WO2011152411A1 - チエノピリミジン誘導体の結晶 - Google Patents
チエノピリミジン誘導体の結晶 Download PDFInfo
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions
- the present invention relates to 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid useful as a therapeutic agent for dysuria or the like (
- the present invention relates to a crystal of “Compound A”), a medicine containing the crystal, and a method for producing the crystal.
- Compound A is a compound described in International Publication No. 2006/135080 pamphlet (see Patent Document 1) and has a high PDE9 inhibitory action and a mild PDE5 inhibitory action. It is a useful compound. However, Patent Document 1 does not clearly indicate the specific properties of the obtained compound A, and does not describe or suggest the presence of a crystal polymorph.
- An object of the present invention is to provide a crystal of compound A.
- the present invention [1] In a powder X-ray diffraction spectrum, diffraction angles represented by 2 ⁇ are 6.7 ⁇ 0.2 °, 8.3 ⁇ 0.2 °, 8.9 ⁇ 0.2 °, 14.0 ⁇ 0.
- DSC differential scanning calorimetry
- the method for producing a crystal according to any one of claims 1 to 6, comprising [12] An aqueous suspension of 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid 1 to 96 hours at less than 50 ° C, 0.5 to 32 hours at 50 to 60 ° C, 0.5 to 24 hours at 60 to 70 ° C, 0.1 to 12 hours at 70 to 80 ° C, The method for producing a crystal according to the above [1] or [2], comprising a step of heating at 80 ° C. or more and less than 90 ° C. for 0.05 to 6 hours or 90 ° C. or more and 100 ° C.
- a novel crystal of compound A that is not solvated can be obtained.
- the crystals can be produced by a simple method suitable for industrial mass production, and the obtained crystals are easier to filter than amorphous and are suitable for industrial mass production.
- the crystal of the present invention is suitable as an active ingredient of medicine in terms of stability, solubility, absorbability and the like.
- FIG. 1 is a diagram illustrating a powder X-ray diffraction pattern of Form I crystal of Compound A (Example 1).
- FIG. 2 is a diagram showing an infrared absorption spectrum (paste method) of Compound I Form I crystal (Example 1).
- FIG. 3 is a diagram showing a powder X-ray diffraction pattern of Compound A type II crystals (Example 2).
- FIG. 4 is a diagram showing an infrared absorption spectrum (paste method) of a type II crystal of compound A (Example 2).
- FIG. 5 is a diagram showing a powder X-ray diffraction pattern of crystals of an isopropanol solvate of Compound A (Reference Example 1).
- FIG. 1 is a diagram illustrating a powder X-ray diffraction pattern of Form I crystal of Compound A (Example 1).
- FIG. 2 is a diagram showing an infrared absorption spectrum (paste method) of Compound
- FIG. 6 is a diagram showing an infrared absorption spectrum (paste method) of crystals of isopropanol solvate of Compound A (Reference Example 1).
- FIG. 7 is a diagram showing a powder X-ray diffraction pattern of crystals of dimethylacetamide solvate of Compound A (Reference Example 2).
- FIG. 8 is a diagram showing an infrared absorption spectrum (paste method) of crystals of a dimethylacetamide solvate of Compound A (Reference Example 2).
- FIG. 9 is a diagram showing a powder X-ray diffraction pattern of crystals of a dimethylformamide solvate of Compound A (Reference Example 3).
- FIG. 10 is a diagram showing an infrared absorption spectrum (paste method) of crystals of a dimethylformamide solvate of Compound A (Reference Example 3).
- FIG. 11 is a diagram showing a powder X-ray diffraction pattern of 1,3-dimethyl-2-imidazolidinone solvate of Compound A (Reference Example 4).
- FIG. 12 is a diagram showing an infrared absorption spectrum (paste method) of a crystal of 1,3-dimethyl-2-imidazolidinone solvate of Compound A (Reference Example 4).
- FIG. 13 is a diagram showing a powder X-ray diffraction pattern of an N-methylpyrrolidone solvate crystal of Compound A (Reference Example 5).
- FIG. 14 is a diagram showing an infrared absorption spectrum (paste method) of a crystal of N-methylpyrrolidone solvate of Compound A (Reference Example 5).
- FIG. 15 is a diagram showing a DSC chart of Form I crystal of Compound A (Example 1).
- FIG. 16 is a diagram showing a DSC chart of a type II crystal of compound A (Example 2).
- FIG. 17 is a view showing an HPLC chart showing the photostability of Compound A (Test Example 7).
- Example 36-a) of Patent Document 1 which describes production in the same manner as in Example 1.
- ester hydrolysis is carried out by heating and refluxing the ester in an alkaline aqueous solution to obtain a carboxylic acid, which is acidified with dilute hydrochloric acid, and the precipitated crystals are collected by filtration.
- carboxylic acid which is acidified with dilute hydrochloric acid
- precipitated crystals are collected by filtration.
- Amorphous materials generally have disadvantages such as low stability to light and heat, and glassy properties that make them difficult to handle. Amorphous tends to be mixed with impurities compared to crystals. Furthermore, as described above, the compound A obtained in an amorphous form is not suitable for industrial mass production because it causes clogging during suction filtration. Therefore, in order to use Compound A as an active pharmaceutical ingredient and for industrial mass production, it has been desired to obtain Compound A in a crystalline form.
- solvate crystals often have stability problems, such as the solvent being dissociated and transferred more easily than unsolvated crystals, except when stable crystals such as hydrate crystals are obtained. There is concern about the difficulty of handling it as a medicine. Moreover, since it contains a considerable amount of organic solvent, it is necessary to consider the safety of the solvent itself, and various difficulties are expected to develop it as a medicine.
- An amorphous compound A can be obtained as a solidified body that precipitates by neutralizing or acidifying an alkaline aqueous solution of compound A with an acid.
- Examples of the method for obtaining the coagulum from an aqueous suspension include filtration, centrifugation, precipitation, and discarding the supernatant. Among these, filtration is simple and preferable, but a filter is preferred. This method is very time consuming and clogged, and there is still room for improvement for industrial production.
- the alkaline aqueous solution of Compound A may contain an organic solvent miscible with water.
- organic solvent examples include alcohols (eg, methanol, ethanol, propanol, isopropanol, etc.), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.), ethers (eg, tetrahydrofuran, dioxane, etc.). Etc.).
- the amount of the solvent used is preferably 0.01 to 0.1 times (v / v) with respect to water.
- An alkaline aqueous solution of Compound A can be prepared by dissolving Compound A or a salt thereof (for example, sodium salt, potassium salt, etc.) in an alkaline aqueous solution.
- the alkaline aqueous solution include aqueous solutions of sodium hydroxide, potassium hydroxide, potassium carbonate and the like.
- the amount of alkali used can be about 1 to 5 moles per mole of Compound A, but is preferably 2 moles or more, and particularly preferably 2 to 2.4 moles. If the amount of alkali used is less than this range, compound A is difficult to dissolve in the aqueous alkali solution.
- the alkaline aqueous solution of Compound A is an ester of Compound A (for example, 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3, produced in Production Example 10 of Patent Document 1).
- a reaction solution obtained by alkaline hydrolysis of a C 1-6 alkyl ester of compound A such as ethyl 4-dihydrothieno [2,3-d] pyrimidine-6-carboxylate) may be used.
- the hydrolysis reaction of the ester of Compound A is carried out according to a method known per se, for example, the ester of Compound A is suspended in water or a mixed solvent obtained by adding water to alcohols such as methanol, ethanol, isopropanol.
- the reaction in the dissolved state, in the presence of an alkali such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc., the reaction is carried out at a temperature within the range of 0 ° C. to the reflux temperature of the reaction mixture, preferably room temperature to the reflux temperature of the reaction mixture. be able to.
- the ratio of the alkali to be used with respect to the ester of Compound A is not particularly limited, but in general, the alkali can be used within a range of about 1 to 20 moles per mole of the ester of Compound A.
- the concentration of the alkaline aqueous solution of Compound A is preferably about 0.5 to 2 mol / L.
- Examples of the acid used for neutralization or acidification of the alkaline aqueous solution of Compound A include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, oxalic acid and the like, and diluted hydrochloric acid is preferable.
