WO2012026434A1 - 三環性ピラゾロピリミジン誘導体の結晶 - Google Patents
三環性ピラゾロピリミジン誘導体の結晶 Download PDFInfo
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- WO2012026434A1 WO2012026434A1 PCT/JP2011/068890 JP2011068890W WO2012026434A1 WO 2012026434 A1 WO2012026434 A1 WO 2012026434A1 JP 2011068890 W JP2011068890 W JP 2011068890W WO 2012026434 A1 WO2012026434 A1 WO 2012026434A1
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- chloro
- methoxy
- thia
- ray diffraction
- amino
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- ZXQDKZYIRFMRMW-UHFFFAOYSA-N CC1(C)OC(CC(c(c(Cl)nc(N)n2)c2Cl)O)CO1 Chemical compound CC1(C)OC(CC(c(c(Cl)nc(N)n2)c2Cl)O)CO1 ZXQDKZYIRFMRMW-UHFFFAOYSA-N 0.000 description 1
- POQQJDCUZHDJHR-YFUCEKMRSA-N CCC(COC)/C=N\[C@H](C)[C@H](C)CCl Chemical compound CCC(COC)/C=N\[C@H](C)[C@H](C)CCl POQQJDCUZHDJHR-YFUCEKMRSA-N 0.000 description 1
- LTJSIGKQZAIKKM-UHFFFAOYSA-N Cc(cnc(C[n]1nc2c3c1nc(N)nc3SCC(CC(NC)=O)=C2)c1Cl)c1OC Chemical compound Cc(cnc(C[n]1nc2c3c1nc(N)nc3SCC(CC(NC)=O)=C2)c1Cl)c1OC LTJSIGKQZAIKKM-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—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 three hetero rings
- C07D495/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Definitions
- the present invention relates to a hydrochloride of a compound having a tricyclic pyrazolopyrimidine skeleton that inhibits the action of heat shock protein 90 (heat shock protein 90, HSP90).
- HSP90 is a major chaperone protein in the cell.
- a chaperone protein is a protein that binds to various proteins and assists the folding of the bound proteins.
- a group of proteins that require HSP90 for folding is collectively referred to as HSP90 client protein (HSP90 client protein).
- HSP90 In addition to HSP90, the folding mechanism of client proteins by HSP90 involves a plurality of proteins such as cochaperone, partner protein, and immunophilin, and these cooperate to form HSP90 client. Although it is thought to assist protein folding (Non-Patent Document 1), the details have not yet been fully elucidated.
- HSP90 client protein forms a complex with HSP90, co-chaperone, etc., and then undergoes a conformational change, and is considered to be matured. If it is not normally folded by HSP90, it is ubiquitinated and proteasome It is considered to be decomposed (Non-Patent Document 1 to Non-Patent Document 4).
- HSP90 inhibitors have been used as candidates for therapeutic agents for various diseases (for example, neurodegenerative diseases such as cancer, Alzheimer's disease, cardiovascular diseases, infectious diseases, autoimmune diseases or diseases associated with cell damage due to apoptosis). It is expected (Non-Patent Document 2).
- HSP90 inhibitors are expected as candidates for anticancer drugs.
- HSP90 client proteins a plurality of proteins involved in the development and enhancement of cancer such as Her2, Raf, Akt, and telomerase are known as HSP90 client proteins (Non-patent Document 1).
- HSP90 is a protein that is present not only in cancer cells but also in normal cells. Compared to normal cells, HSP90 has a higher affinity for client proteins in cancer cells and also has an ATPase activity necessary for its chaperone activity.
- Non-Patent Documents 1 to 3 HSP90 inhibitors can simultaneously inactivate a plurality of cancer-related proteins specifically in cancer cells, and are expected as candidates for anticancer agents having a strong and wide antitumor spectrum.
- Non-patent Document 1 to Non-patent Document As HSP90 inhibitors, geldanamycin, herbimycin, 17-allylaminogeldanamycin, 17-AAG, etc. have been known for some time (Non-patent Document 1 to Non-patent Document). Reference 4). These compounds inhibit the function of HSP90 as a chaperone protein by binding to the ATP binding pocket on the N-terminal side of HSP90 and inhibiting the binding of HSP90 and ATP. In addition to the above, various compounds have been reported as compounds that inhibit HSP90 (Patent Document 1, Patent Document 2, Patent Document 3, Non-Patent Document 5, and Non-Patent Document 6), and tricyclic pyrazolo. A pyrimidine derivative has also been reported (Patent Document 4).
- Patent Documents 5 to 5 9
- Non-Patent Document 7 9
- Non-Patent Document 8 9
- Tricyclic pyrazolopyrimidine derivatives exhibit excellent HSP90 inhibitory activity and are expected to be used as pharmaceuticals, particularly as anticancer agents. Furthermore, if it is possible to improve the effectiveness by improving the physical properties such as solubility of these derivatives to enhance the absorbability, or to reduce the side effects by reducing the dose, The usefulness is further improved.
- substances used in pharmaceuticals are required to have a particularly high purity so that unexpected side effects (for example, toxicity) due to the impurities do not occur.
- the present inventors have improved solubility, purity, stability, etc. in order to inhibit the ATPase activity of HSP90 and enhance the medical usefulness of a tricyclic pyrazolopyrimidine derivative, which is a novel compound exhibiting antitumor activity.
- the inventors have intensively studied the salt of the derivative including its production.
- dihydrochloride and monohydrochloride that are more soluble than the tricyclic pyrazolopyrimidine derivative itself (free form) are not only superior in solubility, but also have a lower impurity content and a residual solvent content.
- the monohydrochloride of the tricyclic pyrazolopyrimidine derivative was found which is excellent in stability in addition. Furthermore, a method for reliably producing each of these salts was established, and the present invention was completed.
- 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2,7-dihydro-6-thia has HSP90 inhibitory activity
- the more soluble dihydrochloride and monohydrochloride of -1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide are provided.
- monohydrochloride having a low impurity content, a small amount of residual solvent, and excellent stability is also provided.
- the compounds of the present invention are useful as antitumor agents.
- FIG. 4 is a powder X-ray diffraction pattern of the crystal obtained in Example 2.
- the vertical axis (the numerical values attached to the scales are 0, 10, 20, 30, 40 in order from the bottom) indicates the diffraction intensity (Lin (Counts)), and the horizontal axis (the numerical values attached to the scales are: 3, 10, 20, 30, 40) from the left indicate the value of the diffraction angle 2 ⁇ .
- 4 is a powder X-ray diffraction pattern of the crystals obtained in Example 3.
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 6.
- the vertical axis (the numerical values attached to the scales are 0, 10, 20, 30, 40, 50, 60, 70 in order from the bottom) indicates the diffraction intensity (Lin (Counts)), and the horizontal axis (on the scales).
- FIG. 4 is a diagram in which a peak number is attached to a powder X-ray diffraction pattern of a crystal obtained in Example 2.
- the vertical axis (the numerical values attached to the scales are 0, 10, 20, 30, 40 in order from the bottom) represents the diffraction intensity (Lin (Counts)), and the horizontal axis (the numerical values attached to the scales is the left 3, 10, 20, 30, and 40) indicate the value of the diffraction angle 2 ⁇ .
- FIG. 4 is a diagram in which a peak number is assigned to the powder X-ray diffraction pattern of the crystal obtained in Example 3.
- FIG. 6 is a diagram in which a peak number is assigned to the powder X-ray diffraction pattern of the crystal obtained in Example 6.
- the vertical axis (the numerical values attached to the scales are 0, 10, 20, 30, 40, 50, 60, 70 in order from the bottom) indicates the diffraction intensity (Lin (Counts)), and the horizontal axis (on the scales). In the attached numerical values, 3, 10, 20, 30, 40) in order from the left indicate the value of the diffraction angle 2 ⁇ . 4 is a powder X-ray diffraction pattern of the crystals obtained in Example 1.
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- 4 is a powder X-ray diffraction pattern of the crystal obtained in Example 4.
- FIG. The vertical axis in the figure (the numerical values attached to the scales are 0, 200, 400, 600, 800, 1000, 1200, 1400 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis ( As for the numerical values attached to the scales, 10.000, 20.000, 30.000) in order from the left indicates the value of the diffraction angle 2 ⁇ .
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 5.
- FIG. 7 is a powder X-ray diffraction pattern of the crystals obtained in Example 7.
- the vertical axis (the numerical values attached to the scales are 0, 1000, 2000, 3000, and 4000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the numerical values attached to the scales). Are, in order from the left, 10.000, 20.000, 30.000) the value of the diffraction angle 2 ⁇ .
- FIG. 7 is a powder X-ray diffraction pattern of the crystals obtained in Example 8.
- the vertical axis (numbers attached to the scales are 0, 500, 1000, 1500, 2000 in order from the bottom) indicates the diffraction intensity in counts / seconds (cps), and the horizontal axis (the numerical values attached to the scales).
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 9.
- the vertical axis (numbers attached to the scales are 0, 1000, 2000, 3000, 4000, 5000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the scales are attached).
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 10.
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 11.
- FIG. 6 is a powder X-ray diffraction pattern of the crystals obtained in Example 12.
- FIG. 14 is a powder X-ray diffraction pattern of the crystals obtained in Example 13.
- the vertical axis (the numerical values attached to the scales are 0, 1000, 2000, 3000, 4000, 5000, 6000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (on the scales). In the numerical values attached, 10.000, 20.000, 30.000) in order from the left indicates the value of the diffraction angle 2 ⁇ .
- 14 is a powder X-ray diffraction pattern of the crystals obtained in Example 14.
