JPH05239078A - New oxazolidinone derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound, having inhibiting action on phospholipase A2 and useful as a therapeutic agent for a wide range of diseases such as inflammation, allergy, rheumatism, cardiac infarction or asthma. CONSTITUTION:The objective compound of formula I or II [R<1> is alkyl, R<2> is hydroxy or (alkyl)amino; A and B are alkylene] and its salts, e.g. (S)-3- dodecanoyl-4-phosphatidyloholinohydroxymethyl-2-oxazolidinone. This compound is preferably obtained by reacting a compound of formula III (R<3> is H) with 2-chloro-2-oxo-1,3,2-dioxaphospholane, providing a derivated compound of formula III (R<3> is formula IV) and then reacting the resultant compound with an amine. The intermediate of formula III (R<3> is H or formula IV) is a new substance and the compound of formula III (R<3> is H) is obtained by silylating, e.g. a compound of formula V, subsequently hydrolyzing the prepared compound under basic conditions, then converting the obtained product into a compound of formula VI with an acylating agent and subsequently desilylating the compound of formula VI under acidic conditions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel oxazolidinone derivative useful as a medicine.

[0002]

2. Description of the Related Art Phosphatidylcholine is a phospholipid contained in soybean and the like, and its various uses have been studied. On the other hand, many studies have been conducted on its chemical modification, and a derivative in which an acylamino group has been introduced at the 2-position of phosphatidylcholine has been reported (JP-A-54-148727, JP-A-5-148727).
5-118494, JP-A-58-43942, JP-A-SHO-6
1-24519, JP-A-62-12754 and others). These references report various carbon chains of the alkyl chain of the acyl moiety and the alkylene group bonded to the phosphate moiety.

[0003]

However, there have been almost no reports of those having a cyclic structure,
In particular, nothing was known about oxazolidinone derivatives.

[0004]

Therefore, the present inventors have focused on a phosphatidylcholine derivative having a cyclic structure, particularly an oxazolidinone derivative, and as a result of diligent studies on its synthesis, succeeded in obtaining a novel oxazolidinone derivative. Furthermore, when the pharmacological action of these compounds was investigated, it was found that they also have a phospholipase A ₂ inhibitory action.

[0005]

The present invention includes the following general formula [I] or [I
I] and a salt thereof (hereinafter referred to as the present compound), and a compound represented by the general formula [III] as a synthetic intermediate thereof.

[Chemical 4] [In the formula, R ¹ represents an alkyl group. R ² represents a hydroxy group, an amino group or an alkylamino group. A and B are the same or different and each represents an alkylene group. ] R ³
Represents a hydrogen atom or Chemical formula 5. same as below. ]

[Chemical 5]

Explaining in more detail the above-defined groups, the alkyl groups are methyl, ethyl, pentyl,
Undecyl, heptadecyl, octadecyl, eicosyl, isopropyl, t-butyl and other linear or branched alkyl are shown, and the alkylene group is methylene, ethylene,
A linear or branched alkylene group such as hexamethylene or (dimethyl) methylene is shown. The alkylamino group refers to one in which an amino group is substituted with 1 to 3 alkyl groups, and examples thereof include methylamino, dimethylamino, trimethylamino, and the like, but the nitrogen atom bears a positive charge,
The whole molecule may be betaine type.

Examples of the salts include pharmaceutically acceptable salts such as sodium salt, potassium salt, calcium salt and magnesium salt.

The following are typical methods for synthesizing the compounds [I] and [II] of the present invention.

[Chemical 6]

First, a compound represented by the formula [IV] (a compound of the formula [III] in which R ³ is a hydrogen atom) is treated with 2-chloro-
A compound of formula [V] (R ^{3 of} formula [III] is a compound of formula 5) is obtained by reacting with 2-oxo-1,3,2-dioxaphosphorane and then reacted with an amine. Alternatively, the compound of the present invention represented by the formula [I] or [II] can be obtained by treating the compound with an acid such as acetic acid.

Next, a representative synthetic route of the compound represented by the formula [III] which is a synthetic intermediate is shown below.

