6.3, 15.3 Hz, 1H), 7.90 (s, 1H).

Example 20 Ceramide Derivative 20

(2S, 3R, E) -2- (4- Heptyl -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (81 mg, 89%, 20) as a white solid using 1-nonine as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.6 Hz, 3H), 0.90 (t, J = 6.6 Hz 3H), 1.18-1.35 (m, 28H), 1.66 (m, 2H) , 1.87 (m, 2H), 2.67 (t, J = 7.1 Hz, 2H), 4.10 (m, 2H), 4.35 (t, J = 7.8 Hz 1H), 4.47 (m, 1H), 5.26 (dd, J = 7.5, 15.0 Hz, 1H), 5.49 (dt, J = 6.6, 15.3 Hz, 1H), 7.90 (s, 1H).

Example 21 Ceramide Derivative 21

(2S, 3R, E) -2- (4-decyl-1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16, using 1-dodecine as 1-alkane to obtain the target compound (46 mg, 82%, 21) as a white solid.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.6 Hz, 6H), 1.18-1.35 (m, 36H), 1.66 (m, 2H), 1.87 (m, 2H), 2.67 (t , J = 7.1 Hz, 2H), 4.10 (m, 2H), 4.35 (t, J = 7.8 Hz 1H), 4.47 (m, 1H), 5.26 (dd, J = 7.5, 15.0 Hz, 1H), 5.49 ( dt, J = 6.6, 15.3 Hz, 1 H), 7.87 (s, 1 H).

Example 22 Ceramide Derivative 22

(2S, 3R, E) -2- (4- Tridecyl -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (50 mg, 90%, 22) as a white solid using 1- pentadecine as 1-alkine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (app.t, J = 5.5 Hz, 6H), 1.20-1.40 (m, 42H), 1.73 (m, 2H), 1.93 (m, 2H) , 2.84 (t, J = 7.7 Hz, 2H), 4.68 (m, 1H), 4.82 (m, 1H), 5.01 (m, 1H), 5.23 (qt, J = 3.6, 3.6 Hz, 1H) 5.81 (m , 2H), 8.15 (s, 1H).

Example 23 Ceramide Derivatives 23

(2S, 3R, E) -2- (4- Hexadecyl -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (40 mg, 85%, 23) as a white solid using 1-octadecine as 1-alkine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (app.t, J = 5.5 Hz, 6H), 1.20-1.40 (m, 47H), 1.73 (m, 2H), 1.94 (m, 2H) , 2.83 (t, J = 7.7 Hz, 2H), 4.68 (m, 1H), 4.82 (m, 1H), 5.01 (m, 1H), 5.22 (qt, J = 3.6, 3.6 Hz, 1H) 5.83 (m , 2H), 8.15 (s, 1H).

Example 24 Ceramide Derivatives 24

(2S, 3R, E) -2- (4- Tricosyl -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (53 mg, 89%, 24) as a white solid using 1-pentacin as 1-alkaine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (app.t, J = 5.5 Hz, 6H), 1.20-1.40 (m, 62H), 1.73 (m, 2H), 1.93 (m, 2H) , 2.83 (t, J = 7.7 Hz, 2H), 4.67 (m, 1H), 4.82 (m, 1H), 4.99 (m, 1H), 5.22 (qt, J = 3.6, 3.6 Hz, 1H) 5.83 (m , 2H), 8.14 (s, 1H).

Example 25 Ceramide Derivative 25

(2S, 3R, E) -2- (4- Tetracosyl -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (80 mg, 88%, 25) as a white solid using 1-hexacosine as 1-alkine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (m, 6H), 1.15-1.40 (m, 64H), 1.74 (m, 2H), 1.94 (m, 2H), 2.83 (t, J = 7.7 Hz, 2H), 4.67 (m, 1H), 4.84 (m, 1H), 5.07 (m, 1H), 5.21 (qt, J = 3.9, 3.9 Hz, 1H) 5.83 (m, 2H), 8.15 (s , 1H).

Example 26 Ceramide Derivative 26

(2S, 3R, E) -2- (4- Pentacosyl -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (40 mg, 84%, 26) as a white solid using 1-heptacosine as 1-alkine.

¹ H NMR (300 MHz, C ₅ D ₅ N) d 0.86 (m, 6H), 1.15-1.40 (m, 66H), 1.74 (m, 2H), 1.94 (m, 2H), 2.83 (t, J = 7.7 Hz, 2H), 4.67 (m, 1H), 4.84 (m, 1H), 5.07 (m, 1H), 5.21 (qt, J = 3.9, 3.9 Hz, 1H) 5.83 (m, 2H), 8.15 (s , 1H).

