USOO8609833B2

(12) United States Patent (10) Patent No.: US 8,609,833 B2 Jagtap et al. (45) Date of Patent: Dec. 17, 2013

(54) PURINE DERVATIVES ASADENOSINE A1 6,448,236 B1 9/2002 Monaghan RECEPTORAGONSTS AND METHODS OF 6,525,032 B2 2/2003 Mantell et al. 6,528.494 B2 3/2003 Cox et al. USE THEREOF 6,531.457 B2 3/2003 Linden et al. (75) Inventors: Prakash Jagtap, N. Andover, MA (US); 6,534,486 B1 3/2003 Allen et al. Csaba Szabo, Gloucester, MA (US); 6,638.914 B1 10/2003 Fishman et al. 6,753,322 B2 6/2004 Mantell et al. Andrew L. Salzman, Herzliya (IL) 6,903,079 B2 6/2005 Jagtap et al. 6,921,753 B2 7/2005 Mantell et al. (73) Assignee: Inotek Pharmaceuticals Corporation, 7,423,144 B2* 9/2008 Jagtap et al...... 536,27.81 Lexington, MA (US) 2001/0051612 A1 12/2001 Cristalli 2003, OO13675 A1 1/2003 Yeadon et al. (*) Notice: Subject to any disclaimer, the term of this 2003/005.5021 A1 3/2003 DeNinno et al. patent is extended or adjusted under 35 2006.0034.941 A1 2/2006 Dobson U.S.C. 154(b) by 0 days. 2007/0238694 A1 10, 2007 Salzman et al. (21) Appl. No.: 13/451,613 FOREIGN PATENT DOCUMENTS CN 1164122 11, 1997 (22) Filed: Apr. 20, 2012 DE 2342479 * 3, 1975 ...... CO7H21/02 DE 2342479 A1 3, 1975 (65) Prior Publication Data FR 2186470 1, 1974 KR 20030005241 1, 2003 US 2012/O2647O6A1 Oct. 18, 2012 WO 94f02497 A1 2, 1994 WO 95,02604 A1 1, 1995 Related U.S. Application Data WO 95/11681 A1 5, 1995 WO 96.O2553 A2 2, 1996 (60) Continuation of application No. 12/221,539, filed on WO 97.33590 A1 9, 1997 Aug. 4, 2008, now Pat. No. 8,183.224, which is a WO 97.33879 A1 9, 1997 division of application No. 1 1/137,632, filed on May WO 98.08855 A2 3, 1998 25, 2005, now Pat. No. 7,423,144. WO 98.50047 A1 11, 1998 (Continued) (60) Provisional application No. 60/574,805, filed on May OTHER PUBLICATIONS 26, 2004, provisional application No. 60/588.263, filed on Jul. 15, 2004. Kristinsson et al. Herbicidally Active Sulfamoyl Nucleosides: Iso lation and Synthesis Synthesis and Chemistry anf Agrochemicals IV. (51) Int. C. published 1995 by American Chemical Society, chapter 19, pp. 206 C07H 19/167 219.* (2006.01) Epple et al., “Solid-Phase Synthesis of Nucleoside Analogues' Jour (52) U.S. C. nal of Combinatorial Chemistry (2003) vol. 5 pp. 292-310.* CPC ...... C07H 19/167 (2013.01) Al-Mughales, J. et al., “The chemoattractant activity of rheumatoid synovial fluid for human lymphocytes is due to multiple cytokines.” ------536/27.3 Clin. Exp. Immunol., vol. 106:230-236 (1996). (58) Field of Classification Search Baraldi, Pier Giovanni et al., “Synthesis and Biological Activity of a None New Series of N6-Arylcarbamoyl, 2-(Ar)alkynyl-N6 See application file for complete search history. arylcarbamoyl, and N6-Carboxamido Derivatives of Adenosine-5'- N-ethyluronamide as A1 and A3 Adenosine Receptor Agonists. J. Med. Chem., vol. 41:3174-3185 (1998). (56) References Cited Beukers, Margot W. et al., “N6-Cyclopentyl-2-(3- phenylaminocarbonyltriazene-1-yl)adenosine (TCPA), a Very Selec U.S. PATENT DOCUMENTS tive Agonist with High Affinity for the Human Adenosine Al Recep tor.” J. Med. Chem., vol. 46:1492-1503 (2003). 3,819,613 A 6, 1974 Kawazoe et al. Beukers, Margot W. et al., “New, Non-Adenosine, High-Potency 3,832,341 A 8/1974 Duschinsky Agonists for the Human Adenosine A2B Receptor with an Improved 4,242.505 A 12, 1980 Kawahara et al. Selectivity Profile Compared to the Reference Agonists 4,968,697 A 11, 1990 Hutchison N-Ethylcarboxamidoadenosine.” Journal of Medicinal Chemistry, 5,140,015 A 8, 1992 Olsson et al. vol. 47(15):3707-3709 (2004). 5,206,222 A 4, 1993 Forman et al. 5,219,840 A 6, 1993 Gadient et al. (Continued) 5,278, 150 A 1/1994 Olsson et al. 5,280,015 A 1/1994 Jacobson et al. Primary Examiner — Eric S Olson 5,304.277 A 4, 1994 Ohara et al. (74) Attorney, Agent, or Firm — Nelson Mullins Riley & 5,407,793 A 4/1995 Del Nido et al. Scarborough LLP; Jane E. Remillard, Esq.; Cynthia L. Kanik 5,443,836 A 8/1995 Downey et al. 5,589.467 A 12/1996 Lau et al. (57) ABSTRACT 5,604,210 A 2/1997 Nagaoka et al. The invention relates to Purine Derivatives; compositions 5,789,416 A 8, 1998 Lumet al. comprising an effective amount of a Purine Derivative; and 5,801,159 A 9, 1998 Miller et al. methods for reducing an animals rate of metabolism, pro 6,180,615 B1 1/2001 Zablocki et al. tecting an animals heart against myocardial damage during 6,214,807 B1 4/2001 Zablocki et al. cardioplegia; or for treating or preventing a cardiovascular 6,326,359 B1 12/2001 Monaghan et al. disease, a neurological disorder, an ischemic condition, a 6,358,536 B1 3, 2002 Thomas reperfusion injury, obesity, a wasting disease, or diabetes, 6,368,573 B1 4/2002 Leung comprising administering an effective amount of a Purine 6,403,567 B1 6, 2002 Zablocki et al. Derivative to an animal in need thereof. 6.426,337 B1 7/2002 Cox et al. 6,440,948 B1 8, 2002 Zablocki et al. 7 Claims, 5 Drawing Sheets US 8,609,833 B2 Page 2

(56) References Cited Klotz, K.-N. et al., “Comparative pharmacology of human adenosine receptor Subtypes—characterization of stably transfected receptors in CHO cells.” Naunyn-Schmiedeberg's Arch. Pharmacol., vol. FOREIGN PATENT DOCUMENTS 357: 1-9 (1998). WO 99.20284 A1 4f1999 Klotz, Karl-Norbert et al., “Photoaffinity Labeling of All-adenosine WO 01, 19360 A2 3, 2001 Receptors.” The Journal of Biological Chemistry, vol. WO Of 40245 A1 6, 2001 260(27): 14659-14664 (1985). WO O1/45715 A2 6, 2001 Knutsen, Lars J.S. et al., "N-Substituted Adenosines as Novel WO O2/O55085 A2 T 2002 Neuroprotective Al Agonists with Dimished Hypotensive Effects.” J. WO 02/083152 A1 10, 2002 Med. Chem., vol. 42:3463-3477 (1999). WO O3,029.264 A2 4/2003 Kunkel, Steven L. et al., “The role of chemokines in inflammatory joint disease.” Journal of Leukocyte Biology, vol. 59:6-12 (1996). OTHER PUBLICATIONS Lichtenthaler, F.W. et al., “Nucleosides, XVIII1. Improved Prepara Bouma, Maarten G. et al., “Differential Regulatory Effects of tion of Nucleoside 5'-Nitrates.” Synthesis, vol. 27: 199-201 (1973). Adenosine on Cytokine Release by Activated Human Monocytes.” Lohse, Martin J. et al., “8-Cyclopentyl-1,3-dipropylxanthine The Journal of Immunology, vol. 153:4159-4168 (1994). (DPCPX)—a selective high affinity antagonist radioligand for A1 Bradley, Karri K. et al., “Purine Nucleoside-Dependent Inhibition of adenosine receptors. Naunyn-Schmiedeberg's Arch. Pharmacol., Cellular Proliferation in 1321N1 Human Astrocytoma Cells.” The vol. 336:204-210 (1987). Journal of Pharmacology and Experimental Therapeutics, vol. Mager, P.P. et al., “Molecular simulation applied to 2-(N'- 299(2):748-752 (2001). alkylidenehydrazino)- and 2-(N-aralkylidenehydrazino) adenosine Broadley, Kenneth J. et al., “Drugs modulating adenosine receptors A2 agonists.” Eur, J. Med. Chem., vol. 30:15-25 (1995). as potential therapeutic agents for cardiovascular diseases.” Exp. Matsuda, Akira et al., "Nucleosides and Nucleotides. 103. Opin. Ther. Patents, vol. 10(11):1669-1692 (2000). 2-Alkynyladenosines: A Novel Class of Selective Adenosine A2 Bruns, Robert F. "Adenosine receptor activation in human fibro Receptor Agonists with Potent Antihypertensive Effects.” J. Med. blasts: nucleoside agonists and antagonists. Can. J. Physiol. Chem., vol. 35:241-252 (1992). Pharmacol., vol. 58:673-691 (1980). McKenzie, Sheila G. et al., “Effects of Adenosine and Related Com Bruns, Robert F. et al., “Characterization of the A2 Adenosine Recep pounds on Adenylate Cyclase and Cyclic AMP Levels in Smooth tor Labeled by 3HTNECA in Rat Striatal Membrans.” Biological Muscle.” European Journal of Pharmacology, vol. 41:193-203 Pharmacology, vol. 89:331-346 (1986). (1977). Camaioni, Emidio et al., “Adenosine Receptor Agonists: Synthesis McWhinney, Charlene D. et al., “Activation of adenosine A3 recep and Biological Evaluation of the Diastereoisomers of 2-(3-Hydroxy tors on macrophages inhibits tumor necrosis factor-a, European 3-phenyl-1-propyn-1-yl)NECA.” Bioorganic & Medicinal Chemis Journal of Pharmacology, vol. 310:209-216 (1996). try, vol. 5(12):2267-2275 (1997). Missiaen, Ludwig et al., “Effect of adenine nucleosides on myo Cristalli, Gloria et al., “2-Alkynyl Derivatives of Adenosine-5'-N- inositol-1,4,5-trisphosphate-induced calcium release.” Biochem. J., ethyluronamide: Selective A2 Adenosine Receptor Agonists with vol. 325:661-666 (1997). Potent Inhibitory Activity on Platelet Aggregation.” J. Med. Chem. Moos, Walter H. et al., “N6-Cycloalkyladenosines. Potent Al-Selec vol. 37: 1720-1726 (1994). tive Adenosine Agonists,” Journal of Medicinal Chemistry, vol. Cristalli, Gloria et al., “2-Alkynyl Derivatives of Adenosine and 28(10): 1383-1384 (1985). Adenosine-5'-N-ethyluronamide as Selective Agonists at A2 Müller, C.E. et al., “Adenosine Receptor Ligands-Recent Develop Adenosine Receptors.” J. Med. Chem., vol. 35:2363-2368 (1992). ments Part I. Agonists.” Current Medicinal Chemistry, vol. 7:1269 Cristalli, Gloria et al., “2-Aralkynyl and 2-Heteroalkynyl Derivatives 1288 (2000). of Adenosine-5'-N-ethyluronamide as Selective A2a Adenosicne Nair, Vasu et al., “Novel, Stable Congeners of the Antiretroviral Receptor Agonists.” J. Med. Chem., vol. 38:1462-1472 (1995). Compound 2',3'-Dideoxyadenosine” J. Am. Chem. Soc., vol. Dalpiaz, Alessandro et al., “Synthesis and Study of 5'-Ester Prodrugs 1 11:8502-8504 (1989). of N6-Cyclopentyladenosine, a Selective Al Receptor Agonist.” Niiya, Kazunori et al., “2-(N-Alkylidenehydrazino)adenosines: Pharmaceutical Research, vol. 18(4):531-536 (2001). Potent and Selective Coronary Vasodilators.” J. Med. Chem... vol. De Lean, Andre et al., “Validation and Statistical Analysis of a Com 35:4557-4561 (1992). puter Modeling Method for Quantitative Analysis of Radioligand Ohno, Michihiro et al., “Modulation of adenosine receptor affinity Binding Data for Mixtures of Pharmacological Receptor Subtypes.” and intrinsic efficacy in adenine nucleosides Substituted at the 2-po Molecular Pharmacology, vol. 21:5-16 (1982). sition.” Bioorganic & Medicinal Chemistry, vol. 12:2995-3007 Deninno, Michael P. et al., “3'-Aminoadenosine-5'-uronamides: Dis (2004). covery of the First Highly Selective Agonist at the Human Adenosine Ongini, Ennio et al., “Pharmacology of adenosine A2A receptors.” A3 Receptor.” J. Med. Chem., vol. 46:353-355 (2003). TiPS, vol. 17:364-372 (1996). Fisher, Charles J. Jr. et al., “Treatment of Septic Shock with the Parmely, Michael J. et al., “Adenosine and a Related Carbocyclic Tumor Necrosis Factor Receptor : Fc Fusion Protein.” N. Engl. J. 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Reinhart, Konrad et al., “Assessment of the safety and efficacy of the Chem., vol. 34:2570-2579 (1991). monoclonal anti-tumor necrosis factor antibody-fragment, MAK Haskö, György et al., “Adenosine Receptor Agonists Differentially 195F, in patients with sepsis and septic shock: A multicenter, ran Regulate IL-10, TNF-a, and Nitric Oxide Production in Raw 264.7 domized, placebo-controlled, dose-ranging study.” Crit. Care Med., Macrophages and in Endotoxemic Mice.” The Journal of Immunol vol. 24(5): 733-742 (1996). ogy, vol. 157:4634-4640 (1996). Reinstein, Leon J. et al., “Suppression of Lipopolysaccharide-stimu Homma, Hiroshi et al., "Nucleosides and Nucleotides. 112. lated Release of Tumor Necrosis Factor by Adenosine: Evidence for 2-(1Hexyn-1-yl)adenosine-5'-uronamides: A New Entry of Selective A2 Receptors on Rat Kupffer Cells.” Hepatology, vol. 19:1445-1452 A2 Adenosine Receptor Agonists with Potent Antihypertensive (1994). Activity.” J. Med. Chem., vol. 35:2881-2890 (1992). Riché, Florence et al., “High tumor necrosis factor serum level is Hutchison, Alan J. et al., “2-(Arylalkylamino)adenosin-5'- associated with increased Survival in patients with abdominal septic uronamides: A New Class of Highly Selective Adenosine A2 Recep shock: A prospective study in 59 patients.” Surgery, vol. 120(5):801 tor Ligands.” J. Med. Chem., vol. 33:1919-1924 (1990). 807 (1996). US 8,609,833 B2 Page 3

(56) References Cited VanDerWenden, Eleonora M. et al., “5'Substituted Adenosine Ana logs as New High-Affinity Partial Agonists for the Adenosine A1 OTHER PUBLICATIONS Receptor.” J. Med. Chem., vol.41:102-108 (1998). Van Tilburg, Erica W. et al., “2,5'-Disubstituted Adenosine Deriva Rieger, Jayson M. et al., “Design, Synthesis, and Evaluation of Novel tives: Evaluation of Selectivity and Efficacy for the Adenosine A1, A2A Adenosine Receptor Agonists,” J. Med. Chem... vol. 44:531-539 A2A and A3 Receptor.” J. Med. Chem., vol. 45:420-429 (2002). Virág, László et al., “Effects of poly(ADP-ribose) polymerase inhi (2001). bition on inflammatory cell migration in a murine model of asthma.” Roelen, Harlof et al., “N6,C8-Disubstituted Adenosine Derivatives Med. Sci. Monit., vol. 10(3):BR77-83 (2004). as Partial Agonists for Adenosine Al Receptors.” J. Med. Chem... vol. Vitrori, Sauro et al., “2-Alkenyl and 2-Alkyl Derivatives of 39: 1463-1471 (1996). Adenosine and Adenosine-5'-N-Ethyluronamide: Different Affinity Sajjadi, Fereydoun G. et al., “Inhibition of TNF-a Expression by and Selectivity of E- and Z-Diastereomers at A2AAdenosine Recep Adenosine.” The Journal of Immunology, vol. 156:3435-3442 tors.” J. Med. Chem. vol. 39:4211-4217 (1996). (1996). Vitrori, Sauro et al., “N-Cycloalkyl Derivatives of Adenosine and Schleef, Raymond R. et al., “The Effect of Fibrin on Endothelial Cell 1-Deazaadenosine as Agonists and Partial Agonists of the A1 Adenosine Receptor.” J. Med. Chem., vol. 43:250-260 (2000). Migration in Vitro. Tissue & Cell, vol. 14 (4):629-636 (1982). Viziano, Monica et al., “2-N'-(3-Arylal Shuman, Dennis A. et al., “The Synthesis of Nucleoside Sulfamates lylidene)hydrazinoadenosines Showing A2a Adenosine Agonist Related to Nucleocidin.” Journal of the American Chemical Society, Properties and Vasodilation Activity.” J. Med. Chem... vol. 38:3581 vol. 92(11):3434-3440 (1970). 3585 (1995). Soulere, Laurent et al., “Synthesis and Uptake of Nitric Oxide-Re Witte, M.B. et al., “Nitric oxide enhances experimental wound heal leasing Drugs by the P2 Nucleoside Transporter in Trypanosoma ing in diabetes.” British Journal of Surgery, vol. 89:1594-1601 equiperdum. Bioorganic & Medicinal Chemistry Letters, vol. (2002). 10:1347-1350 (2000). Supplementary European Search Report for Application No. Thompson, Robert D. et al., “Activity of N6-Substituted 05757108, dated Jun. 4, 2007. 2-Chloroadenosines at A1 and A2 Adenosine Receptors,” J. Med. Chem., vol. 34:3388-3390 (1991). * cited by examiner U.S. Patent Dec. 17, 2013 Sheet 1 of 5 US 8,609,833 B2

pg/ml (plasma Concentration) 5000

4000

3000

2000

1000

TNF-0 MIP-10 Fig. 1

Animals alive (%)

O 10 20 30 40 50 Time (h) Fig. 2 U.S. Patent Dec. 17, 2013 Sheet 2 of 5 US 8,609,833 B2

Fig. 3

1500 ck

O' 10' Isch 30'rep 5' rep 10' rep 15' rep 20'rep 30'rep 40' Fig. 4 U.S. Patent Dec. 17, 2013 Sheet 3 of 5 US 8,609,833 B2

120 - 100 - s

O 10 20 30 40 50 60 70 80 90 100 Time post drug (min) Fig. 5

60

50

40 30 20 10

- 10 First Phase SeCOnd Phase Fig. 6 U.S. Patent Dec. 17, 2013 Sheet 4 of 5 US 8,609,833 B2

1 O -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Time post-drug (min) Fig. 7

50 baseline 45

-30 -15 O 15 30 45 60 Time (min) Fig. 8 U.S. Patent Dec. 17, 2013 Sheet 5 of 5 US 8,609,833 B2

50 60 45 40 50 9235 S240 C 30 2 S 25 -0-R 30 3 20 -HL 3

H 105 "N-N- H 10 -HL-0-R O O -10 0 10 20 30 40 50 60 70 -10 0 10 20 30 40 50 60 70 Min, after drugs Min. after drugs

70 60 60 50 S5 S 40 GE2 40 2 30 3 30 20 -0-R -0-R 10 -HL 10 -HL O O - 10 0 10 20 30 40 50 60 70 -10 0 10 20 30 40 50 60 70 Min. after drugs Min. after drugs

Fig. 9 US 8,609,833 B2 1. 2 PURINE DERVATIVES ASADENOSINE A1 to ischemia and hypoxia and protect cardiac tissue during and RECEPTORAGONSTS AND METHODS OF after trauma (preconditioning). Adenosine agonists thus are USE THEREOF useful as cardioprotective agents. The preparation and use of a number of adenosine A CROSS-REFERENCES TO RELATED 5 receptor agonists have been described (Moos et al., J. Med. APPLICATIONS Chem. 28:1383-1384 (1985); Thompson et al., J. Med. Chem. 34:3388-3390 (1991); Vittori et al., J. Med. Chem. 43:250 This application is a continuation application of U.S. 260 (2000); Roelen et al., J. Med. Chem., 39:1463-1471 patent application Ser. No. 12/221,539, filed Aug. 4, 2008, (1996); van der Wenden et al., J Med. Chem. 41102-108 which is a divisional application of U.S. patent application " (1998); Dalpiaz et al., Pharm. Res. 18:531-536 (2001), Bea Ser. No. 1 1/137,632, filed May 25, 2005, issued as U.S. Pat. kers et al., J. Med. Chem. 46, 1492-1503 (2003); U.S. Pat. No. No. 7,423,144, which claims the benefit of U.S. provisional 5,589,467 to Lau et al.; U.S. Pat. No. 5,789,416, to Lumet al.: application No. 60/574,805, filed May 26, 2004, and of U.S. and C. E. Muller, Current Medicinal Chemistry 2000, 7, provisional application No. 60/588.263, filed Jul. 15, 2004. 15 1269-1288). The disclosures of each of the aforementioned applications Nucleoside 5'-nitrate esters are reported in Lichtenthaler et are incorporated by reference herein in their entirety. al., Synthesis, 199-201 (1974), and U.S. Pat. No. 3,832,341 to Duchinsky et al. 1. FIELD OF THE INVENTION The citation of any reference in Section 2 of this applica 2O tion is not an admission that the reference is prior art to this The invention relates to Purine Derivatives; compositions application. comprising an effective amount of a Purine Derivative; and methods for reducing an animals rate of metabolism, pro 3. SUMMARY OF THE INVENTION tecting an animals heart against myocardial damage during cardioplegia; or for treating or preventing a cardiovascular In one embodiment, the invention provides compounds disease, a neurological disorder, an ischemic condition, a 25 having the Formula (Ia): reperfusion injury, obesity, a wasting disease, or diabetes, comprising administering an effective amount of a Purine Derivative to an animal in need thereof. (Ia) A O D 2. BACKGROUND OF THE INVENTION 30 Adenosine is a naturally occurring purine nucleoside that is ubiquitous in mammalian cell types. Adenosine exerts its B C biological effects by interacting with A, A (further Subclas sified as A and A) and A cell surface receptors, which 35 and pharmaceutically acceptable salts thereof, modulate important physiological processes. wherein The A and A receptor Subtypes are believed to play A is CHOSONH; complementary roles in adenosines regulation of a cells B and C are –OH: energy Supply. Adenosine, which is a metabolic product of D is: ATP, diffuses from the cell and locally activates the A recep 40 torto decrease the oxygen demand or activates the A recep tor to increase the oxygen Supply, thereby reinstating the NHR balance of energy Supply and demand within the tissue. The combined action of A and A Subtypes increases the amount N n of available oxygen to tissue and protects cells against dam 45 ( N age caused by a short-term imbalance of oxygen. One of the important functions of endogenous adenosine is to prevent 1. tissue damage during traumas Such as hypoxia, an ischemic *4. N R2; condition, hypotension and seizure activity. In addition, modulation of A receptors slows conduction 50 velocity in the hearts atrioventricular node, resulting in the A and B are trans with respect to each other; normalization of supraventricular tachycardias and control of B and C are cis with respect to each other; ventricular rate during atrial fibrillation and flutter. Modula C and Dare cis or trans with respect to each other; tion of A receptors also regulates coronary vasodilation. R" is —C-Cs monocyclic cycloalkyl, -C-Cs monocy Adenosine is also a neuromodulator, which modulates 55 clic cycloalkenyl, -(CH2)—(C-C monocyclic molecular mechanisms underlying many aspects of physi cycloalkyl). —(CH), (C-C monocyclic cycloalkenyl). ological brain function by mediating central inhibitory —Cs-C bicyclic cycloalkyl, or—Cs-C bicyclic cycloalk effects. An increase in neurotransmitter release follows trau enyl: mas Such as hypoxia, ischemia and seizures. Neurotransmit R is -halo, CN, NHR, OR, SR, NHC(O) ters are ultimately responsible for neural degeneration and 60 OR, NHC(O)R, NHC(O)NHR, NHNHC(O)R, neural death, which can cause brain damage or death. NHNHC(O)OR, NHNHC(O)NHR, or NH N–C Adenosine is thought to be an endogenous anticonvulsant (R)R7; agent that inhibits glutamate release from excitory neurons R" is -H, -C-Cls alkyl, -aryl, -(CH2)-aryl, and neuronal firing. Adenosine agonists, therefore, are useful —(CH2)-(3- to 7-membered monocyclic heterocycle), as antiepileptic agents. 65 —(CH)-(8- to 12-membered bicyclic heterocycle), Adenosine plays an important role as a cardioprotective —(CH), (C-C monocyclic cycloalkyl). —(CH), (C- agent. Levels of endogenous adenosine increase in response Cs monocyclic cycloalkenyl), —(CH), (C-C bicyclic

US 8,609,833 B2 7 8 cycloalkyl). —(CH2)-(3- to 7-membered monocyclic het In another embodiment, the invention provides compounds erocycle), or —(CH)-(8- to 12-membered bicyclic hetero having the Formula (Ih): cycle); and each n is independently an integer ranging from 1 to 5. In another embodiment, the invention provides compounds (Ih) having the Formula (If):

(If) 10 and pharmaceutically acceptable salts thereof, wherein A is —CHONO; 15 B and C are –OH: and pharmaceutically acceptable salts thereof, D is wherein A is —CHONO; B and C are –OH: NHR D is S1SN 25 l A and B are trans with respect to each other; B and C are cis with respect to each other; and 30 C and Dare cis or trans with respect to each other; and R" is cyclopent-1-ol-2-yl, or cyclopent-1-ol-3-yl. A and B are trans with respect to each other; In another embodiment, the invention provides compounds B and C are cis with respect to each other; having the Formula (II): C and D are cis or trans with respect to each other; R" is —Cs-Cs monocyclic cycloalkyl; and 35 R is Hor-halo. (II) In another embodiment, the invention provides compounds having the Formula (Ig): 40 (Ig) and pharmaceutically acceptable salts thereof, wherein 45 A is CH-OH: B and C are –OH: D is and pharmaceutically acceptable salts thereof, wherein A is —CHONO; 50 B and C are –OH: N n D is / N 55 & es R2

A and B are trans with respect to each other; 60 B and C are cis with respect to each other; C and Dare cis or trans with respect to each other; each R' is independently -H, -C-Cio alkyl, -(CH2)- (3- to 7-membered monocyclic heterocycle), —(CH)-(8- A and B are trans with respect to each other; to 12-membered bicyclic heterocycle), —(CH), (C-C2 B and C are cis with respect to each other; 65 bicyclic cycloalkyl). —(CH), (C-C bicyclic cycloalk C and D are cis or trans with respect to each other; and enyl), or -(CH2)-aryl, or both R" groups together with the R is Hor-halo. carbon atom to which they are attached form a —C-Cs

