WO2001038295A1 - Sphingosine derivatives - Google Patents

Abstract

Sphingosine derivatives represented by general formula (I), or pharmaceutically acceptable salts thereof, wherein R?1 and R2¿ are each hydrogen or the like; Z is NR7 (wherein R7 is hydrogen or the like); Y is oxygen or NR8 (wherein R8 is hydrogen or the like); W is oxygen or sulfur; and k is an integer of 1 to 20. The derivatives and the salts are useful as preventive or therapeutic drugs for cerebrovascular disorders such as cerebral hemorrhage and cerebral infarction; head injuries; senile dementia; degenerative diseases of cranial nerve such as Alzheimer disease and Parkinson disease; diabetes; obesity; arteriosclerosis; inflammatory diseases; immunologic diseases; cancers; kidney diseases; and heart diseases.

Description

 Specification

 Sphingosine derivative

Technical field

 The present invention relates to a novel sphingosine derivative useful as various medicines by inhibiting neutral sphingomyelinase. Background art

 Sphingomyelinase is an enzyme that decomposes into ceramide and phosphocholine using sphingomyelin, which is one of the sphingolipids mainly present in cell membranes, as a substrate. It is roughly divided into gender type. While the acidic type is localized in the lysosome, the neutral type is present in the cell membrane or cytoplasm, but both types are thought to be involved in the production of ceramide by sphingomyelin metabolism.

The ceramide produced by sphingomyelinase plays an important role as a lipid second messenger in various cell functions such as apoptosis, cell proliferation and differentiation, and this metabolic pathway is called the sphingomyelin pathway. I have. Sphingomyelinase is activated by various stresses such as ischemia, TNF- «, IL-1 / 3, IFN-α, 1,25-dihydroxyvitamin D ₃ , anticancer drugs and radiation. The sphingomyelin pathway may be involved in various pathological conditions that cause the onset and progression of these chemical and physical stresses.For example, the sphingomyelin pathway is activated during cerebral ischemia. Addition of sphingomyelinase or ceramide to cells causes cell death by apoptosis. In addition, during cerebral ischemia, production of TNF-α and IL-1 / 3 is increased and neuronal cell death is induced. However, TNF-solubilised receptor and IL-1 / 3 receptor antagonist Inhibits nerve cell death due to ischemia.

In addition to the above cerebrovascular disorders, increased production of TNF-α and IL-1 / 3 is widely involved in cerebral neurodegenerative diseases such as head trauma, senile dementia, Alzheimer's disease, and Parkinson's disease. In non-insulin-dependent diabetes mellitus and obesity, the production of TNF- in adipocytes is enhanced and insulin resistance is induced, and this involves the activation of the sufingomyelin pathway by TNF-α. In addition, IL-1 i3 is involved in the development of insulin-dependent diabetes mellitus, but ceramide exerts the same action as IL_lβ.

 TNF-α and IL-1 / 3 are involved in the onset and progression of arteriosclerosis. In other words, TNF-α and IL-1 / 3 express the adhesion factor ICAM-1 in vascular endothelial cells, and promote adhesion of monocytes to vascular endothelial cells and migration into subendothelium. In addition, TNF-α causes apoptosis of vascular endothelial cells via activation of the sphingomyelin pathway. Activation of the sphingomyelin pathway also promotes LDL aggregation in vascular smooth muscle, forms lesions, and destabilizes plaques through apoptosis of vascular smooth muscle.

 The physiological activities of ceramides in inflammatory immune system cells are extremely diverse, including 分化 cell and Β cell differentiation and activation, production of various cytokins, induction of apoptosis, production of inflammatory prostaglandin, etc. It is deeply involved in the onset and progress of various inflammatory diseases and immunological diseases. In addition, the activation of the sphingomyelin pathway involves numerous chemical and physical stresses, including TNF-α and IL-11; 3. It is considered that the routes are crosstalking with each other in a complicated manner.

 Based on the above, specific inhibitors for sphingomyelinase are cerebrovascular disorders such as cerebral hemorrhage and cerebral infarction, head trauma, senile dementia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and diabetes. It can be used as a preventive or remedy for obesity, arteriosclerosis, inflammatory disease, immune disease, cancer, kidney disease and heart disease.

 As a sphingosine derivative having sphingomyelinase inhibitory activity, 3-0-alkylsphingomyelin has been reported (Mark D. Lister, et al., Biochimic a et Biophysica Acta, 1995, 1256, 25). The chemical structure differs from the compound of the invention. Disclosure of the invention

The present invention provides a novel compound having a sufingomyelinase inhibitory action As a result, the present inventors have conducted intensive studies and found that a certain sphingosine derivative has a neutral sphingomyelinase inhibitory activity, thereby completing the present invention. That is, the present invention provides a compound represented by the general formula (I):

HN——R ¹ W

^C k ^H 2k ₊ i-OH = CH— C oH— CH -CH, -Y- C- R2

 I '-

[Wherein, R ¹ represents a hydrogen atom, C ₂ - _2. Arukanoiru group, Benzoiru group, "halogen atom, CI- 5 alkyl group, a hydroxyl group, Ci ₅ alkoxy groups, C ₂ - ₅ Arukanoiru group, forces Rupokishiru group, C ₂ - ₅ alkoxycarbonyl group, an amino group, C, - ₅ 1 or 2 with substituted amino group of the alkyl group, C ₂ - ₅ alkanoylamino Noi Rua amino group, C ₂ - ₅ alkoxycarbonyl Cal Poni Rua amino group, C i is substituted with 1 to 5 halogen atoms - ₅ alkyl group, Shiano group, a nitro group, a mercapto group or CI- 5 Benzoiru group substituted with an alkylthio group ", C ₄ - 8 cycloalkyl Cal Poni Le group, C 2 - 2. Alkoxy force Lupo group, the formula _{^{- COC (R 3) 2 NHR}} 4 ( wherein, R ³ is a hydrogen atom or CI- ₅ alkyl group, R ⁴ is a hydrogen atom or a C ₂ - is a ₅ alkoxycarbonyl group. group or the formula represented by) -. COC_〇 ₂ R ³ (wherein, R ³ is a group represented by a hydrogen atom or a C _s alkyl group), R ² is a hydrogen atom, d ₈ alkyl group, wherein CH _{2) n} R ⁵ (wherein, R ⁵ is a hydroxyl group, an amino group, C, - ₅ 1 3 or in substituted amino group of the alkyl group, the force Rupokishiru group, C ₂ - ₅ alkoxycarbonyl Cal Poni group, force Rubamoiru group An aminocarbonyl group substituted with one or two Ci-5 alkyl groups, a rubamoyloxy group, an aminocarbonyloxy group substituted with one or two C- ₅ alkyl groups, a phenyl group, Halogen atom, d-5 alkyl group, hydroxyl group, d-5 alkoxy group, C