- the vertical axis (the numerical values attached to the scales are 0, 1000, 2000, 3000, 4000, 5000, 6000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (on the scales). In the numerical values attached, 10.000, 20.000, 30.000) in order from the left indicates the value of the diffraction angle 2 ⁇ .
- 18 is a powder X-ray diffraction pattern of the crystals obtained in Example 15.
- FIG. 14 is a powder X-ray diffraction pattern of the crystals obtained in Example 16.
- the vertical axis (numbers attached to the scales are 0, 1000, 2000, 3000, 4000, 5000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the scales are attached).
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- 18 is a powder X-ray diffraction pattern of the crystals obtained in Example 17.
- the vertical axis (numbers attached to the scales are 0, 1000, 2000, 3000, 4000, 5000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the scales are attached).
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- 18 is a powder X-ray diffraction pattern of the crystals obtained in Example 18.
- the vertical axis (numbers attached to the scales are 0, 1000, 2000, 3000, 4000, 5000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the scales are attached).
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- 20 is a powder X-ray diffraction pattern of the crystals obtained in Example 19.
- the vertical axis (numbers attached to the scales are 0, 1000, 2000, 3000, 4000, 5000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the scales are attached).
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- 20 is a powder X-ray diffraction pattern of the crystals obtained in Example 20.
- the vertical axis (numbers attached to the scales are 0, 500, 1000, 1500, 2000, 2500, 3000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (on the scales). In the numerical values attached, 10.000, 20.000, 30.000) in order from the left indicates the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal obtained in Example 21.
- the vertical axis (numbers attached to the scales are 0, 500, 1000, 1500, 2000, 2500, 3000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (on the scales).
- the vertical axis (the numerical values attached to the scales are 0, 1000, 2000, 3000, and 4000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the numerical values attached to the scales). Are, in order from the left, 10.000, 20.000, 30.000) the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal obtained in Example 24.
- the vertical axis (numbers attached to the scales are 0, 2000, 4000, 6000, and 8000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the numerical values attached to the scales).
- FIG. 26 is a powder X-ray diffraction pattern of the crystals obtained in Example 25.
- the vertical axis (numbers attached to the scales are 0, 1000, 2000, 3000, 4000, 5000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the scales are attached).
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- FIG. 26 is a powder X-ray diffraction pattern of the crystals obtained in Example 26.
- FIG. 14 is a powder X-ray diffraction pattern of the crystals obtained in Example 27.
- the vertical axis (the numerical values attached to the scales are 0, 1000, 2000, 3000, 4000, 5000, 6000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (on the scales).
- 10.000, 20.000, 30.000) in order from the left indicates the value of the diffraction angle 2 ⁇ .
- the powder X-ray diffraction pattern of the crystal obtained in Example 28.
- the vertical axis (the numerical values attached to the scales are 0, 1000, 2000, 3000, and 4000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the numerical values attached to the scales). Are, in order from the left, 10.000, 20.000, 30.000) the value of the diffraction angle 2 ⁇ .
- 20 is a powder X-ray diffraction pattern of the crystals obtained in Example 29.
- the vertical axis (numbers attached to the scales are 0, 500, 1000, 1500, 2000, 2500, 3000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (on the scales). In the numerical values attached, 10.000, 20.000, 30.000) in order from the left indicates the value of the diffraction angle 2 ⁇ .
- 4 is a powder X-ray diffraction pattern of the crystals obtained in Example 30.
- the vertical axis (numbers attached to the scales are 0, 500, 1000, 1500, 2000, 2500, 3000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (on the scales). In the numerical values attached, 10.000, 20.000, 30.000) in order from the left indicates the value of the diffraction angle 2 ⁇ .
- 4 is a powder X-ray diffraction pattern of the crystals obtained in Example 31.
- the vertical axis (numbers attached to the scales are 0, 1000, 2000, 3000, 4000, 5000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the scales are attached).
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- 4 is a powder X-ray diffraction pattern of the crystal obtained in Example 32.
- the vertical axis (numbers attached to the scales are 0, 1000, 2000, 3000, 4000, 5000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the scales are attached).
- the numerical values in order from the left are 10.000, 20.000, 30.000) indicate the value of the diffraction angle 2 ⁇ .
- 4 is a powder X-ray diffraction pattern of the crystals obtained in Example 33.
- the vertical axis (the numerical values attached to the scales are 0, 1000, 2000, 3000, and 4000 in order from the bottom) indicates the diffraction intensity in units of count / second (cps), and the horizontal axis (the numerical values attached to the scales). Are, in order from the left, 10.000, 20.000, 30.000) the value of the diffraction angle 2 ⁇ .
- 2 is a differential scanning calorimetry diagram of the crystal obtained in Example 1.
- the vertical axis represents differential scanning calorimetry (DSC) (mcal / s)
- the horizontal axis represents temperature (° C.).
- FIG. 5 is a differential scanning calorimetry diagram of the crystal obtained in Example 4.
- FIG. 12 is a differential scanning calorimetry diagram of the crystal obtained in Example 11.
- the vertical axis represents differential scanning calorimetry (DSC) (mcal / s)
- the horizontal axis represents temperature (° C.).
- the present invention is the following formula (1)
- a crystal means a solid whose internal structure is made up of regularly repeated constituent atoms (or a group thereof) in a three-dimensional manner, and is distinguished from an amorphous solid that does not have such a regular internal structure.
- crystals of the same compound may produce crystals (crystal polymorphs) having a plurality of different internal structures and physicochemical properties depending on the crystallization conditions. Any form may be sufficient and the mixture of two or more crystal polymorphs may be sufficient.
- the crystal of the present invention shown as a preferred crystal form below is present only when the crystal form is included, when it is included in a mixture with other crystals, or when included in a mixture with amorphous. The form does not matter.
- the crystal of the present invention absorbs moisture by being left in the atmosphere, and forms a hydrate by adhering water or heating to 25 to 150 ° C. under normal atmospheric conditions. There is a case. Furthermore, the crystal
- the crystal of the present invention may be represented based on powder X-ray diffraction data.
- powder X-ray diffraction is usually measured and analyzed by a technique used in this field. It can be carried out by the method described in the examples.
- the lattice constant of hydrates and dehydrates changes depending on the attachment and detachment of crystal water, which may change the diffraction angle (2 ⁇ ) in powder X-ray diffraction.
- the intensity of the peak may change due to a difference in crystal growth surface or the like (crystal habit).
- the “characteristic peak” means a peak having a relative intensity of 50 or more when the maximum peak intensity is 100 in the powder X-ray diffraction diagram.
- main peak means a peak having a relative intensity of 15 or more when the maximum peak intensity is 100 in the powder X-ray diffraction diagram.
- Another preferred form of the crystal of the present invention is a monohydrochloride crystal of compound (1).
- the “main peak” means a peak having a relative intensity of 30 or more when the maximum peak intensity is 100 in the powder X-ray diffraction diagram.
- the “main peak” means a peak having a relative intensity of 12 or more when the maximum peak intensity is 100 in the powder X-ray diffraction diagram.
- the solvent used is 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2,7-dihydro-6-thia-1,2,3.
- 5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide and hydrogen chloride are not particularly limited as long as they dissolve to some extent and do not inhibit hydrochloric acid chlorination.
- solvents examples include hydrocarbons such as pentane, hexane, heptane, octane, isooctane, cyclohexane, methylcyclohexane, benzene, toluene, xylene; halogenated compounds such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and the like.
- Hydrocarbons ethers such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methylcyclopentyl ether; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, etc.
- Esters ; acetone, methyl ethyl ketone, cyclopentanone, cyclohexanone and other ketones; acetonitrile, propionitrile and other nitriles; N, N- Methylformamide, N, N-dimethylacetamide, N, N′-dimethylimidazolidinone, amides such as hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide; methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol Alcohol, water, and a mixture thereof, and the like, preferably ketones, alcohols, water, or a mixture thereof, more preferably alcohols, water, or a mixture thereof. More preferably, it is methanol, ethanol, water, or a mixture thereof.
- the concentration of the hydrogen chloride solution to be used is not particularly limited, but is usually from 0.1 mol / L to a saturated solution, preferably from 0.5 mol / L to a saturated solution.
- the temperature of hydrochloric acid chloride is not particularly limited as long as the solvent to be used is not solidified, but is usually ⁇ 70 ° C. to 70 ° C., preferably ⁇ 20 ° C. to 50 ° C.
- the amount of hydrogen chloride used is usually 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2, 7-Dihydro-6-thia-1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide is not particularly limited as long as it is in an amount necessary for dihydrochlorination. However, it is usually 2 to 100 equivalents, preferably 2 to 20 equivalents, more preferably 2 to 10 equivalents.
- the amount of hydrogen chloride used is 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2,7- Dihydro-6-thia-1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide is less than the amount necessary for monohydrochlorination and the amount of dihydrochloride is not precipitated. If there is no particular limitation. The amount depends on the type of solvent used, the amount of solvent used, and the temperature, and is usually 1 equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents, more preferably 1 equivalent to 3 equivalents. .
- seed crystals When producing dihydrochloride, seed crystals may be added.
- the timing for adding seed crystals is not particularly limited, but is usually added in the vicinity of the hydrogen chloride concentration at which dihydrochloride is supersaturated.
- the hydrogen chloride concentration varies depending on the solvent composition, it is usually necessary to add about 2 equivalents or more of hydrogen chloride.
- 0.0000001 equivalent or more and 1 equivalent or less Preferably it is 0.000001 equivalent or more and 0.5 equivalent or less, More preferably, it is 0.00001 equivalent or more and 0.1 equivalent or less. is there.
- a seed crystal of monohydrochloride to be obtained may be added.
