Southern Research Institute

The United States of America

The Government of the United States of America

Robert D Elliott

John A Montgomery

Carroll G Temple, Jr

Glynn P Wheeler

Jerry D Rose

1,2-Dihydropyrido[3,4-b]pyrazines are provided which possess anticancer activity. The compounds have the structure: ##STR1## wherein Y is CH.sub.2 or N(CH.sub.3); R.sub.1 is a lower alkyl group; e.g., an alkyl group containing up to six carbon atoms such as methyl, ethyl, propyl, butyl, etc.; R.sub.2 is a member selected from the group consisting of hydrogen, CH.sub.3 O or Cl; and R.sub.3 and R.sub.4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group.

Intermediates for preparing 1,2-dihydropyrido[3,4-b]-pyrazines

There are disclosed novel intermediates useful in the preparation of pyrido[2,3-d]pyrimidines having the following structures: ##STR1## wherein R is CH.sub.3, CH.sub.3 CH.sub.2, CH.sub.3 CH.sub.2 CH.sub.2, CH.sub.2 .dbd.CHCH.sub.2 or CH.tbd.CCH.sub.2 ; and ##STR2## wherein R is CH.sub.3, CH.sub.3 CH.sub.2, CH.sub.3 CH.sub.2 CH.sub.2, CH.sub.2 .dbd.CHCH.sub.2 or CH.tbd.CCH.sub.2. These intermediates have the formulas: ##STR3## wherein Y is CHO, CH.sub.2 OH or CH.sub.2 Br; and Z is CH.sub.2 OH or CH.sub.2 Br.

Pyrido(2,3-D)pyrimidines

1,2-dihydropyrido[3,4-b]pyrazines

There are disclosed novel intermediates useful in the preparation of pyrido[2,3-d]pyrimidines having the following structure: ##STR1## wherein R is CH.sub.3, CH.sub.3 CH.sub.2, CH.sub.3 CH.sub.2 CH.sub.2, CH.sub.2 .dbd.CHCH.sub.2 or CH.tbd.CCH.sub.2. The intermediate has the formula: ##STR2## wherein Z is CH.sub.2 OH or CH.sub.2 Br.

2-Amino-4(3H)-oxopyrido[2,3-d]pyrimidino

There is disclosed a novel intermediate useful in the preparation of pyrido [2,3-d] pyrimidines, which includes N-[4-[(2-amino-4(3H)-oxopyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]-L -glutamic acid (5-deazafolic acid), N-[4-[[2-amino-4(3H)-oxopyrido[2,3-d]-pyrimidin-6-yl)methyl]methylamino]be nzoyl]-L-glutamic acid (5-deaza-N.sup.10 -methylfolic acid), N-(4-[(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]-L-gluta mic acid (5-deazaaminopterin), and N-[4-[[2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methyl]methylamino]benzoyl]- L-glutamic acid (5-deazamethotrexate). This intermediate is the compound 2,4-diamino-6-(hydroxymethyl)pyrido-[2,3-d]pyrimidine.

2,4-Diamino-6-(hydroxymethyl)pyrido[2,3-d]pyrimidine

Compounds of the formulas ##STR1## where the substituents are as defined within are disclosed as intermediates to make antifungal 1,2-Dihydropyrido[3,4-b]pyrazines.

