JP3157456B2 - Oxazolidinone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a phospholipase A
(2) A novel oxazolidinone derivative and a synthetic intermediate thereof having an inhibitory activity and useful as a therapeutic agent for a wide range of diseases such as inflammation, allergy, rheumatism, myocardial infarction, and asthma.

[0002]

2. Description of the Related Art Phosphatidylcholine has been studied for various uses as a phospholipid contained in soybeans and the like. On the other hand, many studies have been made on the chemical modification, and derivatives having an acylamino group introduced at the 2-position of phosphatidylcholine have been reported (Japanese Patent Application Laid-Open Nos. 54-148727, 55-118494, 58-58494). 43942, JP-A-61-24519, JP-A-62-12754, etc.). These documents report that the alkyl chain of the acyl moiety or the carbon chain of the alkylene group bonded to the phosphoric acid moiety is changed to various types. However, there have been few reports on phosphatidylcholine derivatives having a cyclic structure, and particularly with respect to those having an oxazolidinone skeleton, only the compounds disclosed in JP-A-5-239078 have been reported. Japanese Patent Application Laid-Open No. Hei 5-23907
The compound disclosed in No. 8 is an oxazolidinone ring 4
-Substituted by a phosphatidyl group at the -position.

[0003]

However, there is no report on an oxazolidinone derivative substituted with a phosphatidyl group at the 5-position, and a study on the synthesis of the derivative and a study on its action and effect has been desired.

[0004]

Therefore, the present inventor has proposed the
As a result of intensive studies on the synthesis of oxazolidinone derivatives substituted with a phosphatidyl group at the 1-position, we succeeded in creating a new compound. Furthermore, when the effects of these novel compounds were also studied, they were found to have better phospholipase A2 inhibitory activity than oxazolidinone derivatives substituted with a phosphatidyl group at the 4-position.

[0005]

The present invention relates to a novel oxazolidinone derivative represented by the following general formula [ I ] and a synthetic intermediate represented by the following general formula [ II ].

[0006]

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[0007]

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[Wherein, R1 represents an alkyl group. R2 represents a hydrogen atom or an alkyl group. R3 represents an alkyl group. A1 and A2 represent an alkylene group. same as below. ]

The group defined above will be described in more detail. An alkyl group is a straight or branched lower alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and hexyl. A linear or branched higher alkyl group having 7 to 20 carbon atoms such as heptyl, decyl, undecyl, dodecyl, pentadecyl, icosyl and the like. The alkylene group refers to a linear or branched lower alkylene group having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, (dimethyl) methylene, and hexamethylene.

As R1, a higher alkyl group having 7 to 20 carbon atoms is preferable, and an undecyl group having 11 carbon atoms is particularly preferable. As R2, a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms is preferable, and a propyl group having 3 carbon atoms is particularly preferable. R3 is preferably a lower alkyl group having 1 to 6 carbon atoms, and particularly preferably a methyl group having 1 carbon atom. A
1 represents a lower alkylene group having 1 to 6 carbon atoms, and a methylene group having 1 carbon atom is particularly preferable. A2 represents a lower alkylene group having 1 to 6 carbon atoms, and an ethylene group having 2 carbon atoms is particularly preferable.

The preferred combination of the substituents in the compound represented by the general formula [ I ] is that R1 has 7 carbon atoms.
R2 is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, R3 is a lower alkyl group having 1 to 6 carbon atoms, and A1 and A2 are lower alkylene groups having 1 to 6 carbon atoms. It is a combination of Particularly preferred is
R1 is an undecyl group, R2 is a hydrogen atom or a propyl group, R3 is a methyl group, A1 is a methylene group, and A2 is a combination of ethylene groups. Particularly preferred compounds include 3-dodecanoyl- (5S) -phosphatidylcorinohydroxymethyl- (4S) -propyl-2-oxazolidinone, 3-dodecanoyl- (5R) -phosphatidylcorinohydroxymethyl- (4S) -propyl-2-. Oxazolidinone, 3-dodecanoyl- (5S)
-Phosphatidylcorinohydroxymethyl-2-oxazolidinone and 3-dodecanoyl- (5R) -phosphatidylcorinohydroxymethyl-2-oxazolidinone.

As a combination of substituents in the synthetic intermediate represented by the general formula [ II ], R1 is preferably a higher alkyl group having 7 to 20 carbon atoms, and R2 is a hydrogen atom or a C1 to C6 alkyl group. A1 is a lower alkyl group having 1 carbon atom
To 6 lower alkylene groups. Particularly preferred is a combination of R1 being an undecyl group, R2 being a hydrogen atom or a propyl group, and A1 being a methylene group. Particularly preferred compounds include 3-dodecanoyl-
(5S) -hydroxymethyl- (4S) -propyl-2
-Oxazolidinone, 3-dodecanoyl- (5R) -hydroxymethyl- (4S) -propyl-2-oxazolidinone, 3-dodecanoyl- (5S) -hydroxymethyl-2-oxazolidinone and 3-dodecanoyl-
(5R) -hydroxymethyl-2-oxazolidinone.

