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(12) United States Patent (10) Patent No.: US 8,357,723 B2 Satyam (45) Date of Patent: Jan US008357723B2 (12) United States Patent (10) Patent No.: US 8,357,723 B2 Satyam (45) Date of Patent: Jan. 22, 2013 (54) PRODRUGS CONTAINING NOVEL "Nitric Oxide Donors and Cardiovascular Agents Modulating the BO-CLEAVABLE LINKERS Bioactivity of Nitric Oxide: An Overview” by Louis J. Ignarro, et al., Circulation Research, vol. 90, No. 1, pp. 21-22 (Jan. 11, 002). (75) Inventor: Apparao Satyam, Mumbai (IN) “Bis3-(4-substituted phenyl)prop-2-enedisulfides as a new class of (73) Assignee: Piramal Enterprises Limited and antihyperlipidemic compounds' by Meenakshi Sharma, et al., Apparao Satyam, Mumbai (IN) Bioorganic and Medicinal Chemistry Leters, vol. 14, No. 21, pp. (*) Notice: Subject to any disclaimer, the term of this 5347-5350 (Nov. 1, 2004). patent is extended or adjusted under 35 Abstract Only "Spectrophotometric determination of binary mix U.S.C. 154(b) by 0 days. tures of pseudoephedrine with some histamine H1-receptor antago nists using derivative radio spectrum method' by H. Mahgouh, et al., (21) Appl. No.: 12/977,929 J. Pham Biomed Anal, vol. 31, No. 4, pp. 801-809 Mar. 26, 2003. (22) Filed: Dec. 23, 2010 Peter D. Senter et al., Development of Drug-Release Strategy Based (65) Prior Publication Data on the Reductive Fragmentation pf Benzyl Carbamate Disulfides. Journal of Organic Chemistry, 1990, 55, 2975-2978. Published by US 2011 FO269709 A1 Nov. 3, 2011 American Chemical Society (USA). Related U.S. Application Data Vivekananda M. Virudhula et al., Reductively Activated Disulfide Prodrugs of Paclitaxel. Biorganic & Medicinal Chemistry Letters, (62) Division of application No. 1 1/213,396, filed on Aug. 2002, 12, 3591-35-94, Published by Elsvier Sciences LTD. (USA). 26, 2005, now Pat. No. 7,932,294. Samuel Zalipsky et al., New Detachable Poly(ethylene glycol) Con jugates: Cysteinecleavable Lipopolymers Regenerating Natural (60) Provisional application No. 60/604,632, filed on Aug. Phospholipid, Diacyl Phosphatidylethanolamine. Bioconiugate 26, 2004. Chemistry, Published by American Chemical Society (USA). 1999, (30) Foreign Application Priority Data vol. 10, No. 5, pp. 703-707. Kexin Yang et al., Synthesis of novel organic nitrate esters: guanylate Jan. 7, 2005 (IN) ........................... 779/MUM/2005 cyclase activation and tissue relaxation. Journal of Chemical Society, Perkin Transitions 1, 1996, 1073-1075, Publised by Royal Society of (51) Int. Cl. Chemistry (UK). A6 IK3I/O5 (2006.01) Sergei I. Zavorin et al., Nitrate Esters as Nitric Oxide Donors: SS C07C323/2 (2006.01) Nitrates. Organic Letters, 2001.3 (8), 1113-1116. Published by (52) U.S. Cl. .......................................... 514/707:568/22 American Chemical Society (USA). Abstract, Zhdanovich, E.S., et al. Zhumal Obshchei Khimi (1967), (58) Field of Classification Search .................. 514/707; 37(2), 361-3. 568/22 Abstract, Oiry, Joel, et al. “Centre National de la Recherche See application file for complete search history. Scientifique, Fr.” Fr. Demande (1983) (FR 2528042). Abstract, Joel, et al. “Centre National de la Recherche Scientifique, (56) References Cited Fr” Eur, Patent Applin. 131500 (1885) 64 pp. Abstract, Barcelo, Gerard, et al. (Soceite Nationale des Pourdes et U.S. PATENT DOCUMENTS Explosifs, Fr. Fr. Demande (1987), FR 25898.60. 5,767,134 A 6, 1998 Li et al. Abstract, Davidovich, Yu, et al. Izvestiya Akademii Nauk SSSR, 5,807,847 A 9, 1998 Thatcher et al. Seriya Khimicheskaya (1989), (8), 1918-20. 5,883,122 A 3, 1999 Thatcher et al. Abstract, Vecsei, Laszlo, et al. Progress in Neuro-Psychopharmacol 6,369,071 B1 4/2002 Haj-Yehia ogy & Biological Psychiatry (1990), 14(6),835-62. 6,566,509 B1 5, 2003 Griffin et al. Abstract, Guetschow, Michael, et al. DD 293807 (Ger. (East)) (1991). 2003/0044845 A1 3/2003 Jenkins et al. Abstract, Oiry, J. et al. European Journal of Medicinal Chemistry 2004/O147598 A1 7/2004 Haj-Yehia (1992), 27(8), 809-17. 2005.0002942 A1 1/2005 Vlahov et al. Abstract, Thoene, Jess G. et al. WO9306832 1993. FOREIGN PATENT DOCUMENTS Smith et al. “Urethans of 2-Mercaptoethanol” Journal of the Ameri can Chemical Society, 1959, vol. 81, pp. 161-163. EP O317956 5, 1989 WO 97,46521 12/1997 WO 98.42661 10, 1998 * cited by examiner WO 99.58152 11, 1999 WO OO,54756 9, 2000 Primary Examiner — Joseph Kosack WO OO64483 11, 2000 (74) Attorney, Agent, or Firm — Ladas & Parry LLP WO O1? 13957 3, 2001 WO O1/49275 A2 T 2001 (57) ABSTRACT WO O3,000643 A1 1, 2003 WO 03/040 104 5, 2003 The invention provides the compounds of formula (I) or phar WO 2004/004648 A2 1, 2004 maceutically acceptable salts thereof. The invention also pro WO 2004/O12659 A2 2, 2004 WO 2004/O39771 5, 2004 vides pharmaceutical compositions comprising one or more WO 2004/0691.59 8, 2004 compounds of formula I or intermediates thereof and one WO 2004f1 10432 A1 12/2004 more of pharmaceutically acceptable carriers, vehicles or WO 2005/030 135 A2 4/2005 diluents. The invention further provides methods of prepara tion and methods of use of prodrugs including NO-releasing OTHER PUBLICATIONS prodrugs, double prodrugs and mutual prodrugs comprising Lartia et al. “New reagent for the preparation of oligonucleotides the compounds of formula I. involving a 5'-thiophosphate or a 5'-phosphate group” Tetrahedron Letters, 2004, pp. 5949-5952.