US2009029939A1PendingUtilityA1
Pre-organized tricyclic integrase inhibitor compounds
Est. expiryOct 16, 2022(expired)· nominal 20-yr term from priority
A61P 31/18C07D 471/04C07D 207/404A61P 43/00A61P 31/12C07D 487/04C07D 498/20
55
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Claims
Abstract
Tricyclic compounds according to the structure below, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed. A 1 and A 2 are moieties forming a five, six, or seven membered ring. L is a bond or a linker connecting a ring atom of Ar to N. X is O, S, or substituted nitrogen. Ar is aryl or heteroaryl, Q is N, + NR, or CR 4 . The aryl carbons may be independently substituted with substituents other than hydrogen. The compounds may include prodrug moieties covalently attached at any site.
Claims
exact text as granted — not AI-modified1 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having the structure:
wherein:
A 1 is independently selected from C(R 2 ) 2 , CR 2 OR, CR 2 OC(═O)R, C(═O), C(═S), CR 2 SR, and C(═NR),
A 2 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ) and C(═O)C(R 3 ) 2 ;
Q is CR 4 ;
L is selected from a bond, O, S, S—S, S(═O), S(═O) 2 , S(═O) 2 NR, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH 2 ) n , or (CH 2 CH 2 O) n , where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR 2 , N—CR 2 OR and N—CR 2 NR 2 ;
Ar is selected from (a) a C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R 2 or two R 3 may form a spiro ring;
R 1 is independently selected from CR 3 , NRSO 2 R, OC(═O)NR 2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C 1 -C 8 alkyl, C 1 -C8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R X2 is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y═Z is C═C(OH), X is O, A 1 is C(═O), A 2 is C(R 2 )═C(R 3 ), and Q is CH, then L is not a bond; and
further comprising a therapeutically effective amount of an AIDS treatment agent selected from an HIV inhibitor agent, an anti-infective agent, and an immunomodulator.
2 . The pharmaceutical composition of claim 1 wherein the HIV inhibitor agent is an HIV-protease inhibitor.
3 . The pharmaceutical composition of claim 1 wherein the HIV inhibitor agent is a nucleoside reverse transcriptase inhibitor.
4 . The pharmaceutical composition of claim 3 wherein said nucleoside reverse transcriptase inhibitor is 3′-azido-3′-deoxythymidine (zidovudine, AZT), 2′-deoxy-3′-thiacytidine (3TC), 2′,3′-dideoxy-2′,3′-didehydroadenosine (D4A), 2′, 3′-dideoxy-2′, 3′-didehydrothymidine (D4T), carbovir (carbocyclic 2′,3′-dideoxy-2′,3′-didehydroguanosine), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxyadenosine (ddA), 2′,3′-dideoxyinosine (ddI), PMEA, or PMPA.
5 . The pharmaceutical composition of claim 1 wherein the HIV inhibitor agent is a non-nucleoside reverse transcriptase inhibitor.
6 . A process for making a pharmaceutical composition comprising combining a pharmaceutically acceptable carrier and a compound having the structure:
wherein:
A 1 is independently selected from C(R 2 ) 2 , CR 2 OR, CR 2 OC(═O)R, C(═O), C(═S), CR 2 SR, and C(═NR),
A 2 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ) and C(═O)C(R 3 ) 2 ;
Q is CR 4 ;
L is selected from a bond, O, S, S—S, S(═O), S(═O) 2 , S(═O) 2 NR, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C] 2 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH 2 ) n , or (CH 2 CH 2 0) n , where n is optionally 1,2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR 2 , N—CR 2 OR and N—CR 2 NR 2 ;
Ar is selected from (a) a C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R 2 or two R 3 may form a spiro ring;
R 1 is independently selected from CR 3 , NRSO 2 R, OC(═O)NR 2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R X2 is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y=Z is C═C(OH), X is O, A 1 is C(═O), A 2 is C(R 2 )═C(R 3 ), and Q is CH, then L is not a bond.
