Ethanesulfonic acid salts of quinoline derivatives

Abstract

The present invention relates to N-{5-[(6, 7-dimethoxy-4-quinolinyl) oxy]-2-pyridyl}-2, 5-dioxo-1-phenyl-1, 2, 5, 6, 7, 8-hexahydro-3-quinolinecarboxamide ethanesulfonate, a crystal thereof, and a pharmaceutical composition thereof, which have Axl inhibitory activity and can be used as a drug for the prevention and / or treatment of immune system diseases, cancers and the like, and more particularly, to N-{5-[(6, 7-dimethoxy-4-quinolinyl) oxy]-2-pyridyl}-2, 5-dioxo-1-phenyl-1, 2, 5, 6, 7, 8-hexahydro-3-quinolinecarboxamide ethanesulfonate, a crystal thereof, and a pharmaceutical composition thereof.

Description

[0001] This application is a divisional application based on the invention patent application with application date of January 25, 2018, application number 201880008442.7 (PCT application number PCT / JP2018 / 002250), and invention name: "Ethylsulfonate of quinoline derivative". Technical Field

[0002] The present invention relates to N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate (also referred to as ethanesulfonate) and its crystals (hereinafter, also referred to as the compound of the present invention), which have Axl inhibitory activity and can be used as a drug for preventing and / or treating immune system diseases, cancer, etc. The present invention also relates to a pharmaceutical composition thereof. Background Art

[0003] Axl (also known as UFO, ARK, Tyro7) is a receptor tyrosine kinase belonging to the TAM family (Axl, Mer and Tyro3) cloned from tumor cells. Gas6 (growth arrest-specific protein 6), which was cloned as a gene specifically expressed during cell proliferation arrest, is known to be a ligand for Axl. Axl activated by binding to Gas6 transmits a signal through phosphorylation. Since this signal activates the Erk1 / 2 pathway or the PI3K / Akt pathway, the activation of Axl is believed to be involved in pathological symptoms such as cancer, immune system diseases, and circulatory system diseases (see Non-Patent Document 1).

[0004] In particular, the relationship between Axl and various types of cancer is well known. For example, it is known that the expression of Axl is related to the metastasis and prognosis of breast cancer (see, non-patent document 2), and Axl is related to the pathological symptoms of acute myeloid leukemia (AML) (see non-patent document 3). Therefore, it is believed that compounds that inhibit Axl activation are useful for treating various types of cancer, immune system diseases and circulatory system diseases.

[0005] As a prior art of the compound of the present invention, the compound represented by the general formula (A) is a known Axl inhibitor (see Non-Patent Document 1):

[0006] [Chemical formula 1]

[0007]

[0008] (In the above formula, A A Represents CR 10A and N; B A Represents CR11A and N;D A represents the following heterocyclic ring, etc.,

[0009] [Chemical formula 2]

[0010]

[0011] Where R 1A , R 4A and R 88A independently represent -H, -F, -Cl, -Br, -I, -OH, -NH2, -OCH3, -OC2H5, etc.; R 2A and R 3A Independently expressed -R 88A etc.; R 5A and R 6A may be the same as or different from each other and represent -H, -F, -Cl, -Br, -I, -CN, -NO2, -CH3, etc.; R 7A , R 8A , R 10A and R 11A may be the same as or different from each other and represent -H, -F, -Cl, -Br, -I, -CN, -NO2, -CH3, etc.; R 9A Indicates -H, etc.; R 12A Represents -CN, phenyl, etc.; R 13A Represents -H, -F, -Cl, -Br, -I, -NO2, -CH3, etc.; R 14A represents -H, -F, -Cl, -Br, -I, -NO2, -CN, etc. (the definitions of the groups mentioned are optional)).

[0012] In addition, the compound represented by the general formula (B) is a known Axl inhibitor (see Patent Document 2):

[0013] [Chemical formula 3]

[0014]

[0015] (E B and G B independently represents a hydrogen atom, optionally substituted by 1-6 R 19B Substituted C1-6 alkyl, optionally substituted with 1-6 R 19B Substituted C6-11 aryl, etc.; X B Indicates N or CR 4B ; Y B Indicates N or CR 1dB ;D B Indicates -O-, -S-, -NH-, etc.; W B Represents CH or N; R aB, R bB , R cB , R dB , R 1aB , R 1bB , R 1cB , R 1dB and R 4B independently represent a hydrogen atom, -OR 110B etc.; R 19B Represents a halogen atom, -CN, etc.; R 110B represents a hydrogen atom, optionally with 1 to 6 R 129B Substituted C1-6 alkyl, etc.; R 129B represents C1-6 alkyl, C1-6 haloalkyl, etc. (wherein the definition of the group mentioned is optional)).

[0016] On the other hand, it is known that a compound having a quinoline skeleton and represented by the following general formula (C) has an ASK1 inhibitory activity.

[0017] [Chemical formula 4]

[0018]

[0019] It is a drug for preventing and / or treating amyotrophic lateral sclerosis (ALS) (see Patent Document 3).

[0020] In addition, the compound represented by the general formula (D) is a known c-Met inhibitor (see Patent Document 4):

[0021] [Chemical formula 5]

[0022]

[0023] (where R D express

[0024] [Chemical formula 6]

[0025]

[0026] etc.; T D Represents phenyl, etc.; Z D Indicates N or CR 7D ; W D represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted 6-membered nitrogen-containing heteroaryl group, etc.; X D Indicates O, S, S(=O), etc.; Y D Indicates -NR aD C(=O)-(CR 3D R 4D ) pD - etc.; R aD represents a hydrogen atom, an alkyl group, etc.; and R 1D express

[0027] [Chemical formula 7]

[0028]

[0029] etc.; J 2D Indicates O or CR 4aD R 4aD ;Q D represents a 1- to 5-membered saturated or partially unsaturated alkyl chain, etc.; R 1D represents an optionally substituted phenyl group or a phenyl group which may be condensed with an optionally substituted 5- to 6-membered heterocyclic ring; R 3D and R 4D Each independently represents a hydrogen atom, an alkyl group, an aryl group, etc.; R 4aD Does not exist or represents a hydrogen atom, a halogen atom, etc.; R 8D represents one or more substituents independently selected from hydrogen atom, cyano group, hydroxyl group and the like (wherein the definitions of the groups are abstracted)).

[0030] In addition, Patent Document 5 describes N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide in Example 5, which is a free base of the compound of the present invention (hereinafter referred to as Compound A). In addition, Patent Document 5 mentions that Compound A is a compound having Axl-selective inhibitory activity and low CYP inhibitory effect. On the other hand, Patent Document 5 does not include specific examples of acid addition salts of Compound A. Moreover, regarding the ethanesulfonate of Compound A, there is neither description nor suggestion of the fact that the ethanesulfonate has Axl-selective inhibitory activity and low CYP inhibitory activity, and has low hygroscopicity and stability to moisture and light among various acid addition salts of Compound A.

[0031] Prior art literature

[0032] Patent Literature

[0033] [Patent Document 1] WO2012 / 028332(A)

[0034] [Patent Document 2] WO2013 / 074633(A)

[0035] [Patent Document 3] WO2012 / 011548(A)

[0036] [Patent Document 4] WO2006 / 116713(A)

[0037] [Patent Document 5] WO2015 / 012298(A)

[0038] Non-patent literature

[0039] [Non-patent document 1] Clinical Science, Vol. 122, pp. 361-368, 2012

[0040] [Non-patent document 2] Proceedings of the national academy of sciences of the United States of America, Vol. 107, No. 3, pp. 1124-1129, 2010

[0041] [Non-patent document 3] Blood, Vol. 121, pp. 2064-2073, 2013 Summary of the invention

[0042] Technical issues

[0043] The problem to be solved by the present invention is to provide a salt which has Axl-selective inhibitory activity, low CYP inhibitory effect, and low hygroscopicity among various acid addition salts of compound A, and is stable to moisture and light as an active pharmaceutical ingredient, thereby providing a drug for preventing and / or treating diseases associated with Axl expression, such as cancer.

[0044] Problem Solving

[0045] The inventors of the present invention have intensively studied to solve the above problems and have found that the compound of the present invention is a salt having low hygroscopicity among various acid addition salts of compound A and is stable to moisture and light, thereby completing the present invention.