[Chemical 7]

The compound of the formula [III] which is a synthetic intermediate includes the compounds of the formula [IV] and the formula [V]. The synthetic method of the compound of the formula [V] is shown above. Therefore, a method for synthesizing the compound represented by the formula [IV] is shown here.

First, a compound represented by the formula [VII] (reference: CHEMISTRY LETTERS 1245-1248, 1991) is silylated with a silylating agent such as t-butyldimethylsilyl chloride to obtain a compound represented by the formula [VII]. After that, the compound is hydrolyzed under basic conditions to obtain the compound represented by the formula [VIII]. Next, the compound of formula [IX] is prepared using an acylating agent such as acid chloride, and then desilylated under acidic condition to obtain the compound of formula [IV].

Since the compound of the present invention has an optically active carbon atom, optical isomers occur, all of which are included in the present invention. Since the above-mentioned synthetic method is a method capable of maintaining the configuration, when an optically active compound is used as a raw material compound, an optically active product can be obtained.

A large number of studies have been conducted on derivatives that form an amide bond at the 2-position of phosphatidylcholine. The research is mainly related to the conversion of an acyl group forming an amide bond and the conversion of an alkylene group forming a phosphoric acid. These references report a large number of compounds having an acyl group or an alkylene group having 1 or 2 carbon atoms to those having more than 20 carbon atoms, and also disclose application to pharmaceuticals such as antitumor agents. There is.

However, there have been almost no reports of compounds having a cyclic structure, and nothing has been known about oxazolidinone derivatives. Therefore,
As a result of intensive studies on the synthesis, the present inventors have succeeded in obtaining a novel oxazolidinone derivative.

Furthermore, when the pharmacological action of these compounds was examined, it was found that they also have a phospholipase A ₂ inhibitory action. Phospholipase A ₂
Compounds having an inhibitory action have been reported to be useful for various diseases, and the compounds of the present invention are also expected to be therapeutic agents for a wide range of diseases such as inflammation, allergy, rheumatism, myocardial infarction, and asthma.

The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, granules, capsules, soft capsules, injections and the like, which may be formulated using a commonly used technique. For example, tablets, granules, capsules, oral preparations such as soft capsules are lactose, starch, crystalline cellulose, bulking agents such as vegetable oil, magnesium stearate, lubricants such as talc, hydroxypropyl cellulose, etc. A formulation may be prepared by adding a binder such as polyvinylpyrrolidone and a disintegrating agent such as calcium methylcellulose calcium.

[0018]

【Example】

Reference Example 1 (R)-(-)-3-t-butyldimethylcytyl-4-
Benzoyloxymethyl-2-oxazolidinone (Compound 1) (R)-(−)-4-benzoyloxymethyl-2-oxazolidinone (1 g, 4.5 mmol) in dimethylformamide (6.8 ml) solution under cooling with triethylamine. (1.90 ml, 13.56 mmol), 4-dimethylaminopyridine (552 mg, 4.52 mmo
1) was added, and further t-butyldimethylsilyl chloride (1.362 g, 9.04 mmol) was added. The reaction mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 12 minutes.
Stir for hours. Distilled water was added to the reaction mixture under cooling, followed by extraction with ethyl acetate. The obtained organic layers were collected, washed with saturated saline and the solvent was distilled off to obtain an oily substance. This is subjected to silica gel column chromatography, elution solvent hexane / ethyl acetate (5: 1-3: 1)
The eluate was collected and the solvent was evaporated under reduced pressure to give the title compound (1.438 g) as crystals (yield 94.8).
%).

