JPS6011916B2 - Triazole-4-carboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel triazole-4-carboxylic acid which can be used as an antibacterial agent, particularly as a therapeutic agent for humans and other animals in the treatment of infectious diseases caused by gram-negative amphoteric bacteria, including Pseudomonas aeruginosa. Regarding derivatives.

The present inventors have successfully synthesized a novel triazole-4-carboxylic acid derivative represented by the general formula, and further demonstrated that this derivative exhibits antibacterial activity.
In particular, the present inventors have discovered that it exhibits remarkable antibacterial activity against Gram-negative campobacteria, including Pseudomonas aeruginosa, and can be used as an antibiotic, leading to the completion of the present invention.

However, X has a hydrogen atom, a methyl group, an ethyl group, a phenyl group, or an amino group, and R has a substituent (the substituents include methyl, methoxy, ethoxy, benzyloxy, nitro, amino, chloro, and hydroxy). It is one of a kind.

) or no phenyl group, R2 is a phenyl group or p
-Hydroxyphenyl group, respectively. The amino acid constituting the triazole-4-carboxylic acid derivative of the present invention is, for example, phenylglycine (in the above formula, R2 is a phenyl group) 4-hydroxyphenylglycine (in the above formula, R2 is a 4-hydroxyphenyl group), and L - body, D
Both the - body and the DL- body can be adopted.

In terms of antibacterial activity, the D-form is preferred in many cases. The hydrogen atom of the carboxyl group in the above-mentioned formula is, for example, sodium,
Items substituted with metals such as potassium, calcium, and aluminum, or substituted with ammonium such as triethylammonium, brocaine, dibenzyl, ammonium, and N-penzyl-8-phenethylammonium. Triazole-4-carboxylic acid derivatives of the present invention also include triazole-4-carboxylic acid derivatives in the form of hydrates.

Of course, pharmaceutically non-toxic substituents are employed in this case. Conventionally, penicillins having an amino group at the Q-position, represented by the general formula (R2 is the same as defined above), have been shown to exhibit antibacterial properties not only against Gram-positive bacteria but also against Gram-negative amphoteric bacteria. Are known.

However, it has the disadvantage that it does not exhibit effective antibacterial properties against Pseudomonas aeruginosa and Mycobacterium marcescens, which are known to cause serious clinical infections. *・The above triazole-4-carboxylic acid derivative of the present invention not only exhibits antibacterial properties against Gram-positive and Gram-negative bacteria, but also has a wide range of antibacterial properties that are effective against Pseudomonas aeruginosa and M. It has a unique spectrum and is therefore an extremely practical compound. In order to produce the target compound of the present invention, Q-aminobenicillin represented by the general formula is preferably condensed with a reactive derivative of triazole-4-carboxylic acids represented by the general formula.

For the condensation reaction, a known condensation reaction may be used.
Note that R,, R2, and X are the same as defined above. Suitable reactive derivatives include, for example, acid halides,
Examples include mixed acid anhydrides, activated amides, activated esters, etc., but particularly commonly used ones include acid chloride, acid azide, dialkyl phosphoric acid mixed anhydride, phenyl phosphoric acid mixed anhydride, diphenyl phosphoric acid mixed anhydride, and dibenzyl phosphoric acid. Mixed anhydrides, halogenated phosphoric acid mixed anhydrides, dialkyl phosphorous acid mixed anhydrides, sulfite mixed anhydrides, thiosulfuric acid mixed anhydrides, sulfuric acid mixed anhydrides, alkyl carbonic acid mixed anhydrides, aliphatic carboxylic acids (e.g. bivalic acid, bentane acid, isobentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid) mixed anhydride,
Acid anhydrides such as aromatic carboxylic acid (e.g. benzoic acid) mixed anhydrides, symmetrical acid anhydrides, acid amides with imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, cyanomethylester hamethoxymethyl esters, Vinyl ester, fu. p-nitrophenyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, bentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, Nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piveridyl ester, 8-quinolyl thioester, N・N-dimethylhydroxylamine, 1-hydroxy-2-(IH) −
Pyridone, N-hydroxysuccinimide or N-
Examples include esters such as esters with hydroxyphthalimide. Next, to synthesize a reactive derivative, for example, to synthesize an acid chloride, the triazole-4-
Carboxylic acids are reacted with, for example, thionyl chloride or phosphorous pentachloride.

In addition, active esters such as 2,4-dinitrophenyl ester can be obtained by reacting 2,4-dinitrophenol with dicyclohexylcarbodimide or the like. The reaction between the above-mentioned reactive derivatives and the above-mentioned Q-aminobenicillins and cephalosporins is carried out in the presence of a base such as an alkali metal bicarbonate, an alkali metal carbonate, a trialkylamine, or pyridine.

When a solvent is used, examples of the solvent include water, acetate, etc.
Dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, and dimethylformamide (DMF) are employed. Hydrophilic organic solvents can also be used in the form of a mixture with water. The reaction is usually preferably carried out under cooling or at room temperature. It is also possible to react with a reactive derivative in which the carboxyl group in the above general formula is converted to an ester such as t-butyl ester, pendyl ester, silyl ester, trichloroethyl ester, etc.

