WO2006004359A1

WO2006004359A1 - Sphingolipid derivatives and the composition for anti-cancer containing the same

Info

Publication number: WO2006004359A1
Application number: PCT/KR2005/002102
Authority: WO
Inventors: Jinwook Kim; Sungjin Park; Ho-Jae Lee; Changseo Park; Yong-Woo Kim; Won-Koo Lee; Hyun-Joon Ha
Original assignee: Doosan Corporation; Imagene Co., Ltd.
Priority date: 2004-07-01
Filing date: 2005-07-01
Publication date: 2006-01-12
Also published as: KR20060002290A

Abstract

Disclosed are a novel sphingolipid derivative having a sphingosine kinase suppressing activity and a composition containing the same. When the newly synthesized sphingolipid derivative of the invention is used, it is possible to maintain concentrations of ceramide and sphingosine to be high by preventing ceramide and sphingosine from being phosphorylated due to sphingosine kinase since an activity of sphingosine kinase is suppressed. In addition, since the apoptosis is induced in a cancer cell by ceramide and sphingosine, it is possible to treat or prevent a cancer or disease related to the cancer. Further, it is possible to treat or prevent a hyper- proliferative disease such as cancer or proliferation-promoting activity of sphingosine kinase. Accordingly, the composition containing the same can be used as a composition for suppressing sphingosine kinase and a composition for treating or preventing a cancer or hyper-proliferative disease.

Description

SPHINGOLIPID DERIVATIVES AND THE COMPOSITION FOR ANTI-CANCER CONTAINING THE SAME

Technical Field

[1] The present invention relates to a novel sphingolipid derivative having a sphingosine kinase suppressing activity and a composition containing the same. Background Art

[2] Sphingolipid was firstly found by Thudichum in 1884 and named as a sphinx like substance. It was known as a substance playing a substantial role in life phenomena as well as regulating cell growth, proliferation and differentiation.

[3] The sphingolipid in a human body has sphingosine, phytosphingosine or sphinganine backbones and 300 or more kinds of derivatives including ceramide having fatty acids connected to the backbones.

[4] The sphingolipid is a main ingredient constituting a cell membrane together with phospholipid and has polar and non-polar parts. Ceramide having a fatty acid connected to sphingolipid is known as a substance playing an important role in causing various action mechanisms occurring in a cell. In particular, it takes part in a cell pro¬ liferation, a cell differentiation, a temporary growth arrest of the cell proliferation and an apoptosis.

[5] Since 1990's, functions of the sphingolipid have been analyzed in earnest. In particular, the researches thereof have been actively performed as a protein kinase inhibiting effect of sphingosine was validated by Hannun and Bell, etc. In addition, as it was found that an important life phenomenon such as the cell differentiation, growth, aging and death is regulated by ceramide, it was become a core of a biology research.

[6] The ceramide is a substance causing an apoptosis which is an importance mechanism for a cancer treatment and thus development of an anti-cancer drug is focused on the ceramide. It is analyzed that many anti-cancer drugs, which are being currently used or developed, influence on a biosynthesis pathway of the ceramide and thus exhibit their effects.

[7] An allylic alcohol group located at a C-3 position of ceramide has a biological effect and a main stage of the effect is such that a C-3 hydroxyl group is oxidized to produce reactive oxygen species (ROS) in mitochondria. Further, it is known that ceramide regulates phosphorylation of protein and an amount of calcium in the human body.

[8] As a treatment for killing a cancer cell, ceramide and ceramide derivative and analog are directly treated to the cancer cell or a substance inducing or starting a de novo synthesis of ceramide may be used as an anti-cancer drug.

[9] Accordingly, since a substance regulating an activity of enzyme participating in biosynthesis of ceramide and sphingolipid is highly possibly to be developed as an anti-cancer drug, it is recently taken intensive interests. Serine palmitoyl transferase (SPT), ceramidase, sphingomyelinase (SMase), gluco-sylceramide (GlcCer) synthase and sphingosine kinase, etc. are enzymes participating in synthesis and hydrolysis of ceramide, and substances for activating and inhibiting such enzymes suggest a possibility of properly regulating a content of ceramide in a cancer cell and thus inducing an apoptosis of the cancer cell.

[10] In addition, as glycosylation of sphingolipid turned out to play an important role in drug resistances in recent years, an anti-cancer drug using sphingolipid also suggested a possibility of overcoming the drug resistances.

[11] Researches on substances regulating a content of ceramide in a cell can be confined to developments of derivatives and analogs of sphingolipid and cermide and include many kinds of substances, for example, functional fatty acids, vitamins, androgen and ROS (reactive oxygen species: hydroxyperoxide, nitric oxide releasing compound) in¬ fluencing on biosynthesis of sphingolipid, and substances influencing on a glutathione (GSH) level and a lecithin level.

[12] Among them, P-drug, which has been actively researched as an anti-cancer drug in recent years, is a ceramide analog of aminoalcohols. PDMP (D-threo-l-phenyl-2-decanoylamino-3-moφholino-l-propanol) among them is an initial synthesis substance which is most developed and exhibits an excellent effect as an inhibitor of a synthesis of GlcCer(glucosyl ceramide) greatly influencing on a cell cycle. PPMP (D-threo-l-phenyl-2-palmitoylamino-3-moφholino-l-propanol) having a better effect than PDMP is a homolog having a longer chain and PPPP (P4D-threo-l-phenyl-2-palmitoylamino-3-pyrrolidino-l-propanol) is also an analog exhibiting an inhibitory effect higher than PDMP. The P-drug is expected to exhibit an anti-cancer effect for a general cancer cell and to inhibit a synthesis of GlcCer relating to tolerance to the anti-cancer drug, thereby contributing to a prevention of drug resistance.

[13] In addition, B 13 or N-oleoylethanolamine, which are ceramidase inhibitors, is also a ceramide analog and inhibits a decomposition of the ceramide to induce a death of the cancer cell. Further, there are ceramide biosynthesis inhibitors having a structure similar to those of sphingolipid and ceramide, such as FTY-720, fumonisin and myriosin, etc.

