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 The leading web portal for pharmacy resources, news, education and careers March 28, 2017
Pharmacy Choice - Pharmaceutical News - "Prodrug Compounds and Their Uses" in Patent Application Approval Process (USPTO 20170056429) - March 28, 2017

Pharmacy News Article

 3/20/17 - "Prodrug Compounds and Their Uses" in Patent Application Approval Process (USPTO 20170056429)

By a News Reporter-Staff News Editor at Diabetes Week A patent application by the inventor Zhi, Lin (San Diego, CA), filed on February 11, 2015, was made available online on March 9, 2017, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also Pharmaceutical Companies).

This patent application is assigned to Ligand Pharmaceutical, Inc.

The following quote was obtained by the news editors from the background information supplied by the inventors: "The following description of the background is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art,

"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) are designed by tissue selective activation or deactivation to achieve therapeutic advantages (See J. Rautio, et al. Nature Reviews Drug Discovery 7:255-270 (2008)).

"Certain cyclic phosphate, phosphonate, phosphonamidate, and phosphoramidate prodrugs are disclosed in U.S. Pat. No. 6,312,662 and U.S. Pat. No. 7,205,404 and designed for liver-targeting of pharmacological agents. These prodrugs are activated by liver cytochrome P450 enzymes CYP3As that are predominantly expressed in 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 toxicological 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, et al. J Pharm Exp Ther 312:554-60 (2005)). Example activation of these cyclic phosph(on)ate and phosphoramidate compounds are illustrated below:

"##STR00001##

"In the above example, the cyclic prodrugs (X=O or N) are oxidized by Cyp3A in the liver and undergo a ring opening and .beta.-elimination 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 by-product.

"Certain oral available pharmaceutical agents have been described to have certain liver-targeted property (e.g. see X. J. Zhou, et al. 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."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventor's summary information for this patent application: "Novel prodrug compounds of acid/alcohol derivatives such as phosphates, phosphonates, phosphonamidates, phosphoramidates, carboxylates, phenolates, and alkoxylates, 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 cells, 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. glucose, cholesterol, fatty acids, bile acids, triglycerides, lipoproteins, apolipoproteins, and sex hormone-binding globulin (SHBG). Examples of such diseases include diabetes, hyperlipidemia, atherosclerosis, obesity and the like. In another aspect, prodrugs are used to prolong pharmacodynamic half-life of a drug. In some embodiments, the prodrug methodology can be used to achieve sustained delivery of the parent drug. In another aspect, prodrugs are used to increase the therapeutic index of the drug. In some embodiments, the prodrugs are useful in the delivery of diagnostic imaging agents to the liver. Some additional embodiments relate to a method of making prodrugs.

"Some embodiments relate to a compound of Formula I:

"##STR00002##

"wherein:

"R.sup.1 and R.sup.2 are each independently selected from the group consisting of H, M, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 acyloxy, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.3 is selected from the group consisting of H and an optionally substituted C.sub.1-C.sub.6 alkyl; or R.sup.3 optionally forms an optionally substituted ring with R.sup.2; or R.sup.3 together with R.sup.2 form a methylene or its derivative; or R.sup.3 together with R.sup.2 form an oxo (.dbd.O) or its derivative; or R.sup.3 optionally forms a bond with Z or Y' when Z or Y' is N;

"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 Cl, OR.sup.4, NR.sup.4R.sup.5, an optionally substituted C.sub.1-C.sub.6 alkyl, and M;

"Y and Y' are each independently O or NR.sup.4; or Y' is CH.sub.2 or null;

"Z is selected from the group consisting of O, NR.sup.5, CR.sup.8R.sup.6, C.dbd.O, C.dbd.NR.sup.7, and null; or Z is a 2-5 atom spacer selected from an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.4 is selected from the group of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"R.sup.5 is selected from the group consisting of H, M, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, and an optionally substituted C.sub.1-C.sub.6 acyl;

"R.sup.6 is selected from the group consisting of F, Cl, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl, or R.sup.6 is H provided that R.sup.1 or R.sup.2 or R.sup.8 is connected to a cyclic core carbon atom through an oxygen-carbon (OC) bond;

"R.sup.7 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"R.sup.8 is selected from the group consisting of F, Cl, M, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl; or R.sup.8 is H provided that R.sup.1 or R.sup.2 is connected to a cyclic core carbon atom through an oxygen-carbon (OC) bond;

