JPH0635471B2 - Diethylenetriamine triacetic acid carbonyl methyl ester compounds and their production process - Google Patents

Description

TECHNICAL FIELD The present invention relates to a diethylenetriamine triacetic acid ester compound, and more particularly to a ursodeoxycholyldiethylenetriamine triacetic acid ester compound having a gallstone-dissolving action and a method for producing them.

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 hydrogen, a benzyl group, or a linear or branched alkyl group having 1 to 3 carbon atoms.) A diethylenetriamine triacetate compound represented by the formula and a method for producing the same are provided.

As a first method for producing the diethylenetriaminetriacetate compound of the above general formula [II], the above diethylenetriaminetriacetate compound [I] and the following general formula [III] HOCH ₂ COO-R [III] (wherein R is , Hydrogen, a benzyl group, or a linear or branched alkyl group having 1 to 3 carbon atoms).

The reaction ratio is diethylenetriaminetriacetic acid compound [I]
To glycolic acid or glycolic acid ester
The amount is 10000 times the molar amount. Examples of the glycolic acid ester include methyl glycolate, ethyl glycolate, n-propyl glycolate or isopropyl glycolate. Examples of the condensing agent include acid catalysts, 1-ethoxycarbonyl-2-ethoxy-1,2-hydrohydroquinoline, chloroformates and the like.

When an acid catalyst is used as the condensing agent, the acid catalyst is
Mineral acids such as sulfuric acid or hydrochloric acid or organic acids such as benzenesulfonic acid or p-toluenesulfonic acid are suitable.
The reaction temperature is 20 to 180 ° C., preferably 60 to 140
The reaction time is 30 minutes to 5 hours, preferably 1 to 30 hours.

When 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline is used as the condensing agent, tetrahydrofuran or 1,4-dioxane is suitable as the reaction solvent. The reaction temperature is -10 to 60 ° C, preferably 2
The reaction time is 30 minutes to 10 hours, preferably 1 to 4 hours.

When a chloroformate is used as the condensing agent, ethyl chloroformate, isobutyl chloroformate or the like is suitable as the chloroformate. As the reaction solvent, tetrahydrofuran or 1,4-dioxane is suitable. 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.

As a second method for producing the diethylenetriamine triacetate compound [II], the following structural formula [IV] And a potassium salt represented by the following general formula [V] X-CH ₂ COO-R [V] (wherein R represents hydrogen, a benzyl group or a linear or branched alkyl group having 1 to 3 carbon atoms). , X is chlorine,
Represents bromine or iodine. There is a method of reacting a halogenated acetic acid or a halogenated acetic acid ester represented by the formula

The reaction ratio is such that the above halogenated acetic acid or halogenated acetic acid ester is 3 to 60 times the molar amount with respect to the potassium salt [IV]. Examples of the halogenated acetic acid ester include benzyl bromoacetate. Acetone or methyl ethyl ketone is suitable as the reaction solvent. The reaction temperature is 0 to 8
The reaction temperature is 0 ° C, preferably 30 to 80 ° C, and the reaction time is 5 minutes to 20 hours, preferably 1 to 6 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.

Of the diethylenetriamine triacetate compound [II], the following structural formula [VI] The diethylenetriaminetriacetic acid tri (carboxymethyl) ester compound represented by the following structural formula [VI] can be used as a third manufacturing method in addition to the above two manufacturing methods.
I] There is a method of catalytically reducing a diethylenetriaminetriacetic acid tri (benzyloxanecarbonylmethyl) ester compound represented by the formula (3) in the presence of a catalyst.

Examples of the catalyst include a palladium-carbon type catalyst. Suitable reaction solvent is methanol, ethanol or ethyl acetate. The reaction temperature is in the range of 10 to 70 ° C., preferably 20 to 70 ° C., and the reaction time is 30 minutes to
The time is 10 hours, preferably about 1 to 5 hours.

Action The oral absorbability of diethylenetriamine triacetate compound [II] is described below. The oral absorbability was evaluated by the excretion rate of the diethylenetriaminetriacetic acid compound [I] into the bile upon oral administration.