- an acid equivalent to the base contained in the alkaline aqueous solution may be added.
- the pH is not particularly limited, but it is preferable to add an acid so that the pH is about 5 to 7.
- the precipitated coagulum is obtained by filtration, centrifugation, etc., and then washed and dried to obtain Compound A amorphous.
- the filter is likely to be clogged even if it is sucked during filtration, and filtration takes time. Accordingingly, acquisition by filtration is suitable for industrial production. Absent.
- Form I and Form II of Compound A can be produced by heating an aqueous suspension of Compound A for a certain period of time.
- the aqueous suspension of compound A may contain an organic solvent miscible with water, and examples of the organic solvent include alcohols (for example, methanol, ethanol, propanol, isopropanol, etc.). Since an organic solvate crystal may be formed, it is preferable that no organic solvent is contained.
- the amount of the solvent used is preferably 0.001 to 0.3 times (v / v) with respect to water. When the amount of the organic solvent is larger than this range, organic solvate crystals may be formed.
- the form of Compound A in the suspension in the “aqueous suspension of Compound A” is not particularly limited, but amorphous is preferable.
- An aqueous suspension of Compound A can be prepared by adding Compound A to water or a mixed solvent of water and an organic solvent and stirring.
- a suspension in which an amorphous form of Compound A is precipitated by adding an acid to an alkaline aqueous solution of Compound A can be used as an aqueous suspension of Compound A.
- a suspension in which an amorphous form of Compound A obtained by adding an acid to a reaction solution obtained by alkaline hydrolysis of an ester of Compound A is used as an aqueous suspension of Compound A.
- the Compound A Form I crystals and Form II crystals can be obtained in one pot in the post-treatment without once removing the Compound A from the reaction vessel. Since it can be prepared, it is particularly advantageous in industrial production.
- I-type crystals and II-type crystals By appropriately adjusting the heating time and the heating temperature under the heating conditions of the aqueous suspension of compound A, it is possible to produce I-type crystals and II-type crystals, or mixed crystals thereof. That is, by heating an aqueous suspension of compound A in a predetermined temperature range for a predetermined time, first, I-form crystals can be generated. Further, by heating at a higher temperature and / or longer time, the I-type crystal is transformed into the II-type crystal, and the II-type crystal or a mixed crystal of the I-type crystal and the II-type crystal can be obtained.
- heating an aqueous suspension of compound A in a predetermined temperature range for a predetermined time is referred to as “aging”.
- the aqueous suspension may be allowed to stand, and for example, stirring, shaking, or convection can be performed, but stirring is preferable.
- the relationship between aging temperature and time requires a relatively long aging at lower temperatures and a relatively short time at higher temperatures.
- I-type crystals can be obtained by aging.
- the aging temperature and time are, for example, 1 to 96 hours (more preferably 8 to 48 hours) at 40 ° C. or more and less than 50 ° C., 0.5 to 32 hours (more Preferably 4 to 24 hours), 60 ° C. or more and less than 70 ° C. for 0.5 to 24 hours (more preferably 2 to 6 hours), 70 ° C. or more and less than 80 ° C. for 0.1 to 12 hours (more preferably 1. 5 to 4 hours), 80 to 90 ° C.
- aging is preferably performed at 70 ° C. or more and less than 80 ° C. for 0.1 to 12 hours. Aging is preferably carried out at a temperature below 1.5 ° C. for 1.5 to 4 hours. Note that at higher temperatures (eg, 90 ° C. or more and 100 ° C. or less), ripening is completed during the temperature rise, and I-type crystals may be obtained when the temperature is reached.
- the aging temperature and time are, for example, 1 to 96 hours (more preferably 8 to 48 hours) at 40 ° C. or more and less than 50 ° C., and 0.5 to 48 at 50 ° C. or more and less than 60 ° C. Time (more preferably 4 to 24 hours), 0.5 to 24 hours (more preferably 2 to 6 hours) at 60 ° C. or more and less than 70 ° C., 0.1 to 12 hours (more preferably) at 70 ° C. or more and less than 80 ° C. 1.5 to 4 hours), 80 to 90 ° C. for 0.05 to 6 hours (more preferably 0.5 to 3 hours), or 90 to 100 ° C. for 0.01 to 3 hours (more preferably) Can also be obtained for 0.1 to 2 hours).
- the aging temperature and time are, for example, 40 ° C. or more and less than 50 ° C. for 1 to 96 hours (more preferably 8 to 48 hours), 50 ° C. or more and less than 60 ° C. for 0.5 to 32 hours (more preferably 4 to 24 hours), 0.5 to 24 hours (more preferably 2 to 6 hours) at 60 ° C. or more and less than 70 ° C., 0.1 to 12 hours (more than 70 ° C. to less than 80 ° C.) Preferably 1.5 to 4 hours), 0.05 to 6 hours (more preferably 0.5 to 3 hours) at 80 ° C. or more and less than 90 ° C., or 0.01 to 4 hours (more than 90 ° C. to 100 ° C.)
- the crystal of type I can also be obtained by setting it to preferably 0.1 to 2 hours.
- the aging time for obtaining the I-form crystal may vary somewhat depending on the experimental conditions.
- the aging temperature and time are, for example, from 60 ° C. to less than 70 ° C. for 144 hours or more (more preferably 155 hours or more), from 70 ° C. to less than 80 ° C. for 25 hours or more (more preferably 30 hours or more). ), 23 hours or more (more preferably 25 hours or more) at 80 ° C. or more and less than 90 ° C., or 16 hours or more (more preferably 20 hours or more) at 90 ° C.
- aging is preferably performed at 90 ° C. or higher and 100 ° C. or lower for 16 hours or longer, and particularly preferably aging is performed at 90 ° C. or higher and 100 ° C. or lower for 20 hours or longer.
- the aging temperature and time are set such that the aging temperature and time are, for example, 60 ° C. or more and less than 70 ° C. for 70 hours or more (more preferably 80 hours or more), 70 ° C. or more and less than 80 ° C. 25 hours or more (more preferably 30 hours or more), 80 ° C. or more and less than 90 ° C.
- aging is preferably performed at 90 ° C. or more and 100 ° C. or less for 5 hours or more, particularly preferably aging at 90 ° C. or more and 100 ° C. or less for 8 hours or more.
- the upper limit of the aging time for obtaining type II crystals is not particularly limited, but may be further ripened for about 1 to 2 hours from the lower limit of the aging time. Further, the aging time for obtaining the type II crystal may slightly change depending on the experimental conditions.
- a mixed crystal of Form I crystals and Form II crystals can be obtained.
- sampling is performed, and the amount ratio of Form I crystals to Form II crystals is monitored by powder X-ray diffraction, DSC, etc.
- a mixed crystal of type I crystal and type II crystal can be obtained.
- the crystals can be filtered by a normal method, washed with water or the like as necessary, and further dried.
- powder X-ray diffraction is preferable. Further, infrared absorption spectrum, solid state NMR, differential scanning calorimetry (DSC), thermogravimetric / differential thermal analysis (TG-DTA), etc. may be used in combination. Although these measurement conditions are not specifically limited, It is preferable to measure on the measurement conditions as described in this specification. Further, each spectrum obtained by these analysis methods has a certain measurement error due to its property. A crystal having a peak whose spectral error is within the error range is also included in the scope of the present invention.
- a crystal having a peak within an error range of ⁇ 0.2 ° at a diffraction angle peak represented by 2 ⁇ is included in the present invention.
- an error range of ⁇ 5 ° C. is allowed in the differential scanning calorimetry (DSC), and an error range of ⁇ 0.5% is allowed in the infrared absorption spectrum.
- the I-type crystal of the present invention has a diffraction angle represented by 2 ⁇ of 6.7 °, 8.3 °, 8.9 °, 14.0 °, 14.8 ° when CuK ⁇ ray is used as the X-ray.
- X-ray diffraction patterns showing characteristic diffraction peaks at 26.4 ° and 26.4 ° ( ⁇ 0.2 °, respectively), preferably 6.7 °, 8.3 °, 8.9 °, 13.
