JP3920041B2 - Hydrates and crystals of neuraminic acid compounds - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to hydrates and crystals of neuraminic acid compound (I) having excellent sialidase inhibitory activity, and medicaments, particularly anti-influenza agents, containing the hydrates or crystals as active ingredients.
[0002]
[Prior art]
Japanese Laid-Open Patent Publication No. 10-330373 discloses a neuraminic acid compound represented by formula (I) (hereinafter referred to as compound (I)). Compound (I) exhibits an excellent sialidase inhibitory action and can be expected to be useful as an influenza therapeutic agent and prophylactic agent. However, in order to put this compound into practical use as a drug substance, storage stability and ease of handling are required.
[0003]
[Problems to be solved by the invention]
As a result of intensive studies on the compound (I), the inventors have found that a hydrate of the compound (I) can be obtained as a crystal exhibiting excellent stability. The hydrate crystals of Compound (I) are remarkably more storage stable and easier to handle than the trifluoroacetate salt of Compound (I) described as Example 35 in JP-A-10-330373. The present invention has been completed by finding out that it has been improved and is extremely useful for practical use as a medicine.
[0004]
[Means for solving problems]
The present invention
(1) Formula (I)
[0005]
[Chemical 3]
[0006]
Hydrate of the compound represented by
(2) Formula (I)
[0007]
[Formula 4]
[0008]
A crystal containing a compound represented by:
(3) In (2), a hydrate crystal of the compound represented by formula (I),
And (4) In (2) and (3), in the powder X-ray diffraction obtained by irradiation with copper Kα rays, the interplanar spacing is 4.0, 4.4, 4.7, 7.5 and 10.2. It is a hydrate crystal of the compound represented by the formula (I) showing a main peak in angstroms.
The crystal of the present invention refers to a solid whose internal structure is composed of regularly repeated constituent atoms (or a group thereof) in a three-dimensional manner, and is distinguished from an amorphous solid that does not have such a regular internal structure. .
[0009]
Even crystals of the same compound may produce crystals (crystal polymorphs) having a plurality of different internal structures and physicochemical properties depending on the crystallization conditions. Any form may be sufficient and the mixture of two or more crystal polymorphs may be sufficient.
[0010]
Since compound (I) has a guanidino group and a carboxyl group in the molecule, it can form a pharmacologically acceptable salt by binding to an acid or base that is not pharmacologically toxic.
[0011]
Examples of pharmacologically acceptable salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; nitrates, perchlorates and sulfates. Inorganic salts such as phosphates; alkane sulfonates such as methanesulfonate, ethanesulfonate and trifluoromethanesulfonate; arylsulfones such as benzenesulfonate and p-toluenesulfonate Acid salts; organic acid salts such as acetate, trifluoroacetate, citrate, tartrate, oxalate, maleate; glycine, lysine, arginine, ornithine, glutamate, aspartate Amino acid salts such as lithium salts, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum Metal salts such as um salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt; ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, ethylenediamine salt, guanidine salt, diethylamine Salt, triethylamine salt, dicyclohexylamine salt, procaine salt, ethanolamine salt, diethanolamine salt, piperazine salt, organic amine salt such as tetramethylammonium salt, and the like, preferably lithium salt, sodium salt Alkali metal salts such as potassium salts; organic acid salts such as acetates and trifluoroacetates; or inorganic acid salts such as hydrochlorides and sulfates.
[0012]
Compound (I) and a pharmacologically acceptable salt thereof may be left in the air or mixed with water or an organic solvent to absorb water or a solvent to form a hydrate or solvate. There is.
[0013]
The crystal containing the compound (I) of the present invention includes a crystal composed of a pharmacologically acceptable salt, hydrate or solvate of the compound (I) in addition to a crystal composed of the compound (I). Of these crystals containing compound (I), hydrate crystals are preferred.
[0014]
As one form of the crystal containing the compound (I) of the present invention, for example, in powder X-ray diffraction obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å), the interplanar spacing d = 4.0, Examples thereof include crystals having main peaks at 4.4, 4.7, 7.5, and 10.2 angstroms. Here, the main peak is a peak having a relative intensity of 80 or more when the intensity of the peak showing the inter-plane distance d = 4.7 angstrom is 100. In the powder X-ray analysis pattern of FIG. 1, the vertical axis represents diffraction intensity in units of count / second (cps), and the horizontal axis represents diffraction angle 2θ (degrees). Further, the surface interval d (unit: angstrom) can be calculated as n = 1 in the formula 2dsinθ = nλ.
