Optically Active Tetrahydronaphthalene Derivative
A compound represented by the following formula (I), a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof, which shows not only a C5a receptor antagonistic activity but also high activity in the biological availability, as compared to its racemate.
1 - 44 . (canceled)
45 . (1S)-(−)-N-[(1-Ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide represented by the following formula (I)
a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof.
46 . A crystal of (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof.
47 . The crystal of claim 46 , which is a crystal of (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide.
48 . The crystal of claim 47 , which shows a peak at a diffraction angle 2θ of about 14.6° (±0.2°) in powder X-ray diffraction spectrum.
49 . The crystal of claim 47 , which shows a peak at a diffraction angle 2θ of about 10.0° (±0.2°) in powder X-ray diffraction spectrum.
50 . The crystal of claim 47 , which shows a peak at a diffraction angle 2θ of about 8.5° (±0.2°) in powder X-ray diffraction spectrum.
51 . The crystal of claim 47 , which shows peaks at a diffraction angle 2θ of about 20.1 and 23.2° (±0.2°, respectively) in powder X-ray diffraction spectrum.
52 . The crystal of claim 47 , which shows characteristic peaks at a diffraction angle 2θ of about 8.5, 10.0, 14.6, 20.1 and 23.2° (each ±0.2°) in powder X-ray diffraction spectrum.
53 . The crystal of claim 47 , which has a melting point (extrapolation-onsest temperature) of about 171 to about 176° C.
54 . The crystal of claim 47 , which has a melting point (extrapolation-onsest temperature) of about 176° C.
55 . The crystal of claim 47 , which has the physicochemical property shown in the following A and/or B:
A: having a powder X-ray diffraction pattern shown in FIG. 1
B: having a differential scanning calorimetry curve shown in FIG. 2 .
56 . The crystal of claim 47 , which shows a peak at a diffraction angle 2θ of about 5.9° (±0.2°) in powder X-ray diffraction spectrum.
57 . The crystal of claim 47 , which shows a peak at a diffraction angle 2θ of about 15.6° (±0.2°) in powder X-ray diffraction spectrum.
58 . The crystal of claim 47 , which shows a peak at a diffraction angle 2θ of about 11.9° (±0.2°) in powder X-ray diffraction spectrum.
59 . The crystal of claim 47 , which shows a peak at a diffraction angle 2θ of about 21.3° (±0.2°) in powder X-ray diffraction spectrum.
60 . The crystal of claim 47 , which shows characteristic peaks at a diffraction angle 2θ of about 5.9, 11.9, 15.6 and 21.3° (±0.2°, respectively) in powder X-ray diffraction spectrum.
61 . The crystal of claim 47 , which has a melting point (extrapolation-onsest temperature) of about 96° C.
62 . The crystal of claim 47 , which has the physicochemical property shown in the following C and/or D:
C: having a powder X-ray diffraction pattern shown in FIG. 3
D: having a differential scanning calorimetry curve shown in FIG. 4 .
63 . An amorphous form of (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof.
64 . The amorphous form of claim 63 , which is an amorphous form of (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide.
65 . The amorphous form of claim 64 , which has the physicochemical property shown in the following E:
E: having a powder X-ray diffraction pattern shown in FIG. 5 .
66 . The (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof of claim 45 , whose pharmacologically acceptable salt is a hydrochloride.
67 . The (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof of claim 66 , whose pharmacologically acceptable salt is a monohydrochloride.
68 . The (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof of claim 45 , whose pharmacologically acceptable salt is a hydrobromide.
69 . The (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof of claim 68 , whose pharmacologically acceptable salt is a monohydrobromide.
70 . A pharmaceutical agent comprising the compound of claim 45 .
71 . A pharmaceutical composition comprising the compound of claim 45 , and a pharmaceutically acceptable additive.
72 . A method for the prophylaxis or treatment of a disease caused by binding of C5a with a C5a receptor, which comprises administering a pharmaceutically effective amount of the compound of claim 45 as an active ingredient to a patient in need of the prophylaxis or treatment.
73 . The method of claim 72 , wherein the disease caused by the binding of C5a with a C5a receptor is autoimmune disease, sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, allergic disease, atherosclerosis, myocardial infarction, cerebral infarction, psoriasis, Alzheimer's disease, or organ injury caused by leukocyte activation due to ischemia reperfusion, trauma, bum or surgical invasion.