Intermediate for preparing antifungal 1,2-dihydropyrido[3,4-b]-pyrazines

There are disclosed certain 2H-pyrido[4,3-b][1,4]oxazines and 2H-pyrido[4,3-b][1,4]thiazines which possess biological activity. The compounds have the structure: ##STR1## wherein n has a value of 1,2 or 3; X is oxygen or sulfur; R.sub.1 is a lower alkyl group, e.g., an alkyl group containing up to six carbon atoms such as methyl, ethyl, propyl, butyl, etc.; R.sub.2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, preferably from about one to about six carbon atoms; alkenyl radicals having from about two to about 15 carbon atoms; preferably from about two to about 10 carbon atoms; cycloalkyl radicals having from about three to about 20 carbon atoms, preferably from about three to about 15 carbon atoms; aryl, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, preferably from about six to about 15 carbon atoms; a halogen radical, e.g., chlorine, fluorine, bromine and iodine; a hydroxyl group; an amino group; an alkoxy or aryloxy group; a carboxyl group or an alkylcarboxyl group having from about one to about 10 carbon atoms, preferably from about one to about five carbon atoms; an alkythio group or an arylthio group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; a sulfonic acid group or alkyl- or arylsulfonyl group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; an alkyl- or arylsulfinyl group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; an alkyl- or aryl mono- or diamino group having from about one to about 20 carbon atoms, preferably from about one to about 15 carbon atoms; a hydrocarbyl group, such as defined above, carrying halogen, hydroxyl, amino, alkoxy or aryloxy; when taken together with the aromatic ring to which it is attached, a fused ring structure such as naphthyl; and, when taken together with R.sub.3, an alkylene radical containing from about one to about 12 carbon atoms, preferably from about one to about six carbon atoms; R.sub.3 is hydrogen, methyl, phenyl or, when taken with R.sub.2, an alkylene radical as previously defined; R.sub.4 is hydrogen or methyl; R.sub.3 and R.sub.4, when taken together are the radical .dbd.0; and R.sub.5 and R.sub.6 are both hydrogen, or one is hydrogen and the other is the radical ##STR2## or where taken together are the radical .dbd.CHN(CH.sub.3).sub.2.

Pyrido[4,3-b][1,4]oxazines and pyrido[4,3-b][1,4]thiazines

1,2-Dihydropyrido[3,4-b]pyrazines are provided which possess antifungal and anticancer activity. The compounds have the structure: ##STR1## wherein x has a value of 1, 2 or 3; R.sub.1 is a lower alkyl group, R.sub.2 is a member selected from the group consisting of hydrogen, alkyl radicals having from about one to about 12 carbon atoms, alkenyl radicals having from about two to about 15 carbon atoms, cycloalkyl radicals having from about three to about 20 carbon atoms, aralkyl and alkaryl radicals having from about six to about 20 carbon atoms, a halogen radical, provided that when x has a value of 1 and R.sub.2 is in the para position and R.sub.3 and R.sub.4 are both hydrogen, R.sub.2 is not chlorine; a hydroxyl group; an amino group; an alkoxy or aryloxy group; a carboxyl group or an alkylcarboxyl group having from about one to about 10 carbon atoms, an alkylthio group or an arylthio group having from about one to about 20 carbon atoms, a sulfonic acid group or alkyl- or arylsulfonyl group having from about one to about 20 carbon atoms, an alkyl- or arylsulfinyl group having from about one to about 20 carbon atoms, an alkyl- or aryl mono- or diamino group having from about one to about 20 carbon atoms, a hydrocarbyl group, such as defined above, carrying halogen, hydroxyl, amino, alkoxy or aryloxy; and, when taken together with the aromatic ring to which it is attached, a fused ring structure such as naphthyl; and R.sub.3 and R.sub.4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group.

1,2-Dihydropyrido[3,4-b]-pyrazines and method and intermediates for

There is disclosed a novel intermediate useful in the preparation of pyrido[2,3-d]pyrimidines, which includes N-[4- [(2-amino-4(3H)-oxopyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glut amic acid (5-deazafolic acid), N-[4-[[(2-amino-4(3H)-oxopyrido[2,3-d]-pyrimidin-6-yl)methyl]methylamino]b enzoyl]-L-glutamic acid (5-deaza-N.sup.10 -methylfolic acid), N-[4-[(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methylamino]benzoyl]-L-gluta mic acid (5-deazaaminopterin), and N-[4-[[(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methyl]methylamino]benzoyl] -L-glutamic acid (5-deazamethotrexate). This intermediate is the compound 2,4-diaminopyrido[2,3-d]pyrimidine-6-carboxaldehyde.

Pyrido[2,3-d]-pyrimidines

Improved methods for the preparation and purification of citrovorum factor are disclosed. The method includes improved procedures for hydrogenation of 10-formylfolic acid as well as for the reduction of folic acid. Also disclosed are improved procedures for opening of the imidazoline ring, and a non-chromatographic method for the purification of crude samples of citrovorum factor.

Growing community of inventors

Birmingham, AL, United States of America

Robert D Elliott