US 8,609,833 B2 11 12 A and B are trans with respect to each other; NH-N=CHRI B and C are cis with respect to each other; C and Dare cis or trans with respect to each other; R" is -C-Cio alkyl, -(CH2)-(3-to 7-membered mono cyclic heterocycle), —(CH)-(8- to 12-membered bicyclic heterocycle), —(CH), (C-C bicyclic cycloalkyl). —(CH), (C-C bicyclic cycloalkenyl), —(CH), (C- Cs monocyclic cycloalkyl). —(CH), (C-C monocyclic cycloalkenyl) or —(CH)-aryl, or R' and R'' together with 10 the carbon atom to which they are attached form a —C-Cs A and B are trans with respect to each other; monocyclic cycloalkyl, a -C-C monocyclic cycloalkenyl, B and C are cis with respect to each other; a —Cs-C bicyclic cycloalkyl, or a —Cs-C bicyclic C and D are cis or trans with respect to each other; cycloalkenyl: R" is —Cs-Cs monocyclic cycloalkylor-C-Cs monocy R" is —C-C monocyclic cycloalkyl or -C-Cs mono clic cycloalkenyl: 15 cyclic cycloalkenyl; R° is OR, SR, NHNHC(O)R, NHNHC(O) R’ is -H, -halo, CN, OR, SR, N(R), NHR, NHNHC(O)OR, or NH N=C(R)R: NHNHC(O)R, NHNHC(O)NHR, NHNHC(O) R is -H, -C-Cio alkyl, -(CH2)-(3- to 7-membered OR, or NH N–C(R)R; monocyclic heterocycle), —(CH2)-(8- to 12-membered each R is independently -H, -C-Cio alkyl, -(CH), bicyclic heterocycle), —(CH), (C-C monocyclic (3-to 7-membered monocyclic heterocycle), —(CH)-(8- to cycloalkyl). —(CH), (C-C monocyclic cycloalkenyl). 12-membered bicyclic heterocycle). —(CH), (C-Cs —(CH), (C-C bicyclic cycloalkyl). —(CH), (Cs monocyclic cycloalkyl). —(CH), (C-C monocyclic C. bicyclic cycloalkenyl), —(CH), aryl, -C=C-(C- cycloalkenyl), —(CH), (C-C bicyclic cycloalkyl). Coalkyl) or C=C-aryl; —(CH), (C-C bicyclic cycloalkenyl), —(CH2)-aryl, 25 Ris-C-Cio alkyl, -(CH2)-(3- to 7-membered mono —C=C (C-C alkyl) or C=C-aryl; cyclic heterocycle), —(CH)-(8- to 12-membered bicyclic R" and Rare each independently —H, -C-Cio alkyl, heterocycle), —(CH), (C-C monocyclic cycloalkyl). —(CH2)-(3- to 7-membered monocyclic heterocycle), —(CH), (C-C monocyclic cycloalkenyl), —(CH), —(CH)-(8- to 12-membered bicyclic heterocycle), (C-C bicyclic cycloalkyl). —(CH2)-aryl, -C=C-(C- —(CH), (C-C monocyclic cycloalkyl). —(CH), (C- 30 Co alkyl) or —C=C-aryl; Cs monocyclic cycloalkenyl), —(CH), (C-C bicyclic R and Rare each independently —H, -C-Cio alkyl, cycloalkyl). —(CH), (C-C bicyclic cycloalkenyl). —(CH)-(3- to 7-membered monocyclic heterocycle), —(CH2)-aryl, -phenylene-(CH2)COOH, or -phenylene —(CH)-(8- to 12-membered bicyclic heterocycle), (CH2)COO (C-Clo alkyl), or RandR together with the —(CH), (C-C monocyclic cycloalkyl). —(CH), (C- carbon atom to which they are attached form a C-C mono 35 Cs monocyclic cycloalkenyl), —(CH), (C-C bicyclic cyclic cycloalkyl, a C-C monocyclic cycloalkenyl, a —Cs cycloalkyl). —(CH), (C-C bicyclic cycloalkenyl), C. bicyclic cycloalkyl, or a —Cs-C bicyclic cycloalkenyl: —(CH2)-aryl, -phenylene-(CH2)COOH, or -phenylene and (CH2)COO (C-Clo alkyl), or RandR together with the each n is independently an integer ranging from 0 to 5. carbon atom to which they are attached form a C-C mono In another embodiment, the invention provides compounds 40 cyclic cycloalkyl, a C-C monocyclic cycloalkenyl, a —Cs having the Formula (V): C. bicyclic cycloalkyl, or a —Cs-C bicyclic cycloalkenyl: m is an integer ranging from 0 to 3; and each n is independently an integer ranging from 0 to 5. (V) A compound of Formula (Ia), (Ib), (Ic). (Id). (Ie). (If). (Ig), A O D 45 (Ih), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, (a “Purine Derivative') is useful for: (i) treating or preventing a cardiovascular disease, a neurological disor der, an ischemic condition, a reperfusion injury, obesity, a B C wasting disease, or diabetes (each being a "Condition'); (ii) 50 reducing an animals rate of metabolism; or (iii) protecting an and pharmaceutically acceptable salts thereof, animals heart against myocardial damage during cardiople wherein g1a. The invention also provides compositions comprising an A is —CH-OH: effective amount of a Purine Derivative and a physiologically B and C are –OH: 55 acceptable carrier or vehicle. The compositions are useful for: D is (i) treating or preventing a Condition; (ii) reducing an ani mals rate of metabolism; or (iii) protecting an animals heart against myocardial damage during cardioplegia. NH-N=C(R) (Ra); The invention further provides methods for: (i) treating or 60 preventing a Condition; (ii) reducing an animals rate of N n N metabolism; or (iii) protecting an animals heart against myo cardial damage during cardioplegia, comprising administer {ll ing an effective amount of a Purine Derivative to an animal in *4. 4N need thereof. 65 The details of the invention are set forth in the accompa nying description below. Other features, objects, and advan tages of the invention will be apparent from the description US 8,609,833 B2 13 14 and from the claims. All patents, patent applications and effect of buprenorphine (0.3 mg/kg) and the bottom right publications cited in this specification are incorporated herein graph shows the effect of co-administration of Compound 17 by reference for all purposes. (0.1 mg/kg) and buprenorphine (0.3 mg/kg). Line -0- repre sents the response of the control leg and line -- represents 4. BRIEF DESCRIPTION OF THE DRAWINGS the response of the treated leg. FIG. 1 shows the effect of Compound 17 on lipopolysac 5. DETAILED DESCRIPTION OF THE charide induced plasma TNF and MIP production in male INVENTION BALB/c mice. The unshaded bars represent LPS, adminis tered i.p. at a dose of 1 mg/kg and the shaded bars represent 10 5.1 Definitions Compound 17, administered orally at a dose of 0.03 mg/kg, followed 30 minutes later by LPS, administered i.p. at a dose The term "C-Cls alkyl as used herein refers to a straight of 1 mg/kg. TNF and MIP levels were measured 90 minutes or branched chain, saturated hydrocarbon having from 1 to 15 after LPS administration. carbon atoms. Representative C-C alkyl groups include, FIG.2 shows the effect of Compound 17 in survival studies 15 but are not limited to methyl, ethyl, propyl, isopropyl, butyl, in male BALB/c mice, expressed as the percentage of Surviv sec-butyl, tert-buty, pentyl, isopentyl, neopentyl, hexyl, iso ing animals at 10-hour time intervals. Line -- represents hexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, isooctyl, LPS, administered i.p. at a dose of 55 mg/kg, and line -0- neooctyl, nonyl, isononyl, neononyl, decyl, isodecyl, neode represents Compound 17, administered orally at a dose of cyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl. In 0.03 mg/kg, followed 30 minutes later by LPS, administered one embodiment, the C-C alkyl group is substituted with i.p. at a dose of 55 mg/kg. one or more of the following groups: -halo. —O—(C-C, FIG.3 shows the effects of Compound 17 on the duration alkyl), -OH, -CN, -COOR', OC(O)R', N(R'), of ischemia-induced arrhythmias in isolated perfused rat - NHC(O)R’ or –C(O)NHR' groups wherein each R" is hearts. The bar graph from left to right, represents: a non independently —H or unsubstituted —C-C alkyl. Unless treated control group, Compound 17 administered at 10 pM, 25 indicated, the C-C alkyl is unsubstituted. Compound 17 administered at 30 pM, and Compound 17 The term "C-C alkyl as used herein refers to a straight administered at 100 pM, respectively. or branched chain, saturated hydrocarbon having from 1 to 10 FIG. 4 shows the effect of Compound 17 on function recov carbon atoms. Representative C-C alkyl groups include, ery in isolated perfused rat hearts after 30 minute no-flow but are not limited to methyl, ethyl, propyl, isopropyl, butyl, ischemia followed by 40 minute reperfusion. Line -A- rep 30 sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, iso resents a non-treated control group (n=13) and line -- rep hexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octyl, isooctyl, resents administration (n=9) of Compound 17 at a concentra neooctyl, nonyl, isononyl, neononyl, decyl, isodecyl and neo tion of 1 nM, administered 10 minutes prior to induction of decyl. In one embodiment, the C-C alkyl group is substi ischemia. tuted with one or more of the following groups:-halo. —O— FIG. 5 shows the effect of Compound 17 and/or buprenor 35 (C-C alkyl). -OH, -CN, -COOR', OC(O)R', phine in an acute pain model in mice using a tail flickassay. - N(R'), -NHC(O)R’ or - C(O)NHR' groups wherein The X-axis represents Maximum Possible Effect (MPE) and each R" is independently —H or unsubstituted—C-C alkyl. the Y-axis represents time after administration of Compound Unless indicated, the C-Co alkyl is unsubstituted. 17 and/or buprenorphine. Line -O- represents co-administra The term "C-C alkyl as used herein refers to a straight or tion of buprenorphine (1.0 mg/kg) and Compound 17 (3.0 40 branched chain, Saturated hydrocarbon having from 1 to 6 mg/kg), line -- represents buprenorphine (1.0 mg/kg), line carbonatoms. Representative C-C alkyl groups include, but -A-represents Compound 17 (3.0 mg/kg), line-X- represents are not limited to methyl, ethyl, propyl, isopropyl, butyl, co-administration of buprenorphine (0.3 mg/kg) and Com sec-butyl, tert-buty, pentyl, isopentyl, neopentyl, hexyl, iso pound 17 (3.0 mg/kg), and line -)K- represents buprenor hexyl, and neohexyl. Unless indicated, the C-C alkyl is phine (0.3 mg/kg). 45 unsubstituted. FIG. 6 shows the effect of Compound 17 in a mouse for The term “aryl as used herein refers to a phenyl group or malin pain model pain. The bar graph from left to right shows a naphthyl group. In one embodiment, the aryl group is Sub the first phase of the test (no response) and the second phase stituted with one or more of the following groups: -halo, of the test (shaded bar). -O-(C-C alkyl), -OH, -CN, COOR', OC(O)R', FIG. 7 shows the effect of Compound 17 on allodynia in a 50 - N(R'), -NHC(O)R’ or - C(O)NHR' groups wherein mouse model of diabetic neuropathy. The X-axis represents each R" is independently —H or unsubstituted—C-C alkyl. the animals pain threshold and the Y-axis represents time Unless indicated, the aryl is unsubstituted. after administration of Compound 17. Line -O- represents The term "C-C monocyclic cycloalkyl as used herein is treatment with Compound 17 (1.0 mg/kg). a 3-, 4-, 5-, 6-, 7- or 8-membered Saturated non-aromatic FIG. 8 shows the effect of Compound 17 on mechanically 55 monocyclic cycloalkyl ring. Representative C-C monocy induced pain threshold in a carrageenan rat model. The clic cycloalkyl groups include, but are not limited to, cyclo X-axis represents the animal’s pain threshold and the Y-axis propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and represents time after administration of Compound 17. Line cyclooctyl. In one embodiment, the C-C monocyclic -O- represents vehicle and line --represents Compound 17 cycloalkyl group is substituted with one or more of the fol (5.0 mg/kg). 60 lowing groups: -halo. —O—(C-C alkyl). —OH, -CN. FIG.9 shows the effect of Compound 17 and/or buprenor COOR, OC(O)R', N(R'), -NHC(O)R’ or C(O) phine on pain threshold in a mouse model of Sciatic nerve NHR'groups wherein each R" is independently —Horunsub ligation. The X-axis represents the animal’s pain threshold stituted—C-C alkyl. Unless indicated, the C-C monocy and the Y-axis represents time after administration of Com clic cycloalkyl is unsubstituted. pound 17 and or buprenorphine. The top left graph shows the 65 The term "C-C monocyclic cycloalkenyl' as used herein effect of vehicle, the top right graph shows the effect of is a 3-, 4-, 5-, 6-, 7- or 8-membered non-aromatic monocyclic Compound 17 (0.1 mg/kg), the bottom left graph shows the carbocyclic ring having at least one endocyclic double bond, US 8,609,833 B2 15 16 but which is notaromatic. It is to be understood that when any 7-membered monocyclic heterocycles are attached via a ring two groups, together with the carbon atom to which they are carbonatom. Representative examples of a 3- to 7-membered attached form a C-C monocyclic cycloalkenyl group, the monocyclic heterocycle group include, but are not limited to carbon atom to which the two groups are attached remains furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, tetravalent. Representative C-C monocyclic cycloalkenyl isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazo groups include, but are not limited to, cyclopropenyl, lidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, cyclobutenyl, 1.3-cyclobutadienyl, cyclopentenyl, 1.3-cyclo phenanthrolinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pentadienyl, cyclohexenyl, 1.3-cyclohexadienyl, cyclohepte pyrazolidinyl, pyrazolinyl, pyrazolyl pyridazinyl, pyridoox nyl, 1.3-cycloheptadienyl, 1.4-cycloheptadienyl, -1,3,5-cy azole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidi cloheptatrienyl, cyclooctenyl, 1.3-cyclooctadienyl, 1,4- 10 nyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofura cyclooctadienyl, -1,3,5-cyclooctatrienyl. In O embodiment, the C-C monocyclic cycloalkenyl group is nyl, thiadiazinyl, thiadiazolyl, thienyl, thienothiazolyl, Substituted with one or more of the following groups: -halo, thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophe —O (C-C alkyl). -OH, -CN, COOR', OC(O)R', nyl, triazinyl, triazolyl. In one embodiment, the 3- to 7-mem - N(R'), -NHC(O)R’ or - C(O)NHR' groups wherein 15 bered monocyclic heterocycle group is substituted with one each R' is independently —H or unsubstituted—C-C alkyl. or more of the following groups: -halo. —O—(C-C alkyl). Unless indicated, the C-C monocyclic cycloalkenyl is -OH,-CN, COOR, OC(O)R', N(R), NHC(O) unsubstituted. R' or —C(O)NHR' groups wherein each R" is independently The term "C-C bicyclic cycloalkyl as used herein is a —H or unsubstituted—C-C alkyl. Unless indicated, the 3 8-, 9-,10-, 11- or 12-membered saturated, non-aromatic bicy to 7-membered monocyclic heterocycle is unsubstituted. clic cycloalkyl ring system. Representative C-C bicyclic The term “8- to 12-membered bicyclic heterocycle” refers cycloalkyl groups include, but are not limited to, decahy to a bicyclic 8- to 12-membered aromatic or non-aromatic dronaphthalene, octahydroindene, decahydrobenzocyclo bicyclic cycloalkyl in which one or both of the of the rings of heptene, and dodecahydroheptalene. In one embodiment, the the bicyclic ring system have 1-4 of its ring carbon atoms Cs-C bicyclic cycloalkyl group is substituted with one or 25 independently replaced with a N, O or Satom. Included in this more of the following groups: -halo, —O—(C-C alkyl). class are 3- to 7-membered monocyclic heterocycles that are OH, CN, COOR', OC(O)R', N(R') - NHC(O) fused to a benzene ring. A non-aromatic ring of an 8- to R' or —C(O)NHR' groups wherein each R" is independently 12-membered monocyclic heterocycle is attached via a ring nitrogen, Sulfur, or carbon atom. An aromatic 8- to 12-mem —H or unsubstituted—C-C alkyl. bered monocyclic heterocycles are attached via a ring carbon Unless indicated, the C-C bicyclic cycloalkyl is unsub 30 atom. Examples of 8- to 12-membered bicyclic heterocycles stituted. include, but are not limited to, benzimidazolyl, benzofuranyl, The term "C-C bicyclic cycloalkenyl” as used herein is benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthia a 8-, 9-, 10-, 11- or 12-membered non-aromatic bicyclic Zolyl, benztriazolyl, benztetrzolyl, benzisoxazolyl, ben cycloalkyl ring system, having at least one endocyclic double Zisothiazolyl, benzimidazolinyl, cinnolinyl, decahydro bond. It is to be understood that when any two groups, 35 together with the carbonatom to which they are attached form quinolinyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, a C-C bicyclic cycloalkenyl group, the carbon atom to indolyl, isobenzofuranyl, isolindazolyl, isoindolyl, isoindoli which the two groups are attached remains tetravalent. Rep nyl, isoquinolinyl, naphthyridinyl, octahydroisoquinolinyl, resentative C-C bicyclic cycloalkenyl groups include, but phthalazinyl, pteridinyl, purinyl, quinoxalinyl, tetrahydroiso are not limited to, octahydronaphthalene, hexahydronaphtha 40 quinolinyl, tetrahydroquinolinyl, and Xanthenyl. In one lene, hexahydroindene, tetrahydroindene, octahydrobenzo embodiment, each ring of a the -8- to 12-membered bicyclic cycloheptene, hexahydrobenzocycloheptene, tetrahydroben heterocycle group can Substituted with one or more of the Zocyclopheptene, decahydroheptalene, octahydroheptalene, following groups: -halo. —O—(C-C alkyl). —OH, -CN. hexahydroheptalene, and tetrahydroheptalene. In one COOR', OC(O)R', N(R'), NHC(O)R’ or C(O) embodiment, the C-C bicyclic cycloalkyl group is Substi 45 NHR'groups wherein each R" is independently —Horunsub tuted with one or more of the following groups:-halo. —O— stituted —C-C alkyl. Unless indicated, the 8- to 12-mem (C-C alkyl), -OH, -CN, COOR', OC(O)R', bered bicyclic heterocycle is unsubstituted. - N(R'), -NHC(O)R’ or - C(O)NHR' groups wherein Representative examples of a “phenylene group' are each R' is independently —H or unsubstituted—C-C alkyl. depicted below: Unless indicated, the Cs-C bicyclic cycloalkenyl is unsub 50 stituted. The term “effective amount’ as used herein refers to an amount of a Purine Derivative that is effective for: (i) treating or preventing a Condition; (ii) reducing an animals rate of metabolism; or (iii) protecting an animals heart against myo 55 cardial damage during cardioplegia. The term "halo' as used herein refers to —F. —Cl, —Br or Old —I. The term “3- to 7-membered monocyclic heterocycle” refers to: (i) a 3- or 4-membered non-aromatic monocyclic 60 cycloalkyl in which 1 of the ring carbon atoms has been replaced with an N, O or Satom; or (ii) a 5-, 6-, or 7-mem bered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently The phrase “pharmaceutically acceptable salt, as used replaced with a N, O or S atom. The non-aromatic 3- to 65 herein, is a salt of an acid and a basic nitrogenatom of a Purine 7-membered monocyclic heterocycles can be attached via a Derivative. Illustrative salts include, but are not limited, to ring nitrogen, Sulfur, or carbon atom. The aromatic 3- to Sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, US 8,609,833 B2 17 18 nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, Substantially free of its corresponding other anomer contains lactate, salicylate, acid citrate, tartrate, oleate, tannate, pan no more than about 0.5% by weight of its corresponding other tothenate, bitartrate, ascorbate. Succinate, maleate, gentisi anomer. In still another embodiment a Purine Derivative that nate, fumarate, gluconate, glucaronate, Saccharate, formate, is substantially free of its corresponding other anomer con benzoate, glutamate, methanesulfonate, ethanesulfonate, tains no more than about 0.1% by weight of its corresponding benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., other anomer. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The Some chemical structures herein are depicted using bold pharmaceutically acceptable salt can also be a camphorsul and dashed lines to represent chemical bonds. These bold and fonate salt. The term “pharmaceutically acceptable salt also dashed lines depict absolute stereochemistry. A bold line refers to a salt of a Purine Derivative having an acidic func 10 tional group, such as a carboxylic acid functional group, and indicates that a substituent is above the plane of the carbon a base. Suitable bases include, but are not limited to, hydrox atom to which it is attached and a dashed line indicates that a ides of alkali metals such as Sodium, potassium, and lithium; substituent is below the plane of the carbon atom to which it hydroxides of alkaline earth metal Such as calcium and mag is attached. For example, in the illustration below: nesium; hydroxides of other metals, such as aluminum and 15 Zinc, ammonia, and organic amines, such as unsubstituted or hydroxy-Substituted mono-, di-, or tri-alkylamines, dicyclo hexylamine; tributyl amine; pyridine; N-methyl, N-ethy lamine; diethylamine; triethylamine; mono-, bis-, or tris-(2- 2 OH-lower alkylamines). Such as mono-, bis-, or tris-(2- A B hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris (hydroxymethyl)methylamine, N,N-di-lower alkyl-N- group A is above the plane of the carbon atom to which it is (hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2- attached and group B is below the plane of the carbonatom to hydroxyethyl)amine O tri-(2-hydroxyethyl)amine; which it is attached. N-methyl-D-glucamine; and amino acids such as arginine, 25 The following abbreviations are used herein and have the lysine, and the like. The term “pharmaceutically acceptable indicated definitions: AcO is acetic anhydride; ATP is salt also includes a hydrate of a Purine Derivative. adenosine triphosphate: CCPA is 2-chloro-N'-cyclopenty An “animal' is a mammal, e.g., a human, mouse, rat, ladenosine; CPA is N'-cyclopentyladenosine; CSA is cam guinea pig, dog, cat, horse, cow, pig, or non-human primate, phorsulfonic acid; CHO is chinese hamster ovary; DMF is Such as a monkey, chimpanzee, baboon or rhesus. In one 30 N,N-dimethylformamide: EGTA is ethylene glycol bis(3- embodiment, an animal is a human. aminoethyl ether)-N.N.N',N'-tetraacetic acid; EtnH is ethy The term "isolated and purified as used herein means lamine; EtOAc is ethyl acetate; EtOH is ethanol; LiHMDS is separate from other components of a reaction mixture or lithium hexamethyldisilazide; MeOH is methanol; MS is natural source. In certain embodiments, the isolate contains at mass spectrometry; NECA is adenosine-5'-(N-ethyl)car least 30%, at least 35%, at least 40%, at least 45%, at least 35 boxamido: NMR is nuclear magnetic resonance; R-PIA is 50%, at least 55%, at least 60%, at least 65%, at least 70%, at N'-(2-phenyl-isopropyl) adenosine, R-isomer; TFA is trif least 75%, at least 80%, at least 85%, at least 90%, at least luoroacetic acid; THF is tetrahydrofuran: TMSOTf is trim 95% or at least 98% of a Purine Derivative by weight of the ethylsilyl trifluoromethanesulfonate. isolate. In one embodiment, the isolate contains at least 95% of a Purine Derivative by weight of the isolate. 40 5.2 The Purine Derivatives The term “substantially free of its corresponding opposite enantiomer as used herein, means that a Purine Derivative 5.2.1 The Purine Derivatives of Formula (Ia) contains no more than about 10% by weight of its correspond ing opposite enantiomer. In one embodiment the Purine As stated above, the present invention encompasses Purine Derivative that is substantially free of its corresponding oppo 45 Derivatives having the Formula (Ia): site enantiomer contains no more than about 5% by weight of its corresponding opposite enantiomer. In a further embodi ment a Purine Derivative that is substantially free of its cor (Ia) responding opposite enantiomer contains no more than about 1% by weight of its corresponding opposite enantiomer. In 50 another embodiment a Purine Derivative that is substantially free of its corresponding opposite enantiomer contains no more than about 0.5% by weight of its corresponding oppo site enantiomer. In still another embodimenta Purine Deriva tive that is Substantially free of its corresponding opposite 55 wherein A, B, C and D are defined above for the Purine enantiomer contains no more than about 0.1% by weight of its Derivatives of Formula (Ia), and A and B are trans with corresponding opposite enantiomer. respect to each other; B and C are cis with respect to each The term “substantially free of its corresponding other other; and C and Dare cis or trans with respect to each other. anomer as used herein, means that a Purine Derivative con In one embodiment, R' is —Cs-Cs monocyclic cycloalkyl. tains no more than about 10% by weight of its corresponding 60 In a specific embodiment, R' is cyclopenty1. otheranomer. In one embodiment the Purine Derivative that is In another embodiment, R' is —C-C monocyclic Substantially free of its corresponding other anomer contains cycloalkenyl. no more than about 5% by weight of its corresponding other In another embodiment, R' is —Cs-C bicyclic cycloalkyl anomer. In a further embodiment a Purine Derivative that is or —Cs-C bicyclic cycloalkenyl. Substantially free of its corresponding other anomer contains 65 In still another embodiment, R' is -(CH2), (C-Cs no more than about 1% by weight of its corresponding other monocyclic cycloalkyl) or —(CH), (C-C monocyclic anomer. In another embodiment a Purine Derivative that is cycloalkenyl). US 8,609,833 B2 19 20 In one embodiment, R is -halo. In another embodiment, the Purine Derivatives of Formula In a specific embodiment, R is - C1. (Ia) have the formula (Ia"), depicted above, wherein A, B, C In another embodiment, R is —CN. and Dare defined above for the Purine Derivatives of Formula In another embodiment, R is NHR,--OR or -SR. (Ia), and wherein the Purine Derivatives of Formula (Ia") are In a further embodiment, R is NHC(O)R, NHC(O) 5 Substantially free of their corresponding opposite enantiomer. OR or NHC(O)NHR'. In another embodiment, the Purine Derivatives of Formula In another embodiment, R is NHNHC(O)R. (Ia) exist as a mixture of a Purine Derivative of Formula (Ia') NHNHC(O)CR or NHNHC(O)NHR'. In yet another and a Purine Derivative of Formula (Ia") wherein the amount embodiment, R is NH-N=C(R)R’. of the Purine Derivative of Formula (Ia') exceeds the amount In one embodiment, C and D are cis with respect to each 10 of the Purine Derivative of Formula (Ia"). other. In a further embodiment, the Purine Derivatives of For In another embodiment, C and Dare trans with respect to mula (Ia) exist as a mixture of a Purine Derivative of Formula each other. (Ia') and a Purine Derivative of Formula (Ia") wherein the The present invention also provides compositions compris- 15 amount of the Purine Derivative of Formula (Ia") exceeds the ing an effective amount of a Purine Derivative of Formula (Ia) amount of the Purine Derivative of Formula (Ia'). and a physiologically acceptable carrier or vehicle. In another embodiment, the Purine Derivatives of Formula The invention further provides Purine Derivatives of For (Ia) exist as a racemic mixture of a Purine Derivative of mula (Ia) that are in isolated and purified form. Formula (Ia") and a Purine Derivative of Formula (Ia"). The invention still further provides methods for treating or 2O In another embodiment, the Purine Derivatives of Formula preventing a Condition, comprising administering an effec (Ia) can exist in the form of a single enantiomer, for example, tive amount of a Purine Derivative of Formula (Ia) to an that depicted by either formula (Iaa") or (Iaa"): animal in need thereof. The invention further provides methods for reducing an animals rate of metabolism, comprising administering an effective amount of a Purine Derivative of Formula (Ia) to an 25 animal in need thereof. The invention further provides methods for protecting an animals heart against myocardial damage during cardiople gia, comprising administering an effective amount of a Purine Derivative of Formula (Ia) to an animal in need thereof. 30 (Iaa") The Purine Derivatives of Formula (Ia) can exist in the form of a single enantiomer, for example, that depicted by either the Formula (Ia') or Formula (Ia"): 35 (Ia') wherein A, B, C and D are defined above for the Purine Derivatives of Formula (Ia). A Purine Derivative of Formula (Iaa") is the corresponding 40 opposite enantiomer of a Purine Derivative of Formula (Iaa") when group A of the Purine Derivative of Formula (Iaa') is the (Ia") same as group A of the Purine Derivative of Formula (Iaa") and when group D of the Purine Derivative of Formula (Iaa') is the same as group D of the Purine Derivative of Formula 45 (Iaa"). A Purine Derivative of Formula (Iaa") is the corresponding opposite enantiomer of a Purine Derivative of Formula (Iaa') when group A of the Purine Derivative of Formula (Iaa") is the wherein A, B, C and D are defined above for the Purine same as group A of the Purine Derivative of Formula (Iaa') Derivatives of Formula (Ia). 50 and when group D of the Purine Derivative of Formula (Iaa") A Purine Derivative of Formula (Ia') is the corresponding is the same as group D of the Purine Derivative of Formula opposite enantiomer of a Purine Derivative of Formula (Ia") (Iaa"). when group A of the Purine Derivative of Formula (Ia) is the In one embodiment, the Purine Derivatives of Formula (Ia) same as group A of the Purine Derivative of Formula (Ia") and have the formula (Iaa'), depicted above, wherein A, B, C and when group D of the Purine Derivative of Formula (Ia") is the 55 D are defined above for the Purine Derivatives of Formula same as group D of the Purine Derivative of Formula (Ia"). (Ia), and wherein the Purine Derivatives of Formula (Iaa") are A Purine Derivative of Formula (Ia") is the corresponding Substantially free of their corresponding opposite enantiomer. opposite enantiomer of a Purine Derivative of Formula (Ia') In another embodiment, the Purine Derivatives of Formula when group A of the Purine Derivative of Formula (Ia") is the (Ia) have the formula (Iaa"), depicted above, wherein A, B, C same as group A of the Purine Derivative of Formula (Ia) and 60 and Dare defined above for the Purine Derivatives of Formula when group D of the Purine Derivative of Formula (Ia") is the (Ia), and wherein the Purine Derivatives of Formula (Iaa") are same as group D of the Purine Derivative of Formula (Ia'). Substantially free of their corresponding opposite enantiomer. In one embodiment, the Purine Derivatives of Formula (Ia) In another embodiment, the Purine Derivatives of Formula have the formula (Ia), depicted above, wherein A, B, C and D (Ia) exist as a mixture of a Purine Derivative of Formula (Iaa') are defined above for the Purine Derivatives of Formula (Ia), 65 and a Purine Derivative of Formula (Iaa") wherein the amount and wherein the Purine Derivatives of Formula (Ia) are sub of the Purine Derivative of Formula (Iaa") exceeds the amount stantially free of their corresponding opposite enantiomer. of the Purine Derivative of Formula (Iaa"). US 8,609,833 B2 21 22 In a further embodiment, the Purine Derivatives of For a Purine Derivative of Formula (Iaa") wherein the amount of mula (Ia) exist as a mixture of a Purine Derivative of Formula the Purine Derivative of Formula (Ia") exceeds the amount of (Iaa") and a Purine Derivative of Formula (Iaa") wherein the the Purine Derivative of Formula (Iaa"). amount of the Purine Derivative of Formula (Iaa") exceeds In another embodiment, the Purine Derivatives of Formula the amount of the Purine Derivative of Formula (Iaa"). (Ia) exist as a mixture of a Purine Derivative of Formula (Ia") In another embodiment, the Purine Derivatives of Formula and a Purine Derivative of Formula (Iaa") wherein the amount (Ia) exist as a racemic mixture of a Purine Derivative of of the Purine Derivative of Formula (Iaa") exceeds the Formula (Iaa") and a Purine Derivative of Formula (Iaa"). amount of the Purine Derivative of Formula (Ia"). A Purine Derivative of Formula (Iaa") is the corresponding In a further embodiment, the Purine Derivatives of For other anomer of a Purine Derivative of Formula (Ia") when 10 group A of the Purine Derivative of Formula (Iaa") is the same mula (Ia) exist as a equal mixture of a Purine Derivative of as group A of the Purine Derivative of Formula (Ia") and when Formula (Ia") and a Purine Derivative of Formula (Iaa"). group D of the Purine Derivative of Formula (Iaa") is the same as group D of the Purine Derivative of Formula (Ia'). 5.2.2 The Purine Derivatives of Formula (Ib) A Purine Derivative of Formula (Ia') is the corresponding 15 other anomer of a Purine Derivative of Formula (Iaa") when As stated above, the present invention encompasses Purine group A of the Purine Derivative of Formula (Ia) is the same Derivatives having the Formula (Ib): as group A of the Purine Derivative of Formula (Iaa") and when group D of the Purine Derivative of Formula (Ia") is the same as group D of the Purine Derivative of Formula (Iaa"). (Ib) A Purine Derivative of Formula (Iaa") is the corresponding other anomer of a Purine Derivative of Formula (Ia") when group A of the Purine Derivative of Formula (Iaa") is the same as group A of the Purine Derivative of Formula (Ia") and when group D of the Purine Derivative of Formula (Iaa") is the same 25 as group D of the Purine Derivative of Formula (Ia"). A Purine Derivative of Formula (Ia") is the corresponding wherein A, B, C and D are defined above for the Purine other anomer of a Purine Derivative of Formula (Iaa") when Derivatives of Formula (Ib), and A and B are trans with group A of the Purine Derivative of Formula (Ia") is the same respect to each other; B and C are cis with respect to each as group A of the Purine Derivative of Formula (Iaa") and 30 other; and C and Dare cis or trans with respect to each other. when group D of the Purine Derivative of Formula (Ia") is the In one embodiment, R' is H. same as group D of the Purine Derivative of Formula (Iaa"). In another embodiment, R' is —C-C monocyclic In one embodiment, the Purine Derivatives of Formula (Ia) cycloalkyl. have the formula (Iaa'), depicted above, wherein A, B, C and In a specific embodiment, R' is cyclopenty1. D are defined above for the Purine Derivatives of Formula 35 In another embodiment, R' is —C-C monocyclic (Ia), and wherein the Purine Derivatives of Formula (Iaa") are cycloalkenyl. Substantially free of their corresponding other anomer. In another embodiment, R' is —Cs-C2 bicyclic cycloalkyl In another embodiment, the Purine Derivatives of Formula or —Cs-C bicyclic cycloalkenyl. (Ia) have the formula (Iaa"), depicted above, wherein A, B, C In still another embodiment, R' is -(CH2), (C-Cs and Dare defined above for the Purine Derivatives of Formula 40 monocyclic cycloalkyl) or —(CH), (C-C monocyclic (Ia), and wherein the Purine Derivatives of Formula (Iaa") are cycloalkenyl). Substantially free of their corresponding other anomer. In another embodiment, R is —CN. In one embodiment, the Purine Derivatives of Formula (Ia) In another embodiment, R is NHR'. have the formula (Ia), depicted above, wherein A, B, C and D In a further embodiment, R is NHC(O)R. NHC(O) are defined above for the Purine Derivatives of Formula (Ia), 45 OR or NHC(O)NHR'. and wherein the Purine Derivatives of Formula (Ia) are sub In another embodiment, R is NHNHC(O)R, stantially free of their corresponding other anomer. NHNHC(O)OR or NHNHC(O)NHR'. In another embodiment, the Purine Derivatives of Formula In yet another embodiment, R is NH N=C(R)R’. (Ia) have the formula (Ia"), depicted above, wherein A, B, C In one embodiment, C and D are cis with respect to each and Dare defined above for the Purine Derivatives of Formula 50 other. (Ia), and wherein the Purine Derivatives of Formula (Ia") are In another embodiment, C and Dare trans with respect to Substantially free of their corresponding other anomer. each other. In one embodiment, the Purine Derivatives of Formula (Ia) The present invention also provides compositions compris exist as a mixture of a Purine Derivative of Formula (Ia) and ing an effective amount of a Purine Derivative of Formula (Ib) a Purine Derivative of Formula (Iaa") wherein the amount of 55 and a physiologically acceptable carrier or vehicle. the Purine Derivative of Formula (Ia) exceeds the amount of The invention further provides Purine Derivatives of For the Purine Derivative of Formula (Iaa'). mula (Ib) that are in isolated and purified form. In another embodiment, the Purine Derivatives of Formula The invention still further provides methods for treating or (Ia) exist as a mixture of a Purine Derivative of Formula (Ia') preventing a Condition, comprising administering an effec and a Purine Derivative of Formula (Iaa") wherein the amount 60 tive amount of a Purine Derivative of Formula (Ib) to an of the Purine Derivative of Formula (Iaa") exceeds the amount animal in need thereof. of the Purine Derivative of Formula (Ia). The invention further provides methods for reducing an In a further embodiment, the Purine Derivatives of For animals rate of metabolism, comprising administering an mula (Ia) exist as a equal mixture of a Purine Derivative of effective amount of a Purine Derivative of Formula (Ib) to an Formula (Ia') and a Purine Derivative of Formula (Iaa'). 65 animal in need thereof. In one embodiment, the Purine Derivatives of Formula (Ia) The invention further provides methods protecting an ani exist as a mixture of a Purine Derivative of Formula (Ia") and mals heart against myocardial damage during cardioplegia, US 8,609,833 B2 23 24 comprising administering an effective amount of a Purine Derivative of Formula (Ib) to an animal in need thereof. The Purine Derivatives of Formula (Ib) can exist in the form of a single enantiomer, for example, that depicted by either the Formula (Ib") or Formula (Ib"):

