JPWO2016152952A1 - 環状アミン誘導体及びその医薬用途 - Google Patents
環状アミン誘導体及びその医薬用途 Download PDFInfo
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- JPWO2016152952A1 JPWO2016152952A1 JP2016520699A JP2016520699A JPWO2016152952A1 JP WO2016152952 A1 JPWO2016152952 A1 JP WO2016152952A1 JP 2016520699 A JP2016520699 A JP 2016520699A JP 2016520699 A JP2016520699 A JP 2016520699A JP WO2016152952 A1 JPWO2016152952 A1 JP WO2016152952A1
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- Prior art keywords
- mmol
- reaction
- imidazol
- dimethylamino
- cyclic amine
- Prior art date
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- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 28
- 230000000202 analgesic effect Effects 0.000 claims abstract description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 19
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- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
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- 229940100515 sorbitan Drugs 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
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- AKQXKEBCONUWCL-MRVPVSSYSA-N tert-butyl (3r)-3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](N)C1 AKQXKEBCONUWCL-MRVPVSSYSA-N 0.000 description 1
- AKQXKEBCONUWCL-QMMMGPOBSA-N tert-butyl (3s)-3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](N)C1 AKQXKEBCONUWCL-QMMMGPOBSA-N 0.000 description 1
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
一般式(I)で示される環状アミン誘導体(以下、環状アミン誘導体(I)と略す;その他の一般式で示される誘導体についても同様に略す。)は、例えば、塩基存在下又は非存在下、3−ジメチルアミノ環状アミン誘導体(II)とカルボン酸誘導体(III)とを縮合剤を用いて縮合反応することにより得られる。
環状アミン誘導体(I)の薬理学的に許容される塩は、例えば、環状アミン誘導体(I)と酸とを混合することによる塩化反応により得られる。
(工程1)
3−ジメチルアミノ環状アミン誘導体(V)は、ケト環状アミン誘導体(IV)とジメチルアミンとの還元的アミノ化反応により得られる。
3−ジメチルアミノ環状アミン誘導体(V)は、3−アミノ環状アミン誘導体(VI)とホルムアルデヒドとの還元的アルキル化反応により得られる。
3−ジメチルアミノ環状アミン誘導体(II)は、3−ジメチルアミノ環状アミン誘導体(V)の脱保護により得られる。
(工程4)
2−ホルミルイミダゾール誘導体(VIII)は、2−ホルミルイミダゾール誘導体(VII)の塩基による脱プロトン化後にアルキル化試薬(LI)を作用させるアルキル化反応により得られる。
2−ホルミルイミダゾール誘導体(VIII)は、アルコール誘導体(IX)の酸化反応により得られる。
アクリル酸エステル誘導体(X)は、2−ホルミルイミダゾール誘導体(VIII)のオレフィン化反応により得られる。
エステル誘導体(XI)は、アクリル酸エステル誘導体(X)に対し、水素雰囲気下で遷移金属触媒を用いる還元反応により得られる。
カルボン酸誘導体(III)は、エステル誘導体(XI)の加水分解反応により得られる。
1H-NMR (400 MHz, CDCl3) δ: 1.48 (3H, d, J=6.4 Hz), 1.48 (3H, d, J=6.4 Hz), 5.48 (1H, quint, J=6.4 Hz), 7.30 (1H, s), 7.33 (1H, s), 9.83 (1H, s).
ESI-MS: m/z= 139 (M+H)+.
1H-NMR (400 MHz, DMSO) δ: 3.21 (3H, s), 3.61 (2H, d, J=5.2 Hz), 4.53 (2H, d, J=5.2 Hz), 7.27 (1H, s), 7.62 (1H, s), 9.69 (1H, s).
ESI-MS: m/z= 155 (M+H)+.
1H−NMR(400 MHz, CDCl3) δ:5.16 (2H, q, J=8.0 Hz), 7.25 (1H, brs), 7.38 (1H, brs), 9.83-9.85 (1H, m).
ESI-MS: m/z= 179 (M+H)+.
1H−NMR(400 MHz, CDCl3) δ: 3.97 (3H, s), 7.24 (1H, s), 9.70 (1H, s).
ESI-MS: m/z= 145 (M+H)+.
1H−NMR(400 MHz, CDCl3) δ: 3.76 (3H, s), 3.81 (3H, s), 6.82 (1H, d, J=15.6 Hz), 6.98 (1H, brs), 7.16 (1H, brs), 7.53 (1H, d, J=15.6Hz).
