JP2001213858A - Derivative of sphingosine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound having a sphingomyelinase antagonism. SOLUTION: This compound is a derivative of sphingosine or its pharmaceutically permissible salt expressed by general formula I [R1 is H, a 2-20C alkanoyl, benzoyl or the like, R2 is H, a 1-8C alkyl, -(CH2)nR5 (R5 is hydroxyl, an amino, a pyridyl, a pyrazyl, a morpholinyl, a thiazolyl, a tetrazolyl or the like, n is an integer of 0-5) or SOmR6 (R6 is phenyl or a substituted phenyl substituted with a halogen, a 1-5C alkyl, hydroxyl, an amino, an ureide group or the like, m is 0, 1 or 2.), Z is NR7 (R7 is H, hydroxyl or a 1-5C alkyl), Y is oxygen or NR8 (R8 is H or hydroxyl or a 1-5C alkyl), W is oxygen or sulfur, k is an integer of 1-20].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel sphingosine derivative which is useful as various medicines by inhibiting neutral sphingomyelinase.

[0002]

2. Description of the Related Art Sphingomyelinase is an enzyme which mainly decomposes sphingomyelin, one of sphingolipids present in the cell membrane, into ceramide and phosphocholine. 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 metabolism of sphingomyelin.

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 production pathway is called sphingomyelin pathway.

[0004] Sphingomyelinase ischemia, TNF-
It is activated by various stresses such as α, IL-1β, IFN-γ, 1α, 25-dihydroxyvitamin D ₃ , anticancer drugs and radiation, and these chemical and physical stresses cause It is considered that the sphingomyelin pathway is involved in certain pathological conditions. For example, sphingomyelin pathway is activated during cerebral ischemia, but addition of sphingomyelinase or ceramide to brain neurons causes cell death by apoptosis. Also, during cerebral ischemia, TNF-α and IL-
1β production is enhanced and neuronal cell death is induced.
F-α solubilized receptors and IL-1β receptor antagonists suppress nerve cell death due to ischemia.

[0005] In addition to the above-mentioned cerebrovascular disorders, increased production of TNF-α and IL-1β 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-α in adipocytes is enhanced and insulin resistance is induced, which involves the activation of the sphingomyelin pathway by TNF-α. I have. In addition, IL-
1β is involved in the development of insulin-dependent diabetes, whereas ceramide exerts a similar effect as IL-1β.

[0007] TNF-α and IL-1β are also involved in the onset and progression of arteriosclerosis. In other words, TNF-α and IL-1β are adhesion factors ICA in vascular endothelial cells.
Expresses M-1 and promotes 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 to form lesions and destabilizes plaques via apoptosis of vascular smooth muscle.

[0008] The biological activity of ceramide in inflammatory immune system cells is extremely diverse, and differentiation and activation of T cells and B cells,
It is deeply involved in the onset and progress of various inflammatory diseases and immune diseases through production of various cytokines, induction of apoptosis, production of inflammatory prostaglandins, and the like. In addition, activation of the sphingomyelin pathway involves TNF-α and IL-
Since numerous chemical and physical stresses including 1β are involved, it is considered that many cell lines and signal pathways cross-talk with each other in these pathological conditions in a complicated manner.

From the above, specific inhibitors for sphingomyelinase 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, and diabetes , Obesity, arteriosclerosis, inflammatory disease, immune disease, cancer, kidney disease and heart disease.

3-O-alkyl sphingomyelin has been reported as a sphingosine derivative having a sphingomyelinase inhibitory activity (Mark D. Lister, et al., B
iochimica et Biophysica Acta, 1995, 1256, 25), which differs in chemical structure from the compounds of the present invention.

[0011]

An object of the present invention is to provide a novel compound having a sphingomyelinase inhibitory action.

[0012]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that a certain sphingosine derivative has a neutral sphingomyelinase inhibitory activity. completed. That is,
The present invention relates to a compound of the general formula (I)

[0013]

Embedded image [Wherein, R ¹ represents a hydrogen atom, a C _2-20 alkanoyl group, a benzoyl group, a “halogen atom, a C _1-5 alkyl group, a hydroxyl group, a C _1-5 alkoxy group, a C _2-5 alkanoyl group, a carboxyl group, A C _2-5 alkoxycarbonyl group, an amino group,
An amino group substituted with one or two C _1-5 alkyl groups, a C _2-5 alkanoylamino group, a C _2-5 alkoxycarbonylamino group, a C _1-5 substituted with 1 to 5 halogen atoms A benzoyl group substituted with an alkyl group, a cyano group, a nitro group, a mercapto group or a C _1-5 alkylthio group, a C _4-8 cycloalkylcarbonyl group, a C _2-20 alkoxycarbonyl group, and a compound of the formula —COC (R ³ ) ₂ NHR ⁴ (wherein
R ³ is a hydrogen atom or a C _1-5 alkyl group, and R ⁴ is a hydrogen atom or a C _2-5 alkoxycarbonyl group. Or a group represented by the formula —COCO ₂ R ³ , wherein R ³ is a hydrogen atom or a C _1-5 alkyl group.
R ² is a hydrogen atom, a C _1-8 alkyl group, a formula — (CH ₂ ) _n R
⁵ (wherein R ⁵ represents a hydroxyl group, an amino group, an amino group substituted with 1 to 3 C _1-5 alkyl groups, a carboxyl group,
_2-5 alkoxycarbonyl group, carbamoyl group, aminocarbonyl group substituted with one or two _C1-5 alkyl groups, carbamoyloxy group, aminocarbonyl substituted with one or two _C1-5 alkyl groups Oxy group, phenyl group, "halogen atom, _C1-5 alkyl group, hydroxyl group, _C1-5 alkoxy group, _C2-5 alkanoyl group, carboxyl group, _C2-5 alkoxycarbonyl group, amino group,
An amino group substituted with one or two C _1-5 alkyl groups, a C _2-5 alkanoylamino group, a C _2-5 alkoxycarbonylamino group, a C _1-5 substituted with 1 to 5 halogen atoms Alkyl group, cyano group, nitro group, ureido group,
A phenyl group, a pyridyl group, or a pyridyl group substituted with a C _1-5 alkoxy group, which is substituted with a ureido group, a mercapto group, or a C _1-5 alkylthio group substituted with one or two C _1-5 alkyl groups. , A pyrazyl group, a pyrrolidyl group, a piperidyl group, a piperazyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, a tetrazolyl group, a quinolyl group or a 1H-indazolyl group, and n is an integer of 0 to 5. . Group or wherein -SO _m R ⁶ (wherein represented by), R ⁶ is a phenyl group or "halogen atom, C _1-5 alkyl groups, hydroxyl group, C _1-5 alkoxy, C _2-5 alkanoyl group, a carboxyl Group, C
_2-5 alkoxycarbonyl group, amino group, amino group substituted by one or two C _1-5 alkyl groups, C _2-5 alkanoylamino group, C _2-5 alkoxycarbonylamino group, A C _1-5 alkyl group, a cyano group, a nitro group, a ureido group, a ureido group substituted with one or two C _1-5 alkyl groups, a mercapto group or a C _1-5 alkylthio group substituted with ₅ ” And m is 0, 1 or 2. Z is NR ⁷ (where R ⁷ is a hydrogen atom, a hydroxyl group or a C _1-5 alkyl group), and Y is an oxygen atom or NR ⁸ (R ⁸ is a hydrogen atom , A hydroxyl group or a C _1-5 alkyl group), and W is an oxygen atom or a sulfur atom;
k is an integer of 1 to 20. Or a pharmaceutically acceptable salt thereof.

In the present invention, a C _2-20 alkanoyl group means a linear or branched alkanoyl group having 2 to 20 carbon atoms, such as acetyl, propanoyl, isopropanoyl, butyryl, Examples include an isobutyryl group, a valeryl group, a pivaloyl group, a myristyl group, and a stearyl group.

The C _2-5 alkanoyl group means one having 2 to 5 carbon atoms among the above.

The C _4-8 cycloalkylcarbonyl group means a cycloalkylcarbonyl group having 4 to 8 carbon atoms, for example, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl and the like. Can be.

The C _2-5 alkoxycarbonyl group means a linear or branched alkoxycarbonyl group having 2 to 5 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, A tert-butoxycarbonyl group and the like can be mentioned.

A C _1-20 alkyl group is one having 1 to 20 carbon atoms.
Means a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, Heptyl group, octyl group, nonyl group, decyl group, tridecyl group,
Nonadecyl group and the like can be mentioned.

The C _1-8 alkyl group means one having 1 to 8 carbon atoms among the above, and the C _1-5 alkyl group means one having 1 to 5 carbon atoms among the above.

An amino group substituted with 1 to 3 C _1-5 alkyl groups means that the nitrogen atom of the amino group is substituted with a C _1-5 alkyl group, and three amino groups are substituted. Means a quaternary salt.

The term "C _2-5 alkanoylamino group" means that the nitrogen atom of the amino group is substituted by one of the C _2-5 alkanoyl groups, and examples thereof include an acetylamino group and an isopropionylamino group. Can be.

The C _2-5 alkoxycarbonylamino group means that the nitrogen atom of the amino group is substituted with one of the C _2-5 alkoxycarbonyl groups, such as methoxycarbonylamino, butoxycarbonylamino, etc. Can be mentioned.

The halogen atom is a fluorine, chlorine, bromine or iodine atom. One of the halogen atoms
The C _1-5 alkyl group substituted by 5 to 5 means a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms substituted by the halogen atom, such as a trifluoromethyl group. be able to.

A C _1-5 alkoxy group is one having 1 to 5 carbon atoms.
, A methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a heptoxy group and the like.

A C _1-5 alkylthio group is a C _1-5 alkylthio group.
5 means a linear or branched alkylthio group, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, te
Examples thereof include an rt-butylthio group, a pentylthio group, and a hexylthio group.

Examples of the hydroxyl-protecting group include acyl groups such as acetyl group and benzoyl group; trisubstituted silyl groups such as trimethylsilyl group, t-butyldimethylsilyl group and benzyldimethylsilyl group; tetrahydropyranyloxy group and methoxymethyl group. And the like.

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

The pharmaceutically acceptable salts refer to acid or alkali addition salts. In this case, the acid or alkali used is not particularly limited, but as the acid, hydrochloric acid, sulfuric acid, nitric acid,
Acetic acid, benzenesulfonic acid and the like can be mentioned. As the alkali, metal ions such as sodium and potassium,
Examples thereof include ammonium ions such as alkyl ammonium.

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 following method.

Hereinafter, in the present specification, Boc is a tert-butoxycarbonyl group, TFA is a trifluoroacetic acid, Pv is a pivaloyl group, DBU is 1,8-diazabicyclo [5.4.0] undec-7-ene, TCF is trichloromethyl chloroformate, TBDMS
Is tert-butyldimethylsilyl group, WSC / HCl is 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HOBt may represent 1-hydroxybenzotriazole, respectively.

First, N-Boc-sphingosine, which is a synthetic raw material, was prepared by the method of P. Herold et al. (Helv. Chim. Acta., 1988, 71,
354), and then the intermediate compound (1) can be synthesized by the method shown in Formula 1.

[0033]

Embedded image The compound (3) in which Y and W are oxygen atoms and Z is NR ⁷ in the compound of the general formula (I) can be produced by the method shown in the formula 2. That is, compound (1)
Compound (2) can be obtained by treating with trichloromethyl chloroformate or di-tert-butyl dicarbonate in the presence of a base and then reacting with a corresponding amine compound. The compound (2) can also be obtained by reacting the intermediate (1) with the corresponding isocyanate. Furthermore, 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.

[0034]

Embedded imageIn the compound of the general formula (I), Y is NH and W is an acid
An element atom and Z is NR ⁷Is a compound represented by the formula (4):
It can be manufactured by the method described above. That is, the compound
(1) in dimethyl sulfoxide, sulfur trioxide pyridine
Oxidized with complex and triethylamine to form aldehyde
After that, sequentially react with hydroxylamine and acetic anhydride,
The generated acetoxyimine is converted to sodium borohydride
To convert to amine compound (4). Equation 3
Of using TBDMS as protecting group for hydroxyl group
Is shown, but by using the other protecting groups described above.
Or by deprotection under conventional conditions,
An amine compound can be produced. Then the compound
(4) is replaced with phenyl chloroformate or di-tert-butyl dicarbonate.
After treatment with chill, react with the corresponding amine compound
Thereby, compound (6) can be obtained. Also,
Reacting compound (4) with the corresponding isocyanate
Thus, compound (6) can be obtained. Further, compound (6)
To give compound (7) by desilylation of
Wear. Reactions such as reagents, time, temperature and solvent in these reactions
The reaction conditions can be performed under the conditions generally used.

[0035]

Embedded imageIn the compound of the general formula (I), Y is NH and W is sulfur
A yellow atom and Z is NR ⁷Is a compound represented by the formula (5):
It can be manufactured by the method described above. That is, the compound
After reacting (4) with phenyl chlorothionoformate,
React with an amine compound or
By reacting with isocyanate and further desilylation.
Compound (8) can be obtained. Trials in these reactions
Reaction conditions such as drug, time, temperature and solvent are usually used.
Under the following conditions.

[0036]

Embedded image In the compounds of the general formula (I), R ² is of the formula — (CH ₂ ) _n R ⁵
(R ⁵ is a phenyl group substituted with an amino group or a C _2-5 alkanoylamino group) Compound (10) and compound (11) can be produced by the method shown in Formula 6. . That is, the compound (9) obtained by any one of the methods represented by the above formulas 2 to 5 is converted to Boc with trifluoroacetic acid.
Is removed to obtain a compound (10). When an acetylamino group is used, the compound is further reacted with acetic anhydride to
(11) can be converted. The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

[0037]

Embedded image In the compounds of the general formula (I), R ² is of the formula — (CH ₂ ) _n R ⁵
(R ⁵ is a quaternary amine) is a group represented by the compound (13)
Can be produced by the method shown in Equation 7. That is, the compound (13) can be obtained by reacting the compound (12) obtained by any of the methods represented by the above formulas 2 to 5 with a corresponding alkyl halide. Reaction conditions such as reagents, time, temperature, and solvent in this reaction can be performed under commonly used conditions.

[0038]

Embedded image (In the formula, R ⁹ represents a C _1-5 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 carbamoyl Oxy group or C _1-5
Compound (15), which is a group represented by the formula (8), which is an aminocarbonyloxy group substituted by one or two alkyl groups:
It can be manufactured by the method shown in FIG. That is, the compound (1) obtained by any of the methods represented by the above formulas 2 to 5
After treating 4) with trichloromethyl chloroformate, the compound is reacted with a corresponding amine compound, and further subjected to desilylation to obtain compound (15). The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

[0039]

Embedded image In the compounds of the general formula (I), R ² is of the formula — (CH ₂ ) _n R ⁵
(R ⁵ is a carboxyl group or a phenyl group substituted with a carboxyl group).
As shown in the above, the compound (16) obtained by any one of the above formulas 2 to 5 can be hydrolyzed by a usual method of hydrolyzing an ester.

Further, compound (18) can be obtained by treating compound (17) with diphenylphosphoric acid azide and reacting with the corresponding amine compound. The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

[0041]

Embedded image As shown in Formula 10, the compound (2) is obtained by desilylation of the compound (19) derived from N-Boc-sphingosine.
0) can be obtained. Then, the compound obtained here
Compound (21) can be obtained by treating (20) with trifluoroacetic acid. Furthermore, compound (23) can be obtained by condensing compound (21) with amino acid derivative (22). Compound (23) is treated with trifluoroacetic acid to give compound
(24). The reaction conditions such as reagents, time, temperature, and solvent in these reactions can be performed under commonly used conditions.

[0042]

Embedded image Further, as shown in Formula 11, compound (21) is replaced with compound (27)
To give compound (25). Further, 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.

[0043]

Embedded image

The novel sphingosine derivative of the present invention is
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, immune disease, cancer, kidney disease and It can be used as a prophylactic or therapeutic agent for heart disease.

[0044]

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

2-N- (tert-butoxycarbonyl) -D-erythro-sphingosine was produced according to the method described in the literature (P. Herold, et al., Helv. Chim. Acta., 1988, 71, 35).
Four).