A structural feature of the compound of the present invention resides in that a phosphatidyl group is substituted at the 5-position of the oxazolidinone ring. Since the compound of the present invention has an asymmetric carbon atom, there are stereoisomers, which are all included in the present invention. See below

As will be described in the section of the present invention, the method used for producing the compound of the present invention is a method capable of maintaining the steric configuration. Therefore, when an optically active substance is used as a raw material, the product is also optically active. Is obtained. Further, a hydrate may be obtained depending on production conditions, and the hydrate is also included in the present invention. The same applies to the synthetic intermediate.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION An example of a method for producing the compound of the present invention will be described below in the form of a reaction formula.

1. Method for producing compounds wherein R2 is an alkyl group a)

[0016]

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The above reaction yields a synthetic intermediate, and the following reaction yields the final compound.

[0018]

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B)

[0020]

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A synthetic intermediate is obtained by the above reaction, and then a final compound is obtained by the following reaction.

[0022]

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2. Method for producing compound wherein R2 is a hydrogen atom

[0024]

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The synthetic intermediate is obtained by the above reaction, and then the final compound is obtained by the following reaction.

[0026]

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The above reaction is commonly used for the (S) -form and the (R) -form.

[0028]

【Example】

[Production Example] Reference Example 1 Synthesis of (2R), (3R) -epoxy-1-hexanol

Embedded image D-Diethyl tartrate (1.158 ml) and tetraisopropyl orthotitanate (1.248 ml) were added to a powdered suspension of 4A molecular sieve (5.08 g) in methylene chloride (84.4 ml) with stirring. ° C
Add in. Next, a methylene chloride solution of t-butyl hydroperoxide (5.4N, 4N) was added to the reaction mixture.
7.0 ml) was added dropwise over 5 minutes. The reaction mixture was -20
After stirring at 30 ° C. for 30 minutes, a solution of trans-2-hexen-1-ol (10 ml) in methylene chloride (42.2 ml) was added dropwise over 20 minutes, and the reaction mixture was further stirred at −15 to 20 ° C. for 3 hours. . Then, after raising the temperature to 0 ° C,
An aqueous solution (100 ml) of iron sulfide pentahydrate (33 g) and citric acid (11 g) was added, and the mixture was stirred for 10 minutes. The reaction mixture was extracted with methylene chloride, and a 30% aqueous sodium hydroxide solution (20 ml) and sodium chloride (4 g) were added to the organic layer at 0 ° C.
Stirred for 0 minutes. After dilution with water and extraction with methylene chloride, the organic layer was dried and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (7.002 g).
(71%) as an oil. NMR (CDCl3): δ = 0.97 (t, 3H, J =
7.2 Hz), 1.46-1.56 (m, 4H), 2.
21 (t, 1H, J = 6.4 Hz), 2.93 (m, 2
H), 3.61 (m, 1H), 3.91 (m, 1H) IR (CHCl3, cm-1): 3400, 2962,
1466, 1378, 1065 [α] D + 40.5 (C = 0.742, CHCl 3)

Reference Example 2 Synthesis of (3S) -azide and (2S) -hydroxy-1-hexanol

Embedded image Trimethylsilyl azide (5.14 ml) and tetraisopropyl orthotitanate (5.72 ml) were added to a solution of (2R) and (3R) -epoxy-1-hexanol (1.5 g) in benzene (64.6 ml) at room temperature. It was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with ether, added with 5% hydrochloric acid, and the solidified reaction mixture was extracted with methylene chloride. The extract was dried and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (1.025 g, 74.8%) as an oil. NMR (CDCl3): δ = 0.97 (t, 3H, J =
7.2 Hz), 1.4 to 1.6 (m, 4H), 3.18
(S, 1H), 3.44 (m, 1H), 3.56 (s, 1H)
1H), 3.67 to 3.73 (m, 3H) IR (neat, cm-1): 3400, 2964,2
112, 1260, 1066 [α] D + 7.11 (C = 1.35, CHCl 3)

Reference Example 3 (3S) -tert-butoxycarbonylamino- (2S)-
Synthesis of hydroxy-1-hexanol

Embedded image (3S) -azide, (2S) -hydroxy-1-hexanol (900 mg) in methanol (17.0 ml)
Then, at room temperature, t-butoxycarboxylic anhydride (Boc anhydride, 0.936 ml) and palladium on carbon (180
mg), and the mixture was stirred overnight at room temperature under a hydrogen stream. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography to give the title compound 1.
080 g (82.0%) were obtained as crystals. mp 90.5-91.2 ° C NMR (CD3OD): δ = 0.927 (t, 3H, J
= 7.2 Hz), 1.27 to 1.43 (m, 12H),
1.66 (m, 1H), 3.49 (m, 4H) IR (KBr, cm-1): 3364, 2960, 16
86, 1388, 1366, 1244, 1168, 10
58 [α] D-25.9 (C = 0.56, CHCl3)