2 - 5 Arukanoiru group, carboxyl group, C ₂ - ₅ alkoxycarbonyl Cal Poni group, an amino group, C ₅ 1 or 2 in substituted Amino group of the alkyl group, C _2-5 Arukanoirua amino group, C ₂ - ₅ alkoxy force Ruponiruamino group, C ₅ alkyl group substituted with 1 to 5 halogen atoms, Shiano group, a nitro group, Ulei de group, C, ₅ alkyl 1 or 2 in substituted Urei de group, mercapto or C ! - ₅ alkylthio Phenyl group, pyridyl group, pyridyl group substituted with C! -Alkoxy group, virazyl group, pyrrolidyl group, piperidyl group, piperazyl group, morpholinyl group, thiomorpholinyl group, imidazolyl group, thiazolyl group, A thiadiazolyl group, a tetrazolyl group, a quinolyl group or a 1 H indazolyl group, and n is an integer of 0-5. Group or the formula represented by) - S_〇 _m R ⁶ (wherein, R ⁶ is phenyl group or "halogen, d - ₅ alkyl group, a hydroxyl group, C i ₅ alkoxy group, C _{2 5} Al force Noiru group, a force Rupokishiru groups, C alkoxy Cal Poni group, an amino group, one or two with substituted amino group d § alkyl groups, C ₅ alkanoyloxy Noi Rua amino groups, C ₂ - ₅ alkoxycarbonyl Cal Poni Le amino group, 1 to halogen atoms 5 Substituted with one or two C 2alkyl, cyano, nitro, ureido, or C 、 alkyl substituted 丄, mercapto, or d- ₅ alkylthio groups. Z is NR ⁷ (where R ⁷ is a hydrogen atom, a hydroxyl group or a C, ₅ alkyl group). And Y is an oxygen atom or NR ⁸ (R ⁸ is a hydrogen atom, hydroxyl W is an oxygen atom or a sulfur atom, and k is an integer of 1 to 20. ] Or a pharmaceutically acceptable salt thereof.

In the present invention, C ₂ - _2. An alkanoyl group means a linear or branched alkanoyl group having 2 to 20 carbon atoms, for example, acetyl group, propanoyl group, isopropanol group, butyryl group, isoptyryl group, valeryl group, vivaloyl group, millivalent group. Examples thereof include a styryl group and a stearyl group.

The C ₂₅ alkanoyl group means one having 2 to 5 carbon atoms among the above. C ₄ - ₈ and the cycloalkylcarbonyl group means a cycloalkyl force Lupo two Le group 4-8 carbon atoms, such as cyclopropyl group, cyclopentyl Cal Boniru group, Kishirukaruponiru group cyclohexylene, Puchirukaruponiru group cyclohexylene And so on.

C ₂ is a ₅ alkoxycarbonyl group means a straight or branched § Rukokishikarubo two Le group having 2 to 5 carbon atoms, such as methoxycarbonyl group, Etokishikarupo group, ethoxy Cal Poni group, propoxy carboxymethyl sulfonyl group , Tert butoxyl Ponyl groups and the like can be mentioned.

 C alkyl group means a straight or branched chain alkyl group having 120 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl. Group, isopentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group, tridecyl group, nonadecyl group and the like.

The C i- ₈ alkyl group means one having 18 carbon atoms among the above, and the C ₅ alkyl group means one having 15 carbon atoms among the above.

C, - ₅ nitrogen atoms 1 3 with substituted Amino groups and Amino group of the alkyl group is C, - ₅ means that it is substituted with an alkyl group, quaternary and are three substituents It is a salt.

C 2 - 5 nitrogen atoms Arca Noi Rua amino group and the Amino group C ₂ - means that it is substituted with one ₅ Arukanoiru groups such Asechiruamino group, and the like Isopuropio Niruamino group.

 A C 2-5 alkoxy group means that the nitrogen atom of the amino group is substituted with one of the C 2-5 alkoxycarbonyl groups, for example, a methoxycarbonylamino group or a butoxycarbonylamino group. Can be mentioned.

 A halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The C-5 alkyl group substituted with 15 halogen atoms means a linear or branched alkyl group having 15 carbon atoms and substituted with the halogen atom, for example, a trifluoromethyl group And the like.

C ₅ The alkoxy group means a straight or branched alkoxy group having a carbon number of 1 5, for example a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and the like heptoxy .

C -! ₅ The alkylthio group means a straight-chain or branched alkylthio O group having a carbon number of 1 5, such as methylthio, Echiruchio group, propylthio group, isopropenyl Piruchio group, Puchiruchio group, Isopuchiruchio group, tert- Examples include a butylthio group, a pentylthio group, and a hexylthio group. Examples of hydroxyl-protecting groups include acetyl groups, benzoyl groups and other acyl groups; trimethylsilyl groups, t-butyldimethylsilyl groups, benzyldimethylsilyl groups and other trisubstituted silyl groups; tetrahydropyranyloxy groups, methoxymethyl groups and the like. Case-type protective groups.

 When a plurality of substituents represented by the same symbol are present in one general formula, they may be the same or different.

 The pharmaceutically acceptable salts refer to acid or alkali addition salts. The acid or alkali used in this case is not particularly limited. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and benzenesulfonic acid, and examples of the alkali include sodium, metal ions such as sodium hydroxide, and alkylammonium. Ammonia ions such as aluminum.

 The compound of the present invention may be a single optically active compound or a mixture of stereoisomers.

The compound of the present invention can be produced, for example, according to the method shown below. Hereinafter, in the present specification, Boc is a tert-butoxycarbonyl group, TFA is trifluoroacetic acid, Pv is a pivaloyl group, DBU is 1,8-diazabicyclo [5.4.0] didec-7-ene, TCF is trichloromethyl chloroformate, TBDMS is tert-butyldimethylsilyl group, WSC'HCl is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and HOBt is 1-hydroxybenzotriazole. May be indicated. First, N-Boc-sphingosine, which is a raw material for synthesis, was synthesized from serinal according to the method of P. Herold et al. (Helv. Chim. Acta., 1988, 71, 354). Intermediate compound (1) can be synthesized.