7 . A method of inhibiting HIV integrase, comprising the administration to a mammal in need of such treatment of a therapeutically effective amount of a compound having the structure:
wherein:
A 1 is independently selected from C(R 2 ) 2 , CR 2 OR, CR 2 OC(═O)R, C(═O), C(═S), CR 2 SR, and C(═NR),
A 2 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ) and C(═O)C(R 3 ) 2 ;
Q is CR 4 ;
L is selected from a bond, O, S, S—S, S(—O), S(═O) 2 , S(═O) 2 NR, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH 2 ) n , or (CH 2 CH 2 O) n , where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR 2 , N—CR 2 OR and N—CR 2 NR 2 ;
Ar is selected from (a) a C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R 2 or two R 3 may form a spiro ring;
R 1 is independently selected from CR 3 , NRSO 2 R, OC(═O)NR 2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R X2 is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof,
with the proviso that when Y═Z is C═C(OH), X is O, A 1 is C(═O), A 2 is C(R 2 )═C(R 3 ), and Q is CH, then L is not a bond.
8 . A method of treating infection by HIV, or of treating AIDS or ARC, comprising administration to a mammal in need of such treatment of a therapeutically effective amount of a compound having the structure:
wherein:
A 1 is independently selected from C(R 2 ) 2 , CR 2 OR, CR 2 OC(═O)R, C(═O), C(═S), CR 2 SR, and C(═NR),
A 2 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ) and C(═O)C(R 3 ) 2 ;
Q is CR 4 ;
L is selected from a bond, O, S, S—S, S(═O), S(═O) 2 , S(═O) 2 NR, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH 2 ) n , or (CH 2 CH 2 O) n , where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR 2 , N—CR 2 OR and N—CR 2 NR 2 ;
Ar is selected from (a) a C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R 2 or two R 3 may form a spiro ring;
R 1 is independently selected from CR 3 , NRSO 2 R, OC(═O)NR 2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R X2 is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y=Z is C═C(OH), X is O, Al is C(═O), A 2 is C(R 2 )═C(R 3 ), and Q is CH, then L is not a bond.
9 . A method of treating a disorder affecting white blood cells, comprising: administering to a patient in need of white-blood-cell targeting a phosphonate prodrug of a compound having the structure:
wherein:
A 1 is independently selected from C(R 2 ) 2 , CR 2 OR, CR 2 OC(═O)R, C(═O), C(═S), CR 2 SR, and C(═NR),
A 2 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ) and C(═O)C(R 3 ) 2 ;
Q is CR 4 ;
L is selected from a bond, O, S, S—S, S(═O), S(═O) 2 , S(═O) 2 NR, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH 2 ), or (CH 2 CH 2 O) n , where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR 2 , N—CR 2 OR and N—CR 2 NR 2 ;
Ar is selected from (a) a C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R 2 or two R 3 may form a spiro ring;
R 1 is independently selected from CR 3 , NRSO 2 R, OC(═O)NR 2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R X2 is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y=Z is C═C(OH), X is O, A 1 is C(═O), A 2 is C(R 2 )═C(R 3 ), and Q is CH, then L is not a bond.
10 . A method of targeting a compound to white blood cells, comprising:
(a) selecting a compound having a first structure:
wherein:
A 1 is independently selected from C(R 2 ) 2 , CR 2 OR, CR 2 OC(═O)R, C(═O), C(═S), CR 2 SR, and C(═NR),
A 2 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ) and C(═O)C(R 3 ) 2 ;
Q is CR 4 ;
L is selected from a bond, O, S, S—S, S(═O), S(═O) 2 , S(═O) 2 NR, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH 2 ) n , or (CH 2 CH 2 O) n , where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR 2 , N—CR 2 OR and N—CR 2 NR 2 ;
Ar is selected from (a) a C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R 2 or two R 3 may form a spiro ring;
R 1 is independently selected from CR 3 , NRSO 2 R, OC(═O)NR 2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R X2 is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y=Z is C═C(OH), X is O, A 1 is C(═O), A 2 is C(R 2 )═C(R 3 ), and Q is CH, then L is not a bond; and
having a desired pharmaceutical activity; and
(b) modifying said first structure by replacing one or more atoms of said first structure with an organic substituent comprising a phosphonate group or incipient phosphonate group to provide a compound having a second structure.
