A1 adenosine receptor antagonists

Abstract

Compounds of the general formula (I) are described: wherein A is a 5- or 6-membered aromatic or heteroaromatic ring. Compositions comprising such compounds and methods of use thereof are also described.

1 . A hydrate of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a 5- or 6-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; 
 R 2  is of the formula (i):
   (CH 2 ) r -A′-R 4   (i) 
 
 
       wherein:
 A′ is a 6-membered aromatic ring or heteroaromatic ring containing 1 to 4 nitrogen atoms; 
 r is an integer ranging from 1 to 20; 
 R 4  is selected from the group consisting of H, NH 2 , (CH 2 ) s OH, wherein s is an integer ranging from 1 to 8, R 14 COOH, wherein R 14  is an alkylene or alkylidene group having 1 to 8 carbon atoms, halo, NHR 8 , NR 8 R 9 , NHCOR 8 , NR 8 COR 9 , SO 3 H and PO 3 H 2 ; 
 R 3  is selected from the group consisting of H, NH 2 , R 15 COOH, wherein R 15  is an alkylene or alkylidene group having 1 to 8 carbon atoms, and (CH 2 ) t OH, wherein t is an integer ranging from 1 to 8, halo, NHR 8 , NR 8 R 9 , NHCOR 8 , NR 8 COR 9 , SO 3 H and PO 3 H 2 ; 
 q is an integer ranging from 1 to 8; and 
 R 1  is a C 1 -C 8  alkanyl group, C 2 -C 8 -alkenyl- or C 2 -C 8 -alkynyl-group which is optionally substituted by —CN, —CH 2 NR 6 R 7 OH, —OR 8 , —NR 6 R 7 , —NHCOR 8 , NHCONR 6 R 7 , halogen, —OCOR 8 , —OCH 2 COOH, —OCH 2 COOR 8 , —SO 2 R 5 , —S—R 5 , —OCH 2 —CONR 6 R 7 , —OCH 2 CH 2 OH, —SO 2 —CH 2 —CH 2 —O—COR 8 , —OCH 2 —CH 2 —NR 6 R 7 , —SO 2 —CH 2 —CH 2 —OH, —CONHSO 2 R 8 , —CH 2 CONHSO 2 R 8 , —OCH 2 CH 2 OR 8 , —COOH, —COOR 8 , —CONR 6 R 7 , —CHO, —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 3 H, —PO 3 H 2 , —SO 2 NR 6 R 7 , —OCH 2 —CH 2 OCOR 8 , —CH═NOH, —CH═NOR 8 , —COR 9 , —CH(OH)R 9 , —CH(OR 8 ) 2 , —CH═CH—R 10 , —OCONR 6 R 7 , 
 R 5  is C 1 -C 4 -alkyl, optionally substituted by OH, OCOR 8 , NH 2 , NR 6 R 7  or NHCOR 8 , 
 R 6  and R 7  are each independently hydrogen, an optionally substituted C 3-6 -cycloalkyl group, a branched or unbranched alkyl-, alkenyl- or alkynyl group having up to 10 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino, or it denotes —(CH 2 ) m —NHCOOR 8 , wherein m=1, 2, 3 or 4; 
 R 8  is hydrogen, C 1 -C 8 -alkyl or C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted with CO 2 H, a benzyl- or phenyl-group, which is optionally mono- or polysubstituted by OCH 3 ; 
 R 9  is C 1 -C 8 -alkyl or C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted with CO 2 H, optionally substituted phenyl, optionally substituted benzyl, C 3 -C 6 -cycloalkyl; and 
 R 10  is —COOR 8 , —CH 2 OR 8 , —CONR 6 R 7 , hydrogen, C 1 -C 3 -alkyl, optionally substituted phenyl, —CH 2 NR 6 R 7 ; and 
 wherein the hydrate is in a salt form. 
 
