Patent EA-005211-B1 (EA)
Title: Polycycloalkylpurines as adenosine receptor antagonists
Inventor: KIESMAN WILLIAM F
IPC: C07D473/06
Filed: 2000-11-13
Abstract: 1. A compound comprising the formula: wherein R1 and R2 are independently selected from the group consisting of: a) hydrogen, b) C1-6-alkyl, unsubstituted or functionalized with C1-6-alkoxy or halo; and c) substituted aryl or substituted aryl-C1-6-alkyl; R3 is selected from the group consisting of: (a) a bicyclic, tricyclic or pentacyclic group selected from the group consisting of: wherein the bicyclic or tricyclic group is either unsubstituted or functionalized with one or more substituents selected from the group consisting of: (i) C1-6-alkyl and C3-6-alkenyl; wherein each alkyl or alkenyl group is either unsubstituted or functionalized with one or more substituents selected from the group consisting of (amino) (R5) C1-6-acylhydrazinylcarbonyl, (amino) (R5) C1-6-acyloxycarboxy, (hydroxy) (carboxy-C1-6-alkoxy) C1-6-alkyl carbamoyl, C1-6-acyloxy, aldehydo, C3-6-alkenyl sulfonylamino, C1-6-alkoxycarbonyl, C1-6-alkylamino, C1-6-alkylphosphono, C1-6-alkyl sulfonylamino, carbamoyl, -R5, R5-C1-6-alkoxy, cyano, cyano-C1-6-alkyl carbamoyl, C3-8-cycloalkyl amino, di-C1-6-alkylamino, di-C1-6-alkylamino-C1-6-alkylamino, di-C1-6-alkylphosphono, heterocyclyl, heterocyclyl-C1-6-alkylamino, heterocyclylcarbamoyl, hydroxy, hydroxy-C1-6-alkyl sulfonylamino, oximino, phosphono, substituted aryl-C1-6-alkylamino, substituted arylcarboxy-C1-6-alkoxycarbonyl, substituted heteroarylsulfonylamino, substituted heterocyclyl, and thiocarbamoyl; and (ii) (C1-6-alkoxycarbonyl) C1-6-alkylcarbamoyl, (C1-6-alkoxycarbonyl) aryl-C1-6-alkylcarbamoyl, aldehydo, C3-6-alkenoxy, C3-6-alkenylsulfonylamino, C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkoxycarbonylamino, (C1-6-alkoxycarbonyl) hydroxyl-C1-6-alkylcarbamoyl, C1-6-alkylsulfonylamino, C1-6-alkylsulfonyloxy, amino, amino-C1-6-alkylcarbamoyl, aryl-C1-6-alkoxycarbonylamino, aryloxy, R5-arylsulfonylamino, R5-arylsulfonyloxy, carbamoyl, carbonyl, -R5, R5-C1-6-alkoxy, R5-C1-6-alkylamino, (R5-C1-6-alkyl)C1-6-alkylamino, R5-C1-6-alkyl carbamoyl, R5-C1-6-alkysulfonyl, R5-C1-6-alkylsulfonylamino, R5-C1-6-alkylthio, R5-aryl-C1-6-alkylcarbamoyl, R5-heterocyclylcarbonyl, cyano, C3-8-cycloalkylamino, di-C1-6-alkylamino-C1-6-alkylcarbamoyl, halogen, heterocyclyl, heterocyclyl-C1-6-alkylamino, hydroxy, phosphate, substituted aryl-C1-6-alkylamino, substituted heterocyclyl, substituted heterocyclyl-C1-6-alkylamino, substituted heterocyclylsulfonylamino, sulfoxy-C1-6-acylamino, and thiocarbamoyl; and (b) the tricyclic group: wherein the tricyclic group is functionalized with one or more substituents selected from the group consisting of: (i) C1-6-alkyl functional[zed with one or more substituents selected from the group consisting of -R5 and hydroxy; and (ii) amino-C1-6-alkylaryl-C1-6-alkylcarbamoyl, amino-C1-6-alkylcarbamoyl, amino-C1-6-alkylheterocyclyl-C1-6-alkylcarbamoyl, amino-C3-8-cycloalkyl-C1-6-alkyl-C3-8-cycloalkylcarbamoyl, amino-C3-8-cycloalkylcarbamoyl, carbamoyl, -R5, and heterocyclyl; R5 is selected from the group consisting of -COOH, -CH2COOH, -OCH(CF3)2, -CH3, -NH2, -OPO3H2, -SO3H, and the following: X2 is independently selected from the group consisting of O and S; Z is selected from the group consisting of a single bond and -(CH2)1-3-; and R6 is selected from the group consisting of hydrogen and aryl-C1-6-alkyl. 2. The compound of claim 1, wherein the compound is in a form selected from the group consisting of an achiral compound, a racemate, an optically active compound, a pure diastereomer, a mixture of diastereomers, and a pharmacologically acceptable addition salt. 3. The compound of claim 1, wherein R1 and R2 are each C1-6-alkyl groups. 4. The compound of claim 1, wherein R1 and R2 are each n-propyl. 5. The compound of claim 1, wherein R1 is n-propyl and R2 is aryl-C1-6-alkyl. 6. The compound of claim 4, wherein Z is a single bond. 7. The compound of claim 6, wherein R3 is: and wherein R3 is either unsubstituted or functionalized with one or more substituents selected from the group consisting of hydroxy, R5-, and R5- C3-6-alkenyl. 