11 . A method of accumulating an HIV integrase inhibitor compound inside a white blood cell, comprising:
(a) selecting a composition comprising a compound having a structure:
wherein:
A 1 is independently selected from C(R 2 ) 2 , CR 2 OR, CR 2 OC(═O)R, C(═O), C(═S), CR 2 SR, and C(═NR),
A 2 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ) and C(═O)C(R 3 ) 2 ;
Q is CR 4 ;
L is selected from a bond, O, S, S—S, S(═O), S(═O) 2 , S(═O) 2 NR, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH 2 ) n , or (CH 2 CH 2 O), where n is optionally 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR 2 , N—CR 2 OR and N—CR 2 NR 2 ;
Ar is selected from (a) a C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R 2 or two R 3 may form a spiro ring;
R 1 is independently selected from CR 3 , NRSO 2 R, OC(═O)NR 2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R X2 is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group;
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof;
with the proviso that when Y=Z is C═C(OH), X is O, A 1 is C(═O), A 2 is C(R 2 )═C(R 3 ), and Q is CH, then L is not a bond; and
(b) administering said composition to a sample.
12 . A method of claim 11 wherein said sample is a patient.
13 . A compound having the structure:
wherein:
A 1 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ), C(═O)C(R 3 ) 2 , C(R 2 ) 2 —C(R 3 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 )—C(R 3 ) 2 , and C(R 2 ) 2 —C(R 3 );
A 2 is independently selected from C(R 2 ) 2 —C(R 3 ) 2 , C(R 2 )═C(R 3 ), and C(═O)C(R 3 ) 2 ;
Q is CR 4 ;
L is selected from a bond, O, S, S—S, S(═O), S(═O) 2 , S(═O) 2 NR, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH 2 ) n , or (CH 2 CH 2 O) n , where n may be 1, 2, 3, 4, 5, or 6;
X is selected from O, S, NH, NR, N—OR, N—NR 2 , N—CR 2 OR and N—CR 2 NR 2 ;
Ar is selected from (a) a C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;
R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
when taken together on a single carbon, two R 2 or two R 3 may form a spiro ring;
R 1 is independently selected from CR 3 , NRSO 2 R, OC(═O)NR 2 OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 3 -C 12 carbocycle, C 3 -C 12 substituted carbocycle, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
R X2 is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group selected from the group consisting of benzyhydryl (CHPh 2 ), trialkylsilyl (R 3 Si), 2-trimethylsiloxyethyl, alkoxymethyl (CH 2 OR), and ester (C(═O)R);
and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof.
14 . A compound of claim 13 selected from the structures:
15 . A compound of claim 13 selected from the structures:
16 . A compound of claim 13 wherein R 1 is selected from R, OR, NR 2 , NHR, NHSO 2 R and NRSO 2 R.
17 . A compound of claim 13 selected from the structures:
18 . A compound of claim 13 wherein R X2 is a protecting group selected from the group consisting of benzyhydryl (CHPh 2 ), trialkylsilyl (R 3 Si), 2-trimethylsiloxyethyl, alkoxymethyl (CH 2 OR), and ester (C(═O)R).
19 . A compound of claim 13 having the structure:
20 . A compound of claim 13 having Formula I:
wherein R X2 is H and X is O.
21 . A compound of claim 13 wherein L is not a bond.
22 . A compound of claim 13 wherein R 4 is H.
23 . A compound of claim 13 wherein Ar is C 6 -C 20 substituted aryl.