     
     
         2 . The hydrate of  claim 1 , wherein at least one of R 3  and R 4  is independently selected from the group consisting of SO 3 H and PO 3 H 2 . 
     
     
         3 . The hydrate of  claim 1 , wherein R 1  is a C 1 -C 8  alkanyl group, C 2 -C 8 -alkenyl group or C 2 -C 8  alkynyl group which is optionally substituted by NR 6 R 7 , —SO 3 H, or —PO 3 H 2 . 
     
     
         4 . The hydrate of  claim 1 , wherein A is selected from the group selected from the group consisting of pyridyl, thiophenyl, thiazolyl, and tetrazolyl. 
     
     
         5 . The hydrate of  claim 1 , wherein A′ is phenyl. 
     
     
         6 . The hydrate of  claim 1 , wherein:
 R 1  is a C 1 -C 8  alkanyl group, C 2 -C 8 -alkenyl group or C 2 -C 8  alkynyl group which is optionally substituted by NR 6 R 7  or —SO 3 H;   A is selected from the group consisting of pyridyl, thiophenyl, thiazolyl, and tetrazolyl; and   A′ is phenyl.   
     
     
         7 . The hydrate of  claim 6 , wherein at least one of R 3  and R 4  is independently selected from the group consisting of SO 3 H and PO 3 H 2 . 
     
     
         8 . The hydrate of  claim 1 , wherein said compound is selected from the group consisting of:
 3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine;   3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine;   3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine; and   3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.   
     
     
         9 . The hydrate of  claim 1 , wherein the salt is an HCl salt. 
     
     
         10 . A composition comprising a hydrate of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         11 . A hydrate of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a 5- or 6-membered aromatic ring; 
 R 2  is of the formula (i):
   (CH 2 ) r -A′-R 4   (i) 
 
 
       wherein:
 A′ is a 6-membered aromatic ring or a heteroaromatic ring containing 1 to 4 nitrogen atoms; 
 r is an integer ranging from 1 to 20; 
 R 4  is selected from the group consisting of NH 2 , halo, NHR 8 , NR 8 R 9 , NHCOR 8 , NR 8 COR 9 , SO 3 H, and PO 3 H 2 ; 
 R 3  is selected from the group consisting of H, NH 2 , R 15 COOH, wherein R 15  is an alkylene or alkylidene group having 1 to 8 carbon atoms, and (CH 2 ) t OH, wherein t is an integer ranging from 1 to 8, halo, NHR 8 , NR 8 R 9 , NHCOR 8 , NR 8 COR 9 , SO 3 H and PO 3 H 2 ; 
 q is an integer ranging from 1 to 8; and 
 R 1  is a C 1 -C 8  alkanyl-group, C 2 -C 8 -alkenyl-, or C 2 -C 8 -alkynyl-group which is optionally substituted by —CN, —CH 2 NR 6 R 7 OH, —OR 8 , —NR 6 R 7 , —NHCOR 8 , —NHCONR 6 R 7 , halogen, —OCOR 8 , —OCH 2 COOH, —OCH 2 COOR 8 , —SO 2 R 5 , —S—R 5 , —OCH 2 —CONR 6 R 7 , —OCH 2 CH 2 OH, —SO 2 —CH 2 —CH 2 —O—COR 8 , —OCH 2 —CH 2 —NR 6 R 7 , —SO 2 —CH 2 —CH 2 —OH, —CONHSO 2 R 8 , —CH 2 CONHSO 2 R 8 , —OCH 2 CH 2 OR 8 , —COOH, —COOR 8 , —CONR 6 R 7 , —CHO, —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 3 H, —PO 3 H 2 , —SO 2 NR 6 R 7 , —OCH 2 —CH 2 OCOR 8 , —CH═NOH, —CH═NOR 8 , —COR 9 , —CH(OH)R 9 , —CH(OR 8 ) 2 , —CH═CH—R 10 , —OCONR 6 R 7 , 
 R 5  is C 1 -C 4 -alkyl, optionally substituted by OH, OCOR 8 , NH 2 , NR 6 R 7  or NHCOR 8 , 
 R 6  and R 7  are each independently hydrogen, an optionally substituted C 3-6 -cycloalkyl group, a branched or unbranched alkyl-, alkenyl- or alkynyl group having up to 10 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or it denotes —(CH 2 ) m —NHCOOR 8 , wherein m=1, 2, 3 or 4; 
 R 8  is hydrogen, C 1 -C 8 -alkyl or C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted with CO 2 H, a benzyl- or phenyl-group, which is optionally mono- or polysubstituted by OCH 3 ; 
 R 9  is C 1 -C 8 -alkyl or C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted with CO 2 H, optionally substituted phenyl, optionally substituted benzyl, C 3 -C 6 -cycloalkyl; and 
 R 10  is —COOR 8 , —CH 2 OR 8 , —CONR 6 R 7 , hydrogen, C 1 -C 3 -alkyl, optionally substituted phenyl, —CH 2 NR 6 R 7 ; and 
 wherein the hydrate is in a salt form. 
 
