JP5102230B2 - Crystal, amorphous or salt of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid - Google Patents

Description

  The present invention relates to crystals, amorphous bodies, salts and salt hydrates of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid.

さらに、特許文献２には、ＰＤＥ４阻害作用を有する、特許文献１記載の化合物がアレルギー性疾患の治療に有用であるとの記載がなされている。Compounds having a phosphodiesterase 4 (PDE4) inhibitory action are expected to be useful for the treatment of allergic diseases such as atopic dermatitis. For example, Patent Document 1 discloses a compound having the following structural formula as a compound having a PDE4 inhibitory action.

Furthermore, Patent Document 2 describes that the compound described in Patent Document 1 having a PDE4 inhibitory action is useful for the treatment of allergic diseases.

WO 99/37622 pamphlet International Publication No. 06/093226 Pamphlet

  The inventors of the present invention are methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid as a PDE4 inhibitor superior to the compound described in Patent Document 1. Etc. An object of the present invention is to provide crystals, amorphous bodies and salts of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. .

The present inventors have found the present invention as a result of diligent efforts.
That is, the present invention provides the following <1> to <13>.
<1> Crystal of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid or a hydrate thereof.
<2> In powder X-ray diffraction, methyl N- [, characterized by having a diffraction peak at a diffraction angle (2θ ± 0.2 °) of 8.2 °, 16.5 ° and / or 24.5 ° Crystal of 3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid.
<3> In powder X-ray diffraction, methyl N- [, characterized by having a diffraction peak at a diffraction angle (2θ ± 0.2 °) of 9.4 °, 16.8 ° and / or 23.3 ° Crystal of 3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid.
<4> In powder X-ray diffraction, methyl N- [, characterized by having a diffraction peak at a diffraction angle (2θ ± 0.2 °) of 8.6 °, 9.1 ° and / or 23.2 ° 3- (6,7-Dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrate crystals.
<5> In powder X-ray diffraction, a diffraction angle (2θ ± 0.2 °) having a diffraction peak at 7.0 °, 10.4 ° and / or 12.6 ° is methyl N- [ 3- (6,7-Dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrate crystals.
<6> In powder X-ray diffraction, methyl N- [, characterized by having diffraction peaks at diffraction angles (2θ ± 0.2 °) of 5.4 °, 10.9 ° and / or 11.9 ° 3- (6,7-Dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrate crystals.
<7> Amorphous of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid.
<8> Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid salt or hydrate thereof.
<9> Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid inorganic acid salt or hydrate thereof.
<10> Organic acid salt of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid or a hydrate thereof.
<11> Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazoline-4] according to <9>, wherein the inorganic acid salt is hydrochloride, hydrobromide, sulfate or phosphate -Yl) phenyl] terephthalamic acid inorganic acid salt or hydrate thereof.
<12> Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl according to <10>, wherein the organic acid salt is methanesulfonate or p-toluenesulfonate. ] A terephthalic acid organic acid salt or a hydrate thereof.
<13> Methyl N- [3- (6,7-dimethoxy, characterized by having a peak at a chemical shift of about 146.19 ppm, about 102.78 ppm and / or about 27.47 ppm in a ¹³ C solid state NMR spectrum. Crystal of 2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid.

  According to the present invention, crystals, amorphous, salts and hydrates of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid are as follows: It has a PDE4 inhibitory action and is useful for the treatment of allergic diseases such as atopic dermatitis.

4 is a diagram illustrating a powder X-ray diffraction pattern of crystals obtained in Example 2. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of crystals obtained in Example 3. FIG. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of the crystal obtained in Example 4. 6 is a diagram illustrating a powder X-ray diffraction pattern of crystals obtained in Example 5. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of crystals obtained in Example 6. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of an amorphous material obtained in Example 7. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of the crystal obtained in Example 8. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of hydrochloride obtained in Example 9. FIG. 2 is a diagram illustrating a powder X-ray diffraction pattern of a hydrobromide obtained in Example 10. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of a sulfate obtained in Example 11. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of methanesulfonate obtained in Example 12. FIG. 4 is a diagram illustrating a powder X-ray diffraction pattern of p-toluenesulfonate obtained in Example 13. FIG. 6 is a diagram illustrating a powder X-ray diffraction pattern of phosphorus hydrochloride obtained in Example 14. FIG. It is a figure which shows the frequency | count of the curettage action of an oxazolone induction mouse | mouth. It is a figure which shows the result of the skin symptom findings (after 1 day) of an oxazolone induction mouse | mouth. 3 is a diagram illustrating a ¹³ C solid state NMR spectrum of the crystal obtained in Example 2. FIG.

  The contents of the present invention will be described in detail below.

The first crystal of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid has a diffraction angle (2θ ± 0.2) in powder X-ray diffraction. °) Has diffraction peaks at 8.2 °, 16.5 ° and / or 24.5 °. The crystals have a peak at a chemical shift of about 146.19 ppm, about 102.78 ppm and / or about 27.47 ppm in the ¹³ C solid state NMR spectrum.

  The second crystal of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid has a diffraction angle (2θ ± 0.2) in powder X-ray diffraction. °) Has diffraction peaks at 9.4 °, 16.8 ° and / or 23.3 °.

  The first crystal of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrate has a diffraction angle of 2θ in powder X-ray diffraction. ± 0.2 °) with diffraction peaks at 8.6 °, 9.1 ° and / or 23.2 °.

  A second crystal of hydrate of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid has a diffraction angle (2θ) in powder X-ray diffraction. ± 0.2 °) has diffraction peaks at 7.0 °, 10.4 ° and / or 12.6 °.

  A third crystal of hydrate of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid has a diffraction angle (2θ in powder X-ray diffraction). ± 0.2 °) has diffraction peaks at 5.4 °, 10.9 ° and / or 11.9 °.

  In general, the diffraction angle (2θ) in powder X-ray diffraction may cause an error within a range of ± 0.2 °. Therefore, the value of the diffraction angle includes a value within a range of about ± 0.2 °. Need to be understood. Therefore, the present invention includes not only a crystal in which the diffraction angle in powder X-ray diffraction completely matches but also a crystal in which the diffraction angle matches within an error range of ± 0.2 °.

  Further, “having a diffraction peak at diffraction angle (2θ ± 0.2 °) α °, β ° and / or γ °” means having at least one diffraction peak among the diffraction peaks.

In ^{general, 13} C solid state NMR chemical shifts in the spectrum (ppm) is from can occur some ^{errors, 13} C solid state NMR peaks in the spectrum (chemical shift) not only completely crystallized match, normal measurement conditions or the, A ¹³ C solid state NMR spectrum measurement is performed under substantially the same conditions as in the specification, and it means a crystal having a peak with substantially the same chemical shift, but specifically within a range of about ± 0.5 ppm. It is understood that the numerical value of is also included. That is, the present invention includes not only crystals in which the peak (chemical shift) in the ¹³ C solid state NMR spectrum completely coincides but also crystals in which the peak (chemical shift) coincides with an error of about ± 0.5 ppm.

  Further, “having a peak at a chemical shift of about α ppm, about β ppm and / or about γ ppm” means having at least one of the chemical shift peaks.

  Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid can be produced, for example, by the method described in Example 1 below.

