Whitby Research, Inc.

Discovery Therapeutics, Inc.

Donald A McAfee

Luiz Belardinelli

Pauline L Martin

Geoffrey Allan

Richard J Barrett

In the present invention, a method is provided which reduces or prevents restenosis following revascularization procedures. It has now been found that selective stimulation of adenosine A receptors can reduce or prevent such restenosis. This method may be achieved either by: (a) the administration of selective adenosine A receptor agonists, (b) the administration of a selective adenosine A antagonist in combination with either a selective adenosine A receptor agonist or a non-selective adenosine agonist, or (c) the administration of a selective adenosine A antagonist in order to block adenosine A receptor activation by endogenously-released adenosine. The present invention is also directed to an improved surgical procedure that relies upon selective stimulation of adenosine A receptors.

Compositions and methods for preventing restenosis following revascularization procedures

The present invention discloses a method for measuring myocardial function in a mammal in need of such measurement by:

Diagnostic uses of hydrazinoadenosines

Melatonin compounds are disclosed of the formula ##STR1## where R is hydrogen or C.sub.1 to C.sub.6 linear or branched alkylene substituted with phenyl; R.sub.1 is hydrogen, substituted benzyl, naphthylmethyl or taken together with R.sub.2 and the two carbon atoms of the five-membered hetero ring form the group ##STR2## where R.sub.1 ' is C.sub.1 to C.sub.6 linear or branched alkanoyl and R.sub.1 ' is hydrogen, C.sub.1 to C.sub.6 linear or branched alkyl or phenyl optionally substituted with one or more halogen, amino, nitro, hydroxy, alkyl, alkoxy or haloalkyl; R.sub.2 is hydrogen, 1-pyrrolyl, 1-pyrrolyl substituted with one or more alkyl or alkoxy, the group --(CH.sub.2).sub.m --NHR.sub.2 '1, where m is 1 to 3 and R.sub.2 ' is phenyl sulfonyl, the phenyl group optionally substituted with alkyl, or --C(O)--R.sub.2 ', where R.sub.2 ' is C.sub.1 to C.sub.6 linear or branched alkylene substituted with a substituent selected from the group consisting of hydrogen, phenyl, alkoxy, alkoxy substituted with phenyl, carboxylic acid or the alkyl esters thereof, carbamoyloxy alkyl, substituted carbamoyloxy alkyl and amino or 5-(2-alkanoyl) tetrazole; R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are the same or different and are hydrogen, C.sub.1 to C.sub.6 linear or branched alkyl, C.sub.1 to C.sub.6 linear or branched alkoxy, phenoxy or phenoxy substituted with one or more C.sub.1 to C.sub.6 linear or branched alkyl. The compounds display melatonin antagonist and are antiproliferative agents.

Compounds useful as antiproliferative agents

A method and composition of determining the viability of tissue in a region of an organism having a vascular circulatory system that supplies blood to said region is disclosed. The composition includes the combination of adenosine or an adenosine antagonist in combination with an A.sub.1 adenosine receptor which may be: ##STR1## wherein R.sub.1 is hydrogen or R.sub.2 ; R.sub.2 is selected from the group consisting of endo-2-norbornyl or cyclopentyl; R.sub.3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, alkyl radicals having 1 to 10 carbon atoms, cycloalkyl radicals having from 3 to 8 ring carbon atoms, thio sulfonate, sulfonamide, sulfone, sulfoxamide, phenyl, alkyl-substituted amine, and cycloalkyl substituted amine; R.sub.4 is selected from the group consisting of benzyl, phenyl, alkyl groups comprising from 1 to 4 carbon atoms, wherein said alkyl group can be substituted with oxygen, for instance ethers and alcohols; and R.sub.5 is selected from the group consisting of hydrogen, hydroxy, sulfonate, halogen, alkoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms.

Composition for determining viability of tissue

Melatonin compounds are disclosed of the formula ##STR1## where R is hydrogen or C.sub.1 to C.sub.6 linear or branched alkylene substituted with phenyl; R.sub.1 is hydrogen, substituted benzyl, naphthylmethyl or taken together with R.sub.2 and the two carbon atoms of the five-membered hetero ring form the group ##STR2## where R.sub.1 ' is C.sub.1 to C.sub.6 linear or branched alkanoyl and R.sub.1 ' is hydrogen, C.sub.1 to C.sub.6 linear or branched alkyl or phenyl optionally substituted with one or more halogen, amino, nitro, hydroxy, alkyl, alkoxy or haloalkyl; R.sub.2 is hydrogen, 1-pyrrolyl, 1-pyrrolyl substituted with one or more alkyl or alkoxy, the group --(CH.sub.2).sub.m --NHR.sub.2 '1, where m is 1 to 3 and R.sub.2 ' is phenyl sulfonyl, the phenyl group optionally substituted with alkyl, or --C(O)--R.sub.2 ', where R.sub.2 ' is C.sub.1 to C.sub.6 linear or branched alkylene substituted with a substituent selected from the group consisting of hydrogen, phenyl, alkoxy, alkoxy substituted with phenyl, carboxylic acid or the alkyl esters thereof, carbamoyloxy alkyl, substituted carbamoyloxy alkyl and amino or 5-(2-alkanoyl) tetrazole; R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are the same or different and are C.sub.1 to C.sub.6 linear or branched alkyl, C.sub.1 to C.sub.6 linear or branched alkoxy, phenoxy or phenoxy substituted with one or more C.sub.1 to C.sub.6 linear or branched alkyl. The compounds display melatonin antagonist and are antiproliferative agents.

A method and composition for determining the viability of tissue in a region of an organism having a vascular circulatory system that supplies blood to said region including the steps of dilating said vascular circulation system by introducing adenosine or an adenosine agonist into said vascular circulation system in order to increase the flow of blood into said region; introducing a blood flow marking medium into said region; alleviating the non-dilating effects of adenosine or said adenosine agonist by introducing an A.sub.1 adenosine receptor antagonist into said vascular circulatory system; and determining the amount of marking medium in said region. A composition is disclosed which includes the combination of adenosine or an adenosine agonist in combination with an A.sub.1 adenosine receptor which may be: ##STR1## wherein R.sub.1 is hydrogen or R.sub.2 ; R.sub.2 is selected from the group consisting of endo-2-norbornyl or cyclopentyl; R.sub.3 is selected from the group consisting of hydrogen, halogen, amine, carboxy, alkyl radicals having 1 to 10 carbon atoms, cycloalkyl radicals having from 3 to 8, preferably 5 to 6, ring carbon atoms, thio, sulfonate, sulfonamide, sulfon, sulfoxamide, phenyl, alkyl-substituted amine, and cycloalkyl substituted amine; 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 instance ethers and alcohols; and R.sub.5 is selected from the group consisting of hydrogen; hydroxy; sulfonate; halogen; alkoxy and cycloalkoxy groups comprising 1 to 6 carbon atoms.

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Richmond, VA, United States of America

Donald A McAfee