JP2534907B2 - Novel glycerin derivative - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel glycerin derivative.

BACKGROUND OF THE INVENTION In recent years, platelet activating factor [Platelet Activat
ing Factor, hereinafter abbreviated as PAF], and various physiological actions have been clarified.

That is, it has been found that PAF is involved in allergy, inflammation, and platelet aggregation as in vivo functions, and on the other hand, has a strong hypotensive action. [Nature, Volume 285, 193 (1980): European Journal of Pharm
acalogy, 65 , 185-192 (1980)] Therefore, various studies have been carried out for the purpose of utilizing the blood pressure lowering action of PAF while reducing the undesirable action such as platelet aggregation action of PAF.

The following formula, which is a structure similar to the glycerin derivative of the present invention: [Where alkyl is a saturated linear or branched hydrocarbon group having 6 to 20 carbon atoms or such an olefinically unsaturated hydrocarbon group containing 1 or 2 double bonds] And R represents methyl or ethyl] (JP-A-57-53492) and a compound represented by the following formula: [In the formula, R ¹ is an alkoxy group, or an alkenyloxy group,
Acyloxy group, acylamino group, R ² is a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an acyloxy group,
Aryloxy group, alkylthio group, arylthio group,
Thiadiazolylthio group, lower alkylsulfonyl group, alkoxycarbonylamino group, acylamino group, A is 2
-Representing a tolylalkylaminoethyl group] (JP-A-63-104988) and the like are known.

However, there is no known compound such as the compound of the present invention in which the 1- and 3-position oxygen atoms of glycerol are replaced with sulfur atoms.

SUMMARY OF THE INVENTION The present invention relates to a PAF derivative, and more specifically an object thereof is to provide a novel glycerin derivative represented by the following formula.

The novel glycerin derivative of the present invention has the general formula: [In the formula, R ¹ represents a linear or branched alkyl group having 10 to 22 carbon atoms, R ² represents a linear or branched acyl group having 1 to 6 carbon atoms, and Y represents (However, R ³ , R ⁴ and R ⁵ are each independently a carbon number of 1 to 1.
4 represents a linear or branched alkyl group of 4), and n is 0 or an integer of 1 to 3].

[Effects of the Invention] The novel glycerin derivative of the present invention has a platelet aggregation inhibitory action, an anti-asthma action, an anti-allergic action, an anti-inflammatory action,
It has excellent effects on blood pressure lowering action and antitumor action.

DETAILED DESCRIPTION OF THE INVENTION In the general formula (I), R ¹ is decyl, undecyl,
Dodecyl, tridecyl, tetradecyl, pentadecyl,
A linear or branched alkyl group having 10 to 22 carbon atoms such as hexadecyl, heptadecyl, octadecyl, nonadecyl, aicosyl, henaicosyl, and doicosyl is shown. R ¹
Is particularly preferably a linear or branched alkyl group having 12 to 20 carbon atoms.

R ² represents a straight chain or branched chain acyl group having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl.

In the group represented by Y, R ³ , R ⁴ and R ⁵ are methyl,
It represents a linear or branched alkyl group having 1 to 4 carbon atoms such as ethyl, propyl, n-butyl, t-butyl.

Specific examples of typical compounds of the glycerin derivative of the present invention include the following compounds.

Thiophosphoric acid 2-trimethylammonioethyl S-
(3-Hexadecylthio-2-acetoxy) propyl The production method of the present invention is carried out, for example, by the method shown below.

(In the above formula, R ¹ , R ² and Y are the same as those described above, Ts is tosyl, R ′ is an alkyl group having 1 to 3 carbon atoms, and X is a halogen atom or a tosyloxy group. The glycerin derivative of the present invention is used as, for example, tablets, granules, powders, capsules, syrups, suppositories, and injections.

Usually, as an active ingredient, 0.1m per dose for oral administration
It is preferably g / kg to 50 mg / kg, depending on the symptoms 1 to
It is convenient to administer four doses. The dose may be appropriately increased or decreased depending on the condition of the target patient and the administration method.

In the production of the above-mentioned various preparations, various carriers or excipients usually used can be used.

 Next, examples of the present invention will be described.

Example 1 i) 3- (Hexadecylthio) -1,2-propanediol To a solution of thioglycerol (7.78 g, 29.8 mmol) in ethanol, potassium hydroxide (1.96 g, 35.0 mmol).
Was dissolved. Hexadecyl chloride (3.54
g, 32.8 mmol) was added and the mixture was heated under reflux for 3 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, and the residue was extracted with ethylene chloride. The extract was dried over sodium sulfate, the solvent was evaporated, and the residue was recrystallized from benzene to give the title compound (5.88 g, yield 60%).

