JP2575590B2 - Triazolylthiomethylthiocephalosporin hydrochloride and its hydrate crystals and their preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a triazolylthiomethylthiocephalosporin compound useful as an active ingredient in an antibiotic preparation for oral administration, and more particularly to a low toxicity, pharmaceutically stable 7β-[( Z) -2- (2-amino-4-
Thiazolyl) -2-hydroxyiminoacetamide] -3-
(1,2,3-triazol-4-yl) thiomethylthio-3-
The present invention relates to a hydrochloride of cephem-4-carboxylic acid (hereinafter abbreviated as S-1090), a hydrate crystal thereof, and a method for producing the same.

[0002]

2. Description of the Related Art A triazolylthiomethylthiocephalosporin derivative which is orally active has been already produced and disclosed (JP-A-5-59066, EP-A-467647). Among them, S-1090, which has particularly excellent antibacterial activity, was synthesized as a pale yellow powder substance (see above), and was expected to be useful in clinical practice. It was not enough.

[0003]

That is, the conventional S-10
90 had the following disadvantages. 1. Due to water absorption, the water content fluctuates during operations such as pulverization and formulation, resulting in low reliability of product quality retention, active ingredient content, and operability. 2. Since it is insoluble in water to the extent necessary for recrystallization and amorphous, the removal of impurities is incomplete. 3. It is difficult to reduce the residual solvent after drying to a pharmaceutically acceptable amount.

[0004]

Means for Solving the Problems The present inventors have found that S-pharmaceuticals are stable in pharmaceutically quality, have a small amount of residual solvent, and are clinically advantageous.
As a result of intensive studies aimed at obtaining a 1090 derivative, they have found that hydrochloride and hydrochloride hydrate crystals have excellent properties of low toxicity, high solubility, and high stability, and have led to the present invention. The hydrochloride hydrate crystal of the present invention shows an X-ray diffraction image shown in Table 1 below and FIG. 1 and a differential scanning calorimetry curve shown in FIG.

[0005]

[Table 2] Table 1 X-ray diffraction images 2θ intensity 2θ intensity 2θ intensity 2θ intensity 6.24 164 22.04 84 30.30 269 38.44 150 10.50 117 22.54 57 30.50 405 39.20 133 10.94 1549 23.16 1461 30.74 271 39.96 214 12.22 997 23.74 379 31.04 74 43.06 222 12.54 687 24.32 432 31.80 317 44.24 104 14.10 1057 24.54 504 31. 25.30 259 32.56 58 45.38 68 17.90 155 25.94 521 32.98 105 45.68 94 18.74 381 26.14 947 33.36 458 47.20 63 18.94 462 26.44 422 33.76 231 48.18 65 20.04 160 27.46 362 34.44 99 55.54 67 20.74 217 28.02 205.25 21.188. 21.36 478 29.08 179 37.38 187 21.68 315 29.50 104 37.70 127 Measurement conditions) tube: Cu; tube voltage: 40 kV; tube current: 20 mA; sampling angle: 0.02 °

The S-1090 hydrochloride hydrate crystals of the present invention hardly lose water and show a water content corresponding to 1-2 dihydrate under a wide range of drying conditions. It usually stabilizes as crystals exhibiting a water content corresponding to about 1.1 to 1.3 hydrate. When dried at low humidity or high temperature, it becomes an anhydrous crystal, but if it is left under humidified conditions, it is equivalent to 1.2 to 1.3 hydrate even in the air, and equivalent to 1.8 hydrate depending on the conditions Rapidly absorbs and stabilizes water content up to The 2θ value of X-ray diffraction depends on the structure of the crystal lattice, and the peak intensity depends on the crystal growth direction, the crystallization ratio, and the like. A change in only the intensity often does not mean a change in the structure of the crystal lattice. This S-109
O-hydrochloride hydrate crystals have a low residual amount of solvent, have low toxicity and are stable in quality, and are particularly useful clinically.

