JPH0375553B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel oral cephalosporin represented by the general formula () and a pharmacologically acceptable salt thereof. [Wherein, X is -CH ₂ OCOCH ₃ , -CH ₃ , -Cl, -
OCH ₃ , -H or -CH ₂ SHet (Het is a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur), R ₁ ,
R ₂ , R ₃ is a hydrogen atom, or R ₁ , R ₂ , R ₃ is a general formula

[Formula] (R ₅ is hydrogen or a lower alkyl group, R ₆ is a lower alkyl group or lower alkoxy group) or a phthalidyl group, and R ₄ is hydrogen or a methoxy group. ] Penicillin and cephalosporin antibiotics, which are currently widely used as drugs for the treatment and prevention of infectious diseases, contain compounds with very excellent antibacterial activity, but many of them are oral (intestinal absorption). ) is extremely poor. Therefore, when treating patients, the administration of drugs has required a skilled medical technician. Therefore, there are great expectations for cephalosporin antibiotics, which can be administered orally and have strong antibacterial activity, and have been the subject of research for a long time. In particular, regarding cephalosporin antibiotics, only compounds with limited structures, such as cephalexin or its analogues, are in practical use. Much of the research toward this goal has focused on making the 4-carboxylic acid of cephalosporins lipophilic, for example.
There are acetoxymethyl ester derivatives, pivaloyloxymethyl ester derivatives, methoxymethyl ester derivatives, etc., but cephalosporins have low intestinal absorption and have not been put to practical use. The present inventors have discovered that cephalosporin derivatives have an effect of promoting intestinal absorption, and have already filed a patent application (Japanese Patent Application Laid-Open No. 142988/1988). Subsequently, we continued extensive research on the relationship between oligopeptides and the absorption mechanism using the intestinal absorption channel, including modifying the basic core of cephalosporin. It was discovered that it has excellent antibacterial activity and high antibacterial activity (Japanese Patent Application Laid-Open No. 57-212189). As a result of further extensive studies, the present inventors discovered the fact that cephalosporin represented by the above general formula () has high antibacterial activity and also has a very high blood concentration, and thus completed the present invention. I've reached it. The compound of general formula () according to the present invention can exist as an intramolecular ion, but it can also be used as a pharmacologically acceptable salt such as an alkali metal salt such as a sodium salt or a basic organic substance such as L-lysine. In addition, inorganic acid salts such as hydrochloric acid, organic acid salts such as acetic acid, etc. may be present. Furthermore, although D and L stereoisomers of histidine may exist, the present invention may be any of D, L, and DL stereoisomers. R ₁ , R ₂ , R ₃ in general formula () are hydrogen atoms or
Either R ₁ , R ₂ , or R ₃ is a general formula

[Formula] (R ₅ is hydrogen or a lower alkyl group, R ₆ is a lower alkyl group or a lower alkoxy group) or a phthalidyl group, and examples of the group represented by the above general formula () include the following: is used.

【formula】

【formula】

[Formula] -CH ₂ -O-CO- OCH ₃ R ₄ represents hydrogen or a methoxy group. X in general formula () is -CH ₂ OCOCH ₃ , -CH ₃ ,
In addition to -Cl, -OCH ₃ and -H, -CH ₂ SHet (Het is a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur) is used. , _-CH2SHet include the following compounds.

