JP2003081985A - Sphingomyelin anaologue and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound having a sphingomyelinase inhibiting activity. SOLUTION: This new sphingomyelin analogue is expressed by formula (1) (wherein, R<1> , R<2> are each the same or different, and a 1-20C alkyl or the like, which may have unsaturated bond), and an efficient method for producing the same is also provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel sphingomyelin analog which is expected as a substance that acts on the catalytic site of sphingomyelinase, which is a phospholipid hydrolase, and competitively inhibits its substrate, and its production. Concerning the law.

[0002]

BACKGROUND OF THE INVENTION Sphingomyelinase is an enzyme that hydrolyzes a phosphate ester portion of sphingomyelin, and by this action, sphingomyelin is decomposed into ceramide and phosphocholine. It has been clarified that ceramide, which is a metabolite, functions as a signal transduction factor for cell differentiation and apoptosis derivatives and inhibits the enzyme activity of protein kinase C.
Since sphingolipids such as sphingomyelin are considered to play an important role in the cellular functions such as proliferation, differentiation and apoptosis as second messengers, the importance of sphingomyelinase has been noted and its action mechanism Clarification is desired. Sphingomyelinase is the extent to which only a small part of the primary structure has been elucidated in many types, and the details of its higher-order structure and hydrolysis mechanism have not been clarified. It is desired to develop a substance that can be used as an agent, and to mass-produce it at low cost.

[0003]

The present inventors have succeeded in synthesizing a novel sphingomyelin analog represented by the following formula (1). It was also found that the sphingomyelin analog of the present invention can be efficiently synthesized by using a compound represented by the following formula (2) obtained from γ-butyrolactone as a starting material. When synthesizing an optically active compound, it is important that the operation is simple, the yield is good, and the optical purity is kept high. As a production method that meets such demands, there is a method of synthesizing a chiral intermediate which is easily chemically converted and producing an intended product through this compound. The important point in this method is that this chiral intermediate is easy to handle in terms of operation and is inexpensive and available in large quantities. The compound according to the present invention often exists as an optical isomer, and the method of the present invention also satisfies these needs. That is, the present invention particularly relates to a sphingomyelin analog that is expected as a substance that acts on the catalytic site of sphingomyelinase, which is a phospholipid hydrolase, and inhibits the substrate antagonistically, and a method for producing the same, particularly efficient production. To provide the law. The present invention is represented by the following general formula (1)

[0004]

[Chemical formula 26] (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. The sphingomyelin analog represented by Among the groups represented by R ¹ , specific examples of the alkyl group having 1 to 20 carbon atoms include a methyl group,
Examples include an ethyl group, a propyl group, a butyl group, a pentyl group, a heptyl group, an octyl group, a decyl group, an undecyl group, a heptadecyl group, an allyl group, and a 1-pentadecenyl group, and a preferable group is a heptyl group or a 1-pentadecenyl group. is there. Among the groups represented by R ¹ , specific examples of the aryl group include a phenyl group, a 4-methoxyphenyl group, and a 4 group.
-Ethoxyphenyl group is mentioned, and a preferable group is a phenyl group. Among the groups represented by R ¹ , specific examples of the aryl group-substituted alkyl group having 1 to 6 carbon atoms include a benzyl group and a 1-phenethyl group, and a preferable group is the benzyl group.

Of the groups represented by R ² above, the number of carbon atoms is 1 to
Specific examples of the alkyl group of 20 include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a heptyl group,
Examples thereof include an octyl group, a decyl group, an undecyl group, a heptadecyl group, an allyl group, and a 1-pentadecenyl group. Preferred groups are a heptyl group and a heptadecyl group. R above
Among the groups represented by ² , specific examples of the aryl group include:
Examples thereof include a phenyl group, a 4-methoxyphenyl group, and a 4-ethoxyphenyl group, and a preferable group is the phenyl group.
Of the groups represented by R ² , the aryl group-substituted carbon number 1
Specific examples of the alkyl group of ~ 6 include benzyl group, 1-
A phenethyl group and the like, and a preferable group is a benzyl group.