Melting point: 68 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.87 (3H, t) 1.27 (26H, s) 1.58 (2H, m) 2.53 (2H, t) 2.59−2.73 (2H, m) 3.50-3.60 (1H , m) 3.75 (1H, dd) 3.80 (1H, dd) IR (nujol) cm ^-1 : 3400,1100,1060,1010 ii) p-toluenesulfonic acid 3- (hexadecylthio) -2-hydroxypropyl ester i) 80m anhydrous methylene chloride of the compound obtained in (4.43g, 13.3mmol)
5 ml of anhydrous pyridine and p-toluenesulfonyl chloride (3.63 g, 19.0 mmol) were added to the solution of 1 and stirred at room temperature for 3 days. After completion of the reaction, the methylene chloride solution was washed successively with 1N-HCl, saturated aqueous sodium hydrogen carbonate solution and water, and then dried over sodium sulfate. After that, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain 3.63 g (yield 57%) of the title compound. ¹ H NMR (CDCl ₃ ) δ: 0.88 (3H, t) 1.26 (26H, s) 1.49-1.57 (2H, m) 2.46 (3H, s) 2.49 (2H, t) 2.55 (1H, dd) 2.69 (1H , dd) 3.90 (1H, dddd) 4.05 (1H, dd) 4.10 (1H, dd) 7.36 (2H, d) 7.80 (2H, d) IR (solution cell, CHCl ₃ ) cm ^-1 : 3500,2900,2850 , 1320,1140 iii) Di- (3-hexadecylthio-2-hydroxypropyl) disulfide ii) A solution of the compound obtained (1.08 g, 2.04 mmol) in 10 ml of dimethylformamide was added sodium iodide (0.
34 g, 2.25 mmol) was added and heated at 100 ° C. for 30 minutes.
After cooling to room temperature, sodium hydrosulfide (0.252g, 4.
(50 mmol) was added and stirred for 4 hours. After completion of the reaction, methylene chloride was added to the reaction mixture, and the organic layer was washed with 1N-HCl,
After washing with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in that order, the solvent was distilled off under reduced pressure to obtain crystals. The crystals were recrystallized from ethyl acetate to give the title compound (0.578 g, yield 82%).
%) Was obtained.