[14] There are many substances which have been already used as an anti-cancer drug, among the substances participating in the ceramide biosynthesis. Vincristine, gemcitabine, camptothecin, homocamptothecin, irinotecan, etc, are representative examples, most of which promote an activity of SMase. However, since GlcCer and sphingosine 1 -phosphate (SlP) produced from ceramide promote a cancer cell growth, it is expected that a development of a selective inhibitor of GlcCer synthase, ceramidase or sphingosine kinase (SPHK) will be an efficient treatment strategy for cancer. In particular, the SPHK inhibitor is a development target for a new anti-cancer drug and thus being recently researched.

[15] As a new anti-cancer target, many concerns have been recently focused on dimethylsphingosine (DMS) produced by methylation of sphingosine and safingol which is an isomer of sphinganine, which are known as a SPHK inhibitor. In fact, according to a study of a M.D. Anderson cancer research institute, the DMS was shown to have an efficacy for an acute leucosis exhibiting a drug resistance and a possibility of being developed into an anti-cancer drug was confirmed. In addition, researches on a specific structure capable of regulating contents of sphingolipid and ceramide in a cell by using such substances have been actively progressed.

[16] In addition, various substances have been suggested to increase practical uses of sphingolipid and ceramide. In particular, since ceramide having polyethylene glycol connected thereto renders a liposome be easily formed and increases a circulation lifetime, researches on such substances and a composition for liposome formation are being progressed. Disclosure of Invention Technical Problem

[17] The inventors synthesized derivatives having a novel structure and an efficacy through a medical chemistry molecule design by applying various changes of a functional group to a basic structure of sphingolipid and then analyzed an anti-cancer efficacy. As a result of that, it was validated that the derivatives exhibited a more excellent efficacy, compared to DMS or safingol.

[18] An object of the present invention is to suppress an activity of sphingosine kinase using derivatives of sphingolipid and thus to prevent ceramide and sphingosine from being phosphorylated, thereby maintaining concentrations of ceramide and sphingosine to be high and inducing apoptosis of a cancer cell by ceramide and sphingosine to treat or prevent a cancer or disease related to the cancer. The other object of the invention is to suppress a cell proliferation-promoting activity of sphingosine kinase, thereby treating or preventing a hyper-proliferative disease such as cancer and psoriasis. Still another object of the invention is to provide a composition having such efficacies. Technical Solution

[19] In order to accomplish the objects, there is provided a sphingolipid derivative having a following chemistry figure 1, an isomer thereof or a pharmaceutically acceptable salt thereof. [20] ChemistryFigure 1

[21] wherein R is hydrogen, or alkyl group, alkenyl group, acyl group or aryl group of

C 1-40 ;

[22] R is hydrogen, or alkyl group, alkenyl group, acyl group or aryl group of C ;

[23] R is hydrogen, or alkyl group, alkenyl group, acyl group or aryl group of C , or

3 1-40 heterocyclic group comprising pyrrolidine group and morpholine group; [24] R is hydrogen comprising hydroxyl group, or alkyl group, alkenyl group, acyl

4 group or aryl group of C ; and

1-40

[25] R is hydrogen, or alkyl group, alkenyl group, acyl group or aryl group of C .

5 1-40

[26] In addition, the sphingolipid derivative represented by the chemistry figure 1 is preferably selected from a group consisting of compounds having the following chemistry figures 2, 7, 13, 16, 18 and 21.

[27] ChemistryFigure 2

[28] wherein R is hydrogen or alkyl group of C .

[29] The sphingolipid derivative represented by the chemistry figure 2 is preferably a compound having a following chemistry figure 3 (hereinafter, SG-I), 4 (hereinafter,

SG-2), 5 (hereinafter, SG-3) or 6 (hereinafter, SG-4). [30] ChemistryFigure 3

SG-1 [31] ChemistryFigure 4

SG-2

[32] ChemistryFigure 5

SG~3

[33] ChemistryFigure 6

SG 4

[34] ChemistryFigure 7

[35] wherein R is hydrogen or alkyl group of C . [36] The sphingolipid derivative represented by the chemistry figure 7 is preferably a compound having a following chemistry figure 8 (hereinafter, SG- 13), 9 (hereinafter, SG-14), 10 (hereinafter, SG-15), 11 (hereinafter, SG-IO) or 12 (hereinafter, SG-16).

[37] ChemistryFigure 8

SG -13

[38] ChemistryFigure 9

SG -14

[39] ChemistryFigure 10

SG -15

[40] ChemistryFigure 11

SG -10

[41] ChemistryFigure 12

[42] ChemistryFigure 13

[43] wherein R and R are hydrogen or alkyl group of C [44] The sphingolipid derivative represented by the chemistry figure 13 is preferably a compound having a following chemistry figure 14 (hereinafter, SG-5) or 15 (hereinafter, SG-6).

[45] ChemistryFigure 14

SG-5

[46] ChemistryFigure 15

SG-6

[47] ChemistryFigure 16

[48] wherein R is hydrogen or alkyl group of C . [49] The sphingolipid derivative represented by the chemistry figure 16 is preferably a compound having a following chemistry figure 17 (hereinafter, SG-7). [50] ChemistryFigure 17

7

SG-7

[51] ChemistryFigure 18

[52] wherein R is hydrogen or alkyl group of C . [53] The sphingolipid derivative represented by the chemistry figure 18 is preferably a compound having a following chemistry figure 19 (hereinafter, SG-9) or 20 (hereinafter, SG-12).

[54] ChemistryFigure 19

SG-9

[55] ChemistryFigure 20 7

SG-12

[56] ChemistryFigure 21

N

[57] wherein R is hydrogen or alkyl group of C .

1-40

[58] The sphingolipid derivative represented by the chemistry figure 21 is preferably a compound having a following chemistry figure 22 (hereinafter, SG-Il). [59] ChemistryFigure 22

SG-11

[60] According to the invention, there is provided a composition for suppressing sphingosine kinase containing the sphingolipid derivative represented by the chemistry figure 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an effective ingredient.

[61] According to an embodiment of the invention, the composition for suppressing sphingosine kinase may be used to treat or prevent a cancer or disease relate to the cancer.

[62] According to the invention, there is provided a composition for inducing an apoptosis containing the sphingolipid derivative represented by the chemistry figure 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an effective ingredient.

[63] According to an embodiment of the invention, the composition for inducing an apoptosis may be used to treat or prevent a cancer or disease relate to the cancer.