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 over time. The solvent was distilled off, and to the residue were added aqueous methanol (water: methanol = 12 ml: 200 ml) and then potassium carbonate (3.8 g), and the mixture was stirred 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 compound obtained here was dissolved in tetrahydrofuran (60 ml), and triethylamine (5.1 ml, 37 ml) was added under ice cooling.
mol) and then pivaloyl chloride (1.8 ml, 15 mmol) was added dropwise. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography to give 2-N-pivaloyl.
-D-erythro-sphingosine (3.4 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.08
-1.47 (m, 22H), 1.21 (s, 9H), 1.95-2.13 (m, 2H), 2.83-3.07
(m, 2H), 3.69 (m, 1H), 3.78-4.02 (m, 2H), 4.29 (m, 1H), 5.51
(dd, J = 6.5,15.4Hz, 1H), 5.77 (dt, J = 15.4,6.9Hz, 1H), 6.42
(d, J = 6.8Hz, 1H)

Reference Example 2 The compound (0.90 g, 2.3 mmol) obtained in Reference Example 1 was pyridine
(8ml) and cooled at -10 ° C, pivaloyl chloride (0.35ml)
Was added dropwise, and the mixture was stirred at the same temperature for 3 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain 2-N, 1-O-dipivaloyl-D-erythro-sphingosine (0.90 g). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.19
(s, 9H), 1.20 (s, 9H), 1.23-1.42 (m, 22H), 1.99-2.10 (m, 2
H), 3.09 (bs, 1H), 4.14 (dd, J = 3.9,11.4Hz, 1H), 4.17 (m, 1
H), 4.24 (m, 1H), 4.34 (dd, J = 7.0,11.4Hz, 1H), 5.46 (ddt, J =
6.6,15.4,1.3Hz, 1H), 5.75 (ddt, J = 0.9,15.4,1.3Hz, 1H),
6.09 (d, J = 7.6Hz, 1H)

Reference Example 3 The compound (2.3 g, 5.0 mmol) obtained in Reference Example 2 was dissolved in N, N-dimethylformamide (10 ml), and imidazole (2.72
g, 10 mmol), and then tert-butyldimethylsilyl chloride (2.7 g, 18 mmol) was added, followed by stirring at 60 ° C. for 17 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography, and 3-O- (tert-butyldimethylsilyl) -2-N, 1-O-dipivaloyl-D-erythro-sphingosine (2.8 g) was used. ). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.01 (s, 3H), 0.04 (s, 3H),
0.88 (t, J = 6.7Hz, 3H), 0.88 (s, 9H), 1.15 (s, 9H), 1.16 (s, 9H
H), 1.22-1.38 (m, 22H), 1.93-2.04 (m, 2H), 3.29 (dd, J = 4.6,
9.0Hz, 1H), 3.63 (dd, J = 3.6,9.0Hz, 1H), 3.91 (m, 1H), 4.17
(dd, J = 6.7,7.4Hz, 1H), 5.42 (dd, J = 7.4,15.4Hz, 1H), 5.57
(dt, J = 15.4,6.7Hz, 1H), 5.91 (d, J = 8.6Hz, 1H)

Reference Example 4 The product obtained in Reference Example 3 (2.8 g, 4.8 mmol) was dissolved in anhydrous methanol (30 ml), and 1,8-diazabicyclo [5.4.0] was added.
Undec-7-ene (0.68 g, 4.5 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 3-O- (tert-butyldimethylsilyl) -2-N-pivaloyl-D-erythro-sphingosine (2.2 g). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.03 (s, 3H), 0.06 (s, 3H),
0.87 (t, J = 6.5Hz, 3H), 0.90 (s, 9H), 1.02-1.44 (m, 22H), 1.1
5 (s, 9H), 1.93-2.11 (m, 2H), 3.42 (d, J = 9.8Hz, 1H), 3.56 (dd
d, J = 3.0,9.8,11.0Hz, 1H), 3.76 (m, 1H), 4.00 (dd, J = 2.3,1
1.0Hz, 1H), 4.42 (m, 1H), 5.44 (dd, J = 6.3,15.4Hz, 1H), 5.76
(dt, J = 15.4,6.6Hz, 1H), 6.52 (d, J = 7.0Hz, 1H)

Reference Example 5 2-N- (tert-butoxycarbonyl) -D-erythro-sphingosine (2.0 g, 5.0 mmol) was dissolved in pyridine (20 ml).
Under cooling at 0 ° C., pivaloyl chloride (0.66 g, 5.5 mmol) was added dropwise. After returning the reaction solution to room temperature over 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography. 2-N- (tert-butoxycarbonyl) -1-O-pivaloyl-D-erythro-sphingosine (2.2 g) ). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.21
(s, 9H), 1.21-1.41 (m, 22H), 1.44 (s, 9H), 2.00-2.08 (m, 2
H), 2.33 (bs, 1H), 3.94 (m, 1H), 4.12 (dd, J = 4.4,11.4Hz, 1
H), 4.15 (m, 1H), 4.26 (dd, J = 6.6,11.4Hz, 1H), 4.80 (bd, J =
7.8Hz, 1H), 5.49 (dd, J = 6.8,15.4Hz, 1H), 5.75 (dt, J = 15.4,
(6.8Hz, 1H)

Reference Example 6 The compound (2.2 g, 4.5 mmol) obtained in Reference Example 5 was added to trifluoroacetic acid (14 ml) under ice cooling, and the temperature was raised to room temperature over 3 hours. After the reaction solution was concentrated under reduced pressure, ethanol was added and the mixture was concentrated again. The residue was tetrahydrofuran (14 ml)
And triethylamine (1.4 g, 14 mmol) was added under ice cooling, then isobutyric anhydride (0.85 g, 5.4 mmol) was added, and the mixture was stirred at the same temperature for 1.5 hours. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated. Residue is N, N-dimethylformamide
(14 ml), imidazole (1.6 g, 24 mmol) was added,
Then tert-butyldimethylsilyl chloride (1.2 g, 8.1 mm
ol), 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-O- (tert-butyldimethylsilyl)-
2-N-Isobutyryl-1-O-pivaloyl-D-erythro-sphingosine (2.3 g) was obtained.

The obtained compound (2.3 g, 4.0 mmol) was dissolved in dehydrated methanol (30 ml), and 1,8-diazabicyclo
[5.4.0] undec-7-ene (0.92 g, 6.4 mmol) was added,
Stirred at room temperature for 28 hours. The reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography, and 3-O- (tert-
Butyldimethylsilyl) -2-N-isobutyryl-D-erythro-sphingosine (1.9 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.02 (s, 3H), 0.05 (s, 3H),
0.85 (t, J = 6.7Hz, 3H), 0.89 (s, 9H), 1.13 (d, J = 6.8Hz, 6H),
1.08-1.44 (m, 22H), 1.94-2.14 (m, 2H), 2.38 (m, 1H), 3.31
(m, 1H), 3.54 (m, 1H), 3.77 (m, 1H), 4.01 (dd, J = 3.0,11.3Hz,
1H), 4.42 (dd, J = 2.9,6.0Hz, 1H), 5.44 (dd, J = 6.2,15.4Hz, 1
H), 5.71 (dt, J = 15.4,6.8Hz, 1H), 6.29 (d, J = 7.4Hz, 1H)

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

[0055]

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7] Example 1 3-O- (tert-butyldimethylsilyl) -2-N-pivaloyl
-D-erythro-sphingosine (99 mg, 0.2 mmol) was dissolved in dichloromethane (5 ml), pyridine (142 mg, 1.8 mmol) was added, and the mixture was cooled to -78 ° C. To this solution was added dropwise trichloromethyl chloroformate (22 μl, 0.3 mmol), and over 1 hour-
The temperature was raised to 15 ° C. Add 25% ammonia water to this reaction solution.
(2 ml) was added dropwise, and the temperature was raised to 15 ° C. over 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography to obtain 3-O- (tert-butyldimethylsilyl) -1-O-carbamoyl-2-N-pivaloyl-D-erythro-sphingosine (72 mg).

The obtained compound (72 mg, 0.13 mmol) was dissolved in pyridine (6 ml), a 2% solution of hydrofluoric acid in acetonitrile (34 ml) was added under ice cooling, and the mixture was stirred at room temperature for 7 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate and drying over magnesium sulfate. The solvent was distilled off, the residue was purified by column chromatography, and 1-O-carbamoyl-2-N-pivaloyl-D-
Erythro-sphingosine (51 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 3H), 1.19
(s, 9H), 1.21-1.40 (m, 22H), 2.03 (m, 2H), 3.34 (d, J = 5.1Hz,
1H), 4.10 (dd, J = 3.8, 11.8 Hz, 1H), 4.14 (m, 1H), 4.21 (m, 1
H), 4.41 (dd, J = 7.6,11.7Hz, 1H), 4.74 (bs, 2H), 5.45 (dd, J =
6.7,15.4Hz, 1H), 5.74 (dt, J = 15.4,6.7Hz, 1H), 6.29 (d, J =
7.5Hz, 1H) MS (SIMS) m / e: 427 (M + H) + C 24 H 46 N 2 O 4 (426)

Examples 2 to 63 The compounds of Examples 2 to 63 were prepared in the same manner as in the method of Example 1.
Manufactured. Of each compound ¹H-NMR spectrum, mass
The physicochemical data of the spectrum etc. are shown below. Example 2
Compound of¹ H-NMR (CDCl_Three) δ (ppm): 0.88 (t, J = 6.8Hz, 3H), 1.19
(s, 9H), 1.20-1.43 (m, 22H), 2.04 (m, 2H), 2.71 (d, J = 4.5Hz,
1H), 4.19 (d, J = 5.3Hz, 1H), 4.24 (m, 1H), 4.30 (dd, J = 3,6,1
1.5Hz, 1H), 4.43 (dd, J = 7.8,11.6Hz, 1H), 5.47 (dd, J = 6.6,1
5.4Hz, 1H), 5.76 (dt, J = 15.4,6.7Hz, 1H), 6.05 (bs, 1H), 6.2
1 (d, J = 7.8Hz, 1H), 7.19 (bs, 1H) MS (SIMS) m / e: 505 (M + Na)⁺ C₂₈H₄₈0_Four(504)

Compound ^{1 of} Example 3 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 7.0 Hz, 3H), 1.17
(s, 9H), 1.20-1.42 (m, 22H), 1.90-2.08 (m, 4H), 2.93 (s, 6
H), 3.16-3.34 (m, 4H), 4.14 (m, 2H), 4.30 (m, 1H), 5.44 (dd, J
= 6.7,15.3Hz, 1H), 5.77 (dt, J = 15.3,6.7Hz, 1H), 6.05 (m, 1
H), 6.32 (d, J = 8.0Hz, 1H) MS (SIMS) m / e: 512 (M + H) + C 29 H 57 N 3 0 4 (511)

Compound ^{1 of} Example 4 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 1H), 1.20
(s, 9H), 1.22-1.40 (m, 22H), 2.03 (m, 2H), 2.82 (s, 6H), 3.14
(m, 2H), 3.45 (m, 1H), 3.57 (m, 1H), 4.12-4.34 (m, 2H), 5.49
(dd, J = 6.4,15.3Hz, 1H), 5.78 (dt, J = 15.3,6.7Hz, 1H), 5.92
(m, 1H), 6.47 ( d, J = 7.6Hz, 1H) MS (SIMS) m / e: 498 (M + H) + C 28 H 55 N 3 0 4 (497)

Compound ^{1 of} Example 5 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.01
(d, J = 6.4Hz, 12H), 1.18 (s, 9H), 1.20-1.40 (m, 22H), 2.02
(m, 2H), 2.58 (m, 2H), 3.01 (m, 2H), 3.15 (m, 2H), 3.78 (m, 1
H), 4.01-4.26 (m, 3H), 4.42 (dt, J = 6.7,11.8Hz, 1H), 5.44 (d
d, J = 6.6,15.4Hz, 1H) , 5.72 (dt, J = 15.3,6.7Hz, 1H) MS (SIMS) m / e: 554 (M + H) + C 32 H 63 N 3 O 4 (553 )

Compound ^{1 of} Example 6 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 0.92
(s, 9H), 1.19 (s, 9H), 1.20-1.40 (m, 22H), 1.41 (m, 2H), 2.02
(m, 2H), 3.05-3.25 (m, 2H), 3.68 (d, J = 5.5Hz, 1H), 3.95-4.3
0 (m, 3H), 4.42 (dd, J = 7.4,11.7Hz, 1H), 4.70 (m, 1H), 5.44 (d
d, J = 6.5,15.4Hz, 1H), 5.73 (dt, J = 15.4,6.6Hz, 1H), 6.41
(d, J = 7.1Hz, 1H ) MS (SIMS) m / e: 511 (M + H) + C 30 H 58 N 2 O 4 (510)

Compound ^{1 of} Example 7 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.5 Hz, 3H), 1.17
(s, 9H), 1.20-1.42 (m, 22H), 2.02 (m, 2H), 3.19 (m, 1H), 4.19
(m, 1H), 4.22-4.32 (m, 2H), 4.52 (dd, J = 8.0,12.7Hz, 1H), 5.
49 (dd, J = 6.7,15.4Hz, 1H), 5.76 (dt, J = 15.3,6.8Hz, 1H), 6.
22 (d, J = 7.4Hz, 1H), 7.02 (m, 1H), 7.70 (m, 1H), 7.94 (m, 1H),
8.13 (bs, 1H), 8.27 (m, 1H) MS (SIMS) m / e: 504 (M + H) + C 29 H 49 N 3 O 4 (503)

Compound ^{1 of} Example 8 1H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.8 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 2.04 (m, 2H), 4.21 (m, 1H), 4.27
-4.35 (m, 2H), 4.52 (dd, J = 8.2,12.4Hz, 1H), 5.50 (dd, J = 6.
7,15.4Hz, 1H), 5.78 (dt, J = 15.4,6.5Hz, 1H), 6.17 (d, J = 7.8
Hz, 1H), 7.45 (bs, 1H), 8.22 (m, 1H), 8.32 (m, 1H), 9.29 (m, 1
H) MS (SIMS) m / e: 505 (M + H) + C 28 H 48 N 4 O 4 (504)

Compound ^{1 of} Example 9 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.17
(s, 9H), 1.20-1.40 (m, 22H), 2.03 (m, 2H), 4.15-4.40 (m, 3
H), 4.50 (dd, J = 7.5,10.9Hz, 1H), 5.49 (dd, J = 6.5,15.4Hz, 1
H), 5.78 (dt, J = 15.4,6.6Hz, 1H), 6.19 (d, J = 7.7Hz, 1H), 7.3
5 (d, J = 6.3Hz, 1H), 7.48 (s, 1H), 8.47 (d, J = 6.3Hz, 1H) MS (SIMS) m / e: 504 (M + H) + C 29 H 49 N ₃ O ₄ (503)

Compound ^{1 of} Example 10 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 7.1 Hz, 3H), 1.17
(s, 9H), 1.20-1.40 (m, 22H), 2.03 (m, 2H), 3.91 (s, 3H), 4.12
-4.33 (m, 3H), 4.50 (dd, J = 4.7,12.4Hz, 1H), 5.47 (dd, J = 6.
5,15.4Hz, 1H), 5.75 (dt, J = 15.4,6.7Hz, 1H), 6.25 (bd, J = 6.
2Hz, 1H), 6.73 (d, J = 8.9Hz, 1H), 6.78 (bs, 1H), 7.75 (bs, 1
H), 8.09 (bs, 1H ) MS (SIMS) m / e: 534 (M + H) + C 29 H 49 N 3 O 4 (533)

Compound ^{1 of} Example 11 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 2.03 (m, 2H), 2.82 (d, J = 4.1Hz,
1H), 4.27 (m, 2H), 4.43 (dd, J = 2.6,11.2Hz, 1H), 4.62 (dd, J =
3.6, 11.1Hz, 1H), 5.54 (J = 6.3, 15.3Hz, 1H), 5.78 (dt, J = 15.
4,6.7Hz, 1H), 6.47 (d, J = 7.6Hz, 1H), 8.77 (s, 1H), 12.2 (bs,
1H) MS (SIMS) m / e: 511 (M + H) + C 26 H 46 N 4 O 4 S (510)

Compound ^{1 of} Example 12 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.8 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 2.03 (m, 2H), 3.12 (d, J = 3.1Hz,
1H), 4.20 (m, 1H), 4.22 (dd, J = 3.9,11.8Hz, 1H), 4.31 (m, 1H
H), 4.53 (dd, J = 7.7,11.7Hz, 1H), 5.49 (dd, J = 6.6,15.4Hz, 1
H), 5.77 (dt, J = 15.3,6.7Hz, 1H), 6.28 (d, J = 7.2Hz, 1H), 6.9
3 (bs, 1H), 7.30 (d, J = 8.5Hz, 1H), 7.45 (d, J = 8.9Hz, 1H), 7.8
6 (bs, 1H), 8.03 (s, 1H), 10.1 (bs, 1H) MS (SIMS) m / e: 543 (M + H) + C 31 H 50 N 4 O 4 (542)

