JPS6321675B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel protoporphyrin germanium complex and a method for producing the same.

More specifically, the present invention provides the general formula Bis-substituted 7,12-diethenyl- (in the formula, Y represents a halogen atom or a hydroxyl group)
3,8,13,17-tetramethyl-2,18-di(2
-carboxyethyl)porphynatogermanium derivative and general formula Bis-substituted 7,12-diethenyl- (in the formula, Y represents a halogen atom or a hydroxyl group)
3,8,13,17-tetramethyl-2,18-di(2
-methoxycarbonylethyl) porphynatogermanium () by reacting with an acid or alkali, or the formula 7,12-diethenyl-3,8,13,17
-Tetramethyl-21H, 23H-porphine-2,
Bis-substitution by reacting 18-dipropionic acid with germanium halide-7,12-diethenyl-3,8,13,17-tetramethyl-2,18-
This is a method for producing di(2-carboxyethyl)porphynatogermanium ().

Until now, the germanium complex of protoporphyrin is unknown, but the present inventors have already synthesized a germanium complex of protoporphyrin dimethyl ester, which is its ester derivative (Japanese Patent Application No. 86,094/1989).

As a result of further intensive research, the present inventors succeeded in synthesizing not a protoporphyrin derivative but a protoporphyrin germanium complex, and completed the present invention.

That is, the compound represented by the general formula (1) can be prepared by reacting the germanium complex of the protoporphyrin dimethyl ester represented by the general formula (2) with an acid or alkali in the presence or absence of a solvent, or by reacting the compound represented by the formula ( It can be obtained by directly reacting protoporphyrin shown in 3) with germanium halide, usually in a solvent. The acid used in this reaction is preferably a mineral acid, especially a hydrohalic acid, and the alkali includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc. Hydroxides are preferably used. That is, when using an acid, dissolve the raw material compound represented by formula (2) in an appropriate solvent, add hydrohalic acid and stir at room temperature for several hours to several hours, or when using an alkali, Usually, the desired bis-substituted 7,12-diethenyl-3,8,13,17-tetramethyl-2,18- is obtained by stirring in a hydrous alcohol at room temperature or under heating for several hours to over ten hours.
Di(2-carboxyethyl)porphynatogermanium () is obtained.

The reaction is carried out in an amount of 1 to 8 per mole of the starting compound formula (2).
When reacted with molar amount of acid or caustic alkali at room temperature or under heating for several hours to over ten hours, bis-substituted-7,12-diethenyl-3,8,13,17-
Tetramethyl-2,18-di(2-carboxyethyl)porphynatogermanium () is produced.

When synthesizing the target compound formula (1) by directly reacting protoporphyrin of compound formula (3) with a germanium compound, pyridine, quinoline, pyrrole,
The reaction is completed when the formula (3) and the germanium compound are heated in a pressure-resistant reaction vessel for several hours to more than ten hours in a solvent such as pyrazine or phenol.

As the germanium compound used as a reagent, germanium halides such as germanium tetrachloride and germanium tetrabromide are usually used. The mixing ratio of protoporphyrin and germanium halide as raw materials is not particularly limited, but usually 2 to 8 moles of germanium halide is used in a slight excess with respect to 1 mole of raw material formula (3).

The germanium complexes of protoporphyrin thus obtained are all new compounds, and can be easily converted into various inorganic salts by conventional methods if necessary. The compound formula (1) of the present invention has excellent liver dysfunction-improving activity and anticancer activity, and is extremely useful as a pharmaceutical.

In particular, the inorganic salt of formula (1) has good solubility in water,
It is convenient for treatment and use as a medicine.

When this compound is used as a medicine, administration methods include oral administration in the form of tablets, capsules, powders, granules, syrups, etc., as well as parenteral administration in the form of injections, suppositories, pellets, dusting powders, etc. It can be administered to

When used as a therapeutic agent for liver dysfunction associated with gallstones and cholecystitis, 30 mg to 500 mg per day per adult can be administered orally or parenterally.

The present invention will be explained below with reference to Examples.

Example 1 Bischloro-7,12-diethenyl-3,8,
Synthesis of 13,17-tetramethyl-2,18-di(2-carboxyethyl)porphynatogermanium (1) Bischloro-7,12-diethenyl-3,8,
After dissolving 530 mg (0.73 mmol) of 13,17-tetramethyl-2,18-di(2-methoxycarbonylethyl)porphynatogermanium () in 20 ml of chloroform, add 20 ml of 25% hydrochloric acid and stir at room temperature for 20 hours. . The precipitated crystals are collected by filtration, washed with chloroform and then with water, and dried to obtain 95 mg of the desired product as black-purple powder crystals. Melting point over 300℃.

Germanium content (atomic absorption method) Theoretical value (%) 10.31 Experimental value (%) 9.57 Visible absorption maximum (measured in methanol) 408nm 540nm 577nm Infrared absorption spectrum: As shown in Figure 1 of the attached drawing.

Nuclear magnetic resonance spectrum: As shown in Figure 2 of the attached drawing.

(2) Bishydroxy-7,12-diethenyl-
When the same procedure as (1) was performed using 3,8,13,17-tetramethyl-2,18-di(2-methoxycarbonylethyl)porphynatogermanium (), the desired product was obtained with a yield of 17%. It will be done.

