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  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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  • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
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  • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
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  • C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
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Definitions

• compositions and methods in the field of medicine and chemistry are disclosed. Some of the disclosed embodiments are directed to medicinal prodrug compounds, medicinal compositions, as well as processes for their preparation and methods of their use. Some embodiments include prodrug compounds of acid/alcohol derivatives, their preparation and their uses. In some embodiments, such prodrug compounds are useful to selectively deliver the acid/alcohol derivatives to the liver.
• Prodrugs are frequently used to improve certain properties of pharmacological agents for a preferred route of administration, including physicochemical, biopharmaceutical or pharmacokinetic properties.
• Certain prodrugs also called soft drugs
• tissue selective activation or deactivation to achieve therapeutic advantages (See J. Rautio, et al. Nature Reviews Drug Discovery 7: 255-270 (2008)).
• cyclic phosphate, phosphonate, phosphonamidate, and phosphor am idate prodrugs are disclosed in US Patent No. 6,312,662 and US Patent No. 7,205,404 and designed for liver-targeting of pharmacological agents. These prodrugs are the target tissue and designed to achieve the selective delivery of pharmacological agents to the liver. Since the prodrugs are not active outside the liver, the liver-targeting strategy reduces any pharmacological or toxicologieal effects of a biologically active agent outside the targeting tissue. As a result, once used to treat liver diseases or to treat diseases via intervening in molecular pathways in the liver, the liver-targeting strategy significantly improves patient benefit/risk ratio of a pharmacological agent (e.g. see M. D. Erion, ei ai. J Pharm Exp Ther 312:554-60 (2005)). Example activation of these cyclic phosph(on)ate and phosphoramidate compounds are illustrated below:
• the cyclic prodrugs (X ::: () or N) are oxidized by Cyp3A in the liver and undergo a ring opening and ⁇ -eiimination sequence to provide the active drugs and an aryl vinyl ketone (Intermediate).
• the latter is rapidly conjugated with glutathione (GSH) that exists in millimole levels in the liver to yield the conjugate byproduct.
• GSH glutathione
• liver-targeted property e.g. see X. J. Zhou, ei ai. 2009 EASL meeting poster #966).
• the liver-targeting effects of these agents are based on liver first-pass metabolism of an orally administered agent and the liver-targeting efficiency varies widely, depending upon the pharmacokinetic property of the agent, and are not as efficient as the Cyp3A activated prodrugs.
• Novel prodrug compounds of acid/alcohol derivatives such as phosphates, phosphonates, phosphonarnidates, phosphoramidates, carboxylates, phenolates, and alkoxyiates, their preparation and their uses are described.
• Some embodiments are related to novel prodrug compounds that do not, generate a vinyl keto reactive intermediate in the activation process. Some embodiments are directed to the use of the prodrugs to enhance oral drug delivery. Another aspect includes the use of prodrugs to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and ceils, including but not limited to hepatitis, cancer, liver fibrosis, fatty liver, malaria, other viral and parasitic infections, and metabolic, cardiovascular, and/or hormonal diseases where the liver is involved in the production and/or the homeostasis control of the biochemical end products, e.g.
• prodrugs are used to prolong pharmacodynamic half-life of a drug.
• the prodrug methodology can be used to achieve sustained deli ver ⁇ ' of the parent drug.
• prodrugs are used to increase the therapeutic index of the drug.
• the prodrugs are useful in the delivery of diagnostic imaging agents to the liver.
• M is a biological agent, or part of a biological agent or a prodrug of a biological agent
• X is selected from the group consisting of CI, OR 4 , NR 4 R 5 , an optionally substituted Q-Ce alkyl, and M;
• Y and Y' are each independently O or NR 4 ; or Y' is CH 2 or null;
• R 4 is selected from the group of H, an optionally substituted Cj-Ce alkyl, and an optionally substituted C ⁇ -Ce heteroalkyl;
• R " is selected from the group consisting of H, M, an optionally substituted Ci-Ce alkyl, an optionally substituted C-.-Ce heteroalkyl, and an optionally substituted Q-Ce acyl;
• R 6 is selected from the group consisting of F, CI, an optionally substituted C] -C 6 alkyl, and an optionally substituted C ⁇ -Ce heteroalkyl; or R & is H provided that R ! or R " or R '' is connected to a cyclic core carbon atom through an oxygen-carbon (0-C) bond;
• R ' is selected from the group consisting of H, an optionally substituted Q- Ce alkyl, and an optionally substituted Ci-Ce heteroalkyl;
• R 5 is selected from, the group consisting of F, CI, M, an optionally substituted Cj-Ce alkyl, and an optionally substituted Cj-CV, heteroalkyl; or R s is H provided that R 1 or R z is connected to a cyclic core carbon atom through an oxygen-carbon (O-C) bond;
• the compound is a compound of Formula la:
• R 1 is selected from the group consisting of H, an optionally substituted Cj- C(, alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R 2 and R 3 are each independently selected from the group consisting of H and an optionally substituted C]-C 6 alkyl; or R and R optionally form an optionally substituted ring; or R 2 and R 3 optionally form a methylene or its derivative; or R and R J optionally form an oxo or its derivative;
• M is a biological agent, part of a biological agent or a prodrug of a biological agent
• Y and Y' are each independently O or NR 4 ; or Y' is CH 2 ;
• R 4 is selected from the group consisting of H, an optionally substituted Cj- C* alkyl, and an optionally substituted Ci-Ce heteroalkyl;
• R 5 is selected from the group consisting of H, an optionally substituted C] ⁇ C6 alkyl, an optionally substituted Ci-Ce heteroalkyl, and an optionally substituted Ci -Ce acyl;
• R 6 is selected from the group consisting of F, CI, an optionally substituted C ⁇ -Ce alkyl, and an optionally substituted Cj -C 6 heteroalkyl; or R 6 is H provided that R 1 or R 2 or R 8 is connected with the cyclic core carbon atom through an oxygen-carbon (O-C) bond;
• R ? is selected from the group consisting of H, an optionally substituted C - C 6 alkyl, and an optionally substituted C C 6 heteroalkyl;