Mp 77.9-78.9 ° C. NMR (CDCl ₃ ) 0.37 (s, 6H), 0.9
9 (s, 9H), 4.07 (m, 1H), 4.16
(M, 1H), 4.19-4.45 (m, 3H), 7.
44-8.03 (m, 5H) IR (CHCl ₃ , cm ^-1 ) 1730, 1700 [α] _D ²¹ -51.0 ° (c = 1.34, CHCl 3
₃ )

Reference Example 2 (R)-(+)-4-t-Butyldimethylcytyloxymethyl-2-oxaziridinone (Compound 2) Potassium hydroxide (1.051 g, 18.73 m) under cooling.
(1 mol) in a solution of methanol (9 ml) in
g, 14.90 mmol) in methanol (26 ml) was added dropwise, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 30 minutes. 5 to the reaction mixture under cooling
% Citric acid was added to neutralize the reaction solution, and methanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The obtained organic layers were collected, washed with saturated saline and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain an oily substance. This oily substance was subjected to silica gel column chromatography, and the eluted portion with an elution solvent hexane / ethyl acetate (3: 1) was collected to obtain the title compound (3.193 g) as crystals (yield 92.6%).

Mp 58.5-60.0 ° C. NMR (CDCl ₃ ) 0.06 (s, 6H), 0.8
8 (s, 9H), 3.61 (d, 2H), 3.92
(M, 1H), 4.17 (q, 1H), 4.44 (t,
1H) IR (CHCl ₃ , cm ⁻¹ ) 3320, 1740 [α] _D ²¹ 13.4 ° (c = 1.445, CHCl 3
₃ )

Reference Example 3 (R) -3-Dodecanoyl-4-t-butyldimethylcytyloxymethyl-2-oxazolidinone (Compound 3) A solution of Compound 2 (1 g, 4.322 mmol) in tetrahydrofuran (10.8 ml) was added. , Triethylamine (1.204 ml, 8.64 mmol) under cooling, 4-dimethylaminopyridine (316 mg, 2.59 mmol)
Was added, and dodecanoyl chloride (1.891) was added.
g, 8.64 mmol) was added. The reaction mixture was stirred at 0 ° for 10 minutes and then at room temperature for 14 hours.
Distilled water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The obtained organic layers were collected, washed with saturated saline, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain an oily substance. This was subjected to silica gel column chromatography, the elution portion with hexane / ethyl acetate (5: 1) was collected, and the solvent was evaporated under reduced pressure to give the title compound (1.924 g) as an oil.

NMR (CDCl ₃ ) 0.06 (s, 6
H), 0.88 (s, 9H), 3.61 (d, 2H),
3.2 (m, 1H), 4.17 (q, 1H), 4.44
(T, 1H)

Example 1 (R)-(-)-3-dodecanoyl-4-hydroxymethyl-2-oxazolidinone (Compound 4)

[Chemical 8] Compound 3 (1.924 g) in tetrahydrofuran (2
4.1 ml) solution under cooling with 2N hydrochloric acid (4.83 ml)
Was added dropwise, and the resulting mixture was stirred at the same temperature for 10 minutes and then at room temperature for 11 hours. Distilled water was added to the reaction mixture, and extraction was performed with ethyl acetate. The obtained organic layers were collected, washed with saturated saline and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain an oily substance. This oil was subjected to silica gel column chromatography, and elution solvent hexane / ethyl acetate (5: 1-3: 1).
The fractions eluted by the above were collected to obtain the title compound (1.018 g) as crystals (total yield from Reference Example 3: 78.8).
%).

Mp 67.5-68.5 ° C. NMR (CDCl ₃ ) 0.85 (t, 3H), 1.3
0 (s, 16H), 1.65 (m, 2H), 2.65
(OH, 1H), 2.95 (m, 2H), 3.83
(M, 2H), 4.34 (m, 1H), 4.43 (t,
1H), 4.55 (m, 1H) IR (CHCl ₃ , cm ^-1 ) 3460, 1780, ¹
700 [α] _D ²¹ -51.8 ° (c = 1.06, CHCl
₃ )

Example 2 (S) -3-dodecanoyl-4- (2-oxo-1,
3,2-Dioxaphosphoran-2-yl) oxymethyl-2-oxazolidinone (Compound 5)

[Chemical 9] Compound 4 (200 mg, 0.669) under an argon stream.
mmol) in anhydrous benzene (10 ml) under cooling with triethylamine (0.139 ml, 1.00 mmo).
l), 4-dimethylaminopyridine (32 mg, 0.2
68 mmol) was added, and further 2-chloro-2-oxo-1,3,2-dioxaphosphorane (142 mg,
1.00 mmol) was added. The reaction mixture was stirred at 0 ° C for 10
After stirring for 1 minute, the mixture was further heated to 35 ° C. and stirred for 18 hours. The reaction mixture was filtered under an argon stream in an anhydrous state, and the solvent was evaporated under reduced pressure to give the title compound. This cyclic phosphate was used for the next reaction without purification.