Compound ^{1 of} Example 13 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 3H), 1.16
(s, 9H), 1.20-1.40 (m, 22H), 2.01 (m, 2H), 4.12 (m, 2H), 4.19
(m, 1H), 4.43-4.54 (m, 3H), 5.45 (dd, J = 6.7,15.4Hz, 1H), 5.
72 (dt, J = 15.4,6.7Hz, 1H), 5.96 (m, 1H), 6.36 (d, J = 7.1Hz, 1
H), 7.18-7.30 (m, 2H ), 7.68 (m, 1H), 8.55 (m, 1H) MS (SIMS) m / e: 518 (M + H) + C 30 H 51 N 3 O 4 (517 )

Compound ^{1 of} Example 14 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.15
(s, 9H), 1.20-1.40 (m, 22H), 2.02 (m, 2H), 4.13 (m, 2H), 4.21
(m, 1H), 4.38 (m, 2H), 4.43 (dd, J = 7.7,11.6Hz, 1H), 5.38 (m, 1H)
1H), 5.45 (dd, J = 6.7,15.4Hz, 1H), 5.73 (dt, J = 15.4,6.7Hz,
1H), 6.28 (d, J = 7.4Hz, 1H), 7.29 (m, 1H), 7.65 (m, 1H), 8.55
(m, 2H) MS (SIMS ) m / e: 518 (M + H) + C 30 H 51 N 3 O 4 (517)

Compound ^{1 of} Example 15 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.5 Hz, 3H), 1.15
(s, 9H), 1.20-1.44 (m, 22H), 2.02 (m, 2H), 3.72 (m, 1H), 4.13
-4.17 (m, 3H), 4.34-4.48 (m, 3H), 5.45 (dd, J = 6.6,15.4Hz, 1
H), 5.74 (dt, J = 15.3,6.6Hz, 1H), 6.29 (d, J = 7.4Hz, 1H), 7.2
0 (m, 2H), 8.57 (m, 2H) MS (SIMS) m / e: 518 (M + H) + C 30 H 51 N 3 O 4 (517)

Compound ^{1 of} Example 16 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 3H), 1.17
(s, 9H), 1.20-1.40 (m, 22H), 2.01 (m, 2H), 2.97 (m, 2H), 3.61
(m, 2H), 4.06 (m, 2H), 4.16 (m, 1H), 4.42 (dd, J = 7.3,11.9Hz,
1H), 5.43 (dd, J = 6.6,15.3Hz, 1H), 5.71 (dt, J = 15.4,6.6Hz,
1H), 6.39 (d, J = 7.2Hz, 1H), 7.16 (m, 2H), 7.62 (m, 1H), 8.53
(m, 1H) MS (SIMS ) m / e: 532 (M + H) + C 31 H 53 N 3 O 4 (531)

Compound ^{1 of} Example 17 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.20
(s, 9H), 1.20-1.40 (m, 22H), 2.03 (m, 2H), 2.82 (m, 2H), 3.37
(m, 1H), 3.52 (m, 1H), 4.10-4.37 (m, 4H), 5.40 (bs, 1H), 5.47
(dd, J = 6.6,15.4Hz, 1H), 5.74 (dt, J = 15.6,6.3Hz, 1H), 6.37
(d, J = 7.0Hz, 1H ), 6.83 (s, 1H), 7.59 (s, 1H) MS (SIMS) m / e: 521 (M + H) + C 29 H 52 N 4 O 4 (520)

Compound ^{1 of} Example 18 H-NMR (CDCl ₃ ) δ (ppm): 0.86 (t, J = 6.4 Hz, 3H), 1.07
-1.42 (m, 22H), 1.15 (s, 9H), 1.87-2.10 (m, 4H), 3.02-3.23
(m, 3H), 4.00 (t, J = 6.8Hz, 2H), 4.05-4.27 (m, 3H), 4.37 (dd,
J = 7.0,10.9Hz, 1H), 5.44 (dd, J = 6.3,15.4Hz, 1H), 5.62-5.8
2 (m, 2H), 6.32 (d, J = 7.4Hz, 1H), 6.92 (bs, 1H), 7.03 (bs, 1
H), 7.03 (bs, 1H ), 7.52 (bs, 1H) MS (SIMS) m / e: 535 (M + H) + C 30 H 54 N 4 O 4 (534)

Compound ^{1 of} Example 19 H-NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 0.81 (t, J = 6.5 Hz, 3
H), 0.96-1.40 (m, 22H), 1.84-2.08 (m, 2H), 4.02-4.50 (m, 6
H), 5.45 (dd, J = 6.4,15.5Hz, 1H), 5.71 (dt, J = 15.5,6.3Hz, 1
H), 7.08 (d, J = 5.4Hz, 2H), 7.22-7.53 (m, 2H), 7.71 (d, J = 6.9
Hz, 2H), 8.28 (d , J = 5.4Hz, 2H) MS (SIMS) m / e: 538 (M + H) + C 32 H 47 N 3 O 4 (537)

Compound ^{1 of} Example 20 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 3H), 1.16
(s, 9H), 1.22-1.40 (m, 22H), 2.02 (m, 2H), 3.56 (bs, 1H), 4.1
1 (m, 2H), 4.20 (m, 1H), 4.36 (m, 2H), 4.45 (dd, J = 7.6,11.8H
z, 1H), 5.16 (m, 1H), 5.44 (dd, J = 6.6,15.3Hz, 1H), 5.72 (dt,
J = 15.4,6.6Hz, 1H), 6.37 (d, J = 7.0Hz, 1H), 7.26-7.40 (m, 5
H) MS (SIMS) m / e: 517 (M + H) + C 31 H 52 N 2 O 4 (516)

Compound ^{1 of} Example 21 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.17
(s, 9H), 1.22-1.40 (m, 22H), 2.02 (m, 2H), 2.94 (s, 6H), 3.69
(d, J = 5.1Hz, 1H), 4.08 (m, 2H), 4.19 (m, 1H), 4.25 (m, 2H), 4.
45 (dd, J = 7.4,11.9Hz, 1H), 5.00 (m, 1H), 5.44 (dd, J = 6.7,1
5.4Hz, 1H), 5.71 (dt, J = 15.3,6.5Hz, 1H), 6.40 (d, J = 7.0Hz,
1H), 6.69 (d, J = 8.5Hz, 2H), 7.14 (d, J = 8.5Hz, 2H) MS (SIMS) m / e: 582 (M + Na) + C 33 H 57 N 3 O 4 ( 559)

Compound ^{1 of} Example 22 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.13
-1.44 (m, 22H), 1.17 (s, 9H), 1.19-2.11 (m, 2H), 3.15-3.43
(m, 2H), 3.35 (bs, 1H), 3.60-3.82 (m, 2H), 4.06-4.36 (m, 4
H), 5.44 (dd, J = 6.3,15.4Hz, 1H), 5.62 (t, J = 5.7Hz, 1H), 5.7
3 (dt, J = 15.4,6.6Hz, 1H), 6.34 (d, J = 5.8Hz, 1H) MS (CI) m / e: 471 (M + H) + C 26 H 50 N 2 O 5 (471 )

Compound ^{1 of} Example 23 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.19
(s, 9H), 1.20-1.40 (m, 22H), 1.72 (m, 2H), 2.03 (m, 2H), 2.25
(m, 1H), 3.32 (m, 1H), 3.39 (dd, J = 5.0,16.1Hz, 1H), 3.71 (m, 1H)
2H), 4.06-4.16 (m, 3H), 4.39 (dd, J = 7.6,11.8Hz, 1H), 5.12
(bs, 1H), 5.45 (dd, J = 6.6,15.4Hz, 1H), 5.73 (dt, J = 15.3,6.
8Hz, 1H), 6.34 (d , J = 7.2Hz, 1H) MS (SIMS) m / e: 485 (M + H) + C 27 H 52 N 2 O 5 (484)

Compound ^{1 of} Example 24 H-NMR (CDCl ₃ ) δ (ppm): 0.86 (t, J = 6.4 Hz, 3H), 1.06
-1.40 (m, 22H), 1.19 (s, 9H), 1.40-1.73 (m, 4H), 1.92-2.08
(m, 2H), 2.32 (t, J = 7.0Hz, 2H), 3.07-3.25 (m, 2H), 3.66 (s, 3
H), 3.76 (bs, 1H), 3.96-4.22 (m, 3H), 4.40 (m, 1H), 5.03 (t, J
= 5.7Hz, 1H), 5.42 (dd, J = 6.3,15.4Hz, 1H), 5.70 (dt, J = 15.
4,6.5Hz, 1H), 6.38 (d , J = 6.9Hz, 1H) MS (SIMS) m / e: 541 (M + H) + C 30 H 56 N 2 O 6 (540)

Compound ^{1 of} Example 25 H-NMR (500 MHz, CDCl ₃ -CD ₃ OD) δ (ppm): 0.85 (t, J =
6.3Hz, 3H), 1.08-1.42 (m, 22H), 1.15 (s, 9H), 1.19-2.12 (m,
2H), 4.16-4.48 (m, 4H), 5.46 (dd, J = 5.5,15.5Hz, 1H), 5.78
(dt, J = 15.5,6.5Hz, 1H ), 6.51 (bs, 1H) MS (SIMS) m / e: 495 (M + H) + C 25 H 46 N 6 O 4 (494)

Compound ^{1 of} Example 26 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 2.03 (m, 2H), 2.46 (m, 2H), 3.35
(d, J = 5.1Hz, 1H), 3.47 (m, 2H), 4.06-4.22 (m, 3H), 4.36 (dd,
J = 7.0,11.7Hz, 1H), 5.35 (bs, 1H), 5.41-5.54 (m, 2H), 5.68
(bs, 1H), 5.72 (dt, J = 15.4,6.4Hz, 1H), 6.25 (d, J = 7.1Hz, 1
H) MS (SIMS) m / e: 498 (M + H) + C 27 H 51 N 3 O 5 (497)

Compound ^{1 of} Example 27 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.17
(s, 9H), 1.20-1.40 (m, 22H), 1.75-1.92 (m, 2H), 1.94-2.05
(m, 2H), 2.90-3.03 (m, 2H), 3.22 (bs, 2H), 3.24-3.36 (m, 2
H), 3.65 (d, J = 4.3Hz, 1H), 4.00-4.25 (m, 3H), 4.34 (m, 1H),
5.44 (dd, J = 5.5,15.1Hz, 1H), 5.74 (dt, J = 15.1,5.9Hz, 1H),
6.11 (bs, 1H), 6.37 (d, J = 6.4Hz, 1H) MS (SIMS) m / e: 484 (M + H) + C 27 H 53 N 3 O 4 (483)

Compound ^{1 of} Example 28 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.4 Hz, 3H), 1.15
(d, J = 6.9Hz, 6H), 1.15-1.47 (m, 22H), 1.93-2.11 (m, 2H), 2.
37 (m, 1H), 3.21 (bs, 1H), 4.04-4.28 (m, 3H), 4.42 (dd, J = 6.
8,11.1Hz, 1H), 5.01 (bs, 2H), 5.45 (dd, J = 6.5,15.4Hz, 1H),
5.73 (dt, J = 15.4,6.6Hz, 1H), 6.06 (d, J = 7.4Hz, 1H) MS (SIMS) m / e: 413 (M + H) + C 23 H 44 N 2 O 4 (412 )

Compound ^{1 of} Example 29 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.4 Hz, 3H), 1.12
-1.45 (m, 22H), 1.15 (d, J = 7.0Hz, 6H), 1.94-2.12 (m, 2H), 2.
38 (m, 1H), 2.74 (bs, 1H), 3.00 (d, J = 4.5Hz, 1H), 3.15-3.47
(m, 2H), 3.58-3.85 (m, 2H), 4.08-4.32 (m, 4H), 5.20 (bs, 1
H), 5.47 (dd, J = 6.3,15.4Hz, 1H), 5.75 (dt, J = 15.4,6.5Hz, 1
H), 6.09 (bs, 1H ) MS (SIMS) m / e: 457 (M + H) + C 25 H 48 N 2 O 5 (456)

Compound ^{1 of} Example 30 H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.14
(d, J = 6.9Hz, 6H), 1.18-1.42 (m, 22H), 1.60-1.80 (m, 2H), 1.
95-2.10 (m, 2H), 2.37 (m, 1H), 2.48 (bs, 1H), 3.22-3.42 (m, 3
H), 3.70 (t, J = 5.6Hz, 2H), 4.04-4.27 (m, 3H), 4.36 (dd, J = 6.
6,10.9Hz, 1H), 5.21 (bs, 1H), 5.45 (dd, J = 6.3,15.4Hz, 1H),
5.73 (dt, J = 15.4,6.6Hz, 1H), 6.12 (d, J = 7.4Hz, 1H) MS (SIMS) m / e: 471 (M + H) + C 26 H 50 N 2 O 5 (470 )

Compound ^{1 of} Example 31 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.14
(d, J = 6.9Hz, 6H), 1.20-1.47 (m, 22H), 1.59-1.86 (m, 4H), 2.
37 (m, 1H), 2.98 (m, 1H), 3.13-3.31 (m, 2H), 3.60-3.75 (m, 2
H), 4.00-4.26 (m, 3H), 4.39 (dd, J = 7.1,9.3Hz, 1H), 4.95 (b
s, 1H), 5.46 (dd, J = 6.7,15.4Hz, 1H), 5.75 (dt, J = 15.4,6.5H
z, 1H), 6.12 (d , J = 6.7Hz, 1H) MS (SIMS) m / e: 485 (M + H) + C 27 H 52 N 2 O 5 (484)

Compound ¹ H-NMR (CDCl ₃ ) δ (ppm) of Example 32: 0.88 (t, J = 6.4 Hz, 3H), 1.08
-1.50 (m, 22H), 1.97-2.14 (m, 2H), 2.30 (s, 3H), 2.62 (m, 1
H), 3.99 (m, 1H), 4.22-4.44 (m, 2H), 4.98 (m, 1H), 5.48 (dd, J
= 8.3,15.3Hz, 1H), 5.82 (dt, J = 15.3,6.6Hz, 1H), 6.64 (s, 1
H), 7.09 (d, J = 8.8Hz, 2H), 7.24 (d, J = 8.8Hz, 2H) MS (SIMS) m / e: 503 (M + H) + C 30 H 50 N 2 O 4 ( 502)

Compound ^{1 of} Example 33 H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.8 Hz,
3H), 1.13 (d, J = 6.4Hz, 3H), 1.14 (d, J = 6.6Hz, 3H), 1.18-1.3
9 (m, 22H), 1.96-2.08 (m, 2H), 2.37 (m, 1H), 3.08 (bs, 1H), 3.
80 (s, 3H), 4.11-4.24 (m, 2H), 4.24 (m, 1H), 4.48 (dd, J = 7.3,
11.6Hz, 1H), 5.49 (dd, J = 7.9,15.4Hz, 1H), 5.70 (dt, J = 15.
4,6.7Hz, 1H), 6.07 (d, J = 8.0Hz, 1H), 6.63 (m, 1H), 6.87 (d, J
= 7.9Hz, 1H), 6.90 ( bs, 1H), 7.09 (bs, 1H), 7.20 (m, 1H) MS (SIMS) m / e: 519 (M + H) + C 30 H 50 N 2 O 5 (518)

Compound ^{1 of} Example 34 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.13
(d, J = 6.9Hz, 3H), 1.14 (d, J = 6.9Hz, 3H), 1.21-1.38 (m, 22
H), 2.00-2.08 (m, 2H), 2.38 (m, 1H), 3.25 (bs, 1H), 3.87 (s, 3
H), 4.11-4.25 (m, 2H), 4.28 (m, 1H), 4.50 (dd, J = 7.0,11.7H
z, 1H), 5.49 (dd, J = 6.7,15.4Hz, 1H), 5.75 (dt, J = 15.4,6.7H
z, 1H), 6.09 (d, J = 7.9Hz, 1H), 6.87 (d, J = 8.0Hz, 1H), 6.96
(m, 1H), 7.02 ( m, 1H), 7.30 (m, 1H), 8.05 (bs, 1H) MS (SIMS) m / e: 519 (M + H) + C 30 H 50 N 2 O 5 ( 518)

Compound ^{1 of} Example 35 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.81 (t, J = 6.4 Hz, 3H), 1.02
-1.40 (m, 22H), 1.04 (d, J = 6.8Hz, 3H), 1.06 (d, J = 6.8Hz, 3
H), 1.87-2.05 (m, 2H), 2.32 (m, 1H), 3.99-4.36 (m, 4H), 5.40
(dd, J = 6.2,15.4Hz, 1H), 5.68 (dt, J = 15.4,6.6Hz, 1H), 6.60
(m, 1H), 6.70 ( d, J = 8.7Hz, 2H), 7.12 (d, J = 8.7Hz, 2H) MS (CI) m / e: 505 (M + H) + C 29 H 47 N 2 O ₅ (504)

