Lidorestat, EML-676, IDD-000676-01, IDD-676, -Drug Synthesis Database

【结构式】

【药物名称】Lidorestat, EML-676, IDD-000676-01, IDD-676

【化学名称】3-(4,5,7-Trifluorobenzothiazol-2-ylmethyl)-1H-indole-1-acetic acid

【CA登记号】245116-90-9

【分子式】C₁₈H₁₁F₃N₂O₂S

【分子量】376.35977

【开发单位】Institute for Diabetes Discovery (Originator), Merck KGaA (Licensee)

【药理作用】Diabetic Nephropathy, Agents for, Diabetic Neuropathy, Agents for, ENDOCRINE DRUGS, Treatment of Diabetic Complications, Aldose Reductase Inhibitors

合成路线1 合成路线2

合成路线1

Acetylation of 2,3,5,6-tetrafluoroaniline (I), followed by treatment of the resulting acetanilide (II) with P2S5, gave thioamide (III). Cyclization of (III) in the presence of NaH produced the benzothiazole (IV), which was subsequently hydrolyzed to amino thiophenol (V) by means of NaOH in ethyleneglycol.

参考文献中间体

【2】 Jones, J.H.; Jones, M.L.; Gunn, D.; Van Zandt, M.C. (The Institutes for Pharmaceutical Discovery, Inc.); Substd. indolealkanoic acids. WO 9950268 .
【3】 Jacot, J.; Sredy, J. (The Institutes for Pharmaceutical Discovery, Inc.); Methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis using substd. indolealkanoic acids. WO 0032180 .
【4】 Boyd, M.; Robinson, D. (The Institutes for Pharmaceutical Discovery, Inc.); Methods for lowering uric acid levels. WO 0151489 .
【5】 Van Zandt, M.; Sredy, J. (The Institutes for Pharmaceutical Discovery, Inc.); Compsns. containing a substd. indolealkanoic acid and an angiotensin converting enzyme inhibitor. WO 0164205 .
【1】 Jones, J.H.; Gunn, D.; Jones, M.L.; Van Zandt, M.C.; Lavoie, D.J.; Sawicki, D.; Sredy, J.; Howard, E.; Podjarny, A.D.; Substituted indolealkanoic acids as novel aldose reductase inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 307.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	44286	2,3,5,6-tetrafluoroaniline; 2,3,5,6-tetrafluorophenylamine	700-17-4	C₆H₃F₄N	详情	详情
(II)	44287	N-(2,3,5,6-tetrafluorophenyl)acetamide		C₈H₅F₄NO	详情	详情
(III)	44288	N-(2,3,5,6-tetrafluorophenyl)ethanethioamide		C₈H₅F₄NS	详情	详情
(IV)	44289	4,5,7-trifluoro-2-methyl-1,3-benzothiazole		C₈H₄F₃NS	详情	详情
(V)	44290	2-amino-3,4,6-trifluorobenzenethiol; 2-amino-3,4,6-trifluorophenylhydrosulfide		C₆H₄F₃NS	详情	详情

合成路线2

Alkylation of 3-indolylacetonitrile (VI) with ethyl bromoacetate provided indoleacetate ester (VII). Condensation of the cyano group of (VII) with amino thiophenol (V) in hot EtOH furnished benzothiophene (VI). The ethyl ester group of (VI) was finally hydrolyzed with NaOH to the title carboxylic acid.

参考文献中间体

【2】 Jones, J.H.; Jones, M.L.; Gunn, D.; Van Zandt, M.C. (The Institutes for Pharmaceutical Discovery, Inc.); Substd. indolealkanoic acids. WO 9950268 .
【3】 Jacot, J.; Sredy, J. (The Institutes for Pharmaceutical Discovery, Inc.); Methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis using substd. indolealkanoic acids. WO 0032180 .
【4】 Van Zandt, M.; Sredy, J. (The Institutes for Pharmaceutical Discovery, Inc.); Compsns. containing a substd. indolealkanoic acid and an angiotensin converting enzyme inhibitor. WO 0164205 .
【5】 Boyd, M.; Robinson, D. (The Institutes for Pharmaceutical Discovery, Inc.); Methods for lowering uric acid levels. WO 0151489 .
【1】 Jones, J.H.; Gunn, D.; Jones, M.L.; Van Zandt, M.C.; Lavoie, D.J.; Sawicki, D.; Sredy, J.; Howard, E.; Podjarny, A.D.; Substituted indolealkanoic acids as novel aldose reductase inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 307.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	44290	2-amino-3,4,6-trifluorobenzenethiol; 2-amino-3,4,6-trifluorophenylhydrosulfide		C₆H₄F₃NS	详情	详情
(VI)	44291	3-Indolylacetonitrile;3-Cyanomethyl-1H-indole;3-(Cyanomethyl)indole;Indole-3-acetonitrile;3-Indoleacetonitrile;2-(3-indolyl)acetonitrile;2-(1H-indol-3-yl)acetonitrile;2-(1H-Indol-3-yl)acetonitrile; 3-Indolylacetonitrile	771-51-7	C₁₀H₈N₂	详情	详情
(VII)	44292	ethyl 2-[3-(2-nitriloethyl)-1H-indol-1-yl]acetate		C₁₄H₁₄N₂O₂	详情	详情
(VIII)	44293	ethyl 2-[3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl]acetate		C₂₀H₁₅F₃N₂O₂S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)