     
     
         12 . The hydrate of  claim 11 , wherein A is phenyl. 
     
     
         13 . The hydrate of  claim 11 , wherein A′ is phenyl. 
     
     
         14 . The hydrate of  claim 11 , wherein:
 A is phenyl;   A′ is phenyl;   r is 2;   R 4  is selected from the group consisting of NH 2 , NHCOR 8 , and SO 3 H;   R 3  is selected from the group consisting of H, NH 2 , halo, SO 3 H, and NHCOR 8 ;   q is 1; and   R 1  is a C 1 -C 8  alkanyl group optionally substituted by —OR 8 , —NR 6 R 7 , or —SO 3 H.   
     
     
         15 . The hydrate of  claim 11 , wherein said compound is selected from the group consisting of:
 3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-propylxanthine;   3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-(4-sulfobenzyl)xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(3-methoxypropyl)xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(3-dimethylamino)propylxanthine;   3-[2-[4-(6-Aminohexanoyl)aminophenyl]ethyl]-8-benzyl-1-propylxanthine;   8-Benzyl-1-propyl-3-[4-(4-sulfophenyl)butyl]xanthine;   8-Benzyl-1-propyl-3-[2-(4-sulfonoxyphenyl)ethyl]xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(3-sulfopropyl)xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-(4-fluorobenzyl)-1-propylxanthine;   8-(2-Acetaminobenzyl)-3-[2-(4-aminophenyl)ethyl]-1-propylxanthine;   8-(2-Aminobenzyl)-3-(2-phenylethyl)-1-propylxanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(8-sulfonoxyoctyl)xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(5-sulfonoxypentyl)xanthine; and   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(5-sulfonoxypentyl)xanthine.   
     
     
         16 . The hydrate of  claim 11 , wherein the salt is an HCl salt. 
     
     
         17 . A composition comprising a hydrate of  claim 11  in a pharmaceutically acceptable carrier. 
     
     
         18 . A hydrate of a compound selected from the group consisting of:
 8-Benzyl-3-[2-(3-carboxyphenyl)ethyl]-1-propylxanthine;   3-[2-(2-carboxyphenyl)ethyl]-8-(3-fluorobenzyl)-1-propylxanthine;   3-[2-(2-carboxyphenyl)ethyl]-8-(3-nitrobenzyl)-1-propylxanthine;   3-[2-(2-carboxyphenyl)ethyl]-1-propyl-8-[(2-pyridyl)methyl]xanthine; and   3-[2-(2-carboxyphenyl)ethyl]-1-propyl-8-[(2-pyridyl)methyl]xanthine; and   wherein the hydrate is in a salt form.   
     
     
         19 . The hydrate of  claim 18 , wherein the salt is an HCl salt. 
     