Example 27 Ceramide Derivatives 27

(2S, 3R, E) -2- (4- ( Hydroxymethyl ) -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior Manufacture

According to the preparation method of Example 16 to obtain the target compound (51 mg, 93%, 27) as a white solid using 1-propyn-1-ol as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.8 Hz, 3H), 1.20-1.35 (m, 22H), 1.90 (m, 2H), 4.10 (m, 2H), 4.39 (app t, J = 7.2 Hz, 1H), 4.53 (dt, J = 4.2, 4.2 Hz, 1H) 4.66 (s, 1H) 5.30 (dd, J = 7.5, 15.0 Hz, 1H), 5.56 (dt, J = 6.6, 15.3 Hz, 1 H), 7.93 (s, 1 H).

Example 28 Ceramide Derivatives 28

(2S, 3R, E) -2- (4- (2- Hydroxyethyl ) -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- D Manufacturing

According to the preparation method of Example 16 to obtain the target compound (50 mg, 90%, 28) as a white solid using 1-butyn-1-ol as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.8 Hz, 3H), 1.20-1.35 (m, 22H), 1.91 (m, 2H), 2.89 (t, J = 6.6 Hz, 2H ), 3.79 (t, J = 6.8 Hz, 2H), 4.08 (m, 2H), 4.37 (t, J = 7.4 Hz, 1H), 4.50 (dt, J = 4.2, 4.2 Hz, 1H), 5.30 (dd , J = 7.5, 15.1 Hz, 1H), 5.55 (dt, J = 6.6, 15.2 Hz, 1H), 7.80 (s, 1H).

Example 29 Ceramide Derivatives 29

(2S, 3R, E) -2- (4- (3- Hydroxypropofyl ) -1H-1,2,3- Triazole -1 day) Oct Preparation of 4-ene-1,3-diol

According to the preparation method of Example 16 to obtain the target compound (53 mg, 92%, 29) as a white solid using 1-pentin-1-ol as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.8 Hz, 3H), 1.20-1.35 (m, 22H), 1.87 (m, 4H), 2.75 (t, J = 6.6 Hz, 2H ), 3.58 (t, J = 6.6 Hz, 2H), 4.08 (m, 2H), 4.36 (t, J = 7.4 Hz, 1H), 4.47 (dt, J = 4.2, 4.2 Hz, 1H), 5.28 (dd , J = 7.5, 15.0 Hz, 1H), 5.52 (dt, J = 6.6, 15.3 Hz, 1H), 7.76 (s, 1H).

Example 30 Ceramide Derivatives 30

(2S, 3R, E) -2- (4- (4- Hydroxybutyl ) -1H-1,2,3- Triazole -1 day) Oct -4-ene-1,3- Dior  Produce

According to the preparation method of Example 16 to obtain the target compound (45 mg, 90%, 30) as a white solid using 1-hexyn-1-ol as 1-alkine.

¹ H NMR (300 MHz, CD ₃ OD) d 0.89 (t, J = 6.8 Hz, 3H), 1.21-1.35 (m, 24H), 1.87 (m, 4H), 2.75 (t, J = 6.6 Hz, 2H ), 3.58 (t, J = 6.7 Hz, 2H), 4.08 (m, 2H), 4.36 (t, J = 7.4 Hz, 1H), 4.47 (dt, J = 4.3, 4.3 Hz, 1H), 5.28 (dd , J = 7.5, 15.0 Hz, 1H), 5.52 (dt, J = 6.6, 15.3 Hz, 1H), 7.75 (s, 1H).

Experimental Example 1 Cytotoxicity Experiments on Various Cancer Cells of Example Compounds

Human colon cancer using a sulforhodamide B (SRB) assay to determine whether the derivative compounds of Formula 1 of the present invention, including 1,2,3-triazole, nourish the natural death of cells Cytotoxicity experiments were performed on various cancer cells (HTC-116, NCI-H358, and K-562, respectively) of human bronchoalveolar alveolar cancer and human chronic myeloid leukemia. Table 1 shows the cytotoxicity test results for cancer cells.

Comparative Example 1 Cytotoxicity Test of Various Cancer Cells of C2-Ceramides

Cytotoxicity experiments were performed under the same conditions as those of Experimental Example 1, using the cell penetrating C2-ceramide of Chemical Formula 2 as a positive control. The cytotoxicity test results for cancer cells of Comparative Example 1 are shown in Table 1 together.

