JP2007297332A - Crystal of benzamidine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a crystal of a benzamidine derivative useful as an inhibitor of activated blood coagulation factor X, a raw material for preparation of prophylactic and/or therapeutic agent of blood coagulative disease. <P>SOLUTION: The invention relates to the crystal of the compound represented by general formula (I), wherein the crystal means a solid comprising an inner structure with regular iteration of three dimensional constituting atoms (or atomic groups) different from an amorphous solid without the regular inner structure. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention has a crystal of a benzamidine derivative having excellent activated blood coagulation factor X inhibitory activity, and also excellent storage stability and ease of handling, and a medicament containing a crystal of a benzamidine derivative as an active ingredient ( In particular, the present invention relates to an activated blood coagulation factor X inhibitor or a prophylactic and / or therapeutic agent for blood coagulation diseases).

  JP 2001-192366 A (WO 01/30756 pamphlet) (Patent Document 1), JP 2003-2832 A (Patent Document 2), JP 2003-40773 A (WO 02/89803 pamphlet) (Patent Document) 3) discloses a benzamidine derivative represented by the following formula (I) (hereinafter referred to as compound (I)). Compound (I) exhibits excellent activated blood coagulation factor X inhibitory activity (anti-factor Xa activity), and is used as an activated blood coagulation factor X inhibitor or an agent for preventing and / or treating blood coagulation diseases. Is expected to be useful.

However, since Compound (I) is an amorphous solid (amorphous), it has a problem in practical use as a medicine, such as poor storage stability and not easy to handle.
JP 2001-192366 A (WO01 / 30756 pamphlet) JP 2003-2832 A JP2003-40773 (WO02 / 89803 pamphlet)

  Therefore, the present inventors have intensively studied for the purpose of providing a novel crystal having excellent storage stability and ease of handling. As a result, the present inventors have found a crystal that is extremely excellent in storage stability and handleability and is useful and suitable as an active ingredient of a medicine, thereby completing the present invention.

That is, the present invention
(1) The following general formula (I):

A crystal of a benzamidine derivative represented by:
(2) In the crystal of the benzamidine derivative described in the above (1), in the powder X-ray diffraction obtained by irradiation of copper Kα rays (wavelength λ = 1.54 angstroms), the interplanar spacing is 16.35, 5.45. 4.83, 4.45, 4.23, 3.79, 3.57 and 3.52 angstroms, crystals having main peaks (A crystal),
(3) In the crystal of the benzamidine derivative described in (1) above, in the powder X-ray diffraction obtained by irradiation with copper Kα rays (wavelength λ = 1.54 angstroms), the surface spacing is 16.98, 6.38. Crystals showing main peaks at 4.18, 4.06, 4.00 and 3.96 angstroms (crystal B),
(4) A pharmaceutical composition comprising, as an active ingredient, crystals of the benzamidine derivative according to any one of (1) to (3),
(5) an activated blood coagulation factor X inhibitor containing a crystal of a benzamidine derivative according to any one of (1) to (3) as an active ingredient, and (6) (1) A prophylactic and / or therapeutic agent for a blood coagulable disease comprising the crystal of the benzamidine derivative (I) according to any one of (1) to (3) as an active ingredient.

  The present invention also provides a crystal of the benzamidine derivative (I) described in any one of (1) to (3) above, the pharmaceutical composition described in (4) above, and (5) above. A blood comprising administering the activated blood coagulation factor X inhibitor described in the above or a prophylactic and / or therapeutic agent for the blood coagulation disease described in (6) above to a warm-blooded animal (preferably human). Methods for preventing and / or treating coagulative diseases are also provided.

  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.

  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.

  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 angstroms), the interplanar spacing d = 16.35. Examples thereof include crystals having main peaks at 45, 4.83, 4.45, 4.23, 3.79, 3.57, and 3.52 angstroms. Here, the main peak is a peak having a relative intensity of 50% or more when the intensity of the peak showing the interplanar spacing d = 16.35 angstrom is 100.