The test was performed by the method described below. The rat was laparotomized under ether anesthesia, and a polyethylene tube was inserted into the common bile duct to allow bile to be excreted out of the body. Immediately after the abdomen was closed, the animal was placed in a Ballman cage, the test compound was orally administered, and excreted bile was collected for 4 hours. The diethylenetriaminetriacetate compound [I] in the collected bile was measured by liquid chromatography, and the bile excretion rate was calculated by the following formula.

Each test compound was administered as a drug solution prepared as follows. That is, the diethylenetriamine triacetate compound [II] is dissolved in a 70 to 83% polyethylene glycol solution, and the diethylenetriamine triacetate compound [I] is dissolved in a pH 6 to 7 buffer solution, and the concentration of each drug solution is 5 mg / m. And Dosage of test compound is 30mg
/ Kg. The results are shown in the table below.

As is clear from the above table, it is recognized that the diethylenetriaminetriacetate compound [II] of the present invention has much better oral absorbability than the diethylenetriaminetriacetate compound [I].

The invention will be further described with reference to examples.

Reference Example 1 (diethylenetriaminetriacetic acid tri (methoxycarbonylmethyl) 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, 100 mg (1.11 mmol) methyl glycolate and 1.4 m tetrahydrofuran was stirred at 40 ° C. for 2 hours. The solvent of this reaction solution was distilled off, and the residue was mixed with a chloroform-methanol mixture (volume ratio 1: 0 to 50:
Silica gel column chromatography using 1) as a developing solution gave 15 mg (yield 8%) of oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid tri (methoxycarbonylmethyl) ester. It was

Infrared absorption spectrum (KBr, cm ^-1 ); 1755, 1650 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.68 (3H, s), 0.93 (3H, d, J = 6H)
z), 0.95 (3H, s), 1.00 to 2.33 (2
6H, m), 2.70 to 2.94 (6H, m), 3.2
9 (2H, q, J = 5Hz), 3.56 (2H, s),
3.51 to 3.65 (2H, m), 3.74 (4H,
s), 3.77 (9H, s), 4.64 (2H, s),
4.66 (4H, s), 6.74 (1H, t, J = 5H
z) Elemental analysis (as _{C 43 H 69 N 3 O 15} ); theory (%) C, 59.50H, 8.01N , 4.84 Found (%) 59.37 8.22 4.69 Example 2 (diethylenetriamine triacetate tri (methoxycarbonyl Methyl) ester compound) N "-ursodeoxycholyldiethylenetriamine-
164 mg (0.21) of N, N, N'-triacetic acid tripotassium salt
4 mmol), methyl bromoacetate 0.13 m (1.4
A mixture of 1 mmol), 80 mg (0.534 mmol) sodium iodide and 4 m of acetone was heated under reflux for 4 hours. The solvent of this reaction solution was distilled off, and the 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.
73 mg (yield 39%) of oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid tri (isopropoxycarbonylmethyl) ester was obtained. Infrared absorption spectrum and nuclear magnetic resonance spectrum of this substance. Was in agreement with that described in Example 1.

Example 3 (Diethylenetriamine triacetic acid tri (isopropoxycarbonylmethyl) ester compound) Almost the same as Example 2 except that 0.18 m (1.39 mmol) of isopropyl bromoacetate was used instead of 0.13 m of methyl bromoacetate. The same treatment was performed to obtain oily N "-
Ursodeoxycholyldiethylenetriamine-N, N,
N'-triacetate tri (isopropoxycarbonylmethyl)
78 mg (38% yield) of ester were obtained.