• R s is selected from the group consisting of F, CL M, an optionally substituted Cj-Cs alkyl, and an optionally substituted C Cg heteroalkyl; or R " is H provided bond:
• the com ound is a compound of Formula lb:
• R z and R 3 are independently selected from the group consisting of H and an optionally substituted Q-Ce alkyl; or R 2 and R 3 optionally form an optionally substituted ring: or R" and R optionally form a methylene or its derivative; or R ⁇ and R " optionally form an oxo ⁇ ( ) ⁇ or its derivative;
• M is a biological agent, part of a biological agent or a prodrug of a biological agent
• X is selected from the group consisting of CI, an optionally substituted Ci ⁇ C 6 alkyl NR 4 R 5 , and OR 4 ;
• Y and Y' are each independently Q or NR"; or Y' is CH 2 or null;
• Z is selected from the group consisting of O, NR 5 , C(R 6 ) 2 , C ( ). C ⁇ ' R ⁇ . and null; or Z is a 2-5 atom spacer selected from an optionally substituted Ci-Ce alkyl, an optionally substituted Q-C 6 alkyloxy, an optionally substituted Ci ⁇ C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R 4 is selected from the group consisting of H, an optionally substituted C3 - C(3 alkyl, and an optionally substituted C-.-Ce heteroalkyl;
• R 3 is selected from the group consisting of H, an optionally substituted Cj- C 6 alkyl, an optionally substituted C C 6 heteroalkyl, and an optionally substituted Ci -Ce acyi;
• R 6 is selected from the group consisting of F, CI, an optionally substituted Ci-Cf, alkyl, and an optionally substituted C Ce heteroalkyl; or R° is 1:1 provided that M or 2 is connected with the cyclic core carbon atom through an oxygen-carbon (O-C) bond; C(3 alkyl, and an optionally substituted C-.-Ce heteroalkyl;
• the compound is a compound of Formula Ic:
• R ! is selected from the group consisting of H, an optionally substituted Cj- C* alkyl, an optionally substituted Q-Ce heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R 3 is selected from the group consisting of H and an optionally substituted Ci-Ce alkyl; or R J together with M form a niethnylene derivative; or R 3 optionally forms a bond with Z or Y' when Z or Y ' is N;
• M is a biological agent, part of a biological agent or a prodrug of a biological agent
• X is selected from the group consisting of CI, OR 4 , NR 4 R 3 , and an optionally substituted Cj-Ce alkyl;
• Y and Y' are each independently O or NR J ;
• R 4 is selected from the group consisting of H, an optionally substituted Q- Cg alkyl, and an optionally substituted Ci-Ce heteroalkyl;
• R 5 is selected from the group consisting of H, an optionally substituted Cj- C 6 alkyl, an optionally substituted C-.-Ce heteroalkyl, and an optionally substituted C-. -Ce Ci-Ce alkyl, and an optionally substituted C Ce heteroalkyl; or R° is H provided that R ! or M is connected with the cyclic core carbon atom through an oxygen-carbon (O-C) bond;
• R is selected from the group consisting of H, an optionally substituted C] ⁇ C6 alkyl, and an optionally substituted Cj-Ce heteroalkyl;
• the compound is a compound of Formula Id or le:
• R 2 and R 3 are independently selected from the group consisting of H and an optionally substituted Q-C6 alkyl; or R 3 together with M or R J form a methylene derivative; or R 3 together with M or R z form an optionally substituted ring; or R J together with R" form an oxo ( :::: 0) or its derivative; or R 3 optionally forms a bond with Z or Y' when Z or Y' is N;
• M is a biological agent, part of a biological agent or a prodrug of a biological agent
• X is selected from the group consisting of CI, OR 4 , and an optionally substituted C 2 -C 6 alkyl;
• Y and Y' are each independently O or N; or Y' is (3 ⁇ 4;
• Z is selected from the group consisting of O and NR 5 ;
• R 4 is selected from the group consisting of H, an optionally substituted C3 - C 6 alkyl, and an optionally substituted C-.-C heteroalkyl;
• R 3 is selected from the group consisting of H, an optionally substituted Cj- C 6 alkyl, an optionally substituted C C 6 heteroalkyl, and an optionally substituted C C 6 acyi;
• R Z! is selected from the group consisting of H, M, an optionally substituted Cj-Ce alky], an optionally substituted Cj-C 6 heteroalkyl, an optionally substituted Cj-C 6 alkyloxy, an optionally substituted C ⁇ -C ⁇ > acyloxy, an optionally substituted aryl, and an optionally substituted heteroaryl;
• M is a biological agent, or part of a biological agent or a prodrug of a biological agent
• Q is an optionally substituted aryl or an optionally substituted heteroaryl
• X 2 is selected from the group consisting of Cl, OR/ '4 , N(R "4 ) 2 an optionally substituted C C6 alkyL and M;
• X' is selected from the group consisting of Cl, N(R 4 ) 2 , and OR 4 ;
• Y" and Y' ' are each independently O or NR J' ;
• R M is selected from the group of H, an optionally substituted C]-C 6 alkyl, and an optionally substituted Ci-Ce heteroalkyl;
• R ' " and R " are each independently selected from the group consisting of CI, OH, NH 2 , an optionally substituted Cj-Ce alkyl, an optionally substituted Cj -C 6 alkvloxy, and an optionally substituted Q-Ce alkylamino;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent
• I X 3 is O or NR 34 ;
• Y 3 is selected from the group consisting of O, NR 54 , and an optionally substituted Ci-Ce alkyl;
• R 34 is selected from the group consisting of H, an optionally substituted Cj -C6 alkyl, and an optionally substituted C j-Ce heteroalkyl;
• R 4i is H; or R 41 optionally forms a bond with M or X 4 when X 4 is N;
• Z 4 is selected from the group consisting of CR 46 R 47 , C(O), ( ' « »(). C(0)NR 48 , S0 2 , an optionally substituted aryl, and an optionally substituted heteroaryl;
• R 4z , R 43 , R "'* , R 4"' , R 46 , and R 4 ' are each independently selected from the group consisting of H, OH, amino, an optionally substituted Ci-Ce alkyl, an optionally substituted Cj-Cs alkvloxy, an optionally substituted Cj-C6 acyloxy, an optionally substituted Ci-Ce hereroalkyl, an optionally substituted phosphate, an optionally substituted phosphonate, an optionally substituted aryl, and an optionally substituted heterocycle; or R 44 and R 45 are independently or together optionally linked with R 4 , R 4 ⁇ R 46 , or R 4 to form an ooppttiioonnaallllyy ssuubbssttiittuutteedd rriinngg:: oorr RR '4 '4 is optionally M; or R' ⁇ ' and R 45 are together optionally to form an oxo (
• X is selected from the group consisting of O, NR * , NC(0)R ' ⁇ , NS(0) 2 R 49 , and NP(O)(R 50 ) 2 ;
• R 48 is selected from the group consisting of H, an optionally substituted Ci-Ce alky , and an optionally substituted Q-Ce heteroalkyl;
• R 49 is selected from the group consisting of NH 2 , an optionally substituted Ct-Ce alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R" G is selected from the group consisting of OH, NH 2 , an optionally substituted C-.-Ce alkyl, an optionally substituted C-. -CVi alkyl oxy, and an optionally substituted C] -C 6 alkylami.no;