ESI-MS: m/z= 167 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.50 (3H, d, J=6.4 Hz), 1.50 (3H, d, J=6.4 Hz), 3.81 (3H, s), 4.62 (1H, quint, J=6.4 Hz), 6.87 (1H, d, J=15.6 Hz), 7.10 (1H, brs), 7.18 (1H, brs), 7.56 (1H, d, J=15.6 Hz).
ESI-MS: m/z= 195 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 3.82 (3H, s), 4.56-4.64 (2H, m), 6.93 (1H, d, J=15.2 Hz), 7.10 (1H, brs), 7.24 (1H, brs), 7.44 (1H, d, J=15.2 Hz).
ESI-MS: m/z= 235 (M+H)+.
1H−NMR(400 MHz, CDCl3) δ: 1.32 (3H, t, J=7.2 Hz), 3.32 (3H, s), 3.63 (2H, t, J=5.2 Hz), 4.20 (2H, t, J=5.2 Hz), 4.26 (2H, q, J=7.2 Hz), 6.84 (1H, d, J=15.4 Hz), 7.08 (1H, brs), 7.16 (1H, brs), 7.52 (1H, d, J=15.4 Hz).
ESI-MS: m/z= 225 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 3.67-3.69 (3H, m), 3.80-3.82 (3H, m), 6.78-6.85 (1H, m), 7.08-7.10 (1H, m), 7.44-7.50 (1H, m).
ESI-MS: m/z= 201 (M+H)+.
1H−NMR(400 MHz, CDCl3) δ: 2.84-2.96 (4H, m), 3.53 (3H, s), 3.70 (3H, s), 6.84 (1H, s).
ESI-MS: m/z= 203 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 2.16(6H, s), 2.62-2.68(2H, m), 2.92-2.98(2H, m), 3.02-3.09(1H, m), 3.60(3H, m), 3.78-3.85(1H, m), 3.93-4.02(2H, m), 4.11-4.17(1H, m), 6.78(1H, d, J=1.2Hz), 6.91(1H, d, J=1.2Hz).
ESI-MS: m/z= 237 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ:1.34-1.44(2H, m), 1.92-2.24(3H, m), 2.30(6H, s), 2.40-2.57(1H, m), 2.78-2.98(5H, m), 3.60(3H, s), 3.79-4.05(1H, m), 4.44-4.67(1H, m), 6.75-6.78(1H, m), 6.88-6.90(1H, m).
ESI-MS: m/z= 265 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ:1.34-1.44(2H, m), 1.92-2.24(3H, m), 2.30(6H, s), 2.40-2.57(1H, m), 2.78-2.98(5H, m), 3.60(3H, s), 3.79-4.05(1H, m), 4.44-4.67(1H, m), 6.75-6.78(1H, m), 6.88-6.90(1H, m).
ESI-MS: m/z= 265 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ:1.38-1.42(6H, m), 2.16(6H, s), 2.67-2.72(2H, m), 2.93-3.09(3H, m), 3.79-3.85(1H, m), 3.95-4.02(2H, m), 4.12-4.18(1H, m), 4.39-4.47(1H, m), 6.89-6.91(1H, m), 6.94-6.95(1H, m).
ESI-MS: m/z= 265 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ:1.39-1.44(6H, m), 1.68-1.83(3H, m), 1.98-2.60(9H, m), 2.80-3.05(5H, m), 3.84-4.09(1H, m), 4.40-4.71(2H, m), 6.89-6.96(2H, m).
ESI-MS: m/z= 293 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.39-1.44(6H, m), 1.68-1.83(3H, m), 1.98-2.60(9H, m), 2.80-3.05(5H, m), 3.84-4.09(1H, m), 4.40-4.71(2H, m), 6.89-6.96(2H, m).
ESI-MS: m/z= 293 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ:2.16(6H, s), 2.62-2.69(2H, m), 2.93-3.10(3H, m), 3.75-3.82(1H, m), 3.92-3.98(2H, m), 4.09-4.16(1H, m), 4.56-4.68(2H, m), 6.87-6.89(1H, m), 6.98-7.00(1H, m).
ESI-MS: m/z= 305 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.32-1.45(2H, m), 1.65-1.85(1H, m), 2.02-2.21(2H, m), 2.29-2.31(6H, m), 2.40-2.56(1H, m), 2.78-3.00(5H, m), 3.74-4.01(1H, m), 4.38-4.75(3H, m), 6.85-6.88(1H, m), 6.96-6.98(1H, m).
