Synthesis of 1-Diethylamino-2,3-epoxypropane, 3-Diethylamino-2-hydroxypropylamine, and 4-Diethylamino-3-hydroxybutylamine<sup>1</sup>

Gilman, Henry; Sherman, Clarence S.; Price, Charles C.; Elderfield, Robert C.; Maynard, John T.; Reitsema, Robert H.; Tolman, Leo; Massie, Samuel P.; Marshall, Frederick J.; Goldman, Leon

doi:10.1021/ja01211a051

Cited by 22 publications

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“…4-[(3-Bromophenyl)amino]-6-[[3-(diethylamino)-2-hydroxypropyl]amino]pyrido[3,4- d ]pyrimidine (5k). A solution of 13 (5.74 g, 18 mmol) and 1-amino-3-(diethylamino)-2-propanol (26.3 g, 180 mmol) in DMSO (27 mL) was heated at 80 °C under N 2 for 23 h. The DMSO was evaporated under reduced pressure (0.1 mm) at 100 °C, and the residue was purified by flash chromatography on silica gel. Elution with a gradient of MeOH in EtOAc containing 2% Et 3 N and pooling of appropriate fractions gave 5k (4.87 g).…”

Section: Methodsmentioning

confidence: 99%

Tyrosine Kinase Inhibitors. 14. Structure−Activity Relationships for Methyl- amino-Substituted Derivatives of 4-[(3-Bromophenyl)amino]-6-(methylamino)- pyrido[3,4-d]pyrimidine (PD 158780), a Potent and Specific Inhibitor of the Tyrosine Kinase Activity of Receptors for the EGF Family of Growth Factors

et al. 1998

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The 4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine PD 158780 is a very potent in vitro inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) (IC50 0.08 nM), and other members of the erbB family, by competitive binding at the ATP site of these signal transduction enzymes. A series of analogues of PD 158780 bearing solubilizing functions off the 6-methylamino substituent were prepared by reaction of the 6-fluoro derivatives with appropriate amine nucleophiles. These were evaluated for their ability to inhibit the tyrosine phosphorylating action of EGF-stimulated full-length EGFR enzyme and for inhibition of autophosphorylation of the EGFR in A431 human epidermoid carcinoma cells in culture. The most effective analogues were those bearing weakly basic substituents through a secondary amine linkage, which proved water-soluble (> 10 mM) and potent (IC50S generally < 1 nM). No clear SAR could be discerned for these compounds with respect to amine base strength or the distance of the cationic center from the chromophore, suggesting that 6-substituents are in a favorable area of bulk tolerance in the enzyme binding site. More distinct SAR emerged for the ability of the compounds to inhibit EGFR autophosphorylation in A431 cells, where analogues bearing lipophilic weak bases were preferred. Representative analogues were evaluated for antitumor effectiveness against four in vivo tumor models. Significant in vivo activity was observed in estrogen-dependent MCF-7 breast and A431 epidermoid tumors. Marginal activity was seen in an EGFR-transfected tumor model, suggesting that while this cell line requires EGF for clone formation in soft agar, other growth factors may be able to replace EGF in vivo. Also, no activity was seen against the SK-OV-3 ovarian cancer model, which is known to express other EGF receptor family members (although it is not clear whether these are absolutely required for growth in vivo). While substantial growth delays were seen in A431 and MCF-7 tumor models, the treated tumors remained approximately the same size throughout therapy, suggesting that the compounds are cytostatic rather than cytotoxic under these test conditions. It remains to be determined if more prolonged therapy has cytotoxic effects in vivo, resulting in net tumor cell kill.

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Section: Methodsmentioning

confidence: 99%

Tyrosine Kinase Inhibitors. 14. Structure−Activity Relationships for Methyl- amino-Substituted Derivatives of 4-[(3-Bromophenyl)amino]-6-(methylamino)- pyrido[3,4-d]pyrimidine (PD 158780), a Potent and Specific Inhibitor of the Tyrosine Kinase Activity of Receptors for the EGF Family of Growth Factors

et al. 1998

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“…N,N-diethylepoxypropylamine (DEEPA) was synthesized according to Gilman (1946). The fraction with boiling temperature 32-35°C/4 mmHg was used for the experiments.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of water-soluble cationic cellulose derivatives with tertiary amino groups

Liesienė

2009

Cellulose

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Water-soluble cellulose derivatives with tertiary amino groups up to substitution degree 0.8 (4.2% of coupled nitrogen) were prepared in a controlled manner by the interaction of cellulose acetate with N,N-diethylepoxypropylamine. It was shown that two reactions take place simultaneously, i.e., hydrolysis of acetyl groups and aminoalkylation of free hydroxyl groups of cellulose. The amino groups coupled to the cellulose are of middle basicity with pK a *9.5. Solubility of the products was found to be determined by the chemical composition of the cellulose derivative.

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“…38 Glycidyl amines can easily be synthesized from reaction with a secondary amine and then subsequent ring closing reaction with NaOH. 39 Aside from ECH, epoxidation of alkenes is a common way to achieve epoxides with a variety of substituents. 40,41 Fig.…”

Section: Epoxide Synthesismentioning

confidence: 99%

A guide to modern methods for poly(thio)ether synthesis using Earth-abundant metals

Ferrier,

Kumbhar,

Crum-Dacon

et al. 2023

Chem. Commun.

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Synthesis of 1-Diethylamino-2,3-epoxypropane, 3-Diethylamino-2-hydroxypropylamine, and 4-Diethylamino-3-hydroxybutylamine¹

Cited by 22 publications

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Synthesis of water-soluble cationic cellulose derivatives with tertiary amino groups

A guide to modern methods for poly(thio)ether synthesis using Earth-abundant metals

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Synthesis of 1-Diethylamino-2,3-epoxypropane, 3-Diethylamino-2-hydroxypropylamine, and 4-Diethylamino-3-hydroxybutylamine1

Cited by 22 publications

References 0 publications

Synthesis of water-soluble cationic cellulose derivatives with tertiary amino groups

A guide to modern methods for poly(thio)ether synthesis using Earth-abundant metals

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Synthesis of 1-Diethylamino-2,3-epoxypropane, 3-Diethylamino-2-hydroxypropylamine, and 4-Diethylamino-3-hydroxybutylamine¹