JP7447803B2 - アドビリン機能促進剤としての環状アミン誘導体並びに新規環状アミン誘導体及びその医薬用途 - Google Patents
アドビリン機能促進剤としての環状アミン誘導体並びに新規環状アミン誘導体及びその医薬用途 Download PDFInfo
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- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 1
- 229950010357 tetrodotoxin Drugs 0.000 description 1
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- ISNYUQWBWALXEY-OMIQOYQYSA-N tsg6xhx09r Chemical compound O([C@@H](C)C=1[C@@]23CN(C)CCO[C@]3(C3=CC[C@H]4[C@]5(C)CC[C@@](C4)(O)O[C@@]53[C@H](O)C2)CC=1)C(=O)C=1C(C)=CNC=1C ISNYUQWBWALXEY-OMIQOYQYSA-N 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Description
1H-NMR (400 MHz, CDCl3) δ: 1.30-1.57 (2H, m), 1.73-1.90 (2H, m), 2.24-2.37 (7H, m), 2.48-2.58 (1H, m), 2.95-3.13 (2H, m), 3.28-3.36 (1H, m), 3.70 (3H, d, J=1.6 Hz), 3.93-4.17 (3H, m), 4.48-4.54 (1H, m), 5.12-5.14 (2H, m), 5.30-5.36 (1H, m), 6.80 (1H, s), 6.96 (1H, s), 7.31-7.39 (5H, m).
ESI-MS: m/z= 429 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.42 (3H, t, J=7.2 Hz), 4.01 (3H, s), 4.40 (2H, q, J=7.2 Hz), 7.01-7.03 (1H, m), 7.13-7.15 (1H, m).
ESI-MS: m/z= 155 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.27 (3H, t, J=7.2 Hz), 4.01 (3H, s), 4.13 (2H, s), 4.21 (2H, q, J=7.2 Hz), 7.05-7.07 (1H, m), 7.15-7.17 (1H, m).
ESI-MS: m/z= 197 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.34 (2H, dd, J=12.0, 4.0 Hz), 1.40 (2H, dd, J=12.0, 4.0 Hz), 1.85 (2H, d, J=12.4 Hz), 2.28 (1H, tt, J=11.2, 4.0 Hz), 3.53-3.63 (6H, m), 3.15 (2H, d, J=12.4 Hz), 3.73 (4H, t, J=4.4 Hz).
ESI-MS: m/z= 171 (M+H)+
1H-NMR (400 MHz, CDCl3) δ: 1.40-1.64 (2H, m), 1.82-1.92 (2H, m), 2.37-2.47 (1H, m), 2.52-2.58 (4H, m), 3.05-3.15 (1H, m), 3.69-3.76 (5H, m), 3.82-3.90 (1H, m), 4.01 (3H, s), 4.16-4.31 (2H, m), 4.58-4.65 (1H, m), 7.04-7.06 (1H, m), 7.13-7.15 (1H, m).
ESI-MS: m/z= 321 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J=7.4 Hz), 1.77-1.85 (2H, m), 4.37 (2H, t, J=7.2 Hz), 7.16 (1H, s), 7.28 (1H, s), 9.82 (1H, s).
1H-NMR (400 MHz, CDCl3) δ: 1.47 (6H, t, J=6.6 Hz), 5.48 (1H, q, J=6.6 Hz), 7.30 (1H, s), 7.33 (1H, s), 9.83 (1H, s).
1H-NMR (400 MHz, CDCl3) δ: 3.98 (3H, s), 7.24 (1H, s), 9.70 (1H, s).
1H-NMR (400 MHz, CDCl3) δ: 3.32 (3H, s), 3.67 (2H, t, J=5.0 Hz), 4.59 (2H, t, J=5.0 Hz), 7.23-7.30 (2H, m), 9.81 (1H, s).
1H-NMR (400 MHz, CDCl3) δ: 2.60-2.72 (2H, m), 4.61 (2H, t, J=6.8 Hz), 7.18 (1H, s), 7.32 (1H, s), 9.83 (1H, s).
1H-NMR (400 MHz, CDCl3) δ: 1.30-1.47 (2H, m), 1.79-1.92 (2H, m), 2.10 (3H, s), 2.25-2.40 (7H, m), 2.53-2.63 (1H, m), 3.01-3.11 (1H, m), 3.81-3.90 (1H, m), 4.58-4.66 (1H, m).