Expression

 _ ^ CHO

 I r

 O ^ Boo

 P. Harold, et al.,

 He I v. Chim. Acta., 1988, 71,354

 Ser inal

 ana I og

In the compounds of formula (I), a compound Y and W is an oxygen atom and Z is NR ⁷ (3) can be produced by the method shown in Equation 2. That is, compound (2) can be obtained by treating compound (1) with trichloromethyl chloroformate or di-tert-butyl dicarbonate in the presence of a base and then reacting with the corresponding amine compound. . Further, the compound (2) can also be obtained by reacting the intermediate (1) with the corresponding isocyanate. Further, the compound (3) can be obtained by desilylation of the compound (2) with hydrofluoric acid or tetrabutylammonium fluoride. The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

Equation 2

HN— R ¹

TCF then HNR ² R ⁷

C _k H _{2k + 1} -H = CH-CH— CH— CH ₂ 0H

TBDMSO or (Boc) ₂ 0 then HNR ² R ⁷

 (1)

 or R2-NC0

HN— Ri HF, Py

 R7

 W.

C _k H _{2k + 1} -CH = CH— CH— CH-CH ゥ -0- GN

or Bu ₄ NF

 TBDMSO

 (2)

一般式 （ I ) の化合物において、 Yが N Hであり Wが酸素原子であり Zが N R ⁷である化合物 (7)は、 式 4に示した方法により製造することができる。 すなわち、 化合物 (1)を、 ジメチルスルホキシド中、 三酸化硫黄ピリジン錯体及びトリェチル ァミンで酸化しアルデヒド体とした後、 ヒドロキシルァミン及び無水酢酸と順次 反応させ、 生成したァセトキシィミン体を水素化ホウ素ナトリウムにより還元し ァミン化合物 (4)へ変換した。 なお、 式 3においては水酸基の保護基として T B D M Sを用いた例を示しているが、 前述の他の保護基を用いることにより、 あるい は慣用の条件で脱保護することにより、 他のアミン化合物を製造することができ る。 次いで化合物 (4)を、 クロ口ぎ酸フエニルあるいは二炭酸ジ- tert -プチルで処 理した後、 対応するァミン化合物と反応させることにより、 化合物 (6)を得ること ができる。 また、 化合物 (4)を対応するイソシァネートと反応させることにより、 化合物 (6)を得ることもできる。 更に、 化合物 (6)を脱シリル化することにより化合 物 (7)を得ることができる。 これら反応での試薬、 時間、 温度及び溶媒等の反応条 件は、 通常用いられる条件で行うことができる。 式 4 ^C k ^H 2k ₊ i- H

In the compounds of formula (I), Y is and Z is NR ⁷ a and W is an oxygen atom is NH compound (7) can be prepared by the method shown in Equation 4. That is, the compound (1) is oxidized in dimethyl sulfoxide with a sulfur trioxide pyridine complex and triethylamine to form an aldehyde form, which is subsequently reacted with hydroxylamine and acetic anhydride, and the resulting acetoximine form is reacted with sodium borohydride. It was reduced and converted to the amine compound (4). Although Formula 3 shows an example in which TBDMS is used as a hydroxyl-protecting group, other amine compounds can be obtained by using the other protecting groups described above or by deprotecting under conventional conditions. Can be manufactured. Next, the compound (4) is treated with phenyl chloroformate or di-tert-butyl dicarbonate and then reacted with the corresponding amine compound to give the compound (6). Compound (6) can also be obtained by reacting compound (4) with the corresponding isocyanate. Further, the compound (7) can be obtained by desilylation of the compound (6). The reaction conditions such as reagents, time, temperature, solvent and the like in these reactions can be performed under commonly used conditions. Equation 4

_{HN- R '1) PyS0 3,} Et, N, DMSO

_{C k H 2kt i -ΪΗ = CH} -CH-CH -CH 2 -OH

TBDMSO w 2) NH ₄ 0H 3) Ac ₂ 0 4) NaBH ₄

HN— R '(Boc) ₂ 0 then W

C _k H _2k "_CH = CH -CH-CH -CH ₂ -NH ₂

or CIC0 ₂ Ph then HNR2R7

 TBDMSO

 or R2NC0

C _k H _m , _iH

HN— R '

C _k H _{2k +} i-CH = CH -CH-CH.- CH, —

 ヽ R2

 OH

(7) In the compound of general formula (I), Y is NH and is W is a sulfur atom and Z is NR ⁷ Compound (8) can be prepared by the method shown in Equation 5. That is, compound (8) is obtained by reacting compound (4) with phenyl chlorothionoformate and then reacting with the corresponding amine compound or with the corresponding isothiocynate and further desilylation. Can be. The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

 Equation 5

HN— R ¹

 1) PhOC (S) CI

C _k H2 _kt , _CH = CH -CH-CH -CH ₂ NH ₂

2) HNR ² R ⁷

 TBDMSO

3) Bu ₄ NF

 (Four)

HN— R 'R7.

C _k H _{2k +} , _CH = CH— CH— CH— CH. One N—CN

 H R2

 OH

(8) In the compound of the general formula (I), R ² is a group represented by the formula — (CH ₂ ) _n R ⁵ (R ⁵ is an amino group or C 2-5 phenyl group substituted by an alkanoylamino group)

0) and compound (11) can be produced by the method shown in Formula 6. That is, the compound (9) obtained by any of the methods represented by the above formulas 2 to 5 is subjected to removal of Boc with trifluoroacetic acid to obtain a compound (10). When an acetylamino group is used, it can be converted to the compound (11) by further reacting with acetic anhydride. The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

The compound (13) in which R ² is a group represented by the formula — (CH ₂ ) _n R ⁵ (R ⁵ is a quaternary amine) in the compound of the general formula (I) is produced by the method shown in the formula 7 be able to. That is, the compound (13) can be obtained by reacting the compound (12) obtained by any one of the formulas 2 to 5 with a corresponding alkyl halide. The reaction conditions such as reagents, time, temperature, solvent and the like in this reaction can be carried out under ordinary conditions.

 : Expression 7 '

HN— R ¹ W

I II R9 _X

CKHJ ^ I _CH = CH -CH-CH -CH.-Y- C -Z _N N (R3) ₂ ― ~~-

■ ': ^0H (11).,.

Ck t-CH = CH _n N * (R ³ ) ₂ R ⁹ -X "

(In the formula, R ⁹ represents a C i- ₅ alkyl group, and X represents a halogen atom.)