[0046] For example, the present invention provides the following embodiments:

[0047] [1] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate,

[0048] [2] Crystals of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate,

[0049] [3] The crystal according to the above [2], wherein in a powder X-ray diffraction spectrum, the crystal has peaks at the following 2θ: about 7.3, about 7.9, about 9.1, about 10.7, about 11.2, about 12.5, about 13.4, about 15.6, about 16.2, about 16.5, about 17.7, about 18.0, about 18.4, about 19.1, about 20.1, about 20.8, about 21.2, about 21.5, about 22.4, about 23.0, about 23.6 and about 24.0 degrees,

[0050] [4] The crystal according to [2] or [3], which has Figure 1 The characteristics of the powder X-ray diffraction spectrum shown in

[0051] [5] The crystal according to [2] to [4] above, wherein in differential scanning calorimetry, the crystal has an endothermic peak at an onset temperature of about 283°C or a peak temperature of about 286°C,

[0052] [6] The crystal according to any one of [2] to [5] above, having Figure 2 The characteristics of the differential scanning calorimetry spectrum shown in

[0053] [7] A pharmaceutical composition comprising N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate or the crystal according to any one of [2] to [6], and a pharmaceutically acceptable carrier,

[0054] [8] The pharmaceutical composition according to [7] above, which is an Axl inhibitor,

[0055] [9] The pharmaceutical composition according to [7] above, which is a preventive and / or therapeutic agent for Axl-related diseases,

[0056]

[10] The pharmaceutical composition according to [9] above, wherein the Axl-related disease is cancer, immune system disease or circulatory system disease,

[0057]

[11] The pharmaceutical composition according to the above

[10] , wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, melanoma, uveal malignant melanoma, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, vaginal cancer, vulvar cancer, renal cell carcinoma, urothelial carcinoma, prostate cancer, testicular cancer, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, pleural mesothelioma or cancer of unknown origin,

[0058]

[12] A method for preventing and / or treating an Axl-related disease, the method comprising administering to a mammal an effective dose of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate or a crystal according to any one of [2] to [6] above,

[0059]

[13] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate or the crystal according to any one of [2] to [6] above, for use in preventing and / or treating Axl-related diseases, and

[0060]

[14] Use of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate or the crystal according to any one of [2] to [6] above in the manufacture of a preventive and / or therapeutic agent for Axl-related diseases,

[0061] etc.

[0062] [Beneficial Effects of the Invention]

[0063] The compounds of the present invention have Axl-selective inhibitory activity, low CYP inhibitory effect, low hygroscopicity in various acid addition salts of compound A, and are stable to moisture and light, and can therefore be used as active pharmaceutical ingredients for preventing and / or treating Axl-related diseases such as cancer, and have excellent stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 The powder X-ray diffraction spectrum of the crystal of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate is shown (at Figure 1 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0065] Figure 2 The differential scanning calorimetry (DSC) chart of the crystals of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate is shown.

[0066] Figure 3The powder X-ray diffraction spectrum of the crystal (C-type crystal) of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide is shown (at Figure 3 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0067] Figure 4 The differential scanning calorimetry (DSC) chart of the crystals of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (C-type crystal) is shown.

[0068] Figure 5 The powder X-ray diffraction spectrum of the crystal (D-type crystal) of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide is shown (at Figure 5 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0069] Figure 6 The differential scanning calorimetry (DSC) chart of the crystals of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (D-type crystal) is shown.

[0070] Figure 7 The powder X-ray diffraction spectrum of the crystal (E-type crystal) of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide is shown (at Figure 7 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0071] Figure 8 The differential scanning calorimetry (DSC) chart of the crystals of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (E-type crystal) is shown.

[0072] Fig. 9The powder X-ray diffraction spectrum of the crystal (F-type crystal) of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide is shown (at Fig. 9 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0073] Fig.10 The differential scanning calorimetry (DSC) chart of the crystals of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (F-type crystal) is shown.

[0074] Fig.11 The powder X-ray diffraction spectrum of the crystal (G-type crystal) of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide is shown (at Fig.11 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0075] Fig.12 The powder X-ray diffraction spectrum of the crystal (H-type crystal) of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide is shown (at Fig.12 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0076] Fig.13 The differential scanning calorimetry (DSC) chart of the crystals (H-type crystals) of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide is shown.

[0077] Fig.14 The powder X-ray diffraction spectrum of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide hydrochloride (C-type crystal) is shown (at Fig.14 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0078] Fig.15The powder X-ray diffraction spectrum of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide methanesulfonate (A-type crystal) is shown (at Fig.15 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0079] Fig.16 The powder X-ray diffraction spectrum of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide p-toluenesulfonate (C-type crystal) is shown (at Fig.16 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0080] Fig.17 The powder X-ray diffraction spectrum of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide sulfate (A-type crystal) is shown (at Fig.17 In FIG. 5 , the ordinate represents intensity (counts), and the abscissa represents 2θ (°).

[0081] Fig.18 The powder X-ray-DSC spectrum of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (E-type crystal) is shown.

[0082] Description of the implementation plan

[0083] The present invention will be described in detail hereinafter.

[0084] In the present invention, the phrase "having Axl-selective inhibitory activity" means having Axl-selective inhibitory activity against tyrosine kinases other than Axl (specifically, against KDR, DDR1, FLT4 and ROS). This property can avoid unpredictable side effects caused by inhibiting these tyrosine kinases other than Axl.

[0085] In the present invention, N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (Compound A) refers to a compound represented by the following structural formula.

[0086] [Chemical formula 8]

[0087]

[0088] [Study of Acid Addition Salt of Compound A]

[0089] Compound A and various acid counters prepared in the following Example 5 were used to produce various acid addition salts of Compound A by the method described in the following Examples. When crystals were obtained, physical property data were measured under the following conditions.

[0090] [1] Powder X-ray diffraction spectrum

[0091] <Measurement conditions>

[0092] Device: BRUKER D8 DISCOVER with GADDS, manufactured by BRUKER axs,

[0093] Target: Cu,

[0094] Filter: Not used,

[0095] Voltage: 40 kV,

[0096] Current: 40 mA.

[0097] [2] Differential Scanning Calorimetry (DSC)

[0098] <Measurement conditions>

[0099] Device: DSC 822e, manufactured by METTLER TOLEDO,

[0100] Sample size: 1 to 2 mg,

[0101] Sample pool: aluminum pan 40 μL,

[0102] Nitrogen flow rate: 40 mL / min,

[0103] Heating rate: 10°C / min (25 to 240°C).

[0104] [3] Hygroscopicity evaluation (DVS; dynamic vapor sorption)

[0105] <Measurement conditions>

[0106] Device: SGA-100, manufactured by TA Instruments,

[0107] Sample size: 10 to 20 mg,

[0108] Measurement temperature: 25°C,

[0109] Drying before measurement: 60°C, 1 hour,

[0110] Initial humidity: 0% RH,

[0111] Maximum humidity: 90% RH,

[0112] Step size: 10% RH,

[0113] Balance standard: weight change rate within 5 minutes is less than 0.01%,

[0114] Sampling interval: 30 seconds,

[0115] Data recording interval: two minutes or the time when the weight change rate becomes 0.01% or more.

[0116] [4] Conditions for simultaneous PXRD-DSC measurements

[0117] <Measurement conditions>

[0118] Device: Rint Ultima, manufactured by Rigaku,

[0119] Target: Cu,

[0120] Voltage: 40 kV,

[0121] Current: 50 mA,

[0122] Scanning speed: 10° / min,

[0123] Heating rate: 2°C / min (from room temperature to 200°C).

[0124] Figure 1 shows the powder X-ray diffraction spectrum of the compound of the present invention, and Figure 2 The differential scanning calorimetry (DSC) spectrum of the compound of the present invention is shown. In addition, the diffraction angle 2θ (°) and the relative intensity (%) in the powder X-ray diffraction spectrum of the compound of the present invention are shown in Table 1 below.

[0125] Table 1

[0126] Diffraction angle 2θ (°) Relative strength (%) 7.3 20.2 7.9 39.7 9.1 9.0 10.7 12.6 11.2 42.5 12.5 20.1 13.4 21.2 15.6 100.0 16.2 19.4 16.5 38.0 17.7 15.8 18.0 15.4 18.4 21.3 19.1 25.9 20.1 21.2 20.8 11.2 21.2 31.3 21.5 32.1 22.4 20.9 23.0 13.7 23.6 43.1 24.0 62.9

[0127] In addition, if Figure 2 As shown in , the compound of the present invention shows endothermic peaks represented by an onset temperature of about 282.7°C and a peak temperature of about 286.1°C, respectively.

[0128] The powder X-ray diffraction spectra of the compound A crystals (C-crystals described in Example 5 (1), D-crystals described in Example 5 (2), E-crystals described in Example 5 (3), F-crystals described in Example 5 (4), G-crystals described in Example 5 (5), and H-crystals described in Example 5 (6)) are shown in FIG. Figure 3 , 5 , 7, 9, 11 and 12. In addition, the differential scanning calorimetry (DSC) spectra of the crystals of Compound A (C-crystal described in Example 5 (1), D-crystal described in Example 5 (2), E-crystal described in Example 5 (3), F-crystal described in Example 5 (4), H-crystal described in Example 5 (6)) are shown in Figure 4 , 6 , 8, 10 and 13. In addition, the diffraction angle 2θ (°) and the relative intensity in the powder X-ray diffraction spectrum of the C-crystal of Compound A are shown in Table 2.

[0129] Table 2

[0130] Diffraction angle 2θ (°) Relative strength (%) 6.6 19.2 7.4 100.0 9.0 14.0 10.7 27.5 11.7 30.2 12.5 14.2 13.0 24.1 13.5 15.4 14.7 30.2 15.2 18.6 15.7 30.4 16.4 25.3 17.9 34.8 18.7 17.9 20.1 21.9 20.6 20.1 23.2 28.7 23.7 23.1

[0131] like Figure 4 As shown in , C-crystal of compound A shows endothermic peaks for melting, which are indicated by an onset temperature of about 160.3°C and a peak temperature of about 175.8°C, respectively.

[0132] Methods for preparing various acid addition salts of Compound A will be described later in Examples, but it was found that since acid addition salts other than the compound of the present invention have crystal polymorphism, it is difficult to control the crystal polymorphism.