The first crystals of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid are methyl N- [3- (6,7-dimethoxy-2 -Methylaminoquinazolin-4-yl) phenyl] terephthalamic acid can be dissolved in acetonitrile and then precipitated to produce crystals. More specifically, methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved in acetonitrile at room temperature or under heating, and the solution is dissolved at 4 ° C. Slow cooling to room temperature to precipitate crystals.
The amount of acetonitrile is the lower limit of the amount of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolved by heating, and the yield of crystals is significantly reduced. The amount not to be used can be appropriately selected as the upper limit.
The heating temperature may be appropriately selected at a temperature at which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolves, preferably from 50 ° C. The reflux temperature of the recrystallization solvent. The slow cooling rate can be performed at 5 to 30 ° C./hour. More specifically, it can be produced according to the method described in Example 2 below. Also, it can be produced according to the method described in Example 8 below.

The second crystal of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is methyl N- [3- (6,7-dimethoxy-2 -Methylaminoquinazolin-4-yl) phenyl] terephthalamic acid can be prepared by dissolving in 2-propanol and then precipitating crystals. More specifically, methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved in 2-propanol at room temperature or under heating, Crystals are precipitated by slow cooling from 4 ° C. to room temperature.
The amount of 2-propanol is the lower limit of the amount of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolved by heating, and the yield of crystals is An amount that does not significantly decrease can be appropriately selected as the upper limit. The heating temperature may be appropriately selected at a temperature at which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolves, preferably from 50 ° C. The reflux temperature of the recrystallization solvent. The slow cooling rate can be performed at 5 to 30 ° C./hour.
More specifically, it can be produced according to the method described in Example 3 below.

The first crystals of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrate are methyl N- [3- (6,7 -Dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid can be dissolved in acetone and then precipitated to produce crystals. More specifically, methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved in acetone at room temperature or under heating, and this solution is dissolved at 4 ° C. Slow cooling to room temperature to precipitate crystals.
The amount of acetone is the lower limit of the amount of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolved by heating, and the yield of crystals is significantly reduced. The amount not to be used can be appropriately selected as the upper limit.
The heating temperature may be appropriately selected at a temperature at which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolves, preferably from 50 ° C. The reflux temperature of the recrystallization solvent. The slow cooling rate can be performed at 5 to 30 ° C./hour.
More specifically, it can be produced according to the method described in Example 4 below.

A second crystal of the hydrate of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is methyl N- [3- (6,7 -Dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid can be prepared by dissolving crystals in methanol and then precipitating crystals.
More specifically, methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved in methanol at room temperature or under heating, and this solution is dissolved at 4 ° C. Slow cooling to room temperature to precipitate crystals. The amount of methanol is the lower limit of the amount by which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved by heating, and the yield of crystals is significantly reduced. The amount not to be used can be appropriately selected as the upper limit.
The heating temperature may be appropriately selected at a temperature at which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolves, preferably from 50 ° C. The reflux temperature of the recrystallization solvent. The slow cooling rate can be performed at 5 to 30 ° C./hour.
More specifically, it can be produced according to the method described in Example 5 below.

The third crystal of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrate is methyl N- [3- (6,7 -Dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved in tetrohydrofuran and then precipitated to produce crystals. More specifically, methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved in tetrohydrofuran at room temperature or under heating, Crystals are precipitated by slow cooling from 4 ° C. to room temperature. Water may be added during crystallization. The amount of tetrohydrofuran is the lower limit of the amount of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolved by heating, and the yield of crystals is An amount that does not significantly decrease can be appropriately selected as the upper limit.
The heating temperature may be appropriately selected at a temperature at which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolves, preferably from 50 ° C. The reflux temperature of the recrystallization solvent. The slow cooling rate can be performed at 5 to 30 ° C./hour.
When water is added, the amount is 0.1 to 10 times (v) methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. / W) is preferably used. More specifically, it can be produced according to the method described in Example 6 below.

The third crystal of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrate is methyl N- [3- (6,7 -Dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved in tetrohydrofuran and then precipitated to produce crystals. More specifically, methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved in tetrohydrofuran at room temperature or under heating, Crystals are precipitated by slow cooling from 4 ° C. to room temperature. Water may be added during crystallization. The amount of tetrahydrofuran is the lower limit of the amount of methyl N- [3- (6,7- dimethoxy-2-methyl-quinazoline-4-yl) phenyl] terephthalamide Mick acid is dissolved by heating, amorphous body The amount that does not significantly reduce the yield of can be selected as the upper limit.
The heating temperature may be appropriately selected at a temperature at which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolves, preferably from 50 ° C. The reflux temperature of the recrystallization solvent. The slow cooling rate can be performed at 5 to 30 ° C./hour.
When water is added, the amount is 0.1 to 10 times (v) methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. / W) is preferably used. More specifically, it can be produced according to the method described in Example 6 below.

  The methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid used in the above production method is an anhydrous or hydrated substance. It may be any crystal or amorphous material, or a mixture thereof.

  The salt of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is methyl N- [3- (6,7-dimethoxy-2-methylamino). There is no particular limitation as long as it forms a salt with quinazolin-4-yl) phenyl] terephthalamic acid and is pharmacologically acceptable. For example, inorganic acid salt, organic acid salt, inorganic base salt, organic salt Examples include basic salts, acidic or basic amino acid salts, and the like. Salt hydrates are also included within the scope of the present invention.

  Preferable examples of the inorganic acid salt include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and particularly preferable hydrochloride, hydrobromide, sulfate or phosphate. It is. Preferable examples of the organic acid salt include, for example, acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, ethanesulfone. Acid salts, p-toluenesulfonates, benzenesulfonates and the like are mentioned, and methanesulfonate and p-toluenesulfonate are particularly preferable.

  Preferable examples of inorganic base salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, ammonium salts and the like, and preferable examples of organic base salts Examples thereof include diethylamine salt, diethanolamine salt, meglumine salt, N, N′-dibenzylethylenediamine salt and the like.

  Preferred examples of the acidic amino acid salt include aspartate and glutamate, and preferred examples of the basic amino acid salt include arginine salt, lysine salt, ornithine salt and the like.

  The salt or hydrate of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is methyl N- [3- (6,7-dimethoxy- 2-Methylaminoquinazolin-4-yl) phenyl] terephthalamic acid and a predetermined acid or base can be dissolved in a solvent, and then the salt can be precipitated from this solution. More specifically, methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid and a solvent are mixed at room temperature or under heating, and further a predetermined acid or Add base and dissolve. The solution is gradually cooled to 4 ° C. to room temperature to precipitate a salt.

The solvent is not particularly limited as long as it dissolves methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid and a predetermined acid or base. Sulfoxide is preferred. The amount of solvent is not particularly limited, but the lower limit is the amount by which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid is dissolved by heating, and the yield of salt Can be appropriately selected as the upper limit.
The heating temperature may be appropriately selected at a temperature at which methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid dissolves, preferably from 50 ° C. The reflux temperature of the recrystallization solvent. The slow cooling rate can be performed at 5 to 30 ° C./hour.
The amount of the acid or base can be used in an amount of 0.1 to 10 equivalents relative to methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. In more detail, it can manufacture according to the method as described in the following Examples 9-14.

  The methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid used in the above production method is an anhydrous or hydrated substance. It may be any crystal or amorphous material, or a mixture thereof.

  When the crystal, amorphous form, salt or salt hydrate of the present invention is used as a medicine, the crystal, amorphous form, salt or salt hydrate of the present invention and an appropriate additive are generally used. Use blended and formulated products. However, the above does not deny that the crystal, amorphous form, salt or salt hydrate of the present invention is used as a raw material as a medicament.

  Examples of the additive include excipients, binders, lubricants, disintegrating agents, coloring agents, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents, etc. Examples include tonicity agents, buffering agents, preservatives, antioxidants, stabilizers, absorption promoters, and the like, and these can be used in appropriate combinations as desired.