In the compound of the general formula (I), R ² is a group represented by the formula — (CH ₂ ) _n R ⁵ (R ⁵ is Compound (15), which is a group represented by the following formula (8): a carbonyl group or an aminocarbonyl group substituted with one or two C alkyl groups). That is, the compound (14) obtained by any of the methods represented by the above formulas 2 to 5 is treated with trichloromethyl chloroformate, reacted with the corresponding amine compound, and further desilylated. Yields compound (15). Reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

In the compound of the general formula (I), the compound (17) wherein R ² is a group represented by the formula — (CH ₂ ) _n R ⁵ (R ⁵ is a phenyl group substituted by a carboxyl group or a carbonyl group) As shown in Formula 9, the compound (16) obtained by any of the methods shown in Formulas 2 to 5 can be hydrolyzed by an ordinary method of hydrolyzing an ester. Furthermore, compound (18) can be obtained by treating compound (17) with diphenylphosphoric acid azide and then reacting with the corresponding amine compound. Reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

~~

 As shown in Formula 10, compound (20) can be obtained by desilylation of compound (19) derived from N-Boc-sphingosine. Next, the compound (20) obtained here is treated with trifluoroacetic acid to obtain a compound (21).

 Further, the compound (23) can be obtained by condensing the compound (21) with the amino acid derivative (22). Compound (23) can be treated with trifluoroacetic acid and converted to compound (24). The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

Two

Further, as shown in Formula 11, compound (25) can be obtained by reacting compound (21) with a halide of compound (27). Furthermore, the compound (25) can be converted to the compound (26) by hydrolysis. The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

発明を実施するための最良の形態

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples.

 2-N- (tert-butoxycarponyl) -D-erythro-sphingosine was produced according to the method described in the literature (P. Herold. Et al., Helv. Chim. Acta., 1988, 71, 354). .

The ¹ H-NMR spectrum values described below were measured at 200 MHz (unless otherwise specified).

Reference example 1

 To a solution of 2-N- (tert-butoxycarbonyl) -D-erythro-sphingosine (5.6 g, 14 mmol) in dichloromethane (60 ml) was added dropwise trifluoroacetic acid (12 ml) under cooling at -20 ° C. The temperature was raised to room temperature. The solvent was distilled off, and to the residue were added hydrated methanol (water: methanol = 12 mh, 200 ml) and then potassium carbonate (3.8 g), followed by stirring at room temperature for 24 hours. After evaporating the solvent, the residue was purified by column chromatography to obtain D-erythro-sphingosine (5.5 g).

The obtained compound was dissolved in tetrahydrofuran (60 ml), and triethylamine (5.1 ml, 37 mmol) was added under ice-cooling, followed by dropwise addition of bivaloyl chloride (1.8 ml, 15 mmol).

Dimension

Dimethylsilyl chloride (1.2 g, 8.1 mmol) was added, the mixture was stirred at room temperature for 8 hours, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the solvent was distilled off, and the residue was purified by column chromatography to give 3-0- (tert-butyldimethylsilyl) -2-N-isobutyryl-1-1-〇-pivaloyl-D-erys- Sphingosine (2.3 g) was obtained.

 The compound obtained here (2.3 g, 4.0 mmol) was dissolved in dehydrated methanol (30 ml), and 1,8-diazabicyclo [5.4.0] pandec-7-ene (0.92 g, 6.4 mmol) was added. Stirred for 28 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 3--0- (tert-butyldimethylsilyl) -2-N-isobutyryl-D-erythro-sphingocin (1.9 g). Was.

_{^{1 H-NMR (CDCl 3)}} (5 (ppm): 0.02 (s, 3H), 0.05 (s, 3H), 0.85 (t, J = 6.7Hz) 3H), 0.89 (s, 9 H), 1.13 ( d, J = 6.8Hz, 6H), 1.08-1.44 (m, 22H), 1.94-2.14 (m, 2H), 2.38 (m, lH), 3.31 (m, lH), 3.54 (m, lH) , 3.77 (m, lH), 4.01 (dd, J = 3.0,11.3Hz, lH), 4.42 (dd, J = 2.9,6.0Hz, lH), 5.44 (dd, J = 6.2,15.4Hz, lH ), 5.71 (dt, J = 15.4,6.8Hz, lH), 6.29 (d, J = 7.4Hz, lH)

The compounds of the present invention prepared in Examples 1 to 104 below are shown in the following table.

o HN 0 HO OCMd! οε o H H H H H o OO ^ d!

 N N N N N

oo H OCMd! ει. 82 oo ΉΝ ει. LZ ε 92

0 HN O 8W ^Z 03 '^^ ^/ ει.η o HN O HO oona ^

O HN O HO oo ⁿ a¾ ει ζζ

O HN O 'oo ⁿ a¾ ζ ι ιζ

0 o ε 81.

 H

O 0, 00 ε L i

Μ person ₇ 0 / 00df / X3d 0 z

H H H H H H H H H H HN O OCHd!

ει

ει

 N N N N N N N N N N

IDO HN 0 O0 ^J d!

o o 0^Z09H

oo 0 ^Z 09H

 OCMd!

0 0 Ϊ 3 03 OCMd! O 0 'ON. OCHd!

N3,

 o 0 OCMd! o 3

 0 OCMd! Ει /.ε o 308HN

 Hi OCMd! O o HO

O0 ^J d! £ 1 9ε

 o o OCMd! ει εε

 9W0

 o o 9W

 OCHd! O HN 0 HO OCMd!

Μ ζ people

OO^geH^uO £1 19 63380 / 00df / X3d I zo HN OH oom ει 29 o HN O

OO ^ge H ^u O £ 1 19

O HN OH 00 ^η 9ΐ 91 09

 3W,

O HN O I OCHd! 0ί 89

 3H ^.

0 HN O H OC d! 01 L9

O HON 0 OCHd! £1 19 O HN O OCHd! 21 09 o HN 0 OCMd! ει. 6fr

O HON 0 OCHd! £ 1 19 O HN O OCHd! 21 09 o HN 0 OCMd! Ει. 6fr

 S o HN O o OCMd! Εΐ. 8fr

O HN O OCMd!

M people

0 / 00df / X3d zz

0 HN HN Ϊ3 ^Ζ 03 oo ⁿ a ^ 2L

O HN HN oo ⁿ a ^ LL

O HN HN H oo ⁿ a ^ £ 1 9

O HN HN N oo ⁿ a ^ s

 9HS

O HN O O0 ^J d!

0 To HN O 03 oo ⁿ a ^ ZL

 9H0

o HN O O0 ^J d! 81 89 o HN O O0 ^J d! ει 9 ld0

O HN O OCHd!

