JPH0635470B2 - Diethylenetriamine triacetic acid alkyl ester compounds and processes for their production - 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 ¹ represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms, and R ² represents hydrogen or R ^1. ) and a diethylenetriamine triacetate compound and a process for producing them. Will be 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] R ¹ —OH [III] (wherein R ¹ is Represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms).

The reaction ratio is diethylenetriaminetriacetic acid compound [I]
On the other hand, the monohydric alcohol [III] is used in a molar amount of 2 to 10,000 times. Examples of the monohydric alcohol [III] include methanol, ethanol, isopropyl alcohol and isopentyl alcohol. As the condensing agent, an acid catalyst, 1-ethoxycarbonyl-2-ethoxy-1,2
-Dihydroquinoline, chloroformates, thionyl chloride and the like.

When an acid catalyst is used as the condensing agent, the acid catalyst is preferably a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as benzenesulfonic acid or p-toluene ester acid. The reaction temperature is 20 to 140 ° C., preferably 60 to 140 ° 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 a chloroformate is used as the condensing agent, ethyl chloroformate, isobutyl chloroformate and the like 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.

When thionyl chloride is used as the condensing agent, the reaction solvent is
Tetrahydrofuran or 1,4-dioxane is suitable. The reaction temperature is -10 to 10 ° C, preferably 20 to
Within the range of 70 ° C, the reaction time is 30 minutes to 20 hours,
It is preferably about 1 to 5 hours.

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

As a second production method of the diethylenetriamine triacetate compound [II], the diethylenetriamine triacetate compound [I] and the following general formula [IV] R ³ —CHN ₂ [IV] (wherein R ³ is hydrogen or carbon) Which represents a linear or branched alkyl group of formulas 1 to 4).

The reaction ratio is diethylenetriaminetriacetic acid compound [I]
On the other hand, diazocalcan [IV] is used in a molar amount of 2 to 100 times. As diazocalcan [IV], diazomethane,
Examples thereof include diazoethane. The reaction temperature is -10 to 3
The temperature is 0 ° C., preferably 0 to 20 ° C., and the reaction time is 5 minutes to 20 hours, preferably 30 minutes to 5 hours.

As a third method for producing diethylenetriamine triacetate compound [II], the following structural formula [V] And a potassium salt represented by the following general formula [VI] R ¹ -X [VI] (In the formula, R ¹ represents a linear or branched alkyl group having 1 to 5 carbon atoms, X represents chlorine, There is a method of reacting an alkyl halide represented by bromine or iodine).

The reaction ratio is 2 to 60 times the molar amount of the alkyl halide [VI] with respect to the potassium salt [V]. Examples of the alkyl halide [VI] include methyl chloride, methyl bromide, methyl iodide, ethyl bromide, isopentyl bromide and the like. Acetone or methyl ethyl ketone is suitable as the reaction solvent. The reaction temperature is 0 to 80 ° C., preferably 30
The reaction time is 5 minutes to 40 hours,
It is preferably about 1 to 8 hours.

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

The reaction ratio is diethylenetriaminetriacetic acid compound [I]
In contrast, 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.

As a fourth method for producing the diethylenetriamine triacetate compound [II], the following structural formula [VII] And a general formula X-CH ₂ COOR ¹ [VII] (wherein R ¹ represents a linear or branched alkyl group having 1 to 5 carbon atoms, and X represents chlorine, bromine or iodine). Represents the reaction) with a halogenated alkyl acetate.

The reaction ratio is such that the alkyl halide [VIII] halide is 3 to 300 times the molar amount of the triamine compound [VII]. Examples of the halogenated alkyl acetate [VIII] include methyl chloroacetate, methyl bromoacetate, methyl iodoacetate, ethyl bromoacetate and the like. The reaction temperature is 10 to
The temperature is 100 ° C, preferably 40 to 80 ° C, and the reaction time is 10 minutes to 10 hours, preferably 30 minutes to 3 hours.

The above triamine compound [VII] is disclosed in Japanese Patent Application No. 1-235.
It can be produced by the method reported in Japanese Patent Publication No. 799.

