JPH0635473B2 - Diethylenetriamine triacetic acid aromatic ester compounds and processes for their preparation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a diethylenetriamine triacetate compound, and more particularly to an ursodeoxycolydiethylenetriamine triacetate compound having a gallstone-dissolving action and a method for producing the same.

BACKGROUND ART Ursodeoxycholic acid and chenodeoxycholic acid are known as drugs commonly used as therapeutic agents for gallstones. Although these bile acids are effective against pure cholesterol stones, other cholesterol gallstones such as
The dissolution effect of calcium-containing cholesterol mixed stones or cholesterol mixed stones, as well as bilirubin calcium stones or calcium carbonate stones, has been questioned.

On the other hand, Japanese Patent Application No. 1-235799 discloses the following structural formula [I] It has been reported that the diethylenetriaminetriacetic acid compound represented by the formula (3) has an effect of strongly dissolving calcium-containing gallstones, particularly calcium carbonate-containing gallstones in bile.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention However, when the above-mentioned diethylenetriaminetriacetate compound [I] is administered as a calcium gallstone dissolving agent, it has been found that bile transfer is excellent but oral absorbability is poor.

In addition, a chelating agent such as diethylenetriaminetriacetate compound [I] may be inactivated by coexisting metal ions in the living body when administered into the living body, and the drug efficacy may be reduced.

From these viewpoints, the present inventors have earnestly studied the above-mentioned derivatives of diethylenetriaminetriacetic acid compound [I], and as a result, have no chelate-forming ability and are easily metabolized to diethylenetriaminetriacetic acid compound [I] in the body. The inventors reached the present invention by knowing that the ester compound has extremely excellent oral absorbability.

Means for Solving the Problems According to the present invention, the following general formula [II] (In the formula, R represents a benzyl group, a phenyl group, or a 5-indanyl group.) A diethylenetriaminetriacetic acid ester compound and a method for producing the same are provided.

A first method for producing the diethylenetriaminetriacetate compound of the general formula [II] is a method of condensing the diethylenetriaminetriacetate compound [I] with benzyl alcohol, phenol or 5-indanol.

The reaction ratio is diethylenetriaminetriacetic acid compound [I]
On the other hand, benzyl alcohol and the like are used in a molar amount of 3 to 10,000 times. Examples of the condensing agent include acid catalysts, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, chloroformates and the like.

When an acid catalyst is used as the condensing agent, a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as benzenesulfonic acid or p-toluenesulfonic acid is suitable as the acid catalyst. The reaction temperature is 10 to 180 ° C., preferably 70 to 120 ° C.
And the reaction time is 30 minutes to 50 hours, preferably 1 to 30 hours.

1-ethoxycarbonyl-2-ethoxy- as a condensing agent
When 1,2-dihydroquinoline is used, the reaction solvent is
Tetrahydrofuran or 1,4-dioxane is suitable. The reaction temperature is −10 to 60 ° C., preferably 20 to
Within the range of 50 ° C., the reaction time is 30 minutes to 10 hours,
It is preferably about 1 to 4 hours.

When chloroformate is used as the condensing agent, ethyl chloroformate, isobutyl chloroformate, etc. are suitable as the chloroformate. Tetrahydrofuran or 1,4-dioxane is suitable as the reaction solvent. The reaction temperature is -20 to 60 ° C, preferably -10 to 30 ° C
And the reaction time is 30 minutes to 20 hours, preferably 1 to 5 hours.

The diethylenetriamine triacetic acid compound [I] can be produced by the method reported in Japanese Patent Application No. 1-235799.

Of the diethylenetriamine triacetate compound [II], the following structural formula [III] The diethylenetriamine triacetic acid tribenzyl ester compound represented by
The following structural formula [IV] There is a method of reacting a potassium salt represented by with benzyl chloride or benzyl bromide.

The reaction ratio is 3 to 60 times the molar amount of benzyl chloride and the like with respect to potassium salt [IV]. . Acetone or methyl ethyl ketone is suitable as the reaction solvent. The reaction temperature is 0
To 80 ° C., preferably 30 to 80 ° C., and the reaction time is 5 minutes to 40 hours, preferably 1 to 8 hours.