Among the compounds of the present invention represented by the general formula (1), preferred compounds are those in which R ¹ is methyl group, ethyl group, propyl group, butyl group, pentyl group, heptyl group, octyl group, decyl group, undecyl group. , Heptadecyl group, allyl group, 1-pentadecenyl group, phenyl group, 4-methoxyphenyl group, 4-ethoxyphenyl group, benzyl group,
1-phenethyl group, R ² is methyl group, ethyl group, propyl group, butyl group, pentyl group, heptyl group, octyl group, decyl group, undecyl group, heptadecyl group, allyl group, 1-pentadecenyl group, phenyl group , 4-methoxyphenyl group, 4-ethoxyphenyl group. Particularly preferred compounds are those wherein R ¹ is a heptyl group, 1-
A pentadecenyl group, a phenyl group, a benzyl group, R
^The compound ² is a pentyl group, a heptyl group, or a heptadecyl group.

The present invention also relates to a process for producing the compound represented by the general formula (1) and intermediates thereof. The production method of the compound (1) of the present invention is described in detail below. The manufacturing process is shown in Scheme 1 below.

[0008]

Embedded image Scheme 1 (In the above formula, R ³ means a hydroxyl protecting group, R ⁴ means an amino protecting group, R ⁵ means an aralkyl group or an alkenyl group, and R ⁶ is an alkyl group having 1 to ⁶ carbon atoms or It means an aralkyl group, and R ¹ and R ² are the same as above.)

The method for producing the compound (1) will be described below. First, the compound represented by the general formula (3) is obtained by protecting the hydroxyl group of the compound represented by the general formula (2). Examples of the protective group include ether-based protective groups such as tetrahydropyran, methoxymethyl and benzyl, and silyl-based protective groups such as trimethylsilyl and t-butyldimethylsilyl. Tetrahydropyran is preferred. Examples of the solvent used include hydrocarbon solvents such as hexane, benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, ester solvents such as ethyl acetate and butyl acetate,
Tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, ether solvent such as triglyme diethylene glycol monomethyl ether, acetone, methyl ethyl ketone, ketone solvent such as methyl isobutyl ketone, nitrile solvent such as acetonitrile, dichloromethane, Examples of the solvent include halogen-based solvents such as 1,2-dichloroethane, an aqueous medium, and a mixed solvent thereof. The reaction temperature is from 0 ° C to the reflux temperature of the solvent, preferably from 0 ° C to room temperature.

The compound represented by the general formula (4) can be obtained by protecting the amino group of the compound represented by the general formula (3). As the amino-protecting group, any known amino-protecting group can be used, but preferably a methoxycarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, an ethoxycarbonyl group, an acetyl group,
Examples thereof include a trifluoroacetyl group and a benzyl group, with the benzyl group being particularly preferred. Then, the compound represented by the general formula (4) is hydrolyzed with a base to open the ring to obtain the compound represented by the general formula (5). Examples of the base to be used include alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate, alkali metal or alkaline earth such as sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide. Examples thereof include metal hydroxides and the like, with preference given to alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide.
The amount of the base used is 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to the substrate.

The solvent used is, for example, hexane,
Hydrocarbon solvents such as benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, ester solvents such as ethyl acetate and butyl acetate, tetrahydrofuran, 1,4-dioxane, 1,
Ether solvent such as 2-dimethoxyethane, diglyme, triglyme diethylene glycol monomethyl ether, ketone solvent such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitrile solvent such as acetonitrile, halogen solvent such as dichloromethane and 1,2-dichloroethane , An aqueous medium, a mixed solvent thereof, and the like. The compound represented by the general formula (6) can be obtained by reacting the obtained general formula (5) with an acid halide in the presence of a base to cause amidation.

Examples of the acid halide used include acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, caproyl chloride, benzoyl chloride and other cyclic or acyclic acyl chlorides having 1 to 20 carbon atoms. The amount of acid halide used is 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to the substrate. Examples of the solvent used include hydrocarbon solvents such as hexane, benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide,
Ethyl acetate, ester solvents such as butyl acetate, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, ether solvents such as triglyme diethylene glycol monomethyl ether, acetone,
Examples thereof include ketone-based solvents such as methyl ethyl ketone and methyl isobutyl ketone, nitrile-based solvents such as acetonitrile, halogen-based solvents such as dichloromethane and 1,2-dichloroethane, aqueous media, and mixed solvents thereof.
As the base used, sodium carbonate, potassium carbonate,
Examples thereof include alkali metal or alkaline earth metal carbonates such as calcium carbonate and cesium carbonate, and alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide. Preferred are alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate. The amount of the base used is 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to the substrate.