[64] According to the invention, there is provided a composition for treating or preventing a hyper-proliferative disease containing the sphingolipid derivative represented by the chemistry figure 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an effective ingredient.

[65] In addition, the hyper-proliferative disease may be psoriasis.

[66] According to the invention, there is provided an anti-cancer composition for treating or preventing a cancer containing the sphingolipid derivative represented by the chemistry figure 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an effective ingredient. Advantageous Effects

[67] The novel sphingolipid derivative and the isomer thereof or the pharmaceutically acceptable salt thereof according to the invention highly suppress an activity of sphingosine kinase to prevent ceramide and sphingosine from being phosphorylated due to sphingosine kinase and thus to maintain concentrations of ceramide and sphingosine to be high, thereby inducing apoptosis of a cancer cell and thus exhibiting an anti-cancer activity. In addition, since the invention suppresses a cell proliferation- promoting activity of sphingosine kinase to treat or prevent a hyper-proliferative disease such as cancer or psoriasis, the composition containing the same can be usefully used as a composition for suppressing sphingosine kinase and a composition for treating or preventing a cancer or hyper-proliferative disease.

Brief Description of the Drawings

[68] FIGS. 1 to 4 show measurement results of sphingosine kinase 1 suppressing efficacies of sphingolipid derivatives which are newly synthesized, wherein FlG. 1 shows sphingosine kinase suppressing effects of SG 1 to 4, FlG. 2 shows sphingosine kinase suppressing efficacies of SG 5 to 7, FlG. 3 shows sphingosine kinase suppressing efficacies of SG 9 to 12 and FlG. 4 shows sphingosine kinase suppressing efficacies of SG 13 to 16; and

[69] FIGS. 5 to 8 show measurement results of sphingosine kinase 2 suppressing efficacies of sphingolipid derivatives which are newly synthesized, wherein FlG. 5 shows sphingosine kinase suppressing effects of SG 1 to 5, FlG. 6 shows sphingosine kinase supressing efficacies of SG 6 to 8, FlG. 7 shows sphingosine kinase suppressing efficacies of SG 9 to 13 and FlG. 8 shows sphingosine kinase suppressing efficacies of SG 14 to 16. Best Mode for Carrying Out the Invention

[70] Novel sphingolipid derivatives of the present invention can be prepared through following steps.

[71] Firstly, a sphingolipid derivative compound (2) represented by the chemistry figure

2 can be obtained by a preparation method comprising steps of: converting menthol ester of a compound (7) into amide, where a compound (8) is obtained by converting menthol ester into a weinreb amide form using O,N-dimethylhydroxy amine (step al); converting amide of the compound (8) obtained in the step al into a ketone form having a benzyle group attached thereto using benzyle bromide and magnesium and then reducing the ketone into a secondary alcohol using lithium aluminum hydride, thereby obtaining a compound (9) (step bl); adding acetic acid to the compound (9) obtained in the step bl so that acetyl group is added and aziridine ring is opened with an aziridine ring opening reaction by nucleophilic attack of the acetyl group, and then substituting hydroxy group for the acetyl group using potassium hydroxide, thereby obtaining a compound (10) (step cl); reducing secondary amine of the compound (10) obtained in the step cl into primary amine using palladium hydroxide and acetic acid, thereby obtaining a compound (11) (step dl); and converting amine of the compound (11) obtained in the step dl into amide using acyl chloride (R: hydrogen or C ~C ) (step el) (refer to a following reaction figure 1). [72] [Reaction Figure 1]

[73]

[74] A sphingolipid derivative compound (3) represented by the chemistry figure 7 can b e obtained by a preparation method comprising steps of: converting menthol ester of a compound (7) into amide, where a compound (8) is obtained by converting menthol ester into a weinreb amide form using O,N-dimethylhydroxy amine (step a2); converting amide of the compound (8) obtained in the step a2 into a ketone form having a benzyle group attached thereto using benzyle bromide and magnesium and then reducing the ketone into a secondary alcohol using lithium aluminum hydride, thereby obtaining a compound (9) (step b2); adding a chlorine group to the compound (9) obtained in the step b2 and opening aziridine ring thereof with an aziridine ring opening reaction by nucleophilic attack of chlorine anion of chlorotrimethylsilane and then substituting pyrrolidine for iodine group by nucleophilic attack of pyrrolidine via a substitution reaction of iodine anion and chlorine anion of sodium iodide, thereby obtaining a compound (13) (step c2); reducing secondary amine of the compound (13) obtained in the step c2 into primary amine using palladium hydroxide and acetic acid, thereby obtaining a compound (14) (step d2); and converting amine of the compound (14) obtained in the step d2 into amide using acyl chloride (R: hydrogen or C -C 40J (step e2) (refer to a following reaction figure 2).

[75] [Reaction Figure 2] [76]

[77] Sphingolipid derivative compounds (4 and 4-1) represented by the chemistry figures 13 and 16 can be obtained by a preparation method comprising steps of: reducing menthol ester of the compound (13) into alcohol using lithium aluminum hydride, thereby obtaining a compound (16) (step a3); forming oxazoline after subjecting the compound (16) obtained in the step a3 to an aziridine ring opening reaction using N,N'-dicarbonylimidazole and substituting iodine for alcohol using iodotrimethylsilane, thereby obtaining a compound (17) (step b3); reducing tertiary amine of the compound (17) obtained in the step b3 into secondary amine using anisole and methane sulfonic acid, thereby obtaining a compound (18) (step c3); replacing the secondary amine of the compound (18) obtained in the step c3 with iodine using triph- enylphosphine, thereby obtaining a compound (19) (step d3); adding lithium hexam- ethyldisilazine to the compound (19) obtained in the step d3 to form phospholan and then forming an alkyl addition reaction and a double bond by a vidic reaction with an aldehyde group, thereby obtaining a compound (20) (step e3); and adding palladium charcoal and hydrogen to the compound (20) obtained in the step e3 to reduce the double bond and then dividing oxazoline into alcohol and amine using lithium hydroxide (step f3), whereby the sphingolipid derivative compound (4-1) represented by the chemistry figure 16 is obtained, and converting the amine obtained in the step f3 into amide using acyl chloride (R: hydrogen or C ~C ) (step g3), whereby the sph-