ESI-MS: m/z= 333 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.37-1.45(2H, m), 1.75-1.81(1H, m), 2.00-2.20(2H, m), 2.31-2.33(6H, m), 2.43-2.57(1H, m), 2.81-3.02(5H, m), 3.32 (3H, s), 3.59-3.62(2H, m), 3.84-4.11(3H, m), 4.49-4.69(1H, m), 6.89-6.93(2H, m).
ESI-MS: m/z= 309 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ:2.17 (6H, s), 2.56-2.69 (2H, m), 2.87-3.00 (2H, m), 3.03-3.09 (3H, m), 3.53 (3H, s), 3.81 (1H, dd, J=9.9, 5.2 Hz), 3.95-4.01 (2H, m), 4.13-4.17 (1H, m), 6.83(1H, s).
ESI-MS: m/z= 271 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ:1.30-1.48(2H, m), 1.68-1.84(1H, m), 1.92-2.22(2H, m), 2.28-2.31(6H, m), 2.40-2.58(1H, m), 2.77-3.00(5H, m), 3.51-3.54(3H, m), 3.75-4.02(1H, m), 4.42-4.64(1H, m), 6.80(1H, s).
ESI-MS: m/z= 299 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ:1.30-1.48(2H, m), 1.68-1.84(1H, m), 1.92-2.22(2H, m), 2.28-2.31(6H, m), 2.40-2.58(1H, m), 2.77-3.00(5H, m), 3.51-3.54(3H, m), 3.75-4.02(1H, m), 4.42-4.64(1H, m), 6.80(1H, s).
ESI-MS: m/z= 299 (M+H)+.
1H-NMR (400 MHz, D2O) δ: 2.74-2.80(2H, m), 2.89(6H, s), 3.21-3.28(2H, m), 3.82(3H, s), 4.12-4.28(2H, m), 4.32-4.50(2H, m), 4.57-4.66(1H, m), 7.28-7.36(2H, m).
ESI-MS: 1−(3−(ジメチルアミノ)アゼチジン−1−イル)−3−(1−メチル−1H−イミダゾール−2−イル)−プロパン−1−オンとして: m/z= 237 (M+H)+.
1H-NMR (400 MHz, D2O) δ: 1.60-1.73(1H, m), 1.85-1.98(2H, m), 2.15-2.30(1H, m), 2.92-3.09(8H, m), 3.20-3.44(5H, m), 3.70-3.80(1H, m), 3.83(3H, s), 4.15-4.35(1H, m), 7.27-7.33(2H, m).
ESI-MS: (S)−1−(3−(ジメチルアミノ)ピペリジン−1−イル)−3−(1−メチル−1H−イミダゾール−2−イル)プロパン−1−オンとして: m/z= 265 (M+H)+.
1H-NMR (400 MHz, D2O) δ: 1.60-1.73(1H, m), 1.85-1.98(2H, m), 2.15-2.30(1H, m), 2.92-3.09(8H, m), 3.20-3.44(5H, m), 3.70-3.80(1H, m), 3.83(3H, s), 4.15-4.35(1H, m), 7.27-7.33(2H, m).
ESI-MS: (R)−1−(3−(ジメチルアミノ)ピペリジン−1−イル)−3−(1−メチル−1H−イミダゾール−2−イル)プロパン−1−オンとして: m/z= 265 (M+H)+.
1H-NMR (400 MHz, D2O) δ:1.47-1.51(6H, m), 2.74-2.80(2H, m), 2.88(6H, s), 3.24-3.30(2H, m), 4.13-4.24(2H, m), 4.33-4.48(2H, m), 4.58-4.74(2H, m), 7.36-7.38(1H, m), 7.49-7.51(1H, m).
ESI-MS: 1−(3−(ジメチルアミノ)アゼチジン−1−イル)−3−(1−イソプロピル−1H−イミダゾール−2−イル)プロパン−1−オンとして: m/z= 265 (M+H)+.
1H-NMR (400 MHz, D2O) δ:1.48-1.70(8H, m), 1.86-1.98(2H, m), 2.12-2.28(1H, m), 2.89-3.12(8H, m), 3.24-3.45(5H, m), 3.71-3.82(1H, m), 4.14-4.36(1H, m), 7.35(1H, brs), 7.50(1H, brs).