Example 3 (S) -3-Dodecanoyl-4-phosphatidylcholinehydroxymethyl-2-oxazolidinone (Compound 6)

[Chemical 10] The crude cyclic phosphate ester (Compound 5) obtained in Example 2 was dissolved in 6 ml of anhydrous benzene and transferred to a pressure resistant tube. Here, trimethylamine (about 2 ml, 22.1
(9 mmol) was added and the tube was sealed, heated to about 75 ° C. and stirred for 3 days. The solvent was distilled off under reduced pressure without post-treatment of the reaction mixture to obtain a semi-solid mixture. This semi-solid mixture was subjected to silica gel column chromatography, and the elution portion with chloroform / methanol / water (65: 25: 4) was collected and the solvent was distilled off under reduced pressure to obtain the title compound (121 mg). Total yield from Example 2 3
9.4%).

NMR (CDCl ₃ ) 0.89 (t, 3
H), 1.28 (s, 16H), 1.64 (t, 2)
H), 2.89 (m, 2H), 3.22 (s, 9H),
3.60 (t, 2H), 4.06 (m, 2H), 4.2
0 (m, 3H), 4.50 (m, 2H), 4.64
(M, 1H) IR (CHCl ₃ , cm ^-1 ) 1790, 1720

The following compounds are obtained by changing the raw materials and operating in the same manner as in Example 3. -(S) -3-Hexanoyl-4-phosphatidylcholinohydroxymethyl-2-oxazolidinone- (S) -3-nonadecanoyl-4-phosphatidylcholinohydroxymethyl-2-oxazolidinone

Example 4 (S) -3-Dodecanoyl-2-oxooxazolidin-4-ylmethoxyphosphoglycol (Compound 7)

[Chemical 11] Using compound 4 (284 mg, 0.950 mmol),
The cyclic phosphate ester obtained by the same operation as in Example 2 was dissolved in acetone (5.2 ml), 50% acetic acid (0.047 ml) was added at room temperature, and the mixture was stirred for 12 hours. The solvent was distilled off under reduced pressure to obtain an oily substance without post-treatment of the reaction mixture. This is subjected to silica gel column chromatography, eluting solvent chloroform / methanol / water (6
5: 25: 4) was collected and the solvent was distilled off under reduced pressure to obtain the title compound (256 mg) (yield 63.
7%).

NMR (CDCl ₃ ) 0.89 (t, 3
H), 1.26 (s, 16H), 1.63 (m, 2)
H), 2.90 (t, 2H), 3.75 (s, 2H),
4.00 (s, 2H), 4.18 (m, 2H), 4.3
7 (t, 1H), 4.65 (m, 1H) IR (CHCl ₃ , cm ^-1 ) 1790, 1715

INDUSTRIAL APPLICABILITY The compound of the present invention has the effect of providing a novel oxazolidinone derivative having a phospholipase A ₂ inhibitory action.

Claims (5)

[Claims] 1. A compound represented by the general formula [I] or [II] and salts thereof. [Chemical 1] [In the formula, R ¹ represents an alkyl group. R ² represents a hydroxy group, an amino group or an alkylamino group. A and B are the same or different and each represents an alkylene group. ] 2. A compound represented by the general formula [III]. [Chemical 2] [In the formula, R ¹ represents an alkyl group, and A represents an alkylene group. R ³ represents a hydrogen atom or Chemical formula 3. ] [Chemical 3] 3. A is --CH _2- , B is --CH ₂ CH _2-.
Wherein R ² is —N ⁺ (CH ₃ ) ₃ ; 4. The compound according to claim 1, wherein the 4-position of oxazolidinone has the (S) configuration. 5. (S) -3-Dodecanoyl-4-phosphatidylcholinohydroxymethyl-2-oxazolidinone.