DMP-444, RP-444, Tc-99m-DMP-444, -Drug Synthesis Database

【结构式】

【药物名称】DMP-444, RP-444, Tc-99m-DMP-444

【化学名称】Trisodium hydrogen [cyclo[L-arginylglycyl-L-aspartyl-3-(aminomethyl)-5-[6-[6-(diazenyl-kappaN2)-3-pyridylcarboxamido]hexanamido]benzoyl-D-valylato(2-)]][N-[2-hydroxy-1,1-bis[(hydroxy-kappaO)methyl]ethyl]glycinato(2-)-kappaN,kappaO][3,3',3''-(phosphinidyne-kappaP)tris(benzenesulfonato)(3-)]technetate(4-)-99Tc

【CA登记号】206763-88-4

【分子式】C₆₂H₇₅N₁₄Na₃O₂₃PS₃Tc

【分子量】1679.50425

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】DIAGNOSTIC AGENTS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

The title ternary ligand technetium-99m complex was formed as a mixture of two isomeric forms by reaction of the hydrazinonicotinamide-derivatized cyclic peptide (I) with trisodium triphenylphosphine-3,3',3''-trisulfonate (II) and tricine (III) in the presence of 99mTc pertechnetate and SnCl2. The 99Tc analogue was similarly prepared for spectroscopic characterization by using (n-Bu4N)(99TcOCl4) or (NH4)(99TcO4).

参考文献中间体

【1】 Liu, S.; et al.; Technetium complexes of a hydrazinonicotinamide-conjugated cyclic peptide and 2-hydrazinopyridine: synthesis and characterization. Inorg Chem 1999, 38, 6, 1326.
【2】 Liu, S.; Edwards, D.S. (DuPont Pharmaceuticals Co.); Ternary radiopharmaceutical complexes. EP 0995761; US 5744120; WO 9631243 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	48084	2-[(5S,11S,14R)-11-(3-[[amino(imino)methyl]amino]propyl)-19-[(6-[[(6-hydrazino-3-pyridinyl)carbonyl]amino]hexanoyl)amino]-14-isopropyl-12-methyl-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazabicyclo[15.3.1]henicosa-1(21),17,19-trien-5-yl]acetic acid	C₃₈H₅₅N₁₃O₉	详情	详情
(II)	37264	trisodium 3-[bis(3-sulfonatophenyl)phosphino]benzenesulfonate	C₁₈H₁₂Na₃O₉PS₃	详情	详情
(III)	37265	4'-(hydroxymethyl)[1,1'-biphenyl]-2-carbonitrile	C₁₄H₁₁NO	详情	详情

合成路线2

In order to stabilize the hydrazino compound (I), a stable hydrazone derivative was prepared by two alternative procedures. Condensation of 6-hydrazinonicotinic acid (IV) with sodium 2-formylbenzenesulfonate (V) gave the hydrazone acid (VI), which was further converted to the succinimidyl active ester (VII) by treatment with N-hydroxysuccinimide and DCC. Coupling of succinimidyl ester (VII) with the aminocaproyl cyclic peptide (VIII) then gave the target hydrazone derivative (IX). Alternatively, (IX) was also prepared by condensation of the hydrazino peptide (I) with sodium 2-formylbenzenesulfonate (V).

参考文献中间体

【1】 Harris, T.D.; et al.; Synthesis of stable hydrazones of a hydrazinonicotinyl-modified peptide for the preparation of 99mTc-labeled radiopharmaceuticals. Bioconjugate Chem 1999, 10, 5, 808.

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)	48084	2-[(5S,11S,14R)-11-(3-[[amino(imino)methyl]amino]propyl)-19-[(6-[[(6-hydrazino-3-pyridinyl)carbonyl]amino]hexanoyl)amino]-14-isopropyl-12-methyl-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazabicyclo[15.3.1]henicosa-1(21),17,19-trien-5-yl]acetic acid		C₃₈H₅₅N₁₃O₉	详情	详情
(IV)	48085	6-hydrazinonicotinic acid		C₆H₇N₃O₂	详情	详情
(V)	48086	Benzaldehyde-2-sulfonic acid sodium; sodium 2-formylbenzenesulfonate	1008-72-6	C₇H₅NaO₄S	详情	详情
(VI)	48087	sodium 2-[[(E)-2-(5-carboxy-2-pyridinyl)hydrazono]methyl]benzenesulfonate		C₁₃H₁₀N₃NaO₅S	详情	详情
(VII)	48088	sodium 2-[[(E)-2-(5-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-pyridinyl)hydrazono]methyl]benzenesulfonate		C₁₇H₁₃N₄NaO₇S	详情	详情
(VIII)	48089	2-[(5S,11S,14R)-19-[(6-aminohexanoyl)amino]-11-(3-[[amino(imino)methyl]amino]propyl)-14-isopropyl-12-methyl-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazabicyclo[15.3.1]henicosa-1(21),17,19-trien-5-yl]acetic acid		C₃₂H₅₀N₁₀O₈	详情	详情
(IX)	48090	sodium 2-[[(E)-2-(5-[[(6-[[(4R,7S,13S)-7-(3-[[amino(imino)methyl]amino]propyl)-13-(carboxymethyl)-4-isopropyl-6-methyl-2,5,8,11,14-pentaoxo-3,6,9,12,15-pentaazabicyclo[15.3.1]henicosa-1(21),17,19-trien-19-yl]amino]-6-oxohexyl)amino]carbonyl]-2-pyridinyl)hydrazono]methyl]benzenesulfonate		C₄₅H₅₈N₁₃NaO₁₂S	详情	详情

合成路线3

The title compound was then obtained by complexation of hydrazone (IX) with phosphine (II) and tricine (III) in the presence of Na99mTcO4 and SnCl2. Under these conditions, the hydrazone protecting group hydrolyzed to the required hydrazine. Some shortcomings caused by SnCl2 could be omitted using a non-SnCl2-containing formulation in the presence of mannitol and pluronic acid as surfactant agents.

参考文献中间体

【1】 Edwards, D.S.; et al.; 99mTc-Labeling of hydrazones of a hydrazinonicotinamide conjugated cyclic peptide. Bioconjugate Chem 1999, 10, 5, 803.
【2】 Liu, S.; et al.; Towards developing A non-SnCl2 formulation for RP444, a new radiopharmaceutical for thrombus imaging. J Pharm Sci 2001, 90, 2, 114.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(II)	37264	trisodium 3-[bis(3-sulfonatophenyl)phosphino]benzenesulfonate	C₁₈H₁₂Na₃O₉PS₃	详情	详情
(III)	37265	4'-(hydroxymethyl)[1,1'-biphenyl]-2-carbonitrile	C₁₄H₁₁NO	详情	详情
(IX)	48090	sodium 2-[[(E)-2-(5-[[(6-[[(4R,7S,13S)-7-(3-[[amino(imino)methyl]amino]propyl)-13-(carboxymethyl)-4-isopropyl-6-methyl-2,5,8,11,14-pentaoxo-3,6,9,12,15-pentaazabicyclo[15.3.1]henicosa-1(21),17,19-trien-19-yl]amino]-6-oxohexyl)amino]carbonyl]-2-pyridinyl)hydrazono]methyl]benzenesulfonate	C₄₅H₅₈N₁₃NaO₁₂S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)