JP2008143887A - Medicine comprising crystal of 1-methylcarbapenem compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find out a crystal improved in preservation stability and the solubility into water from among crystals of compound (I). <P>SOLUTION: The medicine comprises as an effective ingredient a crystal composed of the 1-methylcarbapenem compound represented by formula (I) having a specific main peak in the powder X-ray diffraction obtained by irradiation with the Cu K<SB>α</SB>-line. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to a medicament, particularly a bacterial infection, which contains a crystal composed of a 1-methylcarbapenem compound, which has excellent antibacterial activity and storage stability, and is easy to handle, particularly excellent in water solubility, as an active ingredient. The present invention relates to a pharmaceutical composition for prevention or treatment of infectious diseases.

  Patent Document 1 and Patent Document 2 have formulas

The 1-methylcarbapenem compound represented by these is disclosed. The present compound (I) exhibits excellent antibacterial activity not only for gram-negative bacteria but also for gram-positive bacteria, and can be expected to be useful as an antibacterial agent.

Patent Document 3 and Patent Document 4 disclose specific crystals of the present compound (I) or a pharmacologically acceptable salt thereof. The crystals are superior in storage stability and easy to handle as compared to freeze-dried powder, but nevertheless have no problem at all in terms of storage stability and ease of handling, especially solubility in water. I can't say that.
JP-A-10-204086 JP 11-71277 A JP 2001-72681 A JP 2002-161034 A

It is important that the drug substance can be stored for a long time while maintaining its quality. When storage conditions need to be low, large-scale refrigeration equipment is required to maintain quality, so finding a stable crystal that can be stored at room temperature is industrially meaningful. Also,
In particular, when a medicine is developed as an injection, a crystal that dissolves in water more quickly at the time of formulation in a factory or administration of the preparation to a patient is preferable. From the above, keeping storage stability,
If crystals that dissolve rapidly in water are found, it is considered that the productivity and convenience of medicine can be further improved.

As a result of various studies to solve these problems, the inventors have succeeded in obtaining specific new crystals of 1-methylcarbapenem compounds. This crystal has a storage stability equal to or higher than that of conventionally known crystals, is excellent in solubility in water, and is extremely excellent as a drug substance (especially an antibacterial agent), particularly as an injection drug substance. As a result, the present invention was completed.

The present invention
(1) in the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 13.30,9.
86, 8.17, 7.00, and 4.59 mainly show peaks.
A pharmaceutical comprising as an active ingredient a crystal comprising a 1-methylcarbapenem compound represented by:
(2) in the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 13.30,9.
Formula characterized by showing mainly peaks at 86, 8.17, 7.00 and 4.59

A pharmaceutical comprising a crystal of 1-methylcarbapenem compound / acetone hydrate represented by the formula:
(3) It relates to an antibacterial agent containing the crystal as an active ingredient.

In the above,
The 1-methylcarbapenem compound represented by the formula (I) is a compound disclosed in JP-A-10-204086 and JP-A-11-071277, and is effective against a wide range of bacteria from gram-positive bacteria to gram-negative bacteria. It is a compound having strong antibacterial activity.

  The compound represented by the formula (I-1) is an acetone solvate of the compound (I).

The crystal of the present invention is produced by dissolving the 1-methylcarbapenem compound represented by the formula (I) or a salt thereof in, for example, a water-acetone solution, adding a base as necessary, and precipitating the crystal from this solution. can do.

Examples of the salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate;
Organic acid salts such as carbonate, acetate, benzoate, oxalate, maleate, fumarate, tartrate, citrate; or methanesulfonate, benzenesulfonate, p-toluenesulfonate Acid addition salts such as sulfonates such as salts, sodium salts, potassium salts,
Examples include alkali metal salts such as lithium salts; metal salts such as calcium salts, magnesium salts, and cobalt salts; or base addition salts such as ammonium quaternary salts such as ammonium salts.

In the present invention, when the compound (1) is left in the atmosphere, it absorbs moisture and may adsorb water or become a hydrate, and also absorbs certain other solvents. In some cases, solvates may be obtained, and such hydrates or solvates are also included in Compound (I).

In the present invention, the hydrate or solvate of compound (1) is preferably a hydrate or an acetone solvate, and more preferably an acetone solvate.