The compound represented by the general formula (7) is obtained by protecting the secondary hydroxyl group of the obtained compound represented by the general formula (6). Examples of the protective group include ether-based protective groups such as tetrahydropyran, methoxymethyl and benzyl, and silyl-based protective groups such as trimethylsilyl and t-butyldimethylsilyl. Of these, a benzyl group is preferred. The compound represented by the general formula (8) is obtained by deprotecting the primary hydroxyl group of the compound represented by the general formula (7). Deprotection is performed by a known method depending on the type of protecting group. For example, when the protecting group is tetrahydropyran, deprotection may be performed in a solvent such as methanol in the presence of an acid catalyst such as p-toluenesulfonic acid. it can. In the case of benzyl, deprotection can be performed by catalytic reduction in a solvent under a hydrogen atmosphere or alkali metal-ammonia reduction. A compound represented by the general formula (9) is obtained by oxidizing an alcohol of the compound represented by the general formula (8) to a carboxylic acid. As a method of oxidizing, oxidation using chromic acids, oxidation using potassium permanganate,
It can be oxidized by a known method such as oxidation using ruthenium or oxidation using a nitroxyl compound, but a preferable method is, for example, a method using pyridinium dichromate in dimethylformamide.

The carboxylic acid of the compound represented by the general formula (9) is subjected to a Curtius rearrangement reaction, that is, converted into a protected amine by using, for example, diphenylphosphoryl azide in the presence of an alcohol, whereby the general formula ( 1
A compound represented by 0) is obtained. As the solvent to be used, hydrocarbon solvents such as hexane, benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, tetrahydrofuran,
Examples include ether solvents such as 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, diglyme, triglyme and diethylene glycol monomethyl ether, and mixed solvents thereof. Reaction temperature is 0 ℃
To the reflux temperature of the solvent, preferably room temperature to the reflux temperature of the solvent. As the alcohol used, methanol, ethanol, allyl alcohol, propanol,
Examples thereof include alcohols having 1 to 6 carbon atoms such as t-butanol, and substituted and unsubstituted benzyl alcohols such as benzyl alcohol, chlorobenzyl alcohol and nitrobenzyl alcohol. A preferred alcohol is benzyl alcohol, which is easy to remove.

The compound represented by the general formula (11) is obtained by removing the protecting groups for the amide, hydroxyl group and amine of the compound represented by the general formula (10). If the three protecting groups are different, they must be separately removed by a known method, but if all three are the same, for example, benzyl, they can be easily removed. In this case, as the deprotection condition, catalytic reduction in a solvent under a hydrogen atmosphere or alkali metal-ammonia reduction is used. Examples of the alkali metal include lithium, sodium and potassium.

The compound represented by the general formula (11) is reacted with, for example, 2-chloro-2-oxo-1,3-dioxaphosphorane, and trimethylamine to give the sphingo represented by the general formula (1). A myelin analog is obtained. Examples of the solvent to be used include hydrocarbon solvents such as hexane, benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide, ester solvents such as ethyl acetate and butyl acetate, tetrahydrofuran, 1, Ether-based solvents such as 4-dioxane and 1,2-dimethoxyethane, ketone-based solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone,
Examples thereof include halogen-based solvents such as dichloromethane and 1,2-dichloroethane, aqueous media, and mixed solvents thereof. Examples will be shown below, but the invention is not limited thereto.

[0017]

【Example】

Example 1 Synthesis of tetrahydropyranyl ether (THP) body ( 12 ) (4S)-(2-hydroxyethyl)-(3R)-(5
-Heptyl) -2-oxazolidinone (4.00 g, 17.44 m
Pyridinium paratoluene sulfonate (PPTS) (2.19 g, 8.72) in a dichloromethane (52.3 mL) solution of (mol) at 0 ° C.
mmol) and dihydropyran (2.23 mL, 24.42 mmol) were sequentially added, and the temperature was raised to room temperature. After stirring for 20 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is separated and purified by silica gel chromatography, TH
P-form ( 12 ) (5.47 g, quant.) Was obtained as a mixture of isomers.