24 . A compound of claim 13 having at least one phosphonate group.
25 . A compound of claim 13 wherein substituted alkyl, substituted alkylene, substituted alkyenylene, substituted alkynylene, substituted carbocycle, substituted aryl, and substituted heteroaryl are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, —NH 2 , —NH 3 + , —NHR, —NR 2 , —NR 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R, —SO 2 Ar, —SOAr, —SAr, —SO 2 NR 2 , —SOR, —CO 2 R, —C(═O)NR 2 , 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 3 -C 12 carbocycle, C 6 -C 20 aryl, C 2 -C 20 heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.
26 . The compound of claim 13 wherein A 1 is CH 2 —CH 2 , C(CH 3 ) 2 —CH 2 , CH═CH or CH 2 —CH 2 —CH 2 .
27 . The compound of claim 20 wherein L is CH 2 ; and Ar is substituted phenyl.
28 . The compound of claim 27 wherein Ar is 4-fluorophenyl.
29 . The compound of claim 20 wherein R 2 , R 3 and R 4 are each H.
30 . The compound of claim 20 wherein A 1 is CH═CH; and R 2 , R 3 and R 4 are each H.
31 . The compound of claim 13 wherein Ar-L is selected from the structures:
32 . A compound of claim 20 having the formula
33 . A compound of claim 20 having the structure:
34 . A compound of claim 20 wherein Ar-L is para-fluorobenzyl.
35 . A compound of claim 13 wherein R 1 is selected from CR 3 , C(═O)NR 2 , OC(═O)OR, OC(═O)NR 2 , OC(═O)R, OSO 2 NR 2 (sulfamate), NR 2 , NRSO 2 R, SR, S(O)R, SO 2 R and SO 2 NR 2 (sulfonamide).
36 . The compound of claim 35 wherein at least one R is a prodrug moiety.
37 . A compound of claim 13 wherein at least one of R 1 , R 2 , R 3 , and R 4 is selected from the structures:
38 . A compound of claim 13 wherein at least one of R 1 , R 2 , R 3 , and R 4 is selected from the structures:
39 . A compound of claim 13 wherein at least one of R 1 , R 2 , R 3 , and R 4 is selected from the structures:
40 . A compound of claim 13 wherein at least one of R 1 , R 2 , R 3 , and R 4 is a lactam having the structures:
a sultam having the structures:
41 . A compound of claim 13 wherein Ar is selected from the structures:
where the wavy line indicates the covalent attachment site to L.
42 . A compound of claim 13 wherein Ar is selected from the structures:
where n is 1 to 6.
43 . A compound of claim 13 wherein Ar is selected from the structures:
44 . A compound of claim 13 comprising a prodrug moiety selected from the structures:
wherein R 5 is —CR 2 CO 2 R 7 where R 6 and R 7 are independently H or C 1 -C 8 alkyl.
45 . The compound of claim 13 comprising a phosphonate or prodrug moiety having the structure:
wherein:
Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x ) 2 ;
Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x ) 2 ), —S(O)— (sulfoxide), —S(O) 2 — (sulfone), —S— (sulfide), or —S—S— (disulfide);
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
R y is independently H, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, or a protecting group, or where taken together at a carbon atom, two vicinal R y groups form a carbocycle or a heterocycle; and
R x is independently H, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, or a protecting group, or the formula:
where M1a, M1c, and M1d are independently 0 or 1, and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
46 . The compound of claim 45 wherein the phosphonate or prodrug moiety has the structure:
47 . The compound of claim 46 wherein the phosphonate or prodrug moiety has the structure:
where Y 2b is O or N(R x ).
48 . The compound of claim 46 wherein the phosphonate or prodrug moiety has the structure:
where W 5 is a carbocycle, and Y 2c is O, N(R y ) or S.