Compound ^{1 of} Example 36 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.83 (t, J = 6.4 Hz, 3H), 1.05
(d, J = 6.9Hz, 3H), 1.07 (d, J = 6.8Hz, 3H), 1.12-1.40 (m, 22
H), 1.46 (s, 9H), 1.90-2.07 (m, 2H), 2.33 (m, 1H), 4.02-4.38
(m, 4H), 5.41 (dd, J = 6.1,15.4Hz, 1H), 5.70 (dt, J = 15.4,6.6
Hz, 1H), 6.56 (d , J = 7.8Hz, 1H), 6.90 (bs, 1H), 7.24 (s, 4H) MS (SIMS) m / e: 504 (M + H) + C 29 H 49 N ₃ O ₄ (503)

Compound ^{1 of} Example 37 H-NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 0.82 (t, J = 6.4 Hz, 3
H), 1.04 (d, J = 6.6Hz, 3H), 1.07 (d, J = 6.6Hz, 3H), 1.05-1.41
(m, 22H), 1.88-2.08 (m, 2H), 2.33 (m, 1H), 2.51 (s, 3H), 4.05
-4.40 (m, 4H), 5.42 (dd, J = 6.2,15.4Hz, 1H), 5.71 (dt, J = 15.
4,6.6Hz, 1H), 6.58 (d, J = 7.8Hz, 1H), 7.45 (d, J = 8.8Hz, 2H),
7.86 (d, J = 8.8Hz, 2H) MS (SIMS) m / e: 531 (M + H) + C 31 H 50 N 2 O 5 (530)

Compound ^{1 of} Example 38 ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 0.84 (t, J = 6.2 Hz, 3
H), 1.05 (d, J = 6.9Hz, 3H), 1.08 (d, J = 6.9Hz, 3H), 1.03-1.43
(m, 22H), 1.09-2.09 (m, 2H), 2.34 (m, 1H), 4.07-4.38 (m, 4
H), 5.43 (dd, J = 6.1,15.4Hz, 1H), 5.73 (dt, J = 15.4,6.6Hz, 1
H), 6.49 (d, J = 6.3Hz, 1H), 7.40-7.65 (m, 4H) MS (SIMS) m / e: 514 (M + H) + C 30 H 47 N 3 O 4 (513)

Compound ^{1 of} Example 39 1H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.11
(d, J = 6.8Hz, 3H), 1.13 (d, J = 6.9Hz, 3H), 1.05-1.45 (m, 22
H), 1.88-2.10 (m, 2H), 2.38 (m, 1H), 2.86 (bs, 1H), 4.15-4.5
5 (m, 4H), 5.49 (dt, J = 15.5,6.3Hz, 1H), 5.77 (dd, J = 6.5,15.
5Hz, 1H), 6.08 (d, J = 7.7Hz, 1H), 7.59 (d, J = 9.2Hz, 2H), 8.12
(bs, 1H), 8.18 ( d, J = 9.2Hz, 2H) MS (SIMS) m / e: 534 (M + H) + C 29 H 47 N 3 O 6 (533)

Compound ^{1 of} Example 40 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.08
-1.52 (m, 22H), 1.10 (d, J = 6.8Hz, 3H), 1.12 (d, J = 6.8Hz, 3
H), 1.37 (t, J = 7.1Hz, 3H), 1.90-2.11 (m, 2H), 2.38 (m, 1H),
4.14-4.57 (m, 4H), 4.38 (q, J = 7.1Hz, 2H), 5.48 (dd, J = 6.3,1
5.5Hz, 1H), 5.75 (dt, J = 15.5,6.6Hz, 1H), 6.15 (d, J = 7.8Hz,
1H), 7.46 (d, J = 8.7Hz, 2H), 7.73 (bs, 1H), 7.98 (d, J = 8.7Hz,
2H) MS (SIMS) m / e: 561 (M + H) + C 32 H 52 N 2 O 6 (560)

Compound ¹ H-NMR (CDCl ₃ ) δ (ppm) of Example 41: 0.87 (t, J = 6.4 Hz, 3H), 1.05
(d, J = 6.7Hz, 6H), 1.02-1.47 (m, 22H), 1.90-2.10 (m, 2H), 2.
39 (m, 1H), 3.22 (bs, 1H), 3.92 (s, 3H), 4.13-4.23 (m, 3H), 4.
50 (m, 1H), 5.50 (dd, J = 6.3,15.4Hz, 1H), 5.74 (dt, J = 15.4,
6,5Hz, 1H), 6.05 (d, J = 7.2Hz, 1H), 7.06 (m, 1H), 7.54 (m, 1
H), 8.02 (dd, J = 1.7,8.0Hz, 1H), 8.40 (d, J = 8.4Hz, 1H), 10.6
0 (s, 1H) MS ( SIMS) m / e: 547 (M + H) + C 31 H 50 N 2 O 6 (546)

Compound ^{1 of} Example 42 1H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.11
(d, J = 6.8Hz, 6H), 1.12-1.48 (m, 22H), 1.90-2.12 (m, 2H), 2.
34 (m, 1H), 3.90-4.27 (m, 3H), 4.34 (d, J = 5.8Hz, 2H), 4.42
(m, 1H), 5.29 (t, J = 5.8Hz, 1H), 5.44 (dd, J = 6.3,15.5Hz, 1H)
5.71 (dt, J = 15.5,6.7Hz, 1H), 6.17 (d, J = 7.1Hz, 1H), 7.16-
7.42 (m, 5H) MS ( CI) m / e503: (M + H) + C 30 H 50 N 2 O 4 (502)

Compound ^{1 of} Example 43 1H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.2 Hz, 3H), 1.10
(d, J = 6.8Hz, 6H), 1.17-1,48 (m, 22H), 1.89-2.11 (m, 2H), 2.
34 (m, 1H), 4.08-4.29 (m, 3H), 4.29-4.48 (m, 3H), 5.45 (dd, J
= 5.9,15.3Hz, 1H), 5.60 (t, J = 5.9Hz, 1H), 5.73 (dt, J = 15.3,
6.7Hz, 1H), 6.12 (d, J = 6.9Hz, 1H), 7.19 (d, J = 5.3Hz, 2H), 8.
54 (d, J = 5.3Hz, 2H) MS (SIMS) m / e: 604 (M + H) + C 34 H 57 N 3 O 6 (603)

Compound ^{1 of} Example 44 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.09
(d, J = 6.9Hz, 3H), 1.10 (d, J = 6.9Hz, 3H), 1.17-1.45 (m, 22
H), 1.92-2.10 (m, 2H), 2.32 (m, 1H), 3.40 (bs, 1H), 4.02-4.2
7 (m, 3H), 4.40 (m, 1H), 4.43 (d, J = 6.2Hz, 2H), 5.31-5.51 (m,
2H), 5.70 (dt, J = 15.4, 6.8 Hz, 1H), 6.12 (d, J = 7.2 Hz, 1H), 7.
17-7.43 (m, 4H) MS ( CI) m / e: 537 (M + H) + C 30 H 49 ClN 2 O 4 (536)

Compound ^{1 of} Example 45 H-NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 0.87 (t, J = 6.3 Hz, 3
H), 1.11 (d, J = 6.8Hz, 6H), 1.12-1.45 (m, 22H), 1.92-2.09
(m, 2H), 2.33 (s, 3H), 3.54 (bs, 1H), 4.03-4.26 (m, 3H), 4.29
(d, J = 5.7Hz, 2H), 4.41 (dd, J = 6.8,11.1Hz, 1H), 5.24 (t, J =
5.5Hz, 1H), 5.44 (dd, J = 6.2,15.4Hz, 1H), 5.71 (dt, J = 15.4,
6.3Hz, 1H), 6.19 (d , J = 7.1Hz, 1H), 7.14 (s, 4H) MS (SIMS) m / e: 517 (M + H) + C 31 H 52 N 2 O 4 (516)

Compound ^{1 of} Example 46 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.81 (t, J = 6.4 Hz, 3H), 1.02
-1.40 (m, 22H), 1.04 (d, J = 6.8Hz, 3H), 1.06 (d, J = 6.8Hz, 3
H), 1,87-2.05 (m, 2H), 2.32 (m, 1H), 3.99-4.36 (m, 4H), 5.40
(dd, J = 6.2,15.4Hz, 1H), 5.68 (dt, J = 15.4,6.6Hz, 1H), 6.60
(m, 1H), 6.70 ( d, J = 8.7Hz, 2H), 7.12 (d, J = 8.7Hz, 2H) MS (SIMS) m / e: 561 (M + H) + C 32 H 52 N 2 O ₆ (560)

Compound ^{1 of} Example 47 1H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.3 Hz, 3H), 1.12
(d, J = 6.9Hz, 6H), 1.08-1.48 (m, 22H), 1.91-2.12 (m, 2H), 2.
35 (m, 1H), 2.80 (t, J = 7.0Hz, 2H), 3.31-3.56 (m, 3H), 3.99-
4.26 (m, 3H), 4.38 (dd, J = 6.7,11.2Hz, 1H), 4.92 (t, J = 5.3H
z, 1H), 5.44 (dd, J = 6.3,15.4Hz, 1H), 5.71 (dt, J = 15.4,6.5H
z, 1H), 6.13 (d , J = 7.3Hz, 1H), 7.10-7.38 (m, 5H) MS (CI) m / e: 517 (M + H) + C 31 H 52 N 2 O 4 (516 )

Compound ^{1 of} Example 48 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.4 Hz, 3H), 1.14
(d, J = 6.9Hz, 6H), 1.12-1.45 (m, 22H), 1.93-2.11 (m, 2H), 2.
20-2.56 (m, 8H), 3.18-3.38 (m, 2H), 3.64--3.79 (m, 4H), 4.01
-4.28 (m, 3H), 4.40 (dd, J = 6.4,15.4Hz, 1H), 5.73 (dt, J = 15.
4,6.5Hz, 1H), 6.12 (d , J = 7.1Hz, 1H) MS (CI) m / e526 (M + H) + C 29 H 55 N 3 O 5 (525)

Compound ^{1 of} Example 49 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.83 (t, J = 6.6 Hz, 3H), 1.05
(d, J = 6.7Hz, 3H), 1.07 (d, J = 6.7Hz, 3H), 1.05-1.45 (m, 22
H), 1.85-2.08 (m, 2H), 2.33 (m, 1H), 4.05-4.50 (m, 4H), 5.42
(dd, J = 6.3,15.5Hz, 1H), 5.73 (dt, J = 15.5,6.7Hz, 1H), 6.57
(d, J = 8.0Hz, 1H), 6.87 (d, J = 3.5Hz, 1H), 7.31 (d, J = 3.5Hz, 1H
H) MS (CI) m / e: 496 (M + H) + C 26 H 45 N 3 O 4 S (495)

Compound ^{1 of} Example 50 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.00
-1.45 (m, 22H), 1.11 (d, J = 6.8Hz, 6H), 1.90-2.10 (m, 2H), 2.
35 (m, 1H), 3.05 (bs, 1H), 4.14-4.38 (m, 3H), 4.50 (m, 1H), 5.
50 (dd, J = 6.2,15.5Hz, 1H), 5.75 (dt, J = 15.5,6.6Hz, 1H), 6.
15 (d, J = 7.7Hz, 1H), 7.40 (m, 1H), 7.65 (m, 1H), 7.76 (d, J = 7.
9Hz, 1H), 7.83 (d , J = 8.4Hz, 1H), 8.15 (s, 2H) MS (CI) m / e: 540 (M + H) + C 32 H 49 N 3 O 4 (539)

Compound ^{1 of} Example 51 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 7.0 Hz, 3H), 1.07
(d, J = 6.9Hz, 2H), 1.09 (d, J = 6.9Hz, 2H), 1.18-1.40 (m, 22
H), 1.97-2.09 (m, 2H), 2.32 (m, 1H), 4.13-4.25 (m, 2H), 4.34
(dd, J = 3.2,11.6Hz, 1H), 4.41 (dd, J = 7.6,11.6Hz, 1H), 4.66
(d, J = 15.9Hz, 1H), 4.75 (d, J = 15.9Hz, 1H), 5.48 (dd, J = 6.
3,15.4Hz, 1H), 5.75 (dt, J = 15.4,6.7Hz, 1H), 6.19 (d, J = 7.6
Hz, 1H), 7.26 (d , J = 4.7Hz, 2H), 8.43 (d, J = 4.7Hz, 2H) MS (SIMS) m / e: 520 (M + H) + C 29 H 49 N 3 O ₅ (519)

Compound ^{1 of} Example 52 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.8 Hz, 3H), 1.20
-1.36 (m, 20H), 1.60 (m, 2H), 1.71 (d, J = 6.4Hz, 1H), 2.17 (m,
2H), 4.10-4.19 (m, 2H), 4.21 (m, 1H), 4.27 (m, 1H), 4.35 (d, J
= 2.9Hz, 1H), 5.49 (m, 1H), 5.76 (m, 1H), 6.28 (bd, 1H), 6.38
(bd, 1H), 7.23 (d, J = 5.6Hz, 1H), 8.53 (d, J = 5.3Hz, 1H)

Compound ^{1 of} Example 53 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.3 Hz, 3H), 1.11
(d, J = 6.8Hz, 6H), 1.05-1.50 (m, 22H), 1.90-2.16 (m, 2H), 2.
34 (m, 1H), 3.98-4.52 (m, 6H), 5.34-5.60 (m, 2H), 5.73 (dt, J
= 15.4,6.8Hz, 1H), 6.10 (d, J = 7.1Hz, 1H), 7.19 (d, J = 5.5Hz,
1H), 8.55 (d, J = 5.5Hz, 1H) MS (CI) m / e406 (M + H) + C 22 H 35 N 3 O 4 (405)

Compound ^{1 of} Example 54 H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz,
6H), 1.18-1.40 (m, 34H), 1.53-1.69 (m, 4H), 1.96-2.10 (m, 2
H), 2.11-2.22 (m, 2H), 3.07 (bs, 1H), 4.11-4.20 (m, 2H), 4.2
5 (m, 1H), 4.34-4.44 (m, 3H), 5.31 (t, J = 6.1Hz, 1H), 5.47 (d
d, J = 6.6,15.3Hz, 1H), 5.74 (dt, J = 15.3,6.7Hz, 1H), 6.01
(d, J = 8.0Hz, 1H), 7.20 (d, J = 5.8Hz, 2H), 8.57 (d, J = 5.8Hz, 2
H) MS (SIMS) m / e: 602 (M + H) + C 36 H 63 N 3 O 4 (601)

Compound ^{1 of} Example 55 H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.10
(d, J = 6.8Hz, 6H), 1.12-1.47 (m, 16H), 1.90-2.13 (m, 2H), 2.
33 (m, 1H), 3.40 (bs, 1H), 4.04-4.50 (m, 6H), 5.44 (dd, J = 6.
2,15.5Hz, 1H), 5.57-5.82 (m, 2H), 6.14 (d, J = 7.3Hz, 1H), 7.
23 (d, J = 5.8Hz, 2H), 8.53 (d, J = 5.8Hz, 2H) MS (SIMS) m / e: 462 (M + H) + C 26 H 43 N 3 O 4 (461)

Compound ^{1 of} Example 56 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.3 Hz, 3H), 1.10
(d, J = 6.7Hz, 6H), 1.10-1.46 (m, 16H), 1.90-2.10 (m, 2H), 2.
33 (m, 1H), 3.35 (bs, 1H), 3.90 (s, 3H), 4.04-4.27 (m, 3H), 4.
31-4.51 (m, 3H), 5.33-5.65 (m, 2H), 5.72 (dt, J = 15.2,6.5H
z, 1H), 6.14 (d, J = 7.2Hz, 1H), 7.33 (d, J = 8.1Hz, 2H), 7.99
(d, J = 8.1Hz, 2H ) MS (SIMS) m / e: 519 (M + H) + C 29 H 46 N 2 O 6 (518)

Compound ^{1 of} Example 57 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.3 Hz, 3H), 1.15
(d, J = 6.9Hz, 6H), 1.11-1.46 (m, 16H), 1.94-2.13 (m, 2H), 2.
37 (m, 1H), 3.17 (bs, 1H), 4.06-4.29 (m, 3H), 4.39 (dd, J = 6.
8,11.1Hz, 1H), 4.74 (bs, 2H), 5.45 (dd, J = 6.5,15.3Hz, 1H),
5.74 (dt, J = 15.3,6.7Hz, 1H), 6.06 (d, J = 7.1Hz, 1H) MS (CI) m / e: 371 (M + H) + C 20 H 38 N 2 O 4 (370 )

