Synthesis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diamino-quinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]-cycloheptene substituents at the 6-position as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium

A. Rosowsky, H. Fu, Sherry Queener

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17 Citations (Scopus)

Abstract

The synthesis of four previously undescribed 2,4-diaminopyrido[2,3-d]pyrimidines (3,4) and 2,4-diaminoquinazolines (5,6) with a bulky tricyclic aromatic group at the 6-position is described. Condensation of dibenz[b,f]azepine with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine (8) and 2,4-diamino-6-bromomethylquinazoline (17) in the presence of sodium hydride afforded N-[(2,4-diaminopyrido[2,3-d]-pyrimidin-6-yl)methyl]dibenz[b,f]azepine (3) and N-[(2,4-diaminoquinazolin-6-yl)methyl]dibenz[b,f]-azepine (4), respectively. Condensation of 5-chlorodibenzo[a,d]cycloheptene (19) and 5-chloro-10,11-dihydrodibenzo[a,d]cycloheptene (20) with 2,4,6-triaminoquinazoline (13) afforded 5-[(2,4-diamino-quinazolin-6-yl)amino]-5H-dibenzo[a,d]cycloheptene (5) and the corresponding 10,11-dihydro derivative (6), respectively. The bromides 8 and 17, as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three-step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3-6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liven Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC50 values in the 0.03-0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was 100-fold selectivity for the T. gondii and M. avium enzyme and 21-fold selectivity for the P. carinii enzyme.

Original languageEnglish (US)
Pages (from-to)921-926
Number of pages6
JournalJournal of Heterocyclic Chemistry
Volume37
Issue number4
StatePublished - 2000

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Azepines
Quinazolines
Folic Acid Antagonists
Pyrimidines
Hydrobromic Acid
Enzymes
formic acid
Rats
Condensation
Tetrahydrofolate Dehydrogenase
Nitriles
Nickel
Bromides
Acetic Acid
Salts
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{fc0c8aa0bf5948b09c971f54bcbbd64c,
title = "Synthesis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diamino-quinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]-cycloheptene substituents at the 6-position as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium",
abstract = "The synthesis of four previously undescribed 2,4-diaminopyrido[2,3-d]pyrimidines (3,4) and 2,4-diaminoquinazolines (5,6) with a bulky tricyclic aromatic group at the 6-position is described. Condensation of dibenz[b,f]azepine with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine (8) and 2,4-diamino-6-bromomethylquinazoline (17) in the presence of sodium hydride afforded N-[(2,4-diaminopyrido[2,3-d]-pyrimidin-6-yl)methyl]dibenz[b,f]azepine (3) and N-[(2,4-diaminoquinazolin-6-yl)methyl]dibenz[b,f]-azepine (4), respectively. Condensation of 5-chlorodibenzo[a,d]cycloheptene (19) and 5-chloro-10,11-dihydrodibenzo[a,d]cycloheptene (20) with 2,4,6-triaminoquinazoline (13) afforded 5-[(2,4-diamino-quinazolin-6-yl)amino]-5H-dibenzo[a,d]cycloheptene (5) and the corresponding 10,11-dihydro derivative (6), respectively. The bromides 8 and 17, as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three-step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3-6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liven Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC50 values in the 0.03-0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was 100-fold selectivity for the T. gondii and M. avium enzyme and 21-fold selectivity for the P. carinii enzyme.",
author = "A. Rosowsky and H. Fu and Sherry Queener",
year = "2000",
language = "English (US)",
volume = "37",
pages = "921--926",
journal = "Journal of Heterocyclic Chemistry",
issn = "0022-152X",
publisher = "Heterocorporation",
number = "4",

}

TY - JOUR

T1 - Synthesis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diamino-quinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]-cycloheptene substituents at the 6-position as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium

AU - Rosowsky, A.

AU - Fu, H.

AU - Queener, Sherry

PY - 2000

Y1 - 2000

N2 - The synthesis of four previously undescribed 2,4-diaminopyrido[2,3-d]pyrimidines (3,4) and 2,4-diaminoquinazolines (5,6) with a bulky tricyclic aromatic group at the 6-position is described. Condensation of dibenz[b,f]azepine with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine (8) and 2,4-diamino-6-bromomethylquinazoline (17) in the presence of sodium hydride afforded N-[(2,4-diaminopyrido[2,3-d]-pyrimidin-6-yl)methyl]dibenz[b,f]azepine (3) and N-[(2,4-diaminoquinazolin-6-yl)methyl]dibenz[b,f]-azepine (4), respectively. Condensation of 5-chlorodibenzo[a,d]cycloheptene (19) and 5-chloro-10,11-dihydrodibenzo[a,d]cycloheptene (20) with 2,4,6-triaminoquinazoline (13) afforded 5-[(2,4-diamino-quinazolin-6-yl)amino]-5H-dibenzo[a,d]cycloheptene (5) and the corresponding 10,11-dihydro derivative (6), respectively. The bromides 8 and 17, as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three-step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3-6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liven Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC50 values in the 0.03-0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was 100-fold selectivity for the T. gondii and M. avium enzyme and 21-fold selectivity for the P. carinii enzyme.

AB - The synthesis of four previously undescribed 2,4-diaminopyrido[2,3-d]pyrimidines (3,4) and 2,4-diaminoquinazolines (5,6) with a bulky tricyclic aromatic group at the 6-position is described. Condensation of dibenz[b,f]azepine with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine (8) and 2,4-diamino-6-bromomethylquinazoline (17) in the presence of sodium hydride afforded N-[(2,4-diaminopyrido[2,3-d]-pyrimidin-6-yl)methyl]dibenz[b,f]azepine (3) and N-[(2,4-diaminoquinazolin-6-yl)methyl]dibenz[b,f]-azepine (4), respectively. Condensation of 5-chlorodibenzo[a,d]cycloheptene (19) and 5-chloro-10,11-dihydrodibenzo[a,d]cycloheptene (20) with 2,4,6-triaminoquinazoline (13) afforded 5-[(2,4-diamino-quinazolin-6-yl)amino]-5H-dibenzo[a,d]cycloheptene (5) and the corresponding 10,11-dihydro derivative (6), respectively. The bromides 8 and 17, as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three-step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3-6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liven Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC50 values in the 0.03-0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was 100-fold selectivity for the T. gondii and M. avium enzyme and 21-fold selectivity for the P. carinii enzyme.

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VL - 37

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JO - Journal of Heterocyclic Chemistry

JF - Journal of Heterocyclic Chemistry

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