Reference Example 4 1-t-butyldimethylsilyloxy- (3S) -t-
Synthesis of butoxycarbonylamino- (2S) -hexanol

Embedded image (3S) -t-butoxycarbonylamino- (2S)-
A solution of hydroxy-1-hexanol (1.5 g) in methylene chloride (12.86 ml) was cooled and cooled with triethylamine (0.896 ml), 4-dimethylaminopyridine (0.157 g) and t-butyldimethylsilyl chloride (1. 018g) and stirred at room temperature for 5 hours.
Water was added to the reaction mixture, extracted with methylene chloride, and the organic layer was dried and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give 2.113 g of the title compound (9
4.5%) as an oil. NMR (CD3OD): δ = 0.04 (s, 6H),
0.86 (m, 13H), 1.30 (m, 3H), 1.
38 (s, 9H), 1.55 (m, 1H), 3.4-
3.6 (m, 4H), 6.27 (d, 1H, J = 9.
0) IR (CHCl3, cm-1): 3440, 2958,
1709, 1504, 1467, 1393, 1368,
1253, 1170, 1093, 1023, 839 [α] D-9.61 (C = 0.51, CHCl 3)

Reference Example 5 (5S) -t-butyldimethylsilyloxymethyl-
Synthesis of (4S) -propyl-2-oxazolidinone

Embedded image 1-t-butyldimethylsilyloxy- (3S) -t-
To a solution of butoxycarbonylamino- (2S) -hexanol (1.3 g) in THF (20.2 ml) was added sodium hydride (180 mg) under cooling, and the mixture was refluxed for 3 hours. The reaction mixture was neutralized with a 5% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure, and the resulting oil was purified by silica gel column chromatography to give the title compound (0.884 g, 86.4%) as an oil. NMR (CDCl 3): δ = 0.08 (s, 6H),
0.89 (s, 9H), 0.95 (t, 3H, J = 7.
4 Hz), 1.30 (m, 1H), 1.45 (m, 1
H), 1.59 (m, 2H), 3.85 (m, 3H),
4.58 (m, 1H), 6.52 (bs, 1H) IR (neat, cm-1): 3272, 2960, 1
760, 1468, 1392, 1254, 838, 77
8 [α] D −5.43 (C = 0.41, CHCl 3)

Reference Example 6 (5S) -t-butyldimethylsilyloxymethyl-3
Synthesis of -dodecanoyl- (4S) -propyl-2-oxazolidinone

Embedded image (5S) -t-butyldimethylsilyloxymethyl-
(4S) -propyl-2-oxazolidinone (950 m
g) THF (10.42 ml) was added with n-butyllithium (1.6 N, 2.45 ml) under cooling and added at 0 ° C. for 30 minutes.
Stirred for minutes. Dodecanoyl chloride (0.884 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
A saturated saline solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give the title compound 1.
409 g (89.0%) were obtained as an oil. NMR (CDCl3): δ = 0.10 (s, 6H),
0.88-0.90 (m, 15H), 1.25-1.3
5 (m, 18H), 1.6-1.7 (m, 3H), 1.
78 (m, 1H), 2.88 (m, 2H), 3.89
(M, 2H), 4.52 (m, 1H) IR (neat, cm-1): 2932, 2860, 1
788, 1706, 1468, 1366, 1256, 1
200,840,780 [α] D + 32.7 (C = 1.13, CHCl 3)

Reference Example 7 1-phenylaminocarboxy- (2R), (3R)-
Synthesis of epoxyhexane

Embedded image After adding pyridine (2.09 ml) to a methylene chloride (38.8 ml) solution of (2R) and (3R) -epoxy-1-hexanol (1.5 g), phenyl isocyanate (3.51 ml) was added dropwise. Stir at room temperature for 17 hours. Water was added to the reaction mixture, concentrated under reduced pressure, and extracted with methylene chloride. The organic layer was dried and concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography to give the title compound (2.645 g, 87.0%) as a solid. mp 29.9-30.0 ° C. NMR (CDCl 3): δ = 0.96 (t, 3H, J =
7.2 Hz), 1.48 (m, 2H), 1.55 (m,
2H), 2.89 (m, 1H), 3.03 (m, 1
H), 3.98 (m, 1H), 4.49 (m, 1H),
6.93 (s, 1H), 7.28 to 7.40 (m, 5
H) IR (neat, cm-1): 3436, 3016, 2
964, 1737, 1601, 1527, 1446, 1
312, 1069, 1029, 690, 504 [α] D +36.6 (C = 1.241, CHCl 3)