[0015]
DETAILED DESCRIPTION OF THE INVENTION
Compound (I) or a pharmacologically acceptable salt thereof can be produced according to the method disclosed in JP-A-10-330373 or a method analogous thereto.
[0016]
A crystal containing compound (I) is prepared by dissolving compound (I) or a pharmacologically acceptable salt thereof in an appropriate solvent, adjusting pH, concentrating the solution, mixing a good solvent and a poor solvent, and the like. (I) It can be produced by introducing a pharmacologically acceptable salt or solvate (including hydrate) into a supersaturated state and precipitating it.
[0017]
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.
[0018]
More specifically, the crystal (especially hydrate crystal) containing the compound (I) of the present invention is prepared by adding an aqueous solution containing the compound (I) or a pharmacologically acceptable salt thereof as appropriate. It can be produced by adjusting the pH, concentrating and cooling to precipitate crystals and then isolating the precipitated crystals.
[0019]
In addition, for crystals (especially hydrate crystals) containing compound (I), an aqueous solution containing the same is purified by a reverse phase silica gel column, and the fraction containing compound (I) is concentrated as necessary. It can also be produced by cooling to precipitate crystals and then isolating the precipitated crystals.
[0020]
The purity and quality of the obtained crystal can be improved by recrystallization or slurry purification.
[0021]
The temperature for crystallizing the crystal containing the compound (I) (particularly the hydrate crystal) is preferably 0 to 40 ° C, more preferably 20 to 30 ° C.
[0022]
The pH suitable for crystallizing the crystal (particularly hydrate crystal) containing the compound (I) is preferably pH 4 to 9, in which the solubility of the hydrate of the compound (I) in water is small, and more preferably Is 5-7.
[0023]
The precipitated crystals can be isolated, for example, by filtration, centrifugation, or gradient methods. The isolated crystals can be washed with a suitable solvent as necessary.
[0024]
When washing the hydrate crystals, a solvent such as water, ethanol, isopropanol, acetone, ethyl acetate, toluene, acetonitrile, methyl acetate or ether can be used, preferably water, acetone, ethyl acetate or Toluene.
[0025]
The isolated crystals (especially hydrate crystals) can be dried usually at a temperature of 10 to 100 ° C., preferably at a temperature of 30 to 50 ° C. until the weight is almost constant. If necessary, the crystals can be dried in the presence of a desiccant such as silica gel or calcium chloride, or under reduced pressure.
[0026]
Dry crystals (especially hydrate crystals) usually weigh approximately 10-30 ° C., 20% to 90% relative humidity, preferably 20-30 ° C., 50% to 80% relative humidity. You may absorb moisture until it becomes constant.
[0027]
The eluent used for the reverse phase silica gel column purification of compound (I) or a pharmacologically acceptable salt thereof is water, acetone, acetonitrile, methanol, ethanol and a mixed solvent thereof, preferably water, methanol and a mixed solvent thereof. It is. As the reversed-phase silica gel, those having the silica gel surface modified with an organic residue such as an alkyl group can be used, but those modified with an octadecyl group are preferred.
[0028]
Recrystallization is achieved by a method usually used in the field of synthetic organic chemistry, such as dissolving a crystal containing Compound (I) in a good solvent and adding a poor solvent to precipitate the crystal.
[0029]
Examples of the good solvent used for recrystallization of the hydrate crystals of compound (I) include alcohols such as methanol and ethanol, and methanol is preferred.
[0030]
Examples of the poor solvent used for recrystallization of the hydrate crystals of compound (I) include water, hexane, diisopropyl ether, t-butyl methyl ether, and the like, preferably water, hexane or diisopropyl ether. More preferably, it is water or diisopropyl ether.
[0031]
Slurry purification is an operation in which a crystal of a compound is suspended in an appropriate solvent and stirred, and then the crystal is isolated again. Solvents used for slurry purification of hydrate crystals include, for example, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, acetonitrile, methylene chloride, toluene, ethanol, isopropanol, tetrahydrofuran, N, N-dimethylformamide, water, hexane, diisopropyl ether. Ether, and the like. Acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, acetonitrile, ethanol or isopropanol are preferable, and acetone or ethyl acetate is more preferable.
[0032]
The crystals obtained by recrystallization and slurry purification can also be isolated in the same manner as described above.