- Powder X-ray diffraction showing diffraction peaks at 1 °, 13.4 °, 14.0 °, 14.8 °, 17.9 °, 21.6 ° and 26.4 ° ( ⁇ 0.2 °, respectively) Has a pattern.
- the form I crystal of the present invention has an endothermic peak having a peak top temperature of about 362 ° C. ( ⁇ 5 ° C.) in differential scanning calorimetry (DSC), and 1713 in the infrared absorption spectrum (paste method). Infrared absorption spectrum patterns having absorption peaks at 1673, 1643, 1590, 1532, 1421, 1265, 1214 and 1034 cm ⁇ 1 ( ⁇ 0.5%, respectively).
- the II type crystal of the present invention has 7.3 °, 11.2 °, 13.3 °, 17.0 °, 25.5 ° as diffraction angles represented by 2 ⁇ when CuK ⁇ ray is used as X-ray. And powder X-ray diffraction patterns showing characteristic diffraction peaks at 27.5 ° ( ⁇ 0.2 °, respectively), preferably 7.3 °, 11.2 °, 13.3 °, 17. It has a powder X-ray diffraction pattern showing diffraction peaks at 0 °, 22.4 °, 23.1 °, 25.5 ° and 27.5 ° (each ⁇ 0.2 °).
- the type II crystal of the present invention has an endothermic peak with a peak top temperature of about 342 ° C.
- the solvate crystal of Compound A can be prepared by a cooling method (slow cooling) using various organic solvents or a heated suspension stirring method.
- the specific procedure of each method is as follows.
- (Cooling method) Compound A is heated and dissolved in a soluble organic solvent, and then slowly cooled at room temperature to precipitate crystals.
- (Heating suspension stirring method) Compound A is suspended in a sparingly soluble organic solvent, heated and stirred.
- Each pseudo-crystal form of 1,3-dimethyl-2-imidazolidinone solvate can be obtained by the cooling method of dimethyl-2-imidazolidinone and N-methylpyrrolidone solvate can be obtained by the cooling method of N-methylpyrrolidone.
- Details of the production method of each solvate crystal and the physical property data of the obtained solvate crystal are as described in Reference Examples below.
- Crystals of the present invention have excellent PDE9 inhibitory action and mild PDE5 inhibitory action, and the degradation of cGMP by PDE9 Diseases involved, such as overactive bladder, frequent urination, urinary incontinence, dysuria associated with benign prostatic hyperplasia, neurogenic bladder, interstitial cystitis, urolithiasis, prostatic hypertrophy, erectile dysfunction, cognitive impairment, nerve Treatment, treatment of disorders, Alzheimer's disease, pulmonary hypertension, chronic obstructive pulmonary disease, ischemic heart disease, hypertension, angina, myocardial infarction, arteriosclerosis, thrombosis, embolism, type I diabetes, type II diabetes It is useful as a drug for
- Patent Document 1 The use of Compound A as a therapeutic or therapeutic agent for dysuria and the like is disclosed in detail in Patent Document 1, and similarly, the crystal of the present invention is used for the treatment and treatment of urinary disorders and the like in humans and other mammals. Therefore, it can be administered orally or parenterally (for example, intramuscular injection, intravenous injection, rectal administration, transdermal administration, etc.).
- the entire disclosure of Patent Document 1 is included in the disclosure of this specification as a reference.
- the crystals of the present invention can be in solid form (eg, tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, troches, etc.), semi-solid forms (eg, tablets, hard capsules, non-toxic additives) , Suppositories, ointments, etc.) or liquid forms (eg, injections, emulsions, suspensions, lotions, sprays, etc.), but can be prepared and used in solid form.
- solid form eg, tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, troches, etc.
- semi-solid forms eg, tablets, hard capsules, non-toxic additives
- liquid forms eg, injections, emulsions, suspensions, lotions, sprays, etc.
- Non-toxic additives that can be used in the above preparation include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyethylene glycol P-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like.
- the formulation may also contain other therapeutically useful agents.
- the content of the crystals of the invention in the formulation depends on the dosage form, but is generally 0.1-50% by weight in the case of solid and semi-solid forms and in the liquid form. Can be contained at a concentration of 0.05 to 10% by weight.
- the dosage of the crystal of the present invention can vary widely depending on the type of warm-blooded animal including the human subject, the type of disease targeted, the route of administration, the severity of symptoms, the diagnosis of the doctor, etc. In general, it can be in the range of 0.01 to 5 mg / kg, preferably 0.02 to 2 mg / kg per day. However, as described above, it is of course possible to administer an amount that is less than the lower limit or greater than the upper limit of the above range, depending on the severity of the patient's symptoms and the diagnosis of the doctor. The above dose can be administered once a day or divided into several times.
- Production Example 1 Production of amorphous 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid 2- (3 4-Dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylate (20.03 g), 5 mol / L aqueous sodium hydroxide solution (30 mL) , A mixture of water (50 mL) and isopropanol (30 mL) was heated to reflux for 1 hour.
- Example 1 Production of Form I Crystal of 2- (3,4-Dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid Production Example 1 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid amorphous (4.995 g) obtained in 1 A mixture of a mol / L aqueous sodium hydroxide solution (27.1 mL) and water (32 mL) was heated for 1 hour to confirm dissolution.
- Example 2 the powder X-ray diffraction pattern of the crystal obtained in Example 1 is shown in FIG. 1, and the diffraction angle (2 ⁇ ) peak and peak intensity are shown in Table 2. Furthermore, an infrared absorption spectrum is shown in FIG.
- Example 2 Production of Form II crystals of 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid Production Example 1 2- (3,4-Dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid amorphous (5.671 g) obtained in 1 A mixture of a mol / L aqueous sodium hydroxide solution (30.8 mL) and water (54 mL) was heated for 1 hour to confirm dissolution.
- Example 2 the powder X-ray diffraction pattern of the crystal obtained in Example 2 is shown in FIG. 3, and the peak and peak intensity of the diffraction angle (2 ⁇ ) are shown in Table 3. Furthermore, an infrared absorption spectrum is shown in FIG.
- Reference Example 2 Production of crystals of dimethylacetamide solvate of 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid
- dimethylacetamide (6 mL) and acetone (12 mL) were used instead of isopropanol, the title crystals were produced.
- Reference Example 5 Crystal of N-methylpyrrolidone hydrate of 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid In the same manner as in Production Reference Example 3, except that N-methylpyrrolidone was used as a solvent, the title crystal was produced.
- the infrared absorption spectrum (paste method) measurement of the crystals obtained in each example was performed under the following conditions. That is, on an agate mortar, liquid paraffin was added to the sample and kneaded well, and the infrared absorption spectrum was measured.
- Example 3 Aging temperature of an aqueous suspension of 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid Examination of aging time 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carvone produced by the method described in Production Example 1 2- (3,4-Dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carvone prepared by conventional methods from amorphous acid and sodium hydroxide A mixture of acid monosodium salt (4.992 g), 1 mol / L aqueous sodium hydroxide solution (12.8 mL) and water (45 mL) was heated to confirm dissolution.
- the reaction solution was allowed to cool to room temperature and acidified with dilute hydrochloric acid, and then aged at each temperature shown in Table 9.
- the precipitated crystals were sampled over time, and powder I-ray diffraction produced Form I and Form II crystals. And disappearance was measured. Specifically, the characteristic powder X-ray diffraction peak 2 ⁇ appears and disappears at about 14.8 ° and about 26.4 ° for the type I crystal, and the characteristic powder X-ray diffraction for the type II crystal.
- the appearance of peaks having peak 2 ⁇ of about 11.2 ° and about 25.5 ° was analyzed. The results are shown in Table 9.
- Test Example 1 Thermal Stability For Form I crystal obtained in Example 1, Form II crystal obtained in Example 2, and Compound A in amorphous form obtained in Production Example 1, 6 hours at 100 ° C. or 200
- the amount of carbonate was measured by HPLC. The results and the color of each specimen at that time are shown in Table 10 below. In the HPLC measurement, the specimen was suspended in the mobile phase and dissolved after adding 1 equivalent of aqueous sodium hydroxide.
- HPLC measurement condition measuring device Waters Alliance HPLC system detector: ultraviolet absorption photometer (measurement wavelength 225 nm) Column: XBridge C18 (Waters) Column temperature: constant temperature around 30 ° C.
