Whitby Research, Inc.

Discovery Therapeutics, Inc.

Ray A Olsson

Robert D Thompson

N-6 substituted-5&prime;-(N-substituted carboxamide)adenosines as cardiac vasodilator and antihypertensive agents

Novel compounds and a method of using them to antagonize adenosine receptors are provided wherein the compounds are selected from the group of racemic mixtures or optically active compounds represented by the general formula: ##STR1## wherein R.sub.2 is selected from the group consisting of cycloalkyl radicals having from 3 to 8, preferably 3 to 7, ring carbon atoms, alkyl radicals having from 1 to 10, carbon atoms, aralkyl radicals having from 7 to 14, preferably 7 to 10, carbon atoms, and heteroatom- and halogen-substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of nitrogen, phosphorus, sulfur and oxygen; R.sub.1 may be hydrogen or R.sub.2, and R.sub.3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, thio, sufonate, sulfonamide, sulfone, sulfoxamide, phenyl, alkyl-substituted amine, cycloalkyl-substituted amine, alkyl radicals having from 1 to 10 carbon atoms, and cycloalkyl radicals having from 3 to 8, preferably 5 to 6, ring carbon atoms. R.sub.4 is selected from the group consisting of benzyl, phenyl, and alkyl groups comprising from 1 to 4 carbon atoms, wherein said alkyl group can be substituted with oxygen, for example ethers and alcohols. R.sub.5 is selected from the group consisting of hydrogen; hydroxy; sulfonate; halogen; alkoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms, wherein said alkoxy and cycloalkoxy groups can be substituted with phenyl; and amine, wherein said amine can be substituted with alkyl, cycloalkyl, or phenyl. Optically active compounds are especially active as antagonists of A.sub.1 adenosine receptors.

N.sup.6 -substituted 9-methyladenines: a new class of adenosine receptor

Compounds of the formula ##STR1## are disclosed, wherein R.sub.1, represents secondary alkyl; aralkyl; cycloalkyl; heteroaryl substituted alkyl; norbornyl; and substituted secondary alkyl, aralkyl, cycloalkyl, heteroaryl substituted alkyl, norbornyl; and para-substituted phenyl groups; and R.sub.2 and R.sub.3 are hydrogen or pharmacologically acceptable acyl groups. The compounds of the invention are useful as cardiovascular vasodilator or anti-hypertensive agents. The therapeutically useful compounds of the invention as well as similar 5'-N and N-6 substituted adenosine 5'-uronamides are prepared, in accordance with a novel process, from isopropylidene (or otherwise suitably blocked) inosine-5' -uronic acid. Isopropylideneinosine-5' -uronic acid is reacted with a suitable inorganic acid halide, such as thionyl chloride, to yield 6-halogeno-9-[ 2',3' -O-isopropylidene-.beta.-D-ribofuranosyl-5-uronic acid halide] -9H-purine. This intermediate is reacted with an amine of the general formula R.sub.4,R.sub.5 NH to give a 6-halogeno substituted, substituted uronic acid amide of the formula ##STR2## wherein X is halogen. Reaction of the latter intermediate with an amine of the formula R.sub.1 --NH.sub.2, and removal of the isopropylidene (or other) blocking groups yields the compounds of the invention.

N-6 substituted-5'-(N-substitutedcarboxamido)adenosines as cardiac

The present invention discloses a compound of the formula: ##STR1## where R.sub.1 is hydrogen or the group ##STR2## where R.sub.3 and R.sub.4 are the same or different and are hydrogen, C.sub.1 to C.sub.12 linear or branched alkyl, C.sub.3 to C.sub.7 cycloalkyl, C.sub.6 to C.sub.10 aryl unsubstituted or substituted with C.sub.1 to C.sub.6 linear or branched alkyl, C.sub.1 to C.sub.6 linear or branched alkoxy, nitro, amino, amino substituted with at least one C.sub.1 to C.sub.6 linear or branched alkyl or phenyl, C.sub.2 to C.sub.10 aralkyl, C.sub.4 to C.sub.8 heteroaryl wherein said heteroatom is nitrogen, phosphorous, sulfur or oxygen, and R.sub.2 is hydrogen, or taken together with R.sub.5, forms a chemical bond, and R is a monosaccharide radical selected from the group consisting essentially of glucose, fructose, ribose, 2-deoxyribose, mannose, galactose, xylose and arabinose.

2-hydrazoadenosines and their utility for the treatmeat of vascular

Compounds are disclosed having the formulae: ##STR1## wherein R.sub.1 is selected from the group, consisting of radicals represented by the general formulae: ##STR2## wherein Y is selected from the group consisting of lower alkyl, lower alkoxy, and halogen; Z is oxygen, sulfur or --NH, Q is --CH or nitrogen; a is zero or an integer of from one to three; and

2-aralkoxy and 2-alkoxy adenosine derivatives as coronary vasodilators

N6-substituted 9-methyladenines: a new class of adenosine receptor

New, N-6 monosubstituted adenosine derivatives are disclosed which have significant cardiac vasodilatory effect. The compounds of the invention include 6-(cyclo-butyl amino)-9-(.beta.-D-ribofuranosyl)-9H-purine, 6-(2-methyl-2-phenyl hydrazino)-9-(.beta.-D-ribofuranosyl)-9H-purine, and compounds of the general formula: ##STR1## wherein R.sub.1 is H, lower alkyl, lower alkoxy, alkylamino, or arylamino, R.sub.2 is H, lower alkyl, hydroxymethyl, phenyl or substituted phenyl, R.sub.3 is H, lower alkyl, phenyl, substituted phenyl, R.sub.3 is H, lower alkyl, phenyl, substituted phenyl, 2 or 3-thienyl, or 2 or 3-pyridyl, R.sub.4 is H or lower alkyl, and R.sub.5 is H or lower acyl. Particularly active as a cardiac vasodilator is the compound (-)-6-(R-1-phenyl-2-butyl amino)-9-(.beta.-D-ribofuranosyl)-9H-purine.

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Tampa, FL, United States of America

Ray A Olsson