[0018]

[Chemical 28] ¹ H NMR (CDCl ₃ , 400 MHz) δ: 5.82 (a pair of s, 1H),
4.62 4.52 (m, 2H), 3.97-3.80 (m, 3H), 3.62-
3.48 (m, 2H), 1.84-1.28 (m, 20H), 0.88 (t, J = 6.
8 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 159.1, 159.0, 99.5, 9
9.4, 79.9, 79.8, 65.6, 64.8, 63.3, 62.9, 55.2, 54.
2, 31.7, 30.7, 30.5, 29.5, 29.5, 29.4, 29.4,29.3,
29.0, 25.8, 25.2, 22.6, 20.0, 19.9, 14.0; IR (NaCl neat): 3289, 2928, 2859, 1748 cm ^-1 .

Synthesis of benzyl compound ( 13 ) DHP (23.1 m) of THP compound ( 12 ) (2.41 g, 7.69 mmol)
L) solution at 0 ^° C. with 62.5% sodium hydride (443 mg,
11.54 mmol), benzyl bromide (1.37 mL, 11.54 mmo
l) were sequentially added and the temperature was raised to room temperature. After stirring for 2 hours,
A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is separated by silica gel chromatography.
Purification gave the benzyl form ( 13 ) (3.07 g, 98.8%) as a mixture of isomers.

[0020]

[Chemical 29] ¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.27 7.37 (m, 5H), 4.8
1 (dd, J = 2.2, 15.4 Hz, 1H), 4.40 4.51 (m, 2H),
4.12 (dd, J = 6.8, 15.4 Hz, 1H), 3.66 3.81 (m, 3
H), 3.47 (m, 1H), 3.36 (m, 1H), 1.20 1.94 (m, 20
H), 0.88 (t, J = 7.1 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 158.4, 136.3, 128.69,
128.68, 128.0, 127.9,99.1, 98.9, 78.2, 64.0, 63.9,
62.4, 55.6, 55.5, 46.2, 46.1, 31.7, 30.5, 29.5, 2
9.3, 27.2, 27.1, 25.8, 25.3, 22.6, 19.52, 19.46, 1
4.0; IR (KBr disk): 2928, 1752, 1416, 1123, 1080, 1036
cm ^-1

Synthesis of ring-opened product ( 14 ) Benzyl compound ( 13 ) (100 mg, 0.25 mmol) in ethanol
An aqueous solution of 8N potassium hydroxide (4.00 mL) was added to the solution (5.00 mL), and the mixture was stirred and then heated to 100 ° C. After stirring for 5 hours, the temperature was returned to 0 ° C., and a 2N hydrochloric acid aqueous solution was added to neutralize the reaction mixture. After ethanol was distilled off under reduced pressure, it was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to give the ring-opened product ( 14 ) (81 m
g, 86.5%) was obtained as a mixture of isomers.

[0022]

[Chemical 30] ¹ H NMR (CDCl ₃ , 400 MHz) δ7.22-7.35 (m, 5H), 4.53
(a pair of dd, J = 2.7,3.4 Hz, J = 3.2, 3.7 Hz, 1H),
3.70-3.90 (m, 5H), 3.43-3.51 (m, 2H), 2.72 (ddd, J
= 3.7, 3.9, 7.6 Hz, 1H), 2.72 (br s, 1H), 1.27-1.80
(m, 20H), 0.88 (t, J = 6.8 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 140.3, 128.4, 128.2, 1
28.1, 127.0, 98.9, 98.8, 70.1, 70.0, 66.0, 65.7, 6
2.2, 60.5, 60.3, 51.63, 51.61, 32.6, 32.5, 31.8, 3
0.6, 30.5, 29.7, 29.2, 28.04, 27.97, 26.4, 25.3, 2
2.6, 19.4, 14.1; IR (NaCl neat): 3428, 3347, 2928, 1456, 1123, 107
6, 1034 cm ^-1

Synthesis of acyl compound ( 15 ) Ring-opened compound ( 14 ) (757 mg, 2.01 mmol) in THF (6.01 m
L) and water (6.01 mL) at 0 ° C in a mixed solvent, potassium carbonate
(2.77 mg, 20.05 mmol) and caproyl chloride (0.42 mL,
(3.01 mmol) was sequentially added, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, and this was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to give the acyl derivative ( 15 ) (954 mg, quan
t.) was obtained as a mixture of isomers.