- Mobile phase A Acetonitrile mobile phase B: 5 mmol / L ammonium bicarbonate (pH 8.0) Gradient method of mobile phase A and mobile phase B: mobile phase A 23% (0-15 minutes), mobile phase A 23% ⁇ 55% (15-30 minutes), mobile phase A 55% (30-50 minutes) 0mL / min
- Test Example 2 Solubility 50 mg each of Form I crystal obtained in Example 1, Form II crystal obtained in Example 2, and amorphous form Compound A obtained in Production Example 1 were added to 20 mL of 0.5% Tween 80 aqueous solution. After suspension and sonication, 180 mL of 0.5% Tween 80 aqueous solution was added and stirred at 37 ° C. At the time of 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours from the start of stirring, the same conditions as in Test Example 1 (the mobile phase was acetonitrile / 5 mmol / L ammonium bicarbonate (pH 8. 0) (isocratic method using (27:73)) The solubility was measured by HPLC.
- the amorphous form of Compound A was about 0.5 hour
- the Form I crystal was about 1 hour
- the Form II crystal was 2 Since the saturated state was reached in about the time, the value at the third hour was taken as the solubility.
- Table 11 The results are shown in Table 11 below together with the results of Test Example 3 below.
- Test Example 3 Dissolution rate 100 mg each of Form I crystal obtained in Example 1, Form II crystal obtained in Example 2, and amorphous form Compound A obtained in Production Example 1 were molded with magnesium stearate. Was compressed and molded into a disk having a diameter of 12 mm. Each disk was added to 900 mL of 0.5% Tween 80 aqueous solution at 37 ° C, and the dissolution test apparatus paddle method (50 rpm) was maintained at 37 ° C, every 10 minutes until the first hour, and every hour after the first hour.
- Test Example 4 Thermal Analysis The differential scanning calorimetry (DSC) of the type I crystal obtained in Example 1 and the type II crystal obtained in Example 2 was measured using aluminum oxide as a control.
- the measurement conditions are as follows. Sample container: Open Heating temperature: Up to 400 ° C 10.0 ° C / min Measurement temperature range: 50-400 ° C Atmospheric gas: Nitrogen gas The DSC chart of each crystal is shown in FIGS. 15 and 16.
- Test Example 5 Comparison of filtration speed The speeds of filtration from an aqueous suspension were measured for Compound I in the form of Form I, Form II, and amorphous.
- the test used the same synthetic
- Test Example 5-a 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid amorphous filtration rate 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid monosodium salt (2.501 g), 1 mol / L water A mixture of an aqueous sodium oxide solution (9.6 mL) and water (39.4 mL) was stirred and dissolved.
- the reaction mixture was ice-cooled, ethanol (10 mL) was added, the internal temperature was adjusted to about 2 ° C., 1 mol / L hydrochloric acid (16.0 mL) was added to neutralize, and water (25.0 mL) was added. (Solvent amount was set to 100 mL)
- the suspension was poured into a G2 glass filter having a diameter of 3 cm, and pressure reduction was started at 50 hpa.
- the time taken for the pressure to rise after the filtration was completed was 42 minutes 52 seconds.
- the height of the solid substance at that time was 4.3 cm (bulk was 30.4 cm 3 ). Washing with water was impossible due to clogging.
- Test Example 5-b Filtration rate of I-form crystals of 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid monosodium salt (2.502 g), 1 mol / A mixture of L aqueous sodium hydroxide solution (6.4 mL) and water (22.5 mL) was heated and stirred to dissolve.
- the reaction mixture was allowed to cool at room temperature, neutralized by adding 1 mol / L hydrochloric acid (12.8 mL), water (8.3 mL) was added, and the mixture was stirred at about 75 ° C. for 1.5 hr, followed by water (50 mL). ) Was added (the amount of solvent was 100 mL), and the mixture was cooled to about 21 ° C.
- the suspension was poured into a G2 glass filter having a diameter of 3 cm, pressure reduction was started at 50 hpa, and the time taken for the pressure to rise after the filtration was completed was 4 minutes 14 seconds. Moreover, the height of the solid substance at that time was 2.3 cm (bulk was 16.2 cm 3 ).
- Test Example 5-c Filtration rate of 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid Form II crystals 2- (3,4-dichlorobenzyl) -5-methyl-4-oxo-3,4-dihydrothieno [2,3-d] pyrimidine-6-carboxylic acid monosodium salt (2.503 g), 1 mol / A mixture of L aqueous sodium hydroxide solution (6.4 mL) and water (22.5 mL) was heated and stirred to dissolve.
- the reaction solution was allowed to cool at room temperature, neutralized by adding 1 mol / L hydrochloric acid (12.8 mL), added with water (8.3 mL), stirred for 8 hours under heating to reflux, and further about 70 ° C. After stirring for 8 hours, water (50 mL) was added (the amount of solvent was 100 mL), and the mixture was cooled to about 21 ° C.
- the suspension was poured into a G2 glass filter having a diameter of 3 cm, pressure reduction was started at 50 hpa, and the time taken for the pressure to rise after filtration was completed was 4 minutes and 5 seconds. Moreover, the height of the solid substance at that time was 2.1 cm (bulk was 14.8 cm 3 ).
- Test Example 6 Dog Absorption Test A dog absorption test was conducted on Form I, Form II and amorphous of Compound A under the following conditions. The results are shown in Table 13. Compound A Form I, Form II and amorphous showed good pharmacokinetics as a pharmaceutical. Specimen: Except for amorphous, the type I crystal and the type II crystal were prepared by wet classification (using two types of sieves and running water) and having particles aligned to 20 to 63 ⁇ m. Adjustment method: 25 mL of water was added to 3 g of the sample, lightly pulverized in a mortar, classified by pressure, and dried by ventilation. As the amorphous material, a sample pulverized with an agate mortar was used. Method: Nine dogs, 3 ⁇ 3 crossover, 0.3 mg / kg orally
- Test Example 7 Light Stability Test A light stability test was conducted on Compound I Form I, Form II and amorphous under the following conditions. The results are shown in FIG. Light source: Xenon lamp 180,000 Lxs Conditions: A sample (6 mg) was weighed into a transparent sample bottle and exposed to light for 8 hours. HPLC conditions: the same as in Test Example 1 Forms I and II crystals were relatively stable, but amorphous produced more than 0.2% impurities.
- the crystal of the present invention can be produced by a simple method suitable for industrial mass production, and is suitable as an active ingredient of a medicine for treatment, treatment, etc. of urination disorders such as stability.