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

[Formula] The compound of general formula () is produced, for example, by the following method. General formula () (In the formula, R ₁ and R ₂ have the same meaning as above, and Y
represents a halogen atom. ) and the general formula () ( _{wherein ,}
It can be obtained by reacting in water or a mixed solvent thereof. In the above manufacturing method, Y in the general formula () is chlorine, bromine, iodine, or fluorine,
Fluorine is preferably used. In the above production method, the solvents usually used are DMF, tetrahydrofuran, dioxane,
Examples include, but are not limited to, chloroform, methanol, acetonitrile, benzene, water, acetone, and mixed solvents thereof. The above production method can be carried out in the presence of an acid. Examples include, but are not limited to, organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, and butyric acid, and inorganic acids such as hydrochloric acid, sulfuric acid, and carbonic acid. In the above production method, the reaction temperature is usually 0°C to
It is carried out at 150°C, and the reaction time is usually 30 minutes to 20 hours. In the above manufacturing method, any of R ₁ , R ₂ , and R ₃ of general formula () and () is

In the case of a group represented by [Formula] (R ₅ and R ₆ are as described above) or a phthalidyl group,
These protecting groups can usually be easily removed with acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, or other methods. Moreover, some of these substances can also be removed by catalytic reduction. Among the compounds of general formula (), those in which X is -SHet can also be produced, for example, by the following method. General formula () (In the formula, R ₁ , R ₂ , R ₃ , and R ₄ have the same meanings as above.) and the general formula ( 4 heteroatoms in a 5- or 6-membered ring) by a commonly used reaction method, for example, PH = 6 to 7.
It can _be obtained by carrying _{out the} reaction in water or a water-containing solvent while controlling the

A group represented by the formula (R ₅ and R ₆ are as described above) or a phthalidyl group can be obtained by further chemical treatment. In the above production method, the reaction temperature is preferably in the range of 15 to 80°C, and the reaction time is in the range of 1 to 10 hours. In the above production method, the solvent used together with water is preferably acetone, methanol, ethanol, or the like. Next, the compound having the general formula () exhibits a wide range of antibacterial activity as shown in Table 1, and also exhibits a high blood concentration, so it can be administered orally alone or with an appropriate pharmaceutical carrier or diluent. I can do it. Suitable pharmaceutical carriers or diluents include lactose, sucrose, starch, cellulose, calcium sulfate, gelatin, and the like; such compositions may be formulated as powdered tablets or filled into capsules. Subject to administration. These compounds can also be mixed with a liquid and administered as a suspension or solution. Hereinafter, the explanation will be given with reference to examples, but in the examples,
The blood concentration of each compound in animals was measured according to the following method. Animal species: Wistar rat (〓) (weight 180~
250g) was used and fasted from the night before the experiment.
Water was provided ad libitum. Blood concentration value is E.coli NIHJ
A bioassay method was conducted using the JC-2 strain as an indicator strain. Furthermore, measurements using high-performance liquid chromatography were also performed. A normal medium was used as the medium, and the standard solution preparation method and other procedures were conducted in accordance with the Japanese Antibiotic Pharmaceutical Standards. The blood concentration was measured over time after oral administration in 6 animals per group, and the blood concentration value was determined as the average value of the blood concentrations of the 6 animals. Example 1 7-β[4-(2'-Amino-2'-carboxy)ethylimidazol-2-yl-amino]3-acetoxymethyl-3-cephem-4-carboxylic acid in anhydrous DMF (17.5 ml) A suspension of toluene-p-sulfonic anhydride (0.74 g) and 7-amino-3-acetoxymethylcef-3-em-4-carboxylic acid (1.17 g) was stirred at 20°C for 15 minutes to partially dissolve. Ta. 2-fluoro-L-histidine N
-tert-butyloxycarbonylated (2.34g) was added and the mixture was stirred at 90°C for 2 hours. After concentrating the reaction solution under reduced pressure, it was purified by column chromatography using Amberlite XAD-.
-tert-butyloxycarbonylated 7-β
1.0 g of [4-(2'-amino-2'-carboxy)ethylimidazol-2-yl-amino]-3-acetoxymethyl-3-cephem-4-carboxylic acid was obtained. Next, dissolve this in 10ml of formic acid and heat to 15-20℃.
The reaction was carried out under stirring for 1 hour. After that, the reaction solution was concentrated under reduced pressure, and 20 ml of ethyl acetate was added to the residue.
When the mixture was stirred under ice-cooling, 0.8 g of the tert-BOC-depleted target product was obtained.

