C-4' modified adenosine kinase inhibitors
AssigneeMetabasis Therapeutics, Inc.
InventorsSerge H. Boyer, Bheemarao G. Ugarkar, Mark D. Erion
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Abstract
This invention relates to adenosine kinase inhibitors and to nucleoside analogs, C-4' modified pyrrolo2,3-d!pyrimidine and pyrazolo3,4-d!pyrimidine nucleoside analogs having activity as adenosine kinase inhibitors. The invention relates to nucleoside analogs of this kind, having zero substitutions or two substitutions at the C-4' position of the furanose (sugar) moiety. The invention also relates to the preparation and use of these adenosine kinase inhibitors in the treatment of cardiovascular, and cerebrovascular diseases, inflammation and other diseases which can be regulated by increasing the local concentration of adenosine.
Claims32
C-4'-modified pyrrolo2,3-d! and pyrazolo3,4-d!pyrimidine nucleoside analogs of Formula 1 ##STR21## wherein:
- A and B are both hydrogen, or are each independently alkenyl, the group (CH.sub.2).sub.n Q, where n is from 1 to 4 and Q is hydrogen, hydroxy, alkyl, alkoxy, amino, azido, or halogen;
- or A and B together form a ring of from 3 to 6 carbons, the ring containing 0 to 3 heteroatoms selected from oxygen and nitrogen and optionally substituted by Q as defined above;
- D is halogen, aryl, aralkyl, alkyl, alkenyl, alkynyl optionally containing one or more heteroatoms such as nitrogen, oxygen or sulfur, haloalkyl, cyano, or carboxamido;
- E is nothing when Y is nitrogen;
- and is hydrogen, halogen, or alkyl when Y is carbon;
- F is alkyl, aryl, aralkyl, halogen, amino, alkylamino, arylamino, aralkylamino, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio;
- G is hydrogen or halogen;
- Y is carbon or nitrogen;
- Z.sub.1 and Z.sub.2 are independently hydrogen, acyl, or taken together form a cyclic carbonate;
- and pharmaceutically acceptable salts thereof.
C-4'-modified pyrrolo2,3-d! and pyrazolo3,4-d!pyrimidine nucleoside analogs of Formula 1 ##STR22## wherein:
- D is halogen, aryl, aralkyl, alkyl alkenyl, alkynyl optionally containing one or more heteroatoms, haloalkyl, cyano, or carboxamido;
- E is nothing when Y is nitrogen;
- and is hydrogen, halogen, or alkyl when Y is carbon;
- F is alkyl, aryl, aralkyl, halogen, amino, alkylamino, arylamino, aralkylamino, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio;
- G is hydrogen or halogen;
- Y is carbon or nitrogen;
- Z.sub.1 and Z.sub.2 are independently hydrogen, acyl, or taken together form a cyclic carbonate;
- and pharmaceutically acceptable salts thereof.
C-4'-modified pyrrolo2,3-d! and pyrazolo3,4-d!pyrimidine nucleoside analogs of Formula 2 ##STR23## wherein:
- D is halogen, aryl, aralkyl, alkyl, alkenyl, alkynyl optionally containing one or more heteroatoms such as nitrogen, oxygen or sulfur, haloalkyl, cyano, or carboxamido;
- E is nothing when Y is nitrogen;
- and is hydrogen when Y is carbon;
- F is alkyl, aryl, aralkyl, halogen, amino, alkylamino, arylamino, aralkylamino, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, aralkylthio;
- Y is carbon or nitrogen;
- and pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.