3VHN

Q HN 0 O0 ^J d! Ει 9

3W,

 0 9 刚 o I S I € 9

Μ Person ZZ80 / 00df / X3d ε ζ ο ΗΝ Ο Η

00

Η ^ζ 03

ο ΗΝ Ο OCMd!

ο ΗΝ Ο Η^ζ03 OCHd!

ο ΗΝ Ο Η^ζ03 c€o 0 ε ε ε ε ε ε c0b ε ε co. ο ΗΝ Ο Η¾：)へ oonai o o 99 CO 368_ / 6 t€ 2. L- L- 80088080080006600ん 66 6.

ο ΗΝ Ο Η ^ζ 03 OCHd!

ο ΗΝ Ο Η ^ζ 03 c € o 0 ε ε ε ε ε ε ε c0b ε ε co. ο ΗΝ Η¾ Η¾ :) oonai oo 99 CO 368_ / 6 t € 2. L-L- 800 880 800 8000 6600

0 ΗΝ Ο 3 Cheom 0 ^ · ^ OCMd! Ο ΗΝ Ο ΉΝ000 oo ⁿ ai ο ΗΝ Ο HN000 oo ⁿ

S ΗΝ ΗΝ Ν ooⁿa^ 0 ΗΝ Ο _ | ^ε 9Μ + Μ · ^^^ oo ⁿ a *

S ΗΝ ΗΝ Ν oo ⁿ a ^

M person ₇ U 80 / 00df / X3d Example k R ¹ YW

95 13 Boc N 0 NH O

96 13 H H 0 NH 0

97 13 H N 0 NH 0

98 13 H o NH O

実施例 l

Example l

3-O-(tert-butyldimethylsilyl)-2-N-Viva mouth-D-Eris mouth-sphingosine (99 mg, 0.2 mmol) was dissolved in dicum romeyu (5 ml) and pyridine was added. (142 mg, 1.8 mmol) was added and cooled to -78. Trichloromethyl chloroformate (221, 0.3 mmol) was added dropwise to this solution, and the temperature was raised to -15 ° C over 1 hour. To this reaction solution, 25% aqueous ammonia (2 ml) was added dropwise, and the temperature was raised to 15 over 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off. Residue

6 Q

〇 oo o6

-o

o

o

() (Dimension sssεΗ rHΗΖ-) ¥) ()) () ((88 inch sT p dimension 9 H6 inch HK 66εΗH £ orIH ョ E ョ Es-* .-) () () Η88∞60ρ28 Dimensions 9999ε3ΐΓΗ Η1 == s

 H V ε one

(3χ (ε εΗ26εΗΐH¾ ε

) X) thunder) ((0ε dimension 66 p dimension SH9ε ΗHs∞9F¾ΐ2ε ΗH εε —...-

s s _)-0∞0 J ¹ H-NMR (CDCb) δ (ppm): 0.00 (s, 3H), 0.01 (s, 3H), 0.86 (s, 9H), 0.89 (t, 3H), 1.23 (s, 9H), 1.23-1.38 (m ₎ 22H) ₎ 2.08 (m, 2H), 4.48-4.57 (m ₎ 2H), 5.67 (dd, J = 6.0,15.4Hz, lH), 5.89 (dt, J-15.2,7.0Hz, lH), 6.52 (d, J = 6.1Hz, lH), 9.71 (s, lH)

The obtained aldehyde (0.86 g, 1.8 mmol) and hydroxylamine hydrochloride (0.47 g, 6.7 mmol) were dissolved in tetrahydrofuran a2 ml), and Ν, Ν-diisopropylpropylethylamine (1.16 _g , 9.0 mm _O 2) was dissolved. l) was added and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated, and the residue was purified by column chromatography. [Hydroxyiminomethyl-3-heptydecenyl] bivalamide (hydroxylimine compound) (0.88 g) was obtained.

 The obtained hydroxylimine compound (3.18 g, 6.2 mmol) is dissolved in tetrahydrofuran (50 ml), and acetic anhydride (0.70 ml) and pyridine (0.70 ml, 8.7 mmol) are sequentially added under ice-cooling, followed by stirring for 20 minutes. did. Water was added to the reaction solution, which was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated, and the residue was purified by column chromatography to give (l'S, 2'R, 3'Ε) -Ν- [1-acetoxyiminomethyl-2- (tert-butyl Dimethylsilyloxy) -3-heptanecenyl] pivalamide (acetoxyimine compound) (2.53 g) was obtained.

¹ H-NMR (CDC) δ (ppm): 0.01 (s, 3H), 0.04 (s, 3H), 0.88 (s, 9H), 0.88 (t, 3H), 1.21 (s, 9H), 1.21-1.40 (m, 22H), 2.03 (m, 2H), 2.16 (s, 3H), 4.40 (m, lH), 4.66 (m ₎ lH), 5.43 (dd, J = 6.7, l 5.5Hz, lH), 5.74 (dt, J = 15.4,6.8Hz, lH), 6.34 (d, J = 7.3Hz, lH), 7.75 (d, J = 4.6Hz, lH)

 After adding molybdic acid (5.48 g, 37.5 mmol) to a solution of the obtained acetoximimine derivative (2.53 g, 4.6 mmol) in ethanol (200 ml), sodium borohydride (4.79 g) was added under cooling at -30 ° C. g, 127 mmol), and the mixture was heated to 0 and stirred at the same temperature for 48 hours. 10% aqueous ammonia was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated, and the residue was purified by column chromatography to give (1 ′S, 2′R, 3′E) -N- [1-aminomethyl-2- (tert-butyldimethylsilyloxyl). ) -3-Heptadecenyl] pivalamide (amine) (1.32 g) was obtained.

Next, di-tert-butyl dicarbonate (0.15 mg, 0.7 mmol) was added to a solution of 4-dimethylaminopyridine (73 mg, 0.6 mmol) in dichloromethane (5 ml), and then 4-pyridylmethylamine (6 (5 mg, 0.6 mmol) and stirred at room temperature for 30 minutes. To this reaction solution was added the amine (99 mg, 0.2 mmol) obtained in the previous reaction, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction solution, the residue was purified by column chromatography, and (1 ′S, 2′R, 3′E) -N_ [2- (tert-butyldimethylsilyloxy) -1-[[3 -(4-Pyridylmethyl) ureido] methyl] -3-heptadecenyl] pivalamide (ureide) (94 mg) was obtained.