The crystal of the present invention refers to a solid whose internal structure is formed by regular repetition of three-dimensional constituent atoms (or a group thereof), and is distinguished from an amorphous solid that does not have such a regular internal structure. .

Even crystals of the same compound may produce crystals having a plurality of different internal structures and physicochemical properties depending on the crystallization conditions, but the crystal of the present invention is in any of these crystal forms. It may be a mixture of two or more crystal forms.

The crystal of the compound (1) containing even a little of the crystal of the present invention is included in the crystal of the present invention, and the crystal of the present invention is preferably 50% or more, more preferably 70% or more, and still more preferably It is a crystal of the compound (1) containing 80% or more of the crystal of the present invention.

The crystal of the 1-methylcarbapenem compound represented by the formula (I-1) is a copper K _α ray (wavelength λ
= 1.54 Angstroms) In the powder X-ray diffraction obtained by irradiation, the surface separation d = 13
. Main peaks are shown at 30, 9.86, 8.17, 7.00 and 4.59.

The crystals of the present invention have improved storage stability and solubility in water among the crystals of compound (I), and are useful in industrial production.

The 1-methylcarbapenem compound represented by the formula (I) can be produced according to the method disclosed in JP-A-10-204086, JP-A-11-071277 and JP-A-2002-212183 or a method analogous thereto. .

The crystal of the present invention is obtained by, for example, dissolving Compound (I) or a salt thereof in a suitable solvent (good solvent),
Concentrate as necessary, add a poor solvent as necessary, cool as necessary, etc. to lead compound (I) to a supersaturated state, precipitate crystals, then isolate the precipitated crystals and dry Achieved by letting

Crystal precipitation can be initiated spontaneously in the reaction vessel, but can also be initiated or promoted by applying mechanical stimuli such as seed crystal inoculation, ultrasonic stimulation, or rubbing the reactor surface.

When handling a solution of compound (I), in order to suppress decomposition of compound (I), it is usually −10 ° C.
Handle at a temperature of from 60 ° C to 60 ° C, preferably from 0 ° C to 25 ° C.

  The cooling temperature for crystallization is preferably 0 ° C. to 10 ° C.

As a method of concentrating the solution of compound (I), for example, a method of concentrating by evaporating the solvent while heating under normal pressure or reduced pressure using a rotary evaporator or the like, a method of concentrating using a reverse osmotic pressure membrane and so on. The reverse osmosis membrane used for concentration of the aqueous solution can be selected from, for example, a polyacrylonitrile membrane, a polyvinyl alcohol membrane, a polyamide membrane, a cellulose acetate membrane, and the like.

Examples of the good solvent for compound (I) include water, dimethyl sulfoxide, dimethylformamide, and methanol, with water being preferred.

Examples of the poor solvent for the compound (I) include acetone alone or alcohols having 2 to 4 carbon atoms such as ethanol, propanol and butanol; ketones such as methyl ethyl ketone; ethers such as diethyl ether and tetrahydrofuran. A mixed solvent of acetone and a solvent such as esters such as methyl acetate and ethyl acetate can be mentioned, and acetone is preferred.

Compound (I) or a salt thereof as a starting material may be lyophilized powder or isolated as an existing crystal, but since it can be purified by crystallization, compound (I) or a salt thereof can be used. It is also possible to use a solution of the synthetic reaction crude product containing.

The supersaturated state is obtained by, for example, concentrating an aqueous solution of compound (I) to a saturated state under heating at 30 ° C. to 60 ° C. and gradually cooling to 0 ° C. to 10 ° C. It can be obtained by gradually adding a poor solvent such as acetone and cooling as necessary.

The crystal of the present invention is preferably precipitated by concentrating an aqueous solution containing compound (I) as necessary, adding a poor solvent, and further cooling as necessary.

More preferably, the crystal of the present invention is precipitated by concentrating an aqueous solution containing the compound (I) if necessary, adding acetone, and cooling if necessary.

The precipitated crystals can be isolated, for example, by filtration, centrifugation, or gradient methods. The isolated crystals are washed with a suitable solvent as necessary. Washing is preferably performed with the solvent used for crystallization.