The S-1090 hydrochloride of the present invention can be produced by reacting S-1090 with hydrochloric acid according to a conventional method. The S-1090 hydrochloride hydrate crystal is S-10
90 can be produced by crystallization from an aqueous hydrochloric acid solution. Hereinafter, the conditions of the production method of the present invention will be exemplified, but the present invention is not limited thereto. The S-1090 produced by an appropriate method is preferably added to the reaction solution at a pH of about 1 equivalent or more, more preferably 0.1 to 0.1 equivalent.
The amount of hydrochloric acid required to adjust the pH to about 5 is allowed to act at about 0 to 50 ° C, preferably about 5 to 30 ° C, for about 1 to 60 minutes, preferably for about 10 to 30 minutes to produce the hydrochloride. You.

Further, from an aqueous solution or suspension of hydrochloric acid,
If necessary, a crystal of the hydrochloride hydrate can be produced by adding a seed crystal of crude S-1090 hydrochloride and then crystallization. In this case, the concentration of hydrochloric acid is preferably as high as pH 0 to 5 (preferably pH 0 to 3). The crystallization solvent is lower alcohol, ketone,
Conventional industrial organic solvents such as nitriles and esters may be contained. The crystallization temperature is about 0-90 ° C, preferably about 30-50 ° C. The crystallization time under such conditions depends on the composition of the solvent, but is about 10 minutes to about 20 hours.
Preferably, from about 1 to about 6 hours.

Next, the crystals of the hydrochloride or hydrochloride hydrate are heated, at normal temperature, at low temperature, pressurized, at normal pressure, reduced pressure, blown, heated,
Drying is performed using ordinary drying conditions such as dehumidification with a desiccant and fluidized drying. However, in the case of hydrate crystals, dry conditions under which water molecules do not separate are selected. In addition, the hydrate crystal is obtained by dehydrating the crystal, for example, at a temperature of 10 to 30 ° C. and a humidity of 50 to 9
It may be left under 0% humidification condition to re-absorb water. Starting material S-1090 can be produced by the method described in the above-mentioned JP-A-5-59066, for example, by neutralizing S-1090 sodium salt. In addition, S-10
On the triazole ring which is a part of the 3-position side chain of No. 90, the bonding position of the S atom is at the 4-position, but when the hydrogen on the triazole ring moves, it becomes the 5-position. As known to those skilled in the art, the ratio of the bonding position of hydrogen on the triazole ring varies.
It is intended to include both compounds where the bonding position of the atoms is at the 4-position and 5-position.

The S-1090 hydrochloride of the compound of the present invention or a hydrate crystal thereof, when administered to a subject including a human,
Converted to S-1090, showing its strong antibacterial action.
That is, as described in JP-A-5-59066,
S-1090 was tested for its antibacterial activity in vitro and found to be a variety of bacteria, for example, Gram-positive bacteria such as B. aureus, Streptococcus pyogenes, and Proteus vulgaris, Proteus mirabilis, Morgania morganii, Enterobacter. Cloaca, Pseudomonas aeruginosa,
It has been revealed that the antibacterial activity is strong against both Gram-negative bacteria such as Serratia marcescens and Escherichia coli. S-
1090 was particularly effective against Gram-negative bacteria in tests performed with E. coli 7437 and T. cloaca SR233. In addition, in vivo, S-1090 showed an excellent oral absorption rate as a result of blood concentration measurement after oral administration to mice. Therefore, the S-1090 hydrochloride and its hydrate crystals of the present invention have a strong antibacterial activity and are considered to be effective by oral administration.

Accordingly, the present invention provides a method for killing susceptible bacteria by contacting the susceptible bacteria with an effective amount of S-1090 hydrochloride or a hydrate crystal thereof. The subject to which the compound of the present invention is applied covers a wide range not only of humans and animals infected with susceptible bacteria, but also of substances which may be putrefactive and instruments to be sterilized. The present invention also provides a bactericide for pharmaceutical preparations containing S-1090 hydrochloride or a hydrate crystal thereof as an active ingredient. For oral administration, the S-1090 hydrochloride of the present invention or a hydrate crystal thereof is mixed with conventional pharmaceutical carriers, diluents or excipients, and then used as capsules, tablets, granules, powders or suspensions. Formulated into a preparation. For parenteral administration, solutions or suspensions are suitable for subcutaneous, intravenous, intraperitoneal, intramuscular injection and the like. Further, it can be used as a suppository, an external preparation, an eye drop and the like. The dose is generally about 10 mg to 4000 mg per day, preferably 10 mg for oral administration.
It can be 0 mg to 2000 mg. In the case of parenteral administration, about 10 mg to 4000 mg, preferably 50 mg to 2000 mg per day is appropriate.