 Dissolve the perihydrate obtained here (93 mg, 0.15 mmol) in tetrahydrofuran (1.8 ml), add tetrabutylammonium fluoride (1.8 ml as a 1 M solution) under ice cooling, and add the same temperature. Stirred for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated, and the residue was purified by column chromatography to give (1, S, 2'R, 3'E) -N- [2-hydroxy-1-[[3- (4 -Pyridylmethyl) perido] methyl] -3_heptadecenyl] pivalamide (94 mg) was obtained.

_{^{1 H -NMR (CDC1 3) 6}} (ppm): 0.88 (t, J = 6.7Hz, 3H), 1.12 (s, 9H), 1.20-1.40 (m, 22H), 2. 02 (m, 2H), 3.27 (dt, J = 4.9, 14.4 Hz, lH), 3.50 (m, lH), 3.87 (m, lH), 4.10 (m, lH), 4.35 (m, lH), 5.46 (dd, J = 6.6,15.4Hz, lH), 5.58 (bs, lH), 5.64 (bs ₎ lH), 5.73 (dt, J = 15.4,6.6Hz, lH), 6.65 (d, J = 6.4Hz, lH), 7.19 ( d, J = 4.6Hz), 8.51 (bs, lH)

MS (SIMS) m / e: 517 (+ H) + C 3. H ₅₂ N ₄ 0 ₃ (516)

Examples 76 to 78

The compounds of Examples 76 to 78 were produced in the same manner as in the method of Example 75. The physicochemical data of each compound such as ¹ H-NMR spectrum and mass spectrum are shown.

Example 76

¹ H-NMR (CDCla) δ (ppm): 0.88 (t, J = 7.1 Hz, 3H), 1.19 (s, 9H), 1.20—1.40 (m, 22H), 2.04 (m, 2H), 3.25 (m, lH), 3.50 (m, lH), 3.72 (bs, lH), 3.91 (m, lH), 4.11 (m, lH), 4.59 (bs, 2H), 5.28 (bs, lH), 5.47 (dd, J = 6.6,15.4Hz, lH), 5.75 (dt, J = 15.4,6.8Hz, lH), 6.61 (bs, lH)

MS (SIMS) m / e: 426 (M + H) + C 24 H 4 7 N 3 0 3 (425)

Example 7 Compound of 7

_{^{1 H- NMR (CDC1 3) 6}} (ppm): 0.88 (t, J = 6.8Hz, 3 ^, 1.18 (5,9 ^, 1.20-1.40 (111,22 ^, 2. 03 (m, 2H), 2.76 (d, J = 4.9 Hz, lH), 3.25 (dt, J = 14.4, 4.9 Hz, lH), 3.54 (m, lH), 3.90 (m, lH), 4.02 (m, lH), 4.09 (m , LH), 4.59 (bs, lH), 4.96 (t, J = 5.9 Hz, lH), 5.47 (dd, J = 6.5, 15.4 Hz, lH), 5.74 (dt,

m cloud s 齄 kkoί ^^ ¾ "Η H.

 Above <<) (^ 3 ε H s A -m ~ —

(τm— ν

、 TransitionΓΐ Γ) ΜΛ1-Γ a02ε 5 a mouth □ ¾

Interference ^ α) 4 (a ¥ g Dimensions s1O s D a-0GUIε,.

s V i Purification by chromatography was performed, and 3-〇- (tert-butyldimethylsilyl) -1 -〇-[(2-hydroxyethyl) aminocarbonyl] -2-N-pivaloyl-D-erythro-sphingosine (0.22 g) was obtained. Obtained.

_{^{1 H- NMR (CDC1 3) δ}} (ppm): 0.00 (s, 3H), 0.04 (s, 3H), 0.87 (t, J = 6.7Hz, 3H), 0.90 (s, 9 H), 1.17 (s , 9H), l. 12-1.47 (m, 22H), 1.92-2.1 l (m, 2H), 3.08-3.50 (m, 3H), 3.65 (m, lH), 3.78 (m, lH), 4.10- 4.35 (m, 4H), 5.24 (t, J = 5.4Hz, lH), 5.39 (dd, J = 6.5,15.4Hz, lH), 5.66 (dt, J = 15.4,6.6Hz, lH), 6.12 (m , lH)

 After the compound obtained here (80 mg, 0.14 mmol) was dissolved in dichloromethane (3 ml), 4- (dimethylamino) pyridine (17 mg, 0.14 mmol) was added, and the mixture was cooled to _78 ° C. Pyridine (0.1 ml) was added to the reaction solution, followed by trichloromethyl chloroformate (20 l, 0.17 mmol). The reaction solution was heated to -20 over 1 hour. To the reaction solution was added 25% aqueous ammonia (1.4 ml), and the temperature was returned to room temperature over 2 hours. The reaction solution was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and saturated saline. After drying over magnesium sulfate, the solvent is distilled off, and the residue is purified by column chromatography to give 3-〇- (tert-butyldimethylsilyl) -1- 1 _ [[2- (pothamyloxy) ethyl] amino acid Luponyl] -2-N-pivaloyl-D-erythro-sphingosine (80 mg) was obtained.

_{^{1 H- N MR (CDC1 3)}} δ (ppm): -0.02 (s, 3H), 0.01 (s, 3H), 0.86 (t, J = 6.8Hz) 3H), 0.87 (s, 9 H), 1.14 (s, 9H), 1.12-1.44 (m, 22H), 1.90-2.08 (m, 2H), 3.28-3.52 (m, 2H), 4.00-4.26 (m, 5H), 4.39 (m, lH), 4.98 (bs, 2H), 5.30 (t, J = 5.6Hz ₎ lH) ₎ 5.38 (dd, J = 5.6,15.4Hz, lH), 5.64 (dt, J = 15.4,6.6Hz, lH), 6.09 (d, J = 7.8Hz, lH)

 The obtained compound (50 mg, 0.08 mmol) was dissolved in tetrahydrofuran (1 ml), tetrabutylammonium fluoride (tetrahydrofuran 1 M solution, 1.1 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 2.5 hours. . Water was added to the reaction solution, which was extracted with ethyl acetate. After washing with water, drying over magnesium sulfate and distilling off the solvent, the residue was purified by column chromatography, and 1-〇-[[2- (forcerubamoyloxy) ethyl] aminocarboxyl] -2-N -Vivaloyl-D-Eris mouth-sphingosine (25 mg) was obtained.