The isolated crystals are usually dried at a temperature of 10 ° C. to 50 ° C., preferably at a temperature of 20 ° C. to 30 ° C., until the weight is substantially constant. If necessary, dry the crystals using silica gel,
It can also be carried out in the presence of a desiccant such as calcium chloride or under reduced pressure.

The crystals obtained in this way are hydrated crystals, ethanol hydrate crystals, or crystals of compounds that hold both water and ethanol as solvates, and are known to have
It is a crystal with improved storage stability at room temperature, and further excellent in solubility in water as compared with other conventionally known crystals.

This compound represented by the formula (I-1) is a ¼ acetone solvate, and this crystal has a temperature of 45 ° C., 2 ° C.
Pa, dried for 60 hours, and the change in weight is constant, but the same powder X-ray analysis of the crystals in any state from the undried state immediately after filtration to the end of drying As long as a pattern is shown, it is included in the present invention.

The crystal of the present invention exhibits a broad antibacterial spectrum and a strong antibacterial activity against gram positive bacteria, gram negative bacteria and anaerobic bacteria, including cephalosporinase producing bacteria. The antibacterial activity can be measured by the agar plate dilution method. For example, Gram-positive bacteria such as Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, pneumococci and enterococci, It exhibits potent antibacterial activity against a wide range of pathogens including Gram negative bacteria such as Enterobacter, Pseudomonas aeruginosa and anaerobic bacteria such as Bacteroides fragilis. Furthermore, it exhibits a strong antibacterial activity against Helicobacter pylori which is detected at a high rate in chronic gastritis and peptic ulcer.

When the crystals of the present invention are dissolved in a suitable solvent and administered to mice, they show a longer half-life in blood concentration and a higher recovery rate in urine than conventional related drugs.

In addition, the crystal of the present invention exhibits an excellent infection treatment effect by subcutaneous administration in systemic infection of mice by Staphylococcus aureus, pneumococci, Escherichia coli or Pseudomonas aeruginosa. Therefore, the crystal of the present invention is useful as a medicine (particularly, an antibacterial agent) and a bulk powder for production thereof.

When the crystal of the present invention is used as a medicine (particularly an antibacterial agent), it is mixed with itself or an appropriate pharmacologically acceptable excipient, diluent, etc., and is used as a tablet, capsule or granule. Orally by powder or syrup, etc., parenterally by injection or the like, or locally by ointment or the like.

These preparations are made of excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose , Low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate Silicate derivatives such as: Phosphate derivatives such as calcium phosphate; Carbonate derivatives such as calcium carbonate; Sulfate derivatives such as calcium sulfate Body, etc.), binders (for example, the aforementioned excipients; gelatin; polyvinylpyrrolidone; macrogol, etc.), disintegrants (for example, the aforementioned excipients; croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone Such as chemically modified starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; stearic acid metal salts such as calcium stearate, magnesium stearate; colloidal silica; bee gum; beeswax, gay wax, etc. Waxes; boric acid; glycols; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; sodium lauryl sulfate and magnesium lauryl sulfate Lauryl sulfur Acid salts; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients, stabilizers (for example, paraoxybenzoic acid esters such as methylparaben and propylbaraben; chlorobutanol and benzyl alcohol) Alcohols such as phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid and the like; and flavoring agents (eg, commonly used sweeteners, acidulants) , Fragrances, etc.), suspending agents (eg, polysorbate 80, sodium carboxymethyl cellulose, etc.), diluents, solvents for preparation (eg, water, ethanol, glycerin, etc.), solubilizers (nonionic surfactants, anions) Surfactants), local anesthetics (lidocaine hydrochloride, mebivacaine hydrochloride, etc.) It is prepared in a known manner by using additives and the like.

Examples of the dosage form suitable for oral administration include solid preparations such as tablets, coating agents, capsules, troches, powders, fine granules, granules, dry syrups, and liquid preparations such as syrups. Can do. Examples of dosage forms suitable for parenteral administration include injections, drops, suppositories and the like. Examples of dosage forms suitable for topical administration include ointments, tinctures, creams, and gels. These preparations can be prepared by methods known per se in the field of pharmaceutics.