Examples of the excipient include lactose, sucrose, glucose, corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminate metasilicate, Examples thereof include calcium hydrogen phosphate.
Examples of the binder include polyvinyl alcohol, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, macrogol and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, colloidal silica and the like.
Examples of the disintegrant include crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl Examples include starch and sodium carboxymethyl starch.
Examples of the colorant include those allowed to be added to pharmaceuticals such as iron sesquioxide, yellow sesquioxide, carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake, etc. Can be mentioned.
Examples of the flavoring agent include cocoa powder, mint brain, aroma powder, mint oil, dragon brain, and cinnamon powder.
Examples of the emulsifier or surfactant include stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, glyceryl monostearate, sucrose fatty acid ester, and glycerin fatty acid ester.
Examples of the solubilizer include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polysorbate 80, nicotinamide, and the like.
Examples of the suspending agent include hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose in addition to the surfactant.
Examples of the isotonic agent include glucose, sodium chloride, mannitol, sorbitol and the like.
Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate.
Examples of the preservative include methyl paraben, propyl paraben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.
Examples of the stabilizer include those generally used in medicine.
As said absorption promoter, what is generally used for a pharmaceutical can be mentioned.

In addition, the above preparations include oral preparations such as tablets, powders, granules, capsules, syrups, troches, inhalants; suppositories, ointments, eye ointments, tapes, eye drops, nasal drops. In addition, external preparations such as ear drops, poultices, lotions and injections can be mentioned, and an external preparation is preferred because it acts directly on the affected area.
The oral preparation is formulated by appropriately combining the additives. In addition, you may coat these surfaces as needed.
Among the above-mentioned additives, the above external preparations are particularly excipients, binders, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents, isotonic agents, preservatives, antioxidants, Formulation is made by appropriately combining stabilizers or absorption promoters.
Among the above-mentioned additives, the above injection is an emulsifier, surfactant, solubilizer, suspending agent, isotonic agent, buffer, preservative, antioxidant, stabilizer or absorption enhancer. Formulate with appropriate combination.

  The dose of the medicament according to the present invention varies depending on the degree of symptoms, age, sex, body weight, dosage form / salt type, sensitivity difference to the drug, specific type of disease, etc. Is about 30 μg to 10 g (preferably 0.1 mg to 100 mg) of crystals, amorphous substance, salt or salt hydrate by oral administration per day, and 30 μg to 20 g (preferably 100 μg to 10 g) of crystal, amorphous, salt or salt hydrate, in the case of injection, 30 μg to 1 g (preferably 100 μg to 500 mg) of crystal, amorphous, salt or salt Hydrate is used once daily or divided into 2-6 doses.

  The crystal form, amorphous body, salt and salt hydrate according to the present invention can be produced, for example, by the methods described in the following production examples and examples. However, these are illustrative, and the compound of the present invention is not limited to the following specific examples in any case.

The powder X-ray diffraction was measured under the following conditions in accordance with the powder X-ray diffraction measurement method described in the Japanese Pharmacopoeia general test method.
(apparatus)
Science X-ray DTA system: RINT-2000 (manufactured by Rigaku Corporation)
(Method of operation)
The sample was pulverized in an agate bowl, sampled on a copper substrate, and measured under the following conditions.
X-ray used: CuKα tube voltage: 40 kV
Tube current: 200 mA
Divergent slit: 0.3 mm
Scattering slit: 1/2 deg
Scanning speed: 2 ° / min Scanning step: 0.02 °
Measurement range (2θ): 5-40 °

２，４−ジクロロ−６，７−ジメトキシキナゾリン ２５ｇをトルエン：テトラヒドロフラン：２規定炭酸ナトリウム溶液＝１：１：１の混合溶液２．２５Ｌに懸濁した。反応液に３−アミノフェニルホウ素酸１／２硫酸塩２１．５ｇを加えて、混合液を脱気し窒素置換した。反応液にテトラキス（トリフェニルホスフィン）パラジウム（０）２．２３ｇを加え窒素雰囲気下６０℃にて撹拌した。反応開始から１８時間後、反応液に１．２ｇのテトラキス（トリフェニルホスフィン）パラジウム（０）を加え撹拌を継続し、３０時間後さらに１．２ｇのテトラキス（トリフェニルホスフィン）パラジウム（０）を加え撹拌を継続した。反応開始から４８時間後、反応液を冷却後分液ロートに移し有機層を分取した。得られた有機層を飽和食塩水３００ｍｌで洗浄後、無水硫酸マグネシウムで乾燥し２５０ｇのシリカゲルを通して乾燥剤を除去した。シリカゲルを１．５Ｌの酢酸エチルで洗浄し、得られた有機層を合わせて濃縮乾固した。残渣を２００ｍＬの酢酸エチルでトリチュレーションし得られた固体を濾過した。固体をジエチルエーテル１００ｍＬおよびｎ−ヘプタン：酢酸エチル＝１：１の混合溶液２００ｍＬで洗浄し通風乾燥し目的物２８．２ｇを得た。収率９２．５％。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：３．８６（３Ｈ，ｓ），４．０１（３Ｈ，ｓ），５．４０（２Ｈ，ｂｒ），６．７９（１Ｈ，ｄｄ，Ｊ＝１．６，８．０Ｈｚ），６．９３（１Ｈ，ｂｒｄ，Ｊ＝８．０Ｈｚ），７．０２（１Ｈ，ｔ，Ｊ＝１．６Ｈｚ），７．２４（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．４１（１Ｈ，ｓ），７．４３（１Ｈ，ｓ）．Production Example 1
Synthesis of 3- (2-chloro-6,7-dimethoxy-quinazolin-4-yl) phenylamine

25 g of 2,4-dichloro-6,7-dimethoxyquinazoline was suspended in 2.25 L of a mixed solution of toluene: tetrahydrofuran: 2N sodium carbonate solution = 1: 1: 1. To the reaction solution, 21.5 g of 3-aminophenylboronic acid 1/2 sulfate was added, and the mixture was degassed and purged with nitrogen. To the reaction solution, tetrakis (triphenylphosphine) palladium (0) (2.23 g) was added and stirred at 60 ° C. in a nitrogen atmosphere. 18 hours after the start of the reaction, 1.2 g of tetrakis (triphenylphosphine) palladium (0) was added to the reaction solution, and stirring was continued. After 30 hours, an additional 1.2 g of tetrakis (triphenylphosphine) palladium (0) was added. In addition, stirring was continued. 48 hours after the start of the reaction, the reaction solution was cooled and transferred to a separatory funnel to separate the organic layer. The obtained organic layer was washed with 300 ml of saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was removed through 250 g of silica gel. The silica gel was washed with 1.5 L of ethyl acetate, and the resulting organic layers were combined and concentrated to dryness. The residue was triturated with 200 mL of ethyl acetate and the resulting solid was filtered. The solid was washed with 100 mL of diethyl ether and 200 mL of a mixed solution of n-heptane: ethyl acetate = 1: 1 and dried by ventilation to obtain 28.2 g of the desired product. Yield 92.5%.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.86 (3H, s), 4.01 (3H, s), 5.40 (2H, br), 6.79 (1H, dd, J = 1.6, 8.0 Hz), 6.93 (1H, brd, J = 8.0 Hz), 7.02 (1H, t, J = 1.6 Hz), 7.24 (1H, t, J = 8.0 Hz), 7.41 (1H, s), 7.43 (1H, s).