(3) 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-
Dissolve 5 g (8.2 mmol) of the disodium salt of dipropionic acid in 100 ml of pyridine, and make the content 200 ml.
ml pressure-resistant reaction vessel, then add 5 g (23.3 mmol) of germanium tetrachloride and seal it.
Heat and stir at 180°C for 4.5 hours. After cooling, the precipitated insoluble matter is filtered off. The filtrate is concentrated to dryness under reduced pressure and the residue is dissolved in 100 ml of methanol. After removing insoluble matter by filtration, the filtrate was concentrated to dryness under reduced pressure to give 3.6 g.
Obtain the desired object.

Example 2 Bisbromo-7,12-diethenyl-3,8,
Synthesis of 13,17-tetramethyl-2,18-di(2-carboxyethyl)porphynatogermanium () 7,12-diethenyl-3,8,13,17-tetramethyl-21H,23H-porphine-2, 5 g (8.9 mmol) of 18-dipropionic acid in 100 ml of pyridine
dissolve in Add 5g of germanium tetrabromide to this solution.
(12.7 mmol) was added dropwise with stirring, and the mixture was refluxed for about 4.5 hours. After cooling, the precipitated insoluble matter is filtered and washed with 20 ml of pyridine. The filtrate is concentrated to dryness under reduced pressure and the residue is dissolved in 100 ml of methanol. After removing the insoluble matter by filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 4.3 g of the desired product as black-purple powder crystals. Melting point over 300℃.

Germanium content (atomic absorption method) Theoretical value (%) 9.15 Experimental value (%) 10.09 Example 3 Bishydroxy-7,12-diethenyl-3,
8,13,17-tetramethyl-2,18-di(2-
Synthesis of porphynatogermanium (carboxyethyl) (1) 0.3 ml of caustic soda in 30 ml of 95% aqueous methanol
g and bischloro-7,12-diethenyl-3,
8,13,17-tetramethyl-2,18-di(2-
530 mg (0.73 mmol) of porphynatogermanium (methoxycarbonylethyl) was dissolved, stirred at room temperature for 8 hours, and then allowed to stand overnight. After the reaction solution was concentrated to dryness under reduced pressure, 8 ml of water was added to the residue and heated for 10 minutes. After cooling at 0 to 10 DEG C. for 1 hour, the precipitated crystals are collected by filtration, washed with a small amount of cold water and then with chloroform, and dried to obtain 300 mg of black-purple powder crystals of the target disodium salt.
Melting point over 300℃.

Germanium content (atomic absorption method) Theoretical value (%) 10.21 Experimental value (%) 11.05 Visible absorption maximum (measured underwater) 408nm 539nm 577nm Infrared absorption spectrum: As shown in Figure 3 of the attached drawing.

Nuclear magnetic resonance spectrum: As shown in Figure 4 of the attached drawings.

(2) Bishydroxy-7,12-diethenyl-
When the same operation as in (1) is carried out using 3,8,13,17-tetramethyl-2,18-di(2-methoxycarbonylethyl)porphynatogermanium (), the desired product is obtained with a yield of 78%. Obtain the sodium salt.

(3) Bisbromo-7,12-diethenyl-3,8,
Performing the same procedure as in (1) using 13,17-tetramethyl-2,18-di(2-methoxycarbonylethyl)porphynatogermanium () yields the desired disodium salt with a yield of 72%. .

[Brief explanation of drawings]

Figure 1 shows bischloro-7,12-diethenyl-
3,8,13,17-tetramethyl-2,18-di(2
- Infrared absorption spectrum (KBr method) of porphynatogermanium (carboxyethyl), Figure 2 shows its nuclear magnetic resonance spectrum [measured in heavy methanol, using tetramethylsilane (TMS) as an internal standard. ]. Figure 3 shows bishydroxy-7,12-diethenyl-3,8,13,17-
Figure 4 shows the infrared absorption spectrum of the disodium salt of tetramethyl-2,18-di(2-carboxyethyl)porphynatogermanium (), and its nuclear magnetic resonance spectrum (measured in deuterated methanol).

Claims (1)

[Claims] 1. General formula Bis-substituted 7,12-diethenyl- (in the formula, Y represents a halogen atom or a hydroxyl group)
3,8,13,17-tetramethyl-2,13-di(2
-carboxyethyl) porphynatogermanium (). 2 General formula Bis-substituted 7,12-diethenyl- (in the formula, Y represents a halogen atom or a hydroxyl group)
3,8,13,17-tetramethyl-2,13-di(2
A general formula characterized by reacting porphynatogermanium (-methoxycarbonylethyl) with an acid or an alkali. Bis-substituted 7,12-diethenyl- (in the formula, Y represents a halogen atom or a hydroxyl group)
3,8,13,17-tetramethyl-2,13-di(2
-Production method of porphynatogermanium (carboxyethyl). 3 General formula 7,12-diethenyl-3,8,13,17
-Tetramethyl-21H, 23H-porphin-2,
General formula characterized by reacting 18-dipropionic acid and germanium halide Bis-substituted 7,12-diethenyl- (in the formula, Y represents a halogen atom or a hydroxyl group)
3,8,13,17-tetramethyl-2,18-di(2
-Production method of porphynatogermanium (carboxyethyl).