【table】

[Table] The following compounds were obtained in exactly the same manner using the following 3-position substituted product of 7-aminocephalosporanic acid. X- _CH3 -Cl- _OCH3 -H

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【table】

[Table] ｜
｜
_NH2
NH2

[Table] Example 2 7-β[4-(2'-amino-2'-carboxy)ethylimidazol-2-yl-amino]-3-
[(1-Methyl-1H-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid 1-methyl-5-mercapto-1H-1,2,
1.6g of 3,4-tetrazole, 100ml of atone, water
In addition to 100 ml of the solution, 7-β[4-(2'-amino-2'-carboxy)ethylimidazol-2-yl-amino]-3-acetoxymethyl-3-cephem- obtained in Example 1 was added. A solution of 2.6 g of N-tert-butylcarbonylated 4-carboxylic acid dissolved in 30 ml of acetone was added. In a stream of _N2 ,
The reaction was carried out at 50°C for 4 hours while controlling the pH to 6 to 6.4. Return the reaction solution to room temperature and perform XAD
- Purified by column chromatography and tert-butyloxycarbonylated 7-β[4-(2'-amino-2'-carboxy)ethylimidazole-2
-yl-amino]-3-[(1-methyl-1H-1,
1.8 g of 2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid was obtained. Next, dissolve this in 20ml of formic acid and heat to 15-20℃.
The reaction was carried out under stirring for 1 hour. After that, formic acid was concentrated under reduced pressure, and 30 ml of ethyl acetate was added to the residue.
By stirring under ice-cooling, 1.2 g of the tert-BOC-depleted target product was obtained.

[Table] ｜

_NH2

In exactly the same manner, the following compound was obtained using the following 3-position substituted product of 7-aminocephalosporanic acid.

【table】

[Table] ｜


_NH2





Example 3 7-β[4-(2'-amino-2'-carboxy)ethylimidazol-2-yl-amino]-3-
Acetoxymethyl ester of acetoxymethyl-3-cephem-4-carboxylic acid Anhydrous toluene-p-sulfonic acid (0.74 g) and 7-amino-3-acetoxymethylcef-3-em-4 in anhydrous THF (17.5 ml) - a suspension of acetoxymethyl ester of carboxylic acid (1.7 g)
Stir for 15 minutes at 15°C to achieve partial dissolution. N-tert
-Butyloxycarbonylated 2-fluoro-L-histidine (2.34 g) was added and the mixture was stirred at 90°C for 2 hours. After concentrating the reaction solution under reduced pressure, it was purified by Amberlite XAD column chromatography to obtain N-tert-butyloxycarbonylated 7-β[4-(2'-amino-2'-carboxy)ethylimidazole-2 -yl-amino]
1.2 g of -3-acetoxymethyl-3-cephem-4-carboxylic acid was obtained. Next, dissolve this in 10ml of formic acid and heat to 15-20℃.
The reaction was carried out under stirring for 1 hour. Thereafter, the reaction solution was concentrated under reduced pressure and purified by Amberlite XAD- column chromatography to obtain 0.8 g of the target product.

【table】

[Table] The following compounds were obtained in exactly the same manner.

[Table] ｜
_NH2

[Table] ｜
_CH3
Example 4 7-β[4-(2'-amino-2'-acetoxymethyloxycarbonyl)ethylimidazole-2
-yl-amino]-3-[(1-methyl-1H-
1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid Anhydrous toluene-p-sulfonic acid (0.74 g) and 7-amino-3-in anhydrous DMF (20 ml) [(1-
Methyl-1H-1,2,3,4-tetrazole-
A suspension of 5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.41 g) was stirred at 20° C. for 30 minutes to partially dissolve it. Tert-butyloxycarbonylated acetoxymethyl ester of 2-fluoro-L-histidine (3.32 g) was added and the mixture was stirred at 90° C. for 2 hours. After concentrating the reaction solution under reduced pressure, it was purified by column chromatography using Amberlite 2-yl-amino]-3-[(1-methyl-
1H-1,2,3,4-tetrazol-5-yl)
Thiomethyl]-3-cephem-4-carboxylic acid 1.2
I got g. Next, dissolve this in 10 ml of formic acid and store at 0℃ for 2 hours.
The reaction was carried out under stirring for hours. The reaction solution was concentrated under reduced pressure and purified using an Amberlite XAD-column to obtain 0.8 g of the BOC-free target product.