- the timing for adding seed crystals is not particularly limited, but is usually added in the vicinity of the hydrogen chloride concentration at which monohydrochloride is supersaturated.
- the hydrogen chloride concentration varies depending on the solvent composition, it is usually necessary to add about 1 equivalent of hydrogen chloride.
- 0.0000001 equivalent or more and 1 equivalent or less Preferably it is 0.000001 equivalent or more and 0.5 equivalent or less, More preferably, it is 0.00001 equivalent or more and 0.1 equivalent or less. is there.
- the amount of hydrogen chloride to be added is divided into 2 to 10 times little by little near the hydrogen chloride concentration at which the hydrochloride is supersaturated in the reaction solution. Thus, it is desirable to gradually increase the hydrogen chloride concentration.
- the crystal having the powder X-ray diffraction pattern shown in FIG. 3 was excellent in stability, and the amount of residual solvent in the crystal, for example, the amount of residual ethanol in the crystal was low.
- the amount of residual solvent in the crystal is preferably 6000 ppm or less, and more preferably 5000 ppm or less.
- Another aspect of the present invention is a medicament containing the hydrochloride or crystal of the present invention as an active ingredient, and an antitumor agent containing the hydrochloride or crystal of the present invention.
- the present invention also relates to a pharmaceutical composition containing the hydrochloride or crystal of the present invention.
- the medicament containing the hydrochloride or crystal of the present invention as an active ingredient is preferably provided in the form of a pharmaceutical composition comprising the crystal of the present invention and one or more pharmaceutically acceptable carriers.
- the dosage form of the medicament of the present invention is not particularly limited and can be administered orally or parenterally, but is preferably administered orally.
- the pharmaceutical composition of the present invention contains at least a part of the hydrochloride or crystal of the present invention as compound (I).
- a crystal form other than the crystal of the present invention may exist as compound (I).
- the proportion of the crystal of the present invention contained in the pharmaceutical composition is in the range of 0.01% to 99.9% by weight, for example, 0.01% by weight with respect to the whole compound (I) in the pharmaceutical composition.
- % Or more 0.05% or more, 0.1% or more, 0.5% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% % By weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 95% by weight, 96% % By weight or more, 97% by weight or more, 98% by weight or more, 99% by weight or more, 99.5% by weight or more, 99.6% by weight or more, 99.7% by weight or more, 99.8% by weight or more, or 99.9% What is necessary is just to contain the weight% or more. Whether or not the crystal of the present invention is contained in the pharmaceutical composition can be confirmed by an instrumental analysis method described herein (for example, powder X-ray diffraction, thermal analysis, infrared absorption spectrum, etc.).
- the hydrochloride or crystal of the present invention can be used as an HSP90 inhibitor, an ATPase activity inhibitor of HSP90, a binding inhibitor of HSP90 and ATP, and a medicament containing the hydrochloride or crystal of the present invention, particularly preferably an anticancer agent. Can be used.
- the ATPase activity of HSP90 can be examined using an ATPase assay commonly used by those skilled in the art.
- the ATPase activity of HSP90 can be detected using recombinant HSP90 protein and ATP in the presence or absence of a test compound.
- the method described in Analytical Biochemistry 327, 176-183 (2004) or Nature 425, 407-410 (2003) may be performed.
- HSP90 expression can be examined using Northern blotting, Western blotting, ELISA or the like commonly used by those skilled in the art. For example, mRNA collected from cells cultured in the presence or absence of the test compound, Northern blotting was performed, and mRNA recovered from cells cultured in the presence of the test compound compared to the absence of the test compound When the amount of HSP90 mRNA is decreased, the test compound is identified as a compound that inhibits the expression of HSP90. Alternatively, for example, Cancer. Res. 65, 6401-6408 (2005), Western blotting may be performed to determine the protein amount of HSP90.
- Inhibition of the binding between HSP90 and the client protein can be examined using, for example, immunoprecipitation and Western blotting that are commonly used by those skilled in the art. Immunoprecipitation and Western blotting are described, for example, in J. Org. Biol. Chem. 277, 10346-10353 (2002).
- the inhibition of the binding between HSP90 and ATP can be examined using, for example, a binding test between labeled ATP and HSP90.
- a binding test between labeled ATP and HSP90 For example, J. et al. Biol. Chem. 272, 18608-18613 (1997) may be performed to examine the binding of HSP90 and labeled ATP in the presence or absence of the test compound.
- Inhibition of conformational change of HSP90 can be examined using, for example, a conformational assay using bis-ANS (1,1′-bis (4-anilino-5-naphthalene sulphonic acid).
- the conformational assay may be performed, for example, by the method described in J. Med. Chem. 47, 3865-3873 (2004).
- the cell growth inhibitory activity can be examined using a growth inhibition test method commonly used by those skilled in the art.
- the cell growth inhibitory activity is performed, for example, by comparing the degree of proliferation of cells (for example, tumor cells) in the presence or absence of the test compound, as described in Test Example 1 below. Can do.
- the degree of proliferation can be examined, for example, using a test system that measures live cells. Examples of the method for measuring living cells include [ 3 H] -thymidine incorporation test, BrdU method, MTT assay and the like.
- the antitumor activity in vivo can be examined using an antitumor test method usually used by those skilled in the art. For example, after transplanting various tumor cells into mice, rats, etc., and confirming the engraftment of the transplanted cells, the compound of the present invention is administered orally, intravenously, etc. The in vivo antitumor activity of the present invention can be confirmed by comparing the tumor growth in the group and the tumor growth in the compound administration group.
- the hydrochloride or crystal of the present invention is used for tumors or cancers such as lung cancer, digestive cancer, ovarian cancer, uterine cancer, breast cancer, liver cancer, head and neck cancer, blood cancer, renal cancer, testicular tumor, prostate cancer, multiple bone marrow. It can be used for the treatment of skin cancer such as melanoma and malignant melanoma, and sarcoma.
- the hydrochloride or crystal of the present invention has an inhibitory action on HSP90, it can be used for the treatment of cancers that are highly dependent on HSP90.
- cancers that are highly dependent on HSP90 include cancers in which HSP90 client protein is overexpressed, cancers in which HSP90 client protein mutations are observed, and more specifically, for example, Her2 , Cancers in which c-Met, Flt3 and the like are overexpressed, and cancers in which mutations such as c-kit, PDGFR, Raf and the like are observed are included, but are not limited thereto.
- HSP90 downstream of HSP90, there are many factor groups (RAS-MAPK, PI3K, telomerase, etc.) that are considered to be involved in cancer. If HSP90 is inhibited, signal transduction to these factors is inhibited. As a result, the activation of the above factor is also inhibited, so that the hydrochloride or crystal of the present invention, which is an HSP90 inhibitor, can be preferably used for treatment of various cancers from this viewpoint.
- RAS-MAPK factor-MAPK
- PI3K PI3K
- telomerase telomerase
- the pharmaceutical composition of the present invention comprises the hydrochloride or crystal of the present invention and a pharmaceutically acceptable carrier, and is used as various injections such as intravenous injection, intramuscular injection and subcutaneous injection, orally or transdermally. It can be administered by various methods such as administration.
- a pharmaceutically acceptable carrier is a pharmaceutical that is involved in transporting a hydrochloride or crystal of the invention or a composition comprising the hydrochloride or crystal of the invention from one organ or organ to another. Means an acceptable material (eg, excipient, diluent, additive, solvent, etc.).
- an appropriate preparation for example, an oral preparation or an injection
- oral preparations include tablets, powders, granules, capsules, pills, troches, solutions, syrups, elixirs, emulsions, and oily or aqueous suspensions.
- oral administration it may be in the free form or in the salt form.
- Aqueous preparations can be prepared by forming an acid adduct with a pharmaceutically acceptable acid or by forming an alkali metal salt such as sodium.
- stabilizers, preservatives or solubilizers can be used in the preparation.
- a solution that may contain these adjuvants and the like may be stored in a container and then prepared as a solid preparation by lyophilization or the like.
- the single dose may be stored in one container, and the multiple doses may be stored in one container.
- solid preparations include tablets, powders, granules, capsules, pills, and lozenges. These solid preparations may contain pharmaceutically acceptable additives along with the hydrochloride salt or crystals of the present invention.
- the additive include fillers, extenders, binders, disintegrants, dissolution accelerators, wetting agents, and lubricants, which are selected and mixed as necessary. And can be formulated.
- liquid preparations include solutions, syrups, elixirs, emulsions, and suspensions. These liquid formulations may contain pharmaceutically acceptable additives along with the hydrochloride salt or crystals of the present invention.
- the additive include a suspending agent or an emulsifier, and these can be selected and mixed as necessary to prepare a formulation.
- the crystal of the present invention can be used in combination with other antitumor agents.
- antitumor antibiotics for example, antitumor antibiotics, antitumor plant components, BRM (biological response control substances), hormones, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents and the like can be mentioned.
- BRM biological response control substances
- hormones for example, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents and the like can be mentioned.
- an alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambutyl, an aziridine alkylating agent such as carbocon or thiotepa, dibromomannitol or dibromodarsi
- alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambutyl
- an aziridine alkylating agent such as carbocon or thiotepa, dibromomannitol or dibromodarsi
- epoxide-based alkylating agents such as Toll, carmustine, lomustine, semustine, nimustine hydrochloride
- nitrosourea-based alkylating agents such as streptozocin, chlorozotocin or ranimustine, busulfan, improsulfan tosylate or dacarbazine.
- antimetabolites include, for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine, and pyrimidine metabolism antagonists such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine And antifolate inhibitors such as methotrexate or trimethrexate.
- purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine
- pyrimidine metabolism antagonists such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine
- antifolate inhibitors such as methotrexate or trimethrexate.
- Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromomycin A3 Or actinomycin D etc. are mentioned.
- anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromomycin A3 Or actinomycin D etc. are mentioned.
- antineoplastic plant component examples include vinca alkaloids such as vindesine, vincristine and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.
- BRM examples include tumor necrosis factor or indomethacin.
- hormones examples include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, phosfestol, ethinylestradiol, chlormadinone, or medroxyprogesterone.
- vitamins examples include vitamin C and vitamin A.
- Antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, sorafenib, etc.
- antitumor agents include, for example, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocartinostatin, Examples include hydroxyurea, ubenimex, and krestin.
- the present invention also includes a cancer prevention method and / or treatment method characterized by administering hydrochloride or crystals.
- the dosage of the pharmaceutical composition containing the hydrochloride or crystal of the present invention as an active ingredient is not particularly limited, and can be appropriately selected according to various conditions such as the age, weight, and symptoms of the patient. 1 mg to 1000 mg per adult, preferably 5 mg to 500 mg, more preferably 5 mg to 300 mg, even more preferably 5 mg to 100 mg, once to several times per day, preferably once or twice per day, depending on symptoms Is desirable.
- 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridine-2) which is a raw material of 5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide hydrochloride -Yl) methyl] -2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide (free form) is, for example, described below It can be produced according to Reference Example 1.
- Methyl 5-chloro-4-methoxy-6-methylnicotinate (1.0 g) was dissolved in 30 ml of methanol, sodium borohydride (1.75 g) was added, and the mixture was heated to reflux for 1 hour. A saturated aqueous ammonium chloride solution was added under ice-cooling, followed by extraction three times with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain the title compound (0.92 g) as an oily substance. .
- Example 1 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2,7-dihydro-6-thia-1,2,3,5-tetra Azabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide dihydrochloride 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2 , 7-dihydro-6-thia-1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide (1.034 g, 2.243 mmol) in ethanol (29.3 ml), Water (0.74 ml) was added and stirred at 25 ° C.
- Example 2 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2,7-dihydro-6-thia-1,2,3,5-tetra Azabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide dihydrochloride 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2 , 7-dihydro-6-thia-1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide (493.48 mg, 1.11 mmol) in acetone (30 mL) 3M hydrochloric acid (369.6 mL) was added dropwise at room temperature with stirring, and the mixture was further stirred for 12 hours. The obtained crystals were collected by filtration, washed with acetone, and dried
- Example 4 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2,7-dihydro-6-thia-1,2,3,5-tetra Azabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide monohydrochloride 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2 , 7-dihydro-6-thia-1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide (3.53 kg, 7.74 mol) in ethanol (123 L) suspension 3M hydrochloric acid prepared by diluting 36.2% concentrated hydrochloric acid (1.75 kg, 17.4 mol) with water (4.5 L) at 21 to 22 ° C.
- Example 7 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2,7-dihydro-6-thia-1,2,3,5-tetra Azabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide monohydrochloride 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2 , 7-Dihydro-6-thia-1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide (2.044 g, 4.584 mmol) was added with ethanol (70 ml).
- Example 9 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2,7-dihydro-6-thia-1,2,3,5-tetra Azabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide monohydrochloride 2- ⁇ 4-amino-2-[(3-chloro-4-methoxy-5-methylpyridin-2-yl) methyl] -2 , 7-dihydro-6-thia-1,2,3,5-tetraazabenzo [cd] azulen-8-yl ⁇ -N-methylacetamide (2.068 g, 4.485 mmol) was added with ethanol (72 ml).
- Example 34 Measurement of powder X-ray diffraction 1 Using a D8 DISCOVER with GADDS CS X-ray diffractometer manufactured by BrukerAXS, the sample was filled in a glass sample holder and measured under the following conditions. ⁇ Analysis conditions> X-ray: Cu K ⁇ 1 / 40kV / 40mA Goniometer: Vertical 2-axis ( ⁇ , ⁇ ) 2 ⁇ measurement range: 3 to 40 °
- FIG. 4 shows a powder X-ray diffraction pattern obtained by measuring the dihydrochloride crystals obtained in Example 2 by the above method. Table 1 shows peaks having a relative intensity of 15 or more when the maximum peak intensity is 100 in FIG.
- FIG. Table 2 shows peaks having a relative intensity of 30 or more when the maximum peak intensity is 100 in FIG.
- FIG. 6 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 6 by the above method.
- Table 3 shows peaks having a relative intensity of 12 or more when the maximum peak intensity is 100 in FIG.
- Example 35 Measurement of powder X-ray diffraction 2 Using a RINT2200V type X-ray diffractometer manufactured by Rigaku Corporation, the sample was filled in a glass sample holder and measured under the following conditions. ⁇ Analysis conditions> X-ray: Cu K ⁇ 1 / 40kV / 40mA Goniometer: Ultimate + Horizontal goniometer type I 2 ⁇ Scanning range: 5-40 °
- FIG. 7 shows a powder X-ray diffraction pattern obtained by measuring the crystals of dihydrochloride obtained in Example 1 by the above method.
- FIG. 8 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystal obtained in Example 4 by the above method.
- FIG. 9 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 5 by the above method.
- FIG. 10 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 7 by the above method.
- FIG. 11 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 8 by the above-described method.
- FIG. 12 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 9 by the above method.
- FIG. 13 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 10 by the above method.
- FIG. 14 shows a powder X-ray diffraction diagram of the monohydrochloride crystals obtained in Example 11 measured by the above method.
- FIG. 15 shows a powder X-ray diffraction pattern of the monohydrochloride crystals obtained in Example 12 measured by the above method.
- FIG. 16 shows a powder X-ray diffraction pattern of the monohydrochloride crystals obtained in Example 13 measured by the above method.
- FIG. 17 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 14 by the aforementioned method.
- FIG. 18 shows a powder X-ray diffraction pattern of the monohydrochloride crystals obtained in Example 15 measured by the above method.
- FIG. 19 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 16 by the aforementioned method.
- FIG. 20 shows a powder X-ray diffraction pattern of the monohydrochloride crystals obtained in Example 17 measured by the above method.
- FIG. 21 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystal obtained in Example 18 by the above method.
- FIG. 22 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 19 by the aforementioned method.
- FIG. 23 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 20 by the aforementioned method.
- FIG. 24 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 21 by the aforementioned method.
- FIG. 25 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride salt obtained in Example 22 by the aforementioned method.
- FIG. 26 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 23 by the aforementioned method.
- FIG. 27 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 24 by the aforementioned method.
- FIG. 28 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystal obtained in Example 25 by the aforementioned method.
- FIG. 29 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 26 by the aforementioned method.
- FIG. 30 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 27 by the aforementioned method.
- FIG. 31 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 28 by the aforementioned method.
- FIG. 32 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystal obtained in Example 29 by the aforementioned method.
- FIG. 33 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 30 by the aforementioned method.
- FIG. 34 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 31 by the aforementioned method.
- FIG. 35 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 32 by the aforementioned method.
- FIG. 36 shows a powder X-ray diffraction pattern obtained by measuring the monohydrochloride crystals obtained in Example 33 by the aforementioned method.
- FIG. 38 shows a differential scanning calorimetry diagram obtained by measuring the monohydrochloride crystals obtained in Example 4 by the above method.
- FIG. 39 shows a differential scanning calorimetry diagram in which the monohydrochloride crystals obtained in Example 11 were measured by the above method.
- Example 38 Purity test and stability test ⁇ Abuse test conditions> Condition 1: 40 ° C, humidity 75% Condition 2: 60 ° C (no humidity control) The sample under the above abuse test conditions was measured by the following high performance liquid chromatograph method. ⁇ Preparation of 20 mM potassium dihydrogen phosphate aqueous solution> 2.72 g of potassium dihydrogen phosphate was dissolved in 1000 ml of water to obtain a 20 mM potassium dihydrogen phosphate aqueous solution.
- ⁇ Analysis conditions> Column: YMC-Pack Pro C18RS, 3.0 mm ID x 150 mm, particle size 3 ⁇ m Column temperature: about 40 ° C Gradient conditions: 0 to 5 minutes, moving bed A: 100 ⁇ 75 / moving bed B: 0 ⁇ 25 5 to 15 minutes, moving bed A: 75 / moving bed B: 25 15 to 45 minutes, moving bed A: 75 ⁇ 0 / moving bed B: 25 ⁇ 100 45-55 minutes, moving bed A: 0 / moving bed B: 100 Flow rate: 0.7 ml / min Measurement range: 0 to 55 minutes Detection wavelength: 240 nm Sample solution injection volume: 5 ⁇ l ⁇ Calculation> 1) The sample solution was injected to obtain the peak area (A) of each related substance and the peak area (T) of the compound (1).
- Rrt represents the relative retention time of the impurity when the retention time of the compound (1) is 1.
- the anti-cell test was performed using two types of cells (human breast cancer-derived cell line SK-BR-3, human lung cancer-derived cell line NCI-H460).
- Each cell was suspended in a medium and seeded in a 96-well multiwell plate at 2000 cells / 150 ⁇ L / well for SK-BR-3 and 500 cells / 150 ⁇ L / well for NCI-H460.
- Compound (1) was dissolved in DMSO and then diluted with a medium to prepare a sample solution (DMSO concentration of 0.5% or less).
- DMSO concentration 0.5% or less
- 50 ⁇ L each of a DMSO-containing medium hereinafter referred to as DMSO diluted solution; DMSO concentration: 0.5% or less
- the MTT assay was performed immediately after and 72 hours after adding the sample solution or DMSO dilution to the cells.