74 . A method for the prophylaxis and/or treatment of inflammation, which comprises administering a pharmaceutically effective amount of the compound of claim 45 as an active ingredient to a patient in need of the prophylaxis and/or treatment.
75 . A C5a receptor antagonist comprising the compound of claim 45 as an active ingredient.
76 . A method for the prophylaxis and/or treatment of infection with bacterium or virus that invades via a C5a receptor, which comprises administering a pharmaceutically effective amount of the compound of claim 45 as an active ingredient to a patient in need of the prophylaxis and/or treatment.
77 . A method for the prophylaxis and/or treatment of rheumatoid arthritis, which comprises administering a pharmaceutically effective amount of, as an active ingredient, (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof to a patient in need of the prophylaxis and/or treatment.
78 . The method of claim 77 , wherein the active ingredient is (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide.
79 . The method of claim 78 , wherein the active ingredient is a crystal of (1S)-(−)-N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide.
80 . The method of claim 79 , wherein the active ingredient shows characteristic peaks at a diffraction angle 2θ of about 8.5, 10.0, 14.6, 20.1 and 23.2° (each ±0.2°) in powder X-ray diffraction spectrum.
81 . The method of claim 79 , wherein the active ingredient has a melting point (extrapolation-onsest temperature) of about 176° C.
82 . 1-Ethyl-N-(6-isopropylpyridin-3-yl)-1H-pyrazole-4-carboxamide or N-(6-isopropylpyridin-3-yl)-1-vinyl-1H-pyrazole-4-carboxamide, which is represented by the following formula (II)
wherein R is ethyl or vinyl.
83 . [(1-Ethyl-1H-pyrazol4-yl)methyl](6-isopropylpyridin-3-yl)amine or (6-isopropylpyridin-3-yl)[(1-vinyl-1H-pyrazol-4-yl)methyl]amine, which is represented by the following formula (III)
wherein R is ethyl or vinyl.
84 . A 1-ethyl-1H-pyrazole compound represented by the following formula (IV)
wherein Ra is hydroxymethyl.
85 . Ethyl 1-(2-chloroethyl)-1H-pyrazole-4-carboxylate represented by the following formula (V)
86 . A 1-vinyl-1H-pyrazole compound represented by the following formula (VI)
wherein Rb is ethoxycarbonyl, hydroxycarbonyl, hydroxymethyl or formyl.
87 . (1S)-(−)-N-[(1-Ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof of claim 45 , wherein the solvate is a methanol solvate.
88 . (1S)-(−)-N-[(1-Ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide, a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate thereof of claim 87 , wherein the solvate is a monomethanol solvate.
89 . A pharmaceutical composition comprising the compound of claim 46 , and a pharmaceutically acceptable additive.
90 . A pharmaceutical composition comprising the compound of claim 63 , and a pharmaceutically acceptable additive.
91 . A method for the prophylaxis or treatment of a disease caused by binding of C5a with a C5a receptor, which comprises administering a pharmaceutically effective amount of the compound of claim 46 as an active ingredient to a patient in need of the prophylaxis or treatment.
92 . A method for the prophylaxis or treatment of a disease caused by binding of C5a with a C5a receptor, which comprises administering a pharmaceutically effective amount of the compound of claim 63 as an active ingredient to a patient in need of the prophylaxis or treatment.
93 . A method for the prophylaxis and/or treatment of inflammation, which comprises administering a pharmaceutically effective amount of the compound of claim 46 as an active ingredient to a patient in need of the prophylaxis and/or treatment.
94 . A method for the prophylaxis and/or treatment of inflammation, which comprises administering a pharmaceutically effective amount of the compound of claim 63 as an active ingredient to a patient in need of the prophylaxis and/or treatment.
95 . A method for the prophylaxis and/or treatment of infection with bacterium or virus that invades via a C5a receptor, which comprises administering a pharmaceutically effective amount of the compound of claim 46 as an active ingredient to a patient in need of the prophylaxis and/or treatment.
96 . A method for the prophylaxis and/or treatment of infection with bacterium or virus that invades via a C5a receptor, which comprises administering a pharmaceutically effective amount of the compound of claim 63 as an active ingredient to a patient in need of the prophylaxis and/or treatment.