The crystalline 1-methylcarbapenem compound of the present invention is preferably administered parenterally, particularly in the form of injections or drops. The dose varies depending on age, weight, and symptoms, but it is usually divided into 1 to 4 times at a lower limit of 10 mg (preferably 50 mg) and an upper limit of 6000 mg (preferably 4000 mg) per day for adults. Can be administered.

EXAMPLES Hereinafter, although an Example, a test example, and a formulation example are given and this invention is demonstrated in detail, this invention is not restrict | limited to these.

Example 1
(1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-
[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carpapen-2
-M-3-carboxylic acid / acetone solvate

(1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-
[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carpapen-2
-M-3-carboxylic acid (50.0 g) was suspended in water (500 ml), and 1N hydrochloric acid was added to the suspension to adjust the pH to 5 to dissolve the crystals. This solution was diluted with 1N sodium hydroxide aqueous solution.
After adjusting to H9, 2.5 g of activated carbon was added and stirred at room temperature for 10 minutes. After the activated carbon was filtered off, acetone (2250 ml) was added dropwise to the reaction mixture at room temperature, and the mixture was cooled to 0 ° C. and stirred for 1 hour. The precipitated crystals were collected by filtration, washed with 75% aqueous acetone and acetone, and dried under reduced pressure to obtain the title compound (41.20 g). Yield 82.4%.

Infrared absorption spectrum (KBr) νmax (cm ^-1 ): 3409, 3345, 3275, 3185, 2967, 2884, 17
61, 1674, 1644, 1586, 1551, 1452, 1415, 1380, 1369, 1340, 1282, 1254.
Nuclear magnetic resonance spectrum (400MHz, DMSO) δ ppm: 1.13-1.24 (4.5H, m), 1.30 (3H, d, J
= 6.4Hz), 1.57-1.72 (1H, m), 1.93-2.10 (1H, m), 2.15-2.35 (1H, m), 2.27, 2.29 (3H, sX
2), 2.68-2.88 (2H, m), 3.09 (1H, d, J = 10.6Hz), 3.29-3.73 (7H, m), 3.75-3.93 (2H, m),
4.01 (2H, s), 4.12-4.30 (2H, m), 4.38-4.50 (1H, m).
Powder X-ray (Cu Ka, λ = 1.54 angstrom) d (angstrom): 13.30, 9.86
, 8.17, 7.00, 4.59.

Example 2
(1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-
[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carpapen-2
-M-3-carboxylic acid / acetone solvate (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-
[(2S, 4S) -2-[(3S) -3- [2- [3- (4-Nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine-4- [Ilthio] -1-carpapen-2-em-3-carboxylic acid 4-nitrobenzyl ester] -carpapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (46.68 g) in tetrahydrofuran (372 ml) And water (258ml)
Was added followed by ethyl acetate (140 ml), 7.5% palladium on carbon (12.92 g) and activated carbon (9.34 g). The reaction mixture was stirred at room temperature for 4 hours under a hydrogen stream (3 kPa), replaced with nitrogen, and stirred for 40 minutes under ice cooling. The reaction mixture was filtered and washed with 66% aqueous tetrahydrofuran (282 ml). The obtained filtrate was diluted with ethyl acetate (560 m
After washing with l), the aqueous layer was concentrated under reduced pressure to 308 ml. Activated carbon (3.7
3 g) was added and stirred at 5 ° C. for 40 minutes. The activated carbon was filtered off and washed with water (93 ml), and then water (30 ml) was poured into the filtrate. The obtained aqueous solution was diluted with 1N aqueous sodium hydroxide solution.
After adjusting to H8.9, acetone (616 ml) was added dropwise at room temperature. Seed crystals (
70 mg) was added, and the mixture was stirred at room temperature for 1 hour. Acetone (616 ml) was further added dropwise, the mixture was stirred at the same temperature for 1 hour, and further stirred for 1 hour under ice cooling. The precipitated crystals are filtered and 7
After washing with 5% acetone aqueous solution, the title compound (21.03 g) was dried under reduced pressure.
) Yield 78.9%.