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Abstract
Description
しかし、特許文献1には、得られた化合物Aの具体的性状は明示されておらず、結晶多形の存在は記載も示唆もされていない。
特に、特定の物性データを示す溶媒和していない結晶(後掲のI形結晶及びII形結晶)は、各種有機溶媒を用いた再結晶などの通常の結晶化手段では得られず、意外にも、水性懸濁液にて一定時間加熱するという簡便な方法で製造することができることを見出した。
当該方法は、工業的生産において最終工程の後処理において行うことができ、結晶化工程という煩雑な工程を別途設ける必要がなく、さらに得られた結晶はろ過性も優れており、操作性もコストの面でも大量生産に適している。さらに、これら結晶が医薬として優れた特性を有することを見出し、本発明を完成するに至った。
[1]粉末X線回折スペクトルにおいて、2θで表される回折角度として6.7±0.2°、8.3±0.2°、8.9±0.2°、14.0±0.2°、14.8±0.2°及び26.4±0.2°に回折ピークを示す粉末X線回折パターンを有する、2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の結晶;
[2]示差走査熱量測定(DSC)において、ピークトップ温度が362±5℃である吸熱ピークを有する、上記[1]記載の結晶;
[3]粉末X線回折スペクトルにおいて、2θで表される回折角度として7.3±0.2°、11.2±0.2°、13.3±0.2°、17.0±0.2°、25.5±0.2°及び27.5±0.2°に回折ピークを示す粉末X線回折パターンを有する、2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の結晶;
[4]示差走査熱量測定(DSC)において、ピークトップ温度が342±5℃である吸熱ピークを有する、上記[3]記載の結晶;
[5]溶媒和及び水和していない結晶である、上記[1]~[4]のいずれかに記載の結晶;
[6]上記[1]又は[2]記載の結晶及び上記[3]又は[4]記載の結晶を含む、混合結晶;
[7]上記[1]~[6]のいずれかに記載の結晶を有効成分として含む医薬;
[8]上記[1]~[6]のいずれかに記載の結晶及び製薬上許容される担体を含む医薬組成物;
[9]PDE9阻害剤である、上記[7]記載の医薬;
[10]過活動膀胱、頻尿、尿失禁、前立腺肥大症に伴う排尿障害、神経因性膀胱、間質性膀胱炎、尿路結石、前立腺肥大症、勃起障害、認知障害、神経障害、アルツハイマー病、肺高血圧症、慢性閉塞性肺疾患、虚血性心疾患、高血圧、狭心症、心筋梗塞、動脈硬化、血栓症、塞栓症、I型糖尿病又はII型糖尿病の治療剤である、上記[7]記載の医薬;
[11]2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の水性懸濁液を加熱する工程を含む、請求項1~6のいずれかに記載の結晶の製造方法;
[12]2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の水性懸濁液を40℃以上50℃未満で1~96時間、50℃以上60℃未満で0.5~32時間、60℃以上70℃未満で0.5~24時間、70℃以上80℃未満で0.1~12時間、80℃以上90℃未満で0.05~6時間又は90℃以上100℃以下で0.01~3時間加熱する工程を含む、上記[1]又は[2]に記載の結晶の製造方法;
[13]2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の水性懸濁液を60℃以上70℃未満で144時間以上、70℃以上80℃未満で25時間以上、80℃以上90℃未満で23時間以上又は90℃以上100℃以下で16時間以上加熱する工程を含む、上記[3]又は[4]に記載の結晶の製造方法;
[14]2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸のアルカリ水溶液を中和又は酸性にすることにより得られる水性懸濁液を加熱する、上記[11]~[13]のいずれかに記載の製造方法
等に関する。
一般に、溶媒和物の結晶は溶媒和していない結晶に比べ溶媒が解離して転移しやすいなど安定性の問題を有する場合が多く、水和物結晶など安定な結晶が得られる場合を除いて、医薬として取扱いの難しさが懸念される。また、相当量の有機溶媒を含むため、その溶媒自体の安全性も考慮する必要があり、医薬として開発するためには種々の困難が予想される。
さらにまた、加熱の温度と時間を適宜調整することにより、二つの新規な化合物Aの溶媒和していない結晶(以下、I形結晶及びII形結晶と称する)及びそれらの混合結晶を作り分けることができることを見出した。
また、このようにして得られたI形結晶及びII形結晶は、溶解性、安定性、吸収性等の点で医薬として好適な特性をも有するものである。
以下、詳細について説明する。
化合物Aのアモルファスは、化合物Aのアルカリ水溶液を酸により中和又は酸性にすることにより析出する凝固体として取得することができる。該凝固体を水懸濁液から取得する方法としては、例えば、ろ取、遠心分離、沈殿させて上澄みを捨てる方法などが挙げられ、この中、ろ取が簡便であり好ましいが、フィルターが目詰まりして極めて時間がかかり、また水切れも悪いため、工業的生産のためには改善の余地が残る方法である。
化合物Aのアルカリ水溶液は、水と混和する有機溶媒を含んでいてもよい。該有機溶媒としては、アルコール類(例えば、メタノール、エタノール、プロパノール、イソプロパノール等)、アミド類(例えば、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド等)、エーテル類(例えば、テトラヒドロフラン、ジオキサン等)等が挙げられる。当該溶媒の使用量は水に対して0.01~0.1倍(v/v)が好ましい。
化合物Aのエステル体の加水分解反応は、それ自体既知の方法に従い、例えば、水中又はメタノール、エタノール、イソプロパノール等のアルコール類に水を加えた混合溶媒中にて、化合物Aのエステル体が懸濁又は溶解した状態で、水酸化ナトリウム、水酸化カリウム、炭酸カリウム等のアルカリ類の存在下に、0℃乃至反応混合物の還流温度、好ましくは室温乃至反応混合物の還流温度の範囲内の温度で行うことができる。化合物Aのエステル体に対するアルカリ類の使用割合は、特に制限されるものではないが、一般には、化合物Aのエステル体1モルあたりアルカリ類を約1~20モルの範囲内で用いることができる。
中和する場合は、アルカリ水溶液に含まれる塩基に対して当量の酸を添加すればよい。酸性にする場合は、そのpHは特に限定されないが、pH5~7程度となるように酸を加えるのが好ましい。
化合物AのI形結晶及びII形結晶は、化合物Aの水性懸濁液を一定時間加熱することにより製造することができる。
化合物Aの水性懸濁液は、水と混和する有機溶媒を含んでいてもよく、該有機溶媒としては、アルコール類(例えば、メタノール、エタノール、プロパノール、イソプロパノール等)等が挙げられるが、含まれる有機溶媒和物結晶が生成する恐れがあるため、有機溶媒を含まないことが好ましい。
有機溶媒を含む場合の当該溶媒の使用量は水に対して0.001~0.3倍(v/v)が好ましい。有機溶媒の量がこの範囲より多い場合には、有機溶媒和物結晶が生成する恐れがある。
化合物Aの水性懸濁液は、化合物Aを水又は水と有機溶媒の混合溶媒に添加し、攪拌することによって調製することができる。
以下、化合物Aの水性懸濁液を所定の温度範囲で所定時間加熱することを「熟成」と称する。
具体的には、熟成の温度及び時間を、例えば、40℃以上50℃未満で1~96時間(より好ましくは8~48時間)、50℃以上60℃未満で0.5~32時間(より好ましくは4~24時間)、60℃以上70℃未満で0.5~24時間(より好ましくは2~6時間)、70℃以上80℃未満で0.1~12時間(より好ましくは1.5~4時間)、80℃以上90℃未満で0.05~6時間(より好ましくは0.5~3時間)又は90℃以上100℃以下で0.01~3時間(より好ましくは0.1~2時間)などとすることにより、I形結晶を得ることができる。製造効率や結晶化度、他の結晶形の混入の可能性等を勘案すると、これらの中、70℃以上80℃未満で0.1~12時間熟成することが好ましく、特に、70℃以上80℃未満で1.5~4時間熟成することが好ましい。なお、より高温(例えば、90℃以上100℃以下)においては、昇温中に熟成が完了し、当該温度に達した時点でI形結晶が得られている場合もある。
また、別の態様としては、熟成の温度及び時間を、例えば、40℃以上50℃未満で1~96時間(より好ましくは8~48時間)、50℃以上60℃未満で0.5~48時間(より好ましくは4~24時間)、60℃以上70℃未満で0.5~24時間(より好ましくは2~6時間)、70℃以上80℃未満で0.1~12時間(より好ましくは1.5~4時間)、80℃以上90℃未満で0.05~6時間(より好ましくは0.5~3時間)又は90℃以上100℃以下で0.01~3時間(より好ましくは0.1~2時間)などとすることによっても、I形結晶を得ることができる。
また、第三の態様としては、熟成の温度及び時間を、例えば、40℃以上50℃未満で1~96時間(より好ましくは8~48時間)、50℃以上60℃未満で0.5~32時間(より好ましくは4~24時間)、60℃以上70℃未満で0.5~24時間(より好ましくは2~6時間)、70℃以上80℃未満で0.1~12時間(より好ましくは1.5~4時間)、80℃以上90℃未満で0.05~6時間(より好ましくは0.5~3時間)又は90℃以上100℃以下で0.01~4時間(より好ましくは0.1~2時間)などとすることによっても、I形結晶を得ることができる。