• n 0, 1 , 2, or 3;
• Some embodiments relate to a. compound of Formula V:
• R "3 and R "4 are each independently selected from the group consisting of CI, OH, H 2 , an optionally substituted Q-Ce alkyl, an optionally substituted Q-C6 alkyloxy, an optionally substituted Cj-Cs alkyl amino, an optionally substituted Cj-Cs acylamino, an optionally substituted aryloxy, an optionally substituted phosphate, an optionally substituted 5 " c
• R 55 is selected from the group consisting of OH, N3 ⁇ 4, an optionally substituted Cj-Ce alkyl, an optionally substituted Ci-C 6 alkyloxy, an optionally substituted Ci-Ce alkylamino, an optionally substituted aryl, and an optionally substituted heteroaryl; or R 55 is optionally linked to R 5 ' or R j6 to form an optionally substituted ring;
• R 30 is selected from the group consisting of H, a Ci -Ce alkyl, and a Cj-Ce heteroalkyl;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent
• X 5 is O or NR. 56 ;
• n 0, 1 , 2, or 3;
• Some embodiments relate to a com ound of Formula VI:
• R 6i and R 62 are each independently selected from the group consisting of H, an optionally substituted Ci-Ce alkyloxy, an optionally substituted Ci-Ce alkylamino, an optionally substituted Ct-Ce acyloxy, -OCH 2 P(0)(R o ) 2 , and an optionally substituted C . -Ce acylamino; or R 61 and R 62 together optionally form an oxo ( ::: 0) or its derivative;
• R 6 ' , R 64 , and R 0J are each independently selected from the group consisting of H, C0 2 R 67 , C(0)N(R 67 ) 2 , P(0)(R 69 ) 2 , an optionally substituted C C 6 alkyl, an optionally substituted C Ce alkyloxy, an optionally substituted Q-C6 acyloxy, and an optionally substituted Cj-Cg hereroalkyl; or two of R 6j , R 6"* , and R 6i are optionally linked to form an optionally substituted ring; or R 6 ' is optionally linked with R 68 to form an optionally substituted ring; with the proviso that CR 6 R 6'* R 6 > is not a straight chain Cj ⁇ C 4 alkyl when R 6 ' and R 6 form an oxo ( :::: 0); Ci-Ce alkyl, an optionally substituted Cj-Ce alkyloxy, an optionally substituted Ci
• R 67 and R 68 are each independently selected from the group consisting of H, an optionally substituted Ci -Ce alkyl, and an optionally substituted C]-C 6 heteroalkyl;
• R 69 is selected from, the group consisting of OH, an optionally substituted Ci-Ce alkyl, an optionally substituted C1-C3 alkyloxy, and an optionally substituted CVCe alkylamino;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent
• X 6 is O or R 68 ;
• Y° is selected from the group consisting of null, (), NR 65 , and C(R 68 ) 2 ;
• R ' '1 is selected from the group consisting of H, OH, an optionally substituted Cj- V, alkyl, an optionally substituted C] -C 6 heteroalkyl, an optionally substituted Ci-Ce alkyloxy, an optionally substituted phosphate, and an optionally substituted phosphonate;
• X' is O or S
• Y 7 is N or CR 71 ;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent
• the compound is selected from the group consisting of:
• M is a nucleoside antiviral or anticancer agent.
• M is a lipid modulator
• M is selected from the group consisting of HMG- CoA reductase inhibitor, a selective thyroid hormone receptor modulator, a peroxisome proliferator-activated receptor modulator, a fibrate, a nicotinic acid, a bile acid, and a fatty acid.
• M is selected from the group consisting of a peroxisome proliferator-activated receptor modulator, a glucose biosynthesis inhibitor, and a dipeptidyl peptidase 4 inhibitor.
• M is a nuclear hormone receptor modulator.
• Some embodiments relate to a pharmaceutical composition
• a pharmaceutical composition comprising any of the abo ve compounds and a pharmaceutically acceptable excipient.
• Some embodiments relate to a method of treating a disease, disorder or condition comprising administering an effective amount of any of the above compounds to a subject in need thereof.
• the disease, disorder or condition is a disease, disorder or condition of the li ver.
• the disease, disorder or condition is a metabolic, cardiovascular or hormonal disease in which the liver is involved in the production and/or the homeostasis control of the biochemical end products of the disease, disorder or condition.
• the disease, disorder or condition is selected from the group consisting of hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infection, parasitic infection, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia and a hormonal condition.
• Some embodiments relate to a method of treating a liver disease comprising administering an effective amount of any of the above compounds to a. subject in need thereof, wherein M is a nucleoside antiviral or anticancer agent.
• Some embodiments relate to a method of treating dyslipidemia comprising administering to a subject in need thereof an effective amount of any of the above compounds, wherein M is a lipid modulator.
• M is selected from the group consisting of HMG- CoA reductase inhibitor, a selective thyroid hormone receptor modulator, peroxisome proliferator-activated receptor modulator, a fibrate, nicotinic acid, a bile acid, and a fatty acid. administering to a subject in need thereof, an effective amount of any of the above compounds, wherein M is a glucose modulator.
• M is selected from the group consisting of peroxisome proliferator-activated receptor modulator, glucose biosynthesis inhibitor, and dipeptidyl peptidase 4 inhibitor.
• Some embodiments relate to a method of treating a hormonal condition comprising administering to a subject in need thereof, an effective amount of any of the above compounds, wherein M is a nuclear hormone receptor modulator.
• Some embodiments further comprise administering an effective amount of at least one additional therapeutic agent to the subject in need thereof.
• Some embodiments relate to a method of delivering a diagnostic imaging agent to the liver of a subject in need thereof, comprising administering to the subject an effective amount of any of the above compounds.
• the subject is a mammal.
• the subject is human.
• Some embodiments relate to a method of inhibiting viral replication in a cell comprising contacting the cell with any of the above compounds.
• Some embodiments relate to a method of intervening in a molecular pathway or modulating a target in a cell comprising contacting the cell with any of the above compounds.
• the cell is in vivo.
• the cell is ex vivo.
• the cell is a hepatocyte.
• the cell is mammalian.
• the cell is human.
• compositions and methods related to novel prodrug compounds of biologically active acid''alcohol derivatives such as phosphates, phosphonates, phosphonamidates, phosphoramidates, carboxylates, phenolates, stereoisomers and pharmaceutically acceptable salts are represented by the formulae discussed below.