  The surface distance d can be calculated as n = 1 in the equation 2dsin θ = nλ.

  Further, for example, in powder X-ray diffraction obtained by irradiation with copper Kα rays (wavelength λ = 1.54 angstroms), the surface spacing d = 16.98, 6.38, 4.18, 4.06, 4.06. Examples thereof include crystals having main peaks at 00 and 3.96 angstroms. Here, the main peak is a peak having a relative intensity of 40% or more when the intensity of the peak showing the interplanar spacing d = 6.38 angstroms is 100.

In some cases, the crystal of the compound (I) of the present invention is left in the atmosphere or mixed with water or an organic solvent to absorb water or solvent to form a hydrate or solvate. And solvates are also included in the compound (I) of the present invention. The crystal of the compound (I) of the present invention is
In some cases, an anhydride may be obtained by drying at 25 ° C. to 80 ° C. The thus obtained anhydride is also included in the compound (I) of the present invention.

  Since the crystal of the compound having the general formula (I) of the present invention is excellent in storage stability and handling ease, it is a drug synthesized in large quantities in industrial production [especially activated blood coagulation factor X inhibitor, blood coagulation property. It is useful as a manufacturing base of a prophylactic and / or therapeutic agent for diseases (for example, thrombotic diseases such as cerebral infarction, myocardial infarction or peripheral circulatory disorder).

  The compound (I) of the present invention can be produced by the method disclosed in JP 2001-192366 A or JP 2003-40773 A or a method analogous thereto.

  The crystal of compound (I) dissolves compound (I) in a suitable solvent, adjusts pH, concentrates the solution, cools, mixes good and poor solvents, and leads compound (I) to a supersaturated state. Can be produced by precipitation.

  In addition, a certain crystal or amorphous solid can be suspended in a suitable solvent, made into a slurry, and then stirred to carry out solvent-mediated transition to another crystal.

  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.

  The temperature for crystallizing the compound (I) is usually 0 to 60 ° C., preferably 5 to 45 ° C.

  As a method of concentrating the solution of compound (I), for example, a method of concentrating by evaporating the solvent while heating at normal pressure or reduced pressure using a rotary evaporator, a method of concentrating using a reverse osmosis membrane, etc. There is. 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, and a cellulose acetate membrane.

  Examples of the good solvent for producing the A crystal of compound (I) include water, dimethyl sulfoxide, and methanol, and water is preferable.

  Examples of the good solvent for producing the B crystal of compound (I) include water, dimethyl sulfoxide, dimethylformamide, and methanol, and water is preferable.

  The poor solvent for producing the A crystal of compound (I) is ethanol.

  Examples of the poor solvent for producing the B crystal of compound (I) include alcohols having 2 to 4 carbon atoms such as ethanol, propanol and butanol; ketones such as acetone and methyl ethyl ketone; diethyl ether and tetrahydrofuran. Examples thereof include ethers such as methyl acetate and esters such as ethyl acetate; nitriles such as acetonitrile. Ethanol and acetonitrile are preferable, and acetonitrile is most preferable.

  As a starting material for producing a crystal of compound (I), an amorphous solid (amorphous) of compound (I) that has already been isolated as a lyophilized powder may be used, but it may be purified by crystallization. Since it is possible, the solution of the synthetic reaction crude product containing compound (I) can also be used.

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

  The precipitated crystals can be isolated, for example, by filtration, centrifugation, or gradient methods. The isolated crystals may be washed with a suitable solvent as necessary. Washing includes, for example, water; alcohols such as ethanol and isopropanol; ketones such as acetone; esters such as methyl formate, ethyl formate, methyl acetate, and ethyl acetate; aromatic hydrocarbons such as toluene and xylene Nitriles such as acetonitrile; solvents such as ethers such as diethyl ether and tetrahydrofuran and mixed solvents thereof can be used, but it is preferable to use acetonitrile.

  The isolated crystals are usually dried at 10 to 100 ° C., preferably at 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.