(Ibb") (Ib) 10

(Ib") wherein A, B, C and D are defined above for the Purine 15 Derivatives of Formula (Ib). A Purine Derivative of Formula (Ibb') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Ibb") when group A of the Purine Derivative of Formula (Ibb') is the same as group A of the Purine Derivative of Formula (Ibb") and when group D of the Purine Derivative of Formula (Ibb') wherein A, B, C and D are defined above for the Purine is the same as group D of the Purine Derivative of Formula Derivatives of Formula (Ib). (Ibb"). A Purine Derivative of Formula (Ib") is the corresponding A Purine Derivative of Formula (Ibb") is the corresponding opposite enantiomer of a Purine Derivative of Formula (Ib") 25 opposite enantiomer of a Purine Derivative of Formula (Ibb') when group A of the Purine Derivative of Formula (Ib") is the when group A of the Purine Derivative of Formula (Ibb") is same as group A of the Purine Derivative of Formula (Ib") and the same as group A of the Purine Derivative of Formula (Ibb') when group D of the Purine Derivative of Formula (Ib") is the and when group D of the Purine Derivative of Formula (Ibb") same as group D of the Purine Derivative of Formula (Ib"). is the same as group D of the Purine Derivative of Formula A Purine Derivative of Formula (Ib") is the corresponding 30 (Ibb'). opposite enantiomer of a Purine Derivative of Formula (Ib') In one embodiment, the Purine Derivatives of Formula (Ib) when group A of the Purine Derivatives of Formula (Ib") is the have the formula (Ibb'), depicted above, wherein A, B, C and same as group A of the Purine Derivative of Formula (Ib") and D are defined above for the Purine Derivatives of Formula when group D of the Purine Derivative of Formula (Ib") is the 35 (Ib), and wherein the Purine Derivatives of Formula (Ibb') are same as group D of the Purine Derivative of Formula (IN). Substantially free of their corresponding opposite enantiomer. In another embodiment, the Purine Derivatives of Formula In one embodiment, the Purine Derivatives of Formula (Ib) (Ib) have the formula (Ibb"), depicted above, wherein A, B, C have the formula (Ib"), depicted above, wherein A, B, C and D and Dare defined above for the Purine Derivatives of Formula are defined above for the Purine Derivatives of Formula (Ib). 40 (Ib), and wherein the Purine Derivatives of Formula (Ibb") are and wherein the Purine Derivatives of Formula (Ib") are sub Substantially free of their corresponding opposite enantiomer. stantially free of their corresponding enantiomer, represented In another embodiment, the Purine Derivatives of Formula by Formula (Ib"). (Ib) exist as a mixture of a Purine Derivative of Formula (Ibb') In another embodiment, the Purine Derivatives of Formula and a Purine Derivative of Formula (Ibb") wherein the (Ib) have the formula (Ib"), depicted above, wherein A, B, C 45 amount of the Purine Derivative of Formula (Ibb') exceeds the and Dare defined above for the Purine Derivatives of Formula amount of the Purine Derivative of Formula (Ibb"). (Ib), and wherein the Purine Derivatives of Formula (Ib") are In a further embodiment, the Purine Derivatives of For Substantially free of their corresponding enantiomer, repre mula (Ib) exist as a mixture of a Purine Derivative of Formula sented by Formula (IN). (Ibb') and a Purine Derivative of Formula (Ibb") wherein the In one embodiment, the Purine Derivatives of Formula (Ib) 50 amount of the Purine Derivative of Formula (Ibb") exceeds exist as a mixture of a Purine Derivative of Formula (Ib") and the amount of the Purine Derivative of Formula (Ibb'). a Purine Derivative of Formula (Ib") wherein the amount of In another embodiment, the Purine Derivatives of Formula the Purine Derivative of Formula (Ib") exceeds the amount of (Ib) exist as a racemic mixture of a Purine Derivative of the Purine Derivative of Formula (Ib"). 55 Formula (Ibb') and a Purine Derivative of Formula (Ibb"). In another embodiment, the Purine Derivatives of Formula A Purine Derivative of Formula (Ibb') is the corresponding (Ib) exist as a mixture of a Purine Derivative of Formula (Ib') other anomer of a Purine Derivative of Formula (Ib") when and a Purine Derivative of Formula (Ib") wherein the amount group A of the Purine Derivative of Formula (Ibb') is the same of the Purine Derivative of Formula (Ib") exceeds the amount as group A of the Purine Derivative of Formula (Ib") and when of the Purine Derivative of Formula (IN). 60 group D of the Purine Derivative of Formula (Ibb') is the same as group D of the Purine Derivative of Formula (IN). In another embodiment, the Purine Derivatives of Formula A Purine Derivative of Formula (Ib') is the corresponding (Ib) exist as a racemic mixture of a Purine Derivative of other anomer of a Purine Derivative of Formula (Ibb') when Formula (Ib") and a Purine Derivative of Formula (Ib"). group A of the Purine Derivative of Formula (Ib') is the same In another embodiment, the Purine Derivatives of Formula 65 as group A of the Purine Derivative of Formula (Ibb') and (Ib) can exist in the form of a single enantiomer, for example, when group D of the Purine Derivative of Formula (Ib") is the that depicted by either formula (Ibb') or (Ibb"): same as group D of the Purine Derivative of Formula (Ibb'). US 8,609,833 B2 25 26 A Purine Derivative of Formula (Ibb") is the corresponding Illustrative Purine Derivatives of Formula (Ib) include the other anomer of a Purine Derivative of Formula (Ib") when compound listed below: group A of the Purine Derivative of Formula (Ibb") is the same as group A of the Purine Derivative of Formula (Ib") and when s 25 group D of the Purine Derivative of Formula (Ibb") is the same as group D of the Purine Derivative of Formula (Ib"). A Purine Derivative of Formula (Ib") is the corresponding other anomer of a Purine Derivative of Formula (Ibb") when 10 group A of the Purine Derivative of Formula (Ib") is the same as group A of the Purine Derivative of Formula (Ibb") and when group D of the Purine Derivative of Formula (Ib") is the same as group D of the Purine Derivative of Formula (Ibb"). 15 In one embodiment, the Purine Derivatives of Formula (Ib) have the formula (Ibb'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (Ib), and wherein the Purine Derivatives of Formula (Ibb') are 5.2.3 The Purine Derivatives of Formula (Ic) Substantially free of their corresponding other anomer. As stated above, the present invention encompasses Purine In another embodiment, the Purine Derivatives of Formula Derivatives having the Formula (Ic): (Ib) have the formula (Ibb"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula 25 (Ib), and wherein the Purine Derivatives of Formula (Ibb") are (Ic) Substantially free of their corresponding other anomer. In one embodiment, the Purine Derivatives of Formula (Ib) have the formula (Ib'), depicted above, wherein A, B, C and D so are defined above for the Purine Derivatives of Formula (Ib). and wherein the Purine Derivatives of Formula (Ib") are sub stantially free of their corresponding other anomer. wherein A, B, C and D are defined above for the Purine In another embodiment, the Purine Derivatives of Formula Derivatives of Formula (Ic), and A and B are trans with (Ib) have the formula (Ib"), depicted above, wherein A, B, C respect to each other; B and C are cis with respect to each and Dare defined above for the Purine Derivatives of Formula other; and C and Dare cis or trans with respect to each other. (Ib), and wherein the Purine Derivatives of Formula (Ib") are In one embodiment, R' is H. Substantially free of their corresponding other anomer. In another embodiment, R' is -C-Cio alkyl. In one embodiment, the Purine Derivatives of Formula (Ib) 40 In one embodiment, R' is -aryl or -(CH2)-aryl. exist as a mixture of a Purine Derivative of Formula (Ib") and In another embodiment, R is —Cs-Cs monocyclic a Purine Derivative of Formula (Ibb') wherein the amount of cycloalkyl. the Purine Derivative of Formula (Ib") exceeds the amount of In a specific embodiment, R' is cyclopenty1. the Purine Derivative of Formula (Ibb'). In another embodiment, R' is —Cs-Cs monocyclic In another embodiment, the Purine Derivatives of Formula cycloalkenyl. (Ib) exist as a mixture of a Purine Derivative of Formula (Ib') In another embodiment, R' is —Cs-C2 bicyclic cycloalkyl and a Purine Derivative of Formula (Ibb') wherein the amount or —Cs-C bicyclic cycloalkenyl. of the Purine Derivative of Formula (Ibb') exceeds the amount In still another embodiment, R' is -(CH2), (C-Cs of the Purine Derivative of Formula (IN). 50 monocyclic cycloalkyl) or —(CH), (C-C monocyclic In another embodiment, the Purine Derivatives of Formula cycloalkenyl). (Ib) exist as a equal mixture of a Purine Derivative of Formula In another embodiment, R' is -3- to 7-membered mono (Ib") and a Purine Derivative of Formula (Ibb'). cyclic heterocycle or -8- to 12-membered bicyclic hetero cycle. In one embodiment, the Purine Derivatives of Formula (Ib) exist as a mixture of a Purine Derivative of Formula (Ib") and 55 In another embodiment, R is NHR'. --OR or - SR". a Purine Derivative of Formula (Ibb") wherein the amount of In a further embodiment, R is NHC(O)R. NHC(O) the Purine Derivative of Formula (Ib") exceeds the amount of OR or NHC(O)NHR'. the Purine Derivative of Formula (Ibb"). In another embodiment, R is NHNHC(O)R, In another embodiment, the Purine Derivatives of Formula NHNHC(O)CR or NHNHC(O)NHR'. In one embodi (Ib) exist as a mixture of a Purine Derivative of Formula (Ib") ment, R is C(O)O(C-C alkyl). and a Purine Derivative of Formula (Ibb") wherein the In another embodiment, R is C(O)NH(C-C alkyl). amount of the Purine Derivative of Formula (Ibb") exceeds —C(O)N(C-C alkyl), or—C(O)NH-aryl. the amount of the Purine Derivative of Formula (Ib"). In another embodiment, R is —CH(NH)NH, or -CH In another embodiment, the Purine Derivatives of Formula 65 (NH)NH(C-C alkyl). (Ib) exist as a equal mixture of a Purine Derivative of Formula In one embodiment, C and D are cis with respect to each (Ib") and a Purine Derivative of Formula (Ibb"). other. US 8,609,833 B2 27 28 In another embodiment, C and Dare trans with respect to the Purine Derivative of Formula (Ic") exceeds the amount of each other. the Purine Derivative of Formula (Ic"). The present invention also provides compositions compris In another embodiment, the Purine Derivatives of Formula ing an effective amount of a Purine Derivative of Formula (Ic) (Ic) exist as a mixture of a Purine Derivative of Formula (Ic") and a physiologically acceptable carrier or vehicle. and a Purine Derivative of Formula (Ic") wherein the amount The invention further provides Purine Derivatives of For of the Purine Derivative of Formula (Ic") exceeds the amount mula (Ic) that are in isolated and purified form. of the Purine Derivative of Formula (Ic"). The invention still further provides methods for treating or In another embodiment, the Purine Derivatives of Formula preventing a Condition, comprising administering an effec (Ic) exist as a racemic mixture of a Purine Derivative of tive amount of a Purine Derivative of Formula (Ic) to an 10 Formula (Ic") and a Purine Derivative of Formula (Ic"). animal in need thereof. In another embodiment, the Purine Derivatives of Formula The invention further provides methods for reducing an (Ic) can exist in the form of a single enantiomer, for example, animals rate of metabolism, comprising administering an that depicted by either formula (Icc') or (Icc"): effective amount of a Purine Derivative of Formula (Ic) to an 15 animal in need thereof. The invention further provides methods protecting an ani (Icc') mals heart against myocardial damage during cardioplegia, comprising administering an effective amount of a Purine Derivative of Formula (Ic) to an animal in need thereof. The Purine Derivatives of Formula (Ic) can exist in the form of a single enantiomer, for example, that depicted by (Icc") either the Formula (Ic") or Formula (Ic"):

25 (Ic)

wherein A, B, C and D are defined above for the Purine 30 Derivatives of Formula (Ic). A Purine Derivative of Formula (Icc') is the corresponding (Ic") opposite enantiomer of a Purine Derivative of Formula (Icc") when group A of the Purine Derivative of Formula (Icc') is the same as group A of the Purine Derivative of Formula (Icc") 35 and when group D of the Purine Derivative of Formula (Icc') is the same as group D of the Purine Derivative of Formula (Icc"). A Purine Derivative of Formula (Icc") is the corresponding wherein A, B, C and D are defined above for the Purine opposite enantiomer of a Purine Derivative of Formula (Icc') Derivatives of Formula (Ic). 40 when group A of the Purine Derivative of Formula (Icc") is the A Purine Derivative of Formula (Ic") is the corresponding same as group A of the Purine Derivative of Formula (Icc') opposite enantiomer of a Purine Derivative of Formula (Ic") and when group D of the Purine Derivative of Formula (Icc") when group A of the Purine Derivative of Formula (Ic") is the is the same as group D of the Purine Derivative of Formula same as group A of the Purine Derivative of Formula (Ic") and (Icc'). when group D of the Purine Derivative of Formula (Ic") is the 45 In one embodiment, the Purine Derivatives of Formula (Ic) same as group D of the Purine Derivative of Formula (Ic"). have the formula (Icc'), depicted above, wherein A, B, C and A Purine Derivative of Formula (Ic") is the corresponding D are defined above for the Purine Derivatives of Formula opposite enantiomer of a Purine Derivative of Formula (Ic) (Ic), and wherein the Purine Derivatives of Formula (Icc') are when group A of the Purine Derivatives of Formula (Ic") is the Substantially free of their corresponding opposite enantiomer. same as group A of the Purine Derivative of Formula (Ic") and 50 In another embodiment, the Purine Derivatives of Formula when group D of the Purine Derivative of Formula (Ic") is the (Ic) have the formula (Icc"), depicted above, wherein A, B, C same as group D of the Purine Derivative of Formula (Ic). and Dare defined above for the Purine Derivatives of Formula In one embodiment, the Purine Derivatives of Formula (Ic) (Ic), and wherein the Purine Derivatives of Formula (Icc") are have the formula (Ic"), depicted above, wherein A, B, C and D Substantially free of their corresponding opposite enantiomer. are defined above for the Purine Derivatives of Formula (Ic), 55 In another embodiment, the Purine Derivatives of Formula and wherein the Purine Derivatives of Formula (Ic") are sub (Ic) exist as a mixture of a Purine Derivative of Formula (Icc') stantially free of their corresponding enantiomer, represented and a Purine Derivative of Formula (Icc") wherein the amount by Formula (Ic"). of the Purine Derivative of Formula (Icc') exceeds the amount In another embodiment, the Purine Derivatives of Formula of the Purine Derivative of Formula (Icc"). (Ic) have the formula (Ic"), depicted above, wherein A, B, C 60 In a further embodiment, the Purine Derivatives of For and Dare defined above for the Purine Derivatives of Formula mula (Ic) exist as a mixture of a Purine Derivative of Formula (Ic), and wherein the Purine Derivatives of Formula (Ic") are (Icc') and a Purine Derivative of Formula (Icc") wherein the Substantially free of their corresponding enantiomer, repre amount of the Purine Derivative of Formula (Icc") exceeds sented by Formula (Ic"). the amount of the Purine Derivative of Formula (Icc'). In one embodiment, the Purine Derivatives of Formula (Ic) 65 In another embodiment, the Purine Derivatives of Formula exist as a mixture of a Purine Derivative of Formula (Ic") and (Ic) exist as a racemic mixture of a Purine Derivative of a Purine Derivative of Formula (Ic") wherein the amount of Formula (Icc') and a Purine Derivative of Formula (Icc"). US 8,609,833 B2 29 30 A Purine Derivative of Formula (Icc') is the corresponding In another embodiment, the Purine Derivatives of Formula other anomer of a Purine Derivative of Formula (Ic") when (Ic) exist as a equal mixture of a Purine Derivative of Formula group A of the Purine Derivative of Formula (Icc') is the same (Ic") and a Purine Derivative of Formula (Icc"). as group A of the Purine Derivative of Formula (Ic") and when group D of the Purine Derivative of Formula (Icc') is the same 5.2.4 The Purine Derivatives of Formula (Id) as group D of the Purine Derivative of Formula (Ic"). A Purine Derivative of Formula (Ic") is the corresponding As stated above, the present invention encompasses Purine other anomer of a Purine Derivative of Formula (Icc') when Derivatives having the Formula (Id): group A of the Purine Derivative of Formula (Ic") is the same as group A of the Purine Derivative of Formula (Icc') and 10 when group D of the Purine Derivative of Formula (Ic") is the (Id) same as group D of the Purine Derivative of Formula (Icc'). A Purine Derivative of Formula (Icc") is the corresponding other anomer of a Purine Derivative of Formula (Ic") when group A of the Purine Derivative of Formula (Icc") is the same 15 as group A of the Purine Derivative of Formula (Ic") and when group D of the Purine Derivative of Formula (Icc") is the same as group D of the Purine Derivative of Formula (Ic"). wherein A, B, C and D are defined above for the Purine A Purine Derivative of Formula (Ic") is the corresponding Derivatives of Formula (Id), and A and B are trans with other anomer of a Purine Derivative of Formula (Icc") when respect to each other; B and C are cis with respect to each group A of the Purine Derivative of Formula (Ic") is the same other; and C and Dare cis or trans with respect to each other. as group A of the Purine Derivative of Formula (Icc") and In one embodiment, R' is —H. when group D of the Purine Derivative of Formula (Ic") is the In another embodiment, R' is -C-Cio alkyl. same as group D of the Purine Derivative of Formula (Icc"). In one embodiment, R' is -aryl or -(CH2), aryl. In one embodiment, the Purine Derivatives of Formula (Ic) 25 have the formula (Icc'), depicted above, wherein A, B, C and In another embodiment, R' is —C-C monocyclic D are defined above for the Purine Derivatives of Formula cycloalkyl. (Ic), and wherein the Purine Derivatives of Formula (Icc') are In a specific embodiment, R' is cyclopenty1. Substanticly free of their corresponding other anomer. In another embodiment, R' is —C-C monocyclic In another embodiment, the Purine Derivatives of Formula 30 cycloalkenyl. (Ic) have the formula (Icc"), depicted above, wherein A, B, C In another embodiment, R' is —Cs-C2 bicyclic cycloalkyl and Dare defined above for the Purine Derivatives of Formula or —C-C bicyclic cycloalkenyl. (Ic), and wherein the Purine Derivatives of Formula (Icc") are In still another embodiment, R' is -(CH2), (C-Cs Substantially free of their corresponding other anomer. monocyclic cycloalkyl) or —(CH), (C-C monocyclic In one embodiment, the Purine Derivatives of Formula (Ic) 35 cycloalkenyl). have the formula (Ic"), depicted above, wherein A, B, C and D In another embodiment, R' is -3- to 7-membered mono are defined above for the Purine Derivatives of Formula (Ic), cyclic heterocycle or -8- to 12-membered bicyclic hetero and wherein the Purine Derivatives of Formula (Ic") are sub cycle. stantially free of their corresponding other anomer. In one embodiment, R is H. In another embodiment, the Purine Derivatives of Formula 40 In one embodiment, Ris-halo. (Ic) have the formula (Ic"), depicted above, wherein A, B, C In a specific embodiment, R is —Cl. and Dare defined above for the Purine Derivatives of Formula In another embodiment, R is —CN. (Ic), and wherein the Purine Derivatives of Formula (Ic") are In another embodiment, R is NHR'. --OR or - SR". Substantially free of their corresponding other anomer. In a further embodiment, R is NHC(O)R. NHC(O) In one embodiment, the Purine Derivatives of Formula (Ic) 45 OR or NHC(O)NHR'. exist as a mixture of a Purine Derivative of Formula (Ic") and In another embodiment, R is NHNHC(O)R, a Purine Derivative of Formula (Icc') wherein the amount of NHNHC(O)OR or NHNHC(O)NHR'. the Purine Derivative of Formula (Ic") exceeds the amount of In yet another embodiment, R is NH N=C(R)R’. the Purine Derivative of Formula (Icc'). In one embodiment, R is —CHONO. In another embodiment, the Purine Derivatives of Formula 50 In another embodiment, R is —CHOSOH. (Ic) exist as a mixture of a Purine Derivative of Formula (Ic) In one embodiment, C and D are cis with respect to each and a Purine Derivative of Formula (Icc') wherein the amount other. of the Purine Derivative of Formula (Icc') exceeds the amount In another embodiment, C and Dare trans with respect to of the Purine Derivative of Formula (Ic"). each other. In another embodiment, the Purine Derivatives of Formula 55 The present invention also provides compositions compris (Ic) exist as a equal mixture of a Purine Derivative of Formula ing an effective amount of a Purine Derivative of Formula (Id) (Ic") and a Purine Derivative of Formula (Icc'). and a physiologically acceptable carrier or vehicle. In one embodiment, the Purine Derivatives of Formula (Ic) The invention further provides Purine Derivatives of For exist as a mixture of a Purine Derivative of Formula (Ic") and mula (Id) that are in isolated and purified form. a Purine Derivative of Formula (Icc") wherein the amount of 60 The invention still further provides methods for treating or the Purine Derivative of Formula (Ic") exceeds the amount of preventing a Condition, comprising administering an effec the Purine Derivative of Formula (Icc"). tive amount of a Purine Derivative of Formula (Id) to an In another embodiment, the Purine Derivatives of Formula animal in need thereof. (Ic) exist as a mixture of a Purine Derivative of Formula (Ic") The invention further provides methods for reducing an and a Purine Derivative of Formula (Icc") wherein the amount 65 animals rate of metabolism, comprising administering an of the Purine Derivative of Formula (Icc") exceeds the effective amount of a Purine Derivative of Formula (Id) to an amount of the Purine Derivative of Formula (Ic"). animal in need thereof. US 8,609,833 B2 31 32 The invention further provides methods protecting an ani mals heart against myocardial damage during cardioplegia, (Idd') comprising administering an effective amount of a Purine Derivative of Formula (Id) to an animal in need thereof. The Purine Derivatives of Formula (Id) can exist in the form of a single enantiomer, for example, that depicted by either the Formula (Id') or Formula (Id"): (Idd')