Infrared absorption spectrum (KBr, cm ^-1 ); 1755, 1650 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.68 (3H, s), 0.94 (3H, d, J = 6H)
z), 0.95 (3H, s), 1.29 (18H, d,
J = 7 Hz), 1.02 to 2.35 (26 H, m), 2.
69 to 2.94 (6H, m), 3.27 (2H, q, J
= 5 Hz), 3.51 (2H, s), 3.50 to 3.66
(2H, m), 3.70 (4H, s), 4.62 (2
H, s), 4.65 (4H, s), 5.00 (3H, s)
eptet, J = 7 Hz), 6.83 (1H, t, J = 5)
Hz) Elemental analysis value (as C ₄₉ H ₈₁ N ₃ O ₁₅ ); theoretical value (%) C, 61.81H, 8.57N, 4.41 actual measurement value (%) 61.77 8.56 4.54 Example 4 (diethylenetriamine triacetate (benzyloxy) Carbonylmethyl) ester compound) Treatment was conducted in substantially the same manner as in Example 2 except that benzyl bromoacetate 0.22 m (1.39 mmol) was used in place of methyl bromoacetate 0.13 m, and an oily N "-urso Deoxycholyldiethylenetriamine-N, N, N '
-130 mg (yield 55%) of triacetic acid tri (benzyloxycarbonylmethyl) ester was obtained.

Infrared absorption spectrum (KBr, cm ^-1 ); 1750, 1650 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.66 (3H, s), 0.92 (3H, s) 0.94
(3H, d, J = 6Hz), 0.80 to 2.34 (26
H, m), 2.61-2.90 (6H, m), 3.23
(2H, q, J = 5Hz), 3.45 (2H, s), 3.
48 to 3.66 (2H, m), 3.60 (4H, s),
4.65 (2H, s), 4.67 (4H, s), 5.4
8 (6H, s), 6.84 (1H, t, J = 5Hz),
7.25 to 7.43 (15H, m) Elemental analysis value (as C ₆₁ H ₈₁ N ₃ O ₁₅ ); Theoretical value (%) C, 66.83H, 7.45N, 3.83 Measured value (%) 66.91 7.41 3.82 Implemented Example 5 (Diethylenetriamine triacetic acid tri (carboxymethyl) ester compound) N "-ursodeoxycholyldiethylenetriamine-
A mixture of N, N, N'-triacetic acid tri (benzyloxycarbonylmethyl) ester 130 mg (0.119 mmol), palladium-carbon (10%) 20 mg, and methanol 3 m was catalytically hydrogenated at room temperature, and after the reaction, Palladium-carbon was filtered off, the filtrate was evaporated to dryness under reduced pressure, and N "-
Ursodeoxycholyldiethylenetriamine-N, N,
N'-triacetic acid tri (carboxymethyl) ester 98mg
(Yield is quantitative).

Infrared absorption spectrum (KBr, cm ⁻¹ ); 2700 to 2300, 1750 to 1640 Elemental analysis value (as C ₄₀ H ₆₃ N ₃ O ₁₅ ); Theoretical value (%) C, 58.17H, 7.69 N, 5.09 Actual value (%) 58.07 7.81 4.98 Effect of the invention The diethylenetriamine triacetate compound [II] of the present invention can be orally administered as a solubilizer of 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 (4)

[Claims] 1. A general formula (In the formula, R represents hydrogen, a benzyl group, or a linear or branched alkyl group having 1 to 3 carbon atoms.) A diethylenetriamine triacetate compound represented by the formula: 2. A formula And a glycolic acid represented by the general formula HOCH ₂ COO-R (wherein R represents hydrogen, a benzyl group or a linear or branched alkyl group having 1 to 3 carbon atoms). Alternatively, the method for producing a diethylenetriaminetriacetate compound according to claim 1, wherein the glycolic acid ester is condensed. 3. A formula In in the potassium salt represented with the general formula X-CH ₂ COO-R (wherein, R represents hydrogen, benzyl or straight-chain or branched alkyl group having 1 to 3 carbon atoms, X is chlorine,
Represents bromine or iodine. The method for producing a diethylenetriaminetriacetate compound according to claim 1, wherein the halogenated acetic acid or halogenated acetic acid ester represented by the formula (1) is reacted. 4. A formula The formula characterized by catalytically reducing diethylenetriaminetriacetic acid tri (benzyloxycarbonylmethyl) ester compound represented by: in the presence of a catalyst. The manufacturing method of the diethylene triamine triacetic acid tri (carboxymethyl) ester compound shown by these.