- the MTT assay was performed as follows.
- T / C (%) at each concentration was determined, a dose response curve was drawn, and a 50% growth inhibitory concentration (GI 50 value) was calculated.
- T / C (%) (TS) / (CS) ⁇ 100
- Compound (1) showed a GI 50 value of 13 (nM) for SK-BR-3 cells and 26 (nM) for NCI-H460 cells.
Abstract
Description
[1]下記式(1)
[2][1]に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの2塩酸塩の結晶。
[3]銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、図1に示すX線回折図を有する[2]に記載の結晶。
[4]銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=7.73、24.70、26.01および27.29に特徴的ピークを示す[2]に記載の結晶。
[5]銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=7.73、9.78、12.58、14.36、15.84、16.71、17.17、18.40、19.58、21.31、22.85、23.62、24.13、24.70、26.01、27.29、28.58、29.37、30.65、31.38、33.52、35.25、および36.87に主要ピークを示す[2]または[4]に記載の結晶。
[6][1]に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの1塩酸塩の結晶。
[7]銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、図2に示すX線回折図を有する[6]に記載の結晶。
[8]銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=9.43、12.70、13.03、15.33、16.10、16.84、18.55、20.21、20,89、21.32、22.93、24.73、25.10、25.40、26.10、26.53、26.95、27.60、27.88、28.52、29.63、29.95、31.55、32.13、33.40、34.95、および38.70に主要ピークを示す[6]に記載の結晶。
[9]銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、図3に示す粉末X線回折図を有する[6]に記載の結晶。
[10]銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=8.07、9.45、13.07、15.39、16.16、16.90、20.83、24.29、24.80、28.56、28.85、31.26、32.17、32.87、および34.11に主要ピークを示す[6]に記載の結晶。
[11]エタノール含量が5000ppm以下である[1]に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの塩酸塩の結晶。
[12]塩酸塩が1塩酸塩である[11]に記載の結晶。
[13][1]に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの溶液または懸濁液に塩化水素の溶液を滴下することを特徴とする[1]に記載の塩酸塩の製造方法。
[14]請求項1に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの溶液または懸濁液に2当量以上の塩化水素の溶液を滴下することを特徴とする[2]に記載の2塩酸塩の結晶の製造方法。
[15]請求項1に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの溶液または懸濁液に1当量以上5当量以下の塩化水素の溶液を滴下することを特徴とする[6]に記載の1塩酸塩の結晶の製造方法。
[16][1]に記載の塩酸塩を有効成分として含有する医薬。
[17][1]に記載の塩酸塩を含有する抗腫瘍剤。
[18][2]から[12]のいずれか1に記載の結晶を含有する医薬組成物。
以下に実施例を示し、本発明を詳細に説明する。
(1) 1-(2-アミノ-4,6-ジクロロピリミジン-5-イル)-3-ブテン-1-オール
1H-NMR(DMSO-D6)δ:2.55-2.69(2H,m),4.95-5.09(3H,m),5.37(1H,d,J=4.1Hz),5.67-5.77(1H,m),7.42(2H,s).
(2) 1-(2-アミノ-4,6-ジクロロピリミジン-5-イル)-2-(2,2-ジメチル-[1,3]ジオキソラン-4-イル)エタン-1-オール
1H-NMR(DMSO-D6)δ:1.22-1.32(6H,m),1.72-2.23(2H,m),2.50(1H,s),3.50(1H,td,J=14.2,6.9Hz),4.22-3.92(2H,m),5.06-5.36(2H,m),7.43(2H,d,J=12.8Hz).
ESI-MS m/z:308(M+H)+.
(3) 1-(2-アミノ-4,6-ジクロロピリミジン-5-イル)-2-(2,2-ジメチル-[1,3]ジオキソラン-4-イル)エタン-1-オン
1H-NMR(CDCl3)δ:1.37(3H,s),1.42(3H,s),2.98-3.06(1H,m),3.32-3.40(1H,m),3.67-3.72(1H,m),4.25-4.30(1H,m),4.57-4.64(1H,m),5.72(2H,s).
ESI-MS m/z:306(M+H)+.
(4) 4-クロロ-3-[(2,2-ジメチル-1,3-ジオキソラン-4-イル)メチル]-1-(4-メトキシベンジル)-1H-ピラゾロ[3,4-d]ピリミジン-6-アミン
1H-NMR(CDCl3)δ:1.36(3H,s),1.43(3H,s),3.11(1H,dd,J=14.7,8.1Hz),3.43(1H,dd,J=14.7,5.2Hz),3.73-3.78(4H,m),4.08(1H,dd,J=8.1,6.0Hz),4.54-4.61(1H,m),4.77(2H,br s),5.22(2H,s),6.83(2H,d,J=8.5Hz),7.24(2H,d,J=8.5Hz).
ESI-MS m/z:404(M+H)+.
(5) ジ-tert-ブチル {4-クロロ-3-[(2,2-ジメチル-1,3-ジオキソラン-4-イル)メチル]-1-(4-メトキシベンジル)-1H-ピラゾロ[3,4-d]ピリミジン-6-イル}イミドジカーボネート
1H-NMR(CDCl3)δ:1.37(3H,s),1.40(3H,s),1.44-1.46(18H,m),3.21-3.29(1H,m),3.48-3.55(1H,m),3.74-3.81(4H,m),4.09-4.15(1H,m),4.58-4.66(1H,m),5.48(2H,dd,J=17.3,15.1Hz),6.81(2H,d,J=7.8Hz),7.27-7.30(2H,m).
ESI-MS m/z:604(M+H)+.
(6) ジ-tert-ブチル [4-クロロ-3-(2,3-ジヒドロキシプロピル)-1-(4-メトキシベンジル)-1H-ピラゾロ[3,4-d]ピリミジン-6-イル]イミドジカーボネート
1H-NMR(CDCl3)δ:1.46(18H,s),3.15(1H,d,J=3.7Hz),3.23-3.33(2H,m),3.62-3.82(5H,m),4.26-4.34(1H,m),5.49(2H,t,J=15.9Hz),6.82(2H,d,J=8.1Hz),7.25-7.30(2H,m).
ESI-MS m/z:564(M+H)+.
(7) ジ-tert-ブチル [8-ヒドロキシ-2-(4-メトキシベンジル)-2,7,8,9-テトラヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-4-イル]イミドジカーボネート
1H-NMR(CDCl3)δ:1.45(18H,s),2.39(1H,br s),3.29-3.51(4H,m),4.58(1H,br s),3.76(3H,s),5.42-5.49(2H,m),6.82(2H,d,J=8.6Hz),7.30(2H,d,J=8.6Hz).
ESI-MS m/z:544(M+H)+.
(8) 4-[ビス(tert-ブトキシカルボニル)アミノ]-2-(4-メトキシベンジル)-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル アセテート
1H-NMR(CDCl3)δ:1.44(18H,s),2.26(3H,s),3.77(3H,s),3.88(2H,s),5.50(2H,s),6.68(1H,s),6.83(2H,d,J=8.8Hz),7.31(2H,d,J=8.8Hz).
ESI-MS m/z:584(M+H)+.
(9) ジ-tert-ブチル [2-(4-メトキシベンジル)-8-オキソ-2,7,8,9-テトラヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-4-イル]イミドジカーボネート
1H-NMR(CDCl3)δ:1.46(18H,s),3.84(2H,s),3.77(3H,s),4.23(2H,s),5.48(2H,s),6.83(2H,d,J=8.6Hz),7.32(2H,d,J=8.6Hz).
ESI-MS m/z:542(M+H)+.
(10) エチル {4-[ビス(tert-ブトキシカルボニル)アミノ]-2-(4-メトキシベンジル)-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}アセテート
1H-NMR(CDCl3)δ:1.29(3H,t,J=7.1Hz),1.69-1.77(1H,m),2.37-2.40(1H,m),2.46-2.52(1H,m),2.68-2.71(2H,m),4.20(2H,q,J=7.1Hz),5.10-5.13(1H,m),5.20(2H,br s).
ESI-MS m/z:612(M+H)+
(11) 2-(4-アミノ-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル)-N-メチルアセタミド トリフルオロ酢酸塩
ESI-MS m/z:277(M+H)+.
(12) 5-クロロ-4-ヒドロキシ-6-メチルニコチニック アシッド
1H-NMR(CD3OD)δ:2.56(3H,s),8.50(1H,s).
ESI-MS m/z:188(M+H)+
(13) メチル 4,5-ジクロロ-6-メチルニコチネート
ESI-MS m/z:220(M+H)+
(14) メチル 5-クロロ-4-メトキシ-6-メチルニコチネート
1H-NMR(CDCl3)δ:2.67(3H,s),3.95(4H,s),4.00(3H,s),8.76(1H,s).
ESI-MS m/z:216(M+H)+
(15) (5-クロロ-4-メトキシ-6-メチルピリジン-3-イル)メタノール
1H-NMR(CDCl3)δ:2.63(3H,s),4.00(3H,s),4.71(2H,br s),8.33(1H,s)
ESI-MS m/z:188(M+H)+
(16) 3-クロロ-5-(クロロメチル)-4-メトキシ-2-メチルピリジン
1H-NMR(CDCl3)δ:2.64(3H,s),4.05(3H,s),4.61(2H,s),8.35(1H,s).
ESI-MS m/z:206(M+H)+
(17) 3-クロロ-4-メトキシ-2,5-ジメチルピリジン
1H-NMR(CDCl3)δ:2.25(3H,s),2.59(3H,s),3.89(3H,s),8.16(1H,s).