[0133] In the present invention, the crystalline forms of Compound A or various acid addition salts of Compound A are specifically described by the physicochemical data described in this application, but each spectral data should not be strictly understood because they vary in nature.

[0134] For example, in powder X-ray diffraction data, the diffraction angle (2θ) and overall pattern are important for identifying crystals for their properties, and the relative intensities can vary somewhat depending on crystal growth direction, particle size, and measurement conditions.

[0135] Furthermore, in DSC data, the overall pattern is important for the identification of crystals, and it varies depending on the measurement conditions.

[0136] Thus, among the compounds of the present invention, compounds in which the powder X-ray diffraction spectrum or DSC and pattern are generally similar are included in the compounds of the present invention.

[0137] In the present application, the description of the diffraction angle (2θ (°)) in the powder X-ray diffraction pattern and the onset temperature (°C) of the absorption peak in the DSC analysis includes the error range allowed in the data measurement method, and refers to the approximation of the onset value of the diffraction angle and the endothermic peak. For example, the term "about" for the diffraction angle (2θ (°)) in the powder X-ray diffraction is ±0.2° in one aspect and ±0.1° in another aspect. The term "about" for the onset temperature (°C) of the endothermic peak in the DSC analysis is ±2°C in one aspect.

[0138] In an exemplary embodiment of the present invention, each crystalline form of Compound A or various acid addition salts of Compound A is substantially pure. Reference to "substantially pure" means that the specific crystalline form accounts for at least 50% of the compound present. In addition, in another exemplary embodiment, each crystalline form accounts for at least 75%, at least 85%, at least 90%, at least 95%, or about 94% to 98% of the compound A present.

[0139] In the present invention, compound A or various acid addition salts of compound A can be produced by, for example, the methods of the following examples and the same methods as those described above. It should be noted that seed crystals may or may not be used in the recrystallization.

[0140] The compound of the present invention can be converted into a solvate. Preferably, the solvate is low in toxicity and water-soluble. Examples of suitable solvates include solvates with water, alcohol solvents (e.g., ethanol), and the like.

[0141] toxicity

[0142] The toxicity of the compounds of the present invention is sufficiently low, and the compounds can be safely used as medicines.

[0143] Application of drugs

[0144] Since the compounds of the present invention have Axl inhibitory activity, they can be used as drugs for preventing and / or treating Axl-related diseases in mammals, especially humans.

[0145] In the present invention, examples of Axl-related diseases include cancer, kidney disease, immune system disease and circulatory system disease.

[0146] In the present invention, examples of the cancer include leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, and chronic lymphoid leukemia), malignant lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma (e.g., adult T-cell leukemia, follicular lymphoma, and diffuse large B-cell malignant lymphoma)), multiple myeloma, myelodysplasia syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, colorectal cancer, colon cancer, rectal cancer, Intestinal cancer, liver cancer (e.g., hepatocellular carcinoma), gallbladder cancer and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer (e.g., non-small cell lung cancer (e.g., squamous non-small cell lung cancer, non-squamous non-small cell lung cancer), and small cell lung cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer), cervical cancer, uterine corpus cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer (e.g., renal cell carcinoma), urothelial cancer (e.g., urinary bladder cancer, and upper urinary tract cancer), prostate cancer, testicular cancer (e.g., blastoma), bone and soft tissue sarcoma, skin cancer (e.g., uveal malignant melanoma, malignant melanoma (melanoma), and Merkel cell cancer), glioma, brain tumor (e.g., glioblastoma), pleural mesothelioma, and unknown primary cancer.

[0147] In the present invention, examples of the renal disease include glomerulonephritis, chronic nephritis, IgA nephritis, sequential (secondary) nephritis, nephrosis nephritis, acute renal failure, chronic renal failure, diabetic nephropathy, gouty nephropathy, interstitial nephritis and pyelonephritis.

[0148] In the present invention, examples of the immune system disease include psoriasis and rheumatoid arthritis.

[0149] In the present invention, examples of the circulatory system diseases include atherosclerosis and thrombosis.

[0150] Furthermore, since the compounds of the present invention have Axl inhibitory activity, they are useful as metastasis inhibitors against tumor cells.

[0151] The compounds of the present invention can be administered as a combination drug in combination with other drugs to achieve the following purposes:

[0152] 1) supplement and / or enhance the preventive and / or therapeutic effects of the compound; 2) enhance the kinetics, improve absorption and reduce the dosage of the compound; and / or 3) eliminate the side effects of the compound.

[0153] The combination drug of the compounds of this invention and other drugs can be administered in the form of a compounding agent, or can be administered in a separate formulation, wherein the compounding agent is formed by mixing these components into a preparation. Administration with a separate formulation includes simultaneous administration and administration at different times. In administration at different times, the compounds of this invention can be administered before other drugs. Alternatively, other drugs can be administered before the compounds of this invention. The methods of administration of these drugs may be the same as or different from each other.

[0154] The diseases on which the preventive and / or therapeutic effects of the above-mentioned combination drugs act are not particularly limited, but the diseases may be those in which the preventive and / or therapeutic effects of the compound of the present invention are supplemented and / or enhanced.

[0155] Other drugs used to supplement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention on cancer include, for example, alkylating agents, antimetabolites, anticancer agents, antibiotics, plant alkaloids, hormones, platinum compounds, immune checkpoint inhibitors, anti-CD20 antibodies, anti-CD52 antibodies, G-CSF preparations, acute promyelocytic leukemia differentiation inducers, kinase inhibitors, topoisomerase inhibitors, aromatase inhibitors and other anticancer drugs.

[0156] Other drugs used to supplement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention on renal disease include, for example, steroids, immunosuppressants, angiotensin II antagonists, angiotensin converting enzyme inhibitors, antiplatelet drugs and anticoagulants.

[0157] Other drugs used to supplement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention on immune system diseases include, for example, immunosuppressants; steroids; disease-modifying antirheumatic drugs; prostaglandins; prostaglandin synthase inhibitors; phosphodiesterase inhibitors; metalloproteinase inhibitors; anti-cytokine protein preparations, such as anti-TNF-α preparations, anti-IL-1 preparations and anti-IL-6 preparations; cytokine inhibitors; and non-steroidal anti-inflammatory drugs.

[0158] Examples of other drugs used to supplement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention on circulatory system diseases include antiplatelet drugs, angiotensin II antagonists, angiotensin converting enzyme inhibitors, HMG-CoA reductase inhibitors and thiazolidine derivatives.

[0159] Examples of the alkylating agent include nitrogen mustard N-oxide hydrochloride, cyclophosphamide, ifosfamide, melphalan, thiotepa, carboquinone, busulfan, nimustine hydrochloride, dacarbazine, ranimustine, carmustine, chlorambucil, bendamustine, and nitrogen mustard.

[0160] Examples of the antimetabolite include methotrexate, mercaptopurine, 6-mercaptopurine nucleoside, fluorouracil, tegafur, tegafur uracil, carmofur, doxifluridine, cytarabine, enocitabine, tegafur gimestat otastat potassium, gemcitabine hydrochloride, cytarabine ocfosfate, procarbazine hydrochloride, hydroxyurea and the like.

[0161] Examples of anticancer antibiotics include actinomycin D, mitomycin C, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, neocarcinostatis, pirarubicin hydrochloride, epirubicin (hydrochloride), idarubicin hydrochloride, chromomycin A3, bleomycin (hydrochloride), peplomycin sulfate, therarubicin, zinostatin stimalamer, gemtuzumab ozogamicin, and the like.

[0162] Examples of the plant alkaloid drug include vinblastine sulfate, vincristine sulfate, vindesine sulfate, irinotecan hydrochloride, etoposide, flutamide, vinorelbine tartrate, docetaxel hydrate, paclitaxel and the like.

[0163] Examples of the hormone include estramustine sodium phosphate, melastane, cyclothiosteroid, goserelin acetate, fosfostil (diethylstilbestrol diphosphate), tamoxifen citrate, toremifene citrate, fadroxil hydrochloride hydrate, medroxyprogesterone acetate, bicalutamide, leuprolide acetate, anastrozole, aminoglutethimide, androgen bicalutamide, fulvestrant, and the like.

[0164] Examples of the platinum compound include carboplatin, cisplatin, nedaplatin, oxaliplatin and the like.

[0165] Immune checkpoint inhibitors are substances that inhibit the function of immune checkpoint molecules. Immune checkpoint inhibitors are not specifically limited as long as the substance can suppress the function (signal) of immune checkpoint molecules.

[0166] The immune checkpoint inhibitor is preferably an inhibitor of a human immune checkpoint molecule, and more preferably a neutralizing antibody against a human immune checkpoint molecule.

[0167] Examples of immune checkpoint inhibitors include inhibitors of immune checkpoint molecules selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, 2B4, CD160, A2aR, KIR, VISTA, and TIGIT. The following are examples of immune checkpoint inhibitors, but the immune checkpoint inhibitors are not specifically limited thereto.