３−（２−クロロ−６，７−ジメトキシキナゾリン−４−イル）フェニルアミン １４ｇをテトラヒドロフラン：イソプロパノール＝２：１の混合液１３５ｍＬに懸濁し、反応液にメチルアミンのメタノール溶液８９ｍＬを加え、反応液を耐圧封管反応容器中で１３０℃にて２４時間撹拌した。反応液を室温に冷却後、３００ｍＬの酢酸エチルで希釈し、３００ｍＬの水で洗浄した。水層を１００ｍＬの酢酸エチルで抽出し、有機層を合わせて１００ｍLの飽和食塩水で洗浄した。有機層を分離し無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、濃縮乾固し、酢酸エチル：テトラヒドロフラン＝３：１の混合溶媒中でトリチュレーションした。得られた固体を濾過し、酢酸エチルで洗浄後通風乾燥し目的物１０ｇを得た。濾液を５０ｇのシリカゲルカラムに吸着させ、酢酸エチル：メタノール＝９：１の混合溶液で溶離後濃縮乾固した。残渣を酢酸エチル中でトリチュレーションし得られた固体を濾過、ジエチルエーテルで洗浄後通風乾燥し目的物１．４ｇを得た。収率合わせて８２．９％
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ（ｐｐｍ）：３．１２（３Ｈ，ｄ，Ｊ＝５．２Ｈｚ），３．８０（２Ｈ，ｂｒｓ），３．８２（３Ｈ，ｓ），４．０３（３Ｈ，ｓ），５．３０（１Ｈ，ｂｒ），６．８３（１Ｈ，ｄｄ，Ｊ＝１．６，８．０Ｈｚ），６．９９（１Ｈ，ｔ，Ｊ＝１．６Ｈｚ），７．０４（１Ｈ，ｂｒｄ，Ｊ＝８．０Ｈｚ），７．０７（１Ｈ，ｓ），７．１５（１Ｈ，ｓ），７．３０（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ）．Production Example 2
Synthesis of [4- (3-aminophenyl) -6,7-dimethoxyquinazolin-2-yl] methylamine

14 g of 3- (2-chloro-6,7-dimethoxyquinazolin-4-yl) phenylamine was suspended in 135 mL of a mixed solution of tetrahydrofuran: isopropanol = 2: 1, and 89 mL of a methanol solution of methylamine was added to the reaction solution to react. The liquid was stirred at 130 ° C. for 24 hours in a pressure sealed tube reaction vessel. The reaction solution was cooled to room temperature, diluted with 300 mL of ethyl acetate, and washed with 300 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate, and the organic layers were combined and washed with 100 mL of saturated brine. The organic layer was separated and dried over anhydrous magnesium sulfate. The desiccant was filtered off, concentrated to dryness, and triturated in a mixed solvent of ethyl acetate: tetrahydrofuran = 3: 1. The obtained solid was filtered, washed with ethyl acetate, and then dried by ventilation to obtain 10 g of the desired product. The filtrate was adsorbed onto a 50 g silica gel column, eluted with a mixed solution of ethyl acetate: methanol = 9: 1, and concentrated to dryness. The residue was triturated in ethyl acetate, and the resulting solid was filtered, washed with diethyl ether and dried by ventilation to obtain 1.4 g of the desired product. Combined yield 82.9%
¹ H-NMR (CDCl ₃ ) δ (ppm): 3.12 (3H, d, J = 5.2 Hz), 3.80 (2H, brs), 3.82 (3H, s), 4.03 ( 3H, s), 5.30 (1H, br), 6.83 (1H, dd, J = 1.6, 8.0 Hz), 6.99 (1H, t, J = 1.6 Hz), 7. 04 (1H, brd, J = 8.0 Hz), 7.07 (1H, s), 7.15 (1H, s), 7.30 (1H, t, J = 8.0 Hz).

Production Example 3
Alternative method of 3- (2-chloro-6,7-dimethoxy-quinazolin-4-yl) phenylamine (Production Example 1) Under nitrogen flow, 634 g (5.98 mol) of sodium carbonate and 2.91 kg of water The solution was stirred and dissolved. To this solution was added 3.0 L of tetrahydrofuran, 431 g (2.78 mol) of 3-aminophenylboronic acid monohydrate, 30.4 g (0.116 mol) of triphenylphosphine, and 26.0 g of dichloropalladium. (0.116 mol) was added sequentially. While stirring this mixture at 60 ° C., a solution of 2,4-dichloro-6,7-dimethoxyquinazoline 600 g (2.32 mol) in tetrahydrofuran (12.0 L) was added dropwise over 2 hours, and at the same temperature for 16 hours. Stir. To the reaction solution, 3.0 kg of 5% saline and 12.0 L of tetrahydrofuran were sequentially added, and the mixture was stirred at 50 ° C. for 1 hour and then cooled to 25 ° C. The reaction solution was filtered through Celite to remove insoluble matters, and the filtrate was transferred to a separator to separate the organic layer. 150 g of anhydrous magnesium sulfate and 60.0 g of activated carbon were added to the obtained organic layer, stirred at 50 ° C. for 1 hour, and then cooled to 25 ° C. The mixture was filtered through Celite to remove insolubles, and the filtrate was concentrated under reduced pressure. After adding 6.0 L of water to the residue and stirring at room temperature for 1 hour, the precipitated crystals were filtered. The obtained crystals were dried under reduced pressure at 50 ° C. to obtain 730 g (content ratio: 62.2%) of the desired product. Yield 62.1%.

Production Example 4
Alternative Method of [4- (3-Aminophenyl) -6,7-dimethoxyquinazolin-2-yl] methylamine (Production Example 2) 3- (2-Chloro-6,7-dimethoxyquinazolin-4-yl) phenyl 200 g of crude amine (content 124 g: 0.394 mol) was suspended in a mixed solution of 1.2 L of tetrahydrofuran and 0.6 L of isopropanol, and 1.2 L of a methanol solution of methylamine was added thereto, and the mixture was added in 90 SUS autoclave. Stir at 15 ° C. for 15 hours. The reaction solution was cooled to 25 ° C. and concentrated under reduced pressure. To the residue were added 1.0 L of water and 4.0 L of chloroform, and the mixture was stirred at 50 ° C. for 0.5 hour and then cooled to 25 ° C. The reaction solution was filtered through Celite to remove insoluble matters, and the filtrate was transferred to a separator to separate the organic layer. To the obtained organic layer, 50.0 g of anhydrous magnesium sulfate and 20.0 g of activated carbon were added, stirred at 50 ° C. for 1 hour, and then cooled to 25 ° C. The mixture was filtered through Celite to remove insolubles, and the filtrate was concentrated under reduced pressure. To the residue, 904 mL of chloroform was added and stirred at 50 ° C. for 1 hour, and then the heat source was turned off and stirred overnight. Subsequently, the mixture was stirred for 2 hours under ice cooling, and the precipitated crystals were filtered. The obtained crystals were dried under reduced pressure at 50 ° C. to obtain 76.3 g of the desired product.
Yield 38.7%.

Production Example 5
Synthesis of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid

(1) Preparation of [monomethyl terephthalate / N, N-diisopropylethylamine] solution Under nitrogen flow, 1.997 kg (11.08 mol) of monomethyl terephthalate and 15.60 kg of 1,2-dimethoxyethane were suspended. The suspension was stirred while cooling at a jacket temperature of 10 ° C., and 400 mL (5.17 mol) of N, N-dimethylformamide was added thereto, and then 1.323 kg (10.56 mol) of thionyl chloride was added. Washed with 1.00 L of 2-dimethoxyethane. The suspension was heated and stirred at 60 to 73 ° C. for 1 hour and 2 minutes, and then stirred while cooling. While this solution was cooled at a jacket temperature of 0 ° C., 1.36 kg (10.52 mol) of N, N-diisopropylethylamine was added dropwise, and the vessel was washed with 1.00 L of 1,2-dimethoxyethane. Next, the reaction solution was stirred at a jacket temperature of 25 ° C., and stirring was stopped 38 minutes after the internal temperature reached 20 ° C. The reaction liquid was transferred to a plastic container and weighed to obtain 22.00 kg of a [terephthalic acid monomethyl chloride / N, N-diisopropylethylamine] solution (content of terephthalic acid monomethyl chloride: 1.84 kg) as a slightly yellowish brown solution.

