- Substituted Bicyclic Pyrimidine Compounds with Tubulin and Multiple Receptor Inhibition
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This invention provides substituted bicyclic pyrimidine compounds and pharmaceutically acceptable salts, hydrates, and solvates of the compounds, each having tubulin and multiple receptor inhibition properties. Methods of treating a patient diagnosed with
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- Process for the preparation of 9-deazaguanine derivatives
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Derivatives of 9-deazaguanine are prepared by reacting an aldehyde or ketone with a dialkylaminomalonate to form the corresponding enamine. The enamine is then reacted with a base to form a cyclic pyrrole. The cyclic pyrrole is reacted with an urea compound or a derivative of carbamimidoic acid to provide a protected guanidino compound. The guanidino is converted to the desired 9-deazaguanine derivative by reacting with trifluoracetic acid or with an alkoxide or hydroxide followed by neutralization with an acid.
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- Process for the preparation of 9-deazaguanine derivatives
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Derivatives of 9-deazaguanine are prepared by reacting an aldehyde or ketone with a dialkylaminomalonate to form the corresponding enamine. The enamine is then reacted with a base to form a cyclic pyrrole. The cyclic pyrrole is reacted with an urea compound to provide a protected guanidino compound. The guanidino is converted to the desired 9-deazaguanine derivative by reacting with trifluoracetic acid or with an alkoxide or hydroxide followed by neutralization with an acid.
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- An Improved Synthesis of 7-Substituted Pyrrolo[3,2-d]pyrimidines
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Base (NaOMe)-catalyzed condensation of 3,3-dimethoxypropionitrile with aldehydes followed by hydrolysis with 6 N HCl gives the unsaturated cyano aldehydes 5. Catalytic reduction of the double bond followed by reaction with diethyl aminomalonate affords the enamines 7, which cyclize to the aminopyrroles 2 on treatment with NaOMe. While the amino group in 2 is unreactive toward many guanylating reagents, acid (AcOH)-catalyzed guanylation occurs easily with 10 to give 12 along with methyl mercaptan as a byproduct. Subsequent facile removal of the carbamate groups and ring closure to the pyrrolo[3,2-d]pyrimidine ring system occurs on treatment with base. The use of HgCl2 in place of AcOH ties up the mercaptan and eliminates the odor problem. For larger scale reactions where the mercaptan odor and the use of Hg salts are undesirable, the use of the methoxy analogue 11 is preferred. Using this procedure, benzaldehyde has been converted to the 7-(phenylmethyl)pyrrolo[3,2-d]pyrimidine (1a), a potent inhibitor of the enzyme purine nucleoside phosphorylase, in 31% overall yield with only three isolation steps.
- Elliott, Arthur J.,Morris Jr., Philip E.,Petty, Sandra L.,Williams, Carl H.
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p. 8071 - 8075
(2007/10/03)
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- Structure-based design of inhibitors of purine nucleoside phosphorylase. 1. 9-(Arylmethyl) derivatives of 9-deazaguanine
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Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is a salvage enzyme important to the T-cell-mediated part of the immune system and as such is an important therapeutic target. This paper describes the design, synthesis, and enzymatic evaluation of potent, competitive inhibitors of PNP. Potential inhibitors were designed using the three-dimensional structure of the enzyme in an iterative process that involved interactive computer graphics to model the native enzyme and complexes of it with the inhibitors, Monte Carlo-based conformational searching, and energy minimization. Studies of the enzyme/inhibitor complexes were used to determine priorities of the synthetic efforts. The resulting compounds were then evaluated by determination of their IC50 values and by X-ray diffraction analysis using difference Fourier maps. In this manner, we have developed a series of 9-(arylmethyl)- 9-deazapurines (2-amino-7-(arylmethyl)-4H-pyrrolo[3,2-d]-pyrimidin-4-ones) that are potent, membrane-permeable inhibitors of the enzyme. The IC50 values of these compounds range from 17 to 270 nM (in 1 mM phosphate), with 9-(3,4-dichlorobenzyl)-9-deazaguanine being the most potent inhibitor. X-ray analysis explained the role of the aryl groups and revealed the rearrangement of hydrogen bonds in the binding of the 9-deazaguanines in the active site of PNP relative to the binding of the 8-aminoguanines that results in more potent inhibition of the enzyme.
- Montgomery,Niwas,Rose,Secrist III,Babu,Bugg,Erion,Guida,Ealick
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