[0012]

The present invention will be described in more detail with reference to the following examples. Each of the S-1090 hydrochloride hydrate crystals produced in each Example shows an X-ray diffraction image (FIG. 1) and a differential scanning calorimetric curve (FIG. 2) based on the same crystal structure. In the X-ray diffraction image of FIG. 1, the vertical axis indicates intensity and the horizontal axis indicates 2θ. Further, in the differential scanning calorific curve of FIG. 2, the vertical axis indicates the heat flow rate in mW (milliwatts), and the horizontal axis indicates the temperature in ° C. About 70 ° C to about 120 ° C, 105 ° C
An endotherm presumed to be caused by the heat of vaporization of the crystallization water is observed with the vicinity being a local maximum.

Example 1 S-1090 hydrochloride 1) S-1090 hydrochloride 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-)
Thiazolyl) -2-trityloxyiminoacetamide]-
26.0 g of 3- (1,2,3-triazol-4-yl) thiomethylthio) -3-cephem-4-carboxylic acid diphenylmethyl ester was suspended in a mixture of 270 ml of dichloromethane and 51 ml of anisole. While stirring at .5 ° C., a solution of 17.0 g of aluminum chloride in 60 ml of anisole was added dropwise, followed by stirring for 1 hour and 50 minutes. The resulting reaction solution containing S-1090 was mixed with 220 ml of methanol, 114 ml of water and 3 ml of water.
It is poured into a mixture of 29.8 g of 6% hydrochloric acid (with stirring at 0-15 ° C.). The resulting aqueous layer containing S-1090 hydrochloride was separated, washed twice with 100 ml of dichloromethane, and 30 mg of seed crystal (S-1090 crude hydrochloride) was added.
After stirring for 1.5 hours, the mixture was concentrated under reduced pressure to about 150 ml. If the precipitated crystals are collected and washed with 260 ml of water, S-1090
24.5 g of the crude hydrate of the hydrochloride are obtained.

2) S-1090 hydrochloride hydrate 228 ml containing the hydrate of S-1090 hydrochloride obtained in 1)
46 g of a 4% aqueous sodium hydroxide solution are added dropwise to the aqueous suspension of the above, and the mixture is treated with 1.5 g of activated carbon. The precipitate is washed with 20 ml of water. The filtrate containing the S-1090 sodium salt and the washing solution are combined, and 4N hydrochloric acid is added dropwise while stirring at 5 to 10 ° C. to give p.
H2. 50 mg of a seed crystal is added thereto, and 4N hydrochloric acid is added over 1 hour to adjust the pH to 1 (total amount of 4N hydrochloric acid added is 6).
3g). The mixture was stirred at 60 ° C. for 1 hour, brought to 0 ° C., and the precipitated crystals were collected, washed with 160 ml of water and dried to obtain S.
11.0 g of light brown crystals of -1090 hydrochloride hydrate are obtained. mp. 177.6-181.0 ° C (decomposition). The drying was performed using a fluidized-bed dryer under the following conditions. Time: 2 hours, set air temperature: 20 ° C, air flow rate 120
0 cm ³ / min

Example 2 S-1090 hydrochloride hydrate To 10.7 g of S-1090 hydrochloride obtained in Examples 1 and 1), 128 ml of water and 20 ml of 1N aqueous sodium hydroxide were added to dissolve, and this was dissolved with hydrochloric acid. pH 4. Further, 5% hydrochloric acid is added over 1 hour to adjust the pH to 0.5. Mix 40
After stirring at 1 ° C. for 1-5 hours, the temperature was raised to 5-10 ° C., and the precipitated crystals were collected, washed with 70 ml of water and dried to obtain S-1090.
5.0 g of white crystals of the hydrochloride hydrate are obtained. In addition, drying is
The same procedure as in Example 1 was performed under the following conditions. Time: 5 hours, set air temperature: 30 ° C, air flow rate 400
cm ³ / min