• Some embodiments relate to a compound of Formula I:
• R and R are each independently selected from the group consisting of H, M, an optionally substituted Cj-Ce alkyl, an optionally substituted Cj-Ce heteroalkyl, an optionally substituted Ci-Ce alkyloxy, an optionally substituted Ct-Ce aeyloxy, an optionally substituted aryl, and an optionally substituted heteroaryl;
• M is a biological agent, or part of a biological agent or a prodrug of a biological agent
• X is selected from the group consisting of CI, OR 4 , NR 4 R 5 , an optionally substituted Cj-Ce alkyl, and M;
• Y and Y' are each independently O or NR 4 : or Y' is CH 2 or null;
• Z is selected from the group consisting of O, NR 5 , CR 8 R°, ( ). 0 : NR ', and null; or Z is a 2-5 atom spacer selected from an optionally substituted Cj-Ce alkyl, an optionally substituted Cj-Ce alkyloxy, an optionally substituted Ci-Ce heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R 4 is selected from, the group of H, an optionally substituted Cj-Ce alkyl, and an optionally substituted Q-Ce heteroalkyl;
• R J is selected from the group consisting of H, M, an optionally substituted Cj-Ce alkyl, an optionally substituted Cj -Ce heteroalkyl, and an optionally substituted Ci-Ce acyl; 6 ⁇ ' ⁇ 2 8 alkyl, and an optionally substituted Ci-Ce heteroaikyl; or R ' is H provided that R 1 or R or R is connected to a cyclic core carbon atom through an oxygen-carbon (O-C) bond;
• O-C oxygen-carbon
• R' is selected from the group consisting of H, an optionally substituted Cj-Ce alkyl, and an optionally substituted Ci ⁇ C6 heteroaikyl;
• R 8 is selected from the group consisting of F, CI, M, an optionally substituted Ci-Ce alkyl, and an optionally substituted Ci-Ce heteroaikyl; or R 8 is H provided that R 1 or R is connected to a cyclic core carbon atom through an oxygen-carbon (O-C) bond;
• the com ound is a compound of Formula la:
• R 5 is selected from the group consisting of H, an optionally substituted CVCe alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R and R 3 are each independently selected from the group consisting of H and an optionally substituted Ci-Ce alkyl; or R z and R 3 optionally form an optionally substituted ring; or R 2 and R 3 optionally form a methylene or its derivative; or R 2 and R 5 optionally form an oxo or its derivative;
• M is a biological agent, part of a biological agent or a prodrug of a biological agent
• Y and Y' are each independently O or NR 4 ; or Y' is CH 2 ;
• Z is selected from the group consisting of O, NR 5 , CR 8 R b , ( ), ONR', and null; or Z is a. 2-5 atom spacer selected from an optionally substituted Cj-Ce alkyl, an optionally substituted Cj-Ce alkyloxy, an optionally substituted Cj-Ce heteroaikyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R 4 is selected from the group consisting of H, an optionally substituted Cj-Ce alkyl, and an optionally substituted C ⁇ ⁇ Ce heteroaikyl; an optionally substituted Ci-C 6 heteroalkyl, and an optionally substituted Q-Ce acyl;
• R 6 is selected from the group consisting of F, CI, an optionally substituted C-. -Ce alkyi, and an optionally substituted Cj-Ce heteroalkyl; or R° is H provided that R s or R 2 or R 8 is connected with the cyclic core carbon atom through an oxygen-carbon (Q-C) bond;
• R' is selected from the group consisting of H, an optionally substituted Ci -Ce alkyl, and an optionally substituted Ci-Ce heteroalkyl;
• R s is selected from the group consisting of F, Ci, M, an optionally substituted Ci -Ce alkyl, and an optionally substituted Ci-Ce heteroalkyl; or R 8 is H provided that R 1 or R 2 is connected to a cyclic core carbon atom through an oxygen-carbon (Q-C) bond;
• the compound is a compound of Formula lb:
• M is a biological agent, part of a biological agent or a prodrug of a biological agent
• X is selected from the group consisting of CI, an optionally substituted C.-Ce alkyl, R 4 R 5 , and OR 4 ;
• Y and Y' are each independently O or NR 4 ; or Y' is CH 2 or null ;
• R ' is selected from the group consisting of H, an optionally substituted Q-Ce alkyl, an optionally substituted Cj-Ce lieteroalkyl, and an optionally substituted C ⁇ -Ce acyl;
• R 6 is selected from the group consisting of F, CI, an optionally substituted C t -Ce alkyl, and an optionally substituted Ci-Ce heteroalkyl; or R 6 is H provided that M or R 2 is connected with the cyclic core carbon atom through an oxygen-carbon (O-C) bond;
• R' is selected from the group consisting of H, an optionally substituted Cj-Ce alkyl, and an optionally substituted CpCe heteroalkyl;
• the compound is a compound of Formula Ic:
• R 5 is selected from the group consisting of H, an optionally substituted CVCe alkyl, an optionally substituted Ci-Ce heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R 3 is selected from the group consisting of H and an optionally substituted Ci-Cg alkyl; or R 5 together with M form a methnylene derivative; or R ⁇ optionally forms a bond with Z or Y' when Z or Y' is N;
• M is a biological agent, part of a biological agent or a prodrug of a biological agent
• X is selected from the group consisting of CI, OR 4 , NR'R", and an optionally substituted C 1 -C6 alkyl;
• Y and Y' are each independently O or NR ' :
• Z is selected from the group consisting of O, NR 5 , C(R°) 2 , ( ⁇ ), C ::: NR ', and nul l; or Z is a 2-5 atom spacer selected from an optionally substituted Cj-Ce alkyl, an optionally substituted C 1 -C6 alkyloxy, an optionally substituted Ci-Ce heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and an optionally substituted Cj-C 6 heteroalkyl;
• R ' is selected from the group consisting of II, an optionally substituted Q-Ce alkyl, an optionally substituted Cj-Ce heteroalkyl, and an optionally substituted C ⁇ -Ce acyl;
• R 6 is selected from the group consisting of F, CI, an optionally substituted C t -Ce alkyl, and an optionally substituted Ci-Ce heteroalkyl; or R 6 is H provided that R ! or M is connected with the cyclic core carbon atom through an oxygen-carbon (O-C) bond;
• R' is selected from the group consisting of H, an optionally substituted Cj-Ce alkyl, and an optionally substituted CpCe heteroalkyl;
• M is a biological agent, part of a biological agent or a prodrag of a biological agent
• X is selected from the group consisting of CI, OR 4 , and an optionally substituted C 2 - C 6 alkyl;
• Y and Y' are each independe tly O or N; or Y' is CH?;
• Z is selected from the group consisting of O and NR";
• R 4 is selected from the group consisting of H, an optionally substituted Cj-Ce alkyl, and an optionally substituted Ci-C-6 heteroalkyl;
• R "' is selected from the group consisting of H, an optionally substituted Ci -Ce alkyl, an optionally substituted Ci -Ce heteroalkyl, and an optionally substituted Ci-Ce acyl;
• R i is selected from the group consisting of H, M, an optionally substituted Cj-Ce alkyl, an optionally substituted C 1 -G5 heteroalkyl, an optionally substituted C ⁇ -C alkyloxy, an optionally substituted C ⁇ ⁇ C acyloxy, an optionally substituted aryl, and an optionally substituted heteroaryl;