Compound ^{1 of} Example 58 H-NMR (CDCl ₃ ) δ (ppm): 0.86 (t, J = 6.4 Hz, 3H), 1.12
(d, J = 6.9Hz, 6H), 1.13-1.43 (m, 16H), 1.90-2.08 (m, 2H), 2.
21 (s, 6H), 2.36 (m, 1H), 2.40 (t, J = 6.3Hz, 2H), 2.47 (bs, 1H
H), 3.24 (m, 2H), 4.00-4.23 (m, 3H), 4.39 (dd, J = 6.0,11.1H
z, 1H), 5.44 (dd, J = 6.4,15.4Hz, 1H), 5.58 (m, 1H), 5.71 (dt,
J = 15.4,6.4Hz, 1H), 6.29 (d, J = 7.2Hz, 1H) MS (CI) m / e: 442 (M + H) + C 24 H 47 N 3 O 4 (441)

Compound ^{1 of} Example 59 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 3H), 1.19
(s, 9H), 1.20-1.40 (m, 26H), 2.03 (m, 2H), 3.32 (d, J = 5.4Hz,
1H), 4.10 (dd, J = 3.8, 11.9Hz, 1H), 4.14 (m, 1H), 4.21 (m, 1
H), 4.41 (dd, J = 7.6,11.8Hz, 1H), 4.69 (bs, 2H), 5.45 (dd, J =
6.7,15.4Hz, 1H), 5.74 (dt, J = 15.3,6.8Hz, 1H), 6.29 (d, J =
7.4Hz, 1H) MS (SIMS) m / e: 455 (M + H) + C 26 H 50 N 2 O 4 (454)

Compound ^{1 of} Example 60 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.8 Hz, 3H), 1.15
(s, 9H), 1.20-1.40 (m, 26H), 2.02 (m, 2H), 3.33 (bs, 1H), 4.1
3 (m, 2H), 4.20 (m, 1H), 4.32-4.49 (m, 3H), 5.25 (m, 1H), 5.44
(dd, J = 6.7,15.4Hz, 1H), 5.73 (dt, J = 15.4,6.6Hz, 1H), 6.28
(d, J = 7.4Hz, 1H), 7.28 (m, 1H), 7.63 (d, J = 7.7Hz, 1H), 8.55
(m, 2H) MS (SIMS ) m / e: 546 (M + H) + C 32 H 55 N 3 O 4 (545)

Compound ^{1 of} Example 61 H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 6H), 1.08
-1.43 (m, 52H), 1.93-2.10 (m, 2H), 2.17 (t, J = 7.5Hz, 2H), 2.
98 (bs, 1H), 4.10-4.44 (m, 6H), 5.34 (t, J = 6.3Hz, 1H), 5.47
(dd, J = 6.6,15.6Hz, 1H), 5.74 (dt, J = 15.6,6.6Hz, 1H), 6.00
(d, J = 6.9Hz, 1H), 7.20 (d, J = 5.5Hz, 2H), 8.57 (d, J = 5.5Hz, 2
H) MS (SIMS) m / e: 700 (M + H) + C 43 H 77 N 3 O 4 (699)

Compound ^{1 of} Example 62 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.08
-1.45 (m, 22H), 1.93-2.11 (m, 2H), 2.00 (s, 3H), 3.14 (bs, 1
H), 4.03-4.28 (m, 3H), 4.34 (dd, J = 6.2,10.6Hz, 1H), 4.86 (b
s, 2H), 5.47 (dd, J = 6.2,15.4Hz, 1H), 5.74 (dt, J = 15.4,6.5H
z, 1H), 6.13 (d , J = 6.8Hz, 1H) MS (SIMS) m / e: 385 (M + H) + C 21 H 40 N 2 O 4 (384)

Compound ^{1 of} Example 63 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 3H), 1.18
(s, 9H), 1.20-1.44 (m, 22H), 1.90-2.12 (m, 4H), 2.88 (d, J =
4.9Hz, 3H), 2.90 (s, 6H), 2.96-3.54 (m, 4H), 4.12-4.40 (m, 3
H), 5.48 (m, 1H ), 5.78 (dt, J = 15.2,6.6Hz, 1H), 6.33 (m, 1H) MS (SIMS) m / e: 526 (M + H) + C 30 H 59 N ₃ O ₄ (525)

Compound ^{1 of} Example 64 1H-NMR (CDCl ₃ ) δ (ppm): 0.79 (t, J = 6.3 Hz, 3H), 1.00
(d, J = 6.8Hz, 3H), 1.03 (d, J = 6.8Hz, 3H), 1.00-1.40 (m, 22
H), 1.84-2.05 (m, 2H), 2.04 (s, 3H), 2.30 (m, 1H), 3.98-4.35
(m, 4H), 5.38 (dd, J = 6.3,15.4Hz, 1H), 5.66 (dt, J = 15.4,6.6
Hz, 1H), 6.72 (d, J = 7.9Hz, 1H), 7.23 (d, J = 8.9Hz, 2H), 7.35
(d, J = 8.9Hz, 2H ) MS (SIMS) m / e: 546 (M + H) + C 31 H 51 N 3 O 5 (545)

Example 65 3-O- (tert-butyldimethylsilyl) -2-N-isobutyryl-D-erythro-sphingosine (30 mg, 0.062 mmol) was dissolved in tetrahydrofuran (0.5 ml), and triethylamine was dissolved.
(1 drop) and methyl isocyanate (90 mg, 0.92 mmol) were added, and the mixture was stirred at 60 ° C. for 6 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (0.5 ml), and tetrabutylammonium fluoride (tetrahydrofuran 1M
Solution, 0.80 ml) and stirred at room temperature for 4 hours. The residue was purified by column chromatography to obtain 1-O-methylaminocarbonyl-2-N-isobutyryl-D-erythro-sphingosine (16 mg). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.83 (t, J = 6.4 Hz, 3H), 1.12
(d, J = 6.9Hz, 6H), 1.08-1.45 (m, 22H), 1.90-2.10 (m, 2H), 2.
36 (m, 1H), 2.77 (d, J = 4.9Hz, 3H), 3.58 (bs, 1H), 3.98-4.25
(m, 3H), 4.38 (dd, J = 6.8,11.2Hz, 1H), 4.96 (m, 1H), 5.44 (d
d, J = 6.3,15.4Hz, 1H), 5.71 (dt, J = 6.4,15.4Hz, 1H), 6.21
(d, J = 7.1Hz, 1H ) MS (CI) m / e: 427 (M + H) + C 24 H 46 N 2 O 4 (426)

Examples 66 to 72 The compounds of Examples 65 to 71 were prepared in the same manner as in the method of Example 65. The physicochemical data such as ¹ H-NMR spectrum and mass spectrum of each compound are shown. Compound ¹ H-NMR (CDCl ₃ ) δ (ppm) of Example 66: 0.87 (t, J = 6.4 Hz, 3H), 1.12
(d, J = 6.9Hz, 3H), 1.13 (d, J = 6.8Hz, 3H), 1.13-1.46 (m, 22
H), 1.92-2.11 (m, 2H), 2.37 (m, 1H), 3.17 (bs, 1H), 4.10-4.3
7 (m, 3H), 4.47 (dd, J = 6.8,10.8Hz, 1H), 5.48 (dd, J = 6.3,15.
4Hz, 1H), 5.75 (dt, J = 15.4,6.9Hz, 1H), 6.14 (d, J = 7.6Hz, 1
H), 7.07 (m, 1H ), 7.13 (bs, 1H), 7.23-7.44 (m, 4H) MS (CI) m / e489 (M + H) + C 29 H 48 N 2 O 4 (488)

Compound ^{1 of} Example 67 1H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.3 Hz, 3H), 1.11
(d, J = 6.9Hz, 3H), 1.13 (d, J = 6.9Hz, 3H), 1.05-1.42 (m, 22
H), 1.91-2.10 (m, 2H), 2.38 (m, 1H), 3.00 (m, 1H), 4.16-4.57
(m, 4H), 5.48 (dd, J = 6.3,15.4Hz, 1H), 5.78 (dt, J = 15.4,6.5
Hz, 1H), 6.09 (d, J = 7.8Hz, 1H), 7.25-7.49 (m, 2H), 7.49-7.6
5 (m, 2H), 7.72 (bs, 1H) MS (CI) m / e557 (M + H) + C 30 H 47 F 3 N 2 O 4 (556)

Compound ^{1 of} Example 68 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.11
(d, J = 6.8Hz, 3H), 1.13 (d, J = 6.8Hz, 3H), 1.04-1.46 (m, 22
H), 1.92-2.12 (m, 2H), 2.37 (m, 1H), 3.21 (bs, 1H), 3.78 (s, 3
H), 4.10-4.35 (m, 3H), 4.46 (dd, J = 6.7, 10.9Hz, 1H), 5.47 (d
d, J = 6.3,15.4Hz, 1H), 5.74 (dt, J = 15.4,6.6Hz, 1H), 6.11
(d, J = 7.4Hz, 1H ), 6.74-6.94 (m, 2H), 7.14-7.38 (m, 2H) MS (CI) m / e: 519 (M + H) + C 30 H 50 N 2 O ₅ (518)

Compound ^{1 of} Example 69 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.4 Hz, 3H), 1.12
(d, J = 6.8Hz, 3H), 1.14 (d, J = 6.8Hz, 3H), 1.10-1.45 (m, 22
H), 1.92-2.12 (m, 2H), 2.38 (m, 1H), 3.00 (bs, 1H), 3.87 (s, 3
H), 4.14-4.38 (m, 3H), 4.49 (m, 1H), 5.49 (dd, J = 6.3,15.4H
z, 1H), 5.76 (dt, J = 15.4,6.6Hz, 1H), 6.07 (d, J = 7.8Hz, 1H),
7.22 (bs, 1H), 7.38 (m, 1H), 7.62-7.81 (m, 2H), 7.98 (s, 1H) MS (SIMS) m / e: 547 (M + H) + C 31 H 50 N 2 O ₆ (546)

Compound ^{1 of} Example 70 NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.06
(t, J = 6.8Hz, 3H), 1.09 (t, J = 6.8Hz, 3H), 1.11-1.48 (m, 22
H), 1.90-2.12 (m, 2H), 2.32 (m, 1H), 4.08-4.43 (m, 4H), 5.42
(dd, J = 5.9,15.4Hz, 1H), 5.74 (dt, J = 15.4,6.7Hz, 1H), 6.14
(d, J = 7.7Hz, 1H ), 7.47-7.71 (m, 3H), 7.95-8.09 (m, 2H) MS (SIMS) m / e: 575 (M + Na) + C 29 H 48 N 2 O ₆ S (552)

Compound ^{1 of} Example 71 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.21
(s, 9H), 1.20-1.40 (m, 22H), 2.04 (m, 2H), 3.55 (d, J = 7.0Hz,
1H), 4.24 (m, 2H), 4.49 (m, 2H), 5.53 (dd, J = 5.9,15.5Hz, 1
H), 5.82 (dt, J = 15.6,6.7Hz, 1H), 6.58 (d, J = 7.4Hz, 1H), 7.5
1 (m, 2H), 7.62 (m, 1H), 7.85 (m, 1H), 8.31 (s, 1H)

Compound ^{1 of} Example 72 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 1.29 (t, J = 7.1Hz, 3H), 2.02 (m,
2H), 3.20 (bs, 1H), 3.39 (d, J = 5.1 Hz, 2H), 4.05-4.25 (m, 3
H), 4.23 (q, J = 7.2Hz, 2H), 4.45 (dd, J = 6.2,11.1Hz, 1H), 5.3
1 (m, 1H), 5.45 (dd, J = 6.6,15.4Hz, 1H), 5.74 (dt, J = 15.4,6.
5Hz, 1H), 6.26 (d, J = 6.7Hz, 1H)

Example 73 To a solution of 4- (methylthio) aniline (56 mg, 0.4 mmol) in tetrahydrofuran (1 ml) was added di-tert-butyl dicarbonate (109 mg,
0.50 mmol) and then N, N-dimethylaminopyridine (49 mg, 0.4 mmol), followed by stirring at room temperature for 30 minutes.
To this reaction solution, 3-O- (tert-butyldimethylsilyl) -2
-N-isobutyryl-D-erythro-sphingosine (48 mg,
(0.10 mmol) in tetrahydrofuran (1 ml) was added and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography, and 1-O- [4-
(Methylthio) anilinocarbonyl)]-2-N-isobutyryl-3-O- (tert-butyldimethylsilyl) -D-erythro-
Sphingosine (30 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.00 (s, 3H), 0.03 (s, 3H),
0.87 (t, J = 6.7Hz, 3H), 0.90 (s, 9H), 1.09 (d, J = 6.9Hz, 3H),
1.11 (d, J = 6.9Hz, 3H), 1.12-1.55 (m, 22H), 1.92-2.12 (m, 2
H), 2.31 (m, 1H), 2.45 (s, 3H), 4.10-4.30 (m, 3H), 4.48 (m, 1
H), 5.41 (dd, J = 6.2,15.5Hz, 1H), 5.67 (dt, J = 15.5,6.7Hz, 1
H), 5.85 (d, J = 8.1Hz, 1H), 6.95 (s, 1H), 7.15-7.40 (m, 4H)

The obtained compound (30 mg, 0.046 mmol) was dissolved in tetrahydrofuran (1 ml), tetrabutylammonium fluoride (0.5 ml as a 1M solution) was added under ice-cooling, and the mixture was stirred at the same temperature for 5 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 and concentration, the residue was purified by column chromatography and 1-O- [4- (methylthio) anilinocarbonyl] -2-N-isobutyryl-D-erythro-sphingosine.
(14 mg) was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 0.81 (t, J = 6.3 Hz, 3
H), 1.02 (d, J = 6.7Hz, 3H), 1.05 (d, J = 6.9Hz, 3H), 0.90-1.40
(m, 22H), 1.84-2.05 (m, 2H), 2.32 (m, 1H), 3.20 (s, 3H), 3.95
-4.38 (m, 4H), 5.39 (dd, J = 6.2,15.3Hz, 1H), 5.68 (dt, J = 15.
3,6.6Hz, 1H), 6.65 (d, J = 7.9Hz, 1H), 7.15 (d, J = 8.6Hz, 2H),
7.27 (d, J = 8.6Hz, 2H) MS (SIMS) m / e: 535 (M + H) + C 30 H 50 N 2 O 4 S (534)

Example 75 3-O- (tert-butyldimethylsilyl) -2-N-pivaloyl
-D-Erythro-sphingosine (0.90 mg, 1.8 mmol) was dissolved in a mixed solvent of dimethyl sulfoxide (12 ml) and tetrahydrofuran (12 ml), and triethylamine (6 ml) was added, followed by ice cooling. The sulfur trioxide pyridine complex (2.8
4g, 18mmol) and stirred for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, concentrated, and the residue was purified by column chromatography to give (1'S, 2'R, 3'E)-
N- [2- (tert-butyldimethylsilyloxy) -1-formyl-3-heptadecenyl] pivalamide (aldehyde form)
(0.80 g) was obtained. ¹ H-NMR (CDCl ₃ ) 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, 1
H), 5.89 (dt, J = 15.2,7.0Hz, 1H), 6.52 (d, J = 6.1Hz, 1H), 9.7
1 (s, 1H)

The obtained aldehyde compound (0.86 g, 1.8 mm
ol) and hydroxylamine hydrochloride (0.47 g, 6.7 mmol) were dissolved in tetrahydrofuran (12 ml), N, N-diisopropylethylamine (1.16 g, 9.0 mmol) 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.
S, 2'R, 3'E) -N-[-(tert-butyldimethylsilyloxy) -1-hydroxyiminomethyl-3-heptadecenyl]
Pivalamide (hydroxyl imine compound) (0.88 g) was obtained.

The hydroxylimine compound (3.1
8 g, 6.2 mmol) was dissolved in tetrahydrofuran (50 ml), and acetic anhydride (0.70 ml) and pyridine (0.70 ml, 8.7 mmol) were sequentially added under ice-cooling, followed by stirring for 20 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. After drying over magnesium sulfate, concentrate,
The residue was purified by column chromatography, and (1 ′S,
2'R, 3'E) -N- [1-acetoxyiminomethyl-2- (ter
[t-butyldimethylsilyloxy) -3-heptadecenyl] pivalamide (acetoxyimine compound) (2.53 g) was obtained. ¹ H-NMR (CDCl ₃ ) 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, 1H), 4.66 (m, 1H), 5.43 (d
d, J = 6.7,15.5Hz, 1H), 5.74 (dt, J = 15.4,6.8Hz, 1H), 6.34
(d, J = 7.3Hz, 1H), 7.75 (d, J = 4.6Hz, 1H)

The acetoxyimine compound obtained here (2.53
g, 4.6 mmol) in ethanol (200 ml)
After adding (5.48 g, 37.5 mmol), sodium borohydride (4.79 g, 127 mmol) was added under cooling at -30 ° C, the temperature was raised to 0 ° C, and the mixture was 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-butyldimethylsilyloxy) -3-heptadecenyl] pivalamide (amine) (1.32 g) was obtained.