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 diethylenetriamine triacetate 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 far better oral absorbability than the diethylenetriaminetriacetate compound [I].

The invention will be further described with reference to examples and examples.

Reference Example 1 (potassium salt [V]) N ″ -ursodeoxycholyldiethylenetriamine-
700 mg (1.07 mmol) of N, N, N'-triacetic acid,
400 mg of potassium-t-butoxide (purity 90%)
After stirring a mixture of (3.21 mmol) and 10 m of ethanol at room temperature for 10 minutes, the solvent was distilled off. After 3 m of acetone was added to this residue for crystallization, the solvent was distilled off, and 820 mg of white powder of N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid tripotassium salt was obtained. Target).

Example 1 (Diethylenetriamine triacetic acid trimethyl ester compound) N "-ursodeoxycholyldiethylenetriamine-
720 mg (1.10 mmol) of N, N, N'-triacetic acid,
A mixture of 0.1 m (1.80 mmol) of concentrated sulfuric acid and 10 m of methanol was heated under reflux for 20 hours. Water was added to this reaction solution to make it alkaline with 510 mg (6.07 mmol) of sodium hydrogen carbonate, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was mixed with a chloroform-methanol mixture (volume ratio 50:
Silica gel column chromatography using 1) as a developing solution gave 500 mg (yield 66%) of oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid trimethyl ester.

Infrared absorption spectrum (KBr, cm ^-1 ); 1740, 1640 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.68 (3H, s), 0.95 (3H, s), 0.9
5 (3H, d, J = 6Hz), 1.02 to 2.35 (26
H, m), 2.67 to 2.88 (6H, m), 3.27.
(2H, q, J = 5Hz), 3.41 (2H, s), 3.
58 (4H, s), 3.50 to 3.65 (2H, m),
3.70 (3H, s), 3.70 (6H, s), 6.8
6 (1H, t, J = 5Hz) Elemental analysis value (as C ₃₇ H ₆₃ N ₃ O ₉ ); Theoretical value (%) C, 64.04H, 9.15N, 6.06 Measured value (%) 64.01 9.25 6.00 Example 2 (Diethylenetriamine triacetic acid trimethyl 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) of dihydroquinoline, 0.1 m (2.47 mmol) of methanol and 1.4 m of tetrahydrofuran was stirred at 30-40 ° C for 2 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 50: 1) as a developing solution.
Oily N "-ursodeoxycholyldiethylenetriamine-N, N, N'-triacetic acid trimethyl ester 30 mg
(Yield 20%) was obtained. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this material were in agreement with those described in Example 1.

Example 3 (Diethylenetriamine triacetic acid trimethyl 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.
Stir for hours. The solvent of this reaction solution was distilled off, and the resulting residue was mixed with a chloroform-methanol mixture (volume ratio 50:
Silica gel column chromatography using 1) as the eluent gave 16 mg (yield 11%) of oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid trimethyl ester. The infrared absorption spectrum and the nuclear magnetic resonance spectrum were in agreement with those described in Example 1.

Example 4 (Diethylenetriamine triacetic acid trimethyl ester compound) N "-ursodeoxycholyldiethylenetriamine-
To a mixed solution of 140 mg (0.215 mmol) of N, N, N'-triacetic acid, 1.0 m of tetrahydrofuran and 0.1 m (0.717 mmol) of triethylamine was added 0.
After adding 0.05 m (0.689 mmol) of thionyl chloride at -10 ° C and heating under reflux for 2 hours, 1 m of methanol was further added dropwise and reflux under heating for 1 hour. The solvent of this reaction solution was evaporated, the obtained residue was added, the pH was adjusted to 9 with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. This ethyl acetate layer was treated in the same manner as the ethyl acetate layer of Example 1 to obtain 49 mg (yield 33%) of oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid trimethyl ester. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this material were in agreement with those described in Example 1.

