Methods for synthesizing molybdopterin precursor z derivatives

A compound and reaction technology, applied in the field of synthesizing molybdenum pterin precursor Z derivatives, can solve problems such as limited availability of therapeutically active agents

Inactive Publication Date: 2012-11-07
阿莱克申药物国际公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, like most disease replacement therapies, this therapy

Method used

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  • Methods for synthesizing molybdopterin precursor z derivatives
  • Methods for synthesizing molybdopterin precursor z derivatives
  • Methods for synthesizing molybdopterin precursor z derivatives

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Experimental program
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preparation example Construction

[0256] The preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. One skilled in the art can readily determine the need for protection and deprotection and select appropriate protecting groups. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000; March's Advanced Organic chemistry: Reactions, Mechanisms, and Structure, 5 th Ed., Wiley-Interscience Publication, 2001; and Peturssion, S.et al., "Protecting Groups in Carbohydrate Chemistry," J.Chem.Educ., 74 (11), 1297 (1997), the respective full The contents are incorporated into this application by reference.

[0257] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be achieved by spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g....

Embodiment 1

[0712] Example 1. Preparation of Precursor Z (cPMP)

[0713] Program 20

[0714]

[0715]

[0716] test

[0717] Air-sensitive reactions were performed under argon. The organic solution was treated with anhydrous MgSO 4 Dry, and the solvent is evaporated under reduced pressure. Anhydrous and chromatographic solvents were obtained commercially (anhydrous grade solvents were purchased from Sigma-Aldrich Fine Chemicals) and were used without any further purification. Thin layer chromatography (t.l.c.) was coated with 60F 254 Silicone on glass or on aluminum sheets. Organic compounds were visualized as follows: under UV light or using ammonium molybdate (5 wt %) and cerium(IV) sulfate 4H 2 O (0.2wt%) in H 2 SO 4 (2M) solution in aqueous solution, I 2 (0.2%) and one of KI (7%) in H 2 SO 4 Impregnation of solutions in (1M) or 0.1% ninhydrin in EtOH. Chromatography (flash column) was performed on silica gel (40-63 [mu]m) or on an automated system with a continuous g...

Embodiment 2

[0731] Example 2. Comparison of Precursor Z(cPMP) prepared synthetically and Precursor Z(cPMP) prepared by E. coli in the in vitro synthesis of Moco

[0732] The in vitro synthesis of Moco was compared using samples of the synthetic precursor Z (cPMP) and cPMP purified from E. coli. Moco synthesis also included the use of purified components E. coli MPT synthase, bridging protein, molybdate, ATP, and apo-sulfite oxidase. See US Patent 7,504,095; and "Biosynthesis and molecular biology of the molybdenum cofactor (Moco)" in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, Günter, Informa Plc, 2002, Vol. 39, pages 317-68. The assay is based on conversion of cPMP to MPT, subsequent molybdate insertion using recombinant bridging proteins and ATP and finally reconstitution of human apo-sulfite oxidase.

[0733] Such as figure 1 As shown, Moco synthesis from synthetic cPMP was confirmed, and no difference in Moco transformation was found compared to E. coli purified c...

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Abstract

Provided herein are synthetic methods for preparing a compound of formula (I): Also provided herein are synthetic methods for preparing a compound of formula (XIII): The disclosure also provides useful intermediates, derivatives, prodrugs, and pharmaceutically acceptable salts, solvates and hydrates of the formula (I) and formula (XIII) compounds. These compounds are useful for treating diseases associated with molybdenum cofactor deficiency.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Applications 61 / 444,389 filed February 18, 2011, 61 / 498,801 filed June 20, 2011, 61 / 498,808 filed June 20, 2011, and Priority of 61 / 599,314 filed, the entire contents of which are incorporated into this application by reference. technical field [0003] The present application provides a synthetic method for preparing molybdopterin (molybdopterin) derivative precursor Z and a new synthetic intermediate for synthesizing it. The present application also provides useful intermediates, derivatives, prodrugs and pharmaceutically acceptable salts, solvates and hydrates of precursor Z. These compounds are especially useful in the treatment of diseases associated with molybdenum cofactor deficiency. Background technique [0004] Molybdenum coenzyme (Moco) deficiency is a pleiotropic genetic disorder. Moco consists of molybdenum covalently linked to one or two dithiolat...

Claims

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Application Information

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IPC IPC(8): C07F9/6584A61K31/675A61P25/00A61P25/28C07D491/147C07H3/10C07H1/00
Inventor 龙翔天代丹梅A·布伦纳D·K·瓦特K·克林奇S·M·巴亚斯R·A·迪克森G·M·里特尔C·A·S·兰德雷N·G·R·普罗伊塞
Owner 阿莱克申药物国际公司
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