Next, 4-dimethylaminopyridine (73 mg,
0.6 mmol) in dichloromethane (5 ml).
After adding -butyl (0.15 mg, 0.7 mmol) and then 4-pyridylmethylamine (65 mg, 0.6 mmol), the mixture was stirred at room temperature for 30 minutes. The amine compound obtained in the previous reaction (99m
g, 0.2 mmol) and stirred at room temperature for 5 hours. After concentration of 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.

The ureide form obtained here (93 mg, 0.15 mmo)
l) was dissolved in tetrahydrofuran (1.8 ml), tetrabutylammonium fluoride (1.8 ml as a 1M solution) was added under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. 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, the residue was purified by column chromatography, and (1 ′S, 2′R, 3′E) -N- [2-hydroxy-1-[[3- (4-pyridyl) Methyl) ureido] methyl]
[-3-Heptadecenyl] pivalamide (94 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.12
(s, 9H), 1.20-1.40 (m, 22H), 2.02 (m, 2H), 3.27 (dt, J = 4.9,1
4.4Hz, 1H), 3.50 (m, 1H), 3.87 (m, 1H), 4.10 (m, 1H), 4.35 (m,
1H), 5.46 (dd, J = 6.6, 15.4Hz, 1H), 5.58 (bs, 1H), 5.64 (bs, 1
H), 5.73 (dt, J = 15.4,6.6Hz, 1H), 6.65 (d, J = 6.4Hz, 1H), 7.1
9 (d, J = 4.6Hz) , 8.51 (bs, 1H) MS (SIMS) m / e: 517 (M + H) + C 30 H 52 N 4 O 3 (516)

Examples 76 to 78 The compounds of Examples 76 to 78 were prepared in the same manner as in the method of Example 75. The physicochemical data such as ¹ H-NMR spectrum and mass spectrum of each compound are shown. Example 76
Compound ¹ H-NMR (CDCl ₃ ) 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, 1H), 3.50
(m, 1H), 3.72 (bs, 1H), 3.91 (m, 1H), 4.11 (m, 1H), 4.59 (bs, 2
H), 5.28 (bs, 1H), 5.47 (dd, J = 6.6,15.4Hz, 1H), 5.75 (dt, J =
15.4,6.8Hz, 1H), 6.61 (bs , 1H) MS (SIMS) m / e: 426 (M + H) + C 24 H 47 N 3 O 3 (425)

Compound ^{1 of} Example 77 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.8 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 2.03 (m, 2H), 2.76 (d, J = 4.9Hz,
1H), 3.25 (dt, J = 14.4,4.9Hz, 1H), 3.54 (m, 1H), 3.90 (m, 1
H), 4.02 (m, 1H), 4.09 (m, 1H), 4.59 (bs, 1H), 4.96 (t, J = 5.9H
z, 1H), 5.47 (dd, J = 6.5,15.4Hz, 1H), 5.74 (dt, J = 15.4,6.6H
z, 1H), 6.71 (d , J = 6.5Hz, 1H) MS (SIMS) m / e: 462 (M + Na) + C 25 H 49 N 3 O 3 (439)

Compound ^{1 of} Example 78 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.8 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 1.37 (J = 7.1Hz, 3H), 2.01 (m, 2
H), 3.36 (dt, J = 14.5,4.9Hz, 1H), 3.56 (m, 1H), 3.94 (m, 1H),
4.17 (m, 1H), 4.34 (m, 2H), 5.50 (dd, J = 6.4,15.5Hz, 1H), 5.7
7 (dt, J = 15.0,6.7Hz, 1H), 6.01 (bs, 1H), 6.58 (d, J = 7.2Hz, 1
H), 7.45 (d, J = 8.5Hz, 1H), 7.68 (bs, 1H), 7.95 (d, J = 8.7Hz, 1
H) MS (SIMS) m / e: 596 (M + Na) + C 33 H 55 N 3 O 5 (573)

Example 79 (1 ′S, 2′R, 3′E) -N-[-1-aminomethyl-2- (tert-
Pyridine (31 mg, 0.4 mmol) was added to a solution of (butyldimethylsilyloxy)]-3-heptadecenyl] pivalamide (amine) (99 mg, 0.2 mmol) in tetrahydrofuran (4 ml), and -78
After cooling, phenyl chlorothionoformate (41 µl, 0.3 mmol) was added dropwise under cooling at ℃, and the mixture was heated to -20 ° C over 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate and concentration, the residue was purified by column chromatography to give (1'S, 2'R, 3'E)-
N- [2- (tert-butyldimethylsilyloxy) -1- (phenoxythiocarbonylaminomethyl) -3-heptadecenyl] pivalamide (42 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.09 (s, 3H), 0.88 (t, J = 7.1
Hz, 3H), 0.94 (s, 9H), 1.22 (s, 9H), 1.20-1.43 (m, 22H), 2.06
(m, 2H), 3.78-3.92 (m, 2H), 4.10 (m, 1H), 4.34 (m, 1H), 5.46
(dd, J = 6.6,15.4Hz, 1H), 5.76 (dt, J = 15.4,6.7Hz, 1H), 6.32
(d, J = 7.7Hz, 1H), 7.04 (d, J = 7.9Hz, 1H), 7.25 (d, J = 7.9Hz, 1
H), 7.38 (d, J = 7.9Hz, 1H), 7.89 (m, 1H)

The obtained compound (86 mg, 0.14 mmol) was dissolved in dimethyl sulfoxide (1 ml), and then 4-pyridylmethylamine (15 μl) was added, followed by stirring at room temperature for 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 to give (1'S, 2 '
R, 3'E) -N- [2- (tert-butyldimethylsilyloxy)
-1-[[3- (4-Pyridylmethyl) thioureido] methyl]-
3-heptadecenyl] pivalamide (thioureido) (6
1 mg).

The thioureido compound obtained here (60 mg, 0.10
mmol) was dissolved in tetrahydrofuran (1.1 ml), and tetrabutylammonium fluoride (tetrahydrofuran 1
M solution, 1.1 ml) and stirred under ice cooling for 6 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 to give (1'S, 2'R, 3'E) -N-
[2-Hydroxy-1-[[3- (4-pyridylmethyl) thioureido] methyl] -3-heptadecenyl] pivalamide (35 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.15
(s, 9H), 1.20-1.43 (m, 22H), 2.07 (m, 2H), 3.65 (m, 1H), 3.90
(bs, 1H), 4.23 (m, 1H), 4.76 (bs, 2H), 5.50 (dd, J = 6.4,15.3H
z, 1H), 5.81 (dt, J = 15.2,6.9Hz, 1H), 6.44 (bs, 1H), 7.26 (m,
2H), 8.54 (d, J = 5.6Hz, 2H) MS (SIMS) m / e: 533 (M + H) + C 30 H 52 N 4 O 2 S (532)

Example 80 3-O- (tert-butyldimethylsilyl) -2-N-isobutyryl-D-erythro-sphingosine (40 mg, 0.08 mmol) was dissolved in dichloromethane (1 ml), and the mixture was dissolved in pyridine (1-78 ° C) under cooling at -78 ° C. 66m
g, 0.83 mmol), and then trichloromethyl chloroformate (26 mg, 0.13 mmol) was added, and the temperature was raised to −20 ° C. over 1 hour. 4- (tert-Butoxycarbonylamino) aniline (87 mg, 0.42 mmol) was added dropwise to the reaction solution, and the temperature was raised to room temperature over 1 hour. The reaction solution was stirred at room temperature for 13 hours and extracted with chloroform. The extract was washed with 1M hydrochloric acid and then with a saturated aqueous solution of sodium hydrogen carbonate and then with water. After drying over magnesium sulfate and concentration, the residue was purified by column chromatography and 1-O-[[4- (tert-butoxycarbonylamino) phenyl] aminocarbonyl] -3-O- (tert-
(Butyldimethylsilyl) -2-N-isobutyryl-D-erythro-sphingosine (25 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.00 (s, 3H), 0.30 (s, 3H),
0.87 (t, J = 6.7Hz, 3H), 0.90 (s, 9H), 1.09 (d, J = 6.9Hz, 3H),
1.10 (d, J = 6.9Hz, 3H), 1.15-1.42 (m, 22H), 1.50 (s, 9H), 1.9
2-2.09 (m, 2H), 2.30 (m, 1H), 4.05-4.28 (m, 3H), 4.48 (m, 1
H), 5.42 (dd, J = 6.2,15.4Hz, 1H), 5.67 (dt, J = 15.4,6.7Hz, 1
H), 5.86 (d, J = 7.8Hz, 1H), 6.46 (s, 1H), 6.81 (s, 1H), 7.20-
7.33 (m, 4H)

The obtained compound (13 mg, 0.02 mmol) was dissolved in ethyl acetate (0.7 ml), a 4 M hydrogen chloride-ethyl acetate solution (0.3 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography to obtain 1-O-[(4-aminophenyl) aminocarbonyl] -2-N-isobutyryl-D-erythro-sphingosine (8 mg). Was. ¹ H-NMR (CDCl ₃ -CD ₃ CD) δ (ppm): 0.79 (t, J = 6.4 Hz, 3
H), 1.01 (d, J = 6.8Hz, 3H), 1.02 (d, J = 6.9Hz, 3H), 1.00-1.40
(m, 22H), 1.82-2.10 (m, 2H), 2.30 (m, 1H), 3.92-4.30 (m, 4
H), 5.37 (dd, J = 6.3,15.4Hz, 1H), 5.65 (dt, J = 15.4,6.2Hz, 1
H), 6.58 (d, J = 8.4Hz, 2H), 6.74 (bs, 1H), 7.07 (d, J = 8.4Hz, 2
H), 8.20 (s, 1H ) MS (SIMS) m / e: 504 (M + H) + C 29 H 49 N 3 O 4 (503)

Example 81 1-O-[[3- (dimethylamino) propyl] aminocarbonyl] -2-N-pivaloyl-D-erythro-sphingosine (40
mg) in chloroform (1 ml).
5 g), and then methyl iodide (0.5 ml).
Stirred for 16 hours. The precipitate is filtered, concentrated and concentrated to 1-O-
[[3- (Trimethylammonio) propyl] aminocarbonyl] -2-N-pivaloyl-D-erythro-sphingosine
Iodine salt (28 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.6 Hz, 3H), 1.20
(s, 9H), 1.20-1.44 (m, 22H), 2.02 (m, 2H), 2.13 (m, 2H), 3.38
(s, 9H), 3.38 (m, 1H), 3.56 (bs, 1H), 3.84 (m, 2H), 4.17 (m, 2
H), 4.26 (m, 1H), 4.31 (dd, J = 5.6,11.1Hz, 1H), 5.48 (dd, J =
6.8,15.4Hz, 1H), 5.80 (dt, J = 15.2,6.8Hz, 1H), 6.25 (m, 1
H), 6.36 (d, J = 8.5Hz, 1H) MS (SIMS) m / e: 526 (M-127) + C 30 H 60 IN 3 O 4 (654)

Example 82 3-O- (tert-butyldimethylsilyl) -2-N-pivaloyl
-D-erythro-sphingosine (0.20 g, 0.4 mmol) was dissolved in dichloromethane (8 ml) and cooled to -78 ° C. To this solution, pyridine (320 μl, 4.0 mmol) was added, followed by trichloromethyl chloroformate (58 μl, 0.48 mmol), and the temperature was raised to −20 ° C. over 1 hour. 2-aminoethanol (340 μl,
After adding a solution of 4.0 mmol) in dichloromethane (5 ml), the mixture was heated to room temperature over 4 hours. The reaction solution was washed sequentially with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and saturated saline.
After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography. 3-O- (tert-butyldimethylsilyl) -1-O-[(2-hydroxyethyl) aminocarbonyl] -2 -N-Pivaloyl-D-erythro-sphingosine (0.22 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.00 (s, 3H), 0.04 (s, 3H),
0.87 (t, J = 6.7Hz, 3H), 0.90 (s, 9H), 1.17 (s, 9H), 1.12-1.47
(m, 22H), 1.92-2.11 (m, 2H), 3.08-3.50 (m, 3H), 3.65 (m, 1
H), 3.78 (m, 1H), 4.10-4.35 (m, 4H), 5.24 (t, J = 5.4Hz, 1H),
5.39 (dd, J = 6.5,15.4Hz, 1H), 5.66 (dt, J = 15.4,6.6Hz, 1H),
6.12 (m, 1H)

The compound thus obtained (80 mg, 0.14 mmol) was dissolved in dichloromethane (3 ml), and then 4- (dimethylamino) pyridine (17 mg, 0.14 mmol) was added, followed by cooling to -78 ° C. Pyridine (0.1 ml) was added to the reaction, followed by trichloromethyl chloroformate (20 μl, 0.17 mmol). The reaction solution was heated to -20 ° C over 1 hour. 25% in reaction solution
Aqueous ammonia (1.4 ml) was added, and the mixture was returned to room temperature over 2 hours. The reaction solution was 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate,
Washed sequentially with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography to give 3-O- (tert-butyldimethylsilyl) -1-.
O-[[2- (carbamoyloxy) ethyl] aminocarbonyl] -2-N-pivaloyl-D-erythro-sphingosine (80
mg). ¹ H-NMR (CDCl ₃ ) δ (ppm): -0.02 (s, 3H), 0.01 (s, 3H),
0.86 (t, J = 6.8Hz, 3H), 0.87 (s, 9H), 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, 1H), 4.98 (bs, 2H), 5.30 (t, J = 5.6Hz, 1H),
5.38 (dd, J = 5.6,15.4Hz, 1H), 5.64 (dt, J = 15.4,6.6Hz, 1H),
6.09 (d, J = 7.8Hz, 1H)

The compound (50 mg, 0.08 mmol) obtained here was dissolved in tetrahydrofuran (1 ml), and tetrabutylammonium fluoride (1M solution of tetrahydrofuran,
1.1 ml) and 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-O-[[2- (carbamoyloxy) ethyl] aminocarbonyl] -2-N-pivaloyl- D-
Erythro-sphingosine (25 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.10
-1.42 (m, 22H), 1.16 (s, 9H), 1.90-2.10 (m, 2H), 3.33-3.48
(m, 2H), 3.75 (m, 1H), 4.00-4.28 (m, 5H), 4.39 (dd, J = 6.9,1
1.1Hz, 1H), 5.01 (bs, 2H), 5.43 (dd, J = 6.4,15.4Hz, 1H), 5.7
2 (dt, J = 15.4,6.5Hz, 1H), 6.33 (d, J = 7.3Hz, 1H) MS (SIMS) m / e: 514 (M + H) + C 27 H 51 N 3 O 6 (513 )

Examples 83 and 84 The compounds of Examples 83 and 84 were prepared in the same manner as in Example 82. ¹ H-NMR spectrum of each compound,
Shows physicochemical data such as mass spectra. Compound ¹ H-NMR (CDCl ₃ ) δ (ppm) of Example 83: 0.88 (t, J = 6.7 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 1.82 (m, 2H), 2.02 (m, 2H), 3.26
(m, 2H), 3.55 (d, J = 5.3Hz, 1H), 4.03-4.22 (m, 5H), 4.41 (dd,
J = 7.5,11.8Hz, 1H), 4.75 (bs, 2H), 5.23 (m, 1H), 5.47 (dd, J =
6.5,15.4Hz, 1H), 5.73 (dt, J = 15.3,6.6Hz, 1H), 6.34 (d, J =
7.4Hz, 1H) MS (SIMS) m / e: 528 (M + H) + C 28 H 53 N 3 O 6 (527)

Compound ^{1 of} Example 84 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.14
(d, J = 6.9Hz, 6H), 1.18-1.45 (m, 22H), 1.72-1.90 (m, 2H), 1.
95-2.10 (m, 2H), 2.37 (m, 1H), 2.90 (s, 6H), 3.17-3.33 (m, 2
H), 3.54 (d, J = 5.1Hz, 1H), 4.00-4.16 (m, 3H), 4.16 (t, J = 5.9
Hz, 2H), 4.42 (dd, J = 6.4,11.4Hz, 1H), 5.27 (t, J = 6.1Hz, 1
H), 5.43 (dd, J = 6.4,15.4Hz, 1H), 5.72 (dt, J = 15.4,6.6Hz, 1
H), 6.41 (d, J = 7.4Hz, 1H) MS (SIMS) m / e: 542 (M + H) + C 29 H 55 N 3 O 6 (541)