[0168] Examples of immune checkpoint inhibitors include anti-CTLA-4 antibodies (e.g., ipilimumab (YERVOY (registered trademark)), tremelimumab, AGEN-1884), anti-PD-1 antibodies (e.g., nivolumab (OPDIVO (registered trademark)), REGN-2810, pembrolizumab (KEYTRUDA (registered trademark)), PDR-001, BGB-A317, AMP-514 (MEDI0680), BCD-100, IBI-308, JS-001, PF-06801591 and TSR-042), anti-PD-L1 antibodies (e.g., atezolizumab (RG7446 and MPDL3280A), avelumab (PF-06834635 and MSB0010718C), durvalumab (MEDI4736), BMS-936559, CA-170 and LY-3300054), anti-PD-L2 antibodies (e.g., rHIgM12B7), PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-Tim-3 antibodies (e.g., MBG453), anti-LAG-3 antibodies (e.g., BMS-986016 and LAG525), and anti-KIR antibodies (e.g., Lirilumab). In addition, antibodies comprising the heavy chain and light chain complementary determining regions (CDRs) or variable regions (VR) of the above-mentioned known antibodies are also an embodiment of immune checkpoint inhibitors. Examples of further embodiments of anti-PD-1 antibodies include antibodies comprising the heavy chain and light chain complementary determining regions (CDRs) or variable regions (VR) of nivolumab.

[0169] Examples of the anti-CD20 antibody include rituximab, ibritumomab, ibritumomab tiuxetan, and ocrelizumab.

[0170] Examples of the anti-CD52 antibody include alemtuzumab.

[0171] Examples of the G-CSF preparation include pegfilgrastim, filgrastim, lenograstim, and nartograstim.

[0172] Examples of the differentiation inducing agent for acute promyelocytic leukemia include tamibarotene, retinoic acid, and arsenic trioxide preparations.

[0173] Examples of the kinase inhibitors include EGFR inhibitors, including erlotinib hydrochloride, gefitinib, cetuximab and panitumumab; HER2 inhibitors, including lapatinib and trastuzumab; BCR-ABL inhibitors, including imatinib, dasatinib and nilotinib; multikinase inhibitors, including sunitinib, vandetanib, crizotinib and sorafenib.

[0174] Examples of the topoisomerase include topotecan, teniposide, irinotecan, and sobuzoxane.

[0175] Examples of the aromatase inhibitor include exemestane.

[0176] Examples of the other anticancer drugs include L-asparaginase, octreotide acetate, porfimer sodium, mitoxantrone acetate, acetoglucuronide, ubenimex, eribulin mesilate, cladribine, versicolor polysaccharide, bexarotene, denileukin 2, temozolomide, nelarabine, fludarabine, bevacizumab, pemetrexed, pentostatin, bortezomib, lenalidomide and folinic acid calcium.

[0177] Examples of the immunosuppressant include azathioprine, ascomycin, everolimus, sulfasalazine, cyclosporine, cyclophosphamide, sirolimus, tacrolimus, bucillamine, methotrexate, and leflunomide.

[0178] Examples of the steroid include amcinonide, hydrocortisone sodium succinate, prednisolone sodium succinate, methylprednisolone sodium succinate, ciclesonide, difluprednate, betamethasone propionate, dexamethasone, deflazacort, triamcinolone, triamcinolone acetonide, clofloclide, dexamethasone palmitate, hydrocortisone, flumethasone pivalate, prednisolone tert-butyl ethyl ester, budesonide, prasterone sulfate, mometasone furoate, fluocinolone acetonide, fludroxycortide, flunisolide, prednisolone, alclometasone propionate, clobetasol propionate, dexamethasone propionate, deproton propionate, fluticasone propionate, beclomethasone propionate, betamethasone, methylprednisolone, methylprednisolone sulfonate, and methylprednisolone sulfonate. suleptanate), methylprednisolone sodium suleptanate, dexamethasone sodium phosphate, hydrocortisone sodium phosphate, prednisolone sodium phosphate, diflumethasone valerate, dexamethasone valerate, betamethasone valerate, prednisolone valerate acetate, cortisone acetate, diflorasone acetate, dexamethasone acetate, triamcinolone acetate, flumethasone acetate, halopednisolone acetate, fludrocortisone acetate, prednisolone acetate, methylprednisolone acetate, betamethasone butyrate, hydrocortisone butyrate propionate, and betamethasone butyrate propionate.

[0179] Examples of the angiotensin II antagonist include losartan, candesartan, valsartan, irbesartan, olmesartan, telmisartan and the like.

[0180] Examples of the angiotensin converting enzyme inhibitor include alacepril, imidapril hydrochloride, quinapril hydrochloride, temopril hydrochloride, delapril hydrochloride, benazepril hydrochloride, captopril, trandolapril, perindopril tert-butylamine salt, enalapril maleate, lisinopril and the like.

[0181] Examples of the antiplatelet drug include dipyridamole and dilazodone hydrochloride hydrate.

[0182] Examples of the anticoagulant include warfarin and heparin.

[0183] Examples of the disease-modifying antirheumatic drugs include D-penicillamine, actarit, auranofin, sulfasalazine, hydroxychloroquine, bucillamine, methotrexate, leflunomide, lobenzarit sodium, aurothioglucose, and sodium aurothiomaleate.

[0184] The example of the prostaglandin (hereinafter referred to as "PG") includes PGE1 preparation (example: alprostadil α-cyclodextrin, alprostadil), PGI2 preparation (example: beraprost sodium), PG receptor agonist and PG receptor antagonist. The example of the PG receptor includes PGE receptor (EP1, EP2, EP3 and EP4), PGD receptor (DP and CRTH2), PGF receptor (FP), PGI2 receptor (IP) and TX receptor (TP).

[0185] Examples of the prostaglandin synthase inhibitor include sulfasalazine, mesalazine, olsalazine, 4-aminosalicylic acid, JTE-522, auranofin, carprofen, bifenthrin, flunoprofen, flurbiprofen, indomethacin, ketoprofen, lornoxicam, loxoprofen, meloxicam, oxaprozin, parsatomide, naproxen, piroxicam, piroxicam cinnamate, zaltoprofen and pranoprofen.

[0186] Examples of the phosphodiesterase inhibitors include rolipram, cilomilast, Bay 19-8004, NIK-616, roflumilast (BY-217), sipanthelline (BRL-61063), atizolam (CP-80633), ONO-6126, SCH-351591, YM-976, V-11294A, PD-168787, D-4396 and IC-485.

[0187] Examples of the anti-TNF-α preparation include anti-TNF-α antibodies, soluble TNF-α receptors, anti-TNF-α receptor antibodies and soluble TNF-α binding proteins and particularly infliximab and etanercept.

[0188] Examples of such anti-IL-1 agents include anti-IL-1 antibodies, soluble IL-1 receptors, anti-IL-1Ra antibodies and / or anti-IL-1 receptor antibodies and in particular anakinra.

[0189] Examples of the anti-IL-6 agent include anti-IL-6 antibodies, soluble IL-6 receptors, and anti-IL-6 receptor antibodies, and particularly tocilizumab.

[0190] Examples of the cytokine inhibitor include suplatast tosylate, T-614, SR-31747, and sonatimod.

[0191] Examples of the HMG-CoA reductase inhibitor include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

[0192] Examples of the thiazolidine derivatives include pioglitazone, ciglitazone, rosiglitazone, and troglitazone.

[0193] Furthermore, combination drugs that can be used in combination with the compound of the present invention include not only those that have been discovered so far but also those that may be discovered in the future.

[0194] The compounds of the present invention are usually administered systemically or topically after being formulated into a suitable pharmaceutical composition together with a pharmaceutically acceptable carrier, by oral or parenteral administration. Examples of oral drugs include liquid drugs for oral administration (e.g., elixirs, syrups, pharmaceutically acceptable aqueous bases, suspensions and emulsions) and solid drugs for oral administration (e.g., tablets (including sublingual tablets and orally disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules and microcapsules), powders, granules and lozenges). Examples of parenteral drugs include liquid drugs (e.g., injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drips, etc.), eye drops (e.g., aqueous eye drops (aqueous eye drops, aqueous eye drop suspensions, viscous eye drops, and water-soluble eye drops, etc.) and non-aqueous eye drops (e.g., non-aqueous eye drops and non-aqueous eye drop suspensions)), etc.), external drugs (e.g., ointments (ophthalmic ointments, etc.)), ear drops, etc. These preparations may be controlled release preparations such as rapid release preparations, sustained release preparations, etc. These preparations can be prepared by well-known methods, for example, by the methods described in the Japanese Pharmacopoeia.

[0195] Liquid medicines for oral administration can be prepared by, for example, dissolving or suspending the compound of the present invention in a commonly used diluent (e.g., purified water, ethanol or a mixed liquid thereof). The liquid medicine may contain a wetting agent, a suspending agent, a sweetener, a flavoring, a fragrance, a preservative, a buffer, etc.

[0196] Solid medicines for oral administration are prepared in the following manner, for example, by mixing the compound of the present invention with, for example, a vehicle (e.g., lactose, mannitol, glucose, microcrystalline cellulose and starch), a binder (e.g., hydroxypropylcellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate), a disintegrant (e.g., sodium carboxymethylcellulose), a lubricant (e.g., magnesium stearate), a stabilizer, a dissolution aid (e.g., glutamic acid, aspartic acid), etc., and preparing according to a standard method. If necessary, coating can be achieved with a coating agent (e.g., sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate), and two or more layers of coating can be used.