After the reaction is complete, these ester groups are removed by a conventional method,
It can be converted back to a free carboxyl group. In addition, for the target compound in which the substituent of R in the above general formula is an amino group, first synthesize penicillins in which the substituent is a nitro group, and then obtain the target compound in which the substituent is an amino group by catalytic reduction. I can do things.

The reaction product can be isolated by isolation methods known per se (extraction method,
Column chromatography, recrystallization, etc.) may be used as appropriate.

The triazole-4-carboxylic acid derivative thus obtained can be converted into non-toxic salts such as alkali metal salts, ammonium salts, and organic bases by conventional salt formation methods.

These salts are preferable for formulation because they are water-soluble, for example. Hereinafter, the present invention will be explained in more detail with reference to Examples. In the following examples, silica gel was used for thin layer chromatography, and a developing solvent having a composition of n-butanol:acetic acid:water=6:3:2 was used. The present invention will be explained in detail below with reference to Examples.

Example 1 10% p-penzyloxyphenylhydrazine hydrochloride (0.04 mol) was added to 110% aqueous hydrochloric acid solution 13' while stirring at 0°C, and then ethyl ether 18' was added and quenched. It was made into a liquid. Add 3.5 moles (0.05 moles) of sodium nitrite to this and add 10 moles of water.
The solution was added dropwise at -3 to -5°C. To this was further added 10 parts of ethyl ether and stirred for 2 hours. The reaction solution was transferred to a separatory funnel, the ether layer was separated, dried over calcium chloride, and the solvent was concentrated under reduced pressure to obtain a viscous liquid 6.2 mm. This was added to a solution of 0.92 moles (0.04 mol) of sodium metal dissolved in 20 moles of ethyl alcohol while stirring at 5°C, and then 4.3 moles (0.033 mol) of ethyl acetoacetate was added dropwise. The mixture was heated under reflux for 2 hours. After the reaction, the mixture was cooled and 20% of water was added thereto. Concentrated hydrochloric acid was added to this to adjust the pH to 2, and the precipitated crystals were collected. Recrystallize from a small amount of ethyl alcohol to obtain 3
．． After two evenings, 1-(p-penzyloxyfer)-5-methyl-1,213 triazole-4-carboxylic acid was obtained as a yellowish brown solid. Yield 26%, mp. 190-19 years old○. 1-(p-penzyloxyphenyl)-5-methyl-1,2,3-triazole-4-carboxylic acid obtained as above was chlorinated at room temperature for 1.4 min (M of 4.5). 10% of thionyl was added, and the mixture was heated at 80:00 for 4 hours.

After the reaction was completed, the mixture was concentrated to dryness under reduced pressure to remove thionyl chloride. 10 parts of dry benzene was added to the resulting residue, and the mixture was again concentrated to dryness under reduced pressure. 1-( obtained as a residue
p-penzyloxyphenyl)-5-methyl-1.2.
3-triazole-4-carboxylic acid chloride (Vcoc
l=17623 skin 1) was dissolved in 15 parts of acetonitrile.

On the other hand, D-(1)-Q-aminobenzylbenicillin 3
1.6 parts of the hydrate (4 mM) was cooled on ice in a mixed solvent of 25 parts of water and 10 parts of acetonitrile, and a 2N aqueous solution of sodium hydroxide was gradually added until a homogeneous solution was obtained. At this time, the pH of the solution became 8.5. The above-mentioned acetonitrile solution of acid chloride was gradually added dropwise to the solution while stirring under ice-cooling. At this time, the pH of the reaction solution was adjusted with four 2N aqueous sodium hydroxide solutions so as to always maintain the pH at 7.5 to 8.0. After dropping, cool on ice for 1 hour.
Stirred for 1 hour, then further stirred for 1 hour at room temperature.

During this time, the pH of the reaction solution was adjusted with a 6% aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution so that the pH was always maintained at 7.5 to 8.0. After the reaction, 15 parts of water was added to the reaction solution, and then the acetonitrile was removed under reduced pressure at 30° C. or lower.

Add 100% of ethyl acetate to the remaining aqueous solution, and dropwise add 6% aqueous hydrochloric acid solution while stirring to adjust the pH of the aqueous layer to 1.5.
I made it. After separating the ethyl acetate layer, the aqueous layer was extracted once again with 100 ml of ethyl acetate. The ethyl acetate layers were combined, washed with water, and then dried over anhydrous magnesium sulfate.

The ethyl acetate solution was concentrated to 30 qo or less, and a mixed solvent of 1:1 of ether, petroleum, and ether was added to the resulting residue to powder it.

The obtained solid was collected and dried to obtain the target product D-Q-[1-(
p-penzyloxyphenyl)-5-methyl-1.2.
2.28 g of 3-triazole-4-carboxamide]penzylbenicillin (3.56 mM, yield 89%) was obtained. The above compound was suspended in 10 parts of methanol, and while stirring under ice cooling, 2.14 parts of n-butanol solution of sodium 2-ethylhexanoate (2M/so) was added and stirred for 15 minutes. After removing impurities, 200 ml of ether was added to the mixture under ice cooling and stirring to precipitate a solid.