_{^{J H- NMR (CDC1 3) δ}} (ppm):. 0.87 (t J = 6.4Hz, 3H), 1.10- 1.42 (m, 22H), 1.16 (s, 9H), l 90-2.10 (m, 2H) , 3.33-3.48 (m, 2H), 3.75 (m, lH), 4.00-4.28 (m, 5H) ₎ 4.39 (ddJ = 6.9,11.ΙΗζ, Ι 8

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9 (^εΙ3α3) Η ]ΑΙ Ν - Η _τ Ku —— ロ ^: Γι ェ — α— Mouth N- Ζ Λ (Γι ^ Λ (-^^ Λ (· ^-^)--£

S ¥ i (Ηΐ ' ^ζ Η ^ · = Γ'Ρ) ΐ ^ · 9' (Ηΐ ' ^Ζ Η9 "9 · 9ΐ = Γ ^< ΐΡ) 2 · 9'(ΗΤ'ζΗ ^ · 5ΐ ^ · 9 = Γ 'ΡΡ) ε ^ · 9'(Ηΐ'2ΗΓ9 = Γ

-00 · '(Ηΐ'ζΗΓ9 = ί "' Ρ) · ε (Ηζ ') εεεε- rs'(H9's) 06 '(Ηΐ'ω) ζε'(HS'U OI- Η2'ω) 06 · ΐ- ^ · ΐ '(Η

9 ( ^ε Ι3α3) Η] ΑΙ Ν-Η _τ

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(LZ) ⁹ Ο ^ε Ν ^ε3 Η ^{8 Ζ} 3 ₊ (Η + η) 8Ζ: ^ CSI ^ IS) S Μ

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 8 '£ 8 stroke

S N (S19) ^{90 £} N ^TS H ^{Z z} 3 + (H + Qin IS:

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(H ΐ ' ^ζ Ηε = ί *' Ρ) εε9 '(Ηΐ' ^ζ Η3Η9 · 9Ρ = ηΡ) ^ · 9 '(Ηΐ' ^ζ Η 'SI'9 = Factory PP) £ S' (HS ' ^s q) I0'S' (H

6ZZ80 / 00df / X3d S6Z8C / T0 OAV

s

(HS'm) 6S'8- 6 8 '(Η2'υ ^ ^{Ζ Ζ} ε''(Ηΐ' ^ζ Η8 9 = Γ ^< Ρ) 8 9 '(ΗΓζΗΐ9 = Γΐ) 8 5 '(Ηΐ'ζΗ · 9' ^ · 9ΐ = ηΡ) ^ · '(Ηΐ'ΖΗ ^ · 9ΐ' ·

• I '(H6's) · ΐ' (Η ') 8 · ΐ-Οΐ · Γ (Ηε'ζΗ · 9 = Γ) 8 · 0: (mdd) ρ (ε _13α3 ) ^ ^ _Ν _ _{Η χ}

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导 p 1: 5 ¾ Coco

 (H

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'ΡΡ ^ 8 · ε'(Ηΐ'ζΗ8 · 9ΐ'5 · 9 = ΓΡΡ 9 · ε '(ΗΖ') 20 — 88'I '(H6' ^S ) · ΐ '(Η ^') 03 · ΐ— 0ΐ · ΐ '(Η 6's) 88'0' (HS ' ^z H8'9 = ri) 98'0'(HS's)20'0'(HS' ^s ) I0'0-: (ρ (d) Ν— Η _τ

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Ma ^ ¾ 呦 Bi ¾, chrysanthemum

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ロ , ^^- ε)-ε- ェ -TjQ辛!

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Γし ( 二 く、 -

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Pushi (Two,-

4 ^^ Ψ 口-τ, 缪:

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6ZZ80 / OOdf / X3d S6Z8C / T0 OAV

(dt, J = 15.4,6.8Hz, lH), 7.69 (bs, 2H), 7.92 (d, J = 5.9Hz, lH), 8.54 (d, J = 8.8Hz, lH), 8.73 (bs, 2H ), 13.40 (bs, lH)

MS (SIS) m / e: 507 (M + H) ⁺ C ₂ ? H4 ₃ N ₃ 〇 ₆ (505) Test example [Neutral sphingomyelinase inhibition test]

 (Enzyme preparation)

 Using rat cerebrum as an enzyme source of sphingomyelinase, a microsomal fraction was prepared as follows. After decapitation of 10 Wistar male rats (4 weeks old), the whole brain was removed. Further, the cerebellum was removed, and buffer A (10% sucrose, 20 mM Hepes-KOH (pH 7.4), 20 unit / ml aprotinin, O.lmM PMSF, 10 / g / ml (Putin) 120 ml, and the brain cells were crushed using a homogenizer under 4 cooling. Next, the cell lysate was centrifuged at 600 × g for 10 minutes under 4 cooling, and the supernatant was further centrifuged at 12,000 × g for 15 minutes. The obtained supernatant was ultracentrifuged at 100,000 Xg for 60 minutes, and the precipitate was used as a microsomal fraction. This fraction was further resuspended in 5 ml of Buffer B (10% sucrose, 20 mM Hepes-KOH (pH 7.4), 40 unit / ml aprotinin, 0.2 mM PMSF, 20 g / ml leptin). The solution was stored frozen at -80 and adjusted to a protein concentration of 2 mg / ml with buffer C (20 mM Hepes-KOH (pH 7.4) -2 mM MgC) at the time of use.

 (Preparation of substrate solution)

After 26.5 mg of sphingomyelin (cattle, brain; manufactured by Sigma) was dissolved in 10 w / v% Triton X3751, 14.6 ml of buffer C was added to obtain a sphingomyelin solution. Fresh 400 1 of N- methyl - ¹⁴ C-staple Ingo myelin (bovine, 48mCi / mmol, 25 Ci / ml; Amersham) solvent dryness of, redissolved the residue in ethanol 50 1, The above-mentioned 12 ml of sphingomyelin solution was added to obtain a substrate solution.

 (Test method)

The sphingomyelinase reaction was performed in the following manner: 10 1 dimethyl sulfoxide solution of sample, buffer D (20 mM Hepes-KOH (pH 7.4)-2 mM MgCl ₂ , 70 l of 0.08 w / v% triton X), enzyme solution 10 1.After mixing the substrate solution 10 // 1, incubate at 37 ° C for 3 hours. And by After the completion of the reaction, black form: 500 1 of methanol (2: 1, v / v) was added to perform extraction operation. 150 1 was mixed with 2 ml of Aquazol 2 from the obtained aqueous layer, and the reaction was performed. The product, ¹⁴ C-phosphorylcholine, was measured. The sphingomyelinase activity was calculated as the value obtained by subtracting the measured value when no enzyme was added.

 Table 2 shows the results.