[0197] Externally applied drugs as parenteral drugs can be prepared by well-known methods or commonly used prescriptions. For example, ointments can be prepared by grinding or melting the compounds of the present invention into a matrix material. The ointment matrix material is selected from well-known materials or commonly used materials. For example, a single material or a mixture of two or more materials is selected from higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester and oleic acid ester), waxes (e.g., beeswax, spermaceti and ceresin), surfactants (e.g., polyoxyethylene alkyl ether phosphate), higher alcohols (e.g., cetyl alcohol, stearyl alcohol and cetearyl alcohol), silicone oils (e.g., dimethylpolysiloxane), hydrocarbons (e.g., hydrophilic vaseline, white vaseline, lanolin and liquid paraffin), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol), vegetable oils (e.g., castor oil, olive oil, sesame oil, turpentine), animal oils (e.g., mink oil, egg yolk oil, squalane and squalene), water, absorption promoters and anti-irritants. In addition, moisturizers, preservatives, stabilizers, antioxidants, fragrances, etc. are also included.

[0198] Injections as parenteral drugs include solutions, suspensions, emulsions, and solid injections dissolved or suspended in solvents before use. The injection is used by, for example, dissolving, suspending, or emulsifying the compound of the present invention in a solvent. Examples of the solvent include distilled water for injection, physiological saline, vegetable oils, alcohols, such as propylene glycol, polyethylene glycol, ethanol, and mixtures thereof. In addition, the injection may contain stabilizers, dissolution aids (glutamic acid, aspartic acid, and polysorbate 80 (registered trademark), etc.), suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. This injection is prepared by sterilizing in the final step or using aseptic operation. In addition, sterile solid products, such as prepared freeze-dried products, can also be used, and sterilized in sterile distilled water for injection or other solvents or dissolved in sterile distilled water for injection or other solvents before use.

[0199] The dosage of the compound of the present invention can be appropriately selected according to symptoms, age, preparation, etc. Oral administration may preferably be in a dosage of 1 to 100 mg, more preferably 5 to 30 mg once or more per day (e.g., 1-3 times). Alternatively, the drug may be administered parenterally once or more in the range of 50 μg to 500 mg per day or continuously for 1 to 24 hours.

[0200] Needless to say, as described above, the dosage used varies depending on various conditions. Therefore, in some cases, a dosage lower than the above specific range may be sufficient, while in some cases, a dosage higher than the above specific range is required. Example

[0201] Hereinafter, the present invention is described in detail with reference to the following examples, but the present invention is not limited thereto.

[0202] The solvents given in parentheses shown in chromatographic separation and TLC each indicate an elution solvent or a developing solvent used, and the ratio thereof is expressed as a volume ratio.

[0203] Unless otherwise stated, NMR data are 1 H-NMR data.

[0204] In the NMR data, the description in parentheses indicates the solvent used for the measurement.

[0205] The names of compounds used in this specification are named using ACD / Name (registered trademark) manufactured by Advanced Chemistry Development Inc., which is a computer program for naming compounds according to the rules of IUPAC, or the names of compounds are named according to the nomenclature of IUPAC.

[0206] Example 1 :4-[(6-chloro-3-pyridyl)oxy]-6,7-dimethoxyquinoline

[0207] Under nitrogen flow, a solution of 4-chloro-6,7-dimethoxyquinoline (1.00 g) (CAS registration number: 35654-56-9) in chlorobenzene (9 mL), 6-chloropyridine-3-ol (0.65 g) and triethylamine (11.3 mL) were placed in a 100 mL four-necked flask, and the mixture was stirred at a bath temperature (140°C) for five days. The resulting solution was cooled to room temperature, water and ethyl acetate were added thereto, and the solution was separated. The water layer was extracted again with ethyl acetate, and the combined organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1:8) to obtain the title compound (1.16 g) having the following physical property values.

[0208] TLC: Rf 0.22 (hexane:ethyl acetate = 1:3);

[0209] 1 H-NMR (DMSO-d6): δ 8.52, 8.48, 7.87-7.85, 7.66, 7.49, 7.43, 6.65, 3.95, 3.93.

[0210] Example 2 :5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-aminopyridine

[0211] Under nitrogen flow, a solution of the compound (1.15 g) prepared in Example 1 in tetrahydrofuran (THF) (18 mL), 1.0 mol / L bis(trimethylsilyl) lithium amide (LHDMS) (5.45 mL), tri(dibenzylideneacetone) dipalladium (0) chloroform complex (0.19 g) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.15 g) were placed in a 200 mL four-necked flask, and the mixture was stirred at bath temperature (80°C) for 16.5 hours. In addition, 6 mol / L hydrochloric acid (10 mL) was added thereto, and the mixture was stirred at bath temperature (80°C) for 2 hours. The mixture was cooled to room temperature, saturated sodium bicarbonate aqueous solution and ethyl acetate were then added, and the resulting solution was separated. The water layer was extracted again with ethyl acetate, and the combined organic layer was washed with saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=9:1) to give the title compound (0.80 g) having the following physical property values.

[0212] TLC: Rf 0.51 (ethyl acetate:methanol = 4:1);

[0213] 1 H-NMR (DMSO-d6): δ 8.45, 7.89, 7.51, 7.38-7.36, 6.56, 6.42, 6.05, 3.94.

[0214] Example 3 :2,5-Dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylic acid ethyl ester

[0215] At room temperature, 1,3-cyclohexanedione (CAS Reg. No.: 504-02-9) (13.25 g) was dissolved in N,N-dimethylformamide (DMF) (200 mL), and potassium tert-butoxide (13.26 g) and (E)-2-cyano-3-ethoxy-2-ethyl propenoate (CAS Reg. No.: 94-05-3) (20.00 g) were added thereto, and then stirred for 21 hours. The reaction solution was diluted with ethyl acetate, 2 mol / L aqueous hydrochloric acid solution was added thereto, and the resulting product was stirred. Ethyl acetate and water were further added, and the organic layer was extracted. The resulting product was washed with a saturated saline solution, then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (23.62 g) having the following physical property values.

[0216] TLC: Rf 0.35 (hexane:ethyl acetate = 1:1);

[0217] 1 H-NMR (CDCl3): δ 1.37, 2.19, 2.61, 2.92, 4.36, 8.63.

[0218] Example 4 :2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxylic acid

[0219] At room temperature, the compound (10.00 g) prepared in Example 3 was dissolved in ethanol (200 mL), aniline (3.94 g) was added thereto, and the product therefrom was stirred for 6 hours. The solid precipitated from the reaction solution was collected by Kiriyama funnel filtration and washed with ethanol. The obtained residue was dried under reduced pressure at 60 ° C. The title compound (4.01 g) was obtained, which had the following physical property values.

[0220] TLC: Rf 0.37 (dichloromethane:methanol = 9:1);

[0221] 1 H-NMR (CDCl3): δ 2.11, 2.60, 7.25, 7.63, 9.21.

[0222] Embodiment 5:

[0223] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (Compound A)

[0224]

[0225] The compound prepared in Example 4 (105 mg) and O-(7-aza-1-benzotriazolyl)-N,N,N',N'-tetramethyl Hexafluorophosphate (HATU) (192 mg) was dissolved in DMF (2 mL), diisopropylethylamine (DIPEA) (0.17 mL) and the compound prepared in Example 2 (100 mg) were added thereto, and the resulting product was stirred for 21 hours. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 30:70 → 0:100 → ethyl acetate: methanol = 70:30) to obtain the title compound (116 mg) having the following physical property values.

[0226] TLC: Rf 0.76 (ethyl acetate:methanol = 5:1);

[0227] 1 H-NMR (CDCl3): δ 2.13, 2.60, 4.05, 6.44, 7.25, 7.42, 7.53, 7.63, 8.22, 8.48, 8.51, 9.32, 11.93.

[0228] Example 5 (1) :

[0229] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (C-type crystal)

[0230] Compound A (10 mg) prepared by a method similar to that of Example 5 was placed in a 1.5 mL vial, 17% hydrated acetonitrile (0.9 mL) was added thereto, and the resulting product was stirred at 60 to 80° C. The reaction solution was cooled to room temperature, and the resulting crystals were collected by filtration and dried overnight at room temperature to give the title compound (4 mg) as white crystals.

[0231] Example 5 (2) :

[0232] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (D-type crystal)

[0233] Compound A (60 mg) prepared by the method corresponding to Example 5 was placed in a 10-mL test tube, and acetonitrile (3 mL) was added thereto. The resulting product was stirred at 60 to 80 ° C. The reaction solution was cooled to room temperature, and the resulting crystals were collected by filtration, and dried overnight at room temperature to obtain the title compound (15 mg) as white crystals.

[0234] Example 5 (3) :

[0235] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (E-type crystal)

[0236] Compound A (10 mg) prepared in Example 5 was placed in a 1.5 mL vial, 33% hydrated acetone (0.75 mL) was added thereto, and then stirred at 45 to 55° C. The reaction solution was cooled to room temperature, and the resulting crystals were collected by filtration and dried overnight at room temperature to give the title compound (3 mg) as white crystals. Fig.18As a result, an endothermic peak due to dehydration and a pattern change in the X-ray diffraction spectrum were observed around 55 to 70°C depending on the change in the crystal structure. This indicates that the compound of this example is a hydrate of compound A.