ESI-MS: (S)−1−(3−(ジメチルアミノ)ピペリジン−1−イル)−3−(1−イソプロピル−1H−イミダゾール−2−イル)プロパン−1−オンとして: m/z= 293 (M+H)+.
1H-NMR (400 MHz, D2O) δ: 1.48-1.70(8H, m), 1.86-1.98(2H, m), 2.12-2.28(1H, m), 2.89-3.12(8H, m), 3.24-3.45(5H, m), 3.71-3.82(1H, m), 4.14-4.36(1H, m), 7.35(1H, brs), 7.50(1H, brs).
ESI-MS: (R)−1−(3−(ジメチルアミノ)ピペリジン−1−イル)−3−(1−イソプロピル−1H−イミダゾール−2−イル)プロパン−1−オンとして: m/z= 293 (M+H)+.
1H-NMR (400 MHz, D2O) δ:2.77-2.84(2H, m), 2.89(6H, s), 3.27-3.33(2H, m), 4.13-4.26(2H, m), 4.32-4.47(2H, m), 4.57-4.64(1H, m), 5.08-5.16(2H, m), 7.42-7.46(1H, m), 7.51-7.55(1H, m).
ESI-MS: 1−(3−(ジメチルアミノ)アゼチジン−1−イル)−3−(1−(2,2,2−トリフルオロエチル)−1H−イミダゾール−2−イル)プロパン−1−オンとして: m/z= 305 (M+H)+.
1H-NMR (400 MHz, D2O) δ: 1.42-1.70(1H, m), 1.83-1.94(2H, m), 2.12-2.27(1H, m), 2.87-2.94(6H, m), 3.04-3.14(2H, m), 3.23-3.42(5H, m), 3.70-3.78(1H, m), 4.12-4.32(1H, m), 5.10-5.18(2H, m), 7.43-7.45(1H, m), 7.52-7.54(1H, m).
ESI-MS: (R)−1−(3−(ジメチルアミノ)ピペリジン−1−イル)−3−(1−(2,2,2−トリフルオロエチル)−1H−イミダゾール−2−イル)プロパン−1−オンとして: m/z= 333 (M+H)+.
1H-NMR (400 MHz, D2O) δ: 1.44-1.68(1H, m), 1.74-1.93(2H, m), 2.16-2.24(1H, m), 2.89-2.93(6H, m), 3.00-3.08(2H, m), 3.23-3.41(8H, m), 3.70-3.76(1H, m), 3.82-3.85(2H, m), 4.14-4.30(1H, m), 4.36-4.38(2H, m), 7.33-7.34(1H, m), 7.40-7.42(1H, m).
ESI-MS: (R)−1−(3−(ジメチルアミノ)ピペリジン−1−イル)−3−(1−(2−メトキシエチル)−1H−イミダゾール−2−イル)プロパン−1−オンとして: m/z= 309 (M+H)+.
1H-NMR (400 MHz, D2O) δ:2.78(2H, t, J=7.1 Hz), 2.92(6H, s), 3.26(2H, t, J= 7.1Hz), 3.77(3H, s), 4.17-4.28(2H, m), 4.37-4.41(1H, m), 4.45-4.48(1H, m), 4.61-4.66(1H, m), 7.44(1H, s).
ESI-MS: 3−(5−クロロ−1−メチル−1H−イミダゾール−2−イル)−1−(3−(ジメチルアミノ)アゼチジン−1−イル)プロパン−1−オンとして: m/z= 271 (M+H)+.
1H-NMR (400 MHz, D2O) δ: 1.60-1.71(1H, m), 1.78-1.96(2H, m), 2.14-2.28(1H, m), 2.89-2.96(6H, m), 3.01-3.10(2H, m), 3.23-3.44(5H, m), 3.70-3.80(4H, m), 4.20-4.33(1H, m), 7.43(1H, s).
ESI-MS: (S)−3−(5−クロロ−1−メチル−1H−イミダゾール−2−イル)−1−(3−(ジメチルアミノ)ピペリジン−1−イル)プロパン−1−オンとして: m/z= 299 (M+H)+.
1H-NMR (400 MHz, D2O) δ: 1.60-1.71(1H, m), 1.78-1.96(2H, m), 2.14-2.28(1H, m), 2.89-2.96(6H, m), 3.01-3.10(2H, m), 3.23-3.44(5H, m), 3.70-3.80(4H, m), 4.20-4.33(1H, m), 7.43(1H, s).