[Formula 2]

 compound EC ₅₀ (μM) HTC-116 NCI-H358 K-562 Example 1 13.9 13.2 14.9 Example 2 12.9 12.9 14.5 Example 3 12.0 13.6 13.2 Example 4 12.0 13.7 12.6 Example 5 > 50 > 50 > 50 Example 6 > 50 > 50 > 50 Example 7 > 50 > 50 > 50 Example 8 > 50 > 50 > 50 Example 9 > 50 > 50 > 50 Example 10 > 50 > 50 > 50 Example 11 > 50 > 50 > 50 Example 12 > 50 > 50 > 50 Example 13 36.8 34.4 45.6 Example 14 20.8 19.2 28.8 Example 15 34.8 28.5 35.5 Example 16 16.0 15.7 13.0 Example 17 12.9 13.6 12.3 Example 18 12.7 12.7 10.0 Example 19 12.5 12.8 8.2 Example 20 21.2 24.9 8.0 Example 21 40.1 38.2 32.2 Example 22 > 50 > 50 > 50 Example 23 > 50 > 50 > 50 Example 24 > 50 > 50 > 50 Example 25 > 50 > 50 > 50 Example 26 > 50 > 50 > 50 Example 27 25.6 28.3 39.2 Example 28 16.8 18.3 17.2 Example 29 26.1 26.0 33.8 Example 30 15.8 16.3 13.1 Comparative example 24.5 19.6 35.1

As shown in Table 1 , the cytotoxicity of the derivatives of Formula 1 of the present invention comprising triazoles has a high impact along the length of the chain. The compounds of Examples 1 to 30 have cytotoxicity against the cancer cell line and have been shown to have a great effect on cancer cell growth disorders, of which Example compounds having shorter alkyl chains are more than those of Comparative Example 1 compounds. Good effect. This is because derivatives with short chains are more water soluble and permeable to the cell membrane. Thus, it can be seen that a compound obtained by substituting the azole moiety for the ceramide with the triazole moiety which is biologically conformal can be used as a spinolipid metabolism regulator.

Experimental Example 2 DNA Analysis of K-562 Cancer Cells Regarding Example Compound

DNA cleavage analysis was performed to determine whether the cytotoxicity of Experimental Example 1 was by regulation of cell death induction. The compounds of Examples 2 and 17 with short chains for K-562 cells were treated for 18 hours and DNA samples were electrophoretically extracted and analyzed on agarose gels. C2-ceramide was used as a positive control, and untreated drug DNA was used as a control.

Comparative Example 2 DNA Analysis of K-562 Cancer Cells against C2-Ceramide

DNA analysis of K-562 cancer cells was performed under the same conditions as in Experiment 2 using C2-ceramide as a positive control group.

As shown in Figure 1 , it can be seen that the derivatives of the formula (1) of the present invention affects DNA cleavage of apoptosis. In particular, it was shown that the derivatives of Examples 1 to 15 derived from phytospinosine have a better ability to induce DNA cleavage than the derivatives of Examples 16 to 30 derived from spinosine. The compound of Comparative Example 2 resulted in much lower K-562 DNA cleavage than the ceramide derivatives of Formula 1 of the present invention. Thus, it can be seen that the derivatives of formula 1 of the present invention induce cell death in K-562 cells.

As described above, according to the present invention, the ceramide derivative represented by Chemical Formula 1 is synthesized by changing the amide moiety of the spinolipid to triazole having a biological isomerism, and not only mimics the activity of ceramide, By changing the balance of spinolipid metabolites by regulating them, the ceramide derivatives of the present invention are expected to be developed as agents for preventing or treating apoptosis, or cancer, in various diseases caused by abnormally damaged cells.

Claims (8)

The ceramide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. [Formula 1]

(In the above formula R ₁ is an C ₁ to C ₃₅ alkyl group which is unsubstituted or substituted with 1 or 2 or more substituents, When the alkyl group is substituted, the substituent is halogen, hydroxy group, amino group, amino group substituted with 1 or 2 or more C ₁ ~ C ₂₀ alkyl group, thiol group, cyano, nitro group, sulfonyl group, phenyl group, C ₁ ~ C ₃₀ Alkoxy group, C ₁ to C ₃₀ alkyl group, C ₁ to C ₃₀ haloalkyl group, C ₁ to C ₃₀ hydroxyalkyl group, C ₁ to C ₃₀ alkoxyalkyl group, C ₅ to C ₁₀ aryl group, C ₅ to C ₁₀ heteroaryl group, C ₅ ~ C ₁₀ arylalkyl group or C ₅ ~ C ₁₀ heteroarylalkyl group,

Is a single bond or a double bond, R ₂ is a hydroxy group when the bond is a single bond, When the bond is a double bond, it is hydrogen.) The method of claim 1, wherein R ₁ is a C ₁ to C ₃₀ alkyl group which is unsubstituted or substituted with 1 or 2 or more substituents, and when the alkyl group is substituted, the substituent is a halogen, a hydroxy group, an amino group, 1 or 2 or more C ₁ to C ₁₅ alkyl group Amino group, thiol group, cyano group, nitro group, sulfonyl group, phenyl group, C ₁ ~ C ₂₀ alkoxy group, C ₁ ~ C ₂₀ alkyl group, C ₁ ~ C ₂₀ haloalkyl group, C ₁ ~ C ₂₀ substituted with Hydroxyalkyl group, C ₁ to C ₂₀ alkoxyalkyl group, C ₅ to C ₈ aryl group, C ₅ to C ₈ heteroaryl group, C ₅ to C ₈ arylalkyl group or C ₅ to C ₈ heteroaryl An alkyl group,