I形結晶を取得するための熟成時間は、その実験条件の違いにより多少変化することも有り得る。
具体的には、熟成の温度及び時間を、例えば、60℃以上70℃未満で144時間以上(より好ましくは155時間以上)、70℃以上80℃未満で25時間以上(より好ましくは30時間以上)、80℃以上90℃未満で23時間以上(より好ましくは25時間以上)又は90℃以上100℃以下で16時間以上(より好ましくは20時間以上)などとすることにより、II形結晶を得ることができる。これらの中、90℃以上100℃以下で16時間以上熟成することが好ましく、特に、90℃以上100℃以下で20時間以上熟成することが好ましい。
また、別の態様としては、熟成の温度及び時間を、熟成の温度及び時間を、例えば、60℃以上70℃未満で70時間以上(より好ましくは80時間以上)、70℃以上80℃未満で25時間以上(より好ましくは30時間以上)、80℃以上90℃未満で12時間以上(より好ましくは15時間以上)又は90℃以上100℃以下で5時間以上(より好ましくは8時間以上)などとすることにより、II形結晶を得ることができる。これらの中、90℃以上100℃以下で5時間以上熟成することが好ましく、特に、90℃以上100℃以下で8時間以上熟成することが好ましい。
II形結晶を取得するための熟成時間の上限には特に限定はないが、上記熟成時間の下限からさらに1~2時間程度熟成させてもよい。
また、II形結晶を取得するための熟成時間は、その実験条件の違いにより多少変化することも有り得る。
I形結晶生成後の更なる熟成条件の範囲内で、例えば、サンプリングを行い、粉末X線回折、DSCなどでI形結晶とII形結晶の量比をモニターすることにより、所望の混合比を有するI形結晶とII形結晶の混合結晶を取得することができる。
また、これら解析方法により得られる各スペクトルは、その性質上一定の測定誤差が生じる。スペクトルの誤差が当該誤差範囲にあるピークを有する結晶も本発明の範囲に含まれる。例えば、粉末X線回折の測定の場合は、2θで表される回折角ピークにおいて、±0.2°の誤差範囲内にピークを有する結晶は本発明に含まれる。
また、示差走査熱量測定(DSC)においては、±5℃、赤外吸収スペクトルにおいては、±0.5%の誤差範囲が許容される。
また、本発明のI形結晶は、示差走査熱量測定(DSC)において、ピークトップ温度が約362℃(±5℃)である吸熱ピークを有し、赤外吸収スペクトル(ペースト法)において1713、1673、1643、1590、1532、1421、1265、1214及び1034cm-1(それぞれ、±0.5%)に吸収ピークを示す赤外吸収スペクトルパターンを有する。
また、本発明のII形結晶は、示差走査熱量測定(DSC)において、ピークトップ温度が約342℃(±5℃)である吸熱ピークを有し、赤外吸収スペクトル(ペースト法)において1706、1669、1649、1584、1530、1283、1271、1260、1215、1203、1137、1033cm-1(それぞれ、±0.5%)に吸収ピークを示す赤外吸収スペクトルパターンを有する。
化合物Aの溶媒和物結晶は、各種有機溶媒を用いた冷却法(徐冷)又は加熱懸濁撹拌法により調製することができる。各方法の具体的手順は以下の通りである。
(冷却法)
化合物Aを可溶性有機溶媒に加熱して溶解した後、室温下徐冷して結晶を析出させる。
(加熱懸濁撹拌法)
化合物Aを難溶性有機溶媒に懸濁し、加熱して懸濁撹拌する。
2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸エチル(20.03g)、5モル/L水酸化ナトリウム水溶液(30mL)、水(50mL)及びイソプロパノール(30mL)の混合物を1時間加熱還流した。反応液を氷冷し、希塩酸で酸性にした後、氷冷下で2時間撹拌した。析出した固形物をろ取し、水洗して、80℃で減圧下に24時間乾燥し、17.39gの固形物を得た。なお、ろ取に要した時間は約90分であった。
1H-NMR及びMSにより、製造例1で得られた固形物は、特許文献1の実施例36-a)に記載の2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸と同じ化合物であることを確認した。
1H-NMR(DMSO-d6)δ:2.79(3H,s),3.99(2H,s),7.3-7.7(3H,m),12.71(1H,br s),13.33(1H,br s)
MS(m/z):370(M++2),368(M+)
製造例1で得られた2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸のアモルファス(4.995g)、1モル/L水酸化ナトリウム水溶液(27.1mL)及び水(32mL)の混合物を1時間加熱し、溶解を確認した。反応液を室温下放冷し、希塩酸で酸性にした後、75℃で1.5時間撹拌した。得られた結晶をろ取し、水洗して、40℃で19時間通風乾燥し、4.835gの標記結晶を得た。なお、ろ取に要した時間は約5分であった。
1H-NMR及びMSにより、実施例1で得られた結晶は、特許文献1の実施例36-a)に記載の2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸と同じ化合物であることを確認した。
1H-NMR(DMSO-d6)δ:2.79(3H,s),3.99(2H,s),7.3-7.7(3H,m),12.71(1H,br s),13.33(1H,br s)
MS(m/z):370(M++2),368(M+)
製造例1で得られた2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸のアモルファス(5.671g)、1モル/L水酸化ナトリウム水溶液(30.8mL)及び水(54mL)の混合物を1時間加熱し、溶解を確認した。反応液を室温下放冷し、希塩酸で酸性にした後、75℃で25時間撹拌した。得られた結晶をろ取し、水洗して、40℃で19時間通風乾燥し、5.331gの標記結晶を得た。なお、ろ取に要した時間は約5分であった。
1H-NMR及びMSにより、実施例2で得られた結晶は、特許文献1の実施例36-a)に記載の2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸と同じ化合物であることを確認した。
1H-NMR(DMSO-d6)δ:2.79(3H,s),3.99(2H,s),7.3-7.7(3H,m),12.71(1H,br s),13.33(1H,br s)
MS(m/z):370(M++2),368(M+)
製造例1で得られた2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸のアモルファス(1g)をイソプロパノール(25mL)に懸濁して、1時間加熱還流し、室温まで冷却してからろ取後、40℃で14時間通風乾燥し、1.136gの標記結晶を得た。
1H-NMR(DMSO-d6)δ:1.04(6H,d,J=6.2Hz),2.79(3H,s),3.7-3.8(1H,m),3.99(2H,s),4.2-4.4(1H,m),7.3-7.7(3H,m),12.70(1H,br s),13.34(1H,br s)
上記NMRのデータにより、得られた結晶は、化合物Aの一イソプロパノール和物であると考えられる。
その粉末X線回折パターンを図5に示し、回折角(2θ)のピーク及びピーク強度を表4に示し、赤外線吸収スペクトルを図6に示す。
参考例1と同様にして、ただし、イソプロパノールの代わりにジメチルアセトアミド(6mL)及びアセトン(12mL)を用いて、標記結晶を製造した。
1H-NMR(DMSO-d6)δ:1.96(3H,s),2.7-2.9(6H,m),2.95(3H,s),3.99(2H,s),7.3-7.7(3H,m),12.70(1H,br s),13.34(1H,br s)
上記NMRのデータにより、得られた結晶は、化合物Aの一ジメチルアセトアミド和物であると考えられる。
その粉末X線回折パターンを図7に示し、回折角(2θ)のピーク及びピーク強度を表5に示し、赤外線吸収スペクトルを図8に示す。
製造例1で得られた2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸のアモルファス(1g)をジメチルホルムアミド(14mL)及び水(1mL)に溶解し、室温下24時間放置し、析出した結晶をろ取後、40℃で14時間通風乾燥し、904mgの標記結晶を得た。
1H-NMR(DMSO-d6)δ:2.73(3H,s),2.79(3H,s), 2.89(3H,s),3.99(2H,s),7.3-7.7(3H,m),7.95(1H,s),12.70(1H,br s),13.34(1H,br s)
上記NMRのデータにより、得られた結晶は、化合物Aの一ジメチルホルムアミド和物であると考えられる。
その粉末X線回折パターンを図9に示し、回折角(2θ)のピーク及びピーク強度を表6に示し、赤外線吸収スペクトルを図10に示す。
参考例3と同様にして、ただし、溶媒として1,3-ジメチル-2-イミダゾリジノンを用いて、標記結晶を製造した。
1H-NMR(DMSO-d6)δ:2.63(12H,s),2.79(3H,s),3.20(8H,s),3.99(2H,s),7.3-7.7(3H,m),12.70(1H,br s),13.34(1H,br s)
上記NMRのデータにより、得られた結晶は、化合物Aの二1,3-ジメチル-2-イミダゾリジノン和物であると考えられる。
その粉末X線回折パターンを図11に示し、回折角(2θ)のピーク及びピーク強度を表7に示し、赤外線吸収スペクトルを図12に示す。
参考例3と同様にして、ただし、溶媒としてN-メチルピロリドンを用いて、標記結晶を製造した。