10 (Id')

15 wherein A, B, C and D are defined above for the Purine (Id") Derivatives of Formula (Id). A Purine Derivative of Formula (Idd') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Idd") when group A of the Purine Derivative of Formula (Idd') is the same as group A of the Purine Derivative of Formula (Idd") and when group D of the Purine Derivative of Formula (Idd') is the same as group D of the Purine Derivative of Formula wherein A, B, C and D are defined above for the Purine (Idd"). Derivatives of Formula (Id). 25 A Purine Derivative of Formula (Idd") is the corresponding A Purine Derivative of Formula (Id") is the corresponding opposite enantiomer of a Purine Derivative of Formula (Idd') opposite enantiomer of a Purine Derivative of Formula (Id") when group A of the Purine Derivative of Formula (Idd") is when group A of the Purine Derivative of Formula (Id') is the the same as group A of the Purine Derivative of Formula (Idd') same as group A of the Purine Derivative of Formula (Id") and and when group D of the Purine Derivative of Formula (Idd") when group D of the Purine Derivative of Formula (Id") is the 30 is the same as group D of the Purine Derivative of Formula same as group D of the Purine Derivative of Formula (Id"). (Idd'). A Purine Derivative of Formula (Id") is the corresponding In one embodiment, the Purine Derivatives of Formula (Id) opposite enantiomer of a Purine Derivative of Formula (Id') have the formula (Idd'), depicted above, wherein A, B, C and when group A of the Purine Derivatives of Formula (Id") is the D are defined above for the Purine Derivatives of Formula same as group A of the Purine Derivative of Formula (Id") and 35 when group D of the Purine Derivative of Formula (Id") is the (Id), and wherein the Purine Derivatives of Formula (Idd') are same as group D of the Purine Derivative of Formula (Id'). Substantially free of their corresponding opposite enantiomer. In one embodiment, the Purine Derivatives of Formula (Id) In another embodiment, the Purine Derivatives of Formula have the formula (Id'), depicted above, wherein A, B, C and D (Id) have the formula (Idd"), depicted above, wherein A, B, C are defined above for the Purine Derivatives of Formula (Id), 40 and Dare defined above for the Purine Derivatives of Formula and wherein the Purine Derivatives of Formula (Id') are sub (Id), and wherein the Purine Derivatives of Formula (Idd") are stantially free of their corresponding enantiomer, represented Substantially free of their corresponding opposite enantiomer. by Formula (Id"). In another embodiment, the Purine Derivatives of Formula In another embodiment, the Purine Derivatives of Formula 45 (Id) exist as a mixture of a Purine Derivative of Formula (Idd') (Id) have the formula (Id"), depicted above, wherein A, B, C and a Purine Derivative of Formula (Idd") wherein the and Dare defined above for the Purine Derivatives of Formula amount of the Purine Derivative of Formula (Idd') exceeds the (Id), and wherein the Purine Derivatives of Formula (Id") are amount of the Purine Derivative of Formula (Idd"). Substantially free of their corresponding enantiomer, repre In a further embodiment, the Purine Derivatives of For sented by Formula (Id'). 50 mula (Id) exist as a mixture of a Purine Derivative of Formula In one embodiment, the Purine Derivatives of Formula (Id) (Idd") and a Purine Derivative of Formula (Idd") wherein the exist as a mixture of a Purine Derivative of Formula (Id') and amount of the Purine Derivative of Formula (Idd") exceeds a Purine Derivative of Formula (Id") wherein the amount of the amount of the Purine Derivative of Formula (Idd'). the Purine Derivative of Formula (Id') exceeds the amount of In another embodiment, the Purine Derivatives of Formula the Purine Derivative of Formula (Id"). 55 (Id) exist as a racemic mixture of a Purine Derivative of In another embodiment, the Purine Derivatives of Formula Formula (Idd') and a Purine Derivative of Formula (Idd"). (Id) exist as a mixture of a Purine Derivative of Formula (Id') A Purine Derivative of Formula (Idd') is the corresponding and a Purine Derivative of Formula (Id") wherein the amount other anomer of a Purine Derivative of Formula (Id') when of the Purine Derivative of Formula (Id") exceeds the amount 60 group A of the Purine Derivative of Formula (Idd") is the same of the Purine Derivative of Formula (Id'). as group A of the Purine Derivative of Formula (Ib") and when In another embodiment, the Purine Derivatives of Formula group D of the Purine Derivative of Formula (Idd') is the same (Id) exist as a racemic mixture of a Purine Derivative of as group D of the Purine Derivative of Formula (Id'). Formula (Id') and a Purine Derivative of Formula (Id"). A Purine Derivative of Formula (Id') is the corresponding In another embodiment, the Purine Derivatives of Formula 65 other anomer of a Purine Derivative of Formula (Idd') when (Id) can exist in the form of a single enantiomer, for example, group A of the Purine Derivative of Formula (Id') is the same that depicted by either formula (Idd") or (Idd"): as group A of the Purine Derivative of Formula (Idd') and US 8,609,833 B2 33 34 when group D of the Purine Derivative of Formula (Id") is the Illustrative Purine Derivatives of Formula (Id) include the same as group D of the Purine Derivative of Formula (Idd'). compounds listed below: A Purine Derivative of Formula (Idd") is the corresponding other anomer of a Purine Derivative of Formula (Id") when group A of the Purine Derivative of Formula (Idd") is the same 23 as group A of the Purine Derivative of Formula (Id") and when group D of the Purine Derivative of Formula (Idd") is the same as group D of the Purine Derivative of Formula (Id"). HN A Purine Derivative of Formula (Id") is the corresponding 10 N other anomer of a Purine Derivative of Formula (Idd") when 'N1SN group A of the Purine Derivative of Formula (Id") is the same 2 as group A of the Purine Derivative of Formula (Idd") and O. { N H " when group D of the Purine Derivative of Formula (Id") is the same as group D of the Purine Derivative of Formula (Idd"). 15 orny In one embodiment, the Purine Derivatives of Formula (Id) HG OH have the formula (Idd'), depicted above, wherein A, B, C and 24 D are defined above for the Purine Derivatives of Formula NH2 (Id), and wherein the Purine Derivatives of Formula (Idd") are Substantially free of their corresponding other anomer. N NN In another embodiment, the Purine Derivatives of Formula (Id) have the formula (Idd"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula (Id), and wherein the Purine Derivatives of Formula (Idd") are 25 Substantially free of their corresponding other anomer. In one embodiment, the Purine Derivatives of Formula (Id) have the formula (Id'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (Id), 30 and pharmaceutically acceptable salts thereof. and wherein the Purine Derivatives of Formula (Id') are sub In one embodiment, compound 23 is in the form of its stantially free of their corresponding other anomer. sodium salt. In another embodiment, the Purine Derivatives of Formula In another embodiment, compound 24 is in the form of its (Id) have the formula (Id"), depicted above, wherein A, B, C Sodium salt. and Dare defined above for the Purine Derivatives of Formula 35 (Id), and wherein the Purine Derivatives of Formula (Id") are 5.2.5 The Purine Derivatives of Formula (Ie) Substantially free of their corresponding other anomer. As stated above, the present invention encompasses Purine In one embodiment, the Purine Derivatives of Formula (Id) Derivatives having the Formula (Ie): exist as a mixture of a Purine Derivative of Formula (Id') and 40 a Purine Derivative of Formula (Idd") wherein the amount of the Purine Derivative of Formula (Id') exceeds the amount of (Ie) the Purine Derivative of Formula (Idd'). In another embodiment, the Purine Derivatives of Formula 45 (Id) exist as a mixture of a Purine Derivative of Formula (Id') and a Purine Derivative of Formula (Idd") wherein the amount of the Purine Derivative of Formula (Idd') exceeds the amount of the Purine Derivative of Formula (Id'). wherein A, B, C and D are defined above for the Purine Derivatives of Formula (Ie), and A and B are trans with In another embodiment, the Purine Derivatives of Formula 50 respect to each other; B and C are cis with respect to each (Id) exist as a equal mixture of a Purine Derivative of Formula other; and C and Dare cis or trans with respect to each other. (Id') and a Purine Derivative of Formula (Idd'). In one embodiment, R' is -(CH2), aryl. In one embodiment, the Purine Derivatives of Formula (Id) In another embodiment, R' is —C-C monocyclic exist as a mixture of a Purine Derivative of Formula (Id") and 55 cycloalkyl. a Purine Derivative of Formula (Idd") wherein the amount of In a specific embodiment, R' is cyclopenty1. the Purine Derivative of Formula (Id") exceeds the amount of In another embodiment, R is —Cs-Cs monocyclic the Purine Derivative of Formula (Idd"). cycloalkenyl. In another embodiment, the Purine Derivatives of Formula In another embodiment, R' is —Cs-C bicyclic cycloalkyl 60 or —Cs-C bicyclic cycloalkenyl. (Id) exist as a mixture of a Purine Derivative of Formula (Id") In still another embodiment, R' is —(CH), (C-Cs and a Purine Derivative of Formula (Idd") wherein the monocyclic cycloalkyl) or —(CH), (C-C monocyclic amount of the Purine Derivative of Formula (Idd") exceeds cycloalkenyl). the amount of the Purine Derivative of Formula (Id"). In another embodiment, R' is -3- to 7-membered monocy In another embodiment, the Purine Derivatives of Formula 65 clic heterocycle or -8- to 12-membered bicyclic heterocycle. (Id) exist as a equal mixture of a Purine Derivative of Formula In one embodiment, Ris-halo. (Id") and a Purine Derivative of Formula (Idd") In a specific embodiment, R is —Cl. US 8,609,833 B2 35 36 In another embodiment, R is —CN. In another embodiment, the Purine Derivatives of Formula In another embodiment, R is NHR, OR or - SR". (Ie) have the formula (Ie"), depicted above, wherein A, B, C In a further embodiment, R is NHC(O)R, NHC(O) and Dare defined above for the Purine Derivatives of Formula OR or NHC(O)NHR'. (Ie), and wherein the Purine Derivatives of Formula (Ie") are In another embodiment, R is NHNHC(O)R, 5 Substantially free of their corresponding enantiomer, repre NHNHC(O)OR or NHNHC(O)NHR'. sented by Formula (Ie'). In yet another embodiment, R is NH N=C(R)R’. In one embodiment, the Purine Derivatives of Formula (Ie) In one embodiment, C and D are cis with respect to each exist as a mixture of a Purine Derivative of Formula (Ie') and other. a Purine Derivative of Formula (Ie") wherein the amount of In another embodiment, C and Dare trans with respect to 10 the Purine Derivative of Formula (Ie') exceeds the amount of each other. the Purine Derivative of Formula (Ie"). The present invention also provides compositions compris In another embodiment, the Purine Derivatives of Formula ing an effective amount of a Purine Derivative of Formula (Ie) (Ie) exist as a mixture of a Purine Derivative of Formula (Ie') and a physiologically acceptable carrier or vehicle. 15 and a Purine Derivative of Formula (Ie") wherein the amount The invention further provides Purine Derivatives of For of the Purine Derivative of Formula (Ie") exceeds the amount mula (Ie) that are in isolated and purified form. of the Purine Derivative of Formula (Ie'). The invention still further provides methods for treating or In another embodiment, the Purine Derivatives of Formula preventing a Condition, comprising administering an effec (Ie) exist as a racemic mixture of a Purine Derivative of tive amount of a Purine Derivative of Formula (Ie) to an Formula (Ie') and a Purine Derivative of Formula (Ie"). animal in need thereof. In another embodiment, the Purine Derivatives of Formula The invention further provides methods for reducing an (Ie) can exist in the form of a single enantiomer, for example, animals rate of metabolism, comprising administering an that depicted by either formula (Iee') or (Iee"): effective amount of a Purine Derivative of Formula (Ie) to an animal in need thereof. 25 The invention further provides methods protecting an ani (Iee') mals heart against myocardial damage during cardioplegia, comprising administering an effective amount of a Purine Derivative of Formula (Ie) to an animal in need thereof. The Purine Derivatives of Formula (Ie) can exist in the 30 form of a single enantiomer, for example, that depicted by (Iee") either the Formula (Ie') or Formula (Ie"):

(Ie') 35

wherein A, B, C and D are defined above for the Purine 40 Derivatives of Formula (Ie). (Ie") A Purine Derivative of Formula (Iee') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Iee") when group A of the Purine Derivative of Formula (Iee') is the same as group A of the Purine Derivative of Formula (Iee") 45 and when group D of the Purine Derivative of Formula (Iee') is the same as group D of the Purine Derivative of Formula (Iee"). wherein A, B, C and D are defined above for the Purine A Purine Derivative of Formula (Iee") is the corresponding Derivatives of Formula (Ie). opposite enantiomer of a Purine Derivative of Formula (Iee') A Purine Derivative of Formula (Ie') is the corresponding 50 when group A of the Purine Derivative of Formula (Iee") is the opposite enantiomer of a Purine Derivative of Formula (Ie") same as group A of the Purine Derivative of Formula (Iee') when group A of the Purine Derivative of Formula (Ie') is the and when group D of the Purine Derivative of Formula (Iee") same as group A of the Purine Derivative of Formula (Ie") and is the same as group D of the Purine Derivative of Formula when group D of the Purine Derivative of Formula (Ie') is the (Iee'). same as group D of the Purine Derivative of Formula (Ie"). 55 In one embodiment, the Purine Derivatives of Formula (Ie) A Purine Derivative of Formula (Ie") is the corresponding have the formula (Iee'), depicted above, wherein A, B, C and opposite enantiomer of a Purine Derivative of Formula (Ie') D are defined above for the Purine Derivatives of Formula when group A of the Purine Derivatives of Formula (Ie") is the (Ie), and wherein the Purine Derivatives of Formula (Iee') are same as group A of the Purine Derivative of Formula (Ie') and Substantially free of their corresponding opposite enantiomer. when group D of the Purine Derivative of Formula (Ie") is the 60 In another embodiment, the Purine Derivatives of Formula same as group D of the Purine Derivative of Formula (Ie'). (Ie) have the formula (Iee"), depicted above, wherein A, B, C In one embodiment, the Purine Derivatives of Formula (Ie) and Dare defined above for the Purine Derivatives of Formula have the formula (Ie'), depicted above, wherein A, B, C and D (Ie), and wherein the Purine Derivatives of Formula (Iee") are are defined above for the Purine Derivatives of Formula (Ie), Substantially free of their corresponding opposite enantiomer. and wherein the Purine Derivatives of Formula (Ie') are sub 65 In another embodiment, the Purine Derivatives of Formula stantially free of their corresponding enantiomer, represented (Ie) exist as a mixture of a Purine Derivative of Formula (Iee') by Formula (Ie"). and a Purine Derivative of Formula (Iee") wherein the amount US 8,609,833 B2 37 38 of the Purine Derivative of Formula (Iee') exceeds the amount In one embodiment, the Purine Derivatives of Formula (Ie) of the Purine Derivative of Formula (Iee"). exist as a mixture of a Purine Derivative of Formula (Ie") and In a further embodiment, the Purine Derivatives of For a Purine Derivative of Formula (Iee") wherein the amount of mula (Ie) exist as a mixture of a Purine Derivative of Formula the Purine Derivative of Formula (Ie") exceeds the amount of (Iee') and a Purine Derivative of Formula (Iee") wherein the the Purine Derivative of Formula (Iee"). amount of the Purine Derivative of Formula (Iee") exceeds the amount of the Purine Derivative of Formula (Iee'). In another embodiment, the Purine Derivatives of Formula In another embodiment, the Purine Derivatives of Formula (Ie) exist as a mixture of a Purine Derivative of Formula (Ie") (Ie) exist as a racemic mixture of a Purine Derivative of and a Purine Derivative of Formula (Iee") wherein the amount Formula (Iee') and a Purine Derivative of Formula (Iee"). 10 of the Purine Derivative of Formula (Iee") exceeds the A Purine Derivative of Formula (Iee') is the corresponding amount of the Purine Derivative of Formula (Ie"). other anomer of a Purine Derivative of Formula (Ie') when In another embodiment, the Purine Derivatives of Formula group A of the Purine Derivative of Formula (Iee') is the same (Ie) exist as a equal mixture of a Purine Derivative of Formula as group A of the Purine Derivative of Formula (Ie') and when (Ie") and a Purine Derivative of Formula (Iee"). group D of the Purine Derivative of Formula (Iee') is the same 15 as group D of the Purine Derivative of Formula (Ie'). A Purine Derivative of Formula (Ie') is the corresponding 5.2.6 The Purine Derivatives of Formula (If) other anomer of a Purine Derivative of Formula (Iee') when group A of the Purine Derivative of Formula (Ie') is the same As stated above, the present invention encompasses Purine as group A of the Purine Derivative of Formula (Iee') and Derivatives having the Formula (If): when group D of the Purine Derivative of Formula (Ie') is the same as group D of the Purine Derivative of Formula (Iee'). A Purine Derivative of Formula (Iee") is the corresponding (If) other anomer of a Purine Derivative of Formula (Ie") when group A of the Purine Derivative of Formula (Iee") is the same 25 as group A of the Purine Derivative of Formula (Ie") and when group D of the Purine Derivative of Formula (Iee") is the same as group D of the Purine Derivative of Formula (Ie"). A Purine Derivative of Formula (Ie") is the corresponding other anomer of a Purine Derivative of Formula (Iee") when 30 wherein A, B, C and D are defined above for the Purine group A of the Purine Derivative of Formula (Ie") is the same as group A of the Purine Derivative of Formula (Iee") and Derivatives of Formula (If), and A and B are trans with respect when group D of the Purine Derivative of Formula (Ie") is the to each other; B and C are cis with respect to each other; and same as group D of the Purine Derivative of Formula (Iee"). C and Dare cis or trans with respect to each other. In one embodiment, the Purine Derivatives of Formula (Ie) 35 In one embodiment, R' is —Cs-C monocyclic cycloalkyl. have the formula (Iee'), depicted above, wherein A, B, C and In another embodiment, R' is cyclopenty1. D are defined above for the Purine Derivatives of Formula (Ie), and wherein the Purine Derivatives of Formula (Iee') are In one embodiment, R is —H Substantially free of their corresponding other anomer. In another embodiment R is -halo. In another embodiment, the Purine Derivatives of Formula 40 In another embodiment, R is —Cl. (Ie) have the formula (Iee"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula In one embodiment, C and D are cis with respect to each (Ie), and wherein the Purine Derivatives of Formula (Iee") are other. Substantially free of their corresponding other anomer. In another embodiment, C and Dare trans with respect to In one embodiment, the Purine Derivatives of Formula (Ie) 45 each other. have the formula (Ie'), depicted above, wherein A, B, C and D The present invention also provides compositions compris are defined above for the Purine Derivatives of Formula (Ie), and wherein the Purine Derivatives of Formula (Ie') are sub ing an effective amount of a Purine Derivative of Formula (If) stantially free of their corresponding other anomer. and a physiologically acceptable carrier or vehicle. In another embodiment, the Purine Derivatives of Formula 50 The invention further provides Purine Derivatives of For (Ie) have the formula (Ie"), depicted above, wherein A, B, C mula (If) that are in isolated and purified form. and Dare defined above for the Purine Derivatives of Formula The invention still further provides methods for treating or (Ie), and wherein the Purine Derivatives of Formula (Ie") are preventing a Condition, comprising administering an effec Substantially free of their corresponding other anomer. tive amount of a Purine Derivative of Formula (If) to an In one embodiment, the Purine Derivatives of Formula (Ie) 55 animal in need thereof. exist as a mixture of a Purine Derivative of Formula (Ie') and The invention further provides methods for reducing an a Purine Derivative of Formula (Iee') wherein the amount of animals rate of metabolism, comprising administering an the Purine Derivative of Formula (Ie') exceeds the amount of effective amount of a Purine Derivative of Formula (If) to an the Purine Derivative of Formula (Iee'). animal in need thereof. In another embodiment, the Purine Derivatives of Formula 60 (Ie) exist as a mixture of a Purine Derivative of Formula (Ie') The invention further provides methods protecting an ani and a Purine Derivative of Formula (Iee') wherein the amount mals heart against myocardial damage during cardioplegia, of the Purine Derivative of Formula (Iee') exceeds the amount comprising administering an effective amount of a Purine of the Purine Derivative of Formula (Ie'). Derivative of Formula (If) to an animal in need thereof. In another embodiment, the Purine Derivatives of Formula 65 The Purine Derivatives of Formula (If) can exist in the form (Ie) exist as a equal mixture of a Purine Derivative of Formula of a single enantiomer, for example, that depicted by either (Ie') and a Purine Derivative of Formula (Iee'). the Formula (If) or Formula (If"): US 8,609,833 B2 39 40 -continued (If) (Iff")

(If") wherein A, B, C and D are defined above for the Purine 10 Derivatives of Formula (If). A Purine Derivative of Formula (Iff) is the corresponding opposite enantiomer of a Purine Derivative of Formula (Iff") when group A of the Purine Derivative of Formula (Iff) is the wherein A, B, C and D are defined above for the Purine 15 same as group A of the Purine Derivative of Formula (Iff") Derivatives of Formula (If). and when group D of the Purine Derivative of Formula (Iff) is A Purine Derivative of Formula (If) is the corresponding the same as group D of the Purine Derivative of Formula opposite enantiomer of a Purine Derivative of Formula (If") (Iff"). A Purine Derivative of Formula (Iff") is the corresponding when group A of the Purine Derivative of Formula (If) is the opposite enantiomer of a Purine Derivative of Formula (Iff) same as group A of the Purine Derivative of Formula (If") and when group A of the Purine Derivative of Formula (Iff") is the when group D of the Purine Derivative of Formula (If) is the same as group A of the Purine Derivative of Formula (Iff) and same as group D of the Purine Derivative of Formula (If"). when group D of the Purine Derivative of Formula (Iff") is the A Purine Derivative of Formula (If") is the corresponding same as group D of the Purine Derivative of Formula (Iff). opposite enantiomer of a Purine Derivative of Formula (If) 25 In one embodiment, the Purine Derivatives of Formula (If) when group A of the Purine Derivatives of Formula (If") is the have the formula (Iff), depicted above, wherein A, B, C and D same as group A of the Purine Derivative of Formula (If) and are defined above for the Purine Derivatives of Formula (If). when group D of the Purine Derivative of Formula (If") is the and wherein the Purine Derivatives of Formula (Iff) are sub same as group D of the Purine Derivative of Formula (If). stantially free of their corresponding opposite enantiomer. In one embodiment, the Purine Derivatives of Formula (If) 30 In another embodiment, the Purine Derivatives of Formula have the formula (If), depicted above, wherein A, B, C and D (If) have the formula (Iff"), depicted above, wherein A, B, C are defined above for the Purine Derivatives of Formula (If). and Dare defined above for the Purine Derivatives of Formula and wherein the Purine Derivatives of Formula (If) are sub (If), and wherein the Purine Derivatives of Formula (Iff") are stantially free of their corresponding enantiomer, represented Substantially free of their corresponding opposite enantiomer. by Formula (If"). 35 In another embodiment, the Purine Derivatives of Formula In another embodiment, the Purine Derivatives of Formula (If) exist as a mixture of a Purine Derivative of Formula (Iff) (If) have the formula (If"), depicted above, wherein A, B, C and a Purine Derivative of Formula (Iff") wherein the amount and Dare defined above for the Purine Derivatives of Formula of the Purine Derivative of Formula (Iff) exceeds the amount (If), and wherein the Purine Derivatives of Formula (If") are 40 of the Purine Derivative of Formula (Iff"). Substantially free of their corresponding enantiomer, repre In a further embodiment, the Purine Derivatives of For sented by Formula (If). mula (If) exist as a mixture of a Purine Derivative of Formula In one embodiment, the Purine Derivatives of Formula (If) (Iff) and a Purine Derivative of Formula (Iff") wherein the exist as a mixture of a Purine Derivative of Formula (If) and amount of the Purine Derivative of Formula (Iff") exceeds the a Purine Derivative of Formula (If") wherein the amount of 45 amount of the Purine Derivative of Formula (Iff). the Purine Derivative of Formula (If) exceeds the amount of In another embodiment, the Purine Derivatives of Formula the Purine Derivative of Formula (If"). (If) exist as a racemic mixture of a Purine Derivative of In another embodiment, the Purine Derivatives of Formula Formula (Iff) and a Purine Derivative of Formula (Iff"). (If) exist as a mixture of a Purine Derivative of Formula (If) A Purine Derivative of Formula (Iff) is the corresponding and a Purine Derivative of Formula (If") wherein the amount 50 other anomer of a Purine Derivative of Formula (If) when of the Purine Derivative of Formula (If") exceeds the amount group A of the Purine Derivative of Formula (Iff) is the same of the Purine Derivative of Formula (If). as group A of the Purine Derivative of Formula (If) and when In another embodiment, the Purine Derivatives of Formula group D of the Purine Derivative of Formula (Iff) is the same (If) exist as a racemic mixture of a Purine Derivative of 55 as group D of the Purine Derivative of Formula (If). Formula (If) and a Purine Derivative of Formula (If"). A Purine Derivative of Formula (If) is the corresponding In another embodiment, the Purine Derivatives of Formula other anomer of a Purine Derivative of Formula (Iff) when (If) can exist in the form of a single enantiomer, for example, group A of the Purine Derivative of Formula (If) is the same that depicted by either formula (Iff) or (Iff"): as group A of the Purine Derivative of Formula (Iff) and when 60 group D of the Purine Derivative of Formula (If) is the same as group D of the Purine Derivative of Formula (Iff). (Iff) A Purine Derivative of Formula (Iff") is the corresponding other anomer of a Purine Derivative of Formula (If") when group A of the Purine Derivative of Formula (Iff") is the same 65 as group A of the Purine Derivative of Formula (If") and when group D of the Purine Derivative of Formula (Iff") is the same as group D of the Purine Derivative of Formula (If"). US 8,609,833 B2 41 42 A Purine Derivative of Formula (If") is the corresponding other anomer of a Purine Derivative of Formula (Iff") when 16 group A of the Purine Derivative of Formula (If") is the same as group A of the Purine Derivative of Formula (Iff") and HN when group D of the Purine Derivative of Formula (If") is the same as group D of the Purine Derivative of Formula (Iff"). In one embodiment, the Purine Derivatives of Formula (If) S1s 2 have the formula (Iff), depicted above, wherein A, B, C and D 10 O. {llN C " are defined above for the Purine Derivatives of Formula (If). and wherein the Purine Derivatives of Formula (Iff) are sub stantially free of their corresponding other anomer. HG OH In another embodiment, the Purine Derivatives of Formula 15 17 (If) have the formula (Iff"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula (If), and wherein the Purine Derivatives of Formula (Iff") are Substantially free of their corresponding other anomer. In one embodiment, the Purine Derivatives of Formula (If) have the formula (If), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (If"), 25 and wherein the Purine Derivatives of Formula (If") are sub stantially free of their corresponding other anomer. In another embodiment, the Purine Derivatives of Formula (If) have the formula (If"), depicted above, wherein A, B, C 30 and pharmaceutically acceptable salts thereof. and Dare defined above for the Purine Derivatives of Formula 5.2.7 The Purine Derivatives of Formula (Ig) (If), and wherein the Purine Derivatives of Formula (If") are Substantially free of their corresponding other anomer. As stated above, the present invention encompasses Purine Derivatives having the Formula (Ig): In one embodiment, the Purine Derivatives of Formula (If) 35 exist as a mixture of a Purine Derivative of Formula (If) and a Purine Derivative of Formula (Iff) wherein the amount of (Ig) the Purine Derivative of Formula (If) exceeds the amount of the Purine Derivative of Formula (Iff). 40 In another embodiment, the Purine Derivatives of Formula (If) exist as a mixture of a Purine Derivative of Formula (If) and a Purine Derivative of Formula (Iff) wherein the amount wherein A, B, C and D are defined above for the Purine of the Purine Derivative of Formula (Iff) exceeds the amount 45 Derivatives of Formula (Ig), and A and B are trans with respect to each other; B and C are cis with respect to each of the Purine Derivative of Formula (If). other; and C and Dare cis or trans with respect to each other. In another embodiment, the Purine Derivatives of Formula In one embodiment, R is —H (If) exist as a equal mixture of a Purine Derivative of Formula In another embodiment R is -halo. (If) and a Purine Derivative of Formula (Iff). 50 In a specific embodiment, R is —Cl. In one embodiment, C and D are cis with respect to each In one embodiment, the Purine Derivatives of Formula (If) other. exist as a mixture of a Purine Derivative of Formula (If") and In another embodiment, C and Dare trans with respect to a Purine Derivative of Formula (Iff") wherein the amount of each other. the Purine Derivative of Formula (If") exceeds the amount of 55 The present invention also provides compositions compris the Purine Derivative of Formula (Iff"). ing an effective amount of a Purine Derivative of Formula (Ig) In another embodiment, the Purine Derivatives of Formula and a physiologically acceptable carrier or vehicle. (If) exist as a mixture of a Purine Derivative of Formula (If") The invention further provides Purine Derivatives of For and a Purine Derivative of Formula (Iff") wherein the amount mula (Ig) that are in isolated and purified form. of the Purine Derivative of Formula (Iff") exceeds the amount 60 The invention still further provides methods for treating or of the Purine Derivative of Formula (If"). preventing a Condition, comprising administering an effec tive amount of a Purine Derivative of Formula (Ig) to an In another embodiment, the Purine Derivatives of Formula animal in need thereof. (If) exist as a equal mixture of a Purine Derivative of Formula The invention further provides methods for reducing an (If") and a Purine Derivative of Formula (Iff"). 65 animals rate of metabolism, comprising administering an Illustrative Purine Derivatives of Formula (If) include the effective amount of a Purine Derivative of Formula (Ig) to an compounds listed below: animal in need thereof. US 8,609,833 B2 43 44 The invention further provides methods protecting an ani mals heart against myocardial damage during cardioplegia, (Igg) comprising administering an effective amount of a Purine Derivative of Formula (Ig) to an animal in need thereof. The Purine Derivatives of Formula (Ig) can exist in the form of a single enantiomer, for example, that depicted by either the Formula (Ig) or Formula (Ig"): (Igg")