The obtained solid was collected and dried to obtain the target product D-Q-[1-(p-benzyloxyphenyl)-5-methyl-1,2
・3-triazole-4-carboxamide]penzylbenicillin sodium salt 1.5 hydrate 2.08 hours (3.
02mM, yield 75.5%). Thin layer chromatography Rf=0.87 Elemental analysis: Measured value C57.42% Day 4.70% N1
2.25%C33 days 3,06N6SNa・1. Calculated value for group 20 C57.47% Day 493% N12.1
9% infrared absorption spectrum (Nujol) VC=.

(8-lactam) = 1780 arc-1 nuclear magnetic resonance spectrum (solvent DMSO-d6) 61,42 (S, pan), 1
．． 52 (S, lees) 62.43 (S, 9H) (triazole ring-5-position methyl) 63.87 (S, IH) (3-position 1 day) 65.14 (S, 2H) 65.20 (m, ) (5th place 1 day, 6th place 1 day) 5mi 53
65.86 (d, IH) () 67.00-7.57 (m, 14H) (arom.) The target compound of the present invention was synthesized in the same manner as in Example 1.

The results are shown in Table 1. Table 1 Example 20 30% Pd-BaC037.2 was suspended in 90 ml of water and activated by stirring in an autoclave for 1 hour under an hydrophobic pressure of 3 ml of hydrogen.

To this, D-Q-[1-(p-nitrophenyl)-5-methyl-1,2,3-triazole-4-carpoxyamide]penzylbenicillin sodium salt dihydrate obtained in Example 8 was added. A solution of (4.71 M) in 75 liters of water was added. This was stirred at room temperature for 1 hour under 3 positive pressures of hydrogen to perform a reduction reaction. After the reaction was completed, the catalyst was separated and the pH of the aqueous solution was adjusted to 7, followed by washing with 300 g of ethyl acetate. Add 300% of ethyl acetate to the aqueous layer, and dropwise add 6% aqueous hydrochloric acid solution while stirring to adjust the pH of the aqueous layer to 1.
．． I gave it a 5. After separating the ethyl acetate layer, the aqueous layer was extracted once again with 300 ml of ethyl acetate. The ethyl acetate layers were combined, washed with water, and then dried over anhydrous magnesium sulfate. The ethyl acetate solution was concentrated to 30 oo or less, and ether was added to the resulting residue to powder it.

The obtained solid was collected and dried to obtain the target product D-Q-[1
-(p-aminophenyl)-5-methyl-1,2,3-
1.97 g of triazole-4-rupoxyamide]penzylbenicillin (M of 3.59, yield 76.2%) was obtained. The above compound was dissolved in 10 methanol under ice cooling,
While stirring at the same temperature, 2.15' of sodium 2-ethylhexanoate n-butanol solution (2M/night) was added.
was added to precipitate a solid.

The obtained solid was filtered and dried to obtain the desired product D-Q-[1-(p-aminophenyl)-5-methyl-1,2,3-triazole-4-carboxamide]penzylbenicillin sodium salt 1. pentahydrate 2.0 m (3.34 M
, yield 71%). Thin layer chromatography Rf=0.82 Elemental analysis Measured value C52.83% Day 4.89% N1
5.84%C26 days 2605N, SNa・1. Calculated value for group 20 C52.17% Day 4.85% N16.
39% infrared absorption spectrum (Nujol) VC=.

(3-lactam) 1760-1 nuclear magnetic resonance spectrum (solvent: DMSO-d6) 61.43 (S, general) 1.5
5 (S, 9H) 2.43 (S, 3H) 4.20 (S, IH) 3rd place 5.37-5.67 (m, 2H) 5th place 1 day, 6th place 5 per day
．． 94 (br, d, IH), L 6-67 to 7-67 (m, to H) amm - The target compounds of the present invention were synthesized from the compounds of Examples 9 and 10, respectively, in the same manner as in Example 20. .

The results are shown in Table 2. Table 2 An example of the antibacterial activity of the compounds produced in the above examples is shown in Table 3.

Note that the MIC measurement is based on the standard method of the Japanese Society of Chemotherapy. The results in Table 3 show that the compounds of the present invention have superior antibacterial activity compared to carbenicillin, a commercially available antibiotic, and can be used practically as pharmaceuticals and veterinary drugs.

Claims (1)

[Claims] 1. A 1,2,3-triazole-4-carboxylic acid derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼. However, X is a hydrogen atom, methyl group, ethyl group, phenyl group, or amino group, and R_1 has a substituent (the substituent is methyl, methoxy, ethoxy, benzyloxy, nitro, amino, chloro, or hydroxy). R_2 represents a phenyl group or a p-hydroxyphenyl group, respectively. 2. The derivative according to claim 1, wherein the constituent amino acids are D-form. 3. The derivative according to claim 1, which is present in the form of a salt.