  The dried crystals usually weigh at a temperature of 10 to 30 ° C. and a relative humidity of 20 to 90%, preferably a temperature of 20 to 30 ° C. and a relative humidity of 50 to 80%. You may make it absorb moisture until it becomes substantially constant.

  The purity and quality of the obtained crystal can be improved by recrystallization or slurry purification.

  The recrystallization is performed by (1) a method in which the crystal of compound (I) is dissolved after being heated and cooled, (2) a method in which the solvent is distilled off after concentration, and (3) a method in which the solvent is evaporated and concentrated. It is achieved by a method usually used in the field of organic synthetic chemistry, such as a method for precipitating crystals by adding.

  Slurry purification is a purification method in which crystals of a compound are suspended in an appropriate solvent, the suspension is stirred, and the crystals are collected again.

  Examples of the solvent used for the purification of the slurry of the crystal A of compound (I) include esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as methylene chloride and chloroform; toluene and xylene. Examples include aromatic hydrocarbons; ethanol; aliphatic hydrocarbons such as hexane; solvents such as ethers such as diisopropyl ether and diethyl ether, and mixed solvents thereof, and ethanol is preferable.

  Examples of the solvent used for slurry purification of the B crystal of compound (I) include ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; nitriles such as acetonitrile; Halogenated hydrocarbons such as methylene and chloroform; Aromatic hydrocarbons such as toluene and xylene; Alcohols such as ethanol and isopropanol; Amides such as N, N-dimethylformamide; Water; Aliphatic hydrocarbons; solvents such as ethers such as tetrahydrofuran, diisopropyl ether and diethyl ether, and mixed solvents thereof can be mentioned, and a mixed solvent of water and acetonitrile is preferable.

  The crystals obtained by recrystallization and slurry purification can also be isolated in the same manner as described above.

  The crystals of compound (I) showed activated blood coagulation factor X inhibitory activity (anti-factor Xa activity). Therefore, the crystal of compound (I) is a therapeutic agent or prophylaxis for drugs, particularly activated blood coagulation factor X inhibitors, blood coagulation diseases (for example, thrombotic diseases such as cerebral infarction, myocardial infarction or peripheral circulation disorder) Useful as an agent.

  The crystals of compound (I) showed activated blood coagulation factor X inhibitory activity (anti-factor Xa activity). Accordingly, the crystals of compound (I) can be used to prevent drugs and, in particular, activated blood coagulation factor X inhibitors, blood coagulation diseases (eg, thrombotic diseases such as cerebral infarction, myocardial infarction or peripheral circulation disorder) and / or It is useful as a therapeutic agent.

  When the compound (I) crystal is used as a pharmaceutical, particularly as an activated blood coagulation factor X inhibitor, a therapeutic agent or a prophylactic agent for blood coagulation diseases, it is per se or an appropriate pharmacologically acceptable. Mixed with excipients, diluents, etc., orally or parenterally by tablets, capsules, granules, powders, syrups, injections, ointments, solutions, suspensions, aerosols, lozenges, etc. Can be administered.

  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 metasilicate aluminate 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; macrogol, 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, magnesium stearate; colloidal silica; Carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates 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.).

  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, instillations, suppositories, transdermal agents (eg, preparations for iontophoresis) 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 amount used varies depending on the symptoms, weight, age, etc. of the recipient, but in the case of oral administration, the lower limit is 0.01 mg / kg (preferably 0.1 mg / kg) and the upper limit is 10 mg / kg. (Preferably 5 mg / kg), in the case of intravenous administration, a lower limit of 0.005 mg / kg (preferably 0.05 mg / kg) per dose, and an upper limit of 5 mg / kg (preferably 2.5 mg / kg). mg / kg) should be administered to adults 1 to 6 times daily depending on symptoms.

  Examples, test examples and formulation examples will be shown below to explain the present invention in more detail.

(Example 1) <A crystal>
Compound of Example 161 of JP-A-2003-40773, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl)- Ethanol (40 ml) was added to 2-fluoro-2- (Z) -propenyl] sulfamoylacetic acid dihydrochloride (2.00 g) to dissolve and stirred at 25 ° C. for 1 hour. Furthermore, it cooled to 0 degreeC and stirred for 1 hour 30 minutes. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 1.72 g (yield 86%) of the target crystals.