ESI-MS m/z:172(M+H)+
(18) 3-クロロ-4-メトキシ-2,5-ジメチルピリジン 1-オキシド
1H-NMR(CDCl3)δ:2.24(3H,s),2.62(3H,s),3.87(3H,s),8.07(1H,s).
ESI-MS m/z:188(M+H)+
(19) (3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メタノール
1H-NMR(CDCl3)δ:2.29(3H,s),3.93(3H,s),4.29(1H,br s),4.72-4.74(2H,m),8.26(1H,s).
ESI-MS m/z:188(M+H)+
(20) 3-クロロ-2-(クロロメチル)-4-メトキシ-5-メチルピリジン 塩酸塩
1H-NMR(CDCl3)δ:2.47(3H,s),4.32(3H,s),5.09(2H,s),8.54(1H,s).
ESI-MS m/z:206(M+H)+
(21) 2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド
1H-NMR(CDCl3)δ:2.24(4H,s),2.82(3H,d,J=4.9Hz),3.27(2H,s),3.80(2H,s),3.91(3H,s),5.21(2H,s),5.65(2H,s),5.87(1H,s),6.70(1H,s),8.16(1H,s).
ESI-MS m/z:446(M+H)+.
(実施例1)
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 2塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(1.034g,2.243mmol)にエタノール(29.3ml)、水(0.74ml)を加え25℃にて攪拌した。2M塩酸/エタノール(6.73ml,13.46mmol)を加え3時間45分攪拌した。析出結晶を濾過し、エタノール(5ml)で洗浄後、減圧下40℃にて1時間乾燥して表題化合物(1.118g,2.155mmol)を得た。収率96%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 2塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(493.48mg、1.11mmol)のアセトン(30mL)懸濁液に室温で、攪拌しながら3M塩酸(369.6mL)を滴下し、さらに12時間攪拌した。得られた結晶をろ別し、アセトンで洗浄後、減圧下、25℃で3時間乾燥し、表記化合物(531.01mg、1.02mmol)を得た。収率92%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(5446.6mg、11.6mmol)のエタノール(200ml)懸濁液に、攪拌しながら、25℃で3M塩酸(9.2ml、27.8mmol)を滴下し、3.5間攪拌した。得られた結晶をろ別し、エタノール(50ml)で洗浄後、減圧下、40℃で14時間乾燥し、表記化合物(5436.1mg、116.mmol)を得た。収率99%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(3.53kg、7.74mol)のエタノール(123L)懸濁液に攪拌しながら、21から22℃で、36.2%濃塩酸(1.75kg、17.4mol)を水(4.5L)で希釈して調製した3M塩酸を30分間かけて滴下し、4時間攪拌した。得られた結晶をろ別し、エタノール(17.6L)で洗浄後、減圧下40℃にて17時間乾燥し表記化合物(3.50kg、7.2mol)を得た。収率93%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(306mg、0.686mmol)のエタノール(10.7ml)懸濁液に25℃で、攪拌しながら3M塩酸(0.527ml、1.58mmol)を加え4時間攪拌した。得られた結晶をろ別し、エタノール(1.5ml)で洗浄後、減圧下40℃にて1時間乾燥し表題化合物(295mg、0.612mmol)を得た。収率89%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(527.5mg、1.18mmol)のエタノール(30ml)懸濁液に攪拌しながら、室温で3M塩酸(0.393ml、1.18mmol)を2回に分けて滴下し、その後1時間攪拌した。得られた結晶をろ別し、エタノール(6ml)で洗浄後、減圧下、40℃で30分間乾燥し、表記化合物(525.3mg、1.09mmol)を得た。収率92%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.044g,4.584mmol)にエタノール(70ml)を加え23℃にて攪拌し、1.5M塩酸(3.59ml,5.39mmol)を加え4時間攪拌した。析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて1時間乾燥して表題化合物(1.893g,3.924mmol)を得た。収率86%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え23℃にて攪拌し、1.87M塩酸(0.720ml,1.346mmol)、種晶として2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド1塩酸塩を加え30分攪拌した。3.28M塩酸(0.273ml,0.897mmol)を加え、8分間攪拌し、この操作をさらに8回繰り返した。3.28M塩酸(0.137ml,0.449mmol)を加え、4時間攪拌した。析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて1時間乾燥して表題化合物(2.057g,4.264mmol)を得た。収率95%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え24℃にて攪拌し、1M塩酸(2.691ml,2.691mmol)、種晶として2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩を加え30分攪拌した。9M塩酸(0.100ml,0.897mmol)を加え10分間攪拌し、この操作をさらに8回繰り返し、4時間攪拌した。析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて1時間乾燥して表題化合物(2.044g,4.237mmol)を得た。収率95%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え24℃にて攪拌し、1M塩酸(1.346ml,1.346mmol)、種晶として2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩を加え30分攪拌した。1M塩酸(0.897ml,0.897mmol)を加え8分間攪拌し、この操作をさらに3回繰り返した。1M塩酸(0.449ml,0.449mmol)を加え、2時間30分攪拌した。9M塩酸(0.100ml,0.897mmol)を加え1時間30分攪拌し、9M塩酸(0.050ml,0.449mmol)を加え1時間攪拌した。析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(1.742g,3.611mmol)を得た。収率81%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(20.00g,44.85mmol)にエタノール(700ml)を加え24℃にて攪拌し、1M塩酸(13.46ml,13.46mmol)、種晶として2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩を加え30分攪拌した。1M塩酸(8.97ml,8.97mmol)を9分間かけて滴下し、この操作をさらに3回繰り返した。1M塩酸(4.49ml,4.49mmol)を加え、1時間攪拌した。9M塩酸(1.00ml,8.97mmol)を加え1時間50分攪拌した。析出結晶を濾過し、エタノール(100ml)で洗浄後、減圧下40℃にて1時間乾燥して表題化合物(18.95g,39.28mmol)を得た。収率88%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(80.00g,173.48mmol)にエタノール(2800ml)を加え20℃にて攪拌し、1M塩酸(52.06ml,52.06mmol)、種晶として2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩を加え30分攪拌した。1M塩酸(34.69ml,34.69mmol)を8分間かけて滴下後4分間攪拌し、この操作をさらに3回繰り返した。1M塩酸(17.37ml,17.37mmol)を5分間かけて滴下後4分間攪拌した。9M塩酸(3.87ml,34.83mmol)を5分間かけて滴下後2時間40分攪拌した。析出結晶を濾過し、エタノール(400ml)で洗浄後、減圧下室温にて30分、40℃にて2時間30分乾燥して表題化合物(68.9g,142.8mmol)を得た。収率82%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え24℃にて攪拌し、1M塩酸(1.346ml,1.346mmol)を加え30分攪拌した。1M塩酸(0.897ml,0.897mmol)を5分間かけて加えた後5分間攪拌し、この操作をさらに3回繰り返した。1M塩酸(0.449ml,0.449mmol)を加え、30分攪拌した。濃塩酸(0.299ml,3.588mmol)を加え4時間攪拌した。析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(1.942g,4.026mmol)を得た。収率90%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え23℃にて攪拌し、1M塩酸(1.346ml,1.346mmol)を加え25分攪拌した。1M塩酸(0.897ml,0.897mmol)を4分間かけて加えた後6分間攪拌し、この操作をさらに3回繰り返した。1M塩酸(0.449ml,0.449mmol)を加え、30分攪拌した。濃塩酸(0.299ml,3.588mmol)を加え1時間攪拌した。1時間かけて2℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.011g,4.169mmol)を得た。収率93%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)、水(3.052ml)を加え23℃にて攪拌した。濃塩酸(0.045ml,0.54mmol)を2分間かけて加えた後10分間攪拌し、この操作をさらに9回繰り返した。30分攪拌後、濃塩酸(0.299ml,3.588mmol)を加え4時間攪拌した。析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.022g,4.192mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(36ml)、水(3.052ml)を加え25℃にて攪拌した。濃塩酸(0.045ml,0.54mmol)を1分間かけて加えた後9分間攪拌し、この操作をさらに9回繰り返した。30分攪拌後、濃塩酸(0.299ml,3.588mmol)を加え、エタノール(36ml)を45分かけて加えた後4時間攪拌した。析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.020g,4.187mmol)を得た。収率93%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え24℃にて攪拌し、1M塩酸(1.346ml,1.346mmol)を加え25分攪拌した。1M塩酸(0.897ml,0.897mmol)を4分間かけて加えた後7分間攪拌し、この操作をさらに3回繰り返した。濃塩酸(0.037ml,0.444mmol)を加え、30分攪拌した。濃塩酸(0.374ml,4.488mmol)を8分間かけて加え1時間20分攪拌した。1時間かけて8℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.026g,4.200mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え24℃にて攪拌し、1M塩酸(1.346ml,1.346mmol)を加え25分攪拌した。1M塩酸(0.897ml,0.897mmol)を4分間かけて加えた後7分間攪拌し、この操作をさらに2回繰り返した。濃塩酸(0.037ml,0.444mmol)を1分間かけて加えた後9分間攪拌し、この操作をさらに2回繰り返した後、30分攪拌した。