JP2022526609A - ベンズイミダゾール誘導体及びその使用 - Google Patents
ベンズイミダゾール誘導体及びその使用 Download PDFInfo
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- JP2022526609A JP2022526609A JP2021559275A JP2021559275A JP2022526609A JP 2022526609 A JP2022526609 A JP 2022526609A JP 2021559275 A JP2021559275 A JP 2021559275A JP 2021559275 A JP2021559275 A JP 2021559275A JP 2022526609 A JP2022526609 A JP 2022526609A
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- Japan
- Prior art keywords
- fluoro
- methyl
- benzimidazol
- difluoro
- piperidinamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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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- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- PHKRFWRGEVHCAT-HTQZYQBOSA-N tert-butyl n-[(3r,4r)-4-fluoropiperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1F PHKRFWRGEVHCAT-HTQZYQBOSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
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- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/14—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 three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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Abstract
Description
(3R,4R)-4-フルオロ-1-(5-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R)-1-(5,7-ジフルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R,4R)-4-フルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-4-フルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-5-フルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R)-4,4-ジフルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-1-(5,6-ジフルオロ-1-((5-メチル-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R,4R)-1-(4,6-ジフルオロ-1-((5-メトキシ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R)-1-(1-((5-クロロピリジン-2-イル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロピペリジン-3-アミン;
(3R,4R)-4-フルオロ-1-(5-フルオロ-1-((5-フルオロ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
2-((3R)-3-アミノ-4,4-ジフルオロ-1-ピペリジニル)-1-((5-クロロ-2-ピリジニル)メチル)-1H-ベンズイミダゾール-6-カルボニトリル;
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-4,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
2-((3R,4R)-3-アミノ-4-フルオロ-1-ピペリジニル)-6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾール-4-カルボニトリル;
(3R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R,4R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R,4R)-1-(5,6-ジフルオロ-1-((5-メトキシ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
6-((2-((3R,4R)-3-アミノ-4-フルオロ-1-ピペリジニル)-5,6-ジフルオロ-1H-ベンズイミダゾル-1-イル)メチル)-2-ピリジンカルボニトリル;及び
(3R,4R)-1-(1-((5-クロロピリミジン-2-イル)メチル)-4-フルオロ-6-メトキシ-1H-ベンズイミダゾル-2-イル)-4-フルオロピペリジン-3-アミン
からなる群より選択される、化合物又はその医薬的に許容可能な塩を提供する。
(3R,4R)-4-フルオロ-1-(5-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R)-1-(5,7-ジフルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R,4R)-4-フルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-4-フルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;及び