1H-NMR(DMSO-d6)δ:1.8-2.0(3H,m),2.1-2.3(3H,m),2.69(4.5H,s),2.79(3H,s),3.2-3.4(3H,m),3.99(2H,s),7.3-7.7(3H,m),12.70(1H,br s),13.34(1H,br s)
上記NMRのデータにより、得られた結晶は、化合物Aの一.五N-メチルピロリドン和物であると考えられる。
その粉末X線回折パターンを図13に示し、回折角(2θ)のピーク及びピーク強度を表8に示し、赤外線吸収スペクトルを図14に示す。
X線:CuKα/40kV/40mA
走査軸:2θ/θ
走査範囲:5.0000~45.0000°
サンプリング幅:0.0100°
スキャンスピード:毎分10.000°
赤外吸収スペクトル測定装置:FT/IR-470(日本分光)
製造例1記載の方法で製造される2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸のアモルファスおよび水酸化ナトリウムから常法により製造される2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の1ナトリウム塩(4.992g)、1モル/L水酸化ナトリウム水溶液(12.8mL)及び水(45mL)の混合物を加熱し、溶解を確認した。反応液を室温下放冷し、希塩酸で酸性にした後、表9記載の各温度で熟成し、析出した結晶を経時的にサンプリングし、粉末X線回折により、I形結晶およびII形結晶の生成および消失を測定した。具体的には、I形結晶については特徴的な粉末X線回折ピーク2θが約14.8°と約26.4°のピークの出現および消失、II形結晶については特徴的な粉末X線回折ピーク2θが約11.2°と約25.5°のピークの出現について解析した。結果を表9に示す。
実施例1で得られたI形結晶及び実施例2で得られたII形結晶並びに製造例1で得られたアモルファス形態の化合物Aについて、100℃で6時間又は200℃で6時間加熱したときの、分解物である2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン(化合物Aの脱炭酸物)の量をHPLCで測定した。その結果及びその際の各検体の色を下記表10に示す。なお、HPLC測定において、検体は移動相に懸濁して1当量の水酸化ナトリウム水を加えて溶解した後注入した。
HPLC測定条件
測定装置:ウォーターズ アライアンスHPLCシステム
検出器:紫外吸収光度計(測定波長225nm)
カラム:XBridge C18(Waters)
カラム温度:30℃付近の一定温度
移動相A:アセトニトリル
移動相B:5mmol/L炭酸水素アンモニウム(pH8.0)
移動相Aと移動相Bのグラジエント法:移動相A23%(0~15分)、移動相A23%→55%(15~30分)、移動相A55%(30~50分)流速:1.0mL/min
実施例1で得られたI形結晶及び実施例2で得られたII形結晶並びに製造例1で得られたアモルファス形態の化合物Aそれぞれ50mgを0.5%Tween80水溶液20mLに懸濁して超音波処理後、0.5%Tween80水溶液180mLを加えて37℃で撹拌した。
攪拌開始から0.5時間、1時間、2時間、3時間、4時間、5時間、6時間の時点で、試験例1と同じ条件(移動相はアセトニトリル/5mmol/L炭酸水素アンモニウム(pH8.0)(27:73)を用いるアイソクラティック法)のHPLCで溶解度を測定したところ、アモルファス形態の化合物Aは0.5時間程度で、I形結晶は1時間程度で、II形結晶は2時間程度でほぼ飽和状態に達したため、3時間目の値を溶解度とした。結果を下記試験例3の結果と併せて後記表11に示す。
実施例1で得られたI形結晶及び実施例2で得られたII形結晶並びに製造例1で得られたアモルファス形態の化合物Aそれぞれ100mgを、ステアリン酸マグネシウムで金型を前処理したIR測定用の打錠器で圧縮成型し、直径12mmのディスクに成型した。各ディスクを37℃の0.5%Tween80水溶液900mLに加え、37℃を保ちながら溶出試験装置パドル法(50rpm)にて、1時間目までは10分ごとに、1時間目以降は1時間ごとに3時間目まで、試験例1と同じ条件(移動相はアセトニトリル/5mmol/L炭酸水素アンモニウム(pH8.0)(27:73)を用いるアイソクラティック法)のHPLCで濃度を測定し、それぞれの溶解速度を算出した。結果を上記試験例2の結果と併せて下記表11に示す。
実施例1で得られたI形結晶及び実施例2で得られたII形結晶について、酸化アルミニウムを対照として示差走査熱量(DSC)を測定した。測定条件は次の通りである。
試料容器:開放
加熱温度:400℃まで10.0℃/分
測定温度範囲:50~400℃
雰囲気ガス:窒素ガス
各結晶のDSCチャートを図15及び図16に示す。
I形結晶、II形結晶及びアモルファス形態の化合物Aについて、それぞれ水懸濁液からろ過する際のスピードを測定した。なお、試験は比較のために、同じ合成スケール、同じ溶媒量、同じろ過器(グラスフィルター)及び同じ減圧度を用いた。以下に試験例を示し、その結果を後記表12に示す。
2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の1ナトリウム塩(2.501g)、1モル/L水酸化ナトリウム水溶液(9.6mL)及び水(39.4mL)の混合物を撹拌、溶解した。反応液を氷冷し、エタノール(10mL)を加えて、内温を約2℃とした後、1モル/L塩酸(16.0mL)を加え中和し、水(25.0mL)を加えて(溶媒量を100mLとした)、氷冷下で撹拌して内温が約1℃であることを確認した後、直径3cmのG2グラスフィルターに懸濁液を注ぎ、50hpaで減圧を開始し、ろ過が終了して圧が上昇するまでにかかった時間は42分52秒であった。また、そのときの固形物の高さは4.3cmであった(嵩は30.4cm3)。なお、水による洗浄は目詰まりのため不可能であった。
2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の1ナトリウム塩(2.502g)、1モル/L水酸化ナトリウム水溶液(6.4mL)及び水(22.5mL)の混合物を加熱撹拌し、溶解した。反応液を室温にて放冷した後、1モル/L塩酸(12.8mL)を加え中和し、水(8.3mL)を加え、約75℃で1.5時間撹拌後、水(50mL)を加えて(溶媒量を100mLとした)、約21℃まで冷却した。直径3cmのG2グラスフィルターに懸濁液を注ぎ、50hpaで減圧を開始し、ろ過が終了して圧が上昇するまでにかかった時間は4分14秒であった。また、そのときの固形物の高さは2.3cmであった(嵩は16.2cm3)。次いで得られた固形物を水(25mL)で洗浄し、50hpaで減圧ろ過する操作を3回繰り返し、ろ液のpHが7であることを確認した。このとき、圧が上昇するまでにかかった時間の合計ろ過時間は10分2秒であり、最終的に固形物の高さは1.5cmであった(嵩は10.6cm3)。
2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の1ナトリウム塩(2.503g)、1モル/L水酸化ナトリウム水溶液(6.4mL)及び水(22.5mL)の混合物を加熱撹拌し、溶解した。反応液を室温にて放冷した後、1モル/L塩酸(12.8mL)を加え中和し、水(8.3mL)を加え、加熱還流下にて8時間撹拌し、さらに約70℃で8時間撹拌した後、水(50mL)を加えて(溶媒量を100mLとした)、約21℃まで冷却した。直径3cmのG2グラスフィルターに懸濁液を注ぎ、50hpaで減圧を開始し、ろ過が終了して圧が上昇するまでにかかった時間は4分5秒であった。また、そのときの固形物の高さは2.1cmであった(嵩は14.8cm3)。次いで得られた固形物を水(25mL)で洗浄し、50hpaで減圧ろ過する操作を3回繰り返し、ろ液のpHが7であることを確認した。このとき、圧が上昇するまでにかかった時間の合計ろ過時間は6分33秒であり、最終的に固形物の高さは1.6cmであった(嵩は11.3cm3)。
以下の条件により、化合物AのI形結晶、II形結晶およびアモルファスについてイヌ吸収試験を行った。結果を表13に示す。化合物AのI形結晶、II形結晶およびアモルファスは医薬として良好な体内動態を示した。
検体:非晶質(アモルファス)を除き、I形結晶とII形結晶は湿式分級(2種類の篩いと流水を使用)で20~63μmに粒子を揃えた検体を用いた。
調整方法:試料3gに対し、25mLの水を添加し、乳鉢で軽く粉砕後に加圧で分級し、通風乾燥した。非晶質はメノウ乳鉢で粉砕した試料を用いた。
方法:イヌ9匹、3×3クロスオーバー、0.3mg/kg経口投与
以下の条件により、化合物AのI形結晶、II形結晶およびアモルファスについて光安定性試験を行った。結果を図17に示す。
光源:キセノンランプ18万Lxs
条件:試料(6mg)を透明サンプル瓶に秤量し、8時間曝光した。
HPLC条件:試験例1と同じ
I形およびII形結晶は比較的安定であったが、非晶質(アモルファス)は0.2%を越える不純物を生じた。
本発明がその好ましい態様を参照して提示又は記載される一方、本明細書中において、添付の請求の範囲で包含される発明の範囲を逸脱することなく、形態や詳細の様々な変更をなし得ることは当業者に理解されるであろう。本明細書中に示され又は参照されたすべての特許、特許公報及びその他の刊行物は、参照によりその全体が取り込まれる。
Claims (14)
- 粉末X線回折スペクトルにおいて、2θで表される回折角度として6.7±0.2°、8.3±0.2°、8.9±0.2°、14.0±0.2°、14.8±0.2°及び26.4±0.2°に回折ピークを示す粉末X線回折パターンを有する、2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の結晶。
- 示差走査熱量測定(DSC)において、ピークトップ温度が362±5℃である吸熱ピークを有する、請求項1記載の結晶。