"provided that at least one of R.sup.1, R.sup.2, R.sup.5, R.sup.8 and X is M;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"In some embodiments, the compound is a compound of Formula Ia:

"##STR00003##

"wherein;

"R.sup.1 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.2 and R.sup.3 are each independently selected from the group consisting of H and an optionally substituted C.sub.1-C.sub.6 alkyl; or R.sup.2 and R.sup.3 optionally form an optionally substituted ring; or R.sup.2 and R.sup.3 optionally form a methylene or its derivative; or R.sup.2 and R.sup.3 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.sup.4; or Y' is CH.sub.2;

"Z is selected from the group consisting of O, NR.sup.5, CR.sup.8R.sup.6, C.dbd.O, C.dbd.NR.sup.7, and null; or Z is a 2-5 atom spacer selected from an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.4 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"R.sup.5 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, and an optionally substituted C.sub.1-C.sub.6 acyl;

"R.sup.6 is selected from the group consisting of F, Cl, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl; or R.sup.6 is H provided that R.sup.1 or R.sup.2 or R.sup.8 is connected with the cyclic core carbon atom through an oxygen-carbon (OC) bond;

"R.sup.7 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"R.sup.8 is selected from the group consisting of F, Cl, M, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl; or R.sup.8 is H provided that R.sup.1 or R.sup.2 is connected to a cyclic core carbon atom through an oxygen-carbon (OC) bond;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"In some embodiments, the compound is a compound of Formula Ib:

"##STR00004##

"wherein:

"R.sup.2 and R.sup.3 are independently selected from the group consisting of H and an optionally substituted C.sub.1-C.sub.6 alkyl; or R.sup.2 and R.sup.3 optionally form an optionally substituted ring; or R.sup.2 and R.sup.3 optionally form a methylene or its derivative; or R.sup.2 and R.sup.3 optionally form an oxo (.dbd.O) 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 Cl, an optionally substituted C.sub.1-C.sub.6 alkyl, NR.sup.4R.sup.5, and OR.sup.4;

"Y and Y' are each independently O or NR.sup.4; or Y' is CH.sub.2 or null;

"Z is selected from the group consisting of O, NR.sup.5, C(R.sup.6).sub.2, C.dbd.O, C.dbd.NR.sup.7, and null; or Z is a 2-5 atom spacer selected from an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.4 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"R.sup.5 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, and an optionally substituted C.sub.1-C.sub.6 acyl;

"R.sup.6 is selected from the group consisting of F, Cl, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl; or R.sup.6 is H provided that M or R.sup.2 is connected with the cyclic core carbon atom through an oxygen-carbon (OC) bond;

"R.sup.7 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"In some embodiments, the compound is a compound of Formula Ic:

"##STR00005##

"wherein:

"R.sup.1 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.3 is selected from the group consisting of H and an optionally substituted C.sub.1-C.sub.6 alkyl; or R.sup.3 together with M form a methnylene derivative; or R.sup.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 Cl, OR.sup.4, NR.sup.4R.sup.5, and an optionally substituted C.sub.1-C.sub.6 alkyl;

"Y and Y' are each independently O or NR.sup.4;

"Z is selected from the group consisting of O, NR.sup.5, C(R.sup.6).sub.2, C.dbd.O, C.dbd.NR.sup.7, and null; or Z is a 2-5 atom spacer selected from an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.4 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl:

"R.sup.5 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, and an optionally substituted C.sub.1-C.sub.6 acyl;

"R.sup.6 is selected from the group consisting of F, Cl, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl; or R.sup.6 is H provided that R.sup.1 or M is connected with the cyclic core carbon atom through an oxygen-carbon (OC) bond;

"R.sup.7 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"In some embodiments, the compound is a compound of Formula Id or Ie:

"##STR00006##

"wherein:

"R.sup.2 and R.sup.3 are independently selected from the group consisting of H and an optionally substituted C.sub.1-C.sub.6 alkyl; or R.sup.3 together with M or R.sup.2 form a methylene derivative; or R.sup.3 together with M or R.sup.2 form an optionally substituted ring; or R.sup.3 together with R.sup.2 form an oxo (.dbd.O) or its derivative; or R.sup.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 Cl, OR.sup.4, and an optionally substituted C.sub.2-C.sub.6 alkyl;

"Y and Y' are each independently O or N; or Y' is CH.sub.2;

"Z is selected from the group consisting of O and NR;

"R.sup.4 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"R.sup.5 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, and an optionally substituted C.sub.1-C.sub.6 acyl;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"Some embodiments relate to a compound of Formula II:

"##STR00007##

"wherein:

"R.sup.21 is selected from the group consisting of H, M, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 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.sup.2 is selected from the group consisting of Cl, OR.sup.24, N(R.sup.24).sub.2 an optionally substituted C.sub.2-C.sub.6 alkyl, and M;

"X'.sup.2 is selected from the group consisting of Cl, N(R.sup.24).sub.2, and OR.sup.24;

"Y.sup.2 and Y'.sup.2 are each independently O or NR.sup.24;

"R.sup.24 is selected from the group of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"provided that at least one of R.sup.21 and X.sup.2 is M;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"Some embodiments relate to a compound of Formula III:

"##STR00008##

"wherein:

"R.sup.31 is H; or R.sup.31 optionally forms a bond with M or X.sup.3 when X.sup.3 is N:

"R.sup.32 and R.sup.33 are each independently selected from the group consisting of Cl, OH, NH.sub.2, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, and an optionally substituted C.sub.1-C.sub.6 alkylamino;

"M is a biological agent or part of a biological agent or a prodrug of a biological agent;

"X.sup.3 is O or NR.sup.34;

"Y.sup.3 is selected from the group consisting of O, N.sup.34, and an optionally substituted C.sub.1-C.sub.6 alkyl;

"R.sup.34 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"Some embodiments relate to a compound of Formula IV:

"##STR00009##

"wherein:

"R.sup.41 is H; or R.sup.41 optionally forms a bond with M or X.sup.4 when X.sup.4 is N:

"Z.sup.4 is selected from the group consisting of CR.sup.46R.sup.47, C(O), C(O)O, C(O)NR.sup.48 , SO.sub.2, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.42, R.sup.43, R.sup.44, R.sup.45, R.sup.46, and R.sup.47 are each independently selected from the group consisting of H, OH, amino, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 acyloxy, an optionally substituted C.sub.1-C.sub.6 hereroalkyl, an optionally substituted phosphate, an optionally substituted phosphonate, an optionally substituted aryl, and an optionally substituted heterocycle; or R.sup.44 and R.sup.45 are independently or together optionally linked with R.sup.42, R.sup.43, R.sup.46, or R.sup.47 to form an optionally substituted ring; or R.sup.44 is optionally M; or R.sup.44 and R.sup.45 are together optionally to form an oxo (.dbd.O) or its derivative;

"M is a biological agent or part o: a biological agent or a prodrug of a biological agent;

"X.sup.4 is selected from the group consisting of O, NR.sup.48, NC(O)R.sup.48, NS(O).sub.2R.sup.49, and NP(O)(R.sup.50).sub.2;

"R.sup.48 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"R.sup.49 is selected from the group consisting of NH.sub.2, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.50 is selected from the group consisting of OH, NH.sub.2, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, and an optionally substituted C.sub.1-C.sub.6 alkylamino;

"n is 0, 1,2, or 3;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"Some embodiments relate to a compound of Formula V:

"##STR00010##

"wherein:

"R.sup.51 and R.sup.52 are each independently selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 acyloxy, an optionally substituted C.sub.1-C.sub.6 acylamino, an optionally substituted phosphate, an optionally substituted phosphonate, an optionally substituted phosphoramidate, an optionally substituted C.sub.1-C.sub.6 aryl, and an optionally substituted heteroaryl; or R.sup.51 and R.sup.52 are together optionally to form an oxo (.dbd.O) or its derivative;

"R.sup.53 and R.sup.54 are each independently selected from the group consisting of Cl, OH, NH.sub.2, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 alkylamino, an optionally substituted C.sub.1-C.sub.6 acylamino, an optionally substituted aryloxy, an optionally substituted phosphate, an optionally substituted phosphonate, and an optionally substituted heteroaryloxy; or R.sup.53 is optionally linked with R.sup.51, R.sup.54, or R.sup.56 to form an optionally substituted 5-, 6-, or 7-membered heterocycle:

"R.sup.55 is selected from the group consisting of OH, NH.sub.2, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 alkylamino, an optionally substituted aryl, and an optionally substituted heteroaryl; or R.sup.55 is optionally linked to R.sup.51 or R.sup.56 to form an optionally substituted ring;

"R.sup.56 is selected from the group consisting of H, a C.sub.1-C.sub.6 alkyl, and a C.sub.1-C.sub.6 heteroalkyl;

"M is a biological agent or part of a biological agent or a prodrug of a biological agent:

"X.sup.5 is O or NR.sup.56;