(2) Synthesis of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid [4- (3-aminophenyl ] under nitrogen flow ) -6,7-Dimethoxyquinazolin-2-yl] methylamine (2.000 kg, 6.39 mol) and tetrahydrofuran (71.14 kg) were stirred while cooling at a jacket temperature of 0 ° C. To this suspension, 16.70 kg of [terephthalic acid monomethyl chloride / N, N-diisopropylethylamine] solution (content of terephthalic acid monomethyl chloride: 1.40 kg, 7.03 mol) was added dropwise over 1 hour and 26 minutes. After washing with 1.40 L of 1,2-dimethoxyethane, the mixture was stirred at 0 ° C. for 13 hours and 4 minutes. To this reaction mixture, 36.5 kg of ethyl acetate was added under cooling at 0 ° C., and then 80.1 kg of 5% sodium bicarbonate water was added dropwise, followed by stirring at a jacket temperature of 20 ° C. for 1 hour and 10 minutes. 37.3 kg of ethyl acetate was added, and after stirring, the aqueous layer was separated. The organic layer was washed successively with 40.0 kg of 5% saline, 40.2 kg of water and 40.1 kg of water. The organic layer was concentrated under reduced pressure at a jacket temperature of 40 ° C., and 23.70 kg of methanol was added to the concentrated residue, followed by stirring for 1 hour and 1 minute while heating to 60 to 66 ° C. While stirring this suspension at a jacket temperature of 50 ° C., 23.60 kg of 2-propanol was added dropwise over 1 hour. Then, after slow cooling at 10 ° C / hour, the mixture was stirred at a jacket temperature of 20 ° C for 12 hours and 23 minutes. The precipitated crystals were collected by filtration, washed with a mixed solution of 3.00 L of methanol and 3.00 L of 2-propanol, and further washed with 6.00 L of 2-propanol to obtain 5.52 kg of a crude product of the target product. (Wet body, target product content: 2.57 kg, 5.44 mol) was obtained as pale yellow crystals (yield 85.3%).
Under a nitrogen stream, a suspension of 5.398 kg (target product content: 2.518 kg, 5.33 mol) of a crude product (wet product) and 8.01 L of dimethyl sulfoxide was heated and stirred at 60 to 70 ° C. under a nitrogen stream. Crystals were dissolved. This solution was clarified and rinsed with 2.00 L of dimethyl sulfoxide. The filtrate was transferred to a 210 L reactor previously heated at a jacket temperature of 60 ° C. and washed with 2.01 L of dimethyl sulfoxide. After 18.9 kg of 2-propanol was added dropwise to this solution over 40 minutes, 15.02 g of the target crystal of the target product was added, and 9.44 kg of 2-propanol was added dropwise over 57 minutes. The suspension was stirred at 60 ° C. for 1 hour and 30 minutes, and then the jacket temperature was set to 80 ° C. and heating and stirring was continued for 37 hours and 24 minutes. Next, 56.6 kg of 2-propanol was added dropwise over 2 hours and 8 minutes, and the mixture was gradually cooled to 20 ° C. (10 ° C./hour), and then stirred at the same temperature for 65 hours and 50 minutes. The precipitated crystals were collected by filtration, and the crystals were washed with a mixed solution of 534 mL of dimethyl sulfoxide and 4.81 L of 2-propanol, and further washed with 8.01 L of 2-propanol. The obtained crystals were dried under reduced pressure at a jacket temperature of 50 ° C. to obtain 2.30 kg of the desired product as yellow crystals (yield 90.8%).

［４−（３−アミノフェニル）−６，７−ジメトキシキナゾリン−２−イル］メチルアミン １６．８ｇとピリジン８．６ｇとをテトラヒドロフラン３００ｍＬに溶解させたものに、４−クロロカルボニル安息香酸 メチルエステル１１．８ｇを室温にて加え、反応液を２４時間攪拌した。反応液にジメチルスルホキシド１００ｍＬを加えた後、反応液を酢酸エチル２０００ｍＬ−テトラヒドロフラン１０００ｍＬの混合溶媒と飽和重曹水１０００ｍＬで分配し、有機層を分取した。水層をさらに酢酸エチル５００ｍＬ−テトラヒドロフラン５００ｍＬの混合溶媒で抽出した後、合わせた有機層を飽和重曹水１０００ｍＬ、飽和食塩水１０００ｍＬの順で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を塩基性シリカゲルパッド１００ｇで濾去し、酢酸エチル２０００ｍＬで洗い込んだ。集めた溶出液を減圧濃縮し、得られた粗生成物をテトラヒドロフラン１００ｍＬ−ジエチルエーテル５００ｍＬの混合溶媒に懸濁させてトリチュレーションした。析出した結晶を濾取し、ジエチルエーテル１００ｍＬで２回洗浄後、５０℃にて５時間通風乾燥し、表記化合物の結晶１３．８ｇ（収率５３．２％）を得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８８（３Ｈ，ｄ，Ｊ＝４．４Ｈｚ），３．７４（３Ｈ，ｓ），３．８９（３Ｈ，ｓ），３．９２（３Ｈ，ｓ），６．９９（１Ｈ，ｓ），７．００（１Ｈ，ｂｒｓ），７．１７（１Ｈ，ｓ），７．４６（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５５（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．８７（１Ｈ，ｂｒｄ，Ｊ＝８．０Ｈｚ），８．０８（４Ｈ，ｓ），８．２０（１Ｈ，ｂｒｓ），１０．６１（１Ｈ，ｓ）．Example 1
Synthesis of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid

4-chlorocarbonylbenzoic acid methyl ester was obtained by dissolving 16.8 g of [4- (3-aminophenyl) -6,7-dimethoxyquinazolin-2-yl] methylamine and 8.6 g of pyridine in 300 mL of tetrahydrofuran. 11.8 g was added at room temperature and the reaction was stirred for 24 hours. After adding 100 mL of dimethyl sulfoxide to the reaction solution, the reaction solution was partitioned with a mixed solvent of 2000 mL of ethyl acetate-1000 mL of tetrahydrofuran and 1000 mL of saturated aqueous sodium bicarbonate, and the organic layer was separated. The aqueous layer was further extracted with a mixed solvent of 500 mL of ethyl acetate-500 mL of tetrahydrofuran, and the combined organic layer was washed with 1000 mL of saturated aqueous sodium bicarbonate and 1000 mL of saturated brine in that order and dried over anhydrous magnesium sulfate. The desiccant was filtered off with 100 g of basic silica gel pad and washed with 2000 mL of ethyl acetate. The collected eluate was concentrated under reduced pressure, and the obtained crude product was suspended in a mixed solvent of tetrahydrofuran 100 mL-diethyl ether 500 mL and triturated. The precipitated crystals were collected by filtration, washed twice with 100 mL of diethyl ether, and then dried by ventilation at 50 ° C. for 5 hours to obtain 13.8 g (yield 53.2%) of the title compound crystals.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.88 (3H, d, J = 4.4 Hz), 3.74 (3H, s), 3.89 (3H, s), 3. 92 (3H, s), 6.99 (1H, s), 7.00 (1H, brs), 7.17 (1H, s), 7.46 (1H, d, J = 8.0 Hz), 7 .55 (1H, t, J = 8.0 Hz), 7.87 (1H, brd, J = 8.0 Hz), 8.08 (4H, s), 8.20 (1H, brs), 10.61 (1H, s).