ESI-MS: m/z= 171 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.35 (2H, dd, J=12.0, 3.6 Hz), 1.41 (2H, dd, J=12.0, 3.6 Hz), 1.85 (2H, d, J=12.8 Hz), 1.96-2.06 (2H, br), 2.28 (3H, s), 2.32 (1H, tt, J=11.6, 3.6 Hz), 3.37-3.70 (8H, m), 3.14 (2H, d, J=12.8 Hz).
ESI-MS: m/z= 169 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.32-1.5 (2H, m), 1.80-1.94 (2H, m), 2.22-41 (7H, m), 2.60-2.70 (1H, m), 3.03-3.13 (1H, m), 3.80-3.89 (1H, m), 4.01 (3H, s), 4.23 (2H, dd, J=15.6, 36.8 Hz), 4.55-4.67 (1H, m), 7.05 (1H, s), 7.14 (1H, s).
ESI-MS: m/z= 279 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.38-1.60 (2H, m), 1.82-1.90 (2H, m), 1.95-2.10 (1H, m), 2.27 (3H, s), 2.36-2.68 (9H, m), 3.02-3.12 (1H, m), 3.79-3.88 (1H, m), 3.98 (3H, s), 4.13-4.28 (2H, m), 4.57-4.90 (1H, m), 7.02-7.04 (1H, m), 7.11-7.13 (1H, m).
ESI-MS: m/z= 334 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.02 (6H, t, J=6.8 Hz), 1.37-1.58 (2H, m), 1.73-1.98 (2H, m), 2.48-2.78 (6H, m), 3.01-3.11 (1H, m), 3.80-3.88 (1H, m), 4.00 (3H, s), 4.14-4.28 (2H, m), 4.60-4.70 (1H, m), 7.03-7.05 (1H, m), 7.12-7.14 (1H, m).
ESI-MS: m/z= 307 (M+H)+.
1H-NMR (400 MHz, CDCl3) δ: 1.32-1.53 (2H, m), 1.82-1.92 (2H, m), 2.27-2.41 (7H, m), 2.60-2.72 (1H, m), 2.98-3.23 (3H, m), 3.77 (3H, s), 3.99-4.08 (1H, m), 4.58-4.82 (2H, m), 5.18-5.26 (1H, m), 6.86 (1H, s), 6.93 (1H, s).
ESI-MS: m/z= 281 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 1.08-1.50 (7H, m), 1.60-1.76 (2H, m), 2.36-2.46 (5H, m), 2.75-3.05 (3H, m), 3.64 (3H, s), 3.92-4.02 (1H, m), 4.32-4.42 (1H, m), 4.99-5.08 (1H, m), 5.34-5.49 (1H, m), 6.70-6.72 (1H, m), 7.01-7.03 (1H, m).
ESI-MS: m/z= 323 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 0.85 (3H, t, J=7.4 Hz), 1.00-1.40 (2H, m), 1.61-1.80 (4H, m), 2.10-2.33 (7H, m), 2.45-2.59 (1H, m), 2.73-2.88 (1H, m), 2.93-3.13 (2H, m), 3.86-4.00 (3H, m), 4.25-4.35 (1H, m),4.98-5.05 (1H, m), 5.34-5.40 (1H, m), 6.72 (1H, s), 7.07 (1H, s).
ESI-MS: m/z= 309 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 1.04-1.41 (8H, m), 1.62-1.80 (2H, m), 2.16 (6H, s), 2.25-2.34 (1H, m), 2.48-2.59 (2H, m), 2.76-2.88 (1H, m), 2.95-3.16 (2H, m), 3.90-4.00 (1H, m), 4.27-4.38 (1H, m), 5.05-5.12 (1H, m), 5.36-5.42 (1H, m), 6.77 (1H, s), 7.20 (1H, s).
ESI-MS: m/z= 309 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 1.04-1.21 (1H, m), 1.28-1.40 (1H, m), 1.64-1.80 (2H, m), 2.15 (6H, s), 2.24-2.35 (1H, m), 2.44-2.60 (1H, m), 2.78-2.88 (1H, m), 2.95-3.11 (2H, m), 3.59 (3H, s), 3.90-3.98 (1H, m), 4.27-4.35 (1H, m), 5.00-5.10 (1H, m), 5.50-5.58 (1H, m), 6.85 (1H, s).