1 40 ingolipid derivative compound (4) represented by the chemistry figure 13 is obtained

(refer to a following reaction figure 3). [78] [Reaction Figure 3]

[79]

ϊ Kdπliiin≡tMsiiaii^p

stηιh3

(15) (161 (17)

nieilw sijIFβnir ami npt^jiiiiiliDiiirⁱiif

ilf p d

[j

[80] A sphingolipid derivative compound (5) represented by the chemistry figure 18 can be obtained by a preparation method comprising steps of: converting menthol ester of a compound (7) into amide, where a compound (8) is obtained by converting menthol ester into a weinreb amide form using O,N-dimethylhydroxy amine (step a4); converting amide of the compound (8) obtained in the step a4 into a ketone form having a benzyle group attached thereto using benzyle bromide and magnesium and then reducing the ketone into a secondary alcohol using lithium aluminum hydride, thereby obtaining a compound (21) (step b4); adding acetic acid to the compound (21) obtained in the step b4 so that acetyl group is added and aziridine ring is opened with an aziridine ring opening reaction by nucleophilic attack of the acetyl group, and then substituting hydroxy group for the acetyl group using potassium hydroxide, thereby obtaining a compound (22) (step c4); and reducing secondary amine of the compound (22) obtained in the step c4 into primary amine using palladium hydroxide and acetic acid (step d4) (refer to a following reaction figure 4). [81] [Reaction Figure 4]

[82]

[83] A sphingolipid derivative compound (6) represented by the chemistry figure 21 can be obtained by a preparation method comprising steps of: converting menthol ester of a compound (7) into amide, where a compound (8) is obtained by converting menthol ester into a weinreb amide form using O,N-dimethylhydroxy amine (step a5); converting amide of the compound (8) obtained in the step a5 into a ketone form having a benzyle group attached thereto using benzyle bromide and magnesium and then reducing the ketone into a secondary alcohol using lithium aluminum hydride, thereby obtaining a compound (9) (step b5); adding methane sulfonyl chloride to the compound (9) obtained in the step b5 so that a methane sulfonyl group is introduced to alcohol and thus an activated group is made, and then reducing it using lithium aluminum hydride, thereby obtaining a compound (23) (step c5); adding a chlorine group to the compound (23) obtained in the step c5 and opening aziridine ring thereof with an aziridine ring opening reaction by nucleophilic attack of chlorine anion of chlorotrimethylsilane and then substituting pyrrolidine for iodine group by nu¬ cleophilic attack of pyrrolidine via a substitution reaction of chlorine anion and iodine anion of sodium iodide, thereby obtaining a compound (24) (step d5); reducing secondary amine of the compound (24) obtained in the step d5 into primary amine using palladium hydroxide and acetic acid, thereby obtaining a compound (25) (step e5); and converting amine of the compound (25) obtained in the step e5 into amide using acyl chloride (R: hydrogen or C -C J (step f5) (refer to a following reaction

40 figure 5).

[84] [Reaction Figure 5] [85]

fi: kyfciiii or alki'IariraplC'l- LNOi

(2Sj ϋitp ^β (6}

[86] The spingolipid derivative represented the chemistry figure 1, an isomer thereof or a pharmaceutically acceptable salt thereof can be used as a pharmaceutically acceptable salt form. The salt is not specifically limited as long as it is pharmaceutically acceptable. For example, the salt may include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, metasulfonic acid, benzene sulfonic acid, toluene sulfonic aicd, he spingolipid derivative of the invention, an isomer thereof or a pharmaceutically acceptable salt thereof contains the compound in a concentration of 0.001-20 wt.% of the total composition. That is, when the concentration is less than 0.001 wt.%, it is difficult to achieve the efficacy thereof, and when the concentration is more than 20 wt.%, it can cause an abnormality to the generative function.

[87] It can be expected dual anti-cancer effects such that the novel sphingolipid derivative of the invention suppresses an activity of sphingosine kinase to induce accu¬ mulations of ceramide and sphingosine in a cell which promote death of the cell, and blocks a tumor inducing effect of sphingosine 1-phosphate (SlP), which is a product of sphingosine kinase, at the same time.

[88] The inventors measured a sphingosine kinase suppressing activity of the novel sph¬ ingolipid derivative and confirmed its efficacy. In addition, it was confirmed that the novel derivative had a more excellent sphingosine kinase suppressing efficacy than DMS (Dimethylsphingosine).

[89] A pharmaceutical composition containing the novel sphingolipid derivative, an isomer thereof or a pharmaceutically acceptable salt thereof may further comprise proper carrier, excipient and diluent which are typically used for preparation of phar¬ maceutical composition.

[90] A pharmaceutical administration type of the compound of the invention is as follows. That is, it may be used as a pharmaceutically acceptable salt thereof. Further, it may be used alone or together with other pharmaceutical active compounds in a form of a combination or proper set thereof.

[91] A pharmaceutical composition containing the compound according to the invention may be formulated into any type suitable for a pharmaceutical preparation, including an oral administration-type formulation such as powder, granulum, tablet, capsule, suspension, emulsion, syrup and aerosol, an external preparation such as ointment and cream, suppository, sterilized injection solution and the like.

[92] Although a preferable dosage of the compound of the invention is varies with ages, sexes, weights, symptoms, degrees of diseases, drug forms, administration routes and administration periods, it can be properly selected by a skilled person in the art. However, considering a preferable effect, it is preferred that the compound of the invention is administrated in an amount of 0.001 mg/kg ~ 1000 mg/kg per a day. The administration can be performed one time or many times per a day. In addition, the dosage can be increased or decreased according to the ages, sexes, weights, degrees of diseases, administration routes and the like. Accordingly, the dosage does not limit a scope of the invention in any way.

[93] The compound of the invention can be administrated to a mammal such as rat, mouse, domestic animal and human through various routes, for example, non-oral and oral administrations. All types of the administration can be expected. For instance, it can be administrated with oral, rectum or vein, muscle, hypodermic, and intrauterine dura mater or intracerebroventricular injections.