: Table 2

Example IC ₅₀ (μ Μ) Example IC ₅₀ (Μ)

 1 3.7 38 5.5

 3 4.9 42 6.7

 :-4: ■ 4.1 43 1.8

 ■ 7 7.9 55 6.8

 8 3.7 59 6.6

 9. '■ 2.0 60 4.6

 10 6.2: 64: D 3.5

 12 3.9 65 4.9

 13 5.0 66 6.1

 14 ■ 2.1 68 5.8

 15 3.6 75 2.9

 16 8.4 76 5.4

 17 1.0 77 4.7

 18 7.1 80 2.0

 20 7.0 81 8.7

 21 8.2 82 1.6

 22 0.6 83 1.1

 23 1.2 84 8.5

 24 1.8 86 2.1

 25 6.9 87 1.9

 26 0.6 88 5.3

 27 3.7 90 2.0

 28 8.9 91 5.0

 92 3.6

 93 4.3

産業上の利用可能性

Industrial applicability

 The novel sphingosine derivatives of the present invention include cerebrovascular disorders such as cerebral hemorrhage and cerebral infarction, head trauma, senile dementia, cerebral neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, diabetes, obesity, arteriosclerosis, inflammatory disease, and immunity. It can be used as a prophylactic or therapeutic agent for sexual diseases, cancer, kidney diseases and heart diseases.

Claims

The scope of the claims 1. General formula (I)

[Wherein, R ′ is a hydrogen atom, C _{2 -2} . 1 or 2 of alkanoyl, benzoyl, halogen atom, Ci-alkyl, hydroxyl, d-alkoxy, C ₂ -alkanoyl, hydroxyl group, C-alkoxycarbonyl, amino, Ci-alkyl amino group substituted with number, C ₂ - ₅ alkanoylamino Noi Rua amino group, C ₂ - ₅ alkoxycarbonyl Cal Poni Rua amino group, 1 5 in substituted C _i-5 alkyl group halogen atoms, Shiano group, a nitro A benzoyl group, a C cycloalkylcarbonyl group, or a C _2- group, which is substituted with a “group, a mercapto group or a C i alkylthio group”. Alkoxy force Lupo group, wherein one ^{_{COC (R 3) 2 NHR 4}} ( wherein, R ³ is a hydrogen atom or a C - a ₅ alkyl group, R ⁴ is a hydrogen atom or a C ₂ -! Is ₅ alkoxy Cal Poni Le group Or a group represented by the formula: —C〇C〇 ₂ R ³ (wherein, R ³ is a hydrogen atom or d alkyl group), and R ² is a hydrogen atom, d- ₈ alkyl groups of the formula ^{_{- (CH 2) n R 5}} ( wherein, R ⁵ is a hydroxyl group, an amino group, _d-5 1 3 or in substituted amino group of the alkyl group, the force Rupokishiru group, C ₂ - ₅ alkoxycarbonyl two group, forces Rubamoiru group, _d-5 1 or 2 in substituted Aminokaruponiru the alkyl group, the force Rubamoiruokishi group, C ₅ 1 or 2 that is substituted with § iminocarbonyl O dimethylvinylsiloxy groups of alkyl group, off Eniru group, "halogen atom, C ₅ alkyl group, a hydroxyl group, C -! ₅ alkoxy groups, C Arukanoiru group, force Lupo Xyl group, C ₂ -alkoxycarbonyl group, amino group, amino group substituted with 1 or 2 Ci alkyl groups, C alkanoyl amino group, C alkoxyl group substituted with 15 halogen atoms Ci alkyl, cyano, nitro, ureido, alkyl 1 or 2 with substituted Urei de group, mercapto group or a C i - ₅ alkylthio group "in the substituted phenyl group, a pyridyl group, peak substituted by C ₅ alkoxy group Lysyl group, virazyl group, pyrrolidyl group, piperidyl group, piperazyl group, morpholinyl group, thiomorpholinyl group, imidazolyl group, thiazolyl group, thiadiazolyl group, tetrazolyl group, quinolyl group or 1H_indazolyl group, and n is 0 to 5 Is an integer. Or a group represented by the formula: —SO _m R ⁶ (wherein R ⁶ is a phenyl group or a “halogen atom, d- ₅ alkyl group, hydroxyl group, (: ぃ₅ alkoxy group, C ₂ -alkyl group, A propyloxy group, a C alkoxycarbonyl group, an amino group, an amino group substituted with one or two C alkyl groups, a C alkanoylamino group, C ₂ - ₅ alkoxycarbonyl § amino group, C i alkyl group substituted 1 to 5 halogen atoms, Shiano group, a nitro group, Ulei de group, 1 Moshiku of C have alkyl groups substituted with two A phenyl group substituted by a “ureido group, mercapto group or Ci alkylthio group”, and m is 0, 1 or 2. Wherein Z is NR ⁷ (where R ⁷ is a hydrogen atom, a hydroxyl group or a C ぃ₅ alkyl group), and Y is an oxygen atom or NR ⁸ (R ⁸ is a hydrogen atom, A hydroxyl group or a C alkyl group), W is an oxygen atom or a sulfur atom, and k is an integer of 1 to 20. ] The sphingosine derivative represented by these, or its pharmacologically acceptable salt. 2. The sphingosine derivative or the sphingosine derivative thereof according to claim 1, wherein, in the general formula (I), R ¹ is an isoptyryl group or a bivaloyl group, Y is an oxygen atom, Z is NH, and k is 13. Pharmaceutically acceptable salts. 3. In the general formula (I), R ′ is an isoptyryl group or a bivaloyl group, Y and Z are NH, and k is 13; Salt. 4. The compound according to claim 1 as an active ingredient, cerebrovascular disorders such as cerebral hemorrhage and cerebral infarction, head trauma, senile dementia, cerebral degenerative diseases such as Aruhaimai disease and Parkinson's disease, diabetes, Preventive or therapeutic agent for obesity, atherosclerosis, inflammatory disease, immune disease, cancer, kidney disease and heart disease. 5. Cerebral vascular disorders such as cerebral hemorrhage and cerebral infarction, head trauma, senile dementia, cerebral neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, diabetes, obesity, arteriosclerosis, and inflammatory diseases caused by the compound described in claim 1. A method for preventing or treating diseases, immune diseases, cancer, kidney diseases and heart diseases. 6. Cerebrovascular disorders such as cerebral hemorrhage and cerebral infarction, head trauma, senile dementia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, diabetes, obesity, arteriosclerosis, inflammatory diseases, immune diseases, cancer, Use of the compound according to claim 1 for producing a prophylactic or therapeutic drug for kidney disease and heart disease.