[0237] Example 5 (4) :

[0238] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (F-type crystal)

[0239] Acetone (80 mL) was added to compound A (23.7 g) prepared in the same manner as in Example 5. The product was stirred at 40 ° C for 1 hour, and the powder was collected by filtration. Methanol (120 mL) was added to the collected powder. The product was stirred at 60 ° C for 1 hour. After cooling, the resulting crystals were collected by filtration, and the title compound (21.4 g) was obtained at 80 ° C overnight as white crystals.

[0240] Embodiment 5 (5):

[0241] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (G-type crystal)

[0242] The compound prepared in Example 5 (4) (10 mg) was placed in a 1.5 mL vial, 33% hydrated acetonitrile (0.75 mL) was added thereto, and then stirred at 45 to 55° C. The reaction solution was cooled to room temperature, and the obtained crystals were collected by filtration and dried at room temperature overnight to give the title compound (7 mg) as white crystals.

[0243] Example 5 (6) :

[0244] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide (H-type crystal)

[0245] The compound prepared in Example 5 (4) (60 mg) was placed in a 10-mL test tube, acetonitrile (3 mL) was added thereto, and then stirred at 60 to 80° C. The reaction solution was cooled to room temperature, and the obtained crystals were collected by filtration and dried at room temperature overnight to give the title compound (40 mg) as white crystals.

[0246] Example 6 :

[0247] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate

[0248] Compound A (9 g) prepared in Example 5 was placed in a 50-mL flask, acetone (270 mL) was added thereto, and then stirred at 40 to 50° C. Ethanesulfonic acid (1.31 mL) was added to the reaction solution, and the resulting crystals were collected by filtration and dried overnight at 60° C. Thus, the title compound (11 g) having the following physical property values ​​was obtained as white crystals.

[0249] LC-MS: 563 (M+H) + ;

[0250] 1 H-NMR (DMSO-d6): δ 1.04, 1.93- 2.05, 2.36, 2.45- 2.59, 4.02, 4.03, 7.01, 7.43- 7.50, 7.53, 7.57- 7.69, 7.74, 7.99, 8.44- 8.53, 8.81, 8.98, 12.04.

[0251] Example 7 :

[0252] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide hydrochloride (C-type crystal)

[0253] The compound A (0.5 g) prepared in Example 5 is placed in a 50-mL flask, acetonitrile (80 mL) is added thereto, and then stirred at 15 to 25 ° C. 2 mol / L aqueous hydrochloric acid solution (0.93 mL) is added to the reaction solution, and the mixture is stirred. The solvent is removed by evaporation under reduced pressure, and the title compound (0.53 g) with the following physical property values ​​is obtained at 75 ° C for drying overnight, and it is white crystals.

[0254] LC-MS: 563 (M+H) + ;

[0255] 1H-NMR (DMSO-d6): δ 1.93- 2.06, 2.46- 2.55, 4.02, 4.04, 6.99, 7.44- 7.50, 7.57, 7.58- 7.69, 7.75, 8.00, 8.45- 8.53, 8.81, 8.99, 12.05.

[0256] Example 7 (1):

[0257] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide hydrochloride

[0258] The compound prepared in Example 5 is added to a solvent (e.g., dioxane) or a mixed solvent (e.g., a mixed solvent of acetonitrile and water) and an aqueous hydrochloric acid solution, or an organic solvent solution is added so that its temperature is 25 to 90° C., and then the solvent is removed by evaporation under reduced pressure and dried to give the title compound in an amorphous form.

[0259] Example 7 (2) :

[0260] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide hydrochloride (D-type crystal)

[0261] The compound prepared in Example 7 (1) (40 mg) was placed in a 10-mL test tube, methanol (1.2 mL) was added thereto, and then stirred at 40 to 60° C. The reaction solution was cooled to room temperature, and the obtained crystals were collected by filtration and dried at 60° C. overnight to obtain the title compound (10 mg) as white crystals.

[0262] Example 7 (3) :

[0263] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide hydrochloride (B-type crystal)

[0264] The compound prepared in Example 7 (1) (5 mg) was placed in a 10-mL test tube, acetone (0.6 mL) was added thereto, and then stirred at 40 to 60° C. The reaction solution was cooled to room temperature, and the obtained crystals were collected by filtration and dried at 60° C. overnight to obtain the title compound (3 mg) as white crystals.

[0265] Embodiment 8:

[0266] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide methanesulfonate (A-type crystal)

[0267] Compound A (100 mg) prepared in Example 5 was placed in a 10-mL flask, acetone (3 mL) was added thereto, and then stirred at 40 to 55° C. Methanesulfonic acid (12 μL) was added to the reaction solution, and the resulting crystals were collected by filtration and dried overnight at 75° C. The title compound (112 mg) having the following physical property values ​​was thus obtained as white crystals.

[0268] LC-MS: 563 (M+H) + ;

[0269] 1 H-NMR (DMSO-d6): δ 1.94- 2.06, 2.31, 2.47- 2.55, 4.03, 4.05, 7.04, 7.44-7.51, 7.55, 7.58- 7.70, 7.76, 8.01, 8.46- 8.54, 8.84, 8.99, 12.05.

[0270] Example 8 (1) :

[0271] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide methanesulfonate (B-type crystal)

[0272] The compound prepared in Example 8 is added to a mixed solvent (eg, a mixed solvent of methanol and dioxane), dissolved at 40 to 80° C., and then cooled until crystals are generated. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0273] Example 8 (2) :

[0274] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide methanesulfonate (C-type crystal)

[0275] The compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol), and methanesulfonic acid is added to the solution. Then, the solvent is concentrated, and a solvent (e.g., methanol) is added to the residue. Products therefrom is heated to 30 to 50 ° C and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as a crystal.

[0276] Embodiment 9:

[0277] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide p-toluenesulfonate (C-type crystal)

[0278] The compound (5 g) prepared in Example 5 is placed in a 300-mL flask, acetone (135 mL) is added thereto, and then stirred at 40 to 55 ° C. A solution of p-toluenesulfonic acid-monohydrate (1.86 g) in acetone (15 mL) is added to the reaction solution. The resulting solution is stirred. The resulting crystals are collected by filtration and dried to give crude crystals. 10% hydrated acetone (12 mL) is added to the crude crystals (1 g), and stirred at 40 to 55 ° C. The resulting crystals are collected by filtration, and dried overnight at 75 ° C to obtain the title compound (0.7 g) with the following physical property values, which is a white crystal.

[0279] LC-MS: 563 (M+H) + ;

[0280] 1 H-NMR (DMSO-d6): δ 1.93- 2.06, 2.28, 2.40- 2.59, 4.03, 4.04, 7.02, 7.10, 7.43- 7.50, 7.52, 7.56- 7.69, 7.76, 8.00, 8.45- 8.53, 8.83, 8.99, 12.05.

[0281] Example 9 (1) :

[0282] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide p-toluenesulfonate (A-type crystal)

[0283] The compound prepared in Example 9 is added to a mixed solvent (e.g., a mixed solvent of tetrahydrofuran and water) and dissolved at 50 to 70° C. Then, the obtained product is cooled. Then, the obtained crystals are separated and dried to obtain the title compound as crystals.

[0284] Example 9 (2) :

[0285] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide p-toluenesulfonate (B-type crystal)

[0286] A solvent (eg, acetone) and p-toluenesulfonic acid monohydrate are added to the compound A prepared in Example 5, and the mixture is heated to 30 to 50° C. and stirred. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0287] Example 9 (3) :

[0288] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide p-toluenesulfonate (G-type crystal)

[0289] The compound prepared in Example 9 is added to a mixed solvent (e.g., a mixed solvent of ethanol and water), and the resulting solution is heated to 60 to 80° C. and stirred for more than 12 hours. The resulting crystals are then separated and dried to obtain the title compound as crystals.

[0290] Example 9 (4) :

[0291] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide p-toluenesulfonate (H-type crystal)

[0292] A mixed solvent (e.g., a mixed solvent of water and acetone) is added to the compound A prepared in Example 5, p-toluenesulfonic acid monohydrate is added, the solvent is heated at 30 to 50° C., stirred, and cooled. Then, the resulting crystals are separated and dried to obtain the title compound as crystals.

[0293] Example 10 :

[0294] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide sulfate (A-type crystal)

[0295] Compound A (0.9 g) prepared in Example 5 was placed in a 100-mL flask, acetone (27 mL) was added thereto, and then stirred at 40 to 55° C. To the reaction solution was added a 0.25 mol / L aqueous sulfuric acid solution (370 µL), the resulting crystals were collected by filtration, and dried overnight at 75° C. to obtain the title compound (107 mg) having the following physical property values ​​as white crystals.

[0296] LC-MS: 563 (M+H) + ;

[0297] 1 H-NMR (DMSO-d6): δ 1.94- 2.06, 2.41- 2.61, 4.00- 4.08, 6.98- 7.05, 7.43-7.55, 7.57- 7.70, 7.73- 7.78, 7.96- 8.04, 8.44- 8.54, 8.78- 8.86, 8.97-9.01, 12.02-12.07.