     
         20 . A composition comprising a hydrate of  claim 18  in a pharmaceutically acceptable carrier. 
     
     
         21 . An assay-type probe of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a 5- or 6-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; 
 R 2  is of the formula (i):
   (CH 2 ) r -A′-R 4   (i) 
 
 
       wherein:
 A′ is a 6-membered aromatic ring or heteroaromatic ring containing 1 to 4 nitrogen atoms; 
 r is an integer ranging from 1 to 20; 
 R 4  is selected from the group consisting of H, NH 2 , (CH 2 ) s OH, wherein s is an integer ranging from 1 to 8, R 14 COOH, wherein R 14  is an alkylene or alkylidene group having 1 to 8 carbon atoms, halo, NHR 8 , NR 8 R 9 , NHCOR 8 , NR 8 COR 9 , SO 3 H and PO 3 H 2 ; 
 R 3  is selected from the group consisting of H, NH 2 , R 15 COOH, wherein R 15  is an alkylene or alkylidene group having 1 to 8 carbon atoms, and (CH 2 ) t OH, wherein t is an integer ranging from 1 to 8, halo, NHR 8 , NR 8 R 9 , NHCOR 8 , NR 8 COR 9 , SO 3 H and PO 3 H 2 ; 
 q is an integer ranging from 1 to 8; and 
 R 1  is a C 1 -C 8  alkanyl group, C 2 -C 8 -alkenyl- or C 2 -C 8 -alkynyl-group which is optionally substituted by —CN, —CH 2 NR 6 R 7 OH, —OR 8 , —NR 6 R 7 , —NHCOR 8 , NHCONR 6 R 7 , halogen, —OCOR 8 , —OCH 2 COOH, —OCH 2 COOR 8 , —SO 2 R 5 , —S—R 5 , —OCH 2 —CONR 6 R 7 , —OCH 2 CH 2 OH, —SO 2 —CH 2 —CH 2 —O—COR 8 , —OCH 2 —CH 2 —NR 6 R 7 , —SO 2 —CH 2 —CH 2 —OH, —CONHSO 2 R 8 , —CH 2 CONHSO 2 R 8 , —OCH 2 CH 2 OR 8 , —COOH, —COOR 8 , —CONR 6 R 7 , —CHO, —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 3 H, —PO 3 H 2 , —SO 2 NR 6 R 7 , —OCH 2 —CH 2 OCOR 8 , —CH═NOH, —CH═NOR 8 , —COR 9 , —CH(OH)R 9 , —CH(OR 8 ) 2 , —CH═CH—R 10 , —OCONR 6 R 7 , 
 R 5  is C 1 -C 4 -alkyl, optionally substituted by OH, OCOR 8 , NH 2 , NR 6 R 7  or NHCOR 8 , 
 R 6  and R 7  are each independently hydrogen, an optionally substituted C 3-6 -cycloalkyl group, a branched or unbranched alkyl-, alkenyl- or alkynyl group having up to 10 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino, or it denotes —(CH 2 ) m —NHCOOR 8 , wherein m=1, 2, 3 or 4; 
 R 8  is hydrogen, C 1 -C 8 -alkyl or C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted with CO 2 H, a benzyl- or phenyl-group, which is optionally mono- or polysubstituted by OCH 3 ; 
 R 9  is C 1 -C 8 -alkyl or C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted with CO 2 H, optionally substituted phenyl, optionally substituted benzyl, C 3 -C 6 -cycloalkyl; and 
 R 10  is —COOR 8 , —CH 2 OR 8 , —CONR 6 R 7 , hydrogen, C 1 -C 3 -alkyl, optionally substituted phenyl, —CH 2 NR 6 R 7 , 
 wherein the compound of formula (I) is labeled by a detectable radioactive or non-radioactive group. 
 