Example 3 S-1090 hydrochloride hydrate 200 ml of water and 72 ml of 1N sodium hydroxide solution were added to 51 g of S-1090 hydrochloride obtained in Examples 1 and 1) under ice-cooling to obtain a pH of about 6.2. Solution. The solution is treated with activated carbon and the precipitate is washed with 200 ml of water. Filtration and washing solution are combined, and 6N
400 ml of hydrochloric acid and 50 mg of seed crystals are added, and the mixture is stirred at 40 ° C.
If the precipitated crystals are collected, washed with water and dried, S-1090
16.7 g of white crystals of the hydrochloride hydrate are obtained. The drying was performed in the same manner as in Example 1 under the following conditions. Time: 1 hour, set air temperature: 40 ° C, air flow rate 120
0 cm ³ / min

Example 4 S-1090 hydrochloride hydrate To a solution prepared by adding 190 ml of water and 46 g of 4% aqueous sodium hydroxide to 25.8 g of S-1090 hydrochloride obtained in Examples 1 and 1), a 20% solution was prepared. PH 3.1 with 3.1 g of hydrochloric acid, 36%
It is poured over 40 minutes into a mixture of 148 ml of hydrochloric acid and 128 ml of water (with stirring at 40 ° C.). During this time, when 10 minutes have elapsed, 30 mg of a seed crystal is added. The precipitated crystals are removed and water 130
After washing with ml and drying, 11.0 g of S-1090 hydrochloride hydrate crystals are obtained. mp. 178.1-181.2 ° C (decomposition).

Example 5 S-1090 hydrochloride hydrate About 300 ml of the aqueous solution of S-1090 sodium salt obtained in Examples 1 and 2) was stirred at 5 to 10 ° C. while adding 4N hydrochloric acid dropwise to adjust the pH to 5. I do. This solution is treated with 36% hydrochloric acid 16
It is poured all at once into a mixture of 4 g and 284 ml of water (with stirring at 15 ° C.). 50 mg of seed crystals were added, and the precipitated crystals were collected.
Washing with 145 ml of water and drying gives 12.2 g of white crystals of S-1090 hydrochloride hydrate.

Example 6 S-1090 hydrochloride hydrate 6% hydrochloric acid is added to about 300 ml of the S-1090 sodium salt aqueous solution obtained in Examples 1 and 2) to obtain a pH2 aqueous solution. This solution is poured into a mixture of 187 g of 36% hydrochloric acid and 50 ml of water for 4 minutes under ice-cooling. After 1 hour on ice, the precipitated crystals are collected, washed with 75 ml of water and dried to obtain S-1.
6.6 g of white crystals of 090 hydrochloride hydrate are obtained.

Example 7 S-1090 hydrochloride hydrate 5 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
Was dissolved in a mixture of 20 ml of methanol, 4 ml of water and 0.3 ml of 6N hydrochloric acid, 10 mg of seed crystals were added, and the mixture was concentrated under reduced pressure to 32 g. If the precipitated crystals are collected, washed and dried, S-10
3.0 g of white crystals of 90 hydrochloride hydrate are obtained.

Example 8 S-1090 hydrochloride hydrate 5 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
Was dissolved in 15 ml of methanol and 10N of 1N hydrochloric acid at 40 ° C.
Add dropwise into 0 ml. The precipitated crystals are collected, washed with water and dried to obtain 4.6 g of white crystals of S-1090 hydrochloride hydrate.

Example 9 S-1090 hydrochloride hydrate 8 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
Was dissolved in a mixture of 130 ml of ethanol, 50 ml of water and 4 ml of 6N hydrochloric acid, 10 mg of seed crystals were added, and the mixture was concentrated under reduced pressure to 105 g. If the precipitated crystals are collected, washed with water and dried, S-1
5.9 g of white crystals of 090 hydrochloride hydrate are obtained.