Test example 1
Storage stability test-1
The crystal of the present invention obtained in Example 2 and the crystal described in JP-A No. 2001-72681 ((1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-
[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carpapen-2
-M-3-carboxylic acid, monoethanolate, trihydrate. This is crystal 1. ) Was sealed in a brown glass bottle at a constant temperature of 25 ° C., and the purity after 1 month and 2 months at the start of the test was determined by high performance liquid chromatography (column: Develosil RPAQUEOUS 4.6 × 150 mm, column temperature: 60 ° C.,
Developing solution flow rate: 1.0ml / min, developing solution: 0.02M potassium dihydrogen phosphate aqueous solution / acetonitrile = 9
5/5 to 50/50). The obtained purity is represented by a chromatographic peak area ratio, and the results are shown in Table 1.

Table 1
Storage stability test at room temperature ――――――――――――――――――――――――――――――――――
purity(%)
――――――――――――――――――――――――――
Test crystal At the start of the test 1 month later 2 months later ――――――――――――――――――――――――――――――――――
Crystal of the present invention 98.35 98.43 98.40
Crystal 1 98.45 98.35 98.06
――――――――――――――――――――――――――――――――――

Test example 2
Storage stability test-2
The crystal of the present invention and the crystal 1 obtained in Example 2 were sealed in a brown glass bottle at a constant temperature of 40 ° C., and the purity at the start of the test and after one month was determined by high performance liquid chromatography (column: Dev.
losil RPAQUEOUS 4.6x150mm, column temperature: 60 ° C, developing solution flow rate: 1.0ml / min, developing solution: 0.02
M potassium dihydrogen phosphate aqueous solution / acetonitrile = 95 / 5-50 / 50). The obtained purity is expressed by chromatographic peak area ratio, and the results are shown in Table 2.

Table 2
Storage stability test at 40 ℃ ――――――――――――――――――――――――――――
Test crystal Purity at start of test (%) Purity after 1 month (%)
――――――――――――――――――――――――――――
Crystal of the present invention 98.35 98.35
Crystal 1 98.45 98.26
――――――――――――――――――――――――――――

Test example 3
Water solubility test The crystal of the present invention obtained in Example 2 and the crystal described in JP-A No. 2001-72681 ((1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1 -Methyl-2-
[(2S, 4S) -2-[(3S) -3- (2-guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carpapen-2
-M-3-carboxylic acid. This is crystal 2. ) Was passed through a 150 μm mesh filter, and the time required for complete dissolution of 300 mg of crystals in 10 ml of water at 25 ° C. was measured. The results are shown in Table 3.

Table 3
Solubility test in water ――――――――――――――――――――
Test crystal dissolution time (min)
――――――――――――――――――――
Crystal of the present invention 2.5
Crystal 2 8.0
――――――――――――――――――――
The crystal of the present invention is extremely superior in solubility in water as compared with crystal 2 which is a known crystal.

Formulation Example 1
Injectable Aseptically fill the vial with 250 mg of the crystals of Example 1 and seal. If necessary, a known pharmaceutical additive such as a local anesthetic such as lidocaine hydrochloride can be added to this preparation. This preparation is used after being dissolved in a solvent such as distilled water for injection at the time of administration.

FIG. 1 shows (1R, 5S, 6S) -6-[(1R) -1-hydroxyethyl] -1-methyl-2-[(2S, 4S) -2-[(3S) -3- (2- Guanidinoacetylamino) pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1-carpapent-2-em-3-carboxylic acid / acetone hydrate (I-1) _It is a powder X-ray diffraction pattern obtained by irradiation with _α rays (wavelength λ = 1.54 Å). The vertical axis of the powder X-ray diffraction pattern indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the value of the diffraction angle 2θ.

The crystal of the present invention has improved storage stability and solubility in water, and is extremely useful practically as a medicine, particularly as an antibacterial agent.

Claims (3)

In the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 13.30,9.86
, 8.17, 7.00, and 4.59, mainly showing peaks

The medicine which contains the crystal | crystallization which consists of 1-methylcarbapenem compound represented by this as an active ingredient. In the powder X-ray diffraction obtained by irradiating the copper K _alpha line, plane spacing d = 13.30,9.86
, 8.17, 7.00, and 4.59, mainly showing peaks

A pharmaceutical comprising a crystal of 1-methylcarbapenem compound / acetone hydrate represented by the formula:   An antibacterial agent comprising the crystal according to claim 1 or 2 as an active ingredient.