[0033]
When the crystal (especially hydrate crystal) containing the compound (I) is used as a medicine, particularly a therapeutic or prophylactic agent for influenza, the excipient itself, or appropriate pharmacologically acceptable, It can be mixed with diluents and administered by tablets, capsules, granules, powders, syrups, injections, ointments, solutions, suspensions, aerosols, troches and the like. The medicament of the present invention can be administered orally or parenterally, but is administered by a method in which the active ingredient Compound (I) can be directly delivered to the lung or respiratory tract (including intraoral and intranasal). It is preferable.
[0034]
These formulations include excipients (eg, sugars 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 magnesium aluminometasilicate Silicates such as; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate), binders (eg For example, the above excipients; gelatin; polyvinyl pyrrolidone; tuna gorgol etc.), disintegrants (eg, the above excipients; chemically modified such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, Starch or cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; bee gum; waxes such as beeswax and gallows; boric acid; glycol Carboxylic acids such as fumaric acid and adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic anhydride , Silicic acids such as silicic acid hydrate; starch derivatives in the above-mentioned excipients, stabilizers (for example, parahydroxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol) Alcohols such as: benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.], flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), It is produced by a known method using additives such as a suspending agent (for example, polysorbate 80, sodium carboxymethyl cellulose), a diluent, a solvent for preparation (for example, water, ethanol, glycerin, etc.).
[0035]
The amount used varies depending on the symptoms, body weight, age, etc. of the person to be administered, but the lower limit per day is 0.1 mg (preferably 1 mg), the upper limit is 1000 mg (preferably 500 mg), 1 to several times per day, It is desirable to administer depending on the symptoms.
[0036]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples, Formulation Examples and Test Examples.
(Production Example 1)
5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyrazonic acid hydrate crystals ( 1) Compound of Example 35 (i) of JP-A-10-330373, 5-acetamido-4- (N, N′-bis-t-butyroxycarbonyl) guanidino-9-O-octanoyl-2,3 , 4,5-tetradeoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyranosonic acid diphenylmethyl (3.46 g, 4.1 mmol) was added to methylene chloride (27 ml), trifluoroacetic acid ( 14 ml) and stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and then azeotropically dried three times with toluene (5 ml). The resulting oil was dissolved in ethyl acetate (10 ml). On the other hand, this solution was poured into saturated sodium bicarbonate water (50 ml), and 20% aqueous sodium carbonate solution was added to adjust the pH to 8.5. The mixture was stirred at room temperature for 3 hours, adjusted to pH 5.0 with hydrochloric acid (3 ml), and stirred at room temperature for 1 hour. Further, after stirring for 1 hour under ice cooling, the crystals were suction filtered and dried in vacuum at an external temperature of 50 ° C. for 10 hours. The product was left in the air for 1 day to give the title object compound as crystals. (0.97g, 51%)
Infrared absorption spectrum (KBr) νmax cm ^-1 : 3412, 2929, 2856, 1676, 1401, 1320, 1285, 1205, 1137, 722.
¹ H nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm: 5.88 (1H, d, J = 2.5 Hz), 4.45 (3H, m), 4.27 (1H, dd, J = 10.0 Hz, 10.0 Hz), 4.15 (1H, m), 3.47 (2H, m), 3.42 (3H, s), 2.37 (2H, t, J = 7.4 Hz), 2.10 (3H, s), 1.31 (2H, m), 1.20-1.40 ( 8H, m), 0.85-0.95 (3H, m).
¹³ C nuclear magnetic resonance spectrum (100 MHz, CD ₃ OD) δ ppm: 176.5, 173.7, 164.7, 158.9, 146.7, 108.7, 80.1, 78.0, 69.3, 66.8, 61.4, 52.4, 35.1, 32.8, 30.2, 30.1, 26.0, 23.7 , 22.8, 14.4.
FIG. 1 shows a powder X-ray diffraction pattern of this crystal obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å). The vertical axis of the powder X-ray analysis pattern indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the diffraction angle 2θ (degrees).
(2) The title compound was also obtained by the following method.