The potassium salt [IV] can be produced by reacting the diethylenetriaminetriacetic acid compound [I] with potassium t-butoxide, potassium hydroxide or the like.

The reaction ratio is diethylenetriaminetriacetic acid compound [I]
On the other hand, potassium t-butoxide and the like are used in a 3-fold molar amount. Suitable reaction solvent is methanol or ethanol. The reaction temperature is 0 to 40 ° C., and the reaction time is 1 minute to 1 hour.

Action The diethylenetriamine triacetate compound [II] of the present invention is evaluated for the excretion rate in the bile upon oral administration,
It was confirmed that it had excellent oral absorbability.

The invention will be further described with reference to examples.

Example 1 (diethylenetriamine triacetic acid tribenzyl ester compound) N ″ -ursodeoxycholyldiethylenetriamine-
240 mg (0.368 mmol) of N, N, N'-triacetic acid, 250 mg of p-toluenesulfonic acid hydrate (1.
31 mmol) and 1.0 m of benzyl alcohol were heated at 90-110 ° C. for 3 hours. Water was added to the reaction solution, the pH was adjusted to 9 with an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. Wash this chloroform layer with water,
It was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography using a chloroform-methanol mixed solution (volume ratio 1: 1 to 50: 1) as a developing solution to obtain oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N. ′-
187 mg (yield 55%) of triacetic acid tribenzyl ester was obtained.

Infrared absorption spectrum (KBr, cm ^-1 ); 1720, 1655 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.66 (3H, s), 0.92 (3H, d, J = 6H)
z), 0.94 (3H, s), 0.99 to 2.30 (2
6H, m), 2.64 to 2.89 (6H, m), 3.2
3 (2H, q, J = 5Hz), 3.40 (2H, s),
3.49 to 3.66 (2H, m), 3.61 (4H,
s), 5.12 (6H, s), 6.81 (1H, t, J
= 5Hz), 7.33 (15H, s) Elemental analysis value (as C ₅₅ H ₇₅ N ₃ O ₉ ); Theoretical value (%) C, 71.63H, 8.20N, 4.56 Actual value (%) 71.55 8.34 4.40 Implemented Example 2 (Diethylenetriamine triacetic acid tribenzyl ester compound) N "-ursodeoxycholyldiethylenetriamine-
140 mg (0.215 mmol) of N, N, N'-triacetic acid, 1-ethoxycarbonyl-2-ethoxy-1,2
A mixture of 60 mg (0.243 mmol) dihydroquinoline, 0.1 m (0.97 mmol) benzyl alcohol and 1.4 m tetrahydrofuran at 30-50 ° C.
The mixture was stirred for 2 hours. The solvent of this reaction solution was distilled off, and the resulting residue was subjected to silica gel column chromatography using a chloroform-methanol mixed solution (volume ratio: 1: 0 to 50: 1) as a developing solution to give an oily N "- 17 mg (yield 9%) of ursodeoxycholyldiethylenetriamine-N, N, N'-triacetic acid tribenzyl ester was obtained, the infrared absorption spectrum and nuclear magnetic resonance spectrum of which were:
In agreement with that described in Example 1.

Example 3 (Diethylenetriamine triacetic acid tribenzyl ester compound) N "-ursodeoxycholyldiethylenetriamine-
164 mg (0.21) of N, N, N'-triacetic acid tripotassium salt
4mM), benzyl chloride 0.1m (0.869mMole), sodium iodide 80mg (0.534mMole), and acetone 4m were heated to reflux for 4 hours.
The solvent of this reaction solution was distilled off, and the resulting residue was subjected to silica gel column chromatography using a chloroform-methanol mixed solution (volume ratio: 1: 0 to 50: 1) as a developing solution to give an oily N "- Ursodeoxycholyldiethylenetriamine-N, N, N'-triacetic acid tribenzyl ester 8
8 mg (44% yield) was obtained. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this material were in agreement with those described in Example 1.

Example 4 (Diethylenetriamine triacetic acid triphenyl ester compound) The procedure of Example 2 was repeated, except that 100 mg (1.06 mmol) of phenol was used instead of 0.1 m of benzyl alcohol, and an oily N "-was obtained. 28 mg (yield 15%) of ursodeoxycholyldiethylenetriamine-N, N, N'-triacetic acid triphenyl ester was obtained.