     
     
         22 . The assay-type probe of  claim 21 , wherein said compound is selected from the group consisting of:
 3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine;   3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-[(4-thiazolyl)methyl]xanthine;   3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine; and   3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.   
     
     
         23 . The assay-type probe of  claim 21 , wherein the detectable radioactive group is selected from the group consisting of an electric spin marker, a  19 F NMR probe, a radioactive  18 F isotope marker, a radioactive 125I marker, a radioactive  3 H marker, tritium, and a complex of a metal atom or a metal ion and a chelating agent. 
     
     
         24 . The assay-type probe of  claim 23 , wherein the metal ion is a radioactive isotope of technetium or indium. 
     
     
         25 . The assay-type probe of  claim 23 , wherein the chelating agent is diethylene pentacetic anhydride. 
     
     
         26 . The assay-type probe of  claim 21 , wherein the non-radioactive material is biotin. 
     
     
         27 . The assay-type probe of  claim 26 , wherein the biotin is bonded to a hydroxyl group, an amino group, or a carboxyl group, if present, on the R 3  or R 4  substituent of the compound. 
     
     
         28 . The assay-type probe of  claim 21 , wherein the non-radioactive material is a fluorescent dye. 
     
     
         29 . The assay-type probe of  claim 28 , wherein the fluorescent dye is selected from the group consisting of tetramethylrhodamine, fluorescein isothiocyanate, and mixtures thereof. 
     
     
         30 . The assay-type probe of  claim 21 , wherein the non-radioactive material is selected from the group consisting of nitrobenzoxadiazole; 2,2,6,6-tetramethyl-piperindinyloxy-4-isothiocyanate; and mixtures thereof. 
     
     
         31 . The assay-type probe of  claim 21 , wherein the compound is labeled by the detectable radioactive or non-radioactive group through a spacer component present thereon, wherein the spacer component has a functionality that bonds to an amino functionality, or a hydroxyl functionality, or a carboxyl functionality, if present, on the R 3  or R 4  substituent on the compound. 
     
     
         32 . The assay-type probe of  claim 31 , wherein the spacer component is selected from the group consisting of an oligopeptide, a triglycidyl, and an N-hydroxysuccinimide ester. 
     
     
         33 . An assay-type probe of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a 5- or 6-membered aromatic ring; 
 R 2  is of the formula (i):
   (CH 2 ) r -A′-R 4   (i) 
 