(Ig) 10

15 wherein A, B, C and D are defined above for the Purine (Ig") Derivatives of Formula (Ig). A Purine Derivative of Formula (Igg') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Igg") when group A of the Purine Derivative of Formula (Igg) is the same as group A of the Purine Derivative of Formula (Igg") and when group D of the Purine Derivative of Formula (Igg') is the same as group D of the Purine Derivative of Formula wherein A, B, C and D are defined above for the Purine (Igg"). Derivatives of Formula (Ig). A Purine Derivative of Formula (Igg") is the corresponding 25 opposite enantiomer of a Purine Derivative of Formula (Igg') A Purine Derivative of Formula (Ig) is the corresponding when group A of the Purine Derivative of Formula (Igg") is opposite enantiomer of a Purine Derivative of Formula (Ig") the same as group A of the Purine Derivative of Formula (Igg') when group A of the Purine Derivative of Formula (Ig) is the and when group D of the Purine Derivative of Formula (Igg") same as group A of the Purine Derivative of Formula (Ig") and is the same as group D of the Purine Derivative of Formula when group D of the Purine Derivative of Formula (Ig) is the 30 (Igg). same as group D of the Purine Derivative of Formula (Ig"). In one embodiment, the Purine Derivatives of Formula (Ig) A Purine Derivative of Formula (Ig") is the corresponding have the formula (Igg'), depicted above, wherein A, B, C and opposite enantiomer of a Purine Derivative of Formula (Ig) D are defined above for the Purine Derivatives of Formula when group A of the Purine Derivatives of Formula (Ig") is the (Ig), and wherein the Purine Derivatives of Formula (Igg') are same as group A of the Purine Derivative of Formula (Ig) and 35 Substantially free of their corresponding opposite enantiomer. when group D of the Purine Derivative of Formula (Ig") is the In another embodiment, the Purine Derivatives of Formula same as group D of the Purine Derivative of Formula (Ig). (Ig) have the formula (Igg"), depicted above, wherein A, B, C In one embodiment, the Purine Derivatives of Formula (Ig) and Dare defined above for the Purine Derivatives of Formula have the formula (Ig), depicted above, wherein A, B, C and D 40 (Ig), and wherein the Purine Derivatives of Formula (Igg") are are defined above for the Purine Derivatives of Formula (Ig), Substantially free of their corresponding opposite enantiomer. and wherein the Purine Derivatives of Formula (Ig) are sub In another embodiment, the Purine Derivatives of Formula stantially free of their corresponding enantiomer, represented (Ig) exist as a mixture of a Purine Derivative of Formula (Igg') by Formula (Ig"). and a Purine Derivative of Formula (Igg") wherein the In another embodiment, the Purine Derivatives of Formula 45 amount of the Purine Derivative of Formula (Igg') exceeds the (Ig) have the formula (Ig"), depicted above, wherein A, B, C amount of the Purine Derivative of Formula (Igg"). and Dare defined above for the Purine Derivatives of Formula In a further embodiment, the Purine Derivatives of For (Ig), and wherein the Purine Derivatives of Formula (Ig") are mula (Ig) exist as a mixture of a Purine Derivative of Formula Substantially free of their corresponding enantiomer, repre (Igg) and a Purine Derivative of Formula (Igg") wherein the sented by Formula (Ig). 50 amount of the Purine Derivative of Formula (Igg") exceeds In one embodiment, the Purine Derivatives of Formula (Ig) the amount of the Purine Derivative of Formula (Igg'). exist as a mixture of a Purine Derivative of Formula (Ig) and In another embodiment, the Purine Derivatives of Formula a Purine Derivative of Formula (Ig") wherein the amount of (Ig) exist as a racemic mixture of a Purine Derivative of the Purine Derivative of Formula (Ig) exceeds the amount of Formula (Igg') and a Purine Derivative of Formula (Igg"). the Purine Derivative of Formula (Ig"). 55 A Purine Derivative of Formula (Igg') is the corresponding In another embodiment, the Purine Derivatives of Formula other anomer of a Purine Derivative of Formula (Ig) when (Ig) exist as a mixture of a Purine Derivative of Formula (Ig) group A of the Purine Derivative of Formula (Igg) is the same and a Purine Derivative of Formula (Ig") wherein the amount as group A of the Purine Derivative of Formula (Ig) and when of the Purine Derivative of Formula (Ig") exceeds the amount 60 group D of the Purine Derivative of Formula (Igg') is the same of the Purine Derivative of Formula (Ig). as group D of the Purine Derivative of Formula (Ig). In another embodiment, the Purine Derivatives of Formula A Purine Derivative of Formula (Ig) is the corresponding (Ig) exist as a racemic mixture of a Purine Derivative of other anomer of a Purine Derivative of Formula (Igg') when Formula (Ig) and a Purine Derivative of Formula (Ig"). group A of the Purine Derivative of Formula (Ig) is the same In another embodiment, the Purine Derivatives of Formula 65 as group A of the Purine Derivative of Formula (Igg') and (Ig) can exist in the form of a single enantiomer, for example, when group D of the Purine Derivative of Formula (Ig) is the that depicted by either formula (Igg') or (Igg"): same as group D of the Purine Derivative of Formula (Igg'). US 8,609,833 B2 45 46 A Purine Derivative of Formula (Igg") is the corresponding Illustrative Purine Derivatives of Formula (Ig) include the other anomer of a Purine Derivative of Formula (Ig") when compounds listed below: group A of the Purine Derivative of Formula (Igg") is the same as group A of the Purine Derivative of Formula (Ig") and when s 18 group D of the Purine Derivative of Formula (Igg") is the NH2 same as group D of the Purine Derivative of Formula (Ig"). N A Purine Derivative of Formula (Ig") is the corresponding (1. other anomer of a Purine Derivative of Formula (Igg") when 10 O N Nals H and group A of the Purine Derivative of Formula (Ig") is the same as group A of the Purine Derivative of Formula (Igg") and ory when group D of the Purine Derivative of Formula (Ig") is the HG OH same as group D of the Purine Derivative of Formula (Igg"). 15 19 In one embodiment, the Purine Derivatives of Formula (Ig) NH2 have the formula (Igg'), depicted above, wherein A, B, C and N D are defined above for the Purine Derivatives of Formula NN (Ig), and wherein the Purine Derivatives of Formula (Igg') are 20 Substantially free of their corresponding other anomer. In another embodiment, the Purine Derivatives of Formula (Ig) have the formula (Igg"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula as (Ig), and wherein the Purine Derivatives of Formula (Igg") are Substantially free of their corresponding other anomer. and pharmaceutically acceptable salts thereof. In one embodiment, the Purine Derivatives of Formula (Ig) have the formula (Ig), depicted above, wherein A, B, C and D 5.2.8 THe Purine Derivatives of Formula (Ih) are defined above for the Purine Derivatives of Formula (Ig), 30 and wherein the Purine Derivatives of Formula (Ig) are sub As stated above, the present invention encompasses Purine stantially free of their corresponding other anomer. Derivatives having the Formula (Ih): In another embodiment, the Purine Derivatives of Formula (Ig) have the formula (Ig"), depicted above, wherein A, B, C 35 and Dare defined above for the Purine Derivatives of Formula (Ih) (Ig), and wherein the Purine Derivatives of Formula (Ig") are Substantially free of their corresponding other anomer. In one embodiment, the Purine Derivatives of Formula (Ig) exist as a mixture of a Purine Derivative of Formula (Ig) and 40 a Purine Derivative of Formula (Igg') wherein the amount of the Purine Derivative of Formula (Ig) exceeds the amount of wherein A, B, C and D are defined above for the Purine the Purine Derivative of Formula (Igg'). Derivatives of Formula (Ih), and A and B are trans with respect to each other; B and C are cis with respect to each In another embodiment, the Purine Derivatives of Formula 45 other; and C and Dare cis or trans with respect to each other. (Ig) exist as a mixture of a Purine Derivative of Formula (Ig) In one embodiment, R' is cyclopent-1-ol-2-yl. and a Purine Derivative of Formula (Igg) wherein the amount In another embodiment R' is cyclopent-1-ol-3-yl. of the Purine Derivative of Formula (Igg') exceeds the amount In one embodiment, C and D are cis with respect to each of the Purine Derivative of Formula (Ig). other. In another embodiment, the Purine Derivatives of Formula 50 In another embodiment, C and Dare trans with respect to (Ig) exist as a equal mixture of a Purine Derivative of Formula each other. (Ig) and a Purine Derivative of Formula (Igg'). The present invention also provides compositions compris In one embodiment, the Purine Derivatives of Formula (Ig) ing an effective amount of a Purine Derivative of Formula (Ih) exist as a mixture of a Purine Derivative of Formula (Ig") and 55 and a physiologically acceptable carrier or vehicle. a Purine Derivative of Formula (Igg") wherein the amount of The invention further provides Purine Derivatives of For the Purine Derivative of Formula (Ig") exceeds the amount of mula (Ih) that are in isolated and purified form. the Purine Derivative of Formula (Igg"). The invention still further provides methods for treating or In another embodiment, the Purine Derivatives of Formula preventing a Condition, comprising administering an effec 60 tive amount of a Purine Derivative of Formula (Ih) to an (Ig) exist as a mixture of a Purine Derivative of Formula (Ig") animal in need thereof. and a Purine Derivative of Formula (Igg") wherein the The invention further provides methods for reducing an amount of the Purine Derivative of Formula (Igg") exceeds animals rate of metabolism, comprising administering an the amount of the Purine Derivative of Formula (Ig"). effective amount of a Purine Derivative of Formula (Ih) to an In another embodiment, the Purine Derivatives of Formula 65 animal in need thereof. (Ig) exist as a equal mixture of a Purine Derivative of Formula The invention further provides methods protecting an ani (Ig") and a Purine Derivative of Formula (Igg"). mals heart against myocardial damage during cardioplegia, US 8,609,833 B2 47 comprising administering an effective amount of a Purine Derivative of Formula (Ih) to an animal in need thereof. (Ihh') The Purine Derivatives of Formula (Ih) can exist in the form of a single enantiomer, for example, that depicted by NS wP either the Formula (Ih') or Formula (Ih"): S ? (Ihh") A. 19 D 10

B C

15 wherein A, B, C and D are defined above for the Purine Derivatives of Formula (Ih). A Purine Derivative of Formula (Ihh') is the corresponding opposite enantiomer of a Purine Derivative of Formula (Ihh") when group A of the Purine Derivative of Formula (Ihh') is the same as group A of the Purine Derivative of Formula (Ihh") wherein A, B, C and D are defined above for the Purine and when group D of the Purine Derivative of Formula (Ihh') Derivatives of Formula (Ih). is the same as group D of the Purine Derivative of Formula A Purine Derivative of Formula (Ih') is the corresponding (Ihh"). opposite enantiomer of a Purine Derivative of Formula (Ih") 25 A Purine Derivative of Formula (Ihh") is the corresponding when group A of the Purine Derivative of Formula (Ih') is the opposite enantiomer of a Purine Derivative of Formula (Ihh') same as group A of the Purine Derivative of Formula (Ih") and when group A of the Purine Derivative of Formula (Ihh") is when group D of the Purine Derivative of Formula (Ih') is the the same as group A of the Purine Derivative of Formula (Ihh') same as group D of the Purine Derivative of Formula (Ih"). and when group D of the Purine Derivative of Formula (Ihh") A Purine Derivative of Formula (Ih") is the corresponding 30 is the same as group D of the Purine Derivative of Formula opposite enantiomer of a Purine Derivative of Formula (Ih') (Ihh'). when group A of the Purine Derivatives of Formula (Ih") is the In one embodiment, the Purine Derivatives of Formula (Ih) same as group A of the Purine Derivative of Formula (Ih") and have the formula (Ihh'), depicted above, wherein A, B, C and when group D of the Purine Derivative of Formula (Ih") is the 35 D are defined above for the Purine Derivatives of Formula same as group D of the Purine Derivative of Formula (Ih'). (Ih), and wherein the Purine Derivatives of Formula (Ihh") are In one embodiment, the Purine Derivatives of Formula (Ih) Substantially free of their corresponding opposite enantiomer. have the formula (Ih'), depicted above, wherein A, B, C and D In another embodiment, the Purine Derivatives of Formula are defined above for the Purine Derivatives of Formula (Ih), (Ih) have the formula (Ihh"), depicted above, wherein A, B, C and wherein the Purine Derivatives of Formula (Ih') are sub 40 and Dare defined above for the Purine Derivatives of Formula stantially free of their corresponding enantiomer, represented (Ih), and wherein the Purine Derivatives of Formula (Ihh") are by Formula (Ih"). Substantially free of their corresponding opposite enantiomer. In another embodiment, the Purine Derivatives of Formula In another embodiment, the Purine Derivatives of Formula (Ih) have the formula (Ih"), depicted above, wherein A, B, C 45 (Ih) exist as a mixture of a Purine Derivative of Formula (Ihh') and Dare defined above for the Purine Derivatives of Formula and a Purine Derivative of Formula (Ihh") wherein the (Ih), and wherein the Purine Derivatives of Formula (Ih") are amount of the Purine Derivative of Formula (Ihh') exceeds the Substantially free of their corresponding enantiomer, repre amount of the Purine Derivative of Formula (Ihh"). sented by Formula (Ih'). In a further embodiment, the Purine Derivatives of For In one embodiment, the Purine Derivatives of Formula (Ih) 50 mula (Ih) exist as a mixture of a Purine Derivative of Formula exist as a mixture of a Purine Derivative of Formula (Ih") and (Ihh") and a Purine Derivative of Formula (Ihh") wherein the a Purine Derivative of Formula (Ih") wherein the amount of amount of the Purine Derivative of Formula (Ihh") exceeds the Purine Derivative of Formula (Ih') exceeds the amount of the amount of the Purine Derivative of Formula (Ihh'). In another embodiment, the Purine Derivatives of Formula the Purine Derivative of Formula (Ih"). 55 In another embodiment, the Purine Derivatives of Formula (Ih) exist as a racemic mixture of a Purine Derivative of (Ih) exist as a mixture of a Purine Derivative of Formula (Ih') Formula (Ihh") and a Purine Derivative of Formula (Ihh"). and a Purine Derivative of Formula (Ih") wherein the amount A Purine Derivative of Formula (Ihh') is the corresponding of the Purine Derivative of Formula (Ih") exceeds the amount other anomer of a Purine Derivative of Formula (Ih') when 60 group A of the Purine Derivative of Formula (Ihh') is the same of the Purine Derivative of Formula (Ih'). as group A of the Purine Derivative of Formula (Ih') and when In another embodiment, the Purine Derivatives of Formula group D of the Purine Derivative of Formula (Ihh') is the same (Ih) exist as a racemic mixture of a Purine Derivative of as group D of the Purine Derivative of Formula (Ih'). Formula (Ih') and a Purine Derivative of Formula (Ih"). A Purine Derivative of Formula (Ih') is the corresponding In another embodiment, the Purine Derivatives of Formula 65 other anomer of a Purine Derivative of Formula (Ihh') when (Ih) can exist in the form of a single enantiomer, for example, group A of the Purine Derivative of Formula (Ih') is the same that depicted by either formula (Ihh") or (Ihh"): as group A of the Purine Derivative of Formula (Ihh") and US 8,609,833 B2 49 50 when group D of the Purine Derivative of Formula (Ih') is the Illustrative Purine Derivatives of Formula (Ih) include the same as group D of the Purine Derivative of Formula (Ihh'). compounds listed below: A Purine Derivative of Formula (Ihh") is the corresponding other anomer of a Purine Derivative of Formula (Ih") when 26 group A of the Purine Derivative of Formula (Ihh") is the same HO/ as group A of the Purine Derivative of Formula (Ih") and when group D of the Purine Derivative of Formula (Ihh") is the same as group D of the Purine Derivative of Formula (Ih"). O A Purine Derivative of Formula (Ih") is the corresponding 10 other anomer of a Purine Derivative of Formula (Ihh") when N group A of the Purine Derivative of Formula (Ih") is the same as group A of the Purine Derivative of Formula (Ihh") and (1.als when group D of the Purine Derivative of Formula (Ih") is the O. N H same as group D of the Purine Derivative of Formula (Ihh"). 15 ory In one embodiment, the Purine Derivatives of Formula (Ih) have the formula (Ihh'), depicted above, wherein A, B, C and HG OH D are defined above for the Purine Derivatives of Formula (Ih), and wherein the Purine Derivatives of Formula (Ihh") are Substantially free of their corresponding other anomer. 27 In another embodiment, the Purine Derivatives of Formula HO (Ih) have the formula (Ihh"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula (Ih), and wherein the Purine Derivatives of Formula (Ihh") are 25 HNW Substantially free of their corresponding other anomer. In one embodiment, the Purine Derivatives of Formula (Ih) N have the formula (Ih'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (Ih), 30 (1.als and wherein the Purine Derivatives of Formula (Ih') are sub O. N H stantially free of their corresponding other anomer. ory In another embodiment, the Purine Derivatives of Formula (Ih) have the formula (Ih"), depicted above, wherein A, B, C H6 OH and Dare defined above for the Purine Derivatives of Formula 35 (Ih), and wherein the Purine Derivatives of Formula (Ih") are Substantially free of their corresponding other anomer. 28 In one embodiment, the Purine Derivatives of Formula (Ih) OH exist as a mixture of a Purine Derivative of Formula (Ih") and 40 a Purine Derivative of Formula (Ihh') wherein the amount of the Purine Derivative of Formula (Ih') exceeds the amount of O the Purine Derivative of Formula (Ihh"). In another embodiment, the Purine Derivatives of Formula N (Ih) exist as a mixture of a Purine Derivative of Formula (Ih') 45 and a Purine Derivative of Formula (Ihh') wherein the amount (1. of the Purine Derivative of Formula (Ihh') exceeds the amount O. Nals H of the Purine Derivative of Formula (Ih'). ory In another embodiment, the Purine Derivatives of Formula 50 (Ih) exist as a equal mixture of a Purine Derivative of Formula HG OH (Ih') and a Purine Derivative of Formula (Ihh'). 29 In one embodiment, the Purine Derivatives of Formula (Ih) OH exist as a mixture of a Purine Derivative of Formula (Ih") and a Purine Derivative of Formula (Ihh") wherein the amount of the Purine Derivative of Formula (Ih") exceeds the amount of w the Purine Derivative of Formula (Ihh"). In another embodiment, the Purine Derivatives of Formula N (Ih) exist as a mixture of a Purine Derivative of Formula (Ih") 60 (1. and a Purine Derivative of Formula (Ihh") wherein the N Nals H amount of the Purine Derivative of Formula (Ihh") exceeds the amount of the Purine Derivative of Formula (Ih"). In another embodiment, the Purine Derivatives of Formula 65 (Ih) exist as a equal mixture of a Purine Derivative of Formula (Ih") and a Purine Derivative of Formula (Ihh"). US 8,609,833 B2 51 52 -continued 5.2.9 The Purine Derivatives of Formula (II) 30 HO As stated above, the present invention encompasses Purine Derivatives having the Formula (II):

HN C (II) A O D

10 B C

wherein A, B, C and D are defined above for the Purine Derivatives of Formula (II), and A and B are trans with respect 15 to each other; B and C are cis with respect to each other; and C and Dare cis or trans with respect to each other. In one embodiment, R' is H. In another embodiment, R' is -C-Cio alkyl. 31 In still another embodiment, R' is -(CH2), (Cs-C2 bicyclic cycloalkyl) or —(CH), (C-C bicyclic cycloalkenyl). In another embodiment, R is OR or - SR". In another embodiment, R is NHNHC(O)R. NHNHC(O)OR7 or NHNHC(O)NHR'. 25 In yet another embodiment, R is NH N=C(R)R. In a specific embodiment, R is NH N=CH-cyclopro pyl. In one embodiment, C and D are cis with respect to each other. 30 In another embodiment, C and Dare trans with respect to each other. The present invention also provides compositions compris HG OH ing an effective amount of a Purine Derivative of Formula (II) and a physiologically acceptable carrier or vehicle. The invention further provides Purine Derivatives of For 35 mula (II) that are in isolated and purified form. 32 The invention still further provides methods for treating or HO preventing a Condition, comprising administering an effec tive amount of a Purine Derivative of Formula (II) to an animal in need thereof. 40 The invention further provides methods for reducing an HN animals rate of metabolism, comprising administering an effective amount of a Purine Derivative of Formula (II) to an N n N animal in need thereof. The invention further provides methods protecting an ani 45 mals heart against myocardial damage during cardioplegia, comprising administering an effective amount of a Purine Derivative of Formula (II) to an animal in need thereof. The Purine Derivatives of Formula (II) can exist in the form HG OH of a single enantiomer, for example, that depicted by either 50 the Formula (II) or Formula (II"): 33 OH (II)

HN 55 (1.N N Nals H 60 (II")