Reference Example 8 Synthesis of (3R) -hydroxyhexane-1, (2R) -carbonate

Embedded image 1-phenylaminocarboxy- (2R), (3R)-
Epoxyhexane (3.0 g) in acetonitrile (3
8.25 ml) solution at room temperature with a 5% aqueous solution of perchloric acid (1
2.75 ml) was added dropwise. After stirring the reaction mixture at room temperature overnight, it was extracted with methylene chloride. The organic layer was dried and concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography to obtain 1.440 g (70.5%) of the title compound as an oil. NMR (CDCl3): δ = 0.96 (t, 3H, J =
7.1 Hz), 1.37 to 1.59 (m, 4H), 2.
87 (d, 1H, J = 4.9 Hz), 3.95 (m, 1
H), 4.44-4.53 (m, 2H), 4.58-
4.62 (m, 1H) IR (neat, cm-1): 3020, 2964, 1
800, 1383, 1176, 1079 [α] D + 10.4 (C = 1.40, CHCl 3)

Reference Example 9 Synthesis of (3S) -azidohexane-1, (2R) -carbonate

Embedded image (3R) -hydroxyhexane-1, (2R) -carbonate (1.12 g) in methylene chloride (14.0 ml)
To the solution was added pyridine (0.680 ml) and then-
At 15 ° C., trifluoromethanesulfonic anhydride (1.4
1 ml) and stirred at the same temperature for 30 minutes. After diluting the reaction mixture with dimethylformamide (14.0 ml),
Sodium azide (1.82 g) was added, and the mixture was stirred at room temperature overnight and extracted with ether. The organic layer was dried and concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography to give the title compound (1.032 g, 79.6%) as an oil. NMR (CDCl3): δ = 0.98 (t, 3H, J =
7.3 Hz), 1.4 to 1.8 (m, 4H), 3.44
(M, 1H), 4.34 (dd, 1H, J = 8.5,
6.3 Hz), 4.53 (m, 1H), 4.73 (m,
1H) IR (neat, cm-1): 2964, 2112, 1
808, 1167, 1076 [α] D + 41.4 (C = 1.21, CHCl 3)

Reference Example 10 (3S) -t-butoxycarbonylaminohexane-
Synthesis of 1, (2R) -carbonate

Embedded image As starting materials, (3S) -azidohexane-1, (2
The title compound was obtained in the same manner as in Reference Example 3 using (R) -carbonate. mp 92.6-93.0 ° C. NMR (CDCl 3): δ = 0.947 (t, 3H, J
= 7.3 Hz), 1.36 to 1.45 (m, 12H),
1.56-1.63 (dt, 1H), 3.82 (dt,
1H, J = 8.4, 6.6 Hz), 4.34 (dd, 1
H, J = 7.1, 1.5 Hz), 4.48 (dd, 1
H, J = 8.5, 0.5 Hz), 4.62 (d, 1H,
J = 9.3 Hz), 4.75 (dt, 1H, J = 7.
7, 1.2 Hz) IR (KBr, cm-1): 3312, 2964, 17
86, 1682, 1529, 1395, 1366, 12
53, 1178, 1069, 771, 720, 680 [α] D-55.2 (C = 1.23, CHCl 3)

Reference Example 11 (3S) -t-butoxycarbonylamino- (2R)-
Synthesis of hydroxy-1-hexanol

Embedded image (3S) -t-butoxycarbonylaminohexane-
To a mixed solution of 1, (2R) -carbonate (1.4 g) in dioxane (10.8 ml) and water (5.4 ml) was added 1N aqueous sodium hydroxide solution (5.4 ml) under cooling.
Was added dropwise. After stirring the reaction mixture at room temperature for 1 hour, it was neutralized with a 5% aqueous citric acid solution and extracted with methylene chloride. The organic layer was dried and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (1.078 g, 8%).
5.6%) as a solid. mp 61.7-63.0 ° C. NMR (CDCl 3): δ = 0.94 (t, 3H, J =
7.6 Hz), 1.39 to 1.47 (m, 11H),
1.53 (t, 2H, J = 7.0 Hz), 2.23
(D, 1H, J = 5.2 Hz), 3.18 (dt, 1
H, J = 5.6, 2.0 Hz), 3.49 (dt, 1
H), 3.56 (m, 1H), 3.69 (m, 2H),
4.64 (d, 1H, J = 8.0 Hz) IR (KBr, cm-1): 3362, 2958, 16
80, 1526, 1445, 1392, 1368, 12
51, 1173, 1059, 1001, 874 [α] D-37.1 (C = 0.746, CHCl 3)

Reference Example 12 1-t-butyldimethylsilyloxy- (3S) -t-
Synthesis of butoxycarbonylamino- (2R) -hexanol