ESI-MS: m/z= 315 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 1.04-1.40 (2H, m), 1.62-1.80 (2H, m), 2.10-2.35 (7H, m), 2.46-2.59 (1H, m), 2.80-2.90 (1H, m), 2.95-3.10 (2H, m), 3.24 (3H, s), 3.61 (2H, t, J=5.5 Hz), 3.90-4.00 (1H, m), 4.10-4.38 (3H, m), 5.05-5.11 (1H, m), 5.38-5.42 (1H, m), 6.73 (1H, s), 7.07 (1H, s).
ESI-MS: m/z= 325 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 1.03-1.40 (2H, m), 1.63-1.79 (2H, m), 2.10-2.33 (7H, m), 2.47-2.59 (1H, m), 2.78-2.90 (3H, m), 2.95-3.13 (2H, m), 3.90-3.98 (1H, m), 4.21-4.36 (3H, m), 5.03-5.10 (1H, m), 5.49-5.54 (1H, m), 6.77 (1H, s), 7.17 (1H, s).
ESI-MS: m/z= 363 (M+H)+.
HPLC保持時間:8.4min、機器:株式会社島津製作所製LC-10ADvpシステム、カラム:CHIRALCEL OZ-H、4.6×250mm(株式会社ダイセル製)、溶媒:0.01%エチレンジアミン含有メタノール(v/v)、流量:0.5mL/min、検出法:UV220nm、カラム温度:40℃.
1H-NMR (400 MHz, CDCl3) δ: 1.32-1.53 (2H, m), 1.82-1.92 (2H, m), 2.27-2.41 (7H, m), 2.60-2.72 (1H, m), 2.98-3.23 (3H, m), 3.77 (3H, s), 3.99-4.08 (1H, m), 4.58-4.82 (2H, m), 5.18-5.26 (1H, m), 6.86 (1H, s), 6.93 (1H, s).
ESI-MS: m/z= 281 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 1.45-1.66 (4H, m), 1.87-1.95 (2H, m), 2.26-2.30(3H, s), 2.38-2.70 (8H, m), 2.98-3.23 (3H, m), 3.77 (3H, s), 4.00-4.10 (1H, m), 4.60-4.70 (2H, m), 5.17-5.25 (1H, m), 6.85-6.88 (1H, m), 6.92-6.95 (1H, m).
ESI-MS: m/z= 336 (M+H)+.
1H-NMR (400 MHz, DMSO-d6) δ: 0.94 (6H, t, J=6.8 Hz), 1.05-1.75 (5H, m), 2.42-3.10 (8H, m), 3.64 (3H, s), 3.93-4.02 (1H, m), 4.32-4.43 (1H, m), 5.00-5.08 (1H, m), 5.34-5.42 (1H, m), 6.69-6.71 (1H, m), 7.01-7.03 (1H, m).
ESI-MS: m/z= 309 (M+H)+.
ラットの各組織から調製して得られた膜画分に対する3Hで標識された環状アミン誘導体(I)の結合性を評価することにより、環状アミン誘導体(I)の分子標的を含む組織を明らかにした。
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結合分子を同定するために、環状アミン誘導体(I)を固定化したFG beadsを用いたアフィニティ精製及び網羅的同定を行った。
1H-NMR (400 MHz, CDCl3) δ: 1.30-1.69 (2H, m), 1.88-2.10 (2H, m), 2.40-2.63 (7H, m), 2.88-3.20 (3H, m), 3.21-3.41 (1H, m), 3.74-3.98 (5H, m), 4.09-4.27 (1H, m), 4.63-4.78 (1H, m), 5.20-5.26 (1H, m), 6.84 (1H, s), 6.95 (1H, s).
ESI-MS: m/z= 339 (M+H)+.