[0298] Example 10 (1) :

[0299] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide sulfate (B-type crystal)

[0300] The compound prepared in Example 10 is added to a mixed solvent (e.g., a mixed solvent of dimethyl sulfoxide and water), dissolved at 70 to 90° C., and then cooled to generate crystals. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0301] Example 10 (2) :

[0302] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide sulfate (C-type crystal)

[0303] A solvent (eg, acetone) and sulfuric acid are added to the compound A prepared in Example 5, heated to 30 to 50° C. and stirred. Then, the resulting crystals are separated and dried to obtain the title compound as crystals.

[0304] Embodiment 11 :

[0305] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide phosphate (A-type crystal)

[0306] Compound A (0.10 g) prepared in Example 5 was placed in a 10-mL flask, acetone (3 mL) and 85% phosphoric acid (22 mg) were added thereto, and then stirred at 40 to 55° C. The resulting crystals were collected by filtration and dried at 90° C. for 1 hour to obtain the title compound (0.11 g) having the following physical property values ​​as white crystals.

[0307] LC-MS: 563 (M+H) + ;

[0308] 1 H-NMR (DMSO-d6): δ 1.95- 2.04, 2.47- 2.56, 3.93, 3.95, 6.55, 7.41, 7.45-7.49, 7.52, 7.56- 7.68, 7.87, 8.34- 8.37, 8.40- 8.45, 8.49, 8.98, 11.97.

[0309] Example 11 (1) :

[0310] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide phosphate (B-type crystal)

[0311] A solvent (e.g., methanol) and phosphoric acid are added to the compound A prepared in Example 5, and the resulting product is heated to 30 to 50° C. and stirred until crystals are generated. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0312] Example 11 (2) :

[0313] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide phosphate (C-type crystal)

[0314] To the compound A prepared in Example 5, a solvent (e.g., tetrahydrofuran) and phosphoric acid are added, and the resulting product is heated to 40 to 60° C. and stirred until crystals are generated. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0315] Example 11(3):

[0316] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide phosphate (D-type crystal)

[0317] To the compound A prepared in Example 5, a solvent (e.g., 2-propanol) and phosphoric acid are added, and the resulting product is heated to 60 to 80° C. and stirred until crystals are generated. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0318] Example 11 (4) :

[0319] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide phosphate (E-type crystal)

[0320] A solvent (e.g., ethanol) and phosphoric acid are added to the compound A prepared in Example 5, and the resulting product is heated to 50 to 70° C. and stirred until crystals are generated. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0321] Example 12 :

[0322] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide benzenesulfonate (A-type crystal)

[0323] Compound A (0.10 g) prepared in Example 5 was placed in a 10-mL flask, acetone (3 mL) and benzenesulfonic acid (30 mg) were added thereto, and then stirred at 40 to 55° C. The resulting crystals were collected by filtration and dried at 90° C. for 1 hour to obtain the title compound (0.11 g) having the following physical property values ​​as white crystals.

[0324] LC-MS: 563 (M+H) + ;

[0325] 1 H-NMR (DMSO-d6): δ 1.95- 2.05, 2.47- 2.56, 4.03, 4.05, 7.04, 7.28- 7.34, 7.45- 7.49, 7.53, 7.57- 7.62, 7.62- 7.68, 7.77, 8.01, 8.47- 8.52, 8.84, 9.00, 12.06.

[0326] Example 12 (1):

[0327] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide benzenesulfonate (B-type crystal)

[0328] The compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol), to which benzenesulfonic acid is added. Then, the solvent is concentrated, and a solvent (e.g., ethanol) is added to the residue. The resulting product is heated to 30 to 50 ° C and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as a crystal.

[0329] Example 12(2):

[0330] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide benzenesulfonate (C-type crystal)

[0331] The compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol) and benzenesulfonic acid is added. Then, the solvent is concentrated and a solvent (e.g., tetrahydrofuran) is added to the residue. The resulting product is heated to 30 to 50 ° C and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as a crystal.

[0332] Example 12 (3) :

[0333] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide benzenesulfonate (D-type crystal)

[0334] The compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol) and benzenesulfonic acid is added. Then, the solvent is concentrated and a solvent (e.g., acetonitrile) is added to the residue. The resulting product is heated to 30 to 50 ° C and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as a crystal.

[0335] Embodiment 13 :

[0336] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethane disulfonate (A-type crystal)

[0337] Compound A (0.8 g) prepared in Example 5 was placed in a 30-mL flask, and acetone (24 mL) and a solution of ethanedisulfonic acid (386 mg) in acetone (24 mL) were added thereto, followed by stirring at 40 to 55° C. The resulting crystals were collected by filtration and dried overnight at 90° C. to give the title compound (1.1 g) having the following physical property values ​​as brown crystals with a light yellow color.

[0338] LC-MS: 563 (M+H) + ;

[0339] 1 H-NMR (DMSO-d6): δ 1.94- 2.06, 2.45- 2.55, 2.68, 4.04, 4.06, 7.08, 7.44-7.50, 7.56- 7.70, 7.78, 8.02, 8.47- 8.53, 8.87, 8.99, 12.06.

[0340] Example 13 (1) :

[0341] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethane disulfonate (B-type crystal)

[0342] The compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol) and ethanedisulfonic acid is added. Then, the solvent is concentrated and a solvent (e.g., acetonitrile) is added to the residue. The resulting product is heated to 30 to 50° C. and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as a crystal.

[0343] Example 13 (2) :

[0344] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethane disulfonate (C-type crystal)

[0345] Compound A prepared in Example 13 is added to a solvent (eg, ethyl acetate), heated at 60 to 80° C., and stirred for 20 minutes or more. The resulting crystals are then separated and dried to obtain the title compound as crystals.

[0346] Example 13 (3) :

[0347] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethane disulfonate (D-type crystal)

[0348] The compound prepared in Example 13 is added to a solvent (e.g., dimethylacetamide), heated at 60 to 80° C., and stirred for 20 minutes or more. The resulting crystals are then separated and dried to obtain the title compound as crystals.

[0349] Embodiment 13 (4):

[0350] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethane disulfonate (E-type crystal)

[0351] The compound prepared in Example 13 is added to a solvent (eg, tetrahydrofuran), heated at 40 to 60° C., and stirred for 20 minutes or more. The resulting crystals are then separated and dried to obtain the title compound as crystals.

[0352] Embodiment 14 :

[0353] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide isethionate (A-type crystal)

[0354] Compound A (0.3 g) prepared in Example 5 was placed in a 100-mL flask, acetone (48 mL), isethionic acid (96 mg) and water (3 mL) were added thereto, and then stirred at room temperature. The reaction solution was filtered, the filtrate was concentrated, a small amount of acetonitrile was added, further concentrated, and dried overnight at room temperature to obtain the title compound (375 mg) having the following physical property values ​​as pale yellow crystals.

[0355] LC-MS: 563 (M+H) + ;

[0356] 1 H-NMR (DMSO-d6): δ 1.95- 2.06, 2.47- 2.53, 2.60, 3.62, 4.03, 4.05, 7.02, 7.44- 7.50, 7.53, 7.56- 7.69, 7.76, 8.00, 8.46- 8.53, 8.83, 9.00, 12.05.

[0357] Example 14 (1) :

[0358] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide isethionate (B-type crystal)

[0359] Compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol), and isethionic acid is added. Then, the solvent is concentrated, and a solvent (e.g., ethanol) is added to the residue. The resulting product is heated to 30 to 50° C. and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0360] Example 14 (2) :

[0361] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide isethionate (C-type crystal)

[0362] Compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol), and isethionic acid is added. Then, the solvent is concentrated, and a solvent (e.g., acetonitrile) is added to the residue. The resulting product is heated to 30 to 50° C. and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0363] Example 14 (3) :

[0364] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide isethionate (D-type crystal)

[0365] Compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol), and isethionic acid is added. Then, the solvent is concentrated, and a solvent (e.g., methanol) is added to the residue. The resulting product is heated to 30 to 50° C. and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0366] Example 14 (4) :

[0367] N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide isethionate (E-type crystal)

[0368] Compound A prepared in Example 5 is dissolved in a solvent (e.g., methanol), and isethionic acid is added. Then, the solvent is concentrated, and a solvent (e.g., tetrahydrofuran) is added to the residue. The resulting product is heated to 30 to 50° C. and allowed to stand for four hours. The resulting crystals are separated and dried to obtain the title compound as crystals.

[0369] Experimental Examples

[0370] The following are examples of physical and chemical experiments. Based on these experimental methods, the effects of the compounds of the present invention were verified.

[0371] Physical and Chemical Experiment Example 1: Evaluation of Hygroscopicity (DVS)

[0372] Various acid addition salts of compound A prepared in the embodiments (embodiments 7, 8, 9, 10, 11, 12, 13 and 14) and the compounds of the present invention (embodiment 6) were evaluated for hygroscopicity. Based on the measurement conditions shown in [3] of [the study of the acid addition salt of compound A], hygroscopicity was evaluated. The sample weight was recorded after the weight of the sample at a relative humidity of 10% setting reached equilibrium. After drying, the weight change (%) was converted based on the relative humidity of 0%. The results are shown in Table 3.