• M is a biological agent, or part of a biological agent or a prodrug of a biological agent
• Q is an optionally substituted aryl or an optionally substituted heteroaryl
• X is selected from the group consisting of CI, OR " , N(R” ) 2 an optionally substituted C2-C6 alkyl, and M;
• X' 2 is selected from the group consisting of CI, N(R 24 ) 2 , and OR 2' ;
• Y and Y' 2 are each independently O or NR 4 ;
• R 24 is selected from the group of H, an optionally substituted Cj-Ce alkyl, and an optionally substituted Cj -Ce heteroalkyl;
• R 2 ' and X is M
• R 1 is H; or R j 3 optionally forms a bo d with M or X 3 when X J is N;
• R 3' and R 33 are each independently selected from the group consisting of CI, OH, NH 2 , an optionally substituted Cj-C alkyi, an optionally substituted Cj-Ce alkyloxy, and an optionally substituted Q-Cg alkylamino;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent
• X 3 is O or NR. 34 ;
• Y 3 is selected from the group consisting of O, NR 34 , and an optionally substituted Cj- C 6 alky!;
• R 3" is selected from the group consisting of H, an optionally substituted Cj-CV, alkyl, and an optionally substituted Q-Ce heteroalkyl;
• R 41 is H; or R 4i optionally forms a bond with M or X 4 when X 4 is N;
• Z 4 is selected from the group consisting of CR 6 R 47 , C(O), C(0)0, C(0)NR 4S , S0 2 , an optionally substituted aryl, and an optionally substituted heteroaryl;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent; NP(O)(R 50 ) 2 ;
• R 48 is selected from the group consisting of H, an optionally substituted Q-Ce alkyl, and an optionally substituted C ⁇ ⁇ Ce heteroalkyl;
• R 49 is selected from the group consisting of NH 2 , an optionally substituted Q-Ce alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
• R jJ is selected from the group consisting of OH, N!3 ⁇ 4, an optionally substituted C-. -Ce alkyl, an optionally substituted C] -C 6 alkyloxy, and an optionally substituted Ci -Ce alkylamino;
• n 0, 1 , 2, or 3:
• Some embodiments relate to a compound of Formula Va, Vb, or Vc:
• R 53 and R 54 are each independently selected from the group consisting of CI, OH, Ni3 ⁇ 4, an optionally substituted Cj-CV, alkyl, an optionally substituted Ct-Ce alkyloxy, an optionally substituted Ci-Ce alkylamino, an optionally substituted Q-Ce acylamino, an optionally substituted aryloxy, an optionally substituted phosphate, an optionally substituted phosphonate, and an optionally substituted hetero aryloxy; or R " ⁇ is optionally linked with R 3 ', R 34 , or R 3D to form an optionally substituted 5-, 6-, or 7-membered heterocycle; substituted C1-C3 alkyl, an optionally substituted C-.
• R JJ is optionally linked to R 5] or R 56 to form an optionally substituted ring;
• R 56 is selected from the group consisting of H, a Cj-Ce alkyl, and a Ci -Ce heteroalkyl;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent
• X 5 is O or NR 56 ;
• n 0, 1 , 2, or 3;
• Some embodiments relate to a compound of Formula Via, Vlb or Vic:
• R 6j , R &4 , and R 65 are each independently selected from the group consisting of H, C0 2 R 67 , C(0)N(R 67 ) 2 , P(0)(R 69 ) 2 , an optionally substituted C f -C 6 alkyl, an optionally substituted Ci-Ce alkyloxy, an optionally substituted Ci-Ce acyloxy, and an optionally substituted Ci-C 6 hereroalkyl; or two of R" , R 64 , and R 65 are optionally linked to form an optionally substituted ring; or R 63 is optionally linked with R 68 to form an optionally substituted ring; with the proviso that CR 0, R 64 R 65 is not a straight chain C C 4 alkyl when R 6 ' and R 62 form an oxo ( ::: 0);
• R 66 is selected from the group consisting of H, an optionally substituted Cj-Ce alkyl, an optionally substituted Ci-Cg alkyloxy, an optionally substituted Ci -Ce heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; H, an optionally substituted Cj-Ce alkyl, and an optionally substituted Cj-Ce heteroalkyl;
• R° 9 is selected from the group consisting of OH, an optionally substituted Ci ⁇ C6 alkyl, an optionally substituted Ci-Ce alkyloxy, and an optionally substituted Cj-Ce alkyiamino;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent
• X 6 is O or NR 68 :
• Y 6 is selected from the group consisting of null, O, NR. 68 , and C(R 6S ) 2 ;
• R" is selected from the group consisting of H, OH, an optionally substituted Cj-Ce alkyl, an optionally substituted Cj-Ce heteroalkyl, an optionally substituted Cj-Ce alkyloxy, an optionally substituted phosphate, and an optionally substituted phosphors ate;
• Y 7 is I or CR 75 ;
• M is a biological agent or part of a biological agent or a prodrug of a biological agent
• CYP3A4 is expressed in the liver in a level much higher than other tissues (DeWaziers et al. J Pharrn Exp Ther 253:387 (5990)).
• Prodrug compounds of Formula I- VII are predominantly activated via CYP3A4 in the liver.
• the prodrug compounds of Formulae I- VII have high efficiency in liver-targeting via selective delivery of biologically active agents to the liver.
• the prodrugs are used to may not be active or may be less active outside the liver.
• Certain drugs of phosph(on)ate derivatives are highly charged compounds that have generally poor oral bioavailability due to poor absorption in the gastrointestinal tract.
• Certain dings are highly lipophilic compounds that have generally poor oral bioavailability due to poor absorption in the gastrointestinal tract.
• the prodrug compounds of Formulae I-VII have oral bioavailability superior to the parent drags/agents.
• the compounds are used to treat diseases that benefit from enhanced drag distribution to the liver and like tissues and cells, including but not limited to diseases in the liver, such as hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, other viral and parasitic infections, and metabolic, cardiovascular, and/or hormonal diseases where the liver is involved in the production and/or the homeostasis control of the biochemical end products, e.g.
• glucose diabetes: cholesterol, fatty acids, bile acids, triglycerides (hyperlipidemia) (atherosclerosis) (obesity), lipoproteins, apolipoproteins, and sex hormone- binding globulin (SHBG).
• the disclosed prodrugs are used to prolong pharmacodynamic half-life of the drug.
• the disclosed prodrug methodology can be used to achieve sustained delivery of the parent drug.
• a method of making these prodrugs is described.
• the prodrugs are also useful in the delivery of diagnostic imaging agents to the liver or other tissues.
• compositions and methods provided herein include a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier. second or multiple therapeutic agents in combination with a compound provided herein to the subject in need thereof,
• Some embodiments of the compounds, compositions and methods provided herein include a method of treating a liver disease comprising administering an effective amount of a compound provided herein where is a nucleoside antiviral or anticancer agent to a subject in need thereof.