"n is 0, 1, 2, or 3;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"Some embodiments relate to a compound of Formula VI:

"##STR00011##

"wherein:

"R.sup.61 and R.sup.62 are each independently selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 alkylamino, an optionally substituted C.sub.1-C.sub.6 acyloxy, OCH.sub.2P(O)(R.sup.69).sub.2, and an optionally substituted C.sub.1-C.sub.6 acylamino; or R.sup.61 and R.sup.62 together optionally form an oxo (=O) or its derivative;

"R.sup.63, R.sup.64, and R.sup.65 are each independently selected from the group consisting of H, CO.sub.2R.sup.67, C(O)N(R.sup.67).sub.2, P(O)(R.sup.69).sub.2, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 acyloxy, and an optionally substituted C.sub.1-C.sub.6 hereroalkyl; or two of R.sup.63, R.sup.64, and R.sup.65 are optionally linked to form an optionally substituted ring; or R.sup.63 is optionally linked with R.sup.68 to form an optionally substituted ring; with the proviso that CR.sup.63R.sup.64R.sup.65 is not a straight chain C.sub.1-C.sub.4 alkyl when R.sup.61 and R.sup.62 form an oxo (.dbd.O);

"R.sup.66 is selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

"R.sup.67 and R.sup.68 are each independently selected from the group consisting of H, an optionally substituted C.sub.1-C.sub.6 alkyl, and an optionally substituted C.sub.1-C.sub.6 heteroalkyl;

"R.sup.69 is selected from the group consisting of OH, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, and an optionally substituted C.sub.1-C.sub.6 alkylamino;

"M is a biological agent or part of a biological agent or a prodrug of a biological agent;

"X.sup.6 is O or NR.sup.68;

"Y.sup.6 is selected from the group consisting of null, O, NR.sup.68, and C(R.sup.68).sub.2;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"Some embodiments relate to a compound of Formula VII:

"##STR00012##

"wherein:

"R.sup.71 is selected from the group consisting of H, OH, an optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally substituted C.sub.1-C.sub.6 alkyloxy, an optionally substituted phosphate, and an optionally substituted phosphonate;

"X.sup.7 is O or S;

"Y.sup.7 is N or CR.sup.71;

"M is a biological agent or part of a biological agent or a prodrug of a biological agent;

"or a stereoisomer or a pharmaceutically acceptable salt thereof.

"In some embodiments, the compound is selected from the group consisting of:

"##STR00013## ##STR00014##

"and a stereoisomer or a pharmaceutically acceptable salt thereof.

"In some embodiments, M is a nucleoside antiviral or anticancer agent.

"In some embodiments, M is a lipid modulator.

"In some embodiments, 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.

"In some embodiments, M is a glucose modulator.

"In some embodiments. M is selected from the group consisting of a peroxisome proliferator-activated receptor modulator, a glucose biosynthesis inhibitor, and a dipeptidyl peptidase 4 inhibitor.

"In some embodiments, M is a nuclear hormone receptor modulator.

"Some embodiments relate to a pharmaceutical composition comprising any of the above 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.

"In some embodiments, the disease, disorder or condition is a disease, disorder or condition of the liver.

"In some embodiments, 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.

"In some embodiments, 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.

"In some embodiments, 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.

"Some embodiments relate to method of treating hyperglycemia comprising administering to a subject in need thereof, an effective amount of any of the above compounds, wherein M is a glucose modulator.

"In some embodiments, 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.

"In some embodiments, the subject is a mammal.

"In some embodiments, 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.

"In some embodiments, the cell is in vivo.

"In some embodiments, the cell is ex vivo.

"In some embodiments, the cell is a hepatocyte.

"In some embodiments, the cell is mammalian.

"In some embodiments, the cell is human."

URL and more information on this patent application, see: Zhi, Lin. Prodrug Compounds and Their Uses. Filed February 11, 2015 and posted March 9, 2017. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220170056429%22.PGNR.&OS=DN/20170056429&RS=DN/20170056429

Keywords for this news article include: Ligand Pharmaceutical Inc., Pharmaceutical Companies, Viral, Virus, Anions, Malaria, Prodrugs, Proteins, Hepatitis, Cardiology, Chalcogens, Organelles, Phosphates, Proteomics, Fatty Liver, Microbodies, Biochemicals, Biochemistry, Pharmacology, Therapeutics, Dyslipidemias, Hyperglycemia, Cancer Therapy, Atherosclerosis.

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