[94] In the mean time, since the compound of the invention and the salt containing the same have no serious toxicity and side effect, they can be used for a prevention purpose with safety even when they are used for a long time. Mode for the Invention

[95] Hereinafter, the invention will be more specifically described with embodiments and experimental examples. However, it should be noted that the invention is not limited to the embodiments and experimental examples.

[96] [Embodiment 1] Synthesis of the compound (2) of the chemistry figure 2

[97] (step al) preparation of the compound (8)

[98] 100 mg (0.304 mmol) of (2S)-l-[(lR)-l-phenylethyl]]-2-aziridine carboxylic acid

(-)-menthol ester (the compound (7)) and 45 mg (0.737 mmol) of O,N-dimethylhydroxy amine were added to 1 D of tetrahydrofuran and isopropyl magnesium bromide (2.0 M solution in THF) was slowly droplet-added at 0 °C. After that, the solution was heated to a room temperature under argon environment and stirred for 10 minutes. Then, it was checked by TLC that aziridine menthol ester was disappeared. Then, the extract obtained by adding dichloromethane and water and extracting an organic layer was added with magnesium sulfate to remove water and to concentrate it. The resultant material was purified with a column chromatography, thereby obtaining the compound (8), i.e., (S)-N-methoxy-N-methyl- 1 -((R)- 1 -phenylethyl)aziridine-2-carboxamide).

[99] (step bl^*) preparation of the compound (9^*)

[100] The compound (8) obtained in the step al, i.e., 2 g (8.53 mmol) of

(S)-N-methoxy-N-methyl-l-((R)-l-phenylethyl)aziridine-2-carboxamide) was added to anhydrous tetrahydrofuran (0.3 M) and 800 mg (34.2 mmol) of magnesium and 1.52 D (12.8 mmol) of benzyl bromide were added to the solution at room temperature under argon environment. Then, the solution was refluxed at 100 C for six hours, subject to the extraction with ethyl acetate and water and then added with magnesium sulfate to remove water and to concentrate it. The resultant material was purified with a column chromatography, thereby obtaining 2-phenyl- 1 -((S)- 1 -((R)- 1 -phenylethyl)aziridine-2-yl)ethanone. [101] After that, 2.6 g (9.8 mmol) of

2-phenyl-l -((S)-I -((R)- l-phenylethyl)aziridine-2-yl)ethanone was added to anhydrous tetrahydrofuran (0.3 M). The solution was added with 600 mg (19.6 mmol) of lithium aluminum hydride at 0 °C and stirred for one hour. Then, after completing the reaction with potassium hydrogen sulfate, the solution was subject to the extraction with ethyl acetate and water, and dried and concentrated with magnesium sulfate. The resultant material was purified with a column chromatography, thereby obtaining the compound (9), i.e., 2-phenyl- 1 -((S)- 1 - [(R)- 1 -phenylethyl]aziridine-2-yl)ethanol.

[102] (step cl) preparation of the compound (10)

[103] The compound (9) obtained in the step bl, i.e.,

2-phenyl-l-((S)-l-[(R)-l-phenylethyl]aziridine-2-yl)ethanol was added to dichloromethane (0.5 M) and acetic acid (10 eq) was droplet-added. The solution was stirred at room temperature for 12 hours, added with sodium bicarbonate and subject to the extraction with dichloromethane. The extract was added with magnesium sulfate to remove water and to concentrate it. Then, the resultant material was purified with a column chromatography, thereby obtaining (S)-2[(R)-l-phenylethylamino] - 3-hydroxy-4-phenylbutyl acetate.

[104] After that, 135 mg (0.412 mmol) of (S)-2[(R)-l-phenylethylamino] -

3-hydroxy-4-phenylbutyl acetate was added to methanol (0.3 M) and 46 mg (0.9 mmol) of potassium hydroxide was added to the solution at room temperature and stirred for 3 hours. The solution was subject to the extraction with dichloromethane and then added with magnesium sulfate to dry and concentrate it. The resultant material was purified with a column chromatography, thereby obtaining the compound ( 10), i.e., (S)-2- [(R)- 1 -phenylethylamino]-3-hydroxy-4-phenylbutanol.

[105] (step dlV preparation of the compound (11)

[106] The compound (11) obtained in the step cl, i.e., (S)-2-[(R)-l-phenylethylamino] -

3-hydroxy-4-phenylbutanol was added to a solution of ethanol (0.5 M) and palladium hydroxide, a acetic acid (2 eq.) was added to the solution. Then, the solution was stirred at room temperature under hydrogen atmosphere and the reaction was checked with TLC. Then, the solution was filtered with celite to obtain filtrate. The obtained filtrate was dried and concentrated with magnesium sulfate, thereby obtaining the compound (11) as concentrate.

[107] fstep el^*) preparation of the compound (2) of the chemistry figure 2

[108] The compound (11) obtained in the step dl was dissolved in tetrahydrofuran and

10% sodium hydroxide aqueous solution was added to the mixture. Then, the solution was stirred at room temperature, then added with acyl chloride (2 eq.) after 20 minutes and stirred at room temperature. Then, after completing the reaction by adding sodium bicarbonate, the solution was subject to the extraction with ethyl acetate and dried and concentrated with magnesium, sulfate. After that, the resultant material was purified with a column chromatography, thereby obtaining the compound (2) of the chemistry figure 2 (refer to the reaction figure 1).

[109] [Embodiment 2] synthesis of the compound (3) of chemistry figure 7

[110] (step a2) preparation of the compound (8)

[111] The compound (8) was obtained from (2S)-l-[(lR)-l-phenylethyl] -

2-aziridinecarboxylic acid (-)-menthol ester (the compound (7)) using the method of the step al.

[112] (step b2) preparation of the compound (9)

[113] The compound (9) was obtained from the compound (8) obtained in the step a2, using the method of the step bl.