65 and pharmaceutically acceptable salts thereof. US 8,609,833 B2 53 54 wherein A, B, C and D are defined above for the Purine A Purine Derivative of Formula (IIa") is the corresponding Derivatives of Formula (II). opposite enantiomer of a Purine Derivative of Formula (IIa") A Purine Derivative of Formula (II) is the corresponding when group A of the Purine Derivative of Formula (IIa") is the opposite enantiomer of a Purine Derivative of Formula (II") same as group A of the Purine Derivative of Formula (IIa") and when group A of the Purine Derivative of Formula (II) is the 5 when group D of the Purine Derivative of Formula (IIa") is the same as group A of the Purine Derivative of Formula (II") and same as group D of the Purine Derivative of Formula (IIa'). when group D of the Purine Derivative of Formula (II) is the In one embodiment, the Purine Derivatives of Formula (II) same as group D of the Purine Derivative of Formula (II"). have the formula (IIa'), depicted above, wherein A, B, C and A Purine Derivative of Formula (II") is the corresponding D are defined above for the Purine Derivatives of Formula opposite enantiomer of a Purine Derivative of Formula (II) (II), and wherein the Purine Derivatives of Formula (IIa") are when group A of the Purine Derivatives of Formula (II") is the Substantially free of their corresponding opposite enantiomer. same as group A of the Purine Derivative of Formula (II) and In another embodiment, the Purine Derivatives of Formula when group D of the Purine Derivative of Formula (II") is the (II) have the formula (IIa"), depicted above, wherein A, B, C same as group D of the Purine Derivative of Formula (II'). and Dare defined above for the Purine Derivatives of Formula In one embodiment, the Purine Derivatives of Formula (II) (II), and wherein the Purine Derivatives of Formula (IIa") are have the formula (II), depicted above, wherein A, B, C and D Substantially free of their corresponding opposite enantiomer. are defined above for the Purine Derivatives of Formula (II), In another embodiment, the Purine Derivatives of Formula and wherein the Purine Derivatives of Formula (II) are sub (II) exist as a mixture of a Purine Derivative of Formula (IIa') stantially free of their corresponding enantiomer, represented and a Purine Derivative of Formula (IIa") wherein the amount by Formula (II"). of the Purine Derivative of Formula (IIa') exceeds the amount In another embodiment, the Purine Derivatives of Formula of the Purine Derivative of Formula (IIa"). (II) have the formula (II"), depicted above, wherein A, B, C In a further embodiment, the Purine Derivatives of For and Dare defined above for the Purine Derivatives of Formula mula (II) exist as a mixture of a Purine Derivative of Formula (II), and wherein the Purine Derivatives of Formula (II") are 25 (IIa") and a Purine Derivative of Formula (IIa") wherein the Substantially free of their corresponding enantiomer, repre amount of the Purine Derivative of Formula (IIa") exceeds the sented by Formula (II'). amount of the Purine Derivative of Formula (IIa'). In one embodiment, the Purine Derivatives of Formula (II) In another embodiment, the Purine Derivatives of Formula exist as a mixture of a Purine Derivative of Formula (II) and (II) exist as a racemic mixture of a Purine Derivative of 30 Formula (IIa) and a Purine Derivative of Formula (IIa"). a Purine Derivative of Formula (II") wherein the amount of A Purine Derivative of Formula (IIa') is the corresponding the Purine Derivative of Formula (II") exceeds the amount of other anomer of a Purine Derivative of Formula (II) when the Purine Derivative of Formula (II"). group A of the Purine Derivative of Formula (IIa') is the same In another embodiment, the Purine Derivatives of Formula as group A of the Purine Derivative of Formula (II) and when (II) exist as a mixture of a Purine Derivative of Formula (II) 35 group D of the Purine Derivative of Formula (IIa') is the same and a Purine Derivative of Formula (II") wherein the amount as group D of the Purine Derivative of Formula (II'). of the Purine Derivative of Formula (II") exceeds the amount A Purine Derivative of Formula (II) is the corresponding of the Purine Derivative of Formula (II'). other anomer of a Purine Derivative of Formula (IIa") when In another embodiment, the Purine Derivatives of Formula group A of the Purine Derivative of Formula (II) is the same (II) exist as a racemic mixture of a Purine Derivative of 40 as group A of the Purine Derivative of Formula (IIa") and Formula (II) and a Purine Derivative of Formula (II"). when group D of the Purine Derivative of Formula (II) is the In another embodiment, the Purine Derivatives of Formula same as group D of the Purine Derivative of Formula (IIa'). (II) can exist in the form of a single enantiomer, for example, A Purine Derivative of Formula (IIa") is the corresponding that depicted by either formula (IIa") or (IIa"): other anomer of a Purine Derivative of Formula (II") when 45 group A of the Purine Derivative of Formula (IIa") is the same as group A of the Purine Derivative of Formula (II") and when (IIa) group D of the Purine Derivative of Formula (IIa") is the same as group D of the Purine Derivative of Formula (II"). A Purine Derivative of Formula (II") is the corresponding 50 other anomer of a Purine Derivative of Formula (IIa") when group A of the Purine Derivative of Formula (II") is the same (IIa") as group A of the Purine Derivative of Formula (IIa") and when group D of the Purine Derivative of Formula (II") is the same as group D of the Purine Derivative of Formula (IIa"). 55 In one embodiment, the Purine Derivatives of Formula (II) have the formula (IIa'), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (II), and wherein the Purine Derivatives of Formula (IIa") are wherein A, B, C and D are defined above for the Purine Substantially free of their corresponding other anomer. Derivatives of Formula (II). 60 In another embodiment, the Purine Derivatives of Formula A Purine Derivative of Formula (IIa) is the corresponding (II) have the formula (IIa"), depicted above, wherein A, B, C opposite enantiomer of a Purine Derivative of Formula (IIa") and Dare defined above for the Purine Derivatives of Formula when group A of the Purine Derivative of Formula (IIa') is the (II), and wherein the Purine Derivatives of Formula (IIa") are same as group A of the Purine Derivative of Formula (IIa") Substantially free of their corresponding other anomer. and when group D of the Purine Derivative of Formula (IIa) 65 In one embodiment, the Purine Derivatives of Formula (II) is the same as group D of the Purine Derivative of Formula have the formula (II), depicted above, wherein A, B, C and D (IIa"). are defined above for the Purine Derivatives of Formula (II), US 8,609,833 B2 55 56 and wherein the Purine Derivatives of Formula (II) are sub In a further embodiment, R' is -(CH2), (Cs-Ca. bicy stantially free of their corresponding other anomer. clic cycloalkyl) or —(CH), (C-C bicyclic cycloalk In another embodiment, the Purine Derivatives of Formula enyl). (II) have the formula (II"), depicted above, wherein A, B, C In another embodiment, R' is -(CH2)-aryl. and Dare defined above for the Purine Derivatives of Formula 5 In still another embodiment, two R' groups, together with (II), and wherein the Purine Derivatives of Formula (II") are the carbon atom to which they are attached, form a —C-Cs Substantially free of their corresponding other anomer. monocyclic cycloalkyl, a -C-C monocyclic cycloalkenyl, In one embodiment, the Purine Derivatives of Formula (II) a —Cs-C bicyclic cycloalkyl, or a —Cs-C bicyclic exist as a mixture of a Purine Derivative of Formula (II) and cycloalkenyl. a Purine Derivative of Formula (IIa") wherein the amount of 10 In a specific embodiment, R' is cyclopenty1. the Purine Derivative of Formula (II") exceeds the amount of In one embodiment, m is 0. the Purine Derivative of Formula (IIa) In another embodiment, m is 1. In another embodiment, the Purine Derivatives of Formula In another embodiment, m is 2. (II) exist as a mixture of a Purine Derivative of Formula (II) and a Purine Derivative of Formula (IIa) wherein the amount 15 In still another embodiment, m is 3. of the Purine Derivative of Formula (IIa') exceeds the amount In one embodiment, Ris-halo. of the Purine Derivative of Formula (II'). In a specific embodiment, R is —Cl. In another embodiment, the Purine Derivatives of Formula In one embodiment, R is H. (IIa) exist as a equal mixture of a Purine Derivative of For In another embodiment, R is —CN. mula (II) and a Purine Derivative of Formula (IIa"). In another embodiment, R is N(R), OR or - SR". In one embodiment, the Purine Derivatives of Formula In a further embodiment, R is NHC(O)R, NHC(O) (IIa) exist as a mixture of a Purine Derivative of Formula (II") OR or NHC(O)NHR'. and a Purine Derivative of Formula (IIa") wherein the amount of the Purine Derivative of Formula (II") exceeds the amount In another embodiment, R is NHNHC(O)R, of the Purine Derivative of Formula (IIa"). 25 NHNHC(O)CR or NHNHC(O)NHR'. In yet another In another embodiment, the Purine Derivatives of Formula embodiment, R is NH-N=C(R)R’. (IIa) exist as a mixture of a Purine Derivative of Formula (II") In a specific embodiment, R is NH N=CH-cyclopro and a Purine Derivative of Formula (IIa") wherein the amount pyl. of the Purine Derivative of Formula (IIa") exceeds the amount In one embodiment, R is -ONO, or ONO. of the Purine Derivative of Formula (II"). 30 In another embodiment, R is —OSOH, OSO-NH2, In another embodiment, the Purine Derivatives of Formula —OSONH(C-C alkyl), —OSONCC-C alkyl), or (IIa) exist as a equal mixture of a Purine Derivative of For –OSONH-aryl. mula (II") and a Purine Derivative of Formula (IIa"). In another embodiment, R is N(R). A first subclass of the Purine Derivatives of Formula (II) is In one embodiment, C and D are cis with respect to each that wherein one occurrence of R' is H. 35 other. A second subclass of the Purine Derivatives of Formula (II) In another embodiment, C and Dare trans with respect to is that wherein both R' groups together with the carbonatom each other. to which they are attached, join to form a -C-C monocy clic cycloalkyl. The present invention also provides compositions compris A third subclass of the Purine Derivatives of Formula (II) is 40 ing an effective amount of a Purine Derivative of Formula that wherein R is NH N=C(R)R. (III) and a physiologically acceptable carrier or vehicle. The invention further provides Purine Derivatives of For 5.2.10 The Purine Derivatives of Formula (III) mula (III) that are in isolated and purified form. The invention still further provides methods for treating or As stated above, the present invention encompasses Purine 45 preventing a Condition, comprising administering an effec Derivatives having the Formula (III): tive amount of a Purine Derivative of Formula (III) to an animal in need thereof. The invention further provides methods for reducing an (III) animals rate of metabolism, comprising administering an 50 effective amount of a Purine Derivative of Formula (III) to an animal in need thereof. The invention further provides methods protecting an ani mals heart against myocardial damage during cardioplegia, comprising administering an effective amount of a Purine 55 Derivative of Formula (III) to an animal in need thereof. wherein A, B, C and D are defined above for the Purine Derivatives of Formula (III), and A and B are trans with The Purine Derivatives of Formula (III) can exist in the respect to each other; B and C are cis with respect to each form of a single enantiomer, for example, that depicted by other; and C and Dare cis or trans with respect to each other. either the Formula (III) or Formula (III"): In one embodiment, R' is H. 60 In another embodiment, R' is -C-Cio alkyl. In another embodiment, R' is —(CH)-(3- to 7-mem (III) bered monocyclic heterocycle) or —(CH)-(8- to 12-mem bered bicyclic heterocycle). In still another embodiment, R is -(CH2), (C-Cs 65 monocyclic cycloalkyl) or —(CH), (C-C monocyclic cycloalkenyl), US 8,609,833 B2 57 58 -continued wherein A, B, C and D are defined above for the Purine (III') Derivatives of Formula (III). A Purine Derivative of Formula (IIIa') is the corresponding opposite enantiomer of a Purine Derivative of Formula (IIIa") when group A of the Purine Derivative of Formula (IIIa') is the same as group A of the Purine Derivative of Formula (IIIa") and when group D of the Purine Derivative of Formula (IIIa") is the same as group D of the Purine Derivative of Formula wherein A, B, C and D are defined above for the Purine (IIIa"). Derivatives of Formula (III). 10 A Purine Derivative of Formula (IIIa") is the corresponding A Purine Derivative of Formula (III) is the corresponding opposite enantiomer of a Purine Derivative of Formula (IIIa") opposite enantiomer of a Purine Derivative of Formula (III") when group A of the Purine Derivative of Formula (IIIa") is when group A of the Purine Derivative of Formula (III') is the the same as group A of the Purine Derivative of Formula same as group A of the Purine Derivative of Formula (III") (IIIa) and when group D of the Purine Derivative of Formula and when group D of the Purine Derivative of Formula (III) 15 (IIIa") is the same as group D of the Purine Derivative of is the same as group D of the Purine Derivative of Formula Formula (IIIa'). (III"). In one embodiment, the Purine Derivatives of Formula (III) A Purine Derivative of Formula (III") is the corresponding have the formula (IIIa'), depicted above, wherein A, B, C and opposite enantiomer of a Purine Derivative of Formula (III) D are defined above for the Purine Derivatives of Formula when group A of the Purine Derivatives of Formula (III") is (III), and wherein the Purine Derivatives of Formula (IIIa) are the same as group A of the Purine Derivative of Formula (III) Substantially free of their corresponding opposite enantiomer. and when group D of the Purine Derivative of Formula (III") In another embodiment, the Purine Derivatives of Formula is the same as group D of the Purine Derivative of Formula (III) have the formula (IIIa"), depicted above, wherein A, B, C (III'). and Dare defined above for the Purine Derivatives of Formula In one embodiment, the Purine Derivatives of Formula (III) 25 (III), and wherein the Purine Derivatives of Formula (IIIa") have the formula (III), depicted above, wherein A, B, C and D are substantially free of their corresponding opposite enanti are defined above for the Purine Derivatives of Formula (III), O. and wherein the Purine Derivatives of Formula (III) are sub In another embodiment, the Purine Derivatives of Formula stantially free of their corresponding enantiomer, represented (III) exist as a mixture of a Purine Derivative of Formula by Formula (III"). 30 (IIIa) and a Purine Derivative of Formula (IIIa") wherein the In another embodiment, the Purine Derivatives of Formula amount of the Purine Derivative of Formula (IIIa') exceeds (III) have the formula (III"), depicted above, wherein A, B, C the amount of the Purine Derivative of Formula (IIIa"). and Dare defined above for the Purine Derivatives of Formula In a further embodiment, the Purine Derivatives of For (III), and wherein the Purine Derivatives of Formula (III") are mula (III) exist as a mixture of a Purine Derivative of Formula Substantially free of their corresponding enantiomer, repre 35 (IIIa) and a Purine Derivative of Formula (IIIa") wherein the sented by Formula (III'). amount of the Purine Derivative of Formula (IIIa") exceeds In one embodiment, the Purine Derivatives of Formula (III) the amount of the Purine Derivative of Formula (IIIa"). exist as a mixture of a Purine Derivative of Formula (III) and In another embodiment, the Purine Derivatives of Formula a Purine Derivative of Formula (III") wherein the amount of (III) exist as a racemic mixture of a Purine Derivative of the Purine Derivative of Formula (III") exceeds the amount of 40 Formula (IIIa") and a Purine Derivative of Formula (IIIa"). the Purine Derivative of Formula (III"). A Purine Derivative of Formula (IIIa') is the corresponding In another embodiment, the Purine Derivatives of Formula other anomer of a Purine Derivative of Formula (III) when (III) exist as a mixture of a Purine Derivative of Formula (III) group A of the Purine Derivative of Formula (IIIa') is the same and a Purine Derivative of Formula (III") wherein the amount as group A of the Purine Derivative of Formula (III) and when of the Purine Derivative of Formula (III") exceeds the amount 45 group D of the Purine Derivative of Formula (IIIa') is the same of the Purine Derivative of Formula (III'). as group D of the Purine Derivative of Formula (III'). In another embodiment, the Purine Derivatives of Formula A Purine Derivative of Formula (III') is the corresponding (III) exist as a racemic mixture of a Purine Derivative of other anomer of a Purine Derivative of Formula (IIIa') when Formula (III") and a Purine Derivative of Formula (III"). group A of the Purine Derivative of Formula (III') is the same In another embodiment, the Purine Derivatives of Formula 50 as group A of the Purine Derivative of Formula (IIIa") and (III) can exist in the form of a single enantiomer, for example, when group D of the Purine Derivative of Formula (III') is the that depicted by either formula (IIIa) or (IIIa"): same as group D of the Purine Derivative of Formula (IIIa"). A Purine Derivative of Formula (IIIa") is the corresponding other anomer of a Purine Derivative of Formula (III") when (IIIa) 55 group A of the Purine Derivative of Formula (IIIa") is the same as group A of the Purine Derivative of Formula (III") and when group D of the Purine Derivative of Formula (IIIa") is the same as group D of the Purine Derivative of Formula (III"). 60 A Purine Derivative of Formula (III") is the corresponding (IIIa") other anomer of a Purine Derivative of Formula (IIIa") when group A of the Purine Derivative of Formula (III") is the same as group A of the Purine Derivative of Formula (IIIa") and when group D of the Purine Derivative of Formula (III") is the 65 same as group D of the Purine Derivative of Formula (IIIa"). In one embodiment, the Purine Derivatives of Formula (III) have the formula (IIIa'), depicted above, wherein A, B, C and US 8,609,833 B2 59 60 D are defined above for the Purine Derivatives of Formula 5.2.11 The Purine Derivatives of Formula (IV) (III), and wherein the Purine Derivatives of Formula (IIIa") are Substantially free of their corresponding other anomer. As stated above, the present invention encompasses Purine Derivatives having the Formula (IV): In another embodiment, the Purine Derivatives of Formula 5 (III) have the formula (IIIa"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula (IV) (III), and wherein the Purine Derivatives of Formula (IIIa") are substantially free of their corresponding other anomer. 10 In one embodiment, the Purine Derivatives of Formula (III) have the formula (III), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula (III), wherein A, B, C and D are defined above for the Purine and wherein the Purine Derivatives of Formula (III) are sub 15 Derivatives of Formula (IV), and A and B are trans with stantially free of their corresponding other anomer. respect to each other; B and C are cis with respect to each In another embodiment, the Purine Derivatives of Formula other; and C and Dare cis or trans with respect to each other. In one embodiment, R' is —Cs-Cs monocyclic cycloalkyl. (III) have the formula (III"), depicted above, wherein A, B, C In another embodiment, R is —Cs-Cs monocyclic and Dare defined above for the Purine Derivatives of Formula cycloalkenyl. (III), and wherein the Purine Derivatives of Formula (III") are In a specific embodiment, R' is cyclopenty1. Substantially free of their corresponding other anomer. In one embodiment, R is —H. In one embodiment, the Purine Derivatives of Formula (III) In another embodiment, R is -halo. exist as a mixture of a Purine Derivative of Formula (III) and 25 In a specific embodiment, R is —Cl. a Purine Derivative of Formula (IIIa') wherein the amount of In another embodiment, R is —CN. the Purine Derivative of Formula (III") exceeds the amount of In another embodiment, R is N(R), OR or -SR. the Purine Derivative of Formula (IIIa') In another embodiment, R is NHNHC(O)R. 30 NHNHC(O)CR or NHNHC(O)NHR'. In yet another In another embodiment, the Purine Derivatives of Formula embodiment, R is NH-N=C(R)R. (III) exist as a mixture of a Purine Derivative of Formula (III) In a specific embodiment, R is NH-N=CH-cyclopro and a Purine Derivative of Formula (IIIa") wherein the amount pyl. of the Purine Derivative of Formula (IIIa') exceeds the In one embodiment, C and D are cis with respect to each 35 other. amount of the Purine Derivative of Formula (III'). In another embodiment, C and Dare trans with respect to In another embodiment, the Purine Derivatives of Formula each other. (Ma) exist as a equal mixture of a Purine Derivative of For The present invention also provides compositions compris mula (III) and a Purine Derivative of Formula (IIIa). 40 ing an effective amount of a Purine Derivative of Formula In one embodiment, the Purine Derivatives of Formula (IV) and a physiologically acceptable carrier or vehicle. (Ma) exist as a mixture of a Purine Derivative of Formula The invention further provides Purine Derivatives of For (III") and a Purine Derivative of Formula (IIIa") wherein the mula (IV) that are in isolated and purified form. The invention still further provides methods for treating or amount of the Purine Derivative of Formula (III") exceeds the 45 preventing a Condition, comprising administering an effec amount of the Purine Derivative of Formula (IIIa"). tive amount of a Purine Derivative of Formula (IV) to an In another embodiment, the Purine Derivatives of Formula animal in need thereof. The invention further provides methods for reducing an (Ma) exist as a mixture of a Purine Derivative of Formula animals rate of metabolism, comprising administering an (III") and a Purine Derivative of Formula (IIIa") wherein the 50 effective amount of a Purine Derivative of Formula (IV) to an amount of the Purine Derivative of Formula (IIIa") exceeds animal in need thereof. the amount of the Purine Derivative of Formula (III"). The invention further provides methods protecting an ani mals heart against myocardial damage during cardioplegia, In another embodiment, the Purine Derivatives of Formula comprising administering an effective amount of a Purine (Ma) exist as a equal mixture of a Purine Derivative of For 55 Derivative of Formula (IV) to an animal in need thereof. mula (III") and a Purine Derivative of Formula (IIIa"). The Purine Derivatives of Formula (IV) can exist in the A first subclass of the Purine Derivatives of Formula (III) is form of a single enantiomer, for example, that depicted by that wherein one occurrence of R' is H. either the Formula (IV) or Formula (IV"): A second subclass of the Purine Derivatives of Formula 60 (III) is that wherein one occurrence of R' is Hand the other occurrence of R is —C-Cs monocyclic cycloalkyl. (IV) A third subclass of the Purine Derivatives of Formula (III) is that wherein R is NH-N=C(R)R. 65 A fourth subclass of the Purine Derivatives of Formula (III) is that wherein R is - ONO. US 8,609,833 B2 61 62 -continued wherein A, B, C and D are defined above for the Purine (IV) Derivatives of Formula (IV). A Purine Derivative of Formula (IVa') is the corresponding opposite enantiomer of a Purine Derivative of Formula (IVa") when group A of the Purine Derivative of Formula (IVa") is the same as group A of the Purine Derivative of Formula (IVa") and when group D of the Purine Derivative of Formula (IVa") is the same as group D of the Purine Derivative of Formula wherein A, B, C and D are defined above for the Purine (IVa"). Derivatives of Formula (IV). 10 A Purine Derivative of Formula (IVa") is the corresponding A Purine Derivative of Formula (IV) is the corresponding opposite enantiomer of a Purine Derivative of Formula (IVa") opposite enantiomer of a Purine Derivative of Formula (IV") when group A of the Purine Derivative of Formula (IVa") is when group A of the Purine Derivative of Formula (IV) is the the same as group A of the Purine Derivative of Formula (IVa") same as group A of the Purine Derivative of Formula (IV") and when group D of the Purine Derivative of Formula (IVa") and when group D of the Purine Derivative of Formula (IV) 15 is the same as group D of the Purine Derivative of Formula is the same as group D of the Purine Derivative of Formula (IVa"). (IV"). In one embodiment, the Purine Derivatives of Formula A Purine Derivative of Formula (IV") is the corresponding (IV) have the formula (IVa'), depicted above, wherein A, B, C opposite enantiomer of a Purine Derivative of Formula (IV) and Dare defined above for the Purine Derivatives of Formula when group A of the Purine Derivatives of Formula (IV") is (IV), and wherein the Purine Derivatives of Formula (IVa") are the same as group A of the Purine Derivative of Formula (IV) Substantially free of their corresponding opposite enantiomer. and when group D of the Purine Derivative of Formula (IV") In another embodiment, the Purine Derivatives of Formula is the same as group D of the Purine Derivative of Formula (IV) have the formula (IVa"), depicted above, wherein A, B, C (IV). and Dare defined above for the Purine Derivatives of Formula In one embodiment, the Purine Derivatives of Formula 25 (IV), and wherein the Purine Derivatives of Formula (IVa") (IV) have the formula (IV), depicted above, wherein A, B, C are substantially free of their corresponding opposite enanti and Dare defined above for the Purine Derivatives of Formula O. (IV), and wherein the Purine Derivatives of Formula (IV) are In another embodiment, the Purine Derivatives of Formula Substantially free of their corresponding enantiomer, repre (IV) exist as a mixture of a Purine Derivative of Formula sented by Formula (IV"). 30 (IVa') and a Purine Derivative of Formula (IVa") wherein the In another embodiment, the Purine Derivatives of Formula amount of the Purine Derivative of Formula (IVa") exceeds the (IV) have the formula (IV"), depicted above, wherein A, B, C amount of the Purine Derivative of Formula (IVa"). and Dare defined above for the Purine Derivatives of Formula In a further embodiment, the Purine Derivatives of For (IV), and wherein the Purine Derivatives of Formula (IV") are mula (IV) exist as a mixture of a Purine Derivative of Formula Substantially free of their corresponding enantiomer, repre 35 (IVa') and a Purine Derivative of Formula (IVa") wherein the sented by Formula (IV). amount of the Purine Derivative of Formula (IVa") exceeds In one embodiment, the Purine Derivatives of Formula the amount of the Purine Derivative of Formula (IVa"). (IV) exist as a mixture of a Purine Derivative of Formula (IV) In another embodiment, the Purine Derivatives of Formula and a Purine Derivative of Formula (IV") wherein the amount (IV) exist as a racemic mixture of a Purine Derivative of of the Purine Derivative of Formula (IV) exceeds the amount 40 Formula (IVa") and a Purine Derivative of Formula (IVa"). of the Purine Derivative of Formula (IV"). A Purine Derivative of Formula (IVa') is the corresponding In another embodiment, the Purine Derivatives of Formula other anomer of a Purine Derivative of Formula (IV) when (IV) exist as a mixture of a Purine Derivative of Formula (IV) group A of the Purine Derivative of Formula (IVa") is the same and a Purine Derivative of Formula (IV") wherein the amount as group A of the Purine Derivative of Formula (IV) and when of the Purine Derivative of Formula (IV") exceeds the amount 45 group D of the Purine Derivative of Formula (IVa') is the same of the Purine Derivative of Formula (IV). as group D of the Purine Derivative of Formula (IV). In another embodiment, the Purine Derivatives of Formula A Purine Derivative of Formula (IV) is the corresponding (IV) exist as a racemic mixture of a Purine Derivative of other anomer of a Purine Derivative of Formula (IVa") when Formula (IV) and a Purine Derivative of Formula (IV") group A of the Purine Derivative of Formula (IV) is the same In another embodiment, the Purine Derivatives of Formula 50 as group A of the Purine Derivative of Formula (IVa") and (IV) can exist in the form of a single enantiomer, for example, when group D of the Purine Derivative of Formula (IV) is the that depicted by either formula (IVa') or (IVa"): same as group D of the Purine Derivative of Formula (IVa"). A Purine Derivative of Formula (IVa") is the corresponding other anomer of a Purine Derivative of Formula (IV") when (IVa') 55 group A of the Purine Derivative of Formula (IVa") is the same as group A of the Purine Derivative of Formula (IV") and when group D of the Purine Derivative of Formula (IVa") is the same as group D of the Purine Derivative of Formula (IV"). ES ? 60 A Purine Derivative of Formula (IV") is the corresponding (IVa") other anomer of a Purine Derivative of Formula (IVa") when A, O D group A of the Purine Derivative of Formula (IV") is the same as group A of the Purine Derivative of Formula (IVa") and when group D of the Purine Derivative of Formula (IV") is the B C 65 same as group D of the Purine Derivative of Formula (IVa"). In one embodiment, the Purine Derivatives of Formula (IV) have the formula (IVa'), depicted above, wherein A, B, C US 8,609,833 B2 63 64 and Dare defined above for the Purine Derivatives of Formula -continued (IV), and wherein the Purine Derivatives of Formula (IVa") are 22 Substantially free of their corresponding other anomer. NH-N=CH(cyclopentyl) In another embodiment, the Purine Derivatives of Formula 5 (IV) have the formula (IVa"), depicted above, wherein A, B, C N n and Dare defined above for the Purine Derivatives of Formula N (IV), and wherein the Purine Derivatives of Formula (IVa") 2 are substantially free of their corresponding other anomer. O. N NH-N=CH(cyclopentyl) In one embodiment, the Purine Derivatives of Formula (IV) have the formula (IV), depicted above, wherein A, B, C 10 ry and Dare defined above for the Purine Derivatives of Formula (IV), and wherein the Purine Derivatives of Formula (IV) are Substantially free of their corresponding other anomer. In another embodiment, the Purine Derivatives of Formula 15 and pharmaceutically acceptable salts thereof. (IV) have the formula (IV"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula 5.2.12 The Purine Derivatives of Formula (V) (IV), and wherein the Purine Derivatives of Formula (IV") are Substantially free of their corresponding other anomer. As stated above, the present invention encompasses Purine In one embodiment, the Purine Derivatives of Formula Derivatives having the Formula (V): (IV) exist as a mixture of a Purine Derivative of Formula (IV) and a Purine Derivative of Formula (IVa") wherein the amount of the Purine Derivative of Formula (IV) exceeds the amount (V) of the Purine Derivative of Formula (IVa") In another embodiment, the Purine Derivatives of Formula 25 (IV) exist as a mixture of a Purine Derivative of Formula (IV) and a Purine Derivative of Formula (IVa") wherein the amount of the Purine Derivative of Formula (IVa") exceeds the amount of the Purine Derivative of Formula (IV). In another embodiment, the Purine Derivatives of Formula 30 wherein A, B, C and D are defined above for the Purine (IVa) exist as a equal mixture of a Purine Derivative of For Derivatives of Formula (V), and A and B are trans with mula (IV) and a Purine Derivative of Formula (IVa"). respect to each other; B and C are cis with respect to each In one embodiment, the Purine Derivatives of Formula other; and C and Dare cis or trans with respect to each other. (IVa) exist as a mixture of a Purine Derivative of Formula In one embodiment, R' is -C-Cio alkyl. (IV") and a Purine Derivative of Formula (IVa") wherein the 35 In another embodiment, R' is —(CH)-(3- to 7-mem amount of the Purine Derivative of Formula (IV") exceeds the bered monocyclic heterocycle) or —(CH2)-(8- to 12-mem amount of the Purine Derivative of Formula (IVa"). bered bicyclic heterocycle). In another embodiment, the Purine Derivatives of Formula In another embodiment, R' is —(CH), (Cs-C bicyclic (IVa) exist as a mixture of a Purine Derivative of Formula cycloalkyl) or —(CH), (C-C bicyclic cycloalkenyl). (IV") and a Purine Derivative of Formula (IVa") wherein the 40 In still another embodiment, R' is -(CH2), (C-Cs amount of the Purine Derivative of Formula (IVa") exceeds monocyclic cycloalkyl) or —(CH), (C-C monocyclic the amount of the Purine Derivative of Formula (IV"). cycloalkenyl). In another embodiment, the Purine Derivatives of Formula In a further embodiment, R' is —(CH2)-aryl. (IVa) exist as a equal mixture of a Purine Derivative of For In one embodiment, R" is —Cs-Cs monocyclic mula (IV") and a Purine Derivative of Formula (IVa"). 45 A first subclass of the Purine Derivatives of Formula (IV) is cycloalkyl. that wherein R' is -cyclopentyl. In another embodiment, R" is —C-C monocyclic A second subclass of the Purine Derivatives of Formula cycloalkenyl. (IV) is that wherein R is H. In a specific embodiment, R" is cyclopentyl. A third subclass of the Purine Derivatives of Formula (IV) 50 In another embodiment, R' and R' together with the car is that wherein R is Cl. bon atom to which they are attached form a -C-C mono Illustrative Purine Derivatives of Formula (IV) include the cyclic cycloalkyl, a -C-C monocyclic cycloalkenyl, a compounds listed below: —Cs-C, bicyclic cycloalkyl, or a —C-C bicyclic cycloalkenyl. 55 In one embodiment, R is —OR or - SR". 21 In another embodiment, R is NHNHC(O)R. NH-NFCH(cyclopentyl) and NHNHC(O)CR or NHNHC(O)NHR'. In yet another embodiment, R is NH-N=C(R)R. N NN In a specific embodiment, R is NH N=CH-cyclopro 60 pyl. In one embodiment, C and D are cis with respect to each other. In another embodiment, C and Dare trans with respect to each other. 65 The present invention also provides compositions compris ing an effective amount of a Purine Derivative of Formula (V) and a physiologically acceptable carrier or vehicle. US 8,609,833 B2 65 66 The invention further provides Purine Derivatives of For of the Purine Derivative of Formula (V") exceeds the amount mula (V) that are in isolated and purified form. of the Purine Derivative of Formula (V). The invention still further provides methods for treating or In another embodiment, the Purine Derivatives of Formula preventing a Condition, comprising administering an effec (V) exist as a racemic mixture of a Purine Derivative of tive amount of a Purine Derivative of Formula (V) to an Formula (V) and a Purine Derivative of Formula (V") animal in need thereof. In another embodiment, the Purine Derivatives of Formula The invention further provides methods for reducing an (V) can exist in the form of a single enantiomer, for example, animals rate of metabolism, comprising administering an that depicted by either formula (Va") or (Va"): effective amount of a Purine Derivative of Formula (V) to an animal in need thereof. 10 The invention further provides methods protecting an ani (Va.) mals heart against myocardial damage during cardioplegia, comprising administering an effective amount of a Purine Derivative of Formula (V) to an animal in need thereof. 15 The Purine Derivatives of Formula (V) can exist in the form S ? of a single enantiomer, for example, that depicted by either (Va") the Formula (V) or Formula (V"): A, O D