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F11細胞(ラット後根神経節神経株化細胞)における細胞内アクチンフィラメント量に対する作用を検討した。
ラット脊髄神経結紮モデルの坐骨神経における、アクチンフィラメント量と単量体アクチン量の比に対する環状アミン誘導体(I)又はその薬理学的に許容される塩の作用を検討した。
ラット後根神経節初代培養細胞における神経突起伸展に対する環状アミン誘導体(I)又はその薬理学的に許容される塩の作用を検討した。
本明細書で引用した全ての刊行物、特許及び特許出願はそのまま引用により本明細書に組み入れられるものとする。
Claims (15)
- Aは、一般式(IIa)で示される基である、請求項1記載のアドビリン機能促進剤。
- Aは、一般式(IIb)で示される基である、請求項1記載のアドビリン機能促進剤。
- Xは、-N(R3)-である、請求項3記載のアドビリン機能促進剤。
- R1は、メチル基、n-プロピル基、イソプロピル基、2-メトキシエチル基又は3,3,3-トリフルオロプロピル基である、請求項1~4のいずれか一項記載のアドビリン機能促進剤。
- R2は、水素原子又は塩素原子である、請求項1~4のいずれか一項記載のアドビリン機能促進剤。
- *を付した不斉炭素の立体化学は、S配置である、請求項1~4のいずれか一項記載のアドビリン機能促進剤。
- アドビリン及び/又はアドビリン複合体へ結合することでアドビリンの機能を促進するための、請求項1~7のいずれか一項記載のアドビリン機能促進剤。
- アクチンフィラメント代謝回転調節異常を改善するための、請求項1~8のいずれか一項記載のアドビリン機能促進剤。
- 神経軸索伸展を促進するための、請求項1~8のいずれか一項記載のアドビリン機能促進剤。
- アドビリン及び/又はアドビリン複合体に結合してアクチンフィラメント代謝回転調節異常を改善し、神経軸索伸展を促進するための、請求項1~7のいずれか一項記載のアドビリン機能促進剤。
- 手根管症候群、回内筋症候群、前骨間神経麻痺、尺骨神経管症候群、肘部管症候群、後骨間神経麻痺、橈骨神経麻痺、胸郭出口症候群、腋窩神経麻痺、肩甲上神経麻痺、梨状筋症候群、腰神経叢麻痺、足根管症候群、大腿神経麻痺、坐骨神経麻痺、脛骨神経麻痺、総腓骨神経麻痺、深腓骨神経麻痺、伏在神経麻痺、頸部脊柱管狭窄症、腰部脊柱管狭窄症、顔面神経麻痺、動眼神経麻痺、滑車神経麻痺、外転神経麻痺、ベル麻痺、及びラムゼイ・ハント症候群からなる群より選択される神経軸索損傷に関する疾患の治療剤、又は、巨細胞血管炎、高安動脈炎、結節性多発動脈炎、川崎病、多発血管炎性肉芽腫、顕微鏡的多発血管炎、好酸球性多発血管炎性肉芽腫症、クリオグロブリン血症、IgA血管炎、皮膚白血球破砕性血管炎、全身性エリトマトーデス、シェーグレン症候群、関節リウマチ、混合性結合組織病、多発性筋炎、皮膚筋炎、強皮症、ベーチェット病、細菌・ウイルス感染症、サルコイドーシス、及び悪性腫瘍からなる群より選択されるいずれかの疾患を原因とする神経軸索損傷の治療剤である、請求項1~11のいずれか一項記載のアドビリン機能促進剤。
- 前記細菌・ウイルス感染症が、ライム病、HIV感染症又はハンセン病である、請求項12記載のアドビリン機能促進剤。
- 3-ヒドロキシ-3-(1-メチル-1H-イミダゾール-2-イル)-1-(4-モルホリノピペリジン-1-イル)プロパン-1-オン、1-(4-(ジメチルアミノ)ピペリジン-1-イル)-3-(1-プロピル-1H-イミダゾール-2-イル)-3-ヒドロキシプロパン-1-オン、1-(4-(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)-3-ヒドロキシプロパン-1-オン、3-(5-クロロ-1-メチル-1H-イミダゾール-2-イル)-1-(4-(ジメチルアミノ)ピペリジン-1-イル)-3-ヒドロキシプロパン-1-オン、1-(4-(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)-3-ヒドロキシプロパン-1-オン及び1-(4-(ジメチルアミノ)ピペリジン-1-イル)-3-(1-(3,3,3-トリフルオロプロピル)-1H-イミダゾール-2-イル)-3-ヒドロキシプロパン-1-オンからなる群から選択される一の化合物である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14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。
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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 |
WO2018181860A1 (ja) | 2017-03-31 | 2018-10-04 | 東レ株式会社 | 末梢神経障害の治療剤又は予防剤 |
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