49 . The compound of claim 48 wherein W 5 is selected from the structures:
50 . The compound of claim 46 wherein the phosphonate or prodrug moiety has the structure:
51 . The compound of claim 13 wherein the phosphonate or prodrug moiety has the structure:
wherein Y 2b is O or N(R x ); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; R 1 is H or C 1 -C 6 alkyl;
and the phenyl carbocycle is substituted with 0 to 3 R 2 groups where R 2 is C 1 -C 6 alkyl or substituted alkyl.
52 . The compound of claim 13 wherein the phosphonate or prodrug moiety has the structure:
53 . The compound of claim 45 wherein Rx is selected from the structures:
54 . A compound of claim 13 wherein none of R 2 , R 3 , R 4 , R, or R X2 is a prodrug moiety.
55 . A compound that is
56 . A compound of claim 13 substituted with a phosphonate or phosphonate prodrug moiety and capable of accumulating in human PBMC.
57 . The compound of claim 56 wherein the intracellular half-life of the compound or an intracellular metabolite of the compound in human PBMC is increased by at least about 50% when compared to the analog of the compound not having the a phosphonate or phosphonate prodrug moiety.
58 . The compound of claim 57 wherein the half-life is improved by at least about 100%.
59 . The compound of claim 56 wherein the intracellular half-life of a metabolite of the compound in human PBMC is increased by at least about 50% when compared to the analog of the compound not having the a phosphonate or phosphonate prodrug moiety.
60 . The compound of claim 59 wherein the half-life is improved by at least about 100%.
61 . The compound of claim 60 wherein the half-life is improved by greater than 100%.
62 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 13 and a pharmaceutically acceptable carrier.
63 . The pharmaceutical composition of claim 62 further comprising a therapeutically effective amount of an AIDS treatment agent selected from an HIV inhibitor agent, an anti-infective agent, and an immunomodulator.
64 . The pharmaceutical composition of claim 63 wherein the HIV inhibitor agent is an HIV-protease inhibitor.
65 . The pharmaceutical composition of claim 63 wherein the HIV inhibitor agent is a nucleoside reverse transcriptase inhibitor.
66 . The pharmaceutical composition of claim 65 wherein said nucleoside reverse transcriptase inhibitor is 3′-azido-3′-deoxythymidine (zidovudine, AZT), 2′-deoxy-3′-thiacytidine (3TC), 2′,3′-dideoxy-2′,3′-didehydroadenosine (D4A), 2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T), carbovir (carbocyclic 2′,3′-dideoxy-2′,3′-didehydroguanosine), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxyadenosine (ddA), 2′,3′-dideoxyinosine (ddI), PMEA, or PMPA.
67 . The composition of claim 63 wherein the HIV inhibitor agent is a non-nucleoside reverse transcriptase inhibitor.
68 . A process for making a pharmaceutical composition comprising combining a compound of claim 13 and a pharmaceutically acceptable carrier.
69 . A method of inhibiting HIV integrase, comprising the administration to a mammal in need of such treatment of a therapeutically effective amount of a compound of claim 13 .
70 . A method of treating infection by HIV, or of treating AIDS or ARC, comprising administration to a mammal in need of such treatment of a therapeutically effective amount of a compound of claim 13 .
71 . Method of treating a disorder affecting white blood cells, comprising:
administering a compound of claim 13 comprising a phosphonate prodrug to a patient in need of white-blood-cell targeting.
72 . A method of targeting a compound to white blood cells, comprising:
(a) selecting a compound of claim 13 having a desired pharmaceutical activity and having a first structure; and (b) modifying said first structure by replacing one or more atoms of said first structure with an organic substituent comprising a phosphonate group or incipient phosphonate group to provide a compound having a second structure.
73 . A method of accumulating an HIV integrase inhibitor compound inside a white blood cell, comprising:
(a) selecting a composition comprising a compound of claim 13 ; and (b) administering said composition to a sample.
74 . A method of claim 73 wherein said sample is a patient.Join the waitlist — get patent alerts
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