Example 85 3-O- (tert-butyldimethylsilyl) -2-N-pivaloyl
-D-erythro-sphingosine (0.23 mg, 0.45 mmol) was dissolved in tetrahydrofuran (7 ml), and 4- (dimethylamino)
Pyridine (20 mg, 0.16 mmol) and ethyl isocyanotoacetate
(0.11 mg, 0.9 mmol) and the mixture was stirred at 60 ° C. for 20 hours. After concentrating the reaction solution, the residue was treated with tetrahydrofuran (3 ml).
, And added with tetrabutylammonium fluoride (tetrahydrofuran 1M solution, 3 ml) under ice-cooling.
Stirred for 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.
-O- (ethoxycarbonylmethylaminocarbonyl) -2-
N-pivaloyl-D-erythro-sphingosine (0.20 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.7 Hz, 3H), 1.18
(s, 9H), 1,20-1.40 (m, 22H), 1.29 (t, J = 7.1Hz, 3H), 2.02 (m,
2H), 3.39 (d, J = 5.1Hz, 1H), 3.42 (d, J = 5.5Hz, 2H), 4.05-4.2
5 (m, 3H), 4.23 (q, J = 7.2Hz, 2H), 4.45 (dd, J = 6.2,11.1Hz, 1
H), 5.31 (m, 1H), 5.45 (dd, J = 6.6,15.4Hz, 1H), 5.74 (dt, J = 1
5.4,6.5Hz, 1H), 6.26 (d , J = 6.7Hz, 1H) MS (SIMS) m / e: 513 (M + H) + C 28 H 52 N 2 O 6 (512)

The obtained compound (0.20 g, 0.39 mmol) was dissolved in tetrahydrofuran (3 ml), 2M aqueous sodium hydroxide (2.8 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was acidified with 2M hydrochloric acid and extracted with ethyl acetate. After drying over magnesium sulfate and concentration, the residue was purified by column chromatography to obtain 1-O- (carboxylmethylaminocarbonyl) -2-N-pivaloyl-D-erythro-sphingosine (0.18 g). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.18
(s, 9H), 1.20-1.40 (m, 22H), 2.03 (m, 2H), 3.80-4.10 (m, 2
H), 4.10-4.60 (m, 4H), 5.45 (dd, J = 6.3, 15.4Hz, 1H), 5.76 (d
t, J = 15.4,6.6Hz, 1H) , 5.76 (m, 1H), 6.31 (d, J = 7.5Hz, 1H) MS (SIMS) m / e: 507 (M + Na) + C 26 H 48 N ₂ O ₆ (484)

Examples 86 to 93 The compounds of Examples 86 to 93 were prepared in the same manner as in the method of Example 85. The physicochemical data such as ¹ H-NMR spectrum and mass spectrum of each compound are shown. Compound ¹ H-NMR (CDCl ₃ ) δ (ppm) of Example 86: 0.87 (t, J = 6.3 Hz, 3H), 1.16
(s, 9H), 1.18-1.42 (m, 22H), 1.42-1.76 (m, 4H), 1.93-2.10
(m, 2H), 2.35 (t, J = 6.7Hz, 2H), 3.05-3.24 (m, 2H), 3.98-4.2
7 (m, 3H), 4.38 (dd, J = 7.2,11.1Hz, 1H), 5.34 (t, J = 5.6Hz, 1
H), 5.42 (dd, J = 6.2,15.4Hz, 1H), 5.72 (dt, J = 15.4,6.5Hz, 1
H), 6.43 (d, J = 7.2Hz, 1H) MS (SIMS) m / e: 527 (M + H) + C 29 H 54 N 2 O 6 (526)

Compound ^{1 of} Example 87 H-NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 0.83 (t, J = 6.2 Hz, 3
H), 1.05 (d, J = 6.5Hz, 3H), 1.08 (d, J = 6.5Hz, 3H), 1.08-1.50
(m, 22H), 1.90-2.08 (m, 2H), 2.34 (m, 1H), 4.07-4.40 (m, 4
H), 5.43 (dd, J = 6.3,15.4Hz, 1H), 5.72 (dt, J = 15.4,6.5Hz, 1
H), 6.53 (d, J = 7.9Hz, 1H), 7.43 (d, J = 8.7Hz, 2H), 7.94 (d, J =
8.7Hz, 2H) MS (SIMS) m / e: 533 (M + H) + C 30 H 48 N 2 O 6 (532)

Compound ^{1 of} Example 88 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.10
(d, J = 6.9Hz, 3H), 1.12 (d, J = 6.9Hz, 3H), 1.18-1.41 (m, 22
H), 1.95-2.05 (m, 2H), 2.39 (m, 1H), 4.15 (m, 1H), 4.18-4.27
(m, 2H), 4.36 (m, 1H), 5.48 (dd, J = 6.6,15.4Hz, 1H), 5.76 (d
t, J = 15.4,6.7Hz, 1H), 7.37 (dd, J = 7.5,7.7Hz, 1H), 7.73 (d,
J = 7.7Hz, 2H), 7.97 (s, 1H) MS (SIMS) m / e: 533 (M + H) + C 30 H 49 N 2 O 6 (532)

Compound ^{1 of} Example 89 1H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.08
-1.50 (m, 22H), 1.14 (d, J = 6.8Hz, 6H), 1.88-2.14 (m, 2H), 2.
44 (m, 1H), 4.13-4.58 (m, 4H), 5.50 (dd, J = 6.4,15.4Hz, 1H),
5.78 (dt, J = 15.4,6.4Hz, 1H), 6.41 (d, J = 7.4Hz, 1H), 7.02
(m, 1H), 7.51 (m, 1H), 8.05 (d, J = 8.0Hz, 1H), 8.34 (d, J = 8.3H
z, 1H), 10.72 (s , 1H) MS (CI) m / e: 533 (M + H) + C 30 H 48 N 2 O 6 (532)

Compound ^{1 of} Example 90 H-NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 0.84 (t, J = 6.3 Hz, 3
H), 1.06 (d, J = 6.3Hz, 3H), 1.07 (d, J = 6.3Hz, 3H), 1.05-1.43
(m, 22H), 1.88-2.07 (m, 2H), 2.32 (m, 1H), 3.95-4.42 (m, 6
H), 5.41 (dd, J = 6.1,15.4Hz, 1H), 5.70 (dt, J = 15.4,6.4Hz, 1
H), 6.21 (bs, 1H), 6.44 (d, J = 7.0Hz, 1H), 7.29 (d, J = 8.2Hz, 2
H), 7.95 (d, J = 8.2Hz, 2H) MS (SIMS) m / e: 547 (M + H) + C 31 H 50 N 2 O 6 (546)

Compound ^{1 of} Example 91 H-NMR (500 MHz, CDCl ₃ -CD ₃ OD) δ (ppm): 0.88 (t, J =
6.9Hz, 3H), 1.10 (d, J = 6.8Hz, 3H), 1.12 (d, J = 6.7Hz, 3H), 1.
19-1.40 (m, 16H), 1.95-2.08 (m, 2H), 2.36 (m, 1H), 4.07-4.2
2 (m, 2H), 4.27-4.45 (m, 4H), 5.45 (dd, J = 6.5,15.3Hz, 1H),
5.74 (dt, J = 15.3,6.8Hz, 1H), 7.34 (d, J = 8.0Hz, 2H), 8.00
(d, J = 8.0Hz, 2H ) MS (SIMS) m / e: 505 (M + H) + C 28 H 44 N 2 O 6 (504)

Compound ^{1 of} Example 92 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.6 Hz, 3H), 1.22
(s, 9H), 1.20-1.40 (m, 22H), 2.06 (m, 2H), 3.42-3.66 (m, 2
H), 4.03 (m, 1H), 4.27 (m, 1H), 5.53 (dd, J = 6.5,15.4Hz, 1H),
5.83 (dt, J = 15.4,6.6Hz, 1H), 6.43 (bs, 1H), 6.57 (d, J = 7.1H
z, 1H), 7.63 (d, J = 8.5Hz, 1H), 8.04 (d, J = 8.6Hz, 1H), 8.55 (b
s, 1H), 12.0 (bs , 1H) MS (SIMS) m / e: 546 (M + H) + C 31 H 51 N 3 O 5 (545)

Compound ^{1 of} Example 93 ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.86 (t, J = 6.7 Hz, 3H), 1.07
(s, 9H), 1.20-1.40 (m, 22H), 1.96 (m, 2H), 2.05-2.12 (m, 2
H), 3.73 (m, 1H), 3.93 (m, 1H), 5.02 (bs, 1H), 5.39 (dd, J = 6.
5,15.4Hz, 1H), 5.59 (dt, J = 15.3,6.7Hz, 1H), 5.65 (bs, 2H),
5.88 (t, J = 5.7Hz, 1H), 6.95 (d, J = 8.5Hz, 1H), 7.21 (s, 2H),
8.24 (d, J = 8.0Hz, 1H), 8.39 (s, 1H) MS (SIMS) m / e: 560 (M + H) + C 31 H 53 N 5 O 4 (559)

Example 94 2-N- (tert-butoxycarbonyl) -1-O-pivaloyl-
D-erythro-sphingosine (compound of Reference Example 5) (1.2 g,
2.5 mmol) was dissolved in N, N-dimethylformamide (13 ml), imidazole (1.4 g, 20 mmol) was added, and then tert-butyldimethylsilyl chloride (0.88 g, 5.8 mmol) was added.
Stir at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography,
N- (tert-butoxycarbonyl) -3-O- (tert-butyldimethylsilyl) -1-O-pivaloyl-D-erythro-sphingosine (1.5 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.00 (s, 3H), 0.03 (s, 3H),
0.87 (t, J = 6.6Hz, 3H), 0.88 (s, 9H), 1.07-1.45 (m, 22H), 1.1
9 (s, 9H), 1.42 (s, 9H), 1.93-2.09 (m, 2H), 3.85 (m, 1H), 4.04
-4.30 (m, 3H), 4.64 (d, J = 9.3Hz, 1H), 5.39 (dd, J = 6.6,15.5H
z, 1H), 5.65 (dt, J = 15.5,6.5Hz, 1H)

The compound obtained here (1.3 g, 2.2 mmol) was dissolved in dehydrated methanol (16 ml) and 1,8-diazabicyclo
[5.4.0] undec-7-ene (0.50 g, 3.3 mmol) was added,
Stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography, and 2-N- (tert-
Butoxycarbonyl) -3-O- (tert-butyldimethylsilyl) -D-erythro-sphingosine (1.1 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.02 (s, 3H), 0.07 (s, 3H),
0.87 (t, J = 6.8Hz, 3H), 0.89 (s, 9H), 1.10-1.48 (m, 22H), 1.4
5 (s, 9H), 1.94-2.10 (m, 2H), 3.00 (d, J = 9.6Hz, 1H), 3.44 (m,
1H), 3.56 (m, 1H), 4.03 (m, 1H), 4.47 (m, 1H), 5.34 (d, J = 7.7H
z, 1H), 5.44 (dd, J = 6.1,15.5Hz, 1H), 5.71 (dt, J = 15.5,6.6H
z, 1H)

The obtained compound (0.15 g, 0.29 mmol) was dissolved in dichloromethane (6 ml), and then 4- (dimethylamino) pyridine (35 mg, 0.29 mmol) was added. After adding trichloromethyl (86 mg, 0.44 mmol),
The temperature was raised to -20 ° C over 1 hour. 25%
Aqueous ammonia (1 ml) was added dropwise, and the temperature was raised to room temperature over 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography and 2-N- (tert-butoxycarbonyl) -3-O- (tert-butyldimethylsilyl)-
1-O-carbamoyl-D-erythro-sphingosine (0.15
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): -0.01 (s, 3H), 0.03 (s, 3H),
0.82-0.93 (m, 9H), 0.87 (s, 9H), 1.13-1.52 (m, 22H), 1.43
(s, 9H), 1.92-2.09 (m, 2H), 3.77 (bs, 1H), 4.05-4.30 (m, 3
H), 4.62-4.85 (bs, 3H), 5.38 (dd, J = 6.6,15.4Hz, 1H), 5.65
(dt, J = 15.4,6.6Hz, 1H)

The obtained compound (0.13 g, 0.24 mmol) was dissolved in tetrahydrofuran (1.2 ml), tetrabutylammonium fluoride (tetrahydrofuran 1M solution, 2.0 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 6 hours. did. 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 2-N- (tert-butoxycarbonyl) -1-O-carbamoyl-D-erythro-sphingosine (0.15 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.4 Hz, 3H), 1.05
-1.42 (m, 22H), 1.44 (s, 9H), 1.95-2.11 (m, 2H), 2.73 (bs, 1
H), 3.86 (bs, 1H), 4.04-4.18 (m, 2H), 4.34 (dd, J = 6.0,11.5H
z, 1H), 4.67 (bs, 2H), 4.89 (bs, 1H), 5.48 (dd, J = 6.6,15.0H
z, 1H), 5.74 (dt , J = 15.0,6.0Hz, 1H) MS (SIMS) m / e: 443 (M + H) + C 24 H 46 N 2 O 5 (442)

Example 95 The compound of Example 95 was prepared in the same manner as in the method of Example 94. The physicochemical data such as ¹ H-NMR spectrum and mass spectrum of each compound are shown. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.86 (t, J = 6.4 Hz, 3H), 1.11
-1.48 (m, 22H), 1.41 (s, 9H), 1.92-2.10 (m, 2H), 3.17 (bs, 1
H), 3.87 (m, 1H), 4.05-4.42 (m, 5H), 5.00 (d, J = 8.3Hz, 1H),
5.47 (dd, J = 6.4,15.4Hz, 1H), 5.66 (bs, 1H), 5.72 (dt, J = 15.
4,6.3Hz, 1H), 7.19 (d , J = 5.9Hz, 2H), 8.52 (d, J = 5.9Hz, 2H) MS (SIMS) m / e: 534 (M + H) + C 30 H 51 N ₃ O ₅ (533)

Example 96 2-N- (tert-butoxycarbonyl) -1-O-carbamoyl
To -D-erythro-sphingosine (20 mg), trifluoroacetic acid (0.5 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes.
The reaction solution was concentrated under reduced pressure, ethanol was added to the residue,
Concentrated again. 4M hydrogen chloride-ethyl acetate solution (0.
5 ml), and concentrated under reduced pressure to give 1-O-carbamoyl-D-
Erythro-sphingosine hydrochloride (12 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.84 (t, J = 6.4 Hz, 3H), 1.08
-1.43 (m, 22H), 1.93-2.11 (m, 2H), 3.37 (m, 1H), 4.10 (dd, J =
8.9,12.0Hz, 1H), 4.29 (dd, J = 3.4,12.0Hz, 1H), 4.41 (m, 1
H), 5.39 (dd, J = 6.2,15.2Hz, 1H), 5.83 (dt, J = 15.2,6.8Hz, 1
H) MS (SIMS) m / e: 343 (M + H) + C 19 H 38 N 2 O 3 (342)

Examples 97 and 98 The compounds of Examples 97 and 98 were prepared in the same manner as in the method of Example 96. ¹ H-NMR spectrum of each compound,
Shows physicochemical data such as mass spectra. Example 9
7 Compound ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ (ppm): 0.79 (t, J = 6.2 Hz, 3
H), 1.00-1.42 (m, 22H), 1.88-2.06 (m, 2H), 3.37 (m, 1H), 4.1
3 (m, 1H), 4.22-4.40 (m, 2H), 4.50 (bs, 2H), 5.35 (dd, J = 6.4,
15.3Hz, 1H), 5.79 (dt, J = 15.3,6.8Hz, 1H), 7.89 (d, J = 5.4H
z, 2H), 8.64 (d , J = 5.4Hz, 2H) MS (SIMS) m / e: 434 (M + H) + C 25 H 43 N 3 O 3 (433)

Compound ^{1 of} Example 98 1H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.03
-1.42 (m, 22H), 1.88-2.07 (m, 2H), 3.53 (m, 1H), 4.20-4.60
(m, 3H), 5.41 (dd, J = 6.6,15.4Hz, 1H), 5.28 (dt, J = 15.4,6.8
Hz, 1H), 6.98 (m, 1H), 7.21 (m, 1H), 7.30 (d, J = 8.0Hz, 1H), 7.
59 (s, 1H), 7.97 (d, J = 7.2Hz, 1H) MS (CI) m / e: 453 (M + H) + C 25 H 41 ClN 2 O 3 (452)