(V) B C

n wherein A, B, C and D are defined above for the Purine S 25 Derivatives of Formula (V). (V') A Purine Derivative of Formula (Va) is the corresponding ^, O aD opposite enantiomer of a Purine Derivative of Formula (Va") when group A of the Purine Derivative of Formula (Va') is the same as group A of the Purine Derivative of Formula (Va") 30 and when group D of the Purine Derivative of Formula (Va") B C is the same as group D of the Purine Derivative of Formula (Va"). wherein A, B, C and D are defined above for the Purine A Purine Derivative of Formula (Va") is the corresponding Derivatives of Formula (V). opposite enantiomer of a Purine Derivative of Formula (Va") A Purine Derivative of Formula (V) is the corresponding 35 when group A of the Purine Derivative of Formula (Va") is the same as group A of the Purine Derivative of Formula (Va") and opposite enantiomer of a Purine Derivative of Formula (V") when group D of the Purine Derivative of Formula (Va") is the when group A of the Purine Derivative of Formula (V") is the same as group D of the Purine Derivative of Formula (Va"). same as group A of the Purine Derivative of Formula (V") and In one embodiment, the Purine Derivatives of Formula (V) when group D of the Purine Derivative of Formula (V) is the 40 have the formula (Va"), depicted above, wherein A, B, C and same as group D of the Purine Derivative of Formula (V"). D are defined above for the Purine Derivatives of Formula A Purine Derivative of Formula (V") is the corresponding (V), and wherein the Purine Derivatives of Formula (Va") are opposite enantiomer of a Purine Derivative of Formula (V) Substantially free of their corresponding opposite enantiomer. when group A of the Purine Derivatives of Formula (V") is the In another embodiment, the Purine Derivatives of Formula same as group A of the Purine Derivative of Formula (V) and 45 (V) have the formula (Va"), depicted above, wherein A, B, C when group D of the Purine Derivative of Formula (V") is the and Dare defined above for the Purine Derivatives of Formula same as group D of the Purine Derivative of Formula (V). (V), and wherein the Purine Derivatives of Formula (Va") are In one embodiment, the Purine Derivatives of Formula (V) Substantially free of their corresponding opposite enantiomer. have the formula (V), depicted above, wherein A, B, C and D In another embodiment, the Purine Derivatives of Formula are defined above for the Purine Derivatives of Formula (V), 50 (V) exist as a mixture of a Purine Derivative of Formula (Va") and wherein the Purine Derivatives of Formula (V) are sub and a Purine Derivative of Formula (Va") wherein the amount stantially free of their corresponding enantiomer, represented of the Purine Derivative of Formula (Va) exceeds the amount by Formula (V"). of the Purine Derivative of Formula (Va"). In another embodiment, the Purine Derivatives of Formula In a further embodiment, the Purine Derivatives of For (V) have the formula (V"), depicted above, wherein A, B, C 55 mula (V) exist as a mixture of a Purine Derivative of Formula and Dare defined above for the Purine Derivatives of Formula (Va") and a Purine Derivative of Formula (Va") wherein the (V), and wherein the Purine Derivatives of Formula (V") are amount of the Purine Derivative of Formula (Va") exceeds the Substantially free of their corresponding enantiomer, repre amount of the Purine Derivative of Formula (Va"). sented by Formula (V). In another embodiment, the Purine Derivatives of Formula In one embodiment, the Purine Derivatives of Formula (V) 60 (V) exist as a racemic mixture of a Purine Derivative of exist as a mixture of a Purine Derivative of Formula (V) and Formula (Va") and a Purine Derivative of Formula (Va"). a Purine Derivative of Formula (V") wherein the amount of A Purine Derivative of Formula (Va) is the corresponding the Purine Derivative of Formula (V) exceeds the amount of other anomer of a Purine Derivative of Formula (V") when the Purine Derivative of Formula (V"). group A of the Purine Derivative of Formula (Va') is the same In another embodiment, the Purine Derivatives of Formula 65 as group A of the Purine Derivative of Formula (V) and when (V) exist as a mixture of a Purine Derivative of Formula (V) group D of the Purine Derivative of Formula (Va") is the same and a Purine Derivative of Formula (V") wherein the amount as group D of the Purine Derivative of Formula (V). US 8,609,833 B2 67 68 A Purine Derivative of Formula (V) is the corresponding 1992: Cristalli et al., J. Med. Chem. 37: 1720-1726, 1994; other anomer of a Purine Derivative of Formula (Va") when Cristalli et al., J. Med. Chem. 38:1462-1472, 1995; and group A of the Purine Derivative of Formula (V) is the same Camaioni et al., Bioorg. Med. Chem. 5:2267-2275, 1997), or as group A of the Purine Derivative of Formula (Va") and when by using the synthetic procedures outlined below in Schemes group D of the Purine Derivative of Formula (V) is the same as group D of the Purine Derivative of Formula (Va"). 1-12. A Purine Derivative of Formula (Va") is the corresponding Scheme 1 shows methods for making nucleoside interme other anomer of a Purine Derivative of Formula (V") when diates that are useful for making the Purine Derviatives of group A of the Purine Derivative of Formula (Va") is the same Formulas (Ia), (Ib), (Ic), (Id), (Ie). (If). (Ig), (Ih), (II), (III), as group A of the Purine Derivative of Formula (V") and when (IV) and (V). group D of the Purine Derivative of Formula (Va") is the same 10 as group D of the Purine Derivative of Formula (V"). A Purine Derivative of Formula (V") is the corresponding Scheme 1 other anomer of a Purine Derivative of Formula (Va") when group A of the Purine Derivative of Formula (V") is the same OAc as group A of the Purine Derivative of Formula (Va") and 15 cry when group D of the Purine Derivative of Formula (V") is the . -- same as group D of the Purine Derivative of Formula (Va"). In one embodiment, the Purine Derivatives of Formula (V) have the formula (Va"), depicted above, wherein A, B, C and D are defined above for the Purine Derivatives of Formula X (V), and wherein the Purine Derivatives of Formula (Va") are 1 Substantially free of their corresponding other anomer. C In another embodiment, the Purine Derivatives of Formula (V) have the formula (Va"), depicted above, wherein A, B, C N NN and Dare defined above for the Purine Derivatives of Formula 25 Hibs (V), and wherein the Purine Derivatives of Formula (Va") are ( 2. 2.1. TMSOTfLiHMDS, A Substantially free of their corresponding other anomer. N 4. R. 3. TFA In one embodiment, the Purine Derivatives of Formula (V) have the formula (V), depicted above, wherein A, B, C and D 2 are defined above for the Purine Derivatives of Formula (V), C and wherein the Purine Derivatives of Formula (V) are sub 30 stantially free of their corresponding other anomer. In another embodiment, the Purine Derivatives of Formula ( NN (V) have the formula (V"), depicted above, wherein A, B, C and Dare defined above for the Purine Derivatives of Formula O N Nals R + (V), and wherein the Purine Derivatives of Formula (V") are 35 Substantially free of their corresponding other anomer. -ny In one embodiment, the Purine Derivatives of Formula (V) exist as a mixture of a Purine Derivative of Formula (V) and HG OH a Purine Derivative of Formula (Va") wherein the amount of 3 the Purine Derivative of Formula (V) exceeds the amount of 40 C the Purine Derivative of Formula (Va) In another embodiment, the Purine Derivatives of Formula N (V) exist as a mixture of a Purine Derivative of Formula (V) and a Purine Derivative of Formula (Va") wherein the amount (1. of the Purine Derivative of Formula (Va) exceeds the amount 45 O SN Nals R2 of the Purine Derivative of Formula (V). In another embodiment, the Purine Derivatives of Formula ry (Va) exist as a equal mixture of a Purine Derivative of For mula (V) and a Purine Derivative of Formula (Va"). HG OH In one embodiment, the Purine Derivatives of Formula 50 4 (Va) exist as a mixture of a Purine Derivative of Formula (V") OAc and a Purine Derivative of Formula (Va") wherein the amount Aco1 . of the Purine Derivative of Formula (V") exceeds the amount of the Purine Derivative of Formula (Va"). -- In another embodiment, the Purine Derivatives of Formula 55 (Va) exist as a mixture of a Purine Derivative of Formula (V") and a Purine Derivative of Formula (Va") wherein the amount X of the Purine Derivative of Formula (Va") exceeds the amount 5 of the Purine Derivative of Formula (V"). C In another embodiment, the Purine Derivatives of Formula 60 (Va) exist as a equal mixture of a Purine Derivative of For N NN mula (V") and a Purine Derivative of Formula (Va"). ( Her1. LiHMDS, A 2. TMSOTf 5.3 Methods for Making the Purine Derivatives NH Nals R 65 The Purine Derivatives can be made according to published 2 methods (see Cristalli et al., J. Med. Chem. 35:2363-2369, US 8,609,833 B2 69 70 -continued -continued C NHR

N n N N n N {ll2 2 w O s N R + O. N N R2 Aco1 8. HO

10 X X 6 8 15

where R' and R are defined above herein for the Purine Derivatives. C The 6-chloroadenosine derivative of formula 3a is con Verted to its 2',3'-acetonide using acetone and 2,2-dimethox N ypropane in the presence of camphorsulfonic acid. The acetonide can be further derviatized using an amine of for (1. mula R' NH in the presence of base to provide compounds N als 10, O N R 25 of formula 8. AcO .. Scheme 3 shows a method useful for making the Purine Derivatives of Formula (Ia) X Scheme 3 7 NHR

N n N wherein R is as defined above for the Purine Derviatives of 35 2 1. SO3-pyridine Formulas (Ia), (Ib), (Ic), (Id), (Ie). (If). (Ig), (Ih), (II), (III), O. N N R He (IV) and (V). HO 2. SOCl. The protected ribose compound of Formula 1 can be 3. NH coupled with a purine compound of Formula 2 using lithium 4. TFA/H2O hexamethyldisilazide and trimethylsilyl triflate, followed by 40 acetonide removal using trifluoroacetic acid to provide nucleoside intermediates of Formula 3 and their correspond X ing other anomers of Formula 4. Similarly, the ribose diac 8 etate of Formula 5 can be coupled with a compound of For mula 2 using lithium hexamethyldisilazide and trimethylsilyl 45 NHR triflate to provide acetonide-protected nucleoside intermedi N ates of Formula 6 and their corresponding other anomers of Formula 7. (1. N als Scheme 2 shows a method useful for making the adenosine HNOS O N R intermediates of Formula 8 which are useful for making the Purine Derviatives of Formulas (Ia), (Ib), (Ic), (Id) and (Ie).

HO OH Scheme 2 55 Purine Derivatives of Formula (Ia) C

N where R' and R are defined above herein for the Purine (W n N 1. Acetone2,2-dimethoxypropane Derivatives of Formula (Ia). N % R CSA 60 The adenosine intermediates of formula 8 can be converted O * 2. RI-NH2 to their 5'-sulfonic acid analogs, which can then be chlori HO nated using thionyl chloride to provide the corresponding 5'-chlorosulfonate intermediates. The chlorosulfonate inter

HO OH mediates can then be reacted with ammonia to provide the 65 corresponding 5'-sulfonamide intermediates. Acetonide 3a removal using TFA/water provides the Purine Derivatives of Formula (Ia). US 8,609,833 B2 71 72 Methodology useful for making Purine Derivatives of For -continued mula (Ib) is described in Scheme 4. NHR

N Scheme 4 (1. NHR RHN O. N Nals R2

N n ( N 1. HNO3, Ac2O (or other nitrating agent) 10 2 HO OH O N N He R2 2. TFA/HO Purine Derivatives of Formula (Ic) HO

15 where R', Rand Rare defined above herein for the Purine O O Derivatives of Formula (Ic). The adenosine intermediates of formula 8 can be converted X to their 5'-alkoxyphosphonium perchlorate analogs using CCla-P(NMe), then treating the product of this reaction with ammonium perchlorate. The intermediate 5'-alkoxy phosphonium perchlorates can Subsequently be reacted with an amine of formula NHR to provide the 5'-amino analogs. Acetonide removal using TFA/water provides the Purine Derivatives of Formula (Ic). 25 Methodology useful for making the Purine Derivatives of NHR Formula (Id) wherein R is —CHOSOH is outlined in Scheme 6. N N N

2 30 Scheme 6 O {llN N R2 ONO NHR

N HO OH 35 (1.N als 1. SO3-Pyridine, DMF Purine Derivatives of Formula (Ib) HO O N R -e- 2. NaOH or KOH 3. TFA/HO where R' and R are defined above herein for the Purine 4. H" 40 Derivatives of Formula (Ib). O O The Adenosine intermediates of formula 8 can be con Verted to their 5'-nitrate analogs using nitric acid in the pres ence of acetic anhydride, or other nitrating agents, such as X MsC1/O NO or nitrosonium tetrafluoroborate. Acetonide 45 NHR removal using TFA/water provides Purine Derivatives of For mula (Ib). N n Methodology useful for making the Purine Derivatives of / N Formula (Ic) is outlined below in Scheme 5. 50 HOSO O { es R2

Scheme 5

NHR HO OH 55 N n Purine Derivatives of Formula (Id) wherein R is N -CHOSOH 2 O. N N R2 1. CCI-P(NMe2)3 HO 2. NH4CIO where R' and R are defined above herein for the Purine 3. NHR 60 Derivatives of Formula (Id). 4. TFA/H2O The adenosine intermediates of formula 8 can be treated with sulfur trioxide-pyridine complex to provide the corre O O sponding 5'-sulfonic acid pyridine Salt intermediate. The pyridine Salt intermediate can then be neutralized using X 65 NaOH or KOH, followed by acetonide removal using TFA/ water to provide the corresponding Sodium or potassium salt, respectively, of the Purine Derivatives of Formula (Id) US 8,609,833 B2 73 74 wherein R is —CHOSOH. Treatment of the sodium or -continued potassium salt with strong aqueous acid, such as Sulfuric or NHR hydrochloric acid, provides the Purine Derivatives of For mula (Id) wherein R is CHOSOH. Methodology useful for making the Purine Derivatives of 5 (1. Formula (Id) wherein R is - ONO is outlined in Scheme 7. R3 O. N Nals R2

Scheme 7 10 NHR HO OH Purine Derivatives of Formula (Ie)

N-N1S N 15 where R' and R are defined above herein for the Purine 2 1. NOBF {llN YN1 NR, -e- Derivatives of Formula (Ie). HO 2. TFA/HO The adenosine intermediates of formula 8 can be reacted with sulfur trioxide-pyridine complex to provide the corre sponding 5'-sulfonic acid intermediates, which can Subse quently be treated with thionyl chloride to provide the inter mediate 5'-chlorosulfonate intermediates. The X chlorosulfonate intermediates can then be reacted with an 8 amine of formula HN-(C-C alkyl), HNCC-Co alkyl). NHR 25 or HN-aryl to provide the corresponding 5'-sulfonamide intermediates. Acetonide removal using TFA/water provides N the Purine Derivatives of Formula (Ie) wherein R is —OSONHCC-Co alkyl). —OSONCC-Co alkyl), or (1.als –OSONH-aryl. ONO o, N N R2 30 Methodology useful for making the Purine Derivatives of Formulas (II) is outlined in Scheme 9.

HO OH Scheme 9 Purine Derivatives of Formula (Id) wherein R is -CHONO 35 C where R' and R are defined above herein for the Purine (N NN NH-NH2 Derivatives of Formula (Id). He The adenosine intermediates of formula 8 can be treated 40 O. N Nals R with nitrosonium fluoroborate complex to provide the corre HO sponding nitroSooxy intermediates. Acetonide removal using TFA/water provides the Purine Derivatives of Formula (Id) HO OH wherein R is —CHONO. 45 Methodology useful for making the Purine Derivatives of 3a Formula (Ie) wherein R is —OSONH(C-C alkyl). —OSONCC-Co alkyl), or—OSONH-aryl, is outlined in Scheme 8. 50

Scheme 8 NHR H NH2 O N 1 R1 RI (1.N als 1. SO3-pyridine N n O N R2 Her HO 2. SOCI ( N --10 3. amine 60 2 4. TFA/H2O O. N N R HO O O

HO OH X 65 9 US 8,609,833 B2 75 76 -continued -continued NH-N=C(R)(R) NH-N=C(R)(R)

N-1N N N n N

2 2 {llN - N1 NR, O. N N R2 HO

10 HO OH HO OH Purine Derivatives of Formula (II) Purine Derivatives of Formula (III) where R' and R are defined above herein for the Purine 15 where R', Rand Rare defined above herein for the Purine Derivatives of Formula (II). Derivatives of Formula (III). The 6-chloroadenosine derivatives of Formula 3a can be The compounds of Formula 3b can be protected as their 2',3'-acetonide derivatives and their 5'-OH group can be con converted to their 6-hydrazine derivatives of Formula 9 upon verted to an R group using methodology well known to one reacting with hydrazine. Compounds of Formula 9 can then skilled in the art of organic synthesis. Subsequent removal of be treated with a carbonyl compound of formula 10 to provide the acetonide unit using TFA affords the 6-chloroadenosine the Purine Derivatives of Formula (II). compounds of formula 12 which can be converted to their Methodology useful for making the Purine Derivatives of 6-hydrazino derivatives of formula 13 using hydrazine. The Formula (III) is outlined in Scheme 10. hydrazino compounds of formula 13 can then be treated with a carbonyl compound of formula 10 to provide the Purine 25 Derivatives of Formula (III). Scheme 10 Methodology useful for making the Purine Derivatives of C Formula (IV) is outlined in Scheme 11.

N ( NN 1. 2,2-dimethoxypropane 30 Scheme 11 Acetone es CSA C 3 O. N N R2 Her R 2. Introduce R N n 3. TFA/H2O N 35 2 NH-NH2 HO OH HO O. N N R e 3b C

N 40 HO OH 3a (1.N als NH-NH2 R3 O N. R. --> H NH2 45 nN.1 O HO OH WN NN ls 12 H NH2 ( 2 . 1"14 nN.1 50 HO O N N R2 ->

N (1.als HO OH R3 O N N R 55 9 NH-N=CHR

N HO OH 13 60 (1. N als HO O N R 1.O 10 65 HO OH Purine Derivatives of Formula (IV) US 8,609,833 B2 77 where R' and R are defined above herein for the Purine Derivatives of Formula (IV). Scheme 13 The 6-chloroadenosine derivatives of Formula 3a can be converted to their 6-hydrazine derivatives of Formula 9 upon 1. CBZC. reacting with hydrazine. Compounds of Formula 9 can then HO 2. Et3SiCl, ImH Et3SiO 3. H. Pd/C, MeOH be treated with an aldehyde of formula 14 to provide the -e- -- Purine Derivatives of Formula (IV). Methodology useful for making the Purine Derivatives of HN HN Formula (V) is outlined in Scheme 12. 34 35 10 C

Scheme 12 N C (1.N 2 EtOH 15 N n HO A ( N ->NHNH2 2 O. N N R HO X HO OH 36 3a Et3SiO,

25

HN

N 1. AcO, HNO H NH2 O ( NN 3 1 J 30 -e- RI R1a N Nals H N n HO O ( N --15 O N Nals R2 HO X HO OH 37 9 40 HO,