• Some embodiments of the compounds, compositions and methods provided herein include a method of treating dyslipidemia comprising administering an effective amount, of a compound provided herein where M is a lipid modulator such as a HMG-CoA reductase inhibitor, a selective thyroid hormone receptor modulator, peroxisome proiiferator-activated receptor modulator, a fibrate, nicotinic acid, and an omega-3 fatty acid to a subject in need thereof.
• M is a lipid modulator such as a HMG-CoA reductase inhibitor, a selective thyroid hormone receptor modulator, peroxisome proiiferator-activated receptor modulator, a fibrate, nicotinic acid, and an omega-3 fatty acid
• Some embodiments of the compounds, compositions and methods provided herein include a method of treating hyperglycemia comprising administering an effective amount of a compound provided herein where M is a glucose modulator such as peroxisome proiiferator-activated receptor modulator, glucose biosynthesis inhibitor, and dipeptidyi peptidase 4 inhibitor to a subject in need thereof.
• M is a glucose modulator such as peroxisome proiiferator-activated receptor modulator, glucose biosynthesis inhibitor, and dipeptidyi peptidase 4 inhibitor
• Some embodiments of the compounds, compositions and methods provided herein include a method of treating a hormonal condition comprising administering an effective amount of a compound provided herein where M is a nuclear hormone receptor modulator to a subject in need thereof,
• the subject is mammalian.
• the subject is human.
• Some embodiments of the compounds, compositions and methods provided herein include a method of testing a compound in a cell comprising contacting the cell with the compound of the claims,
• the cell is in vivo.
• the cell is ex vivo.
• the cell is a hepatocyte. [0322] In some embodiments, the cell is human,
• Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a disease in the liver.
• Some embodiments include the use of a compound provided herein in combination with additional therapeutic agent(s) for the treatment of a disease in the liver.
• Some embodiments of the compounds, compositions and methods provided herein include use of a compound provided herein in the treatment of a disease or condition by intervening in a molecular pathway in the liver.
• Some embodiments include the use of a compound provided herein in combination with additional therapeutic agent(s) for the treatment of a disease or condition by intervening in a molecular pathway in the liver.
• ranges and amounts can be expressed as “about” a particular value or range. “About,” also includes the exact amount. Hence “about 10%” means “about 10%” and also “10%.”
• compositions comprising "a therapeutic agent” includes compositions with one or a plurality of therapeutic agents.
• alkyl refers to saturated aliphatic groups including straight- chain, branched chain and cyclic groups, up to and including 50 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, and cyclopropyl. The alkyl group may be optionally substituted with 1 -3 substituents.
• the term "optionally substituted” or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halogen, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylammoaryl, lower alkylajyl, lower alkylaminoalkyl, lower alkoxvaryl, lower arylamino, lower aralkylamino, lower alkylsulfonyl, lower carboxamidoalkylaryl,
• Substituted aryl and “substituted heteroaryl” refers to aryl and heteroaryl groups substituted with 1-6 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halogen, hydroxy, cyano, and amino.
• heteroalkyl refers to alkyl groups containing at least one heteroatom, such as 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen.
• heteroacyl refer to -C(0)-heteroalkyl groups.
• acyloxy refers to -OC(0)R where R is alkyl, or heteroalkyl. heteroalkyl, all optionally substituted.
• oxo derivative refers to :::: NR where R is H, lower alkyl, lower alkoxyl, or lower alkyiamino.
• amino refers to NRR' where R and R' are each independently selected from hydrogen, alkyl, aryi, aralkyl and heterocycloalkvl, all except H are optionally substituted; and R and R' can form a cyclic ring system.
• 'acylammo refers to -NRC(0)R' where R and R' are each independently selected from H, alkyl, or heteroalkyl.
• halogen or "halo” refers to F, CI, Br and I.
• haloalkyl refer to alkyl groups containing at least one halogen, in a further aspect are 1 to 3 haloatoms. Suitable haloatoms include F, CI, and Br.
• haloheteroalkyl refer to alkyl groups containing at least one halogen and one heteroatom.
• haloacyi refer to -C(0)-haloalkyl groups.
• haloheteroacyl refer to -C(0)-haloheteroalkyl groups.
• alkenyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon carbon double bond and includes straight chain, branched chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include aliyl.
• alkynyi refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon carbon triple bond and includes straight chain, branched chain and cyclic groups. Alkynyi groups may be optionally substituted. Suitable alkynyi groups include ethynyl.
• alkylthio refers to the group alkyl-S-.
• amido refers to the NR.2 group next, to an acyl or sulfonyl group as in N R ⁇ ( ' (( ) ⁇ . RC(0)N R-. N R >S( ( ) ) ⁇ and RS-; G) -- ⁇ R-. where R includes 1 1, alkyl, aryl, aralkyl, and heterocycloalkyl.
• perhalo refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include CF 3 and CFC1 2 .
• aryl refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom.
• Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
• Aryl groups may be optionally substituted. Examples of aryl. groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetraiinyl, fraorenyl, indenyl, and indanyl.
• heteroaryl refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted . Examples of heteroaryl groups include, but are not limited to, aromatic C 3-8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms.
• heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cya.no, nitro, alkylamido, acyl, Ci-6-alkoxy, Ci-e-alkyl, Ci-e-hydroxyalkyl, Ci.. 6-aminoalkyl, Ci-6-alkylamino, alkylsulfenyl, alkyisulfinyl, alkylsulfonyi, suifamoyi, or trifluoromethyl.
• substituents independently selected from halo, hydroxy, amino, cya.no, nitro, alkylamido, acyl, Ci-6-alkoxy, Ci-e-alkyl, Ci-e-hydroxyalkyl, Ci.. 6-aminoalkyl, Ci-6-alkylamino, alkylsulfenyl, alkyisulfinyl, alkylsulfonyi, suifamoyi
• heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyriniidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1 ,2,3- benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline.
• the substituents are halo, hydroxy, cyano, O-Ci-g
• aryloxy refers to -O-aryl.
• heteroaryloxy refers to -O-heteroaryl
• terapéuticaally effective amount means an amount of a compound or a combination of compounds that, partially or fully ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition. Such amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective. Repeated administration may be needed to achieve a desired result (e.g., treatment of the disease and/or condition).
• salts of compounds of Formulae I- VII and its prodrugs derived from the combination of a compound of the present embodiments and an organic or inorganic acid or base include acetic acid, adipic acid, benzenesulfonic acid, (+)-7,7-dimethyI-2-oxobicyclo [2.2.1 jheptane- 1 - methanesulfonic acid, citric acid, 1 ,2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemietlianolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, methylbromide acid, methyl sulfuric acid, 2- na
• Suitable bases include NaOH, OH, Ca(OH) 2 , Zn(OH) 2 , Mg(OH) 2 , diethylamine, ethanoiamine, diethanoiamine, choline, lysine, meglumine, benzathine, and tromethamine.