Example 99 2-N- (tert-butoxycarbonyl) -3-O- (tert-butyldimethylsilyl) -1-[(4-pyridyl) methylaminocarbonyl] -D-erythro-sphingosine (46 mg) To the mixture was added trifluoroacetic acid (1 ml) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, ethanol was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in tetrahydrofuran, 1-hydroxybenzotriazole monohydrate (15 mg) and N- (tert-butoxycarbonyl) glycine (19 m
g), and a solution of triethylamine (35 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (21 mg) in chloroform (1 ml) was added under ice-cooling. The mixture was stirred for 3 hours while warming to room temperature. did. 1M hydrochloric acid was added to the reaction solution,
Extracted with chloroform. The extract was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by column chromatography and 2-N- [N- (tert-butoxycarbonyl) glycyl] -3-O- (tert-butyldimethylsilyl) -1-O- [ (4-pyridyl) methylaminocarbonyl]-
D-erythro-sphingosine (25 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): -0.01 (s, 3H), 0.02 (s, 3H),
0.86 (t, J = 6.8Hz, 3H), 0.88 (s, 9H), 1.10-1.50 (m, 22H), 1.4
2 (s, 9H), 1.88-2.02 (m, 2H), 3.67 (dd, J = 5.5,16.8Hz, 1H),
3.82 (dd, J = 6.3,16.8Hz, 1H), 4.06-4.28 (m, 4H), 4.34 (d, J =
6.2Hz, 2H), 5.09 (bt, 1H), 5.38 (dd, J = 6.1,15.3Hz, 1H), 5.5
0-5.75 (m, 2H), 6.35 (d, J = 7.2Hz, 1H), 7.19 (d, J = 5.9Hz, 2
H), 8.53 (d, J = 5.9Hz, 2H)

The compound (22 mg) obtained here was dissolved in tetrahydrofuran (0.5 ml), tetrabutylammonium fluoride (tetrahydrofuran 1M solution, 0.5 ml) was added under ice-cooling, and the mixture was heated at the same temperature for 4 hours and then at room temperature. For 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. After washing with water
After drying over magnesium sulfate and evaporating the solvent, the residue was purified by column chromatography to give 2-N- [N- (ter
[t-butoxycarbonyl) glycyl] -1-O-[(4-pyridyl) methylaminocarbonyl] -D-erythro-sphingosine (17 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.4 Hz, 3H), 1.10
-1.48 (m, 22H), 1.42 (s, 9H), 1.91-2.10 (m, 2H), 3.28 (bs, 1
H), 3.63-3.86 (m, 2H), 4.04-4.40 (m, 6H), 5.30 (bt, 1H), 5.4
5 (dd, J = 5.7,15.4Hz, 1H), 5.74 (dt, J = 15.4,5.7Hz, 1H), 5.8
7 (t, J = 6.1Hz, 1H), 6.78 (d, J = 6.8Hz, 1H), 7.13-7.23 (m, 2
H), 8.49-8.59 (m, 2H ) MS (SIMS) m / e: 591 (M + H) + C 32 H 54 N 4 O 6 (590)

Example 100 To a mixture of 2-N- [N- (tert-butoxycarbonyl) glycyl] -1-[(4-pyridyl) methylaminocarbonyl] -D-erythro-sphingosine (12 mg) under ice cooling. Acetic acid (0.5m
l) was added and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, ethanol was added to the residue, and the mixture was concentrated again. A 4M hydrogen chloride-ethyl acetate solution was added to the residue, and the mixture was concentrated under reduced pressure. The residue was purified by thin-layer chromatography.
2-N-glycyl-1-O-[(4-pyridyl) methylaminocarbonyl] -D-erythro-sphingosine (8 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (t, J = 6.9 Hz, 3H), 1.19
-1.41 (m, 22H), 1.98-2.07 (m, 2H), 3.69-3.83 (m, 2H), 3.93
(m, 1H), 4.16-4.28 (m, 2H), 4.43 (m, 1H), 4.46 (d, J = 17.9Hz,
1H), 4.65 (d, J = 17.9Hz, 1H), 5.47 (dd, J = 6.4,15.3Hz, 1H),
5.77 (dt, J = 15.3,6.7Hz, 1H), 8.05 (d, J = 6.0Hz, 2H), 8.74
(d, J = 6.0Hz, 2H ) MS (SIMS) m / e: 491 (M + H) + C 27 H 46 N 4 O 4 (490)

Examples 101 and 102 Examples 101 and 10 were carried out in the same manner as in Example 100.
Two compounds were prepared. The physicochemical data such as ¹ H-NMR spectrum and mass spectrum of each compound are shown. Compound ^{1 of} Example 101 H-NMR (CDCl ₃ ) δ (ppm): 0.85 (t, J = 6.4 Hz, 3H), 1.12
-1.47 (m, 22H), 1.39 (s, 3H), 1.42 (s, 9H), 1.47 (s, 3H), 1.89
-2.08 (m, 2H), 3.91 (bs, 1H), 4.05-4.38 (m, 6H), 5.08 (s, 1
H), 5.42 (dd, J = 6.1,15.4Hz, 1H), 5.72 (dt, J = 15.4,6.1Hz, 1
H), 5.93 (t, J = 6.0Hz, 1H), 6.83 (d, J = 7.7Hz, 1H), 7.19 (d, J =
5.9Hz, 2H), 8.50 (d , J = 5.9Hz, 2H) MS (SIMS) m / e: 619 (M + H) + C 34 H 58 N 4 O 6 (618)

Compound ^{1 of} Example 102 ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.85 (t, J = 6.3 Hz, 3H), 1.
10-1.40 (m, 22H), 1.43 (s, 3H), 1.48 (s, 3H), 1.85-2.02 (m, 2
H), 3.85-4.10 (m, 3H), 4.28-4.50 (m, 3H), 5.36 (dd, J = 4.2,1
5.0Hz, 1H), 5.89 (dt, J = 15.0,6.3Hz, 1H), 7.85 (d, J = 6.1Hz,
2H), 7.92 (d, J = 5.7Hz, 1H), 8.12 (d, J = 7.1Hz, 1H), 8.27 (bs,
3H), 8.82 (d, J = 5.7Hz, 2H) MS (SIMS) m / e: 519 (M + H) + C 29 H 50 N 4 O 4 (518)

Example 103 2-N- (tert-butoxycarbonyl) -1-O-[(4-pyridyl) methylaminocarbonyl] -D-erythro-sphingosine (65 mg, 0.11 mmol) was cooled with ice and trifluoro Acetic acid (1 ml)
Was added and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, ethanol was added to the residue, and the mixture was concentrated again. The residue was dissolved in tetrahydrofuran (1 ml), triethylamine (23 mg, 0.23 mmol) was added under ice cooling, and then ethyl glyoxylate (14 mg, 0.1 mmol) was added dropwise, followed by stirring at the same temperature for 2 hours. Ethyl acetate was added to the reaction solution for extraction, and the organic layer was washed successively with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by column chromatography to obtain (1 ′S, 2′R, r3′E) -N- [2
-Hydroxy-1-[(4-pyridyl) methylaminocarbonyloxymethyl] -3-heptadecenyl] oxamic acid ethyl ester (23 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.87 (t, J = 6.2 Hz, 3H), 1.10
-1.42 (m, 22H), 1.36 (t, J = 7.1Hz, 3H), 1.90-2.10 (m, 2H), 3.
00 (bs, 1H), 4.12-4.48 (m, 8H), 5.40-5.58 (m, 2H), 5.76 (dt,
J = 15.2,6.5Hz, 1H), 7.19 (d, J = 5.6Hz, 2H), 7.53 (d, J = 7.6H
z, 1H), 8.52 (d , J = 5.6Hz, 2H) MS (SIMS) m / e: 534 (M + H) + C 29 H 47 N 3 O 6 (533)

Example 104 Ethyl (1 ′S, 2′R, 3′E) -N- [2-hydroxy-1-[(4-pyridyl) methylaminocarbonyloxymethyl] -3-heptadecenyl] oxamic acid (Example 103
(18 mg, 0.034 mmol) was dissolved in a mixed solvent of methanol (1.5 ml) and tetrahydrofuran (1 ml), 2M aqueous sodium hydroxide was added, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was adjusted to pH 4.0 by adding 1 M hydrochloric acid, and then concentrated under reduced pressure. The residue was extracted with a mixed solvent of chloroform-methanol, and the filtrate obtained by removing insolubles by filtration was concentrated under reduced pressure to give (1 ′S, 2′R, 3′E) -N- [2-hydroxy-. 1-[(4-
Pyridyl) methylaminocarbonyloxymethyl] -3-heptadecenyl] oxamic acid (10 mg) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.85 (t, J = 6.9 Hz, 3H), 1.
05-1.46 (m, 22H), 1.85-2.02 (m, 2H), 3.86-4.11 (m, 3H), 4.2
6-4.45 (m, 3H), 5.30 (bt, 1H), 5.35 (dd, J = 6.3,15.4Hz, 1H),
5.56 (dt, J = 15.4,6.8Hz, 1H), 7.69 (bs, 2H), 7.92 (d, J = 5.9H
z, 1H), 8.54 (d , J = 8.8Hz, 1H), 8.73 (bs, 2H), 13.40 (bs, 1H) MS (SIMS) m / e: 507 (M + H) + C 27 H 43 N ₃ O ₆ (505)

Test Example [Neutral sphingomyelinase inhibition test] (Preparation of enzyme) 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 u
120 ml of nit / ml aprotinin, 0.1 mM PMSF, 10 μg / ml leupeptin) were added, and the brain cells were crushed using a homogenizer under cooling at 4 ° C. Next, the cell lysate was cooled at 4 ° C,
After centrifugation at 600 xg for 10 minutes, the supernatant was further
Centrifugation was performed at 00 × g for 15 minutes. Finally, the obtained supernatant was subjected to ultracentrifugation at 100,000 × g for 60 minutes, and the precipitate was used as a microsomal fraction. This fraction was further subjected to buffer B (10% sucrose, 20 mM Hepes-KOH (pH 7.4), 40 unit / ml
Aprotinin, 0.2mM PMSF, 20μg / ml leupeptin) 5m
The suspension was re-suspended in 1 l, stored frozen at -80 ° C, and adjusted to a protein concentration of 2 mg / ml with buffer C (20 mM Hepes-KOH (pH 7.4) -2 mM MgCl ₂ ) at the time of use. (Preparation of substrate solution) 26.5 mg of sphingomyelin (cow,
Brain; Sigma) was dissolved in 375 μl of 10 w / v% Triton X,
14.6 ml of buffer C was added to obtain a sphingomyelin solution. Freshly add 400 μl of N-methyl- ^14C- sphingomyelin (bovine, 48 mCi / mmol, 25 μCi / ml; Amersham)
Was evaporated to dryness, the residue was redissolved in 50 μl of ethanol, and the above-mentioned 12 ml of sphingomyelin solution was added to obtain a substrate solution. (Test method) The sphingomyelinase reaction was performed by using 10 µl of a dimethyl sulfoxide solution of a sample, buffer D (20 mM Hep.
es-KOH (pH7.4) -2mM MgCl ₂ , 0.08w / v% Triton X) 70μ
After mixing 10 μl of enzyme solution and 10 μl of substrate solution,
Performed by incubating for hours. After the reaction was completed, 500 μl of chloroform: methanol (2: 1, v / v) was added to carry out an extraction operation, and 150 μl of the obtained aqueous layer was mixed with 2 ml of aquasol 2 to obtain ¹⁴ C as a reaction product. -Phosphorylcholine was measured. The sphingomyelinase activity was calculated as a value obtained by subtracting the measured value when no enzyme was added.

Table 2 shows the results.

[0177]

[Table 8]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61K 31/275 A61K 31/275 31/41 31/41 31/416 31/416 31/4164 31/4164 31 / 426 31/426 31/433 31/433 31/4402 31/4402 31/4406 31/4406 31/4409 31/4409 31/47 31/47 31/4965 31/4965 31/5375 31/5375 A61P 3 / 04 A61P 3/04 3/10 3/10 9/10 9/10 101 101 13/12 13/12 25/14 25/14 25/16 25/16 25/28 25/28 29/00 29/00 35 / 00 35/00 37/00 37/00 43/00 111 43/00 111 C07C 271/16 C07C 271/16 271/18 271/18 271/20 271/20 271/22 271/22 271/28 271 / 28 275/20 275/20 275/42 275/42 311/53 311/53 323/43 323/43 C07D 213/36 C07D 213/36 213/75 213/75 215/38 215/38 231/56 231 / 56 Z 233/64 105 233/64 105 241/20 241/20 257/04 257/04 C 277/48 277/48 285/135 295/12 Z 295/12 285/12 F (72) Inventor Kenichi Goda 2-5-2-2 Jinshu-cho, Toyonaka-shi, Osaka (72) Inventor Minoru Taguchi 3-24-1, Takada, Toshima-ku, Tokyo Taisho Seiyaku Co., Ltd.

Claims (3)

[Claims] 1. A compound of the general formula (I) [Wherein, R ¹ represents a hydrogen atom, a C _2-20 alkanoyl group, a benzoyl group, a “halogen atom, a C _1-5 alkyl group, a hydroxyl group, a C _1-5 alkoxy group, a C _2-5 alkanoyl group, a carboxyl group, A C _2-5 alkoxycarbonyl group, an amino group,
An amino group substituted with one or two C _1-5 alkyl groups, a C _2-5 alkanoylamino group, a C _2-5 alkoxycarbonylamino group, a C _1-5 substituted with 1 to 5 halogen atoms A benzoyl group substituted with an alkyl group, a cyano group, a nitro group, a mercapto group or a C _1-5 alkylthio group, a C _4-8 cycloalkylcarbonyl group, a C _2-20 alkoxycarbonyl group, and a compound of the formula —COC (R ³ ) ₂ NHR ⁴ (wherein
R ³ is a hydrogen atom or a C _1-5 alkyl group, and R ⁴ is a hydrogen atom or a C _2-5 alkoxycarbonyl group. Or a group represented by the formula —COCO ₂ R ³ , wherein R ³ is a hydrogen atom or a C _1-5 alkyl group.
R ² is a hydrogen atom, a C _1-8 alkyl group, a formula — (CH ₂ ) _n R
⁵ (wherein R ⁵ represents a hydroxyl group, an amino group, an amino group substituted with 1 to 3 C _1-5 alkyl groups, a carboxyl group,
_2-5 alkoxycarbonyl group, carbamoyl group, aminocarbonyl group substituted with one or two _C1-5 alkyl groups, carbamoyloxy group, aminocarbonyl substituted with one or two _C1-5 alkyl groups Oxy group, phenyl group, "halogen atom, _C1-5 alkyl group, hydroxyl group, _C1-5 alkoxy group, _C2-5 alkanoyl group, carboxyl group, _C2-5 alkoxycarbonyl group, amino group,
An amino group substituted with one or two C _1-5 alkyl groups, a C _2-5 alkanoylamino group, a C _2-5 alkoxycarbonylamino group, a C _1-5 substituted with 1 to 5 halogen atoms Alkyl group, cyano group, nitro group, ureido group,
A phenyl group, a pyridyl group, or a pyridyl group substituted with a C _1-5 alkoxy group, which is substituted with a ureido group, a mercapto group, or a C _1-5 alkylthio group substituted with one or two C _1-5 alkyl groups. , A pyrazyl group, a pyrrolidyl group, a piperidyl group, a piperazyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, a tetrazolyl group, a quinolyl group or a 1H-indazolyl group, and n is an integer of 0 to 5. . Group or wherein -SO _m R ⁶ (wherein represented by), R ⁶ is a phenyl group or "halogen atom, C _1-5 alkyl groups, hydroxyl group, C _1-5 alkoxy, C _2-5 alkanoyl group, a carboxyl Group, C
_2-5 alkoxycarbonyl group, amino group, amino group substituted by one or two C _1-5 alkyl groups, C _2-5 alkanoylamino group, C _2-5 alkoxycarbonylamino group, A C _1-5 alkyl group, a cyano group, a nitro group, a ureido group, a ureido group substituted with one or two C _1-5 alkyl groups, a mercapto group or a C _1-5 alkylthio group substituted with ₅ ” And m is 0, 1 or 2. Z is NR ⁷ (where R ⁷ is a hydrogen atom, a hydroxyl group or a C _1-5 alkyl group), and Y is an oxygen atom or NR ⁸ (R ⁸ is a hydrogen atom , A hydroxyl group or a C _1-5 alkyl group), and W is an oxygen atom or a sulfur atom;
k is an integer of 1 to 20. Or a pharmaceutically acceptable salt thereof. 2. In the general formula (I), R ¹ is an isobutyryl group or a pivaloyl group, Y is an oxygen atom,
The sphingosine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Z is NH and k is 13. 3. The sphingosine derivative according to claim 1, wherein R ¹ is an isobutyryl group or a pivaloyl group, Y and Z are NH, and k is 13, in the general formula (I). Salt.