【table】

[Table] ｜

N.H.
₂
The following compounds were obtained in exactly the same manner.

【table】

[Table] Example 5 7-β[4-(2'-amino-2'-carboxy)ethylimidazol-2-yl-amino]-7α-
Methoxy-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-
Cefem-4-carboxylic acid 0.74 g of anhydrous toluene-p-sulfonic acid and 7-amino-7α-methoxy-3 in 20 ml of anhydrous DMF
-[(2-methyl-1,3,4-thiadiazole-
1.30 g of 5-yl)thiomethyl]-3-cephem-4-carboxylic acid was added thereto, and the mixture was stirred at 15° C. for 30 minutes while suspended. In this solution, 2-fluoro-D-histidine was N-tert-butyloxycarbonylated.
2.40 g was added and the mixture was stirred at 90° C. for 2 hours. After concentrating the reaction solution under reduced pressure, Amberlite
Purified by XAD- column chromatography, N-
tert-butyloxycarbonylated 7-β
[(2'-amino-2'-carboxy)ethylimidazol-2-yl-amino]-7α-methoxy-3-
[(2-methyl-1,3,4-thiadiazole-5
1.2 g of -yl)thiomethyl]-3-cephem-4-carboxylic acid was obtained. Next, this product was added to a 20 ml tube, and the reaction was carried out at 20°C for 1 hour with stirring. After that, the reaction solution was concentrated under reduced pressure, and 30 ml of ether was added to the residue to form crystals.
0.8g was obtained.

[Table] Example 6 Oral absorption experiments were conducted using rats for the compounds obtained in Examples 1 to 5. Animal species: Wistar rat (〓) (body weight: 180-250 g) The above rat was fasted from the night before,
Water was provided ad libitum. Blood concentration value is E.coli NIHJJC
A bioassay method and a high performance liquid chromatography method were used in combination, using the -2 strain as an indicator strain. A normal medium was used as the culture medium, and the standard solution preparation method and other procedures were performed in accordance with the Japanese Antibiotic Pharmaceutical Standards. Table 1 shows the average blood concentration for 6 animals per group. In addition,
Each sample was dissolved in a pH7 buffer solution and administered orally. In addition, those that did not dissolve were orally administered as a CMC suspension. Furthermore, as a symmetrical example, blood concentrations of existing similar drugs are shown in Table 2.

【table】

【table】

【table】 The 3rd position substituent is

Among the compounds of [Formula], the blood concentrations of all of the compounds at position 7 Z were below 0.5 μg/ml. Example 7 The MIC of the following compounds obtained in Examples 1 and 2 was measured.

【table】

Claims (1)

[Scope of Claims] 1. Oral phalosporin represented by the following general formula (), and a pharmacologically acceptable salt thereof. [Wherein, X is -CH ₂ OCOCH ₃ , -CH ₃ , -Cl, -
OCH ₃ , -H or -CH ₂ SHet (Het is a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur), and R ₁ , R ₂ , R ₃ is a hydrogen atom, or any one of R ₁ , R ₂ , and R ₃ is a group represented by the general formula [Formula] (R ₅ is hydrogen or a lower alkyl group, R ₆ is a lower alkyl group or a lower alkoxy group), or a group represented by phthalidyl The group R ₄ represents hydrogen or a methoxy group. ].