Melting point: 86 ° C. ¹ H NMR (CDCl ₃ ) δ: 0.87 (6H, m) 1.26 (56H, s) 2.20-2.80 (12H, m) 3.70-4.00 (2H, m) IR (solution cell, CHCl ₃ ) cm ^-1 : 3500,2900,2830 iv) Di- (3-hexadecylthio-2-acetoxypropyl) disulfide iii) A solution of the compound (1.89 g, 2.73 mmol) obtained in pyridine in 50 ml of anhydrous pyridine was added to acetic anhydride (11.1 ml, 117 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with 1N-HCl, water, saturated aqueous sodium hydrogen carbonate solution and water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure,
2.13 g of the title compound was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.88 (6H, t) 1.25 (52H, s) 1.50-1.63 (4H, m) 2.08 (6H, s) 2.55 (4H, t) 2.75 (2H, dd) 2.82 (2H , dd) 3.15 (2H, dd) 3.31 (2H, dd) 5.15-5.30 (2H, m) IR (solution cell, CHCl ₃ ) cm ^-1 : 2900,2830,1730 v) Dimethyl thiophosphate S- (3- Hexadecylthio-2-acetoxy) propyl iv) The compound obtained (709 mg, 0.910 mmol) was dissolved in 5 ml of anhydrous toluene. This solution was cooled with an ice-salt bath.
It was cooled to below ℃. Subsequent distilled sulfuryl chloride (0.
11 ml (1.10 mmol) was added dropwise, 20 minutes later, dimethyl phosphite (0.19 ml, 2.10 mmol) was added, and the mixture was further stirred at the same temperature for 3 hours. After completion of the reaction, the toluene solution was washed successively with water, a saturated sodium hydrogen carbonate aqueous solution and saturated saline, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to give the title compound (569 mg, yield 63%). ¹ H NMR (CDCl ₃ ) δ: 0.88 (3H, t) 1.26 (26H, s) 1.52-1.63 (2H, m) 2.10 (3H, s) 2.55 (2H, t) 2.75 (2H, d) 3.06 (1H , ddd) 3.27 (1H, ddd) 3.81 (6H, d) 5.14 (1H, tdd) vi) Sodium thiophosphate Methyl S- (3-hexadecylthio-2-acetoxy) propyl Obtained in v) under nitrogen atmosphere Compound (383mg, 0.7
Dried sodium iodide (115 mg, 0.768 mmol) was added to 8 ml of anhydrous acetone solution (68 mmol), and the mixture was stirred at room temperature for 24 hours. The formed crystals were washed with a small amount of anhydrous acetone to obtain 385 mg of the title compound. ¹ H NMR (CDCl ₃ / DMSO-d ₆ ) δ: 0.88 (3H, t) 1.26 (26H, s) 1.52-1.63 (2H, m) 2.10 (3H, s) 2.55 (2H, t) 2.73 (1H, dd) 2.86 (1H, dd) 2.92-3.10 (2H, m) 3.56 (3H, d) 5.14 (1H, m) IR (nujol) cm ^-1 : 3400,1600,1180,1080,1010 Vii) Bromoethyl thiophosphate Methyl S- (3-
The compound obtained in hexadecylthio-2-acetoxy) propyl vi) (74.5 mg, 0.147 mmol) was azeotroped with anhydrous pyridine several times under reduced pressure. The residue was dissolved in 1 ml of anhydrous pyridine and the solution was cooled to 0 ° C under nitrogen atmosphere. Then, first, 2,4,6-triisopropylbenzenesulfonyl chloride (155.9 mg, 0.515 mmol)
Was added, and 10 minutes later, bromoethanol (0.104 ml, 1.47 mmol) was added, and the mixture was stirred for 3 hours. After the reaction was completed, water was added at 0 ° C., the mixture was extracted with ethyl acetate, and the extract was diluted with 1N-HC.
It was washed successively with 1 and saturated saline and then dried over sodium sulfate. After that, the solvent was distilled off under reduced pressure at low temperature, and the residue was subjected to column chromatography to give 74.4 mg of the title compound.
(Yield 86%) was obtained. ¹ H NMR (CDCl ₃ ) δ: 0.88 (3H, t) 1.26 (26H, s) 1.52-1.63 (2H, m) 2.10 (3H, s) 2.55 (2H, t) 2.75 (2H, d) 3.12 (1H , ddd) 3.33 (1H, ddd) 3.54-3.61 (2H, m) 3.84 (3H, d) 4.34-4.43 (2H, m) 5.14 (1H, tdd) viii) Sodium thiophosphate Bromoethyl S- (3
-Hexadecylthio-2-acetoxy) propyl Under a nitrogen atmosphere, the compound obtained in vii) (74.4 mg,
0.126 mmol) in 1 ml of anhydrous acetone was added dry sodium iodide (20.92 mg, 0140 mmol),
The mixture was stirred at room temperature for 24 hours. The white crystals that formed were filtered and washed with a small amount of anhydrous acetone, while the residue obtained from the mother liquor was isolated by thin layer chromatography (chloroform: methanol: water = 7: 2.5: 0.5) to give the above crystals. 57 mg (75% yield) of the title compound was obtained. ¹ H NMR (CDCl ₃ / DMSO-d ₆ ) δ: 0.88 (3H, t) 1.26 (26H, s) 1.52-1.63 (2H, m) 2.10 (3H, s) 2.55 (2H, t) 2.70-3.00 ( 4H, m) 3.54-3.64 (2H, m) 4.06-4.24 (2H, m) 5.12-5.22 (1H, m) IR (nujol) cm ^-1 : 3400,1180,1080,1000 ix) 2-trimethyl thiophosphate Ammonioethyl S
-(3-Hexadecylthio-2-acetoxy) propyl viii) The compound (49 mg, 0.0817 mmol) obtained in viii) was dissolved in 4 ml of isopropyl alcohol containing 1.6 mmol of trimethylamine, and it was dissolved in a sealed tube containing nitrogen.
The mixture was heated to ℃ and stirred for 10 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography to give the title compound (21 mg, yield 46%) as white crystals. ¹ H NMR (CDCl ₃ / CD ₃ OD) δ: 0.88 (3H, t) 1.26 (26H, s) 1.52-1.63 (2H, m) 2.10 (3H, s) 2.55 (2H, t) 2.71 (1H, dd ) 2.88 (1H, dd) 2.98 (1H, ddd) 3.08 (1H, ddd) 3.32 (9H, s) 3.62-3.68 (2H, m) 4.15-4.25 (2H, m) 5.14 (1H, dddd) ¹³ C NMR (CDCl ₃ ) δ: 14.13 (1c) 22.70 (1c) 29.36 (1c) 29.62 (1c) 29.67,29.72 (1c) 29.71 (13c) 31.92 (1c) 53.42 (3c) 54.66 (1c) 66.31 (1c) 71.53 ( 1c) 170.30 (1c) ³¹ P NMR (CDCl ₃ ) δ: 16.5 IR (nujol) cm ^-1 : 3400,1720,1200,1040

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/685 ACF A61K 31/685 ACF ADU ADU

Claims (1)

(57) [Claims] 1. A general formula: [In the formula, R ¹ represents a linear or branched alkyl group having 10 to 22 carbon atoms, R ² represents a linear or branched acyl group having 1 to 6 carbon atoms, and Y represents (However, R ³ , R ⁴ and R ⁵ are each independently a carbon number of 1 to 1.
4 represents a straight chain or branched chain alkyl group of 4), and n is 0 or an integer of 1 to 3].