HN

NH-N=C(R)(R) 45 N

N (1. O. N. Nals H (1. ONO O N Nals R2 50 HO HO OH 38 HO OH Purine Derivatives of Formula (V) 55 2-Aminocyclopentanol (34) is reacted with carbobenzoy loxychloride (CBZC1) to protect the amino functionality as where R', R'' and Rare defined above herein for the Purine its carbobenzoyloxy derivative. The OH group of the car Derivatives of Formula (V). bobenzoyloxy derivative is then converted to its correspond The 6-chloroadenosine derivatives of Formula 3a can be 60 ing triethylsilyl ether using triethylsilyl chloride in the pres converted to their 6-hydrazine derivatives of Formula 9 upon ence of imidazole. The carbobenzoyloxy protecting group is reacting with hydrazine. Compounds of Formula 9 can then then removed via catalytic hydrogenation to provide amine be treated with a carbonyl compound of formula 15 to provide compound 35. Compound 35 is coupled with compound 36 in the Purine Derivatives of Formula (V). refluxing ethanol to provide compound 37, which is subse Methodology useful for making the Purine Derivatives of 65 quently nitrated using acetic anhydride/nitric acid and then Formula (Ih), wherein R' is cyclopent-1-ol-2-yl is outlined in reacted with trifluoroacetic acid to remove the acetonide Scheme 13. group and provide compound 38. US 8,609,833 B2 79 80 Methodology useful for making the Purine Derivatives of genation to provide amine compound 40. Compound 40 is Formula (Ih), wherein R' is cyclopent-1-ol-3-yl is outlined in coupled with compound 36 in refluxing ethanol to provide Scheme 14. compound 41, which is Subsequently nitrated using acetic anhydride/nitric acid and then reacted with trifluoroacetic acid to remove the acetonide group and provide compound Scheme 14 42. OH 1. CBZC. OSEt 5.4 Therapeutic/Prophylactic Administration and 2. Et3SiCl, ImH Compositions of the Invention 3. H. Pd/C, MeOH Her -- 10 Due to their activity, the Purine Derivatives are advanta HN HN geously useful in Veterinary and human medicine. As 39 40 described above, the Purine Derivatives are useful for: (i) C treating or preventing a Condition in an animal in need 15 thereof; (ii) reducing an animals rate of metabolism; or (iii) N protecting an animals heart against myocardial damage dur ing cardioplegia. (?N 2 EtOH When administered to an animal, the Purine Derivatives O N H -> can be administered as a component of a composition that HO A comprises a physiologically acceptable carrier or vehicle. The present compositions, which comprise a Purine Deriva tive, can be administered orally. The Purine Derivatives can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption 25 through epithelial or mucocutaneous linings (e.g., oral, rectal, X or intestinal mucosa) and can be administered together with 36 another biologically active agent. Administration can be sys OSIEt3 temic or local. Various known delivery systems, including encapsulation in liposomes, microparticles, microcapsules, and capsules, can be used. Methods of administration include, but are not limited to, HN intradermal, intramuscular, intraperitoneal, intravenous, sub N 1. AcO, HNO cutaneous, intranasal, epidural, oral, Sublingual, intracere ( NN 2 R 3 bral, intravaginal, transdermal, rectal, by inhalation, or topi -e- 35 cal, particularly to the ears, nose, eyes, or skin. In some N Nals H instances, administration will result in the release of the HO O Purine Derivatives into the bloodstream. The mode of admin istration can be left to the discretion of the practitioner. In one embodiment, the Purine Derivatives are adminis 40 tered orally. In another embodiment, the Purine Derivatives are admin istered intravenously. X In another embodiment, when the Purine Derivatives are 41 used to reduce an animal's rate of metabolism, the Purine OH 45 Derviatives can be administered by continuous intravenous infusion. In other embodiments, it can be desirable to administer the Purine Derivatives locally. This can be achieved, for example, HN and not by way of limitation, by local infusion during Surgery, topical application, e.g., in conjunction with a wound dress N ing after Surgery, by injection, by means of a catheter, by means of a Suppository or enema, or by means of an implant, (1. said implant being of a porous, non-porous, or gelatinous O. N Nals H ONO material, including membranes, such as Sialastic membranes, or fibers. In certain embodiments, it can be desirable to introduce the Purine Derivatives into the central nervous system, circula HO OH tory system or gastrointestinal tract by any suitable route, 42 including intraventricular, intrathecal injection, paraspinal 60 injection, epidural injection, enema, and by injection adjacent to a peripheral nerve. Intraventricular injection can be facili 3-Aminocyclopentanol (39) is reacted with CBZC1 to pro tated by an intraventricular catheter, for example, attached to tect the amino functionality as its carbobenzoyloxy deriva a reservoir, such as an Ommaya reservoir. tive. The OH group of the carbobenzoyloxy derivative is then Pulmonary administration can also be employed, e.g., by converted to its corresponding triethylsilyl ether using trieth 65 use of an inhaler of nebulizer, and formulation with an aero ylsilyl chloride in the presence of imidazole. The carboben Solizing agent, or via perfusion in a fluorocarbon or synthetic Zoyloxyprotecting group is then removed via catalytic hydro pulmonary Surfactant. In certain embodiments, the Purine US 8,609,833 B2 81 82 Derivatives can be formulated as a suppository, with tradi aqueous or oily Suspensions, granules, powders, emulsions, tional binders and excipients such as triglycerides. capsules, syrups, or elixirs for example. Orally administered In another embodiment the Purine Derivatives can be compositions can contain one or more agents, for example, delivered in a vesicle, in particular a liposome (see Langer, Sweetening agents such as fructose, aspartame or saccharin; Science 249:1527-1533 (1990) and Treat or prevent et al., flavoring agents such as peppermint, oil of wintergreen, or Liposomes in the Therapy of Infectious Disease and Cancer cherry; coloring agents; and preserving agents, to provide a 317-327 and 353–365 (1989)). pharmaceutically palatable preparation. Moreover, where in In yet another embodiment the Purine Derivatives can be tablet or pill form, the compositions can be coated to delay delivered in a controlled-release system or Sustained-release disintegration and absorption in the gastrointestinal tract system (see, e.g., Goodson, in Medical Applications of Con 10 trolled Release, supra, Vol. 2, pp. 115-138 (1984)). Other thereby providing a Sustained action over an extended period controlled or Sustained-release systems discussed in the of time. Selectively permeable membranes Surrounding an review by Langer, Science 249:1527-1533 (1990) can be osmotically active driving a Purine Derivative are also suit used. In one embodiment a pump can be used (Langer, Sci able for orally administered compositions. In these latter plat ence 249:1527-1533 (1990); Sefton, CRC Crit. Ref Biomed. 15 forms, fluid from the environment Surrounding the capsule Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); can be imbibed by the driving compound, which swells to and Saudek et al., N. Engl. J. Med. 321:574 (1989)). In displace the agent or agent composition through an aperture. another embodiment polymeric materials can be used (see These delivery platforms can provide an essentially zero Medical Applications of Controlled Release (Langer and order delivery profile as opposed to the spiked profiles of Wise eds., 1974); Controlled Drug Bioavailability, Drug immediate release formulations. A time-delay material Such Product Design and Performance (Smolen and Ball eds., as glycerol monoStearate or glycerol Stearate can also be used. 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Oral compositions can include standard excipients such as Chem. 2:61 (1983); Levy et al., Science 228:190 (1935); mannitol, lactose, starch, magnesium Stearate, Sodium sac During et al., Ann. Neural. 25:351 (1989); and Howard et al., charin, cellulose, and magnesium carbonate. In one embodi J. Neurosurg, 71:105 (1989)). 25 ment the excipients are of pharmaceutical grade. In yet another embodiment a controlled- or Sustained-re In another embodiment the Purine Derivatives can be for lease system can be placed in proximity of a target of the mulated for intravenous administration. Typically, composi Purine Derivatives, e.g., the spinal column, brain, colon, skin, tions for intravenous administration comprise Sterile isotonic heart, lung, or gastrointestinal tract, thus requiring only a aqueous buffer. Where necessary, the compositions can also fraction of the systemic dose. 30 include a solubilizing agent. Compositions for intravenous The present compositions can optionally comprise a Suit administration can optionally include a local anesthetic Such able amount of a physiologically acceptable excipient. as lignocaine to lessen pain at the site of the injection. The Such physiologically acceptable excipients can be liquids, compositions components can be supplied either separately Such as water and oils, including those of petroleum, animal, or mixed together in unit dosage form, for example, as a dry Vegetable, or synthetic origin, such as peanut oil, soybean oil, 35 lyophilized powder or water-free concentrate in a hermeti mineral oil, Sesame oil and the like. The physiologically cally sealed container Such as an ampule or Sachette indicat acceptable excipients can be saline, gum acacia, gelatin, ing the quantity of Purine Derivative. Where the Purine starch paste, talc, keratin, colloidal silica, urea and the like. In Derivatives are to be administered by infusion, they can be addition, auxiliary, stabilizing, thickening, lubricating, and dispensed, for example, with an infusion bottle containing coloring agents can be used. In one embodiment the physi 40 sterile pharmaceutical grade water or saline. Where the ologically acceptable excipients are sterile when adminis Purine Derivatives are administered by injection, an ampule tered to an animal. Water can be a particularly useful excipient of sterile water for injection or saline can be provided so that when the Purine Derivative is administered intravenously. the ingredients can be mixed prior to administration. Saline solutions and aqueous dextrose and glycerol solutions The Purine Derivatives can be administered by controlled can also be employed as liquid excipients, particularly for 45 release or Sustained-release means or by delivery devices that injectable solutions. Suitable physiologically acceptable are well known to those of ordinary skill in the art. Such excipients also include starch, glucose, lactose, Sucrose, gela dosage forms can be used to provide controlled- or Sustained tin, malt, rice, flour, chalk, silica gel, Sodium Stearate, glyc release of one or more active ingredients using, for example, erol monostearate, talc, Sodium chloride, dried skim milk, hydropropylmethyl cellulose, other polymer matrices, gels, glycerol, propylene, glycol, water, ethanol and the like. The 50 permeable membranes, osmotic systems, multilayer coat present compositions, if desired, can also contain minor ings, microparticles, liposomes, microspheres, or a combina amounts of wetting or emulsifying agents, or pH buffering tion thereof to provide the desired release profile in varying agents. proportions. Suitable controlled- or sustained-release formu The present compositions can take the form of Solutions, lations known to those skilled in the art, including those Suspensions, emulsion, tablets, pills, pellets, capsules, cap 55 described herein, can be readily selected for use with the Sules containing liquids, powders, Sustained-release formu active ingredients of the invention. The invention thus encom lations, Suppositories, emulsions. aerosols, sprays, Suspen passes single unit dosage forms suitable for oral administra sions, or any other form Suitable for use. In one embodiment tion Such as, but not limited to, tablets, capsules, gelcaps, and the composition is in the form of a capsule. Other examples of caplets that are adapted for controlled- or Sustained-release. Suitable physiologically acceptable excipients are described 60 In one embodiment a controlled- or Sustained-release com in Remington's Pharmaceutical Sciences 1447-1676 (Al position comprises a minimal amount of a Purine Derivative fonso R. Gennaro eds., 19th ed. 1995), incorporated herein by to treat or prevent the Condition in a minimal amount of time. reference. Advantages of controlled- or Sustained-release compositions In one embodiment the Purine Derivatives are formulated include extended activity of the drug, reduced dosage fre in accordance with routine procedures as a composition 65 quency, and increased patient compliance. In addition, con adapted for oral administration to human beings. Composi trolled- or Sustained-release compositions can favorably tions for oral delivery can be in the form of tablets, lozenges, affect the time of onset of action or other characteristics, such US 8,609,833 B2 83 84 as blood levels of the Purine Derivative, and can thus reduce When a Purine Derviative is a component of a solution that the occurrence of adverse side effects. is useful for maintaining the viability of an organ ex vivo, the Controlled- or Sustained-release compositions can initially concentration of the Purine Derivative in the solution that is release an amount of a Purine Derivative that promptly pro effective for maintaining the viability of the organ is between duces the desired therapeutic or prophylactic effect, and 5 about 1 nM to about 1 mM. gradually and continually release other amounts of the Purine The Purine Derivatives can be assayed in vitro or in vivo for Derivative to maintain this level of therapeutic or prophylac the desired therapeutic or prophylactic activity prior to use in tic effect over an extended period of time. To maintain a humans. Animal model systems can be used to demonstrate constant level of the Purine Derivative in the body, the Purine safety and efficacy. Derivative can be released from the dosage formata rate that 10 The present methods for treating or preventing a Condi will replace the amount of Purine Derivative being metabo tion, reducing an animals rate of metabolism, or protecting lized and excreted from the body. Controlled- or sustained an animals heart against myocardial damage during car release of an active ingredient can be stimulated by various dioplegia, can further comprise administering another thera conditions, including but not limited to, changes in pH, 15 peutic agent to the animal being administered a Purine changes in temperature, concentration or availability of Derivative. In one embodiment the other therapeutic agent is enzymes, concentration or availability of water, or other administered in an effective amount. physiological conditions or compounds. Effective amounts of the other therapeutic agents are well The amount of the Purine Derivative that is effective for knownto those skilled in theart. However, it is well within the treating or preventing a Condition, reducing an animals rate skilled artisan's purview to determine the other therapeutic of metabolism, or protecting an animals heart against myo agent's optimal effective amount range. In one embodiment cardial damage during cardioplegia, can be determined by of the invention, where, another therapeutic agent is admin standard clinical techniques. In addition, in vitro or in vivo istered to an animal, the effective amount of the Purine assays can optionally be employed to help identify optimal Derivative is less than its effective amount would be where the dosage ranges. The precise dose to be employed can also 25 other therapeutic agent is not administered. In this case, with depend on the route of administration, and the seriousness of out being bound by theory, it is believed that the Purine the condition being treated and can be decided according to Derivatives and the other therapeutic agent act synergisti the judgment of a health-care practitioner. Suitable effective cally. dosage amounts, however, range from about 10 micrograms In one embodiment the other therapeutic agent is an anti to about 5 grams about every 4 h, although they are typically 30 inflammatory agent. Examples of useful anti-inflammatory about 500 mg or less per every 4 hours. In one embodiment the effective dosage is about 0.01 mg 0.5 mg, about 1 mg, agents include, but are not limited to, adrenocorticosteroids, about 50 mg, about 100 mg, about 200 mg, about 300 mg. Such as cortisol, cortisone, fluorocortisone, prednisone, pred about 400 mg, about 500 mg, about 600 mg, about 700 mg. nisolone, 6a-methylprednisolone, triamcinolone, betametha about 800 mg, about 900 mg, about 1 g, about 1.2g, about 1.4 35 Sone, and dexamethasone; and non-steroidal anti-inflamma g, about 1.6 g. about 1.8 g. about 2.0 g, about 2.2g, about 2.4 tory agents (NSAIDs). Such as aspirin, acetaminophen, g, about 2.6 g. about 2.8 g. about 3.0 g, about 3.2g, about 3.4 indomethacin, Sulindac, tolmetin, diclofenac, ketorolac, ibu g, about 3.6 g. about 3.8 g. about 4.0 g, about 4.2g, about 4.4 profen, naproxen, flurbiprofen, ketoprofen, fenoprofen, g, about 4.6 g. about 4.8 g., and about 5.0 g, every 4 hours. oxaprozin, mefenamic acid, meclofenamic acid, piroxicam, Equivalent dosages can be administered over various time 40 meloxicam, nabumetone, rofecoxib, celecoxib, etodolac, and periods including, but not limited to, about every 2 hours, nimeSulide. about every 6 hours, about every 8 hours, about every 12 In another embodiment the other therapeutic agent is an hours, about every 24 hours, about every 36 hours, about anti-diabetic agent. Examples of useful anti-diabetic agents every 48 hours, about every 72 hours, about every week, include, but are not limited to, glucagons; somatostatin; dia about every two weeks, about every three weeks, about every 45 Zoxide; Sulfonylureas, such as tolbutamide, acetohexamide, month, and about every two months. The number and fre tolaZamide, chloropropamide, glybenclamide, glipizide, gli quency of dosages corresponding to a completed course of clazide, and glimepiride; insulin secretagogues. Such as repa therapy can be determined according to the judgment of a glinide, and nateglinide; biguanides, such as metformin and health-care practitioner. The effective dosage amounts phenformin; thiazolidinediones, such as pioglitaZone, described herein refer to total amounts administered; that is, 50 rosiglitaZone, and troglitaZone; and C-glucosidase inhibitors, if more than one Purine Derivative is administered, the effec Such as acarbose and miglitol. tive dosage amounts correspond to the total amount admin In a further embodiment the other therapeutic agent is an istered. anti-cardiovascular-disease agent. Examples of useful anti The amount of a Purine Derivative that is effective for cardiovascular-disease agents include, but are not limited to, treating or preventing a Condition, or protecting an animals 55 carnitine; thiamine; lidocaine; amiodarone; procainamide; heart against myocardial damage during cardioplegia typi mexiletine; bretylium tosylate; propanolol, Sotalol; and mus cally range from about 0.01 mg/kg to about 100 mg/kg of carinic receptor antagonists, such as atropine, Scopolamine, body weight per day, in one embodiment, from about 0.1 homatropine, tropicamide, pirenzipine, ipratropium, tiotro mg/kg to about 50 mg/kg body weight per day, and in another pium, and tolterodine. embodiment, from about 1 mg/kg to about 20 mg/kg of body 60 In another embodiment the other therapeutic agent is an weight per day. analgesic agent. Examples of useful analgesic agents include, The amount of a Purine Derivative that is effective for but are not limited to, buprenorphine, meperidine, morphine, reducing an animals rate of metabolism typically range from codeine, propoyxphene, fentanyl, Sufentanil, etorphine about 1 g/kg to about 10 mg/kg, in one embodiment, from hydrochloride, hydrocodone, hydromorphone, nalbuphine, about 0.1 mg/kg to about 5 mg/kg body weight per day, and in 65 butorphanol, oxycodone, aspirin, ibuprofen, naproxen another embodiment, from about 1 mg/kg to about 2.5 mg/kg Sodium, acetaminophen, Xylazine, metedomidine, carprofen, of body weight per day. naprosin, and pentazocine. US 8,609,833 B2 85 86 In a specific embodiment, the other therapeutic agent is In a further embodiment, the methods for treating a tachy buprenorphine. cardia are useful for lowering the animal's ventricular rate to In another embodiment, the other therapeutic agent is an a rate of not less than about 40 beats per minute. In a specific antiemetic agent. Examples of useful antiemetic agents embodiment, the methods are useful for lowering an animals include, but are not limited to, metoclopromide, domperi ventricular rate to a rate of from about 60 beats per minute to done, prochlorperazine, promethazine, chlorpromazine, tri about 100 beats per minute. methobenzamide, ondansetron, granisetron, hydroxy Zine, acetylleucine monoethanolamine, aliZapride, aZasetron, ben 5.6.2 Protecting an Animal's Heart Against Zquinamide, bietanautine, bromopride, buclizine, clebopride, Myocardial Damage During Cardioplegia cyclizine, dimenhydrinate, diphenidol, dolasetron, mecliz 10 ine, methallatal, metopimazine, nabilone, oxyperndyl. In one embodiment, the invention provides methods for pipamazine, Scopolamine, Sulpiride, tetrahydrocannabinol, inducing cardioplegia comprising administering to an animal thiethylperazine, thioproperazine, tropisetron, or mixtures in need thereof an effective amount of a cardioplegia-induc thereof. ing agent and a Purine Derivative. Cardioplegia-inducing A Purine Derivative and the other therapeutic agent can act 15 agents useful in the present invention include, but are not additively or, in one embodiment, synergistically. In one limited to, potassium chloride, procaine, lidocaine, embodiment, a Purine Derivative is adminsitered concur novocaine, bupivocaine, nicorandil, pinacidil, halothane, St. rently with another therapeutic agent. In one embodiment, a Thomas Solution, Fremes solution, 2,3-butanedione mon composition comprising an effective amount of a Purine Oxime, and esmolol. Derivative and an effective amount of another therapeutic In one embodiment, the cardioplegia-inducing agent is agent can be administered. Alternatively, a composition com lidocaine. prising an effective amount of a Purine Derivative and a In one embodiment, a cardioplegia-inducing agent and a different composition comprising an effective amount of Purine Derivative are present within the same composition. another therapeutic agent can be concurrently administered. The present methods for inducing cardioplegia are useful for In another embodiment, an effective amount of a Purine 25 preventing or minimizing myocardial damage from occurring Derivative is administered prior or Subsequent to administra during cardioplegia. tion of an effective amount of another therapeutic agent. In In still another embodiment, the invention provides meth this embodiment, the Purine Derivative is administered while ods for protecting an animals heart against myocardial dam the other therapeutic agent exerts its therapeutic effect, or the age during cardioplegia, the method comprising administer other therapeutic agent is administered while the Purine 30 ing to an animal in need thereof an effective amount of Derivative exerts its preventative or therapeutic effect for (a) a cardioplegia-inducing agent; and treating or preventing a Condition, reducing an animals rate (b) a Purine Derivative. of metabolism or protecting an animals heart against myo In one embodiment, the cardioplegia-inducing agent is cardial damage during cardioplegia. administered prior to the administration of the Purine Deriva A composition of the invention can be prepared using a 35 tive. method comprising admixing a Purine Derivative and a In another embodiment, Purine Derivative is administered physiologically acceptable carrier or excipient. Admixing prior to the administration of the cardioplegia-inducing agent. can be accomplished using methods well known for admixing In a further embodiment, the cardioplegia-inducing agent a compound (or salt) and a physiologically acceptable carrier and the Purine Derivative are administered concurrently. or excipient. 40 In another embodiment, the cardioplegia-inducing agent and the Purine Derivative are administered such that the 5.6 Therapeutic or Prophylactic Uses of the Purine Purine Derivative exerts its prophylactic effect of protection Derivatives against myocardial damage while the cardioplegia-inducing agent exerts its cardioplegic effect. 5.6.1 Treatment or Prevention of a Cardiovascular 45 Disease 5.6.3 Treatment or Prevention of a Neurological Disorder A cardiovascular disease can be treated or prevented by administration of an effective amount of a Purine Derivative. A neurological disorder can be treated or prevented by Cardiovascular diseases that can be treated or prevented by 50 administration of an effective amount of a Purine Derivative. administering an effective amount of a Purine Derivative Neurological disorders that can be treated or prevented by include, but are not limited to, atherosclerosis, congestive administering an effective amount of a Purine Derivative heart failure, circulatory shock, cardiomyopathy, cardiac include, but are not limited to, a seizure disorder, such as transplant, cardioplegia, and a cardiac arrhythmia. epilepsy; pain, including acute postoperative pain, cancer In one embodiment, the cardiovascular disease is a cardiac 55 pain, neuropathic pain, pain resulting from Surgery, labor pain arrhythmia, congestive heart failure, circulatory shock or car during childbirth, a psychogenic pain syndrome, and head diomyopathy. ache, including migraine headache and cluster headache; In one embodiment, the cardiac arrhthmia is a tachycardia delirium and dementia, Such as Lewy body dementia, Alzhe or an idiotopic arrhythmia. imer's disease, Pick's disease, or a Creutzfeldt-Jakob disease; In another embodiment, the methods for treating a cardio 60 a sleep disorder, Such as insomnia, hypersomnia, a sleep vascular disease are useful for converting a cardiac arrhyth apnea syndrome, restless-leg syndrome, or a parasomnia; a mia to a normal sinus rhythm. cranial nerve disorder, such as Bell’s palsy; a disorder of In still another embodiment, the tachycardia is atrial fibril movement, Such as tremor, dystonia, Tourette's Syndrome, lation, Supraventriculartachycardia, atrial flutter, paroxysmal myoclonus, Huntington's disease, cortico basal degenera Supraventricular tachycardia, paroxysmal atrial tachycardia, 65 tion, chorea, a drug-induced movement disorder, progressive sinus tachycardia, atrioventricular nodal reentry tachycardia, Supranuclear palsy, Parkinson's disease, or a Parkinsonian or tachycardia caused by Wolff-Parkinson-White Syndrome. Syndrome, Such as multiple system atrophy, Wilson's disease US 8,609,833 B2 87 88 or multi-infarct state; a demyelinating disease, such as mul ated with another endocrine disease (such as Cushing’s Syn tiple Sclerosis or amyotrophic lateral Sclerosis; a neuro-mus drome, acromegaly, pheochromocytoma, glucagonoma, cular disease. Such as muscular dystrophy; a cerebrovascular primary aldosteronism or somatostatinoma). Type A insulin disease, such as stroke; a neuroopthalmic disorder, and a resistance syndrome, Type B insulin resistance syndrome, psychiatric disorder, including but not limited to. Somatoform 5 lipatrophic diabetes, and diabetes induced by B-cell toxins. disorders, such as hypochondriasis or body dysmorphic dis In one embodiment, the diabetes is Type I diabetes melli order, dissociation disorders, such as panic disorder, phobic tuS. disorders, or obsessive-compulsive disorders; mood disor In another embodiment, the diabetes is Type II diabetes ders, such as depression or bipolar disorders; personality mellitus. disorders; psychosexual disorders; Suicidal behavior, Schizo 10 phrenia; brief psychotic disorder; and delusional disorder. 5.6.7 Methods for Reducing an Animal's Rate of In one embodiment, the neurological disorder treated or Metabolism prevented is epilepsy, pain, or stroke. In one embodiment, the present methods for treating pain In one embodiment, the invention provides methods for further comprise the administration of an additional analgesic 15 reducing an animals rate of metabolism comprising admin agent. In a specific embodiment, the additional analgesic istering to an animal in need thereof an amount of a Purine agent is buprenorphine. Derivative that is effective to slow the animals rate of metabolism. 5.6.4 Treatment or Prevention of an Ischemic Reducing an animals rate of metabolism is useful for Condition slowing an animals heart rate during heart Surgery; protect ing an animal's tissue from damage during Surgery, particular An ischemic condition can be treated or prevented by heart or brain Surgery; reducing intracranial hypertension administration of an effective amount of a Purine Derivative. caused by brain injury in an animal; or inducing hibernation Ischemic conditions that can be treated or prevented by in an animal. administering an effective amount of a Purine Derivative 25 Accordingly, the present invention encompasses methods include, but are not limited to, stable angina, unstable angina, for slowing an animals heart rate during heart Surgery; pro myocardial ischemia, hepatic ischemia, mesenteric artery tecting an animal's tissue from damage during Surgery, par ischemia, intestinal ischemia, myocardial infarction, critical ticular heart or brain Surgery; reducing intracranial hyperten limb ischemia, chronic critical limb ischemia, erebral sion caused by brain injury in an animal; or inducing ischemia, acute cardiac ischemia, and an ischemic disease of 30 hibernation in an animal, the methods comprising adminis the central nervous system, such as stroke or cerebral tering an effective amount of a Purine Derivative to an animal ischemia. in need thereof. In one embodiment, the ischemic condition is myocardial Reducing an animals rate of metabolism is also useful for ischemia, stable angina, unstable angina, stroke, ischemic reducing an animals rate of oxygen consumption. Accord heart disease or cerebral ischemia. 35 ingly, the present invention provides methods for reducing the rate of an animal’s oxygen consumption, the method com 5.6.5 Treatment or Prevention of a Reperfusion prising administering to an animal in need thereof an amount Injury of a Purine Derivative that is effective to reduce the animals rate of oxygen consumption. An animal’s oxygen Supply A reperfusion injury can be treated or prevented by admin 40 might be compromised due to: (i) a medical procedure. Such istration of an effective amount of a Purine Derivative. Rep as heart Surgery, brain Surgery, organ transplantation, erfusion injury can result following a naturally occurring mechanical occlusion of the vascular Supply, or vascular episode, Such as a myocardial infarction or stroke, or during a Steno sis; (ii) a disorder or medical condition Such as surgical procedure where blood flow in vessels is intention ischemia, a respiratory disorder, respiratory failure, a pulmo ally or unintentionally blocked. 45 nary disorder, anemia, anaphylactic shock, hemmorhagic Reperfusion injuries that can be treated or prevented by shock, dehydration, compartment syndrome, intravascular administering an effective amount of a Purine Derivative thrombus, septic shock, cystic fibrosis, lung cancer, stroke, a include, but are not limited to, intestinal reperfusion injury, burn, or internal bleeding; (iii) an injury Such as drowning, a myocardial reperfusion injury; and reperfusion injury result crush injury to one or more limbs, choking, or Suffocation; ing from cardiopulmonary bypass Surgery, thoracoabrominal 50 (iv) a compromised airway due to asthma, a tumor, a lung aneurysm repair Surgery, carotid endaretectomy Surgery, or injury or a tracheal injury; (V) an external compression of one hemorrhagic shock. or more blood vessels; or (vi) an intrinsic obstruction of one In one embodiment, the reperfusion injury results from or more blood vessels. Reducing an animals rate of oxygen cardiopulmonary bypass Surgery, thoracoabrominal aneu consumption is useful for treating or preventing tissue dam rysm repair Surgery, carotid endarerectomy Surgery or hem 55 age or stroke, resulting from an inadequate Supply of oxygen orrhagic shock. to a cell, a tissue, an organ or an organ System. In one embodiment, an animals rate of oxygen consump 5.6.6 Treatment or Prevention of Diabetes tion is reduced to increase emergency recussitation in an injured animal. Diabetes can be treated or prevented by administration of 60 In another embodiment, an animals rate of oxygen con an effective amount of a Purine Derivative. Sumption is reduced prior to and during heart Surgery. In a Types of diabetes that can be treated or prevented by specific embodiment, the animal is a human child undergoing administering an effective amount of a Purine Derivative pediatric heart Surgery. include, but are not limited to, Type I diabetes (Insulin Depen In another embodiment, a animals rate of oxygen con dent Diabetes Mellitus). Type II diabetes (Non-Insulin 65 Sumption is reduced to treat respiratory failure in an animal. Dependent Diabetes Mellitus), gestational diabetes, insulin In one embodiment, an animals rate of oxygen consump opathy, diabetes due to pancreatic disease, diabetes associ tion is reduced to aid tissue metabolism in an animal whose US 8,609,833 B2 89 90 respiration and ventilation is facilitated by a ventilator. In a in Klotz et al., J. Biol. Chem., 260:14659-14664, 1985; Lohse specific embodiment, the animal whose respiration and ven et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 336:204 tilation is facilitated by a ventilator is a geriatric human. In 210, 1987; and Klotz et al., Naunyn-Schmiedeberg's Arch. another specific embodiment, the animal whose respiration Pharmacol., 357: 1-9, 1998. and ventilation is facilitated by a ventilator is a premature General Methods: human infant. In one embodiment, an organ can be stored ex vivo in a Proton nuclear magnetic resonance (NMR) spectra were composition comprising an effective amount of a Purine obtained from Varian 300 MHz spectrophotometer and Derivative. The composition is useful for preserving an chemical shifts are reported in parts per million. Compounds organ's viability after being removed from a donor and before 10 were characterized on the basis of NMR and Mass spectral the organ is transplanted in a recipient. In one embodiment, (MS) data. 6-Chloroadenosine and 2',3',5'-triacetoxy-2,6- the donor and recipient are the same. dichloroadenosine were purchased from TRC, Ontario, In another embodiment, an effective amount of a Purine Canada. 2',3'-Isopropylideneadenosine and 2-chloroadenos Derivative can be administered to an animal awaiting organ ine were purchased from ACROS Organic, USA. transplantation to reduce the animals rate of oxygen con 15 Sumption prior to or during organ transplantation. 6.1 Example 1 Reducing an animals rate of metabolism is also useful for reducing an animals core body temperature. Accordingly, the present invention provides methods for reducing an ani Synthesis of Compound 16 mals core body temperature, the method comprising admin istering to an animal in need thereof an amount of a Purine Derivative that is effective to reduce the animal’s core body temperature. 16 In one embodiment, the animals core body temperature is reduced to a temperature from about 4°C. to about 34°C. In 25 certain embodiments, the animals core body temperature is reduced to about 34° C., to about 30° C., to about 25°C., to HN about 20° C., to about 15° C., to about 10°C., or to about 4° C. N n N In a specific embodiment, an animals core body tempera 30 2 ture is reduced to induce therapeutic hypothermia. O. {llN Cl 5.6.8 Treatment or Prevention of Obesity ory Obesity can be treated or prevented by administration of an 35 effective amount of a Purine Derivative. HG oH Types of obesity that can be treated or prevented by admin istering an effective amount of a Purine Derivative include, but are not limited to, android obesity, gynoid obesity, 2-Chloro-N'-cyclopentyladenosine abdominal obesity, age-related obesity, diet-induced obesity, 40 fat-induced obesity, hypothalamic obesity, morbid obesity, multigenic obesity, and visceral obesity. 2',3',5'-triacetoxy-2,6-dichloroadenosine (1.5 g) and In one embodiment, the obesity is android obesity. cyclopentylamine (8 eq.) were diluted with ethanol (50 eq.) and the resulting solution was heated at reflux for about 15 5.6.9 Treatment or Prevention of a Wasting Disease 45 hours, then cooled to room temperature and concentrated in In one embodiment, the invention provides methods for vacuo to provide a crude residue which was diluted with a treating or preventing a wasting disease, comprising admin mixture of ethyl acetate and water and transferred to a sepa istering to an animal in need thereof an amount of a Purine ratory funnel. The organic layer was separated, dried over Derivative that is effective to treat or prevent the wasting 50 Sodium sulfate and concentrated in vacuo to provide a crude disease. residue which was purified using flash column chromatogra Types of wasting diseases that can be treated or prevented phy on silica gel (8% MeOH-dichloromethane as eluent) to by administering an effective amount of a Purine Derivative provide 2-chloro-N'-cyclopentyladenosine (0.948 g). MS include, but are not limited to chronic wasting disease, cancer wasting syndrome, and AIDS wasting syndrome. 55 m/Z 370.32 M+H". 6. EXAMPLES 2',3'-Isopropylidene-2-chloro-N'-cyclopentyladenos ine Materials: HINECA was obtained from Du Pont NEN, Dreieich, 60 Germany. Other unlabeled adenosine receptor agonists and 2-chloro-N'-cyclopentyladenosine (900 mg, as prepared antogonists can be obtained from RBI, Natick, Mass. The in the previous step) and 2,2-dimethoxypropane (10 eq.) were 96-well microplate filtration system (MultiScreen MAFC) diluted with acetone (15 mL) and to the resulting solution was was obtained from Millipore, Eschborn, Germany. Penicillin added D-camphorsulphonic acid (1 eq) and the resulting reac (100 U/mL), Streptomycin (100 ug/mL), L-glutamine and 65 tion was allowed to stir at room temperature for 2 hr. The G-418 were obtained from Gibco-Life Technologies, Eggen resulting reaction mixture was concentrated in vacuo, diluted stein, Germany. Other materials can be obtained as described with a mixture of saturated aqueous NaHCO and ethyl US 8,609,833 B2 91 92 acetate, and transferred to a separatory funnel. The organic (m. 2H), 4.55-4.58 (m, 1H), 4.73-4.85 (m, 2H), 5.50 (bs, 1H), layer was separated, dried over Sodium Sulfate and concen 5.61 (bs, 1H), 5.84 (d. J–5.1 Hz, 1H), 8.33 (bs, 2H), MS m/z trated in vacuo to provide a crude residue which was purified 414.85 M+H". using flash column chromatography on silica gel (using 5% MeOH-dichloromethane as eluent) to provide 2',3'-Isopropy 6.2 Example 2 lidene-2-chloro-N'-cyclopentyladenosine (0.905 g). "H NMR (CDC1,300 MHz): & 1.36 (s, 3H), 1.62 (s.3H), 1.66 Synthesis of Compound 17 2.16 (m, 9H), 3.78 (d. J=12.9 Hz, 1H), 3.98 (d. J=12.9 Hz, 1H), 4.51 (bs, 1H), 4.55-4.60 (m. 1H), 5.09-5.17 (m, 2H), 5.81 (bs, 1H), 7.25 (s, 1H), 7.89 (s, 1H). 10 17 2',3'-Isopropylidene-2-chloro-N'-cyclopentyladenos ine-5'-nitrate 15 A solution of nitric acid (2.0 mL, 60%) was added slowly over a period of 30 minutes to acetic anhydride (16.0 mL) at -10 to 10°C. (using acetonitrile-CO, cooling bath) and the reaction mixture was allowed to stir at -10 to 10° C. for 10 minutes. The reaction mixture was then cooled to -30°C. and then a solution of 2',3'-Isopropylidene-2-chloro-N'-cyclo pentyladenosine (655 mg, 0.0016 mol, as prepared in the 25 previous step) in acetic anhydride (8.0 mL) was added slowly. N-Cyclopentyladenosine When addition was complete, the resulting reaction was allowed to warm to -5°C. and monitored using TLC (solvent A Solution of 6-chloroadenosine (43 g) and cyclopenty 5% MeOH-CHC1 or 70% EtOAc-hexane). When the reac 30 lamine (5 eq.) in ethanol (50 eq.) was heated at reflux for 3 hours then cooled to room temperature. The resultant reaction tion was complete, the reaction mixture was poured slowly mixture was concentrated in vacuo and the resultant residue into an ice cold mixture of saturated aqueous NaHCO (300 was diluted with water (400 ml) and ethyl acetate (400 ml). equivalent in 75 mL water) and ethyl acetate (60 mL). The The eoganic layer was separated and the aqueous layer was organic layer was separated and the aqueous layer was back 35 extracted into ethyl acetate (2x400 ml). The combined organic layers were washed with water (2x200 ml), dried over extracted with ethyl acetate. The combined organic layers Sodium sulfate, concentrated in vacuo and dried under were washed with water, dried over sodium sulfate, and con vacuum to provide a solid which was suspended in MeCH (400 mL), filtered and dried to provide N'-cyclopentylad centrated in vacuo to provide a crude residue. The crude 40 residue was purified using flash column (5% methanol enosine (43.8 g). dichloromethane as eluent) to provide 2',3'-Isopropylidene 2',3'-isopropylidene-N'-cyclopentyladenosine 2-chloro-N'-cyclopentyladenosine-5'-nitrate (0.435 g). "H N'-cyclopentyladenosine (43 g) was diluted with acetone NMR (CDC1,300 MHz): & 1.38 (s, 3H), 1.59 (s.3H), 1.66 45 (75 eq.) and to the resultant solution was added 2,2-dimethox 2.13 (m, 9H), 4.50-4.55 (m, 1H), 4.71-4.83 (m, 2H), 5.14 ypropane (5 eq.), followed by D-camphorSulphonic acid (1 eq) and the resultant reaction was allowed to stir at room 5.17 (m, 1H), 5.31 (d. J=5.7 Hz, 1H), 6.04 (s, 1H), 7.24 (s, temperature for 3 hours. The resultant reaction mixture was 1H), 7.81 (s, 1H). MS m/z 455.44 M+H". concentrated in vacuo and the resultant residue was diluted 50 with ethyl acetate, then neutralized to pH 7.0 using concen trated aqueous NaHCO. The organic layer was separated, Compound 16 dried over Sodium Sulfate, concentrated in vacuo and dried