Example 10 S-1090 hydrochloride hydrate 5 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
In 100 ml of a mixture of ethanol and water (1: 1)
Then, the mixture is added dropwise to 100 ml of 1N hydrochloric acid at 40 ° C. The precipitated crystals are collected, washed with water and dried to obtain 4.5 g of white crystals of S-1090 hydrochloride hydrate.

Example 11 S-1090 hydrochloride hydrate 5 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
Was dissolved in a mixture of 20 ml of methanol and 0.2 ml of 6N hydrochloric acid, and concentrated under reduced pressure to 10.5 g. 5m ethanol in the remaining liquid
l and 10 mg of seed crystals. Take the precipitated crystals, wash with water,
When dried, white crystals of S-1090 hydrochloride hydrate 2.5
g. Example 12 S-1090 hydrochloride hydrate

5 g of the dried S-1090 hydrochloride obtained in Examples 1 and 1) was mixed with 30 ml of methanol and 3 g of isopropanol 3
Dissolve in a mixture of 0 ml and 0.5 ml of 6N hydrochloric acid and add 10 mg of seed crystals. If the precipitated crystals are removed, washed and dried, S-
1.9 g of white crystals of 1090 hydrochloride hydrate are obtained.

Example 13 S-1090 hydrochloride hydrate 5 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
Was dissolved in a mixture of 160 ml of acetone, 36 ml of water and 10 ml of 3N hydrochloric acid, 10 mg of seed crystals were added, and the mixture was concentrated under reduced pressure to 85 g. If the precipitated crystals are collected, washed and dried, S-10
0.9 g of white crystals of 90 hydrochloride hydrate are obtained.

Example 14 S-1090 hydrochloride hydrate 5 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
And 20 ml of methanol, 80 ml of methyl ethyl ketone and 6
Dissolve in a mixture of 2 ml of N hydrochloric acid, add 10 mg of seed crystals, and add 62 g
Concentrate under reduced pressure to 4 ml of methanol and 10 mg of seed crystals
Add. If the precipitated crystals are collected, washed and dried,
4.4 g of white crystals of -1090 hydrochloride hydrate are obtained.

Example 15 S-1090 hydrochloride hydrate 5 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
Was dissolved in a mixture of 20 ml of methanol, 30 ml of acetonitrile and 0.5 ml of 6N hydrochloric acid, and 10 mg of seed crystals were added.
Concentrate under reduced pressure to The precipitated crystals are collected, washed with water and dried to obtain 2.0 g of S-1090 hydrochloride hydrate white crystals.

Example 16 S-1090 hydrochloride hydrate 5 g of a dried product of S-1090 hydrochloride obtained in Examples 1 and 1)
Was dissolved in a mixture of methanol (20 ml), ethyl acetate (20 ml) and 6N hydrochloric acid (0.5 ml), and 10 mg of seed crystals were added.
Concentrate under reduced pressure to The precipitated crystals are collected, washed with water and dried to obtain 3.5 g of white crystals of S-1090 hydrochloride hydrate.

Experimental Example 1 The stability of S-1090 hydrochloride and hydrochloride hydrate crystals of the present invention was tested. Table 2 shows the results. In the accelerated stability test under heating, humidification and exposure to light, both the decrease in residual titer and the coloring during the half-month and one month are less than that of the free amine which is the raw powder of S-1090, and the improvement in stability is apparent. This advantage is important in pharmaceutical applications that avoid the contamination of impurities, pharmaceutically stable, low solvent remaining,
A clinically useful drug can be obtained.