Example 2
Anhydrous crystals 1 of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (Example 1)
975 mL of acetonitrile was added to 75.28 mg of the compound obtained in Example 1, dissolved by heating in an oil bath, and cooled to room temperature. The precipitate was collected by filtration and dried overnight at 50 ° C. to obtain the title crystal.
The main X-ray diffraction angles (2θ) of this material were 8.2 °, 16.5 ° and 24.5 °. The X-ray diffraction pattern is shown in FIG.

Example 3
Anhydrous crystals 2 of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (Example 1)
To 52.93 mg of the compound obtained in Example 1, 12 mL of 2-propanol was added, dissolved by heating in an oil bath, and cooled to room temperature. The precipitate was collected by filtration and dried overnight at 50 ° C. to obtain the title crystal.
The main X-ray diffraction angles (2θ) of this material were 9.4 °, 16.8 ° and 23.3 °. An X-ray diffraction pattern is shown in FIG.

Example 4
Hydrate crystal 1 of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (Example 1)
To 75.71 mg of the compound obtained in Example 1, 15 mL of acetone was added, dissolved by heating in an oil bath, and cooled to room temperature. The precipitate was collected by filtration and dried overnight at 50 ° C. to obtain the title crystal.
The main X-ray diffraction angles (2θ) of this material were 8.6 °, 9.1 ° and 23.2 °. This X-ray diffraction pattern is shown in FIG.

Example 5
Hydrate crystal 2 of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (Example 1)
To 75.88 mg of the compound obtained in Example 1, 16 mL of methanol was added, dissolved by heating in an oil bath, and cooled to room temperature. The precipitate was collected by filtration and dried overnight at 50 ° C. to obtain the title crystal.
The main X-ray diffraction angles (2θ) of this material were 7.0 °, 10.4 °, and 12.6 °. This X-ray diffraction pattern is shown in FIG.

Example 6
Hydrate crystal 3 of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (Example 1)
To 49.90 mg of the compound obtained in Example 1, 2 mL of tetrahydrofuran was added, dissolved by heating in an oil bath, cooled to room temperature, and further 10 mL of water was added and allowed to stand. The precipitate was collected by filtration and dried overnight at 50 ° C. to obtain the title crystal.
The main X-ray diffraction angles (2θ) of this material were 5.4 °, 10.9 °, and 11.9 °. This X-ray diffraction pattern is shown in FIG.

Example 7
Amorphous of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (Example 1) Compound obtained in Example 1 To 36.49 mg, 0.2 mL of dimethyl sulfoxide was added and dissolved. Further, 10 mL of water was added and allowed to stand. The precipitate was collected by filtration and dried overnight at 50 ° C. to obtain the title amorphous.
The X-ray diffraction pattern of this material is shown in FIG.

Example 8
Another method for producing anhydrous crystal 1 of methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (Example 1) Monomethyl terephthalate A suspension of 10.00 g (55.51 mmol) and 1,2-dimethoxyethane 90 mL was stirred while being cooled in a cold water bath at 10 ° C., and 2.0 mL of N, N-dimethylformamide and 6.61 g of thionyl chloride were added thereto. (52.75 mmol) was added sequentially. The suspension was heated and stirred at 60 to 65 ° C. for 1 hour, allowed to cool, and further stirred while cooling in an ice-water bath. To this solution, 6.83 g (52.82 mmol) of diisopropylethylamine was added dropwise. Subsequently, the reaction solution was stirred at room temperature, and stirring was stopped 30 minutes after the internal temperature reached 20 ° C. The reaction solution was transferred to a 200 mL eggplant flask and weighed to obtain 109.49 g of a [terephthalic acid monomethyl chloride / diisopropylethylamine] mixed solution (content of terephthalic acid monomethyl chloride: 8.89 g) as a slightly yellowish brown solution.

  Subsequently, a suspension of 9.50 g (30.00 mmol) of [4- (3-aminophenyl) -6,7-dimethoxyquinazolin-2-yl] methylamine and 380 mL of tetrahydrofuran was stirred while cooling at 0 ° C. . To this suspension, 80.71 g of the above-mentioned [terephthalic acid monomethyl chloride / diisopropylethylamine] mixed solution (terephthalic acid monomethyl chloride content 6.55 g, 33.00 mmol) was added dropwise over 1 hour, followed by stirring at 0 ° C. for 11 hours. . To this reaction mixture, 190 mL of ethyl acetate was added under cooling at 0 ° C., and 380 g of 5% sodium bicarbonate water was added dropwise. The reaction solution was transferred to a separatory funnel and washed with 190 mL of ethyl acetate. After extraction, the organic layer was separated and washed sequentially with 190 g of 5% brine and 190 mL of water (twice). The organic layer was concentrated under reduced pressure at 40 ° C., 143 mL of methanol was added to the concentrated residue, and the mixture was stirred while heating to 40 ° C. The oil bath setting was changed to 75 ° C. 33 minutes after the start of stirring, and the oil bath setting was changed to 50 ° C. 30 minutes after the internal temperature exceeded 60 ° C. When the internal temperature dropped to 55 ° C, 143 mL of 2-propanol was added dropwise. Then, after gradually cooling to an internal temperature of 27.3 ° C., the mixture was stirred at 20 ° C. for 17 hours. The precipitated crystals were subjected to suction filtration, and washed with a mixed solution of 14.3 mL of methanol and 14.3 mL of 2-propanol. Liquid was removed by suction for 10 minutes in a vacuum line to obtain 15.72 g (wet body, content of target product 13.31 g) of the target product as pale yellow crystals (yield 93.9%).

A suspension of 15.48 g (target product content: 13.11 g, 27.00 mmol) of a crude product (wet product) of the target product and 40 mL of dimethyl sulfoxide was heated and stirred at 60 ° C. to dissolve the crystals. The solution was clarified and washed with 10 mL of dimethyl sulfoxide. The filtrate was transferred to a 1000 mL four-neck glass container that had been heated in advance with a 60 ° C. warm water jacket, washed with 10 mL of dimethyl sulfoxide, and then stirred while heating at 60 ° C. After dropping 119 mL of 2-propanol into this solution, 49.3 mg of the target seed crystal was added, and 60 mL of 2-propanol was further added dropwise. The suspension was stirred at 60 ° C. for 2 hours, and then the jacket temperature was set to 80 ° C. and heating and stirring was continued for 16.5 hours. Next, 120 mL of 2-propanol was added dropwise, and after 3 hours, 362 mL of 2-propanol was further added dropwise, followed by slow cooling to 20 ° C. (10 ° C./hour) and stirring at the same temperature. After 59.5 hours, the precipitated crystals were collected by filtration, washed with a mixed solution of 2.6 mL of dimethyl sulfoxide and 24 mL of 2-propanol, further washed with 40 mL of 2-propanol, and then removed by suction with a vacuum line. Liquid. The obtained crystals were dried under reduced pressure to obtain 9.84 g of the desired product as yellow crystals (yield 73.7%).
The X-ray diffraction pattern of this material is shown in FIG.

