C - Chemistry – Metallurgy – 07 – D
Patent
C - Chemistry, Metallurgy
07
D
260/265.3
C07D 471/04 (2006.01) C07D 213/75 (2006.01)
Patent
CA 1198111
Abstract Of The Disclosure: 1,2-Dihydropyrido[3,4-b]pyrazines are provided which possess antifungal and anticancer activity. The compounds have the structure: Image I wherein x has a value of 1, 2 or 3; R1 is a lower alkyl group, e.g., an alkyl group containing up to six carbon atoms such as methyl, ethyl, propyl, butyl, etc.; R2 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 6 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; 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, provided that when x has a value of 1 and R2 is in the para position and R3 and R4 are both hydrogen, R2 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, preferably from about one to about 5 carbon atoms; an alkylthio 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; and, when taken together with the aromatic ring to which it is attached, a fused ring structure such as naphthyl; and R3 and R4 are either both hydrogen or one is hydrogen and the other is a lower alkyl group. Compounds of Formula I wherein R3 is hydrogen are prepared by aminating a lower alkyl ester of 6-amino-4-chloro- 5-nitropyridin-2-ylcarbamate having the structure: Image II with the oxime of an alpha-amino ketone having the structure: Image III to give a lower alkyl ester of a 6-amino-5-nitro-4-[12-oxo- ethyl)amino]pyridin-2-ylcarbamate oxime having the structure: Image IV wherein R1, R2, R4 and x are the same as previously defined, further provided that R2 may be a nitro group. The compound of Formula IV is hydrolyzed, e.g., by acid hydrolysis to give the correpsonding ketone having the formula: Image V wherein R1, R2, R4 and x are the same as previously defined, further provided that R2 may be a nitro group. The compound of Formula V is converted to the compound of Formula I by catalytic hydrogenation. An intermediate product formed during hydrogena- tion has the formula: Image VI wherein R1, R2, R4 and x are the same as previously defined. Compounds of Formula I wherein R4 is hydrogen may also be prepared by aminating the compound of Formula II with an alpha-amino alcohol having the structure: Image IIIA to give a compound having the structure: Image VII; which is oxidized to give a ketone having the structure: Image VA wherein R1, R2, R3 and x are the same as previously defined, further provided that R2 may be a nitro group. The compound of Formula VA is converted to a compound of Formula I by catalytic hydrogenation.
399081
Elliott Robert D.
Montgomery John A.
Temple Carroll G. Jr.
Wheeler Glynn P.
Borden Ladner Gervais Llp
Southern Research Institute
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