ESI-MS: (R)−3−(5−クロロ−1−メチル−1H−イミダゾール−2−イル)−1−(3−(ジメチルアミノ)ピペリジン−1−イル)プロパン−1−オンとして: m/z= 299 (M+H)+.
神経障害性疼痛を評価できるマウス坐骨神経部分結紮モデル(Seltzerモデル)を用い、環状アミン誘導体(I)又はその薬理学的に許容される塩の鎮痛作用を検討した。
マウス坐骨神経部分結紮モデルは、Seltzerらの方法(Malmbergら、Pain、1998年、第76巻、p.215−222)に従って作製した。
結果を図1〜12に示す。図において、縦軸はvon Frey試験の総スコア(平均値±標準誤差;図1〜12は、n=4〜6である。)を示し、数値が高いほど痛みが強いことを示す。横軸には被験化合物投与後の時間(hr)を示す。薬効評価は、測定時間毎の「坐骨神経部分結紮+蒸留水」群(図中の「坐骨神経部分結紮+蒸留水」)を対照として、多群の対応のないt検定(Dunnettによる補正)(図1〜3及び10〜12)又は対応のない2群のt検定(図4〜9)により統計処理を行った。図中の*印は、「坐骨神経部分結紮+蒸留水」群との比較で統計学的に有意である(p<0.05)ことを示す。
Claims (6)
- R2は、水素原子又は塩素原子である、請求項1記載の環状アミン誘導体又はその薬理学的に許容される塩。
- R1は、置換されていない炭素数1〜6のアルキル基である、請求項2記載の環状アミン誘導体又はその薬理学的に許容される塩。
- 請求項1〜3のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、医薬。
- 請求項1〜3のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、鎮痛薬。
- 請求項1〜3のいずれか一項記載の環状アミン誘導体又はその薬理学的に許容される塩を有効成分として含有する、神経障害性疼痛治療薬。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005507906A (ja) * | 2001-10-12 | 2005-03-24 | ノボ ノルディスク アクティーゼルスカブ | 置換ピペリジン類、およびヒスタミンh3受容体関連疾患の治療のためのその使用 |
JP2005527519A (ja) * | 2002-03-14 | 2005-09-15 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 新規な置換ピペリジン、これら化合物を含む医薬組成物、その使用及びその調製方法 |
WO2006137465A1 (ja) * | 2005-06-24 | 2006-12-28 | Shionogi & Co., Ltd. | 含窒素複素環誘導体 |
WO2013147160A1 (ja) * | 2012-03-29 | 2013-10-03 | 東レ株式会社 | 環状アミン誘導体及びその医薬用途 |
WO2016136944A1 (ja) * | 2015-02-27 | 2016-09-01 | 東レ株式会社 | 環状アミン誘導体及びその医薬用途 |
JPWO2016152955A1 (ja) * | 2015-03-24 | 2018-01-11 | 東レ株式会社 | 環状アミン誘導体及びその医薬用途 |
JP6409573B2 (ja) * | 2013-09-26 | 2018-10-24 | 東レ株式会社 | 環状アミン誘導体及びその医薬用途 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005507906A (ja) * | 2001-10-12 | 2005-03-24 | ノボ ノルディスク アクティーゼルスカブ | 置換ピペリジン類、およびヒスタミンh3受容体関連疾患の治療のためのその使用 |
JP2005527519A (ja) * | 2002-03-14 | 2005-09-15 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 新規な置換ピペリジン、これら化合物を含む医薬組成物、その使用及びその調製方法 |
WO2006137465A1 (ja) * | 2005-06-24 | 2006-12-28 | Shionogi & Co., Ltd. | 含窒素複素環誘導体 |
WO2013147160A1 (ja) * | 2012-03-29 | 2013-10-03 | 東レ株式会社 | 環状アミン誘導体及びその医薬用途 |
JP6409573B2 (ja) * | 2013-09-26 | 2018-10-24 | 東レ株式会社 | 環状アミン誘導体及びその医薬用途 |
WO2016136944A1 (ja) * | 2015-02-27 | 2016-09-01 | 東レ株式会社 | 環状アミン誘導体及びその医薬用途 |
JPWO2016152955A1 (ja) * | 2015-03-24 | 2018-01-11 | 東レ株式会社 | 環状アミン誘導体及びその医薬用途 |
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