JPH027942B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel nitrate ester derivatives. The compound of the present invention has the general formula () [In the formula, R ¹ is a hydrogen atom or a nitro group, R ² is an ω-(nitrooxy)alkyl group having 1 to 6 carbon atoms, an ω-(carboxy)alkyl group having 2 to 7 carbon atoms, or a general formula () (In the formula, R ¹ is the same as above.) ] and exhibits a vasodilatory effect, making it useful as a therapeutic agent for ischemic heart disease among cardiovascular system therapeutic agents. The compound of the present invention has the following general formula () (In the formula, R ³ represents an alkali metal salt or an alkaline earth metal salt of an ω-hydroxyalkyl group or an ω-carboxyalkyl group.) It can be produced by reacting an alcohol derivative represented by the following in fuming nitric acid at a low temperature. I can do it. On the other hand, the general formula ()
The nitric acid ester in which R ² is a group represented by the general formula () has the general formula () obtained by the above production method. (In the formula, R ¹ is the same as above.) In a solvent such as tetrahydrofuran, chloroform, dichloromethane, etc., in the presence of triethylamine,
It can be produced by reacting with an alkyl chlorocarbonate to form a mixed acid anhydride, and then reacting with cystamine. Regarding the coronary vasodilator effect of panthenol trinitrate, which is a representative compound of the compound of the present invention thus prepared, Life Science Vol. 23, p. 1609,
According to the method described in 1978 (Shoichi Imai et al.), we investigated the coronary vascular perfusion rate when 30 μg was administered using Langendorff's method using isolated heart specimens from guinea pigs.
It was confirmed that the above-mentioned compound of the present invention exhibits approximately 70% of the activity of increasing coronary blood flow when nitroglycerin is administered. The present invention will be explained below using examples. Example 1 A solution of 3.0 g of D-panthenol dissolved in 4 ml of glacial acetic acid is added dropwise to 25 ml of fuming nitric acid (specific gravity 1.52) cooled to 0-2°C in an ice-water bath. After the dropwise addition, the mixture was further stirred for 3.5 hours at 0 to 5°C, and then added with 100 ml of ice water.
Pour inside. The resulting aqueous solution is extracted with chloroform. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oily residue was subjected to column chromatography using 50 g of silica gel, eluted with chloroform, and silica gel thin layer chromatography [developing solvent: chloroform-isopropyl ether (1:1) mixture] to obtain an Rf value of approximately 0.7. Collect the flux that recognizes the spot,
Concentration under reduced pressure yields 2.43 g of colorless prismatic panthenol trinitrate. Melting point 54.5-56℃ NMR (CDCl ₃ , 90MHz) δppm: 1.19, 1.21 (3H, s, -CH ₃ respectively) 2.01 (2H, m, -CH ₂ CH ₂ CH ₂ -) 3.46 (2H, q, ―NHC H ₂ CH ₂ ―) 4.45 (2H, s,

[Formula]) 4.53 (2H, t, - CH ₂ C H ₂ ONO ₂ ) 5.13 (1H, s,

[Formula]) 6.56 (1H, br, -CON H -) Elemental analysis (%) As C ₉ H ₁₆ N ₄ O ₁₀ Calculated value C31.77, H 4.74, N 16.47 Actual value C31.56, H 4.33, N 16.44 The above silica gel column chromatography was further eluted with a mixed solvent of chloroform-acetone (1:1), and the fractions showing an Rf value of about 0.4 in the silica gel thin layer chromatography were combined and concentrated under reduced pressure to form a colorless oily N- (4-nitrooxy-3,3-
0.8 g of dimethyl-2-hydroxybutyl)-3-aminopropyl nitrate is obtained. NMR (CDCl ₃ , 90MHz) δppm: 1.05, 1.07 (3H, s, -CH ₃ respectively) 2.00 (2H, m, -CH ₂ CH ₂ CH ₂ -) 3.43 (2H, q, -NHC H ₂ CH ₂ ―) 4.01 (1H, s,

【formula】) 4.45(2H,s,

[Formula]) 4.55 (2H, t, - CH ₂ C H ₂ ONO ₂ ) 7.13 (1H, br, - CON H -) Example 2 Fuming nitric acid in which 3.0 g of sodium D-pantothenate was cooled to 1 to 3°C (Specific gravity 1.52) Add little by little to 21ml. After the addition is complete, the mixture is further stirred at 2 to 5°C for 3 hours. Thereafter, the reaction solution was poured into 150 ml of ice water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remaining oil is subjected to column chromatography using 35 g of silica gel. Chloroform 500ml
After flushing, chloroform-methanol (20:
Elute with the mixed solvent of 1) and concentrate the obtained fraction under reduced pressure to obtain 3.5 g of pantothenic acid dinitrate as a colorless oil. NMR (CDCl ₃ , 90MHz) δppm: 1.16, 1.18 (3H, s, -CH ₃ respectively) 2.64 (2H, t, -CH ₂ CH ₂ COOH) 3.60 (2H, q, -NHC H ₂ CH ₂ - ) 4.41(2H,s,

【formula】) 5.10 (1H, s,

[Formula]) 7.00 (1H, br, -CON H -) 10.1 (1H, br, -COO H ) Example 3 2.5 g of pantothenic acid dinitrate obtained in Example 2 was mixed with 1.1 g of triethylamine and 20 ml of tetrahydrofuran. Dissolve in mixture and cool in an ice-water bath. A mixture of 0.88 g of ethyl chlorocarbonate and 8 ml of tetrahydrofuran was added dropwise to this, and the mixture was heated at 3 to 5°C.
Stir for 1.5 hours. A mixed solution of 0.91 g of cystamine dihydrochloride, 1.8 g of trimethylamine, and 20 ml of tetrahydrofuran was added dropwise to this solution, followed by stirring at 3 to 5°C for 2 hours. The reaction solution was concentrated under reduced pressure,
Add 100 ml of chloroform to the residue and stir. This solution was mixed with 2N sodium hydroxide aqueous solution, dilute hydrochloric acid,
After sequentially washing with water, drying over anhydrous sodium sulfate and concentrating under reduced pressure, the resulting oily substance was subjected to column chromatography using 40 g of silica gel. Elute with a mixed solvent of chloroform-methanol (20:1), combine the fractions containing the target product, concentrate under reduced pressure, and recrystallize the resulting residue from a chloroform-ether mixture to obtain 1.02 g of pantethine tetranitrate as a colorless powder. get. Melting point 104-108℃ NMR (CDCl ₃ , 90MHz) δppm: 1.18 (12H, s, -CH ₃ × 4) 2.50 (4H, m, -CH ₂ CH ₂ CONH - × 2) 2.83 (4H, m, -C H ₂ -S-S-C H ₂ -) 3.60 (8H, m, -CONH-C H ₂ CH ₂ -×4) 4.41 (4H, s,

【formula】) 5.07(2H,s,

[Formula]) 6.90, 7.60 (2H, br, - CON H - x 2 respectively) Elemental analysis value (%) Calculated value as C ₂₂ H ₃₈ N ₈ O ₁₆ S ₂ C 35.96, H 5.21, N 15.25 Actual value C 35.93, H 5.26, N 14.96

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom or a nitro group, R ² is an ω-(nitrooxy)alkyl group having 1 to 6 carbon atoms, an ω-(carboxy)alkyl group having 2 to 7 carbon atoms, or a general formula (In the formula, R ¹ is the same as above.) ] A nitrate ester derivative represented by.