[0024]

[Chemical 31] ¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.20-7.38 (m, 5H), 5.5
5 (br s, 1H), 4.79 (dd, J = 15.9 Hz, 1H), 4.54 (m, 1
H), 4.34 (dd, J = 16.1 Hz, 1H), 3.27-3.93 (m, 6H), 2.
21-2.53 (m, 3H), 1.41-1.95 (m, 10H), 1.00-1.40 (m,
18H), 0.90 (t, J = 6.8 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3
H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 175.3, 136.7, 128.84,
129.79, 127.93, 127.86, 127.5, 127.4, 99.2, 99.0,
74.8, 74.7, 64.6, 64.3, 63.3, 63.1, 62.5, 54.9, 3
5.1, 34.7, 31.7, 31.5, 31.1, 30.9, 29.3, 29.09, 2
9.06, 25.7, 25.6,25.44, 25.38, 25.13, 25.10, 25.0,
22.6, 22.4, 20.3, 19.7, 14.1, 13.9; IR (NaCl neat): 3403, 2928, 1622, 1452, 1136, 107
8, 1034 cm ^-1

Synthesis of dibenzyl derivative ( 16 ) Acyl derivative ( 15 ) (7.38 g, 15.52 mmol) in DMF (46.55)
mL) solution at 0 ° C with sodium hydride (559 mg, 23.27 mmo
l) and benzyl bromide (2.77 mL, 23.27 mmol) were sequentially added, and the temperature was raised to room temperature. After stirring for 15 hours, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to give the dibenzyl derivative ( 16 ).
(7.59 g, 86.5%) was obtained as a mixture of isomers.

[0026]

[Chemical 32] ¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.13-7.37 (m, 10H), 4.4
0-4.73 (m, 4H), 3.99-4.27 (m, 2H), 3.43-3.87 (m, 4
H), 3.09-3.33 (a pair of m, 1H), 2.51 (m, 1H), 1.1
2-2.25 (m, 27H), 0.83-0.93 (m, 6H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 174.54, 174.52, 139.6,
139.5, 138.7, 138.6,138.22, 138.15, 128.5, 128.3
3, 128.30, 128.2, 128.1, 127.7, 127.63, 127.59, 12
7.51, 127.47, 127.28, 127.25, 127.0, 126.6, 126.2,
126.1, 99.1, 99.0, 98.7, 98.6, 82.1, 77.3, 77.0,
76.7, 72.3, 72.1, 71.2, 71.0, 65.44, 65.40, 63.8,
63.6, 62.5, 62.34, 62.29, 62.2, 57.3, 57.0, 45.4,
45.3, 34.1, 33.6, 33.5, 31.8, 31.7, 31.6, 31.5, 3
0.74, 30.70, 29.9, 29.7, 29.20, 29.26, 28.0, 27.3,
25.8, 25.7, 25.44, 25.35, 25.2, 25.1, 25.02, 24.9
8, 22.62, 22.58, 22.55, 22.53, 22.4, 19.7, 19.61,
19.58, 19.53, 14.2, 14.1, 14.03 14.00, 13.9; IR (NaCl neat): 2928, 1649, 1454, 1034, 731 cm ^-1

Synthesis of de-THP derivative ( 17 ) A solution of dibenzyl derivative ( 16 ) (902 mg, 1.59 mmol) in methanol (7.97 mL) was added at room temperature to paratoluenesulfonic acid (303).
(mg, 1.59 mmol) was added and stirred for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain a THP-free form ( 17 ) (768 mg, quant.).