Is a single bond or a double bond, R ₂ is a hydroxy group when the bond is a single bond, Camide derivative or a pharmaceutically acceptable salt thereof, characterized in that when the bond is a double bond is hydrogen. The method of claim 1, wherein R ₁ is a C ₁ to C ₂₅ alkyl group which is unsubstituted or substituted with 1 or 2 or more substituents, and when the alkyl group is substituted, the substituent is a halogen, a hydroxy group, an amino group, 1 or 2 or more C ₁ to C ₁₀ alkyl group. An amino group substituted with a thiol group, a phenyl group, a C ₁ to C ₂₀ alkyl group, a C ₁ to C ₂₀ haloalkyl group or a C ₁ to C ₂₀ hydroxyalkyl group,

Is a single bond or a double bond, R ₂ is a hydroxy group when the bond is a single bond, Camide derivative or a pharmaceutically acceptable salt thereof, characterized in that when the bond is a double bond is hydrogen. The method of claim 1, wherein R ₁ is an C ₁ ~ C ₂₅ alkyl group which is unsubstituted or substituted with 1 or 2 or more substituents, and when the alkyl group is substituted, the substituent is a hydroxy group,

Is a single bond or a double bond, R ₂ is a hydroxy group when the bond is a single bond, Camide derivative or a pharmaceutically acceptable salt thereof, characterized in that when the bond is a double bond is hydrogen. According to claim 1, wherein the ceramide derivative of Formula 1 is: 1) (2S, 3S, 4R) -2- (4-propyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 2) (2S, 3S, 4R) -2- (4-butyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 3) (2S, 3S, 4R) -2- (4-pentyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 4) (2S, 3S, 4R) -2- (4-hexyl-1H-, 2,3-triazol-1-yl) octane-1,3,4-triol; 5) (2S, 3S, 4R) -2- (4-heptyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 6) (2S, 3S, 4R) -2- (4-decyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 7) (2S, 3S, 4R) -2- (4-tridecyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 8) (2S, 3S, 4R) -2- (4-hexadecyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 9) (2S, 3S, 4R) -2- (4-tricosyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 10) (2S, 3S, 4R) -2- (4-tetracosyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 11) (2S, 3S, 4R) -2- (4-pentacosyl-1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 12) (2S, 3S, 4R) -2- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 13) (2S, 3S, 4R) -2- (4- (hydroxyethyl) -1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 14) (2S, 3S, 4R) -2- (4- (hydroxypropyl) -1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 15) (2S, 3S, 4R) -2- (4- (hydroxybutyl) -1H-1,2,3-triazol-1-yl) octane-1,3,4-triol; 16) (2S, 3R, E) -2- (4-propyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 17) (2S, 3R, E) -2- (4-butyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 18) (2S, 3R, E) -2- (4-pentyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 19) (2S, 3R, E) -2- (4-hexyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 20) (2S, 3R, E) -2- (4-heptyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 21) (2S, 3R, E) -2- (4-decyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 22) (2S, 3R, E) -2- (4-tridecyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 23) (2S, 3R, E) -2- (4-hexadecyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 24) (2S, 3R, E) -2- (4-tricosyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 25) (2S, 3R, E) -2- (4-tetracosyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 26) (2S, 3R, E) -2- (4-pentacosyl-1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 27) (2S, 3R, E) -2- (4- (hydroxymethyl) -1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 28) (2S, 3R, E) -2- (4- (2-hydroxyethyl) -1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol; 29) (2S, 3R, E) -2- (4- (3-hydroxypropofyl) -1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol ; And 30) (2S, 3R, E) -2- (4- (4-hydroxybutyl) -1H-1,2,3-triazol-1-yl) oct-4-ene-1,3-diol or Pharmaceutically acceptable salts thereof. As shown in the following scheme, a method for preparing a ceramide derivative of claim 1 by reacting a compound of formula 2 with an alkane compound as a starting material. Scheme 1

(In Scheme 1, R ₁ is any one selected from various substituents R ₁ defined in Formula 1,

Is a single bond or a double bond, R ₂ is a hydroxy group when the bond is a single bond, When the bond is a double bond, it is hydrogen.) Claims 1 to 5, wherein the ceramide derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient modulator of cell death induction. A pharmaceutical composition for preventing and treating cancer, comprising the ceramide derivative represented by Formula 1 of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

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