[0373] [Table 3]

[0374] Acid addition salt Weight gain at 90% relative humidity (%) Ethysulfonate 0.7 Hydrochloride 8.0 Methanesulfonate 4.0 p-Toluenesulfonate 2.6 Sulfate 7.2 Phosphate 5.5 Benzenesulfonate 7.2 Ethane disulfonate 46.4 Isethionate 14.5

[0375] As a result, among various acid addition salts of Compound A, it was found that only the compound of the present invention, i.e., ethanesulfonate of Compound A, had a small weight change rate after moisture absorption, was highly stable, and could be used as an active pharmaceutical ingredient.

[0376] Physical and Chemical Experiment Example 2: Evaluation of photostability

[0377] (1) Photostability evaluation of active pharmaceutical ingredients

[0378] The ethanesulfonate of Compound A prepared in Example 6 and the p-toluenesulfonate of Compound A prepared in Example 9 were evaluated for photostability. About 1.8 to 2.2 mg of each acid addition salt was weighed in a test tube, covered with a plastic cap, and wrapped with a sealing film. The sample placed in a transparent test tube was used as an exposure sample, the sample placed in a brown test tube was used as a light-shielded sample, and the sample placed in a brown test tube and further covered with aluminum foil was used as a sample completely shielded by aluminum foil. Each sample was exposed to light by exposing to a 2500Lux D65 lamp at 25°C for 20 days, with a total illumination of more than 1200000 Lux･h and a total near-ultraviolet radiation energy of 200 W･h / m 2 above.

[0379] (Measurement conditions)

[0380] Detector: UV spectrometer (measurement wavelength: 215 nm),

[0381] Column: Imtakt Unison UK-C18 (3 μm, inner diameter: 4.6 mm × 150 mm),

[0382] Column temperature: 40°C,

[0383] Mobile phase: Liquid A: 20 mM KH2PO4 aqueous solution (pH 3.0), Liquid B: CH3CN,

[0384] A / B = 80 / 20 (0 minutes) → 20 / 80 (60 minutes),

[0385] Flow rate: 1.0 mL / min,

[0386] Area measurement range: 60 minutes

[0387] Injection volume: 5 μL,

[0388] Sample concentration: 0.5 mg / mL.

[0389] The area percentage of each acid addition salt of the ethanesulfonate of compound A and the p-toluenesulfonate of compound A which were not exposed to light and stored at -20°C and the compound A subjected to the above-mentioned light stability test was calculated under the above-mentioned measurement conditions. Then, in each acid addition salt of compound A, the ratio of the area percentage of the acid addition salt of compound A which was not exposed to light and stored at -20°C (area percentage of the acid addition salt of compound A exposed to light for 20 days / area percentage of the acid addition salt of compound A which was not exposed to light and stored at -20°C × 100) was calculated as the residual rate of each compound. The results are shown in Table 4.

[0390] [Table 4]

[0391]

[0392] (2) Evaluation of the stability of simplified preparations

[0393] Using a spatula, each of the compound A acid addition salts of the compound A ethanesulfonate prepared in Example 6 and the compound A p-toluenesulfonate prepared in Example 9 was mixed with CEOLUS (registered trademark) PH-301 (Asahi Kasei Corporation) at a mixing ratio of 1:5 (weight ratio) on medical paper to prepare a simple preparation. The simple preparation was weighed about 3 mg in a test tube, covered with a plastic cover, and wrapped with a sealing film. In the following, the light exposure conditions and measurement conditions of the compound correspond to the photostability evaluation of the active pharmaceutical ingredient in (1) above. The results are shown in Table 5.

[0394] [Table 5]

[0395] Compound A ethanesulfonate (residual rate %) Compound A p-toluenesulfonate (residual rate %) Transparent bottle 59.3 40.7 Brown bottle 98.4 83.3 Aluminum foil masking 99.7 99.9

[0396] The above results show that Compound A ethanesulfonate is also superior to Compound A p-toluenesulfonate in terms of photostability.

[0397] [Formulation Example]

[0398] Preparation Example 1

[0399] The ingredients specified below are mixed by standard methods and the mixture is then tableted to give 10,000 tablets each containing 10 mg of the active ingredient.

[0400] · N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate…100 g

[0401] · Carboxymethylcellulose calcium (disintegrant)…20 g

[0402] · Magnesium stearate (lubricant)…10 g

[0403] · Microcrystalline cellulose…870 g

[0404] Preparation Example 2

[0405] The ingredients specified below are mixed by a standard method, filtered through a dust filter, filled into ampoules so that each ampoule contains 5 ml, and heat-sterilized in an autoclave to give 10,000 ampoules each containing 20 mg of the active ingredient.

[0406] · N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate…200g

[0407] · Mannitol…20g

[0408] · Distilled water…50L

[0409] [Industrial Applicability]

[0410] The compounds of the present invention have Axl-selective inhibitory activity and low CYP inhibitory effect, and show low hygroscopicity and are stable under moisture in various acid addition salts of compound A. Therefore, the compounds of the present invention are useful as active pharmaceutical ingredients of drugs for preventing and / or treating diseases associated with Axl expression.

[0411] In summary, the present invention relates to the following aspects:

[0412] 1. N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate.

[0413] 2. Crystals of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate.

[0414] 3. The crystal of claim 2, wherein in a powder X-ray diffraction spectrum, the crystal has peaks at the following 2θ: about 7.3, about 7.9, about 9.1, about 10.7, about 11.2, about 12.5, about 13.4, about 15.6, about 16.2, about 16.5, about 17.7, about 18.0, about 18.4, about 19.1, about 20.1, about 20.8, about 21.2, about 21.5, about 22.4, about 23.0, about 23.6 and about 24.0 degrees.

[0415] 4. The crystal of item 2 or 3, which has Figure 1 The characteristics of the powder X-ray diffraction spectrum are shown in .

[0416] 5. The crystal of items 2 to 4, wherein in differential scanning calorimetry, the crystal has an endothermic peak at an onset temperature of about 283°C or a peak temperature of about 286°C.

[0417] 6. The crystal of any one of items 2 to 5, which has Figure 2 Features of the differential scanning calorimetry spectrum shown in .

[0418] 7. A pharmaceutical composition comprising N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridinyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate or a crystal of any one of items 2 to 6, and a pharmaceutically acceptable carrier.

[0419] 8. The pharmaceutical composition of item 7, which is an Axl inhibitor.

[0420] 9. The pharmaceutical composition according to Item 7, which is a preventive and / or therapeutic agent for Axl-related diseases.

[0421] 10. The pharmaceutical composition of claim 9, wherein the Axl-related disease is cancer, an immune system disease or a circulatory system disease.

[0422] 11. The pharmaceutical composition of claim 10, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, melanoma, uveal malignant melanoma, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, vaginal cancer, vulvar cancer, renal cell carcinoma, urothelial carcinoma, prostate cancer, testicular cancer, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, pleural mesothelioma or cancer of unknown origin.

Claims

1. A crystal of N-{5-[(6,7-dimethoxy-4-quinolyl)oxy]-2-pyridyl}-2,5-dioxo-1-phenyl-1,2,5,6,7,8-hexahydro-3-quinolinecarboxamide ethanesulfonate, wherein in a powder X-ray diffraction spectrum, the crystal has peaks at the following 2θ: 7.3±0.2, 7.9±0.2, 9.1±0.2, 10.7±0.2, 11.2±0.2, 12.5 ±0.2, 13.4±0.2, 15.6±0.2, 16.2±0.2, 16.5±0.2, 17.7±0.2, 18.0±0.2, 18.4±0.2, 19.1±0.2, 20.1±0.2, 20.8±0.2, 21.2±0.2, 21.5±0.2, 22.4±0.2, 23.0±0.2, 23.6±0.2 and 24.0±0.2 degrees.

2. The crystal of claim 1, which has the characteristics of the powder X-ray diffraction spectrum shown in FIG1.

3. The crystal of claim 1, wherein in differential scanning calorimetry, the crystal has an endothermic peak at an onset temperature of 283±2°C or a peak temperature of 286±2°C.

4. The crystal of claim 1, which has the characteristics of the differential scanning calorimetry spectrum shown in Figure 2.

5. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 5 , which is an Axl inhibitor. 7 . The pharmaceutical composition according to claim 5 , which is a preventive and / or therapeutic agent for Axl-related diseases.

8. The pharmaceutical composition of claim 7, wherein the Axl-related disease is cancer, an immune system disease or a circulatory system disease.

9. The pharmaceutical composition of claim 8, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, melanoma, uveal malignant melanoma, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, vaginal cancer, vulvar cancer, renal cell carcinoma, urothelial carcinoma, prostate cancer, testicular cancer, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, pleural mesothelioma, or cancer of unknown origin.

10. Use of the pharmaceutical composition of claim 5 in the preparation of an Axl inhibitor.

11. Use of the pharmaceutical composition of claim 5 in the preparation of a preventive and / or therapeutic agent for Axl-related diseases.

12. The use according to claim 11, wherein the Axl-related disease is cancer, immune system disease or circulatory system disease.

13. The method of claim 12, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, melanoma, uveal malignant melanoma, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, vaginal cancer, vulvar cancer, renal cell carcinoma, urothelial carcinoma, prostate cancer, testicular cancer, bone and soft tissue sarcoma, skin cancer, glioma, brain tumor, pleural mesothelioma or cancer of unknown origin.

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