[114] fstep c2^*> preparation of the compound Q 3)

[115] 170 mg (1.1 mmol) of sodium iodide was added to acetonitrile (0.5 M) and the mixture was droplet-added with 0.15 D (1.1. mmol) of chlorotrimethylsilane and then stirred at room temperature. After two hours, the reaction solution was droplet-added with the compound (9) obtained in the step b2, i.e., 100 mg (0.374 mmol) of 2-phenyl-l-((S)-l-[(R)-l-phenylethyl]aziridine-2-yl)ethanol dissolved in 1 D of ace¬ tonitrile at room temperature and then stirred again for two hours. After two hours, the solution was added with 0.1 D (1.1 mmol) of pyrrolidine and then refluxed at 90 °C for two hours. Then, after completing the reaction with 1.2 N of hydrochloric acid, the solution was added with sodium carbonate and subject to the extraction with ethyl acetate at three times. The organic layer was cleaned with brine and then the solution was dried and concentrated with magnesium sulfate. The resultant material was purified with a column chromatography, thereby obtaining the compound (13).

[116] (step d2) preparation of the compound (14)

[117] The compound (14) was obtained from the compound (13) obtained in the step c2, using the method of the step dl.

[118] (step e2) preparation of the compound (3) of the chemistry figure 7

[119] The compound (3) was obtained from the compound (14) obtained in the step d2, using the method of the step el (refer to the reaction figure 2).

[120] [Embodiment 3] synthesis of the compound (4-1) of the chemistry figure 16 and the compound (4) of the chemistry figure 13

[121] fstep a3^*> preparation of the compound Q 6)

[122] The compound (16), i.e., (2R)-l-[(lR)-l-phenylethyl]aziridine-2-yl-methanol was obtained from (2R)-l-[(lR)-l-phenylethyl]-2-aziridiencarboxylic acid (-)-menthol ester (the compound (15) using the method of the step al.

[123] fstep b3^*> preparation of the compound (17)

[124] The compound (16) obtained in the step a3, i.e., 1.3 g of (2R)-l-[(lR)-l-phenylethyl]aziridine-2-yl-methanol was added to acetonitrile (0.3M) and 1.43 g of N,N'-dicarbonylimidazole was droplet-added to the mixture and then stirred at room temperature. After two hours, 1.6 D of iodotrimethylsilane was droplet- added to the solution. After the completion of the reaction, the solution was subject to the extraction with ethyl acetate and then the extracted solution was cleaned with brine and then dried and concentrated with magnesium sulfate. The resultant material was purified with a column chromatography, thereby obtaining the compound (17), i.e., (S)-4-iodomethyl-3-[(R)-l-phenylethyl]oxazolidine-2-one.

[125] (step c3) preparation of the compound (18)

[126] The compound (17) obtained in the step b3, i.e., 1.3 g (3.93 mmol) of

(S)-4-iodomethyl-3-[(R)-l-phenylethyl]oxazolidine-2-one, 1.1 D of anisole and 1.3 D of methane sulfonic acid were added to toluene (0.3 M). Then, the mixture was heated to 50 °C, stirred for two hours and then stirred again while cooling it. Then, the reaction was completed with sodium carbonate, and the organic layer was extracted. The extract was cleaned with brine and dried and concentrated with magnesium sulfate. The resultant material was purified with a column chromatography, thereby obtaining the compound (18), i.e., (S)-4-(iodomethyl)oxazolidine-2-one.

[127] fstep d3^*> preparation of the compound C 19^")

[128] The compound (18) obtained in the step c3, i.e., 800 mg (3.52 mmol) of

(S)-4-(iodomethyl)oxazolidine-2-one and 3 g of triphenylphosphine were added to dimethylformaldehyde (0.3 M) and the mixture was heated to 90 °C and stirred for 24 hours. Then, the solution was added with ethyl ether so as to remove an excessive amount of triphenylphosphine and cleaned with tetra hydrofuran, thereby obtaining the compound (19), i.e., [(4S)-2-oxo-l,3-oxazolidine-4-yl](triphenyl) phosphonium iodide.

[129] (step e3) preparation of the compound (20)

[130] The compound (19) obtained in the step d3, i.e., 200 mg (0.41 mmol) of

[(4S)-2-oxo-l,3-oxazolidine-4-yl](triphenyl) phosphonium iodide was added to anhydrous tetrahydrofuran (0.3 M) and 0.9 D (1.0 M solution) of lithium hexamethyld- isilazine was droplet-added to the mixture at -78 °C and stirred. After one hour, 0.9 D of 4-octylbenzaldehyde was droplet-added to the solution at -78 °C. After stirring the solution at room temperature for two hours, the reaction was completed with ammonium chloride aqueous solution and the solution was subject to the extraction with ethylacetate to obtain filtrate. The obtained filtrate was cleaned with brine and dried and concentrated with magnesium sulfate. Then, the resultant material was purified with a column chromatography, thereby obtaining the compound (20), i.e., (R)-4-(4-octylstyryl)oxazolidine-2-one.

[131] fstep f3^*> preparation of the compound (A-Y) of chemistry figure 16

[132] The compound (20) obtained in the step e3, i.e., 40 mg (0.21 mmol) of (R)-4-(4-octylstyryl)oxazolidine-2-one was added to ethanol (0.3 M) and palladium/ charcoal (20 wt.%) was added to the mixture. Then, the solution was stirred at room temperature for two hours with a hydrogen balloon being suspended and the reaction solution was filtered. The obtained filtrate was concentrated, droplet-added with 87 mg of lithium hydroxide dissolved in ethanol (0.3 M), refluxed for two hours and cooled to room temperature. After that, it was performed the extraction using ethyl acetate and water, and the organic layer was dried and concentrated with magnesium sulfate. The resultant material was purified with a column chromatography, thereby obtaining the compound (4-1) of the chemistry figure 16.

[133] (step g3) preparation of the compound (4) of the chemistry figure 13

[134] The compound (4) of the chemistry figure 13 was obtained from the compound

(4-1) of the chemistry figure 16 obtained in the step f3, using the method of the step gl (refer to the reaction figure 3).

[135] [Embodiment 4] synthesis of the compound (5) of the chemistry figure 18

[136] (step a4^*> preparation of the compound (S)

[137] The compound (8) was obtained from (2S)-l-[(lR)-l-penylethyl] -

2-aziridinecarboxylic acid (-)-menthol ester (the compound (7)), using the method of the step al.

[138] (step b4^*> preparation of the compound (2Y)

[139] The compound (21) was obtained from the compound (8) obtained in the step al, using the method of the step bl.

[140] (step c4) preparation of the compound (22)

[141] The compound (22) was obtained from the compound (21) obtained in the step b4, using the method of the step cl.