 
       wherein:
 A′ is a 6-membered aromatic ring or a heteroaromatic ring containing 1 to 4 nitrogen atoms; 
 r is an integer ranging from 1 to 20; 
 R 4  is selected from the group consisting of NH 2 , halo, NHR 8 , NR 8 R 9 , NHCOR 8 , NR 8 COR 9 , SO 3 H and PO 3 H 2 ; 
 R 3  is selected from the group consisting of H, NH 2 , R 15 COOH, wherein R 15  is an alkylene or alkylidene group having 1 to 8 carbon atoms, and (CH 2 ) t OH, wherein t is an integer ranging from 1 to 8, halo, NHR 8 , NR 8 R 9 , NHCOR 9 , NR 8 COR 9 , SO 3 H and PO 3 H 2 ; 
 q is an integer ranging from 1 to 8; and 
 R 1  is a C 1 -C 8  alkanyl-group, C 2 -C 8 -alkenyl-, or C 2 -C 8 -alkynyl-group which is optionally substituted by —CN, —CH 2 NR 6 R 7 OH, —OR 8 , —NR 6 R 7 , —NHCOR 8 , —NHCONR 6 R 7 , halogen, —OCOR 8 , —OCH 2 COOH, —OCH 2 COOR 8 , —SO 2 R 5 , —S—R 5 , —OCH 2 —CONR 6 R 7 , —OCH 2 CH 2 OH, —SO 2 —CH 2 —CH 2 —O—COR 8 , —OCH 2 —CH 2 —NR 6 R 7 , —SO 2 —CH 2 —CH 2 —OH, —CONHSO 2 R 8 , —CH 2 CONHSO 2 R 8 , —OCH 2 CH 2 OR 8 , —COOH, —COOR 8 , —CONR 6 R 7 , —CHO, —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 3 H, —PO 3 H 2 , —SO 2 NR 6 R 7 , —OCH 2 —CH 2 OCOR 8 , —CH═NOH, —CH═NOR 8 , —COR 9 , —CH(OH)R 9 , —CH(OR 8 ) 2 , —CH═CH—R 10 , —OCONR 6 R 7 , 
 R 5  is C 1 -C 4 -alkyl, optionally substituted by OH, OCOR 8 , NH 2 , NR 6 R 7  or NHCOR 8 , 
 R 6  and R 7  are each independently hydrogen, an optionally substituted C 3-6 -cycloalkyl group, a branched or unbranched alkyl-, alkenyl- or alkynyl group having up to 10 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or it denotes —(CH 2 ) m —NRCOOR 8 , wherein m=1, 2, 3 or 4; 
 R 8  is hydrogen, C 1 -C 8 -alkyl or C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted with CO 2 H, a benzyl- or phenyl-group, which is optionally mono- or polysubstituted by OCH 3 ; 
 R 9  is C 1 -C 8 -alkyl or C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted with CO 2 H, optionally substituted phenyl, optionally substituted benzyl, C 3 -C 6 -cycloalkyl; and 
 R 10  is —COOR 8 , —CH 2 OR 8 , —CONR 6 R 7 , hydrogen, C 1 -C 3 -alkyl, optionally substituted phenyl, —CH 2 NR 6 R 7 , 
 wherein the compound of formula (I) is labeled by a detectable radioactive or non-radioactive group. 
 
     
     
         34 . The assay-type probe of  claim 33 , wherein said compound is selected from the group consisting of:
 3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-propylxanthine;   3-[2-(4-Aminophenyl)ethyl]-1-propyl-8-(4-sulfobenzyl)xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(3-methoxypropyl)xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(3-dimethylamino)propylxanthine;   3-[2-[4-(6-Aminohexanoyl)aminophenyl]ethyl]-8-benzyl-1-propylxanthine;   8-Benzyl-1-propyl-3-[4-(4-sulfophenyl)butyl]xanthine;   8-Benzyl-1-propyl-3-[2-(4-sulfonoxyphenyl)ethyl]xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(3-sulfopropyl)xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-(4-fluorobenzyl)-1-propylxanthine;   8-(2-Acetaminobenzyl)-3-[2-(4-aminophenyl)ethyl]-1-propylxanthine;   8-(2-Aminobenzyl)-3-(2-phenylethyl)-1-propylxanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(8-sulfonoxyoctyl)xanthine;   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(5-sulfonoxypentyl)xanthine; and   3-[2-(4-Aminophenyl)ethyl]-8-benzyl-1-(5-sulfonoxypentyl)xanthine.   
     
     
         35 . The assay-type probe of  claim 33 , wherein the detectable radioactive group is selected from the group consisting of an electric spin marker, a  19 F NMR probe, a radioactive  18 F isotope marker, a radioactive  125 I marker, a radioactive  3 H marker, tritium, and a complex of a metal atom or a metal ion and a chelating agent. 
     
     
         36 . The assay-type probe of  claim 35 , wherein the metal ion is a radioactive isotope of technetium or indium. 
     
     
         37 . The assay-type probe of  claim 35 , wherein the chelating agent is diethylene pentacetic anhydride. 
     
     
         38 . The assay-type probe of  claim 33 , wherein the non-radioactive material is biotin. 
     
     
         39 . The assay-type probe of  claim 38 , wherein the biotin is bonded to a hydroxyl group, an amino group, or a carboxyl group, if present, on the R 3  or R 4  substituent of the compound. 
     