• spacer refers to an atom or group of atoms that separate two or more groups from one another by a desired number of atoms. For example, in some embodiments, it may be desirable to separate two or more groups by one, two, three, four, used to separate those groups by the desired number of atoms. Spacers are optionally substituted. In some embodiments, a spacer comprises saturated or unsaturated alkyls, heteroalkyls and/or haloalkyls. In some embodiments, a spacer comprises atoms that are part of a ring.
• haloalkyl e.g., "haloalkyl”
• substituents there may he one or more substituents present.
• haloaLkyl can include one or more of the same or different halogens.
• ' haloalkyl includes each of the substituents CF 3 , CHF 2 and CFI?F.
• spacers are provided.
• 2 atom spacers include, but are not limit to, the following:
• a and B represent groups which are separated by the desired number of atoms.
• 3 atom spacers examples include, but are not limited to, the following:
• the term "patient” refers to an animal being treated including a mammal, such as a dog, a cat, a cow, a horse, a sheep, and a human.
• the patient is a mammal, either male or female.
• the patient is a male or female human.
• administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each.
• Standard prodrugs are formed using groups attached to functionality, e.g. HO-, HS-, HOOC-, HOOPR 2 -, associated with the drug, that cleave in vivo.
• Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
• the groups illustrated are examples, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs.
• Such prodrugs of the compounds of Formula I fall within this scope.
• Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound.
• the prodrug is biologically active, usually less than the drag itself, and serves to improve drag efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, etc.
• Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site specific delivery of the compound.
• stereoisomer refers to the relative or absolute spatial relationship of the R group(s) and the substituent attached to the phosphorus atom via an exocyclic single bond on the 2-oxo-phosphorus prodrug ring, and refers to individual or any combination of the individual isomers such as a racemic mixture and a diastereomeric mixture.
• R group is attached to the carbon atom in the ring
• stereoisomers there are four stereoisomers.
• the structures A, B, C, and D below show four possible individual isomers. Structures A and D (or B and C) are a pair of two enantiomers (or called optical isomers).
• two R groups attached to two different carbon atoms in the ring there are eight possible stereoisomers.
• liver refers to the liver organ
• liver specificity refers to the ratio:
• the ratio can be determined by measuring tissue levels at a specific time or may represent an AUC (area under a curve) based on values measured at three or more time points.
• liver specificity refers to an increase in liver specificity ratio in animals treated with the prodrug relative to animals treated with the parent drug.
• Compounds disclosed in US Patent No. 8,063,025, US Patent No. 7,666,855, and PCT Pub. No. WO2009/073506, are designed for the liver-specific delivery of nucleosides for the treatment of FICV patients and take advantage of a cytochrome P450 enzyme that is mainly expressed in the liver,
• the term "enhanced oral bioavailability" refers to an increase of at least, about 50% of the absorption of the close of the parent drag. In an additional aspect, the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least about 100%, or a doubling of the absorption. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following parenteral administration .
• therapeutic index refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response relative to the close that produces an undesired response such as death, an elevation of markers that are indicative of toxicity, and/or pharmacological side effects. there is a prolongation of therapeuticaily-effective drug levels due to the presence of the prodrug,
• treating includes inhibiting the disease (slowing or arresting or partially arresting its development), providing relief from the symptoms or side effects of the disease (including palliative treatment), and/or relieving the disease (causing regression of the disease).
• biological agent refers to a compound that has biological activity or that has molecular properties that can be used for diagnosis purpose, such as a compound carrying a radioactive isotope or a heavy atom.
• molecular pathway refers to a series of molecular events in tissues such as a receptor modulating sequence or a biosynthesis sequence that is involved in physiological or pathophysiological functions of a living animal .
• vinyl ketone reactive intermediate refers to compounds of the structure below that are chemically reactive to generate a covalent bond with a molecular entity in the tissues or cell, where R is H, alk l, aryl, or heteroaryl.
• the disclosed compounds may be used alone or in combination with other treatments. These compounds, when used in combination with other agents, may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). The compounds may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy by another agent in a treatment program.
• Examples of pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydro bromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, niethylbromide, methylsulfate, napsylate, nitrate, tannate, tartrate, terphthalate, tosylate, triethiodide, sodium, potassium, calcium, zinc, magnesium, diethyl amine, ethanolamine, diethanol amine, cholinate, lysine, meglumine, benzathine, and tromethamine.
• compositions containing the active ingredient may be in any form suitable for the intended method of administration.
• the compounds of a method and/or composition described herein can be provided via oral administration, rectal administration, transmucosal administration, intestinal administration, enteral administration, topical administration, transdermal administration, intrathecal administration, intraventricular administration, intraperitoneal administration, intranasal administration, intraocular administration and/or parenteral administration.
• compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
• excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay materia] such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
• inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
• granulating and disintegrating agents such as maize starch, or alginic acid
• binding agents such as starch
• Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient can be mixed with an inert solid diluent, for example calcium with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example calcium with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
• Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain, for example, antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the formulations may be presented in unit- dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• unit dosage formulations contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drag. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drags which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
• the following procedures for the preparation of the cyclic prodrug compounds illustrate the general procedures used to prepare the compounds which apply to phosphate, phosphonate, phosphoramidate, carboxylic acid, and alcohol containing drugs.
• Prodrugs can be introduced at different stages of synthesis of a drug. In some embodiments, they are made at a later stage, because of the general sensitivity of these groups to various reaction conditions.
• Optically pure prodrugs containing a single isomer at the phosphorus center can be made, for example, by separation of the diastereomers by a combination of column chromatography and/or erytallyzation, or by enantioselective synthesis of chiral activated phosph(on)ate intermediates.
• the first strategy starts with treatment of a dihydroxyl compound of structure 1 where Z is not a heteroatom with phosphorus oxychloride to generate a cyclic phosphate of structure 2.
• a coupling reaction of a cyclic phosphate chloride of structure 2 with an alcohol derivative compound of structure 3 provides the final compound of structure 4.
• Z is a heteroatom
• an alternative strategy can be used where the alcohol compound of structure 3 is converted to its monophosphate of structure 5 via a two-step sequence of phosphorylation with phosphoras oxychloride and acid hydrolysis by a resin.
• the monophosphate of structure 5 is then treated with a diehloro compound of structure 6 in the presence of silver nitrate to give the final product of structure 4.
• Scheme II describes general strategies of synthesis of cyclic phosphor am idate or phosphonamidate prodrug compounds of Formula I, Treatment of the hydroxylamino compounds of structure 7 (where Z is not a heteroatom) with phosphorus oxychloride provides the cyclic phosphoramidate of structure 8.