濃塩酸(0.374ml,4.488mmol)を加え、1時間攪拌した。1時間かけて10℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.048g,4.246mmol)を得た。収率95%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え24℃にて攪拌し、1.2M塩酸(1.346ml,1.615mmol)を加え25分攪拌した。1.2M塩酸(0.897ml,1.076mmol)を5分間かけて加えた後5分間攪拌し、この操作をさらに2回繰り返した。濃塩酸(0.037ml,0.444mmol)を1分間かけて加えた後9分間攪拌し、この操作をさらに2回繰り返した後、30分攪拌した。濃塩酸(0.374ml,4.488mmol)を加え、1時間攪拌した。1時間かけて10℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.050g,4.250mmol)を得た。収率95%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(41ml)を加え23℃にて攪拌し、1.8M塩酸(0.748ml,1.346mmol)を加え27分攪拌した。1.8M塩酸(0.498ml,0.896mmol)を5分間かけて加えた後5分間攪拌し、この操作をさらに3回繰り返した。1.8M塩酸(0.249ml,0.448mmol)を加え、30分攪拌した。濃塩酸(0.299ml,3.588mmol)を加え1時間攪拌した。50分かけて3℃まで冷却し、2時間20分後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.070g,4.291mmol)を得た。収率96%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(51ml)を加え23℃にて攪拌し、1.4M塩酸(0.961ml,1.345mmol)を加え26分攪拌した。1.4M塩酸(0.641ml,0.897mmol)を4分間かけて加えた後6分間攪拌し、この操作をさらに3回繰り返した。1.4M塩酸(0.320ml,0.448mmol)を加え、30分攪拌した。濃塩酸(0.299ml,3.588mmol)を加え1時間攪拌した。50分かけて2℃まで冷却し、2時間30分後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.048g,4.246mmol)を得た。収率95%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え25℃にて攪拌し、1M塩酸(4.037ml,4.037mmol)を1時間かけて加えた。さらに濃塩酸(0.111ml,1.332mmol)を30分間かけて加えた後30分間攪拌した。濃塩酸(0.374ml,4.488mmol)を6分間かけて加え、1時間攪拌した。1時間かけて5℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.037g,4.223mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩)
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え26℃にて攪拌し、1M塩酸(4.037ml,4.037mmol)を15分かけて加えた。さらに濃塩酸(0.111ml,1.332mmol)を30分間かけて加えた後30分間攪拌した。濃塩酸(0.374ml,4.488mmol)を7分間かけて加え、1時間攪拌した。1時間かけて5℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.037g,4.223mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え26℃にて攪拌し、1M塩酸(4.037ml,4.037mmol)を1時間かけて加えた。さらに濃塩酸(0.111ml,1.332mmol)を5分間かけて加えた後30分間攪拌した。濃塩酸(0.374ml,4.488mmol)を6分間かけて加え、1時間攪拌した。1時間かけて5℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.042g,4.233mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え26℃にて攪拌し、1M塩酸(4.037ml,4.037mmol)を1時間かけて加えた。さらに濃塩酸(0.111ml,1.332mmol)を30分間かけて加えた後30分間攪拌した。濃塩酸(0.374ml,4.488mmol)を6分間かけて加え、30分攪拌した。30分かけて6℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.040g,4.229mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え26℃にて攪拌し、1M塩酸(4.037ml,4.037mmol)を1時間かけて加えた。さらに濃塩酸(0.111ml,1.332mmol)を30分間かけて加えた後、濃塩酸(0.374ml,4.488mmol)を6分間かけて加え、1時間攪拌した。1時間かけて5℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.039g,4.227mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(5.252g,11.21mmol)にエタノール(180ml)を加え26℃にて攪拌し、1M塩酸(10.09ml,10.09mmol)を1時間かけて加えた。さらに濃塩酸(0.280ml,3.360mmol)を30分間かけて加えた後30分間攪拌した。濃塩酸(0.934ml,11.21mmol)を7分間かけて加え、1時間攪拌した。1時間かけて5℃まで冷却し、20時間後析出結晶を濾過し、エタノール(25ml)で洗浄後、減圧下40℃にて1時間乾燥して表題化合物(5.145g,10.67mmol)を得た。収率95%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(1.07kg,2.28mol)にエタノール(36.7L)を加え25℃にて攪拌し、1M塩酸(2.06L,2.06mol)を55分かけて加えた。さらに濃塩酸(57ml,0.68mol)を33分間かけて加えた後30分間攪拌した。濃塩酸(191ml,2.29mol)を11分間かけて加え、1時間攪拌した。76分かけて5℃まで冷却し、22時間後析出結晶を濾過し、エタノール(5L)で洗浄後、減圧下40℃にて18時間乾燥して表題化合物(1.05kg,2.18mol)を得た。収率95%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(1.07kg,2.28mol)にエタノール(36.7L)を加え24℃にて攪拌し、1M塩酸(2.06L,2.06mol)を68分かけて加えた。さらに濃塩酸(57ml,0.68mol)を34分間かけて加えた後30分間攪拌した。濃塩酸(191ml,2.29mol)を9分間かけて加え、1時間攪拌した。76分かけて5℃まで冷却し、22時間30分後析出結晶を濾過し、エタノール(5L)で洗浄後、減圧下40℃にて18時間乾燥して表題化合物(1.05kg,2.18mol)を得た。収率95%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え30℃にて攪拌し、1M塩酸(4.037ml,4.037mmol)を1時間かけて加えた。さらに濃塩酸(0.111ml,1.332mmol)を30分間かけて加えた後30分間攪拌した。濃塩酸(0.374ml,4.488mmol)を6分間かけて加え、1時間攪拌した。74分かけて5℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.031g,4.210mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(2.068g,4.485mmol)にエタノール(72ml)を加え20℃にて攪拌し、1M塩酸(4.037ml,4.037mmol)を1時間かけて加えた。さらに濃塩酸(0.111ml,1.332mmol)を30分間かけて加えた後30分間攪拌した。濃塩酸(0.374ml,4.488mmol)を5分間かけて加え、1時間攪拌した。46分かけて4℃まで冷却し、2時間後析出結晶を濾過し、エタノール(10ml)で洗浄後、減圧下40℃にて30分乾燥して表題化合物(2.043g,4.235mmol)を得た。収率94%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(3.00g,6.40mmol)にエタノール(100.5ml)および水(3.975ml)を加え25℃にて攪拌し、濃塩酸(1.0ml)をエタノール(19.0ml)に希釈して調製した0.585M塩化水素の水‐エタノール溶液(3.28ml,1.92mmol)を加えた。同温にて種晶(0.3mg)を加えた後、0.585M塩化水素の水‐エタノール溶液(6.56ml,3.84mmol)を2時間かけて滴下し、30分間攪拌した。さらに、濃塩酸(0.695ml,8.34mmol)を1時間かけて滴下し、1時間攪拌した。析出した結晶を濾過し、エタノール(15ml)で洗浄後、減圧下40℃にて14時間乾燥して表題化合物(2.89g,5.96mmol)を得た。収率93%。
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド 1塩酸塩
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド(3.00g,6.40mmol)にエタノール(100.5ml)および水(3.975ml)を加え30℃にて攪拌し、濃塩酸(1.0ml)をエタノール(19.0ml)に希釈して調製した0.585M塩化水素の水‐エタノール溶液(3.28ml,1.92mmol)を加えた。同温にて種晶(0.3mg)を加えた後、0.585M塩化水素の水‐エタノール溶液(6.56ml,3.84mmol)を2時間かけて滴下し、30分間攪拌した。さらに、濃塩酸(0.695ml,8.34mmol)を1時間かけて滴下し、1時間攪拌した。析出した結晶を濾過し、エタノール(15ml)で洗浄後、減圧下40℃にて14時間乾燥して表題化合物(2.86g,5.93mmol)を得た。収率93%。
粉末X線回折の測定1
BrukerAXS社製 D8 DISCOVER with GADDS CS型 X線回折装置を用い、試料をガラス製サンプルホルダーに充填し、下記条件にて測定した。
<分析条件>
X線:Cu Kα1/40kV/40mA
ゴニオメータ:縦型2軸(θ,θ)
2θ測定範囲:3~40°
実施例2で得た2塩酸塩の結晶を上記方法で測定した粉末X線回折図を図4に示す。図4において最大ピーク強度を100とした場合の相対強度15以上のピークを表1に示す。
粉末X線回折の測定2
リガク社製 RINT2200V型 X線回折装置を用い、試料をガラス製サンプルホルダに充填し、下記条件にて測定した。
<分析条件>
X線:Cu Kα1/40kV/40mA
ゴニオメータ:Ultima+水平ゴニオメータI型
2θ走査範囲:5~40°
実施例1で得た2塩酸塩の結晶を上記方法で測定した粉末X線回折図を図7に示す。
示差走査熱量測定
<測定方法>
マック・サイエンス社製 DSC3100型 示差走査熱量測定装置を用い、2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの塩酸塩5mgを、測定用アルミ製パンに量り取り、パンをオープンの状態で、室温から250℃まで、毎分10℃の昇温速度で昇温して測定した。
<測定結果>
実施例1で得た2塩酸塩の結晶を上記方法で測定した示差走査熱量測定図を図37に示す。
残留エタノールの分析
以下に示すガスクロマトグラフ法にて分析した。
<標準溶液の調製>
1)エタノール500mg(=WEtOH[mg])を精密に量り、ジメチルスルホキシドで正確に20mlとし、これを[1]液とした。
2)[1]液4mLを正確に量り、ジメチルスルホキシドで正確に20mlとし、これを[2]液とした。
<試料溶液の調製>
2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド1塩酸塩 あるいは2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミド2塩酸塩 50mg(=Wsample[mg])を精密に量り、ジメチルスルホキシド1mlに溶解し、これを試料溶液とした。
<分析条件>
検出器:水素炎イオン化検出器