Embedded image Using (3S) -t-butoxycarbonylamino- (2R) -hydroxy-1-hexanol as a starting material, the title compound was obtained in the same manner as in Reference Example 4. NMR (CDCl 3): δ = 0.07 (s, 6H),
0.89 to 0.95 (m, 12H), 1.37 to 1.4
1 (m, 2H), 1.44 (s, 9H), 1.52-
1.57 (m, 2H), 2.73 (s, 1H), 3.5
1 (m, 1H), 3.64 (dt, 1H, J = 10.
0, 3.9 Hz), 4.84 (d, 1H, J = 9.3H)
z) IR (neat, cm-1): 3444, 2934, 1
706, 1503, 1467, 1393, 1367, 1
254,1171,1090,1060,1004,8
38

Reference Example 13 (5R) -t-butyldimethylsilyloxymethyl-
Synthesis of (4S) -propyl-2-oxazolidinone

Embedded image As a starting material, 1-tert-butyldimethylsilyloxy- (3S) -tert-butoxycarbonylamino- (2R)
The title compound was obtained in the same manner as in Reference Example 5 using hexanol. NMR (CDCl 3): δ = 0.07 (s, 6H),
0.89 (s, 9H), 0.95 (t, 3H, J = 7.
2Hz), 1.33 to 1.41 (m, 2H), 1.52
１．５1.58 (m, 2H), 3.69 (dt, 1H, J =
6.1, 5.4 Hz), 3.74 (dd, 2H, J =
4.6, 1.5 Hz), 4.19 (dt, 1H, J =
9.6, 4.9 Hz), 6.69 (s, 1H) IR (CHCl3, cm-1): 3466, 3266,
2934, 2860, 1754, 1465, 1395,
1254, 1140, 1043, 1006, 838

Reference Example 14 (5R) -t-butyldimethylsilyloxymethyl-3
Synthesis of -dodecanoyl- (4S) -propyl-2-oxazolidinone

Embedded image Using (5R) -t-butyldimethylsilyloxymethyl- (4S) -propyl-2-oxazolidinone as a starting material, the title compound was obtained in the same manner as in Reference Example 6. NMR (CDCl3): δ = 0.05 (s, 6H),
0.84 to 0.90 (s, 12H), 0.96 (t, 3
H, J = 7.3 Hz), 1.26 to 1.35 (m, 18
H), 1.62 to 1.66 (m, 3H), 1.76.
(M, 1H), 2.82 (m, 1H), 2.92 (m,
1H), 3.63 (dd, 1H, J = 11.2, 2.7)
Hz), 3.79 (dd, 1H, J = 11.2, 3.7)
Hz), 4.21 (dt, 1H, J = 2.7, 1.0H
z), 4.34 (dt, 1H, J = 8.4, 3.4H
z) IR (neat, cm-1): 2932, 2860, 1
788, 1706, 1468, 1366, 1256, 1
200, 1116, 840, 780 [α] D 1.32 (C = 1.97, CHCl 3)

Reference Example 15 Synthesis of 1-tert-butoxycarbonylamino-3-benzyloxy- (2R) -propanol

Embedded image Saturated ammonia / isopropanol solution (160ml)
In addition, (S) -benzyl glycidyl ether (1.61 m
l) was added dropwise and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and dioxane (21.12 ml) and water (1
0.56 ml). To this solution, 1N aqueous sodium hydroxide solution (10.56 ml) and t
-Butoxycarboxylic anhydride (Boc anhydride, 2.66
9 g) was added and the mixture was stirred at room temperature for 30 minutes. Add 1 reaction mixture
The mixture was neutralized with 0% citric acid, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure, and the resulting oil was purified by silica gel column chromatography to give the title compound 2.73.
1 g (91.9%) was obtained as an oil. NMR (CDCl 3): δ = 1.43 (s, 9H),
2.99 (d, 1H, J = 3.2 Hz), 3.15 (d
t, 1H), 3.34 (br, 1H), 3.43 (d
d, 1H, J = 9.5, 6.7 Hz), 3.51 (d
d, 1H, J = 9.6, 4.5 Hz), 3.89 (b
r, 1H), 4.54 (s, 2H), 4.97 (br,
1H), 7.29 to 7.37 (m, 5H) IR (CHCl3, cm-1): 3456, 3008,
2980, 2934, 1710, 1511, 1455,
1394, 1368, 1247, 1167, 1114 [α] D-10.03 (C = 1.20, CHCl 3)

Reference Example 16 Synthesis of (5S) -benzyloxymethyl-2-oxazolidinone

Embedded image THF of 1-tert-butoxycarbonylamino-3-benzyloxy- (2S) -propanol (2.731 g)
(97 ml) solution was added sodium hydride (466) under cooling.
mg) and refluxed for 2 hours. The reaction mixture was neutralized with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give 1.756 g (87.
3%) as an oil. NMR (CDCl3): δ = 3.45 (dd, 1H, J
= 7.8, 6.6 Hz), 3.62 (m, 3H), 4.
59 (s, 2H), 4.73 to 4.79 (m, 1H),
6.27 (s, 1H), 7.28 to 7.37 (m, 5
H) IR (CHCl3, cm-1): 3494, 3298,
3015, 1762, 1380, 1242, 1096 [α] D + 9.276 (C = 1.46, CHCl 3)