[142] (step d4) preparation of the compound of the chemistry figure 18

[143] The compound (5) of the chemistry figure 18 was obtained from the compound (22) obtained in the step c4, using the method of the step dl (refer to the reaction figure 4).

[144] [Embodiment 5] synthesis of the compound (6) of the chemistry figure 21

[145] (step a5) preparation of the compound (8)

[146] The compound (8) was obtained from (2S)-l-[(lR)-l-penylethyl] -

[147] f step b5^*> preparation of the compound (9)

[148] The compound (9), i.e., (R)-2-phenyl-l-((S)-l-[(R)-l-penylethyl] aziridine-

2-yl)ethanol was obtained from the compound (8) obtained in the step al, using the method of the step bl.

[149] f step c5^*> preparation of the compound f 23^*)

[150] The compound (9) obtained in the step b5, i.e., 500 mg of (R)-2-penyl-l-((S)-l-[(R)-l-penylethyl]aziridine-2-yl)ethanol was added to dichloromethane (0.3 M) and 0.52 D of triethylamine and methanesulfonylchloride 0.24 D were droplet-added to the mixture at 0 °C. After one hour, it was performed the extraction using dichloromethane and water and the organic layer was dried and con¬ centrated with magnesium sulfate. The resultant material was purified with a column chromatography, thereby obtaining the compound (23).

[151] (step d5) preparation of the compound (24) [152] The compound (24) was obtained from the compound (23) obtained in the step c5, using the method of the step c2.

[153] (step e5) preparation of the compound (25) [154] The compound (25) was obtained from the compound (24) obtained in the step d5, using the method of the step dl.

[155] (step f5) preparation of the compound (6) of the chemistry figure 21 [156] The compound (6) of the chemistry figure 21 was obtained from the compound (25) obtained in the step e5, using the method of the step el (refer to the reaction figure 5).

[157] Experimental example 1: sphingosine kinase activity suppressing efficacy of the novel sphingolipid derivative [158] The following experiments were performed to measure the sphingosine kinase activity suppressing efficacies of the novel sphingolipid derivatives prepared from the above embodiments 1 to 6.

[159] Firstly, a sphingosine kinase activity assay was performed in a manner of developing the sphingosine- 1 -phosphate labeled using P labeled ATP on TLC and then measuring a radiation dose. At this time, NEG 002 (2 uCi/D) of Perkin Elmer was used as the ³²P labeled ATP and compositions of buffered solutions SKl and SK2 for sphingosine kinase assay were shown in Table 1. In addition, 1 mM PMSF and 0.5% aprotinin were used by preparing protease inhibitor cocktail of Roche company with 50X stock solution, 200 mM DTT and IM NaVO which was a phosphate inhibitor were added before using. The protease inhibitor and NaVO were used while keeping them at 4 °C and the DTT was used while keeping it at 20 °C.

[160] [161] Table 1

[162] In sphingosine kinase assay, CHO-Kl (Chinese Hamster Ovary: ATCC Number:

CCL-61, which is a cell strain transfected with sphingosine kinase genes) cell Iy sate, substrate (10-40 mM), the novel sphingolipid derivatives of the embodiments 1 to 6 (10-100 mM) and ATP (0.5 mM, Hot 2uCi/ml) were added to an E-tube and the remaining was added with buffered solutions SKl and SK2 for the sphingosine kinase assay to adapt a reaction volume. In addition, the lysate, which was taken out at -80 °C, was dissolved on ice, subject to sonication with 25-35A for 10 seconds, and then cooled for 5 seconds. This was repeated two times. After that, a proper amount thereof (which was determined by checking an expression level after the transfection) was added to the reaction solution and then an enzyme reaction was performed at 37 °C for 30 minutes. After the enzyme reaction was completed (reaction volume: 50 D), a 200 D of solution (chloroform: methanol: hydrochloric acid = 100: 200: 1) was added and then subject to a vortex for one minute to complete the reaction. After that, 65 D of chloroform and 650 D of IM KCl solution were added to the solution, and subject to the vortex for 5 minutes and a centrifugal separation at 5, 000 rpm for three minutes, and then the resultant supernatant was completely removed and then evaporated. After the evaporation, a 20 D of solution (chloroform: methanol = 2:1) was added and droplet- added on the TLC plate. Then, a development process was performed using a solution (1-butanol: acetic acid: water = 3:1:1) as a development solution and then an radiation exposure process was performed. After that, a radiation dose was measured to calculate a labeled sphingosine- 1-p). At this time, DMS was used as a control group.

[163] As a result of that, the novel sphingolipid derivatives obtained in the embodiments

1 to 6 did not exhibit an excellent efficacy for sphingosine kinase 1 (SPHKl), as can be seen from Figs. 1 to 4 and only a few derivatives (SG-5 to SG-7) exhibited a slight suppressing efficacy from a concentration of 20 uM. On the contrary, as can be seen from Figs. 5 to 8, the novel sphingolipid derivatives exhibited excellent activity suppressing efficacies for sphingosine kinase 2 (SPHK2) involving in the DNA synthesis suppression. In particular, SG-I, SG-5, SG-7, SG-12 and SG-14 exhibited excellent enzyme suppressing efficacies from a concentration of 20 uM.

[164] Formulation examples of the composition are set forth as follows. However, it should be noted that the examples are given only to illustrate the invention, not to limit it.

[165] <Formulation example 1 : SG-5 2% cream> [166] Table 2

[167] Stearyl alcohol, cetyl alcohol, sorbitan monostearate and isopropyl myristate were introduced in a double-walled vessel and then the mixture was heated until it was completely dissolved. The mixture was added to a mixture of purified water, propylene glycol and polysorbate 60 separately prepared using a liquid homogenizer at 70-75 °C. The produced emulsion was continuously mixed and cooled to below 25 °C. Sub¬ sequently, the solution of SG-5, polysorbate 80 and purified water and the anhydrous sodium sulfite solution in the purified water were added to the emulsion while con¬ tinuously mixing the solutions. The cream was homogenized and filled in a proper tube.

[168] <Formulation example 2: SG-5 2% local gel> [169] Table 3

[170] A proper amount of hydrochloric acid was added to be a solution. A proper amount of sodium hydroxide was added to be pH 6.0. A proper amount of purified water was added to be 100 mg.