カラム:DB-624(0.32mmID×30m,膜厚1.8μm,Agilent社製)
カラム温度:40℃を5分間保持し、その後毎分15℃の割合で220℃まで昇温し、3分間保持した。
注入口温度:200℃
検出器温度:240℃
キャリヤーガス:ヘリウム
カラム流量:70kpa
スプリット比:1:20
注入量:1μL
<測定および計算>
1)[3]液を1μL注入し、エタノールのピーク面積(=AEtOH[3])を得た。
2)[4]液を1μL注入し、エタノールのピーク面積(=AEtOH[4])を得た。
3)[5]液を1μL注入し、エタノールのピーク面積(=AEtOH[5])を得た。
6)残留エタノール量[ppm]=1000000×Csample[mg/ml]×1[ml]÷Wsample[mg]として計算した。
<測定結果>
実施例1、4、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32および33で得られた各結晶中の残留エタノール量を上記方法で測定した結果を表4に示す。
純度試験および安定性試験
<虐待試験条件>
条件1:40℃、湿度75%
条件2:60℃(湿度管理なし)
上記虐待試験条件の試料を以下に示す高速液体クロマトグラフ法にて測定した。
<20mM リン酸2水素カリウム水溶液の調製>
リン酸2水素カリウム、2.72gを水、1000mlに溶かし、20mM リン酸2水素カリウム水溶液とした。
<20mM リン酸水素2カリウム水溶液の調製>
リン酸水素2カリウム、3.48gを水、1000mlに溶かし、20mM リン酸水素2カリウム水溶液とした。
<20mM リン酸カリウム緩衝液(pH=6.5)の調製>
20mM リン酸2水素カリウム水溶液に20mM リン酸水素2カリウム水溶液を加えていき、pH=6.5に調整し、20mM リン酸カリウム緩衝液(pH=6.5)とした。
<20mM リン酸カリウム緩衝液(pH=7.0)の調製>
20mM リン酸2水素カリウム水溶液に20mM リン酸水素2カリウム水溶液を加えていき、pH=7.0に調整し、20mM リン酸カリウム緩衝液(pH=7.0)とした。
<移動層>
移動層A:20mM リン酸カリウム緩衝液(pH=6.5)/アセトニトリル=9/1(V/V)
移動層B:20mM リン酸カリウム緩衝液(pH=6.5)/アセトニトリル=3/7(V/V)
<試料溶解液>
20mM リン酸カリウム緩衝液(pH=7.0)/アセトニトリル=3/7を試料溶解液とした。
<試料溶液の調整>
虐待試験検体を試料溶解液に溶かし、約0.5g/Lの溶液とした。
<分析条件>
カラム:YMC-Pack Pro C18RS、3.0mm ID x 150mm、粒子径 3μm
カラム温度:約40℃
グラディエント条件: 0~5分、移動層A:100→75/移動層B:0→25
5~15分、移動層A:75/移動層B:25
15~45分、移動層A:75→0/移動層B:25→100
45~55分、移動層A:0/移動層B:100
流速:0.7ml/min
測定範囲:0~55分
検出波長:240nm
試料溶液注入量:5μl
<計算>
1)試料溶液を注入し、個々の類縁物質のピーク面積(A)と化合物(1)のピーク面積(T)を得た。
2)試料溶解液注入し、個々のブランクのピーク面積(B)を得た
3)個々の類縁物質の量[%]=100×(A-B)÷T
として算出した。
<測定結果>
実施例4で得た1塩酸塩の結晶、実施例12で得た1塩酸塩の結晶、および実施例28で得た1塩酸塩の結晶の虐待試験結果を表5に示す。
2種類の細胞(ヒト乳癌由来細胞株SK-BR-3、ヒト肺癌由来細胞株NCI-H460)を用いて抗細胞試験を実施した。
T/C(%)=(T-S)/(C-S)×100
化合物(1)は、SK-BR-3細胞に対して13(nM)、NCI-H460細胞に対して26(nM)のGI50値を示した。
実施例2、3または6で得られた結晶5g、乳糖115g、トウモロコシデンプン58gおよびステアリン酸マグネシウム2gをV型混合機を用いて混合した後、3号カプセルに180mgずつ充填するとカプセル剤が得られる。
(製剤例2)<錠剤>
実施例2、3または6で得られた結晶5g、乳糖90g、トウモロコシデンプン34g、結晶セルロース20gおよびステアリン酸マグネシウム1gをV型混合機を用いて混合した後、1錠当り150mgの質量で錠剤機で打錠すると錠剤が得られる。
(製剤例3)<懸濁剤>
メチルセルロースを精製水に分散、溶解させた分散媒を調製し、実施例2、3または6で得られた結晶を乳鉢に量りとり、前述した分散媒を少量ずつ加えながらよく練り合わせ、精製水を加えて懸濁液100gを調製する。
Claims (18)
- 請求項1に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの2塩酸塩の結晶。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、図1に示すX線回折図を有する請求項2に記載の結晶。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=7.73、24.70、26.01および27.29に特徴的ピークを示す請求項2に記載の結晶。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=7.73、9.78、12.58、14.36、15.84、16.71、17.17、18.40、19.58、21.31、22.85、23.62、24.13、24.70、26.01、27.29、28.58、29.37、30.65、31.38、33.52、35.25、および36.87に主要ピークを示す請求項2または4に記載の結晶。
- 請求項1に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの1塩酸塩の結晶。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、図2に示すX線回折図を有する請求項6に記載の結晶。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=9.43、12.70、13.03、15.33、16.10、16.84、18.55、20.21、20.89、21.32、22.93、24.73、25.10、25.40、26.10、26.53、26.95、27.60、27.88、28.52、29.63、29.95、31.55、32.13、33.40、34.95、および38.70に主要ピークを示す請求項6に記載の結晶。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、図3に示す粉末X線回折図を有する請求項6に記載の結晶。
- 銅のKα線(波長λ=1.54オングストローム)の照射で得られる粉末X線回折図において、回折角度2θ=8.07、9.45、13.07、15.39、16.16、16.90、20.83、24.29、24.80、28.56、28.85、31.26、32.17、32.87、および34.11に主要ピークを示す請求項6に記載の結晶。
- エタノール含量が5000ppm以下である請求項1に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの塩酸塩の結晶。
- 塩酸塩が1塩酸塩である請求項11に記載の結晶。
- 請求項1に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの溶液または懸濁液に塩化水素の溶液を滴下することを特徴とする請求項1に記載の塩酸塩の製造方法。
- 請求項1に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの溶液または懸濁液に2当量以上の塩化水素の溶液を滴下することを特徴とする請求項2に記載の2塩酸塩の結晶の製造方法。
- 請求項1に記載の式(1)で表される2-{4-アミノ-2-[(3-クロロ-4-メトキシ-5-メチルピリジン-2-イル)メチル]-2,7-ジヒドロ-6-チア-1,2,3,5-テトラアザベンゾ[cd]アズレン-8-イル}-N-メチルアセタミドの溶液または懸濁液に1当量以上5当量以下の塩化水素の溶液を滴下することを特徴とする請求項6に記載の1塩酸塩の結晶の製造方法。
- 請求項1に記載の塩酸塩を有効成分として含有する医薬。
- 請求項1に記載の塩酸塩を含有する抗腫瘍剤。
- 請求項2から12のいずれか1項に記載の結晶を含有する医薬組成物。
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JP2012530660A JP5701884B2 (ja) | 2010-08-23 | 2011-08-22 | 三環性ピラゾロピリミジン誘導体の結晶 |
CN2011800408532A CN103052642A (zh) | 2010-08-23 | 2011-08-22 | 三环吡唑并嘧啶衍生物的晶体 |
EP11819897.7A EP2610260A4 (en) | 2010-08-23 | 2011-08-22 | TRICYCLIC PYRAZOLOPYRIMIDINE DERIVATIVE IN CRYSTALLINE FORM |
BR112013004265A BR112013004265A2 (pt) | 2010-08-23 | 2011-08-22 | cloridrato, cristais de um dicloridrato, de um monocloridrato, e de um cloridrato, métodos para produzir um cloridrato, um cristal de um dicloridrato, e um cristal de um monocloridrato, medicamento, agente antitumor, e, composição farmacêutica |
KR1020137001020A KR20130098982A (ko) | 2010-08-23 | 2011-08-22 | 3 고리성 피라졸로피리미딘 유도체의 결정 |
CA2809120A CA2809120C (en) | 2010-08-23 | 2011-08-22 | Crystal of tricyclic pyrazolopyrimidine derivative |
US13/773,387 US8815880B2 (en) | 2010-08-23 | 2013-02-21 | Crystal of tricyclic pyrazolopyrimidine derivative |
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- 2011-08-22 WO PCT/JP2011/068890 patent/WO2012026434A1/ja active Application Filing
- 2011-08-22 KR KR1020137001020A patent/KR20130098982A/ko not_active Application Discontinuation
- 2011-08-22 TW TW100129898A patent/TW201213333A/zh unknown
- 2011-08-22 CA CA2809120A patent/CA2809120C/en not_active Expired - Fee Related
- 2011-08-22 EP EP14179253.1A patent/EP2810945A1/en not_active Withdrawn
- 2011-08-22 BR BR112013004265A patent/BR112013004265A2/pt not_active IP Right Cessation
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TW201213333A (en) | 2012-04-01 |
JP5701884B2 (ja) | 2015-04-15 |
CN103052642A (zh) | 2013-04-17 |
CA2809120C (en) | 2015-10-13 |
US8815880B2 (en) | 2014-08-26 |
KR20130098982A (ko) | 2013-09-05 |
BR112013004265A2 (pt) | 2016-08-02 |
CA2809120A1 (en) | 2012-03-01 |
JPWO2012026434A1 (ja) | 2013-10-28 |
US20130203989A1 (en) | 2013-08-08 |
EP2610260A4 (en) | 2014-01-15 |
EP2610260A1 (en) | 2013-07-03 |
EP2810945A1 (en) | 2014-12-10 |
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