Example 5 (Diethylenetriamine triacetic acid trimethyl ester compound) N "-ursodeoxycholyldiethylenetriamine-
100 mg (0.153 mmol) of N, N, N'-triacetic acid
The diazomethane-ether solution was gradually added to the methanol solution of. The solvent of this reaction solution was distilled off under reduced pressure,
The residue was mixed with chloroform-methanol (volume ratio 5
This was subjected to silica gel column chromatography using 0: 1) as a developing solution to obtain 50 mg (yield 47%) of oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid trimethyl ester. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the substance were in agreement with those described in Example 1.

Example 6 (Diethylenetriamine triacetic acid trimethyl ester compound) N "-ursodeoxycholyldiethylenetriamine-
164 mg (0.21) of N, N, N'-triacetic acid tripotassium salt
4mM), methyl iodide 0.1m (1.61mMole), and acetone 4m at a temperature of 30-40 ° C.
Stir for hours. The solvent of this reaction solution was distilled off, and the residue was subjected to silica gel column chromatography using a chloroform-methanol mixture (volume ratio 50: 1) as a developing solution to obtain oily N ″ -ursodeoxycholyldiethylenetriamine-N, N. , N'-triacetic acid trimethyl ester 86
mg (yield 58%) was obtained. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this material were in agreement with those described in Example 1.

Example 7 (Diethylenetriamine triacetic acid trimethyl ester compound) N-ursodeoxycholyldiethylenetriamine 1.0
0 g (2.09 mmol), methyl bromoacetate 0.64
m (6.93 mmol), potassium carbonate 960 mg
A mixture of (6.95 mmol) and 12 m of methanol was stirred at 60 ° C. for 1 hour. The insoluble matter of this reaction solution was filtered off, and the solvent of the filtrate was distilled off. The obtained residue was subjected to silica gel column chromatography using a chloroform-methanol mixture (volume ratio 50: 1) as a developing solution to give oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-trimethyl triacetate. Ester 390mg
(Yield 27%) was obtained. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this material were in agreement with those described in Example 1.

Example 8 (Diethylenetriaminetriacetic acid trimethyl ester compound) Treatment was conducted in substantially the same manner as in Example 1 except that 10 m of ethanol was used instead of 10 m of methanol, and an oily N "was obtained.
-Ursodeoxycholyldiethylenetriamine-N,
510 mg of N, N'-triacetic acid trimethyl ester (yield 6
3%) was obtained.

Infrared absorption spectrum (KBr, cm ^-1 ); 1740, 1650 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.68 (3H, s), 0.94 (3H, d, J = 6H)
z), 0.95 (3H, s), 1.27 (9H, t, J
= 7 Hz), 1.01 to 2.36 (26 H, m), 2.6
9-2.88 (6H, m), 3.27 (2H, q, J =
5Hz), 3.39 (2H, s), 3.56 (4H,
s), 3.51 to 3.66 (2H, m), 4.15 (2
H, q, J = 7Hz), 4.16 (4H, q, J = 7H)
z), 6.90 (1H, t, J = 5Hz) Elemental analysis value (as C ₄₀ H ₆₉ N ₃ O ₉ ); Theoretical value (%) C, 65.28H, 9.45N, 5.71 Actual measurement value (%) 65.17 9.54 5.63 Example 9 (Diethylenetriamine triacetic acid trimethyl ester compound) 0.77 m (6.93 mmol) of ethyl bromoacetate was used in place of 0.64 m of methyl bromoacetate,
And 12m ethanol instead of 12m methanol
The same procedure as in Example 7 was repeated except that the oily N ″ -ursodeoxycholyldiethylenetriamine-N, N, N′-triacetic acid trimethyl ester 450 mg was used.
(Yield 29%) was obtained. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this material were in agreement with those described in Example 8.

Example 10 (Diethylenetriaminetriacetic acid diethyl ester compound) N "-ursodeoxycholyldiethylenetriamine-
740 mg (1.14 mmol) of N, N, N'-triacetic acid,
Concentrated sulfuric acid 0.1 m (1.80 mmol), ethanol 1
The 0 m mixture was heated to reflux for 2 hours. Water was added to this reaction solution, sodium hydrogen carbonate was added to adjust the pH to 2-3, and the mixture was extracted with chloroform. This chloroform layer was washed with water and 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 10: 1) as a developing solution, and N'-carboxymethyl-
White powder of N, N-di (ethoxycarbonylmethyl) -N "-ursodeoxycholyldiethylenetriamine 28
0 mg (35% yield) was obtained.