Infrared absorption spectrum (KBr, cm ^-1 ); 1760, 1650 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.62 (3H, s), 0.93 (3H, d, J = 6H)
z), 0.93 (3H, s), 1.00 to 2.31 (2
6H, m), 2.84 to 3.16 (6H, m), 3.3
8 (2H, q, J = 5Hz), 3.49 to 3.74 (2
H, m), 3.83 (2H, s), 3.95 (4H,
s), 6.79 (1H, t, J = 5Hz), 7.03 ~.
7.14 (3H, m), 7.29 to 7.43 (6H,
m) Elemental analysis value (as C ₅₂ H ₆₉ N ₃ O ₉ ); theoretical value (%) C, 70.96H, 7.90N, 4.77 actual measurement value (%) 70.77 8.11 4.63 Example 5 (diethylenetriamine triacetic acid triphenyl ester compound) ) N "-ursodeoxycholyldiethylenetriamine-
To a mixed solution of 140 mg (0.215 mmol) of N, N, N'-triacetic acid, 2.0 m of tetrahydrofuran and 0.11 m (0.789 mmol) of triethylamine,
Isobutyl chloroformate 0.10m at 0-10 ° C
(0.771 mmol) was added, and the mixture was stirred at the same temperature for 1 hour, and a mixed solution of 70 mg (0.744 mmol) of phenol and 2.0 m of tetrahydrofuran was added and the mixture was added to 20 to 3
The mixture was stirred at 0 ° C for 2 hours. The solvent of this reaction solution was distilled off,
The obtained residue was subjected to silica gel column chromatography using a mixed solution of chloroform-methanol (volume ratio: 1: 0 to 50: 1) as a developing solution to obtain oily N "-ursodeoxycholyldiethylenetriamine-N, N, N. 15 mg (8% yield) of'-triacetic acid triphenyl ester were obtained whose infrared absorption spectrum and nuclear magnetic resonance spectrum were in agreement with those described in Example 4.

Example 6 (Diethylenetriaminetriacetic acid tri5-indanyl) ester compound A treatment was conducted in substantially the same manner as in Example 2 except that 130 mg (0.969 mmol) of 5-hydroxyindane was used instead of 0.1 m of benzyl alcohol. , Oily N "-ursodeoxycholyldiethylenetriamine-N, N,
25 mg of N'-triacetic acid tri (5-indanyl) ester
(Yield 12%) was obtained.

Infrared absorption spectrum (KBr, cm ^-1 ); 1760, 1655 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.64 (3H, s), 0.93 (3H, d, J = 6H)
z) 0.94 (3H, s), 0.99 to 2.33 (32
H, m), 2.75 to 3.20 (18H, m), 3.3.
8 (2H, q, J = 5Hz), 3.49 to 3.75 (2
H, m), 3.72 (2H, s), 3.78 (4H,
s), 6.85 (1H, t, J = 5Hz), 7.00
7.48 (9H, m) Elemental analysis value (as C ₆₁ H ₈₁ N ₃ O ₉ ); Theoretical value (%) C, 73.24H, 8.16N, 4.20 Measured value (%) 73.28 8.38 4.09 Effect of the present invention The diethylenetriamine triacetate compound [II] can be orally administered as a dissolution agent for various gallstones containing calcium.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroo Sakakura 12-19 Sachimachi, Higashimatsuyama City, Saitama Prefecture (56) Reference JP-A-60-161996 (JP, A) Pharmaceutical Research Vol. 38 No. 12 P. 409 ~ 421 (1967)

Claims (3)

[Claims] 1. A general formula (In the formula, R represents a benzyl group, a phenyl group, or a 5-indanyl group.) A diethylenetriaminetriacetate compound represented by the formula: 2. A formula The method for producing a diethylenetriaminetriacetate compound according to claim (1), wherein the diethylenetriaminetriacetate compound represented by the formula (1) is condensed with benzyl alcohol, phenol or 5-indanol. 3. A formula The formula characterized by reacting a potassium salt represented by with benzyl chloride or benzyl bromide The manufacturing method of the diethylene triamine triacetic acid tribenzyl ester compound shown by these.