[0028]

[Chemical 33] ¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.21-7.35 (m, 6H), 7.0
7-7.13 (m, 4H), 4.87 (br s, 1H), 4.77 (d, J = 17.8 H
z, 1H), 4.52 (d, J = 17.3 Hz, 1H), 4.35 (d, J = 11.5 H
z, 1H), 3.59-3.65 (m, 3H), 3.32-3.38 (m, 2H), 2.28
(m, 2H), 1.98 (m, 1H), 1.18-1.85 (m, 20H), 0.88
(t, J = 6.8 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) δ: 176.4, 138.5, 138.0,
128.6, 128.1, 127.2, 127.1, 125.8, 80.9, 70.4, 58.
7, 52.5, 47.5, 33.6, 31.8, 31.5, 31.2, 29.8, 29.1,
25.8, 25.3, 22.6, 22.4, 14.0, 13.9; IR (KBr disk): 3428. 2928, 1626, 1454, 1063, 731 c
m-1 [α] _D ^19.0 −29.8 (c = 1.088, CHCl ₃ );

Synthesis of carboxylic acid ( 18 ) D of pyridinium dichromate (PDC) cooled to 0 ° C
In the MF solution, the D-form of de-THP compound ( 17 ) (430 mg, 0.77 mmol)
The MF solution was added dropwise, stirred for 5 minutes, and then warmed to room temperature. After stirring at the same temperature for 17.5 hours, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give a carboxylic acid ( 18 ) (1.77 g,
86.1%) was obtained as a mixture of isomers.

[0030]

[Chemical 34] ¹ H NMR (CDCl ₃ , 400 MHz) δ: 7.15-7.36 (m, 10H), 4.4
4-4.67 (m, 4H), 4.25 (a pair of d, J = 11.22 Hz, 1
H), 3.64 (a pair of m, 1H), 2.81 (a pair of dd, J =
5.1, 16.4 Hz, 1H), 2.69 (a pair of d, J = 11.1 Hz, 1
H), 2.49 (a pair of dd, J = 8.5, 16.8 Hz, 1H), 2.27
(a pair of t, J = 7.3 Hz, 1H), 1.20-1.76 (m, 20H); ¹³ C NMR (CDCl ₃ , 100MHz) δ: 176.4, 175.9, 174.9, 1
74.6, 148.5, 138.9, 138.3, 137.5, 137.0, 128.7, 12
8.4, 128.3, 128.2, 127.8, 127.7, 127.6, 127.5, 12
7.4, 127.3, 126.8, 126.5, 124.1, 80.9, 80.6, 72.4,
71.8, 60.4, 56.8, 56.2, 50.8, 45.4, 34.7, 34.1, 3
4.0, 33.3, 31.8, 31.7, 31.52, 31.46, 29.8, 29.7, 2
9.1, 25.5, 25.2, 25.0, 22.6, 22.5, 22.4, 14.2, 14.
1, 14.0, 13.9; IR (NaCl neat): 3032, 2930, 1730, 1649, 1607, 145
4, 1418, 1074 cm-1

Synthesis of Rearrangement ( 19 ) Carboxylic acid (18) (1.72 g, 3.47 mmol) in toluene (1
0.42 mL) solution at room temperature in triethylamine (0.59 mL, 4.17 mL).
mmol), diphenylphosphoryl azide (1.12 mL, 5.21 m
mol) was sequentially added, the temperature was raised to 60 ^° C., and the mixture was stirred for 3 hours. After that, the temperature was raised to 130 ° C. and the mixture was stirred for 1 hour, benzyl alcohol (0.72 mL, 6.95 mmol) was added, and the mixture was further added to 3
Stir for hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated sodium hydrogen carbonate and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was roughly purified by silica gel chromatography to give the rearranged product ( 1
9 ) and used as such for the next reaction.

[Chemical 35]

Synthesis of aminoceramide compound ( 20 ) Under an argon atmosphere, the reaction vessel was cooled to -78 ° C and ammonia (52.11 mL) was condensed. Metal sodium in this
(1.198 g, 52.11 mmol) was added and stirred for 5 minutes. A solution of the rearranged body ( 19 ) mixture (3.47 mmol) obtained above in THF (52.11 mL) was added dropwise thereto, and then the ice bath was removed and the mixture was refluxed for 3.5 hours. Again, the reaction mixture is -78 ° C.
After cooling, solid ammonium chloride was added to remove ammonia. After ethyl acetate was added to the residue to dilute it, anhydrous magnesium sulfate was added to dry the residue, and the mixture was filtered through Celite and condensed. The obtained residue was recrystallized from ethyl acetate to give an aminoceramide compound ( 20 ) (323 mg, 2-step yield 32.5%) as crystals.

[0033]

[Chemical 36] ¹ H NMR (CD ₃ OD, 400MHz) δ: 3.83 (ddd, J = 4.2, 7.3,
7.8 Hz, 1H), 3.54 (dt, J = 2.9, 7.6 Hz, 1H), 3.04
(m, 1H), 2.80 (dd, J = 8.3, 12.9 Hz, 1H), 2.24
(t, J = 7.6 Hz, 2H), 1.24 1.67 (m, 20H), 0.92 (t,
J = 6.8 Hz, 3H), 0.90 (t, J = 6.8 Hz, 3H); ¹³ C NMR (CD ₃ OD, 100MHz) δ: 176.7, 73.4, 55.6, 42.
8, 37.2, 35.2, 33.0, 32.6, 30.7, 30.4, 26.7, 26.5,
23.7, 23.5, 14.4, 14.3; IR (KBr disk): 3353, 3310, 2922, 1644, 1545, 1464
cm ^-1 . [α] _D ^20.0 −0.515 (c = 1.088, MeOH);

Synthesis of Sphingomyelin Analogue ( 21 ) Aminoceramide derivative ( 20 ) (231 mg,
0.806 mmol) in 10 ° C. benzene (12.1 mL) solution, trimethylamine (0.12 mL, 0.887 mmol), 2-chloro-2
-Oxo-1,3-dioxaphosphorane (0.08 mL, 0.88
(7 mmol) was added sequentially and stirred for 1 hour. This was quickly filtered through Celite to condense the solvent. After completely removing water by azeotropically distilling benzene three times, DMF was added,
The solution was transferred to an autoclave and cooled to -78 ° C. After adding 10 mL of anhydrous trimethylamine to this, it heated up at 60 degreeC and stirred for 2 days. After removing trimethylamine, the mixture was washed with methanol and the solvent was condensed. The residue was applied to high performance liquid chromatography (CH ₃ CN: H
₂ O = 3: 7) and purified to obtain sphingomyelin analog ( 2
1 ) (10 mg, 2.7%) was obtained.

[0035]

[Chemical 37] ¹ H NMR (CD ₃ OD, 400MHz) δ: 4.20-4.38 (m, 3H), 4.17
(m, 1H), 3.66 (t, J = 7.6 Hz, 2H), 3.20-3.23 (m, 10
H), 3.04 (dd, J = 8.3, 12.9 Hz, 1H), 2.26 (t, J = 7.56
Hz, 2H), 1.24-1.67 (m, 20 H), 0.92 (t, J = 6.8 Hz,
3H), 0.90 (t, J = 6.8 Hz, 3H);

[0036]

The novel sphingomyelin analog (1) according to the present invention has sphingomyelinase inhibitory activity,
It is expected to be applied as a medicine, especially as a sphingomyelinase inhibitor. Further, according to the method of the present invention, the sphingomyelin analog (1) having high optical purity or high optical purity can be produced.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07C 233/47 C07C 233/47 271/20 271/20 C07D 263/24 C07D 263/24 // A61K 31/664 A61K 31 / 664 A61P 43/00 111 A61P 43/00 111 C12N 9/99 C12N 9/99 (72) Inventor Naruo Katsumura 3-10-8 Keyakidai, Mita City, Hyogo Prefecture (reference) 4C056 AA01 AB01 AC02 AD01 AE02 BA03 BA08 BB04 BC01 4C086 AA03 AA04 DA42 ZC20 4H006 AA01 BN10 BP10 BS10 BT12 BV22 4H050 AA01 AB20 AB81 AB84 WA12 WA27

Claims (16)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. The sphingomyelin analog represented by. 2. The compound according to claim 1, wherein in the formula (1), R ¹ and R ² are the same or different and each is an alkyl group having 5 to 17 carbon atoms which may have an unsaturated bond. 3. In the formula (1), R ¹ is a heptyl group,
The compound of claim 1, wherein R ² is a pentyl group. 4. The compound according to claim 1, wherein in the formula (1), R ¹ is a 1-pentadecenyl group and R ² is a heptadecyl group. 5. The compound according to claim 1, wherein the compound represented by the formula (1) is optically active. 6. A compound represented by the general formula (2): (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms). Protects the hydroxyl groups of the general formula (3) (Wherein R ³ represents a hydroxyl-protecting group and R ¹ is the same as the above), and then the amino group is protected to obtain a compound represented by the general formula (4): (In the formula, R ⁴ represents an amino protecting group, and R ¹ and R ³
Is the same as above. ), And then ring-opened to give a compound of the general formula (5) (Wherein R ¹ , R ³ and R ⁴ are the same as above) and then amidated to give a compound of the general formula (6) (In the formula, R ² means an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms, and R ¹ , R ³ and R ⁴ is the same as above), and then the secondary hydroxyl group is protected to give a compound of the general formula (7) (In the formula, R ⁵ represents an aralkyl group or an alkenyl group, and R ¹ , R ² , R ³ and R ⁴ are the same as above.), And then the primary hydroxyl group is deprotected. , The general formula (8): (In the formula, R ¹ , R ² , R ⁴ and R ⁵ are the same as above.)
A compound represented by the following formula is obtained and then oxidized to give a compound represented by the general formula (9): (In the formula, R ¹ , R ² , R ⁴ and R ⁵ are the same as above.)
The compound represented by the formula (10) is obtained, and then subjected to Curtius rearrangement reaction to give a compound represented by the general formula (10): (In the formula, R ⁶ represents an alkyl group having 1 to ⁶ carbon atoms or an aralkyl group, and R ¹ , R ² , R ⁴ and R ⁵ are the same as the above.), And then deprotected. General formula (11) (Wherein R ¹ and R ² are the same as above), and then the compound is reacted with 2-halogeno-2-oxo-1,3-dioxaphosphorane and trimethylamine. A general formula (1) characterized by: (In the formula, R ¹ and R ² are the same as above.) A method for producing a sphingomyelin analog. 7. A compound represented by the general formula (9): (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. R ⁴ represents an amino protecting group, and R ^4
5 means an aralkyl group or an alkenyl group. ) Is subjected to a Curtius rearrangement reaction to give a compound represented by the general formula (10): (In the formula, R ⁶ represents an alkyl group having 1 to ⁶ carbon atoms or an aralkyl group, and R ¹ , R ² , R ⁴ and R ⁵ are the same as the above.), And then deprotected. General formula (11) (Wherein R ¹ and R ² are the same as above), and then the compound is reacted with 2-halogeno-2-oxo-1,3-dioxaphosphorane and trimethylamine. A general formula (1) characterized by: (In the formula, R ¹ and R ² are the same as above.) A method for producing a sphingomyelin analog. 8. A compound represented by the general formula (3). [Chemical 17] (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms, and R ³ is a hydroxyl group-protecting group. Means.) 9. A compound represented by formula (4). [Chemical 18] (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms, and R ³ is a hydroxyl group-protecting group. And R ⁴ represents an amino protecting group.) 10. A compound represented by the general formula (5). [Chemical 19] (In the formula, R ¹ represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms, and R ³ is a hydroxyl group-protecting group. , And R ⁴ means an amino protecting group.) 11. A compound represented by the general formula (6). [Chemical 20] (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. , R ³ means a hydroxyl protecting group, and R ⁴ means an amino protecting group.) 12. A compound represented by the general formula (7). [Chemical 21] (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. R ³ means a hydroxyl-protecting group, and R ^3
4 means an amino protecting group, and R ⁵ means an aralkyl group or an alkenyl group. ) 13. A compound represented by the general formula (8). [Chemical formula 22] (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. R ⁴ represents an amino protecting group, and R ^4
5 means an aralkyl group or an alkenyl group. ) 14. A compound represented by the general formula (9). [Chemical formula 23] (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. R ⁴ represents an amino protecting group, and R ^4
5 means an aralkyl group or an alkenyl group. ) 15. A compound represented by the general formula (10). [Chemical formula 24] (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. R ⁴ represents an amino protecting group, and R ^4
5 means an aralkyl group or an alkenyl group, and R ⁶ means an alkyl group having 1 to ⁶ carbon atoms or an aralkyl group. ) 16. A compound represented by the general formula (11). [Chemical 25] (In the formula, R ¹ and R ² are the same or different and each represents an alkyl group having 1 to 20 carbon atoms which may have an unsaturated bond, an aryl group, or an aryl group-substituted alkyl group having 1 to 6 carbon atoms. Yes.)