Example 9
Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrochloride Methyl N- [3- (6,7-dimethoxy-2-] Dimethyl sulfoxide (1 mL) and hydrochloric acid (22 μL) were added to (methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (99.37 mg). After heating, dimethyl sulfoxide (2 mL) was added and dissolved, 2-propanol (3 mL) was added, and the mixture was cooled to room temperature and solidified. The solid was collected by filtration to obtain the title compound (88.65 mg).
X-ray diffraction data (diffraction angle (2θ) / relative intensity): 10.52 ° / 100, 13.52 ° / 23, 14.58 ° / 38, 15.98 ° / 22, 23.32 ° / 23, 24.16 ° / 43, 24.94 ° / 37, 25.98 ° / 29, 26.24 ° / 49, 27.38 ° / 41. Among these, particularly characteristic peaks are 10.52 ° and 14.58 °. An X-ray diffraction pattern is shown in FIG.

Example 10
Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid hydrobromide Methyl N- [3- (6,7-dimethoxy Dimethylsulfoxide (1 mL) and hydrobromic acid (40 μL) were added to 2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (100.90 mg). While warming, 2-propanol (5 mL) was added and cooled to room temperature to solidify. The solid was collected by filtration to obtain the title compound (108.92 mg).
X-ray diffraction data (diffraction angle (2θ) / relative intensity): 7.00 ° / 61, 8.92 ° / 21, 10.44 ° / 100, 13.38 ° / 24, 16.94 ° / 25, 17.30 ° / 23, 18.86 ° / 21, 21.18 ° / 21, 21.82 ° / 25, 23.10 ° / 30, 25.98 ° / 37. Among these, particularly characteristic peaks are 7.00 °, 8.92 ° and 10.44 °. An X-ray diffraction pattern is shown in FIG.

Example 11
Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid sulfate Methyl N- [3- (6,7-dimethoxy-2-] Dimethyl sulfoxide (1 mL) and sulfuric acid (26 μL) were added to (methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (103.92 mg). After heating and dissolving, 2-propanol (3 mL) was added and cooled to room temperature to solidify. The solid was collected by filtration to obtain the title compound (112.12 mg).
X-ray diffraction data (diffraction angle (2θ) / relative intensity): 4.42 ° / 68, 6.76 ° / 100, 7.46 ° / 44, 8.22 ° / 34, 17.88 ° / 33, 22.98 ° / 38. Among these, particularly characteristic peaks are 4.42 °, 6.76 °, and 7.46 °. An X-ray diffraction pattern is shown in FIG.

Example 12
Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid methanesulfonate Methyl N- [3- (6,7-dimethoxy- Dimethylsulfoxide (1 mL) and methanesulfonic acid (22 μL) were added to 2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (98.58 mg). After heating, dimethyl sulfoxide (1.5 mL) was added and dissolved, and then 2-propanol (15 mL) was added and cooled to room temperature to solidify. The solid was collected by filtration to obtain the title compound (119.47 mg).
X-ray diffraction data (diffraction angle (2θ) / relative intensity): 4.92 ° / 46, 8.72 ° / 100, 9.36 ° / 50, 16.90 ° / 79, 17.56 ° / 54, 19.78 ° / 52. Among these, particularly characteristic peaks are 4.92 °, 8.72 ° and 19.78 °. An X-ray diffraction pattern is shown in FIG.

Example 13
Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid p-toluenesulfonate Methyl N- [3- ( 6,7- Dimethyl sulfoxide (1 mL) and p-toluenesulfonic acid monohydrate (47.98 mg) were added to dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (106.56 mg). After heating and dissolving, 2-propanol (5 mL) was added and cooled to room temperature to solidify. The solid was collected by filtration to obtain the title compound (57.34 mg).
X-ray diffraction data (diffraction angle (2θ) / relative intensity): 6.60 ° / 100, 9.24 ° / 10, 14.12 ° / 13, 14.64 ° / 15, 20.06 ° / 14, 23.56 ° / 21. Among these, particularly characteristic peaks are 6.60 °, 9.24 ° and 14.12 °. The X-ray diffraction pattern is shown in FIG.

Example 14
Methyl N- [3- (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid phosphate Methyl N- [3- (6,7-dimethoxy-2) -Methylaminoquinazolin-4-yl) phenyl] terephthalamic acid (96.52 mg) was added with dimethyl sulfoxide (1 mL) and phosphoric acid (25 μL). Dimethyl sulfoxide (0.75 mL) was added under heating and dissolved, and then 2-propanol (2 mL) was added and cooled to room temperature to solidify. The solid was collected by filtration to obtain the title compound (114.15 mg).
X-ray diffraction data (diffraction angle (2θ) / relative intensity): 4.10 ° / 100, 5.12 ° / 83, 8.38 ° / 51, 12.16 ° / 17, 17.98 ° / 50, 18.44 ° / 35. Among these, particularly characteristic peaks are 4.10 °, 5.12 °, and 8.38 °. An X-ray diffraction pattern is shown in FIG.

The ¹³ C solid state NMR spectrum of the resulting crystals in a ¹³ C solid state NMR measurements Example 2 spectra were measured under the following conditions. The spectrum is shown in FIG. 16 and the chemical shifts are summarized in Table 1. Characteristic peaks were observed at 146.19 ppm, 102.78 ppm and 27.47 ppm.
Measuring device: AVANCE400 (Bruker)
Probe: 7mm-CP / MAS (Bruker)
Sample rotation speed: 5000 Hz
Measurement method: CP / TOSS method Contact time: 1 millisecond waiting time: 3 seconds Integration number: 5120
External standard: The chemical shift of the carbonyl carbon of glycine was 176.03 ppm.

[Pharmacological test example]
In order to confirm the effect of the compound of Example 1 as an antipruritic agent, the present inventors conducted the following test.

Test example 1
Evaluation of compounds in oxazolone-induced curettage behavior model <Test method>
As test animals, commercially available 5-week-old NC / Nga female mice (Japan SLC) were used. After a 7 day pre-breeding period for habituation, animals that showed no change in general condition and showed a steady weight gain were used in the study.

1) Sensitization and induction sensitization were carried out once in 6-week-old mice after the acclimation period, and 0.5% 4-ethoxymethylene-2-phenyl-2-oxazoline-5 in the left and right auricles of the mice, respectively. This was carried out by applying 20 μL of an acetone (Wako Pure Chemical Industries, Ltd.) solution containing ON (hereinafter abbreviated as “oxazolone”, Sigma).
Induction is 5 times after sensitization, 2 or 3 days after sensitization, and 3 or 3 days after the above-mentioned day, 3 times in total, 10 μL of 0.3% oxazolone in the left auricle This was done by applying.

2) Measurement of curettage behavior Curettage behavior was automatically measured using a Micro Act device (Neuroscience) for objective evaluation. A piece of magnet (diameter 1 mm, length 3 mm, Neuroscience) was inserted into the subcutaneous skin of the left hind paw of anesthetized diethyl ether (Wako Pure Chemical Industries, Ltd.) by the day before the measurement at the latest. After inducing curettage behavior by applying oxazolone, the mouse was immediately transferred to a coiled chamber (diameter 11 cm, height 18 cm), and the current induced by the movement of the magnet inserted into the mouse foot was measured for a certain period of time. A characteristic waveform reflecting curettage behavior was detected with a Micro Act device, and the frequency of appearance of the detected waveform was counted as the number of curettage behaviors.