• a biological agent having a hydroxyl group of structure 3 is coupled with a prodrug intermediate of structure 8 to yield the final product of structure 9,
• a chloroamino compound of structure 10 (where Z is a heteroatom) is treated with phosphoras oxychloride and then an ion-exchange resin sequentially to give the intermediate of structure 1 1 that undergoes an internal cvclization followed by chlorination to the cyclic phosphoramidate of structure 8,
• Scheme III describes general synthetic procedures of the 2- oxodioxazaphiiiine prodrugs of Formula I
• a biological agent derivative of structure 12 is treated with phosphorus oxychloride to provide an intermediate of structure 13 that is then treated with a base in the presence of an aldehyde of structure 14 to give final product of structure 15,
• the regioisomers of structure 15 are made from a different route where a compound of structure 16 is treated sequentially with diphenyl phosphate under basic a condition to give an intermediate of structure 17.
• Base mediated internal cyclization of the intermediate of structure 17 affords the final product of structure 18.
• Formula Ka Benzaldehyde derivative of structure 19 is treated with phosphorus oxychlo ide to provide an intermediate of structure 20 that is then converted to structure 21 in the presence of a acid chloride derivative of a biologic agent with zinc chloride as the catalyst. Deprotection followed by treatment of a base affords the final product, of structure 22.
• Scheme V describes a procedure for preparing cyclic bisphosphonate prodrug compounds of Formula III via either an acid catalyzed condensation or a base catalyzed alkylation routes.
• Condensation reaction of a bisphosphonate of structure 23 with an aldehyde of structure 24 in the presence of an acid catalyst affords a product of structure 25.
• alkylation of a bisphosphonate of structure 23 with a halide compound of structure 26 in the presence of silver nitrate and/or a base provides the same product of structure 25.
• Scheme VI describes general strategies of synthesis of the cyclic acetal prodrug compounds of Formula IV.
• the dihydroxyl compound of structure 1 is condensed of structure 3.
• Aldehyde compound of structure 2 is prepared from the corresponding earboxy!ic acid by the standard procedure in the literature.
• Compounds 120 and 121 were prepared as a mixture of stereoisomers from oleic acid, nicotinaldehyde, and glycerol. Briefly, nicotinaldehyde was condensed with glycerol in the presence of an acid catalyst to afford a mixture of 5-member-ring and 6- member-ring acetals that were treated with oleic chloride to form the corresponding ester Compounds 120 and 121.
• i V! - l l j calcd for C27H43NO4: 446.32; found: 446.4.
• Compound 122 was prepared from oleic acid, 2,2-dimethylpropane- l ,3- diol, and phosphorus oxychloride. Briefly, 2,2-dimethylpropane- 1 ,3-diol was treated with phosphorus oxychloride to form the corresponding cyclic chlorophosphate that was then reacted with oleic amide to provide Compound 122. [M+H] " calcd for C23H44NO4P: 430.30; found: 430.6. ⁇ NMR (400V! Hz. CD 3 OD) 5.35 (bs, 2H), 4.40 (d, ,/ 10, 21 1 ; ⁇ . 4.01 (dd, ./ 7,2, 3H),
• Compound 123 was prepared as a mixture of stereoisomers from oleic acid, 2,2-dimethyl-l -phenylpropane-l ,3-diol, and phosphorus oxychloride in a reaction sequence same as that of Compound 122. [M+H] + calcd for C29H48NO4P: 50(5.33; found: 506.4.
• Compound 124 was prepared as a mixture of stereoisomers from oleic acid, 2,2-dimethyl-l-phenylpropa.ne- l ,3-diol, and phosphorus oxychloride. Briefly, oleic acid was converted to the acid chloride with treatment of oxalyl chloride in dichloromethane and then the oleic chloride was treated with paraldehyde and zinc chloride in acetonitrile at 60-65 °C to give 1 -chloroethyl oleate.
• Example A In Vitro Activation of Prodrug Analogues by Rat Liver Microsomes. Quantification by LC-MS/MS
• Prodrug compounds are tested for activation by liver microsomes isolated from rats induced with dexamethasone to enhance CYP3A4 activity. Reactions are conducted in 0.1 M KH 2 P0 4 , pH 7.4, in the presence of 2 mM NADPH and liver microsomes (1 nig/mL). Reaction mixtures are incubated for 5 min. in an Eppendorf Thermomixer 5436 (37 °C, speed 6). Reactions are terminated by the addition of 1.5 volumes of methanol. The resulting extracts are clarified by centrifugation at 14,000 rpm in an Eppendorf micro fuge (20 min.). The supernatants (200 ⁇ ..) are evaporated under vacuum and heat to dryness.
• the dried residue is reconstituted with 200 iL of water and the mixture is centrifuged for 10 min at 14,000 rpm, A mixture of 35 ⁇ aliquot of supernatant and 35 uL of mobile phase A is analyzed by LC-MS/MS.
• the active compound is detected by using MS/MS mode and quantified based on comparison to a standard active compound.
• Example B Active compound Accumulation in Hepatocytes Followingin Incubation with
• Prodrug compounds compounds in freshly isolated rat hepatocytes are produced by the following methods: (1) prodrug compounds in freshly isolated rat hepatocytes.
• Hepatocytes are prepared from fed Sprague-Dawley rats (250-300g) according to the procedure of Berry and Friend (Berry, M.N. Friend, D.S., J. Cell Biol. 43:506-520 (1969)) as modified by Groen (Groen, A. . et al., Eur. J. Biochem 122:87-93 (1982)).
• Hepatocytes (20 nig/niL wet weight, >85% trypan blue viability) are incubated at 37 °C in 2 rnL of Krebs-bicarbonate buffer containing 20 mM glucose, and 5 mg/rnL BSA for 2 h in the presence of 1-250 ⁇ a prodrug compound (from 25 mM stock solutions in DMSO). Following the incubation, 1600 fiL aliquot of the cell suspension is centrifuged and 300 ⁇ . of acetonitrile is added to the pellet, vortexed and sonicated until the pellet broke down. Then 200 ⁇ , of water is added to make a 60% acetonitrile solution.
• Example C Tissue Distribution Vol lowing Oral Administration of acts ye compounds and their Prodrugs
• liver specificity of prodrugs is compared relative to their parent active compound in liver and other organs that could be targets of toxicity.
• Nucleoside analogues and their prodrugs are administered at 5-20 mg/kg to fasted rats by oral gavage.
• Plasma and portal vein concentrations of the active and prodrug are determined by HPLC-UV, and the liver, skeletal muscle, cardiac, kidney, small intestine, and other organ concentrations are measured by LC-MS using the standard chromatography method. The results demonstrate the liver targeting of the prodrug compounds and provide by the liver targeting provided by the prodrug.
• the terms “generally parallel” and “substantially parallel” refer to a value, amount, or characteristic that departs from exactly parallel by less than or equal to 15°, 10°, 5°, 3°, 1°, 0.1 °, or otherwise.
• the terms “generally perpendicular” and “substantially perpendicular” refer to a value, amount, or characteristic that departs from exactly perpendicular by less than or equal to 15°, 10°, 5°, 3°, 1°, 0.1 °, or otherwise.

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