     
         40 . The assay-type probe of  claim 33 , wherein the non-radioactive material is a fluorescent dye. 
     
     
         41 . The assay-type probe of  claim 40 , wherein the fluorescent dye is selected from the group consisting of tetramethylrhodamine, fluorescein isothiocyanate, and mixtures thereof. 
     
     
         42 . The assay-type probe of  claim 33 , wherein the non-radioactive material is selected from the group consisting of nitrobenzoxadiazole; 2,2,6,6-tetramethyl-piperindinyloxy-4-isothiocyanate; and mixtures thereof. 
     
     
         43 . The assay-type probe of  claim 33 , wherein the compound is labeled by the detectable radioactive or non-radioactive group through a spacer component present thereon, wherein the spacer component has a functionality that bonds to an amino functionality, or a hydroxyl functionality, or a carboxyl functionality, if present, on the R 3  or R 4  substituent on the compound. 
     
     
         44 . The assay-type probe of  claim 43 , wherein the spacer component is selected from the group consisting of an oligopeptide, a triglycidyl, and an N-hydroxysuccinimide ester. 
     
     
         45 . An assay-type probe of a compound selected from the group consisting of:
 8-Benzyl-3-[2-(3-carboxyphenyl)ethyl]-1-propylxanthine;   3-[2-(2-carboxyphenyl)ethyl]-8-(3-fluorobenzyl)-1-propylxanthine;   3-[2-(2-carboxyphenyl)ethyl]-8-(3-nitrobenzyl)-1-propylxanthine;   3-[2-(2-carboxyphenyl)ethyl]-1-propyl-8-[(2-pyridyl)methyl]xanthine; and   3-[2-(2-carboxyphenyl)ethyl]-1-propyl-8-[(2-pyridyl)methyl]xanthine,   wherein the compound is labeled by a detectable radioactive or non-radioactive group.   
     
     
         46 . The assay-type probe of  claim 45 , wherein the detectable radioactive group is selected from the group consisting of an electric spin marker, a  19 F NMR probe, a radioactive  18 F isotope marker, a radioactive  125 I marker, a radioactive  3 H marker, tritium, and a complex of a metal atom or a metal ion and a chelating agent. 
     
     
         47 . The assay-type probe of  claim 46 , wherein the metal ion is a radioactive isotope of technetium or indium. 
     
     
         48 . The assay-type probe of  claim 46 , wherein the chelating agent is diethylene pentacetic anhydride. 
     
     
         49 . The assay-type probe of  claim 45 , wherein the non-radioactive material is biotin. 
     
     
         50 . The assay-type probe of  claim 49 , wherein the biotin is bonded to a hydroxyl group, an amino group, or a carboxyl group, if present, on a substituent of the C 3  carbon or C 8  carbon of the xanthine compound. 
     
     
         51 . The assay-type probe of  claim 45 , wherein the non-radioactive material is a fluorescent dye. 
     
     
         52 . The assay-type probe of  claim 51 , wherein the fluorescent dye is selected from the group consisting of tetramethylrhodamine, fluorescein isothiocyanate, and mixtures thereof. 
     
     
         53 . The assay-type probe of  claim 45 , wherein the non-radioactive material is selected from the group consisting of nitrobenzoxadiazole; 2,2,6,6-tetramethyl-piperindinyloxy-4-isothiocyanate; and mixtures thereof. 
     
     
         54 . The assay-type probe of  claim 45 , wherein the compound is labeled by the detectable radioactive or non-radioactive group through a spacer component present thereon, wherein the spacer component has a functionality that bonds to an amino functionality, or a hydroxyl functionality, or a carboxyl functionality, if present, on a substituent of the C 3  carbon or C 8  carbon of the xanthine compound. 
     
     
         55 . The assay-type probe of  claim 54 , wherein the spacer component is selected from the group consisting of an oligopeptide, a triglycidyl, and an N-hydroxysuccinimide ester.