  3) Evaluation of test substance

Preparation of test compound: The compound of Example 1 was prepared to a concentration of 0.3% with respect to the mixed solvent (acetone: ethanol = 1: 1).
As the group composition of the test substance, the following three groups : (1) Normal group: mixed solvent (acetone: ethanol = 1: 1) applied group, (2) Control group: mixed solvent (acetone: ethanol = 1: 1) applied Group, (3) The compound application group of Example 1 was set. The mice in each group were divided into groups so that the number of curettages was uniform based on the number of curettages at the time of the second induction.

  Evaluation of test material: The test substance (normal group and control group was applied only with mixed solvent (acetone: ethanol = 1: 1)) was administered at 10 μL 1 hour before the third oxazolone application. Evaluation was carried out using the number of curettages for 2 hours after induction by the third application of oxazolone (the Normal group was applied with a mixed solvent (acetone: ethanol = 1: 1)) as an index. At the same time, evaluation by skin symptoms was performed. That is, 0 to 3 points (0; 0) for each of the items (1) “scratch” and (2) “bleeding / sputum”, which are findings related to curettage behavior on the day before the third application and one day after application or four days after There were no symptoms, 1; mild, 2; moderate, 3; severe), and curettage behavior was evaluated using the difference in scores before and after induction of oxazolone as an index. In addition, scoring was carried out for each item, and the total of them was used as the individual's score.

<Test results>
1) The measurement result of the number of curettage is shown in FIG. (In FIG. 14, the Normal group has n = 11, and the other groups have n = 17.)
2) FIG. 15 shows the measurement results of the skin symptom findings. FIG. 15 is a graph showing the value obtained by subtracting the score before administration from the score one day after administration. (In FIG. 15, n = 11 for the Normal group and n = 17 for the other groups.)
From the above results, it is shown that the compound of Example 1 has an excellent antipruritic effect because it suppresses curettage behavior and suppresses deterioration of skin symptoms caused by curettage behavior. It was.

Test example 2
Drug Metabolizing Enzyme (CYP) Inducibility Evaluation Experiment Using Human Frozen Hepatocytes <Test Procedure>
Human frozen hepatocytes (XenoTech) were rapidly thawed while being stirred at 37 ° C., and living cells were collected using Hepatocytes Isolation Kit (Nippon Agricultural Industrial Co., Ltd.). The obtained hepatocytes were diluted with ice-cooled William's Medium E (10% FBS, + PSG) to 5 × 10 ⁵ cells / mL, and 1 × 10 ⁵ in a 48-well collagen-coated plate (BD Biosciences). ^The cells were seeded at ⁵ cells / cm ² and cultured at 37 ° C. and 5% CO ₂ for 24 hours. Thereafter, the cultured hepatocytes were replaced with Hepato-STIM (registered trademark: BD Biosciences) (+ EGF, PSG, -FBS), and further cultured under conditions of 37 ° C. and 5% CO ₂ for 24 hours. Thereafter, a diluted solution of the test compound, β-naphthoflavone (SIGMA) as a positive control for human CYP1A or rifampicin (Wako Pure Chemical Industries, Ltd.) as a positive control for human CYP3A4 was added to the hepatocytes, respectively, at 37 ° C. The cells were cultured for about 48 hours under 5% CO ₂ conditions. The test compound or each positive control diluted solution was replaced with a new one every 24 hours. The test compound and the positive control were prepared with dimethyl sulfoxide (DMSO: Wako Pure Chemical Industries, Ltd.), and the test compound diluted solution (final concentration: 1 μM, 3 μM, 10 μM) and the positive control diluted solution (final concentration: 10 μM). ) Were prepared using Hepato-STIM (+ EGF, PSG, -FBS), respectively. In all treatments, the final concentration of DMSO was adjusted to 0.1% with respect to Hepato-STIM (+ EGF, PSG, -FBS). As a control, DMSO was added to Hepato-STIM (+ EGF, PSG, -FBS) so that the final concentration was 0.1%. After completion of the culture, the hepatocytes were washed once with PBS, and then total RNA was purified using Total RNA Purification Kit (Applied Biosystems). The purified total RNA was reverse transcribed using TaqMan Reverse Transcription Reagents (Applied Biosystems) to synthesize cDNA.
Oligo dT was used for cDNA synthesis, and the reaction was carried out at 25 ° C. for 10 minutes using Gene Amp PCR system 9700, followed by reaction at 48 ° C. for 60 minutes, and reverse transcriptase was inactivated at 95 ° C. for 10 minutes. . Quantification of CYP1A1 and GAPDH mRNA was performed by ABI7900 (Applied Biosystems) using SYBR Green PCR Core Reagents Kit (Applied Biosystems). Quantification of CYP1A2 and CYP3A4 mRNA was performed with ABI7900 (Applied Biosystems) using Taqman PCR Core Reagents Kit (Applied Biosystems). The primer sequences and PCR conditions used for PCR for mRNA quantification are shown in Tables 2 and 3, respectively.
Primer sequence

ＰＣＲ条件

PCR conditions

※変性、アニーリング、伸長反応を１サイクルとして、５０サイクル繰り返した。

* Denaturation, annealing, and extension reaction were taken as one cycle and repeated 50 cycles.

<Calculation of CYP induction ability>
The CYP1A1 induction ability of the test compound was calculated as follows.
CYP1A1 inducibility of test compound (%) = {[(Amount of CYP1A1 mRNA when test compound is added) / (Amount of GAPDH mRNA when test compound is added)] / [(Amount of CYP1A1 mRNA when DMSO control is added) / (Amount of GAPDH mRNA when DMSO control is added)]-1} / {[(Amount of CYP1A1 mRNA when positive control is added) / (Amount of GAPDH mRNA when positive control is added)] / [(DMSO control when added) CYP1A1 mRNA amount) / (GAPDH mRNA amount when DMSO control is added)]-1} × 100
The induction ability of CYP1A2 and CYP3A4 was calculated in the same manner.

<Test results>
The results of the compound of Example 1 are shown in Table 4. As a comparative example, the compound described in Example 1 of WO99 / 37622 (4- (3-benzoylaminophenyl) -6,7-dimethoxy-2-methylaminoquinazoline) was used.

  From the above results, it was shown that the compound according to Example 1 had a lower CYP induction ability than the compound of Comparative Example.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a crystal, an amorphous body, a salt, and a salt hydrate of a compound that is a useful drug against itching such as atopic disease.

Claims (6)

In the powder X-ray diffraction, the diffraction angle (2θ ± 0.2 °) 8.2 ° , characterized by having a diffraction peak at 16.5 ° and 2 4.5 °, methyl N- [3- Crystals of (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. In the powder X-ray diffraction, the diffraction angle (2θ ± 0.2 °) 9.4 ° , characterized by having a diffraction peak at 16.8 ° and 2 3.3 °, methyl N- [3- Crystals of (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. In the powder X-ray diffraction, the diffraction angle (2θ ± 0.2 °) 8.6 ° , characterized by having a diffraction peak at 9.1 ° and 2 3.2 °, methyl N- [3- Crystal of hydrate of (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. In the powder X-ray diffraction, the diffraction angle (2θ ± 0.2 °) 7.0 ° , characterized by having a diffraction peak at 10.4 ° and 1 2.6 °, methyl N- [3- Crystal of hydrate of (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. In the powder X-ray diffraction, the diffraction angle (2θ ± 0.2 °) 5.4 ° , characterized by having a diffraction peak at 10.9 ° and 1 1.9 °, methyl N- [3- Crystal of hydrate of (6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid. In a ¹³ C solid state NMR spectra, chemical shifts 146.19Ppm, characterized by having a peak at 102.78ppm and 2 7.47Ppm, methyl N- [3- (6,7- dimethoxy-2-methylamino Quinazolin-4-yl) phenyl] terephthalamic acid crystals.

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