(3R,4R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-5-フルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン、又はその医薬的に許容可能な塩
からなる群より選択される化合物が提供される。
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R)-4,4-ジフルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-1-(5,6-ジフルオロ-1-((5-メチル-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R,4R)-1-(4,6-ジフルオロ-1-((5-メトキシ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;及び
(3R)-1-(1-((5-クロロピリジン-2-イル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロピペリジン-3-アミン、又はその医薬的に許容可能な塩
からなる群より選択される化合物が提供される。
(3R,4R)-4-フルオロ-1-(5-フルオロ-1-((5-フルオロ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
2-((3R)-3-アミノ-4,4-ジフルオロ-1-ピペリジニル)-1-((5-クロロ-2-ピリジニル)メチル)-1H-ベンズイミダゾール-6-カルボニトリル;
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-4,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;及び
2-((3R,4R)-3-アミノ-4-フルオロ-1-ピペリジニル)-6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾール-4-カルボニトリル、又はその医薬的に許容可能な塩
からなる群より選択される化合物が提供される。
(3R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R,4R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R,4R)-1-(5,6-ジフルオロ-1-((5-メトキシ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
6-((2-((3R,4R)-3-アミノ-4-フルオロ-1-ピペリジニル)-5,6-ジフルオロ-1H-ベンズイミダゾル-1-イル)メチル)-2-ピリジンカルボニトリル;及び
(3R,4R)-1-(1-((5-クロロピリミジン-2-イル)メチル)-4-フルオロ-6-メトキシ-1H-ベンズイミダゾル-2-イル)-4-フルオロピペリジン-3-アミン、又はその医薬的に許容可能な塩
からなる群より選択される化合物が提供される。
本明細書に開示される化合物は、遊離形態又は医薬的に許容可能な塩の形態で、有用な薬理学的特性、例えば次項目において提供されるインビトロ及びインビボの試験で示されるようなTRPCタンパク質の調節特性、特にTRPC6タンパク質の活性の阻害を示すことから、治療に適応される。
本明細書に記載されている化合物は、当業者に公知の技術を用いて、スキーム1に示す反応順序により、或いは他の方法により調製される。なお、以下のスキームでは、特定の酸、塩基、試薬、カップリング剤、溶媒等を示しているが、他の適切な酸、塩基、試薬、カップリング剤、溶媒等を用いてもよく、これらも本発明の範囲に含まれると理解される。
TRPC6(Transient receptor potential channel family C6)阻害剤の効力は、FLIPRテトラシステム(BD PBX Calcium Assay Kit;BD Biosciences、San Jose CA)を用いて,ヒトTRPC6を安定的にトランスフェクトしたHEK293細胞に対するOAG(1-Oleoyl-2-acetyl-sn-glycerol、Millipore Sigma、O6754)刺激によるカルシウム流入を阻害することで測定した。細胞は、以下の選択試薬(ダルベッコ変法イーグル培地(DMEM)高グルコース、10%ウシ胎児血清、1×PSGlu(ペニシリン-ストレプトマイシン-グルタミン)、1×NEAA(非必須アミノ酸)、1×ピルビン酸Na及び200ug/mLハイグロマイシン)を含む成長培地を用いて、5%CO2下、37℃の加湿環境下で成長させた。培地を除去した後、カルシウムとマグネシウムを含まないPBS(リン酸緩衝生理食塩水)で2回軽く洗浄した。トリプシン(3mL)を37℃で5分間作用させた。フラスコを手のひらでたたくようにして細胞を取り出し、7mLの増殖培地を加えてトリプシンを失活させ、細胞を再び懸濁させた。通常の分割スケジュールは、2~3日ごとに1:5で行った。
Claims (9)
- (3R,4R)-4-フルオロ-1-(5-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R)-1-(5,7-ジフルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R,4R)-4-フルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-4-フルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-5-フルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R)-4,4-ジフルオロ-1-(6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-1-(5,6-ジフルオロ-1-((5-メチル-2-ピリジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R,4R)-1-(4,6-ジフルオロ-1-((5-メトキシ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R)-1-(1-((5-クロロピリジン-2-イル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロピペリジン-3-アミン;