8. The compound of claim 7, wherein the compound is selected from the group consisting of: (a) 5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicycle[3.2.1]octane-1-carboxylic acid; (b) 8-(4-Hydroxy-bicyclo[3.2.1]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; and (c) 5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-2-carboxylic acid. 9. The compound of claim 6, wherein R3 is and wherein R3 is either unsubstituted or functionalized with one or more substituents selected from the group consisting of hydroxy, R5-C1-6-alkyl, -R5, R5-C3-6-alkenyl, C1-6-alkoxycarbonyl, C1-6-alkoxycarbonyl-C1-6-alkyl, C1-6-alkoxycarbonyl-C3-6-alkenyl, hydroxy-C1-6-alkyl, aldehydo, C1-6-alkoxy-C1-6-alkyl, R5-C1-6-alkoxy, phosphate, R5-C1-6-alkylcarbamoyl, 10. The compound of claim 9, wherein the compound is selected form the group consisting of: (a) 8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; (b) 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid; (c) 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde; (d) 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester; (e) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylic acid methyl ester; (f) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester; (g) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylic acid; (h) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid; (i) 4-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-butyric acid; (j) Phosphoric acid mono-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl] ester; (k) {[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-methyl-amino}-acetic acid; (l) {[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbonyl]-amino}-acetic acid; (m) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionic acid; (n) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionic acid methyl ester; (o) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yloxy]-propionic acid t-butyl ester; and (p) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-2-methyl-propionic acid. 11. The compound of claim 6 wherein R3 is and wherein R3 is either unsubstituted or functionalized with one or more substituents selected from the group consisting of R5-C1-6-alkyl, -R5, R5-C3-alkenyl, C1-6-alkoxycarbonyl, C1-6-alkoxycarbonyl-C3-6-alkenyl, hydroxy-C1-6-alkyl, aldehyde, and hydroxy. 12. The compound of claim 11, wherein the compound is selected from the group consisting of: (a) 6-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cubane-3-carboxylic acid; (b) 8-(6-Hydroxymethyl-cuban-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; and (c) 3-[6-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-cuban-3-yl]-acrylic acid. 13. The compound of claim 6 wherein R3 is and wherein Ra is either unsubstituted or functionalized with one or more substituents selected from the group consisting of R5-C1-6-alkyl, -R5, R5-C3-6-alkenyl, R5-C1-6-alkoxy, C1-6-alkoxycarbonyl, C1-6-alkoxycarbonyl-C3-6-alkenyl, hydroxy-C1-6-alkyl, aldehydo, and hydroxy. 14. The compound of claim 13, wherein the compound is selected from the group consisting of: (a) [5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]non-1-yloxy]-acetic acid; (b) 8-(5-Hydroxy-bicyclo[3.2.2]non-1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; and (c) 5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.2]nonane-1-carboxylic acid. 15. The compound of claim 6 wherein R3 is and wherein R3 is either unsubstituted or functionalized with one or more substituents selected from the group consisting of hydroxy, R5-C1-6-alkoxy, R5-C1-6-alkenyl, C1-6-alkoxycarbonyl, and carbonyl. 16. The compound of claim 15, wherein the compound is selected from the group consisting of: (a) 8-(4-Hydroxy-7-methyl-2,6-dioxa-bicyclo[3.3-1]non-1-yl)-1,S-dipropyl-3,7-dihydro-purine-2,6-dione; and (b) [1-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-7-methyl-2,6-dioxa-bicyclo[3.3.1]non-4-yloxy]-acetic acid. 17. A medicament composition comprising a compound of claim 1 together with a suitable excipient. 18. A method of treating a subject suffering from a condition characterized by an elevated adenosine concentration and/or increased sensitivity to adenosine, the method comprising administering to the subject an effective adenosine antagonizing amount of a compound of claim 1. 19. The method of claim 18, wherein the condition is selected from the group consisting of cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, diseases for which diuretic treatment is indicated, Parkinson's disease, depression, traumatic brain damage, post-stroke neurological deficit, respiratory depression, neonatal brain trauma, dyslexia, hyperactivity, cystic fibrosis, cirrhotic ascites, neonatal apnea, renal failure, diabetes, asthma, and edematous conditions. 20. The method of claim 18, wherein the condition is congestive heart failure or renal dysfunction. 21. A method of making an 8-substituted xanthine comprising the steps of: a) obtaining a xanthine unsubstituted at the 8-position; b) protecting the N7 position of the xanthine unsubstituted at the 8-position; c) deprotonating the C8 position with strong base to generate an anion; d) trapping the anion with a carbonyl, aldehyde, or ketone compoun