Heterocyclic Basic Compounds. I. 2-Aminoalkylamino-pyridines<sup>1</sup>

Whitmore, Frank C.; Mosher, Harry S.; Goldsmith, Dale P. J.; Rytina, A. W.

doi:10.1021/ja01219a011

Cited by 14 publications

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“…These alkylation results are consistent with those reported for reactions on 2-aminopyridine by Dome, where mixtures of mono- and dibenzylated products were obtained in moderate yield (35% and 23%, respectively), and by Whitmore, who prepared the 2-(morpholinylpropyl)amino derivative (18%) by heating the preformed anion with 0.5 equiv of the alkyl chloride in toluene. However, selective monoalkylation of 2-aminopyridine in better yield has been reported , via the corresponding 2-formamide or acetamide (whereas 2-sulfonamides reportedly gave alkylation on the ring nitrogen).…”

Section: Chemistrysupporting

confidence: 90%

3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase

et al. 2000

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A series of 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas were prepared and evaluated as inhibitors of the FGF receptor-1 tyrosine kinase. Condensation of 4,6-diaminonicotinaldehyde and substituted phenylacetonitriles gave intermediate naphthyridine-2,7-diamines, and direct reaction of the monoanion of these (NaH/DMF) with alkyl or aryl isocyanates selectively gave the 2-ureas in varying yields (23-93%). For the preparation of more soluble 7-alkylamino-2-ureas, a number of protecting groups for the 2-amine were evaluated (phthaloyl, 4-methoxybenzyl) following selective blocking of the 7-amine (trityl), but these were not superior to the (required) 2-tert-Bu-urea group itself. Direct alkylation of the anion of the (unprotected) 7-amino group with excess 4-(3-chloropropyl)morpholine in DMF gave low (10%) yields of the desired product, but alkylation of the 7-acetamido anion, followed by mild alkaline hydrolysis, raised this to 64%. 3-Phenyl analogues were nonspecific inhibitors of isolated c-Src, FGFR, and PDGFR tyrosine kinases, whereas 3-(2,6-dichlorophenyl) analogues were most effective against c-Src and FGFR, and 3-(3,5-dimethoxyphenyl) derivatives showed high selectivity for FGFR alone. A water-soluble (7-morpholinylpropylamino) analogue retained high FGFR potency (IC(50) 31 nM) and selectivity. Pairwise comparison of the 1, 6-naphthyridines and the corresponding known pyrido[2,3-d]pyrimidine analogues showed little differences in potency or patterns of selectivity, suggesting that the 1-aza atom of the latter is not important for activity. A 7-acetamide derivative inhibited the growth of FGFR-expressing tumor cell lines and was particularly potent against HUVECs (IC(50) 4 nM). This compound was also a very potent inhibitor of HUVEC microcapillary formation (IC(50) 0.01 nM) and Matrigel invasion (IC(50) 7 nM) and showed significant in vivo antitumor effects in a highly vascularized mammary adenocarcinoma 16/c model at nontoxic doses. The compounds are worthy of further evaluation as antiangiogenesis agents.

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Section: Chemistrysupporting

confidence: 90%

3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase

et al. 2000

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“…7,8 The metalation, however, might not be quantitative. As an alternative, activation of the exocyclic amino group facilitates deprotonation, and regioselective alkylation.…”

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Pyridinium N-(2′-Azinyl)Aminides: Regioselective Synthesis of 2-Alkylaminoazines

et al. 2000

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“…Alkylation and heterylation of aminated pyridines and related compounds Many secondary amines have been prepared in good yields by condensing the lithium or sodium derivative of 2-aminopyridine with a variety of halides such as alkyl halides (775, 825), polymethylene dihalides (774), dialkylaminoalkyl halides(175,262,447,484,530,543,559,878), benzyl halides (97, 485), thenyl halides (484, 531), 3-thianaphthenylmethyl chloride (113), haloacetals (482), haloalcohols (898), 2-chlorothiazole (259), and 2-chloropyrimidine(259). The following examples are typical.…”

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The Chemistry of the Alkali Amides.

Levine¹,

Fernelius²

1954

Chem. Rev.

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This review of the chemistry of the alkali amides is a continuation of two earlier reviews (17) which have appeared on this subject. In the present review the authors have summarized the work on the inorganic and organic chemistry of the alkali amides which has appeared in the literature from 1937 through 1952. In addition, a considerable amount of previously unpublished material is discussed. Whenever possible, the authors have tried to interpret and evaluate critically the material presented and to call attention to those areas of research which have not been investigated or which should be studied further. Although it has not been convenient to discuss all of the present material under the same headings as were used previously, the changes have not been so extensive as to make cross references difficult.

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Heterocyclic Basic Compounds. I. 2-Aminoalkylamino-pyridines¹

Cited by 14 publications

References 0 publications

3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase

3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase

Pyridinium N-(2′-Azinyl)Aminides: Regioselective Synthesis of 2-Alkylaminoazines

The Chemistry of the Alkali Amides.

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Heterocyclic Basic Compounds. I. 2-Aminoalkylamino-pyridines1

Cited by 14 publications

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3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase

3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase

Pyridinium N-(2′-Azinyl)Aminides: Regioselective Synthesis of 2-Alkylaminoazines

The Chemistry of the Alkali Amides.

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Heterocyclic Basic Compounds. I. 2-Aminoalkylamino-pyridines¹