(3R,4R)-4-フルオロ-1-(5-フルオロ-1-((5-フルオロ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-3-ピペリジンアミン;
(3R,4R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-6-フルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
2-((3R)-3-アミノ-4,4-ジフルオロ-1-ピペリジニル)-1-((5-クロロ-2-ピリジニル)メチル)-1H-ベンズイミダゾール-6-カルボニトリル;
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-4,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
2-((3R,4R)-3-アミノ-4-フルオロ-1-ピペリジニル)-6-フルオロ-1-((5-フルオロ-2-ピリジニル)メチル)-1H-ベンズイミダゾール-4-カルボニトリル;
(3R)-1-(1-((5-クロロ-2-ピリジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4,4-ジフルオロ-3-ピペリジンアミン;
(3R,4R)-1-(1-((5-クロロ-2-ピリミジニル)メチル)-5,6-ジフルオロ-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
(3R,4R)-1-(5,6-ジフルオロ-1-((5-メトキシ-2-ピリミジニル)メチル)-1H-ベンズイミダゾル-2-イル)-4-フルオロ-3-ピペリジンアミン;
6-((2-((3R,4R)-3-アミノ-4-フルオロ-1-ピペリジニル)-5,6-ジフルオロ-1H-ベンズイミダゾル-1-イル)メチル)-2-ピリジンカルボニトリル;及び
(3R,4R)-1-(1-((5-クロロピリミジン-2-イル)メチル)-4-フルオロ-6-メトキシ-1H-ベンズイミダゾル-2-イル)-4-フルオロピペリジン-3-アミン
から選択される化合物又はその塩。 - 医薬的に許容可能な塩の形態である、請求項1に記載の化合物。
- 医薬的に許容可能な賦形剤、担体、又はアジュバントと、少なくとも1つの請求項1に記載の化合物とを含む医薬組成物。
- 医薬的に許容可能な賦形剤、担体、又はアジュバントと、少なくとも1つの請求項2に記載の医薬的に許容可能な塩を含む医薬組成物。
- 哺乳類においてTRPC6により媒介される疾患又は障害を治療するための方法であって、少なくとも1つの請求項1に記載の化合物若しくはその医薬的に許容可能な塩又はその医薬組成物の治療有効量を、前記哺乳類に投与することを含む方法。
- 前記TRPC6により媒介される疾患又は障害が、ネフローゼ症候群、微小変化型疾患、巣状分節状糸球体硬化症、虚脱性糸球体症、膜性腎症、膜性増殖性糸球体腎炎、IGA腎症、急性腎不全、慢性腎不全、糖尿病性腎症、敗血症、肺高血圧、急性肺障害、急性呼吸窮迫症候群(ARDS)、心不全、脳卒中、悪性腫瘍、及び筋ジストロフィーからなる群より選択される、請求項5に記載の方法。
- 哺乳類においてTRPC6活性を調節するための方法であって、少なくとも1つの請求項1に記載の化合物若しくはその医薬的に許容可能な塩又はその医薬組成物の、前記哺乳類においてTRPC6活性を調節するための量を、前記哺乳類に投与することを含む方法。
- 薬剤として使用するための請求項1に記載の化合物又はその医薬的に許容可能な塩。
- ネフローゼ症候群、微小変化型疾患、巣状分節状糸球体硬化症、虚脱性糸球体症、膜性腎症、膜性増殖性糸球体腎炎、IGA腎症、急性腎不全、慢性腎不全、糖尿病性腎症、敗血症、肺高血圧、急性肺障害、急性呼吸窮迫症候群(ARDS)、心不全、脳卒中、悪性腫瘍、及び筋ジストロフィーを治療するための薬剤の製造に使用するための、請求項1に記載の化合物又はその医薬的に許容可能な塩。
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JP2013521250A (ja) * | 2010-03-01 | 2013-06-10 | サノフイ | アミノインダンの誘導体、これらの調製および治療におけるこれらの適用 |
JP2015500345A (ja) * | 2011-12-16 | 2015-01-05 | トランスポサジェン・バイオファーマシューティカルズ・インコーポレイテッドTransposagen Biopharmaceuticals, Inc. | 疼痛の治療または予防に使用されるtrpc4調節因子 |
WO2019028308A1 (en) * | 2017-08-04 | 2019-02-07 | Goldfinch Bio, Inc. | BENZIMIDAZOLES AND AZA-BENZIMIDAZOLES AND METHODS OF USE |
WO2019079578A1 (en) * | 2017-10-19 | 2019-04-25 | Amgen Inc. | BENZIMIDAZOLE DERIVATIVES AND USES THEREOF |
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JP2015500345A (ja) * | 2011-12-16 | 2015-01-05 | トランスポサジェン・バイオファーマシューティカルズ・インコーポレイテッドTransposagen Biopharmaceuticals, Inc. | 疼痛の治療または予防に使用されるtrpc4調節因子 |
WO2019028308A1 (en) * | 2017-08-04 | 2019-02-07 | Goldfinch Bio, Inc. | BENZIMIDAZOLES AND AZA-BENZIMIDAZOLES AND METHODS OF USE |
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CN114096247A (zh) | 2022-02-25 |
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