  FIG. 1 shows a powder X-ray diffraction pattern obtained by irradiation of copper with Kα rays (wavelength λ = 1.54 Å) for the obtained crystals.

  The main peaks were shown at an interplanar spacing d = 16.35, 5.45, 4.83, 4.45, 4.23, 3.79, 3.57 and 3.52 angstroms.

  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.

(Example 2) <B crystal>
Compound of Example 161 of JP-A-2003-40773, N- [4- (1-acetimidoylpiperidin-4-yloxy) -3-carbamoylphenyl] -N- [3- (3-amidinophenyl)- 2-Fluoro-2- (Z) -propenyl] sulfamoylacetic acid dihydrochloride (1.00 g) was dissolved in a mixed solvent of water (18.6 ml) and acetonitrile (1.4 ml) and stirred at 0 ° C. for 3 hours. Thereafter, it was allowed to stand at 4 ° C. for 2 days. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 0.71 g (yield 71%) of the target crystals.

  FIG. 2 shows a powder X-ray diffraction pattern obtained by irradiation of copper Kα rays (wavelength λ = 1.54 angstroms) with respect to the obtained crystals.

  Main peaks were shown at an inter-plane spacing of d = 16.98, 6.38, 4.18, 4.06, 4.00, and 3.96 angstroms.

(Formulation example 1)
<Hard capsule>
50 mg of the powdered compound of Example 2, 128.7 mg of lactose, 70 mg of cellulose and 1.3 mg of magnesium stearate were mixed and passed through a 60 mesh sieve. Into capsules.

(Formulation example 2)
<Tablets>
50 mg of the powdered compound of Example 2, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate are mixed and compressed by a tableting machine to give 1 tablet of 200 mg. This tablet can be coated or sugar-coated as necessary.

(Formulation example 3)
<Liquid>
The compound of Example 2 was 10% (W / W), benzalkonium chloride was 0.04% (W / W), phenethyl alcohol was 0.40% (W / W), and purified water was 89.56% ( W / W) is prepared.

(Formulation example 4)
<Injection>
1.5% by weight of the compound of Example 2 is stirred in 10% by volume of propylene glycol, adjusted to a constant volume with water for injection, and then sterilized to give an injection.

The powder X-ray diffraction pattern of the crystal | crystallization of the compound represented by General formula (I) obtained in Example 1. FIG. (Crystal of the present invention), the vertical axis of the figure shows the diffraction intensity in units of count / second (cps), and the horizontal axis shows the value of the diffraction angle 2θ. The powder X-ray diffraction pattern of the crystal | crystallization of the compound represented by general formula (I) obtained in Example 2. FIG. (Crystal of the present invention)

Claims (6)

The following general formula (I):

A crystal of a benzamidine derivative represented by:     The crystal of the benzamidine derivative according to claim 1, wherein in the powder X-ray diffraction obtained by irradiation of copper Kα rays (wavelength λ = 1.54 Å), the interplanar spacing is 16.35, 5.45, 4.83. Crystals showing main peaks at 4.45, 4.23, 3.79, 3.57 and 3.52 angstroms.   The crystal of the benzamidine derivative according to claim 1, wherein the surface spacing is 16.98, 6.38, 4.18 in powder X-ray diffraction obtained by irradiation with copper Kα rays (wavelength λ = 1.54 Å). Crystals having main peaks at 4.06, 4.00 and 3.96 angstroms.   The pharmaceutical composition which contains the crystal | crystallization of the benzamidine derivative of any one selected from Claim 1 thru | or 3 as an active ingredient.   The activated blood coagulation factor X inhibitor which contains the crystal | crystallization of the benzamidine derivative of any one selected from Claim 1 thru | or 3 as an active ingredient.   A prophylactic or therapeutic agent for a blood coagulable disease comprising the benzamidine derivative crystal according to any one of claims 1 to 3 as an active ingredient.