[0031]

[Table 3] Table 2 Accelerated stability test (% residual potency / coloring for 2 weeks) Test body Month 50 ° C. sealed 40 ° C. and 75% humidity exposure to light (10,000 lux) free amine 0.5 81.91 skin color 78.75 skin color 87.83 light brown 1.0 67.62 skin color 64.25 skin color 79.98 light brown hydrochloride powder 0.5 83.22 pale brown 95.23 skin color 87.64 skin color 1.0 82.48 pale brown 89.86 Skin color 84.44 Skin color Hydrochloride hydrate 0.5 100.00 White 100.00 White 97.53 Light yellow Crystal 1.0 99.96 White 98.38 White 95.51 Light yellow

Formulation Example 1) Granules S-1090 hydrochloride hydrate crystal 100 mg Lactose 600 mg Corn starch 290 mg Hydroxypropyl cellulose 10 mg Each of the above raw materials is granulated by a wet method according to a conventional method to obtain 1 g of granules. The drug is administered to susceptible bacterial infection patients three times a day.

2) Tablets S-1090 hydrochloride hydrate crystal 200 mg Lactose 65 mg Corn starch 32 mg Hydroxypropyl cellulose 2 mg Magnesium stearate 1 mg Each of the above raw materials is granulated by a conventional wet method and tableted. A tablet weighing 300 mg is administered twice daily to a patient with a susceptible bacterial infection.

3) Hard capsule preparation S-1090 hydrochloride hydrate crystal 50 mg Corn starch 47 mg Magnesium stearate 1.5 mg Talc powder 1.5 mg Each of the above-mentioned raw materials is granulated by a conventional method, and No. 4 hard capsule For susceptible bacterial infections
Administer 3 times a day.

[0035]

Industrial Applicability The S-1090 hydrochloride and hydrochloride hydrate crystals of the present invention are S-1090 in stability under various conditions, which are extremely important properties for use as pharmaceuticals.
Is superior to the free amine that is the raw powder of Therefore, it is useful for the production of a clinically useful formulation with stable pharmaceutically quality and a small amount of residual solvent.

[Brief description of the drawings]

FIG. 1 is an X-ray diffraction image of S-1090 hydrochloride hydrate (the vertical axis indicates intensity, and the horizontal axis indicates 2θ).

FIG. 2 is a differential scanning calorimetry curve of S-1090 hydrochloride hydrate (the ordinate indicates the heat flow rate in MW, and the abscissa indicates the temperature in ° C.).

Claims (5)

(57) [Claims] (1) 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamide] -3- (1,2,3-
Triazol-4-yl) thiomethylthio-3-cephem-
4-carboxylic acid hydrochloride. 2. The compound having the following X-ray diffraction pattern: 7β-[(Z) -2-
(2-Amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3- (1,2,3-triazol-4-yl) thiomethylthio-3-cephem-4-carboxylic acid hydrochloride hydrate crystal . [Table 1] Table 1 X-ray diffraction image 2θ intensity 2θ intensity 2θ intensity 2θ intensity 6.24 164 22.04 84 30.30 269 38.44 150 10.50 117 22.54 57 30.50 405 39.20 133 10.94 1549 23.16 1461 30.74 271 39.96 214 12.22 997 23.74 379 31.04 74 43.06 222 12.54 687 24.32 432 31.80 317 44.24 104 14.10 1057 24.54 504 31. 25.30 259 32.56 58 45.38 68 17.90 155 25.94 521 32.98 105 45.68 94 18.74 381 26.14 947 33.36 458 47.20 63 18.94 462 26.44 422 33.76 231 48.18 65 20.04 160 27.46 362 34.44 99 55.54 67 20.74 217 28.02 205.25 21.188. 21.36 478 29.08 179 37.38 187 21.68 315 29.50 104 37.70 127 Measurement conditions) tube: Cu; tube voltage: 40 kV; tube current: 20 mA; sampling angle: 0.02 ° (3) 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamide] -3- (1,2,3-
Triazol-4-yl) thiomethylthio-3-cephem-
3. A mono-hydrochloride monohydrate crystal of 4-carboxylic acid.
The crystals described. (4) 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamide] -3- (1,2,3-
Triazol-4-yl) thiomethylthio-3-cephem-
The method for producing hydrochloride hydrate crystals according to claim 2 or 3, wherein 4-carboxylic acid is crystallized from an aqueous hydrochloric acid solution. 5. An antibacterial agent comprising the compound according to claim 1, 2, or 3 as an active ingredient.