* 16 Claims, 1 Drawing Sheet U.S. Patent Jan. 22, 2013 US 8,357,723 B2 ru-Aspirin -v--C1-NOPO4 ada -C1-NOPOSA on 1-C1-NOPD5B US 8,357,723 B2 1. 2 PRODRUGS CONTAINING NOVEL Prize in Medicine and Physiology. NO is a major signaling BO-CLEAVABLE LINKERS molecule with important biological roles. See, for example, Kerwin, Jr., J. F. et al., J. Med. Chem. 1995, 38, 4343, and This is a divisional of application Ser. No. 1 1/213,396 filed Williams. R. J. P. Chem. Soc. Rev., 1996, 77. The major on Aug. 26, 2005, now U.S. Pat. No. 7,932.294 claims the 5 biological functions of NO include controlling blood pres benefit thereof and incorporates the same by reference. Sure, Smoothing muscle tone and inhibition of platelet adher This application takes priority from US Provisional Appli ence and aggregation, assisting the immune system in cation Ser. No. 60/604,632 filed 26 Aug. 2004 and Indian destroying tumor cells and intracellular pathogens and par Provisional Application 779/MUM/2005 filed 1 Jul. 2005, ticipating in neuronal synaptic transmission. See, for which are herein incorporated in their entirety. 10 example, Moncada, S. et al., Pharmacol. Rev. 1991, 43, 109: Bredt, D. S. et al., Anuu. Rev. Biochem., 1994, 63, 175; FIELD OF THE INVENTION Schmidt, H. H. W. et al., Cell 1994, 78,919: Feldman, P. L. et al., Chem. and Eng. News. 1993, 71 (20th December issue), The present invention relates to compositions of prodrugs, 26; and Wilsonm E. K., Chem. and Eng. News. 2004 (8' including NO-releasing prodrugs, codrugs, double prodrugs 15 March issue), 39. Endogenously, NO is produced from argi and mutual prodrugs, containing bio-labile linkers and link nine by the catalytic action of nitric oxide synthase. See, for ages, processes for their preparation and pharmaceutical example, Nathan, C. et al., Cell 1994, 78,915, and Marietta, compositions containing them and their use. M.A., Cell 1994, 78,927. NO is a free radical as well as a scavenger of free radicals. BACKGROUND OF THE INVENTION NO reacts quickly with ubiquitously generated reactive oxy gen species (ROS) such as Superoxide (O) to generate a A prodrug is an active drug chemically transformed into a nefarious peroxynitrite (ONOOT) molecule, which is impli per se inactive derivative which by virtue of chemical or cated in many human diseases such as diabetes, heart disease, enzymatic attack is converted to the parent drug within the Alzheimer's disease and multiple Sclerosis. In this setting, body before or after reaching the site of action. The process of 25 NO is often viewed as pathogenic. However, the chemistry of converting an active drug into inactive form is called drug NO can also be a significant factor in lessening the injury latentiation. Prodrugs can be carrier-linked-prodrugs and bio mediated by reactive oxygen species (ROS) and reactive precursors. The carrier-linked prodrug results from a tempo nitrogen oxide species (RNOS). There is a relationship rary linkage of the active molecule with a transport moiety. between NO and oxidation, nitrosation and nitration reac Such prodrugs are less active or inactive compared to the 30 tions. A number of factors determine whether NO promotes, parent active drug. The transport moiety will be chosen for its abates or interconnects these chemistries. See, for example, non-toxicity and its ability to ensure the release of the active Espay, et al. A chemical perspective on the interplay between principle with efficient kinetics. Whereas the bioprecursors NO, reactive oxygen species, and reactive nitrogen oxide result from a molecular modification of the active principle species, Ann N.Y. Acad. Sci. 2002, 962, 195. itself by generation of a new molecule that is capable of being 35 Thus, by being a free radical, along with the ability to a Substrate to the metabolizing enzymes releasing the active Scavenge other free radicals, NO is placed in a pivotal regu principle as a metabolite. latory position. Insight into these pathophysiological pro Prodrugs are prepared to alter the drug pharmacokinetics, cesses and signaling are highly relevant to develop therapeu improve stability and solubility, decrease toxicity, increase tics. specificity, and increase duration of the pharmacological 40 NO deficiency has been implicated in the genesis and evo effect of the drug. By altering pharmacokinetics the drug lution of several disease states. In patients with cardiovascu bioavailability is increased by increasing absorption, distri lar problems, the production of Superoxide is increased and bution, biotransformation, and excretion of the drug.
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