[0037]
Example 35 (ii) of JP-A-10-330373, 5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-O-methyl-D- Glycero-D-galacto-non-2-enopyrazonic acid trifluoroacetate (3.0 g, 5.1 mmol) was subjected to reverse phase column chromatography (Nacalai Tesque Cosmosil 75C18PREP, 100 g) and methanol-water (0 : 1, 1: 1,2: 1) and increasing the methanol content. The fraction containing the desired product was concentrated under reduced pressure, and the precipitated crystals were suction filtered and dried under reduced pressure. The product was left in the air for 1 day to give the title object compound as crystals (1.2 g, 49%). The physical property data of the obtained compound was completely consistent with that obtained in the above (1).
(Test Example 1) Stability Test Amorphous powder of compound (I) described as Example 35 in JP-A-10-330373 as a crystal of compound (I) of Production Example 1 of the present invention and a control Fluoroacetate) was stored in a desiccator at 40 ° C. and 75% relative humidity, and the residual rate after 14 days (2 weeks), 28 days (4 weeks), and 56 days (8 weeks) was measured. The results are shown in Table 1. Furthermore, the residual rate after 14 days (2 weeks), 28 days (4 weeks), and 56 days (8 weeks) in a silica gel desiccator at 60 ° C. was measured separately. The results are shown in Table 2.
[0038]
The residual ratio (%) of the compound was determined from the residual ratio of the compound measured using high performance liquid chromatography (HPLC). The HPLC measurement conditions are as follows.
[0039]
Column: L-column ODS (4.6mm ID x 250mm), manufactured by Chemical Substance Evaluation Research Organization
Mobile phase: 0.1 mol / phosphate buffer (pH 3): acetonitrile (7: 3)
Flow rate: 1mL / min
Detection: 230nm
Column temperature: 30 ° C
As shown in Table 1, the amorphous powder (trifluoroacetate salt) of Compound (I) was extremely unstable in a humidified state at 40 ° C. and decreased to a content of about 10.2% after 56 days. On the other hand, the crystal (hydrate crystal) of the compound (I) of the present invention exhibits a residual rate of 100% under the same conditions and has extremely high storage stability.
As shown in Table 2, the amorphous powder (trifluoroacetate salt) of Compound (I) had low stability even at 60 ° C. in a dry state, and decreased to a content of about 89% after 56 days. In contrast, the crystal (hydrate crystal) of the compound (I) of the present invention exhibits a high residual rate of 99% or more under the same conditions, and has extremely high storage stability.
(Formulation example 1) Solution 1
Compound of Production Example 1 is 10% (W / W), benzalkonium chloride is 0.04% (W / W), phenethyl alcohol is 0.40% (W / W), and purified water is 89.56% ( Adjust the solution so that (W / W).
(Formulation Example 2) Solution 2
Compound of Production Example 1 is 10% (W / W), benzalkonium chloride is 0.04% (W / W), polyethylene glycol 400 is 10% (W / W), propylene glycol is 30% (W / W) ), Adjust the liquid so that the purified water is 39.96% (W / W).
(Formulation example 3) Powder is adjusted so that the compound of the powder manufacture example 1 may be 40% (W / W), and lactose will be 60% (W / W).
(Formulation example 4) 10% (W / W) of the compound of Aerosol Preparation Example 1, 0.5% (W / W) of lecithin, 34.5% (W / W) of Freon 11 and 55 of Freon 12 Adjust the aerosol so that it becomes% (W / W).
[0040]
【The invention's effect】
Crystals (especially hydrate crystals) containing the compound (I) of the present invention are crystals that are excellent in storage stability and practically easy to handle compared to amorphous trifluoroacetate, It is useful as a drug substance for the treatment or prevention of influenza. The hydrate of compound (I) is useful as a molecular form that gives excellent crystals.
[Brief description of the drawings]
FIG. 1 shows 5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5-tetradeoxy-7-O-methyl-D-glycero-obtained in Production Example 1 It is a powder X-ray-diffraction pattern obtained by irradiation of copper Kα rays (wavelength λ = 1.54 Å) for D-galacto-non-2-enopyrazonic acid hydrate crystals. The vertical axis of the powder X-ray analysis pattern indicates the diffraction intensity in units of count / second (cps), and the horizontal axis indicates the diffraction angle 2θ (degrees). The surface distance d (angstrom) can be calculated as n = 1 in the equation 2dsin θ = nλ.

Claims (2)

Formula (I)
Hydrate crystals of the compound represented by   In the powder X-ray diffraction obtained by irradiation of copper Kα rays in claim 1, formulas showing main peaks at interplanar spacings of 4.0, 4.4, 4.7, 7.5, and 10.2 angstroms ( Hydrate crystals of the compound represented by I).