Melting point; 66 to 68 ° C. Infrared absorption spectrum (KBr, cm ⁻¹ ); 1740, 1645 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.67 (3H, s), 0.93 (3H, d, J = 6H
z), 0.94 (3H, s), 0.99 to 2.38 (2
6H, m), 1.27 (6H, t, J = 7Hz), 2.9
4 to 3.20 (6H, m), 3.40 to 3.69 (10
H, m), 4.17 (4H, q, J = 7Hz), 7.65
(1H, bs) Elemental analysis value (as C ₃₈ H ₆₅ N ₃ O ₉ ); Theoretical value (%) C, 64.47H, 9.25N, 5.94 Measured value (%) 64.33 9.28 5.71 Example 11 (triethylenetriaminetriacetate triacetate) Isopentyl ester compound) N "-ursodeoxycholyldiethylenetriamine-
652 mg (1.00 mmol) of N, N, N'-triacetic acid,
A mixture of 250 mg (1.31 mmol) of p-toluenesulfonic acid monohydrate and 4 m of isopentyl alcohol was added to 1 part.
The mixture was stirred at 00 to 120 ° C for 3 hours. Water was added to the reaction solution, 140 mg (1.67 mmol) of sodium hydrogen carbonate was further added, and the mixture was extracted with chloroform. This chloroform layer was washed with water and dried over anhydrous sodium sulfate,
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: 0 to 50: 1) as a developing solution,
Oily N "-ursodeoxycholyldiethylenetriamine-N, N, N'-triacetic acid triiripentyl ester 4
70 mg (yield 55%) was obtained.

Infrared absorption spectrum (KBr, cm ^-1 ); 1745, 1655 Nuclear magnetic resonance spectrum (CDCl ₃ , ppm) δ; 0.68 (3H, s), 0.92 (18H, d, J = 7)
Hz), 0.91 to 0.95 (6H, m), 1.00
2.35 (35H, m), 2.69 to 2.89 (6H,
m), 3.26 (2H, q, J = 5Hz), 3.39 (2
H, s), 3.56 (4H, s), 3.51 to 3.65.
(2H, m), 4.13 (6H, t, J = 7Hz), 6.
92 (1H, t, J = 5Hz) Elemental analysis value (as C ₄₉ H ₈₇ N ₃ O ₉ ); Theoretical value (%) C, 68.26H, 10.17N, 4.87 Measured value (%) 68.21 10.16 4.82 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. 402 ~ 421 (1967)

Claims (5)

[Claims] 1. A general formula (In the formula, R ¹ represents a linear or branched alkyl group having 1 to 5 carbon atoms, and R ² represents hydrogen or R ^1. ) A diethylenetriaminetriacetate compound represented by the formula: 2. A formula And a monohydric alcohol represented by the general formula R ¹ —OH (wherein R ¹ represents a linear or branched alkyl group having 1 to 5 carbon atoms) represented by the formula: The method for producing a diethylenetriaminetriacetate compound according to claim (1), wherein 3. A formula And a diazoalkane represented by the general formula R ³ —CHN ₂ (in the formula, R ³ represents hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms). The method for producing a diethylenetriaminetriacetate compound according to claim 1, wherein 4. A formula And a general formula R ¹ -X (wherein R ¹ represents a linear or branched alkyl group having 1 to 5 carbon atoms, and X represents chlorine, bromine, or iodine). The method for producing a diethylenetriaminetriacetate compound according to claim 1, which comprises reacting an alkyl halide represented by 5. A formula And a general formula X-CH ₂ COOR ¹ (wherein R ¹ represents a linear or branched alkyl group having 1 to 5 carbon atoms, and X represents chlorine, bromine, or iodine). The method for producing a diethylenetriamine triacetate compound according to claim 1, wherein the alkyl halide is represented by the formula (1).