[171] SG-5 was added to a solution of hydroxypropyl b-cyclodextrin in purified water while stirring it. Hydrochloric acid was added to be a solution and then sodium hydroxide was added to be pH 6.0. This solution was added to a dispersion solution of carrageenan PJ in propylene glycol while mixing it. The mixture was heated to 50 °C while slowly mixing, and added with ethyl alcohol and then cooled to about 35 °C. A remaining amount of purified water was added to the mixture and then the mixture was mixed to be homogeneous.

[172] <Formulation example 3: SG-5 nano-dispersion solution> [173] Table 4 SG-5 nano-dispersion solution phase inversion

[174] Migliole 812, SG-5 and polysorbate 80 were mixed. Phosphatidyl choline was dissolved in ethanol and then added to the mixture to obtain a homogeneous clear liquid.

[175] Table 5

SG-5nano-dispersion solution water phase

[176] A water phase containing SG-5 (for example, 94.54 g) was stirred and kept at 50 °C in a vessel. A liquid nano-dispersion solution phase inversion (for example, 5.46 g) was stirred and added to the water phase. Industrial Applicability

[177] The novel sphingolipid derivative and the isomer thereof or the pharmaceutically acceptable salt thereof according to the invention highly suppress an activity of sphingosine kinase to prevent ceramide and sphingosine from being phosphorylated due to sphingosine kinase and thus to maintain concentrations of ceramide and sphingosine to be high, thereby inducing apoptosis of a cancer cell and thus exhibiting an anti-cancer activity. In addition, since the invention suppresses a cell proliferation- promoting activity of sphingosine kinase to treat or prevent a hyper-proliferative disease such as cancer or psoriasis, the composition containing the same can be usefully used as a composition for suppressing sphingosine kinase and a composition for treating or preventing a cancer or hyper-proliferative disease.

Claims

[1] A sphingolipid derivative having a following chemistry figure 1, an isomer thereof or a pharmaceutically acceptable salt thereof, [chemistry figure 1]

wherein R is hydrogen, or alkyl group, alkenyl group, acyl group or aryl group of C 1-40

R is hydrogen, or alkyl group, alkenyl group, acyl group or aryl group of C ; R is hydrogen, or alkyl group, alkenyl group, acyl group or aryl group of C ,

3 1-40 or heterocyclic group comprising pyrrolidine group and morpholine group; R 4 is hydrogen comprising hydroxyl group, or alkyl group, alkenyl group, acyl group or aryl group of C ; and

1-40

R is hydrogen, or alkyl group, alkenyl group, acyl group or aryl group of C .

5 1-40

[2] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the sphingolipid derivative is a compound represented by a following chemistry figure 2. [chemistry figure 2]

wherein R is hydrogen or alkyl group of C .

[3] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 2, wherein the sphingolipid derivative is a compound having a following chemistry figure 3 (SG-I), 4 (SG-2), 5 (SG-3) or 6 (SG-4).

[Chemistry Figure 3]

SG 4

[4] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the sphingolipid derivative is a compound represented by a following chemistry figure 7. [Chemistry Figure 7]

wherein R is hydrogen or alkyl group of C

[5] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 4, wherein the sphingolipid derivative is a compound having a following chemistry figure 8 (SG-13), 9 (SG-14), 10

(SG-15), 11 (SG-10) or 12 (SG-16).

[Chemistry Figure 8]

SG-13

[Chemistry Figure 9]

SG-14 [Chemistry Figure 10]

SG-15

[Chemistry Figure 11]

SG-10

[Chemistry Figure 12]

SG-16

[6] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the sphingolipid derivative is a compound represented by a following chemical figure 13. [Chemistry Figure 13]

wherein R and R are hydrogen or alkyl group of C .

[7] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 6, wherein the sphingolipid derivative is a compound having a following chemistry figure 14 (SG-5) or 15 (SG-6). [Chemistry Figure 14]

SG-5 [Chemistry Figure 15]

SG-6

[8] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the sphingolipid derivative is a compound represented by a following chemistry figure 16. [Chemistry Figure 16]

wherein R is hydrogen or alkyl group of C .

1-40

[9] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 8, wherein the sphingolipid derivative is a compound of a following chemistry figure 17 (SG-7). [Chemistry Figure 17]

7

SG-7

[10] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the sphingolipid derivative is a compound represented by a following chemistry figure 18. [chemistry figure 18]

wherein R is hydrogen or alkyl group of C

1-40. [11] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 10, wherein the sphingolipid derivative is a compound having a following Chemistry Figure 19 (SG-9) or 20 (SG- 12). [Chemistry Figure 19]

SG-9

[Chemistry Figure 20]

SG-12

[12] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 1, wherein the sphingolipid derivative is a compound represented by a following chemistry figure 21. [chemistry figure 21]

wherein R is hydrogen or alkyl group of C .

1-40

[13] The sphingolipid derivative, the isomer thereof or the pharmaceutically acceptable salt thereof according to claim 12, wherein the sphingolipid derivative is a compound represented by a following chemistry figure 22 (SG-11). [chemistry figure 22]

SG-11

[14] A composition for suppressing sphingosine kinase containing the sphingolipid derivative according to any one of claims 1 to 13, the isomer thereof or the phar¬ maceutically acceptable salt thereof as an effective ingredient.

[15] The composition according to claim 14, wherein the composition is used to treat or prevent a cancer or disease relate to the cancer.

[16] A composition for inducing an apoptosis containing the sphingolipid derivative according to any one of claims 1 to 13, the isomer thereof or the pharma¬ ceutically acceptable salt thereof as an effective ingredient.

[17] The composition according to claim 16, wherein the composition is used to treat or prevent a cancer or disease relate to the cancer.

[18] A composition for treating or preventing a hyper-proliferative disease containing the sphingolipid derivative according to any one of claims 1 to 13, the isomer thereof or the pharmaceutically acceptable salt thereof as an effective ingredient.

[19] The composition according to claim 18, wherein the hyper-proliferative disease is psoriasis.

[20] A composition for treating or preventing a cancer containing the sphingolipid derivative according to any one of claims 1 to 13, the isomer thereof or the phar¬ maceutically acceptable salt thereof as an effective ingredient.