- 粉末X線回折スペクトルにおいて、2θで表される回折角度として7.3±0.2°、11.2±0.2°、13.3±0.2°、17.0±0.2°、25.5±0.2°及び27.5±0.2°に回折ピークを示す粉末X線回折パターンを有する、2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の結晶。
- 示差走査熱量測定(DSC)において、ピークトップ温度が342±5℃である吸熱ピークを有する、請求項3記載の結晶。
- 溶媒和及び水和していない結晶である、請求項1~4のいずれかに記載の結晶。
- 請求項1又は2記載の結晶及び請求項3又は4記載の結晶を含む、混合結晶。
- 請求項1~6のいずれかに記載の結晶を有効成分として含む医薬。
- 請求項1~6のいずれかに記載の結晶及び製薬上許容される担体を含む医薬組成物。
- PDE9阻害剤である、請求項7記載の医薬。
- 過活動膀胱、頻尿、尿失禁、前立腺肥大症に伴う排尿障害、神経因性膀胱、間質性膀胱炎、尿路結石、前立腺肥大症、勃起障害、認知障害、神経障害、アルツハイマー病、肺高血圧症、慢性閉塞性肺疾患、虚血性心疾患、高血圧、狭心症、心筋梗塞、動脈硬化、血栓症、塞栓症、I型糖尿病又はII型糖尿病の治療剤である、請求項7記載の医薬。
- 2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の水性懸濁液を加熱する工程を含む、請求項1~6のいずれかに記載の結晶の製造方法。
- 2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の水性懸濁液を40℃以上50℃未満で1~96時間、50℃以上60℃未満で0.5~32時間、60℃以上70℃未満で0.5~24時間、70℃以上80℃未満で0.1~12時間、80℃以上90℃未満で0.05~6時間又は90℃以上100℃以下で0.01~3時間加熱する工程を含む、請求項1又は2に記載の結晶の製造方法。
- 2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸の水性懸濁液を60℃以上70℃未満で144時間以上、70℃以上80℃未満で25時間以上、80℃以上90℃未満で23時間以上又は90℃以上100℃以下で16時間以上加熱する工程を含む、請求項3又は4に記載の結晶の製造方法。
- 2-(3,4-ジクロロベンジル)-5-メチル-4-オキソ-3,4-ジヒドロチエノ[2,3-d]ピリミジン-6-カルボン酸のアルカリ水溶液を中和又は酸性にすることにより得られる水性懸濁液を加熱する、請求項11~13のいずれかに記載の製造方法。
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UAA201214994A UA111589C2 (uk) | 2010-05-31 | 2011-05-31 | Кристалічна форма похідної тієнопіримідину (варіанти) |
MX2012013924A MX2012013924A (es) | 2010-05-31 | 2011-05-31 | Cristal de derivado de tienopirimidina. |
CA2801030A CA2801030C (en) | 2010-05-31 | 2011-05-31 | Crystal of thienopyrimidine derivative and uses thereof as a pde9 inhibitor and as a therapeutic agent |
US13/700,935 US8748437B2 (en) | 2010-05-31 | 2011-05-31 | Crystal of 2-(3,4 dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothien[2,3-D]pyrimidine-6-carboxylic acid |
BR112012030689-8A BR112012030689B1 (pt) | 2010-05-31 | 2011-05-31 | Cristal de derivado de tienopirimidina, medicamento, composição farmacêutica e método de produção e uso do cristal |
EA201291289A EA021987B1 (ru) | 2010-05-31 | 2011-05-31 | Кристаллическое производное тиенопиримидина |
JP2012518407A JP5744017B2 (ja) | 2010-05-31 | 2011-05-31 | チエノピリミジン誘導体の結晶 |
EP11789814.8A EP2594570B1 (en) | 2010-05-31 | 2011-05-31 | Crystal of thienopyrimidine derivative |
AU2011260861A AU2011260861B2 (en) | 2010-05-31 | 2011-05-31 | Crystal of thienopyrimidine derivative |
ES11789814.8T ES2532110T3 (es) | 2010-05-31 | 2011-05-31 | Cristal de un derivado de tienopirimidina |
CN201180037709.3A CN103038238B (zh) | 2010-05-31 | 2011-05-31 | 噻吩并嘧啶衍生物的结晶 |
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IL223267A IL223267A (en) | 2010-05-31 | 2012-11-26 | A crystal of the thienopyrimidine derivative |
ZA2012/09488A ZA201209488B (en) | 2010-05-31 | 2012-12-13 | Crystal of thienopyrimidine derivative |
US14/226,505 US9006253B2 (en) | 2010-05-31 | 2014-03-26 | Crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-D]pyrimidine-6-carboxylic acid |
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US14/226,505 Division US9006253B2 (en) | 2010-05-31 | 2014-03-26 | Crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-D]pyrimidine-6-carboxylic acid |
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US20130123279A1 (en) * | 2010-05-31 | 2013-05-16 | Aska Pharmaceutical Co., Ltd. | Crystal of thienopyrimidine derivative |
US8748437B2 (en) * | 2010-05-31 | 2014-06-10 | Aska Pharmaceutical Co., Ltd. | Crystal of 2-(3,4 dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothien[2,3-D]pyrimidine-6-carboxylic acid |
US9006253B2 (en) | 2010-05-31 | 2015-04-14 | Aska Pharmaceutical Co., Ltd. | Crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-D]pyrimidine-6-carboxylic acid |
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CA2801030C (en) | 2018-11-27 |
MX2012013924A (es) | 2013-05-01 |
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AU2011260861B2 (en) | 2014-11-13 |
US8748437B2 (en) | 2014-06-10 |
AU2011260861A1 (en) | 2013-01-10 |
BR112012030689B1 (pt) | 2021-11-09 |
KR101721288B1 (ko) | 2017-03-29 |
EA201291289A1 (ru) | 2013-05-30 |
JPWO2011152411A1 (ja) | 2013-08-01 |
EP2594570B1 (en) | 2015-02-25 |
IL223267A0 (en) | 2013-02-03 |
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US20130123279A1 (en) | 2013-05-16 |
US9006253B2 (en) | 2015-04-14 |
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