Reference Example 17 3-Dodecanoyl- (5S) -benzyloxymethyl-
Synthesis of 2-oxazolidinone

Embedded image A solution of (5S) -benzyloxymethyl-2-oxazolidinone (1.2 g) in THF (29 ml) was cooled under cooling.
-Butyl lithium (1.6N, 3.98 ml) was added dropwise, and then dodecanoyl chloride (1.473 m) was added.
l) was added and the mixture was stirred at room temperature for 2 hours. A saturated saline solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography to obtain 1.443 g (64.0%) of the title compound as crystals. mp 51.8-52.1 ° C. NMR (CDCl 3): δ = 0.88 (t, 3H, J =
6.8 Hz), 1.2 to 1.4 (m, 16H), 1.6
3 (m, 2H), 2.89 (t, 2H, J = 7.6H
z), 3.60 (dt, 1H, J = 10.7, 3.
9), 3.69 (dt, 1H, J = 10.9, 8.
9), 4.58 (dt, 1H), 4.68 (m, 1H) IR (KBr, cm-1): 2916, 2850, 17
69, 1703, 1399, 1318, 1240, 12
10, 1198, 1135, 1114, 733, 690 [α] D + 31.3 (C = 1.04, CHCl 3)

Example 1 3-Dodecanoyl- (5S) -hydroxymethyl- (4
Synthesis of S) -propyl-2-oxazolidinone

Embedded image (5S) -t-butyldimethylsilyloxymethyl-3
To a solution of -dodecanoyl- (4S) -propyl-2-oxazolidinone (600 mg) in THF (6.58 ml) was added dropwise 2N hydrochloric acid (1.32 ml) under cooling, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give the title compound 4
42 mg (quantitative) were obtained as crystals. mp 59.2-59.7 ° C. NMR (CDCl 3): δ = 0.88 (t, 3H, J =
7.2 Hz), 0.94 (t, 3H, J = 7.3H)
z), 1.25 to 1.35 (m, 18H), 1.57 to
1.75 (m, 3H), 1.75 (dt, 1H), 2.
08 (s, 1H), 2.84 (m, 1H), 2.91
(M, 1H), 3.90 (dd, 1H, J = 12.2,
4.8 Hz), 4.00 (dd, 1H, J = 12.2,
7.3 Hz), 4.59 (m, 2H) IR (KBr, cm-1): 3424, 2924, 28
56, 1756, 1710, 1472, 1394, 13
40, 1302, 1080, 1060, 768, 722 [α] D + 52.9 (C = 0.575, CHCl 3)

Example 2 3-Dodecanoyl- (5R) -hydroxymethyl- (4
Synthesis of S) -propyl-2-oxazolidinone

Embedded image (5R) -t-butyldimethylsilyloxymethyl-3
-Dodecanoyl- (4S) -propyl-2-oxazolidinone was used as a starting material, and the title compound was obtained in the same manner as in Example 1. mp 62.3-63.5 ° C. NMR (CDCl 3): δ = 0.88 (t, 3H, J =
6.8 Hz), 0.97 (t, 3H, J = 7.2H)
z), 1.26-1.36 (m, 18H), 1.62-
1.70 (m, 3H), 1.79 to 1.82 (m, 1
H), 2.42 (s, 1H), 2.87 (m, 2H),
3.70 (dd, 1H, J = 13.3, 4.8 Hz),
3.81 (dd, 1H, J = 12.7, 4.8 Hz),
4.29 (dt, 2H, J = 10.8, 3.2 Hz) IR (KBr, cm-1): 3452, 2920, 28
52, 1752, 1708, 1482, 1394, 13
68, 1064, 1042, 1012, 762, 728 [α] D + 14.6 (C = 1.07, CHCl 3)

Example 3 3-Dodecanoyl- (5S) -hydroxymethyl-2-
Synthesis of oxazolidinone

Embedded image 3-dodecanoyl- (5S) -benzyloxymethyl-
Palladium hydroxide (289) was added to a solution of 2-oxazolidinone (1.443 g) in ethyl acetate (18.53 ml).
mg), and the mixture was stirred at room temperature under a stream of hydrogen for 2 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 914 mg (quantitative) of the title compound as crystals. mp 76.8-77.6 ° C. NMR (CDCl 3): δ = 0.88 (t, 3H, J =
7.0 Hz), 1.2 to 1.4 (m, 16H), 1.6
1-1.68 (m, 2H), 2.48 (s, 1H),
2.89 (t, 2H, J = 6.7 Hz), 3.70-
3.75 (br, 1H), 3.91 (dt, 1H, J =
11.0, 6.6 Hz), 3.95 to 4.00 (br,
1H), 4.03 (dt, 1H, J = 11.0, 9.3
Hz), 4.67 (m, 1H) IR (KBr, cm-1): 3480, 2916, 28
50, 1771, 1710, 1385, 1312, 12
21, 1192, 1030, 764 [α] D + 35.2 (C = 1.22, CHCl 3)

Example 4 3-Dodecanoyl- (5R) -hydroxymethyl-2-
Synthesis of oxazolidinone

Embedded image 3-dodecanoyl- (5R) -benzyloxymethyl-
The title compound was obtained in the same manner as in Example 3 except that 2-oxazolidinone was used as a starting material. This compound is an optical isomer of the target compound of Example 3, and the value of [α] D is opposite to that of the target compound of Example 3 in addition to the above.
R and IR data were the same.

Example 5 Synthesis of 3-dodecanoyl- (5S) -phosphatidylcorinohydroxymethyl- (4S) -propyl-2-oxazolidinone

Embedded image 3-dodecanoyl- (5S) -hydroxymethyl- (4
S) -Propyl-2-oxazolidinone (300mg)
In a benzene (6.15 ml) solution, triethylamine (0.135 ml) and then 2-chloro-2-oxo-.
1,3,2-dioxaphospholane (0.089 ml)
Was added and stirred at room temperature for 30 minutes. The reaction mixture was filtered under anhydrous conditions, and the filtrate was concentrated under reduced pressure. The resulting cyclic phosphate was immediately purified without purification of benzene (6.1
5 ml) and placed in a pressure-resistant tube. -78 ° C pressure tube
, And triethylamine was added thereto.
Stirred for days. The reaction mixture was concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography to give 443 mg (quantitative) of the title compound as a foamy solid. NMR (CD3OD): δ = 0.90 (t, 3H, J =
6.8 Hz), 0.95 (t, 3H, J = 7.3H)
z), 1.25 to 1.40 (m, 18H), 1.62 to
1.76 (m, 4H), 2.78 (m, 1H), 2.9
4 (m, 1H), 3.23 (s, 9H), 3.66
(M, 2H), 4.18 (m, 2H), 4.30 (m, 2H)
2H), 4.61 (m, 1H), 4.81 (m, 1H) IR (neat, cm-1): 2926, 2856, 1
781, 1708, 1469, 1381, 1256, 1
093,968,763 [α] D + 50.1 (C = 0.617, CH3OH)

Example 6 Synthesis of 3-dodecanoyl- (5R) -phosphatidylcorinohydroxymethyl- (4S) -propyl-2-oxazolidinone

Embedded image 3-Dodecanoyl- (5R) -hydroxymethyl- (4
The title compound was obtained in the same manner as in Example 5, except that S) -propyl-2-oxazolidinone was used as a starting material. NMR (CD3OD): δ = 0.90 (t, 3H, J =
6.8 Hz), 0.97 (t, 3H, J = 7.4H)
z), 1.29-1.38 (m, 18H), 1.60-
1.63 (m, 2H), 1.73-1.76 (m, 2
H), 2.75 (m, 1H), 2.95 (m, 1H),
3.22 (s, 9H), 3.63 (t, 2H, J = 4.
8 Hz), 3.95 (m, 1H), 4.04 (m, 1
H), 4.25 (br, 2H), 4.37 (dt, 1
H, J = 7.6, 3.2 Hz), 4.51 (br, 1
H) IR (CHCl3, cm-1): 3318, 2932,
2856, 1774, 1705, 1468, 1384,
1091,969,869 [α] D -4.89 (C = 0.624, CH3OH)

Example 7 Synthesis of 3-dodecanoyl- (5S) -phosphatidylcorinohydroxymethyl-2-oxazolidinone

Embedded image 3-dodecanoyl- (5S) -hydroxymethyl-2-
The title compound was obtained in the same manner as in Example 5 except that oxazolidinone was used as a starting material. NMR (CD3OD): δ = 0.90 (t, 3H, J =
6.8 Hz), 1.24 to 1.40 (m, 16H),
1.63 (m, 2H), 2.87 (m, 2H), 3.2
3 (s, 9H), 3.64 (t, 2H, J = 4.6H)
z), 3.87 (dt, 1H, J = 10.9, 5.9H
z), 3.98 (m, 1H), 4.02 (dt, 1H,
J = 10.7, 9.3 Hz), 4.12 (m, 1H),
4.28 (br, 2H), 4.83 (br, 1H) IR (KBr, cm-1): 3410, 2926, 28
56, 1776, 1701, 1485, 1392, 12
39,1092,970,832,760 [α] D + 36.8 (C = 0.53, CH3OH)

Example 8 Synthesis of 3-dodecanoyl- (5R) -phosphatidylcorinohydroxymethyl-2-oxazolidinone

Embedded image 3-dodecanoyl- (5R) -hydroxymethyl-2-
The title compound was obtained in the same manner as in Example 5 except that oxazolidinone was used as a starting material. This compound is an optical isomer of the target compound of Example 7, and the target compound of Example 7 and N
MR and IR data were the same. Although the value of [α] D is also the same, the absolute value is theoretically the same, except that the plus and minus values are reversed, but the actual measured values of the compound obtained in terms of purity are as follows. [Α] D-34.5 (C = 0.61, CH3OH)

[Dosage form of the compound of the present invention] The general formula [ I ]
Can be administered orally or parenterally. Dosage forms include tablets, granules, capsules,
Examples include soft capsules, injections, eye drops and the like, which can be formulated using widely used formulation techniques. For example, tablets, granules, capsules, oral preparations such as soft capsules, if necessary, lactose, starch, crystalline cellulose,
It can be prepared by adding a bulking agent such as vegetable oil, a lubricant such as magnesium stearate or talc, a binder such as hydroxypropylcellulose or polyvinylpyrrolidone, or a disintegrant such as calcium methylcellulose. Injections,
Parenteral preparations such as eye drops dissolve the compound in sterile purified water,
It can be prepared by adding a preservative, an isotonic agent and the like, if necessary. The dose of the compound can be determined according to the disease, symptom, age, etc., but is usually 1 to 1000 mg per day.
And can be administered once or in several divided doses.

[0054]

The effect of the novel oxazolidinone derivative of the present invention represented by the general formula [ I ] was examined and found to have an excellent phospholipase A2 inhibitory effect. This phospholipase A2 inhibitory activity was examined using phospholipase A2 derived from Japanese viper venom, and the novel oxazolidinone derivative of the present invention shows superior inhibitory activity as compared with the known oxazolidinone derivative in which the phosphatidyl group is substituted at the 4-position. , Inflammation, allergy, rheumatism, myocardial infarction, and asthma are expected to be useful in treating a wide range of diseases. .

Claims (26)

(57) [Claims] 1. A compound represented by the following general formula [ I ]. Embedded image [In the formula, R1 represents an alkyl group. R2 represents a hydrogen atom or an alkyl group. R3 represents an alkyl group. A1 and A2 represent an alkylene group. ] 2. The compound according to claim 1, wherein R1 is a higher alkyl group having 7 to 20 carbon atoms. 3. The compound according to claim 1, wherein R2 is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms. 4. The compound according to claim 1, wherein R3 is a lower alkyl group having 1 to 6 carbon atoms. 5. The compound according to claim 1, wherein A1 is a lower alkylene group having 1 to 6 carbon atoms. 6. The compound according to claim 1, wherein A2 is a lower alkylene group having 1 to 6 carbon atoms. 7. R1 is a higher alkyl group having 7 to 20 carbon atoms, R2 is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, R3 is a lower alkyl group having 1 to 6 carbon atoms, A1 and A2 Is a lower alkylene group having 1 to 6 carbon atoms. 8. The compound according to claim 7, wherein R1 is an undecyl group. 9. The compound according to claim 7, wherein R2 is a hydrogen atom. 10. The compound according to claim 7, wherein R2 is a propyl group. 11. The compound according to claim 7, wherein R3 is a methyl group. 12. The compound according to claim 7, wherein A1 is a methylene group. 13. The compound according to claim 7, wherein A2 is an ethylene group. 14. The compound according to claim 7, wherein R3 is a methyl group, A1 is a methylene group, and A2 is an ethylene group. 15. The compound according to claim 7, wherein R1 is an undecyl group, R2 is a hydrogen atom or a propyl group, R3 is a methyl group, A1 is a methylene group, and A2 is an ethylene group. 16. Dodecanoyl- (5S) -phosphatidyl corinohydroxymethyl- (4S) -propyl-2-oxazolidinone. 17. Dodecanoyl- (5R) -phosphatidyl corinohydroxymethyl- (4S) -propyl-2-oxazolidinone. 18. Dodecanoyl- (5S) -phosphatidyl corinohydroxymethyl-2-oxazolidinone. 19. Dodecanoyl- (5R) -phosphatidyl corinohydroxymethyl-2-oxazolidinone. 20. A compound represented by the following general formula [ II ]. Embedded image [In the formula, R1 represents an alkyl group. R2 represents a hydrogen atom or an alkyl group. A1 represents an alkylene group. ] 21. The method according to claim 20, wherein R1 is a higher alkyl group having 7 to 20 carbon atoms, R2 is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and A1 is a lower alkylene group having 1 to 6 carbon atoms. Compound. 22. The compound according to claim 20, wherein R1 is an undecyl group, R2 is a hydrogen atom or a propyl group, and A1 is a methylene group. 23. 3-Dodecanoyl- (5S) -hydroxymethyl- (4S) -propyl-2-oxazolidinone. 24. 3-Dodecanoyl- (5R) -hydroxymethyl- (4S) -propyl-2-oxazolidinone. 25. 3-Dodecanoyl- (5S) -hydroxymethyl-2-oxazolidinone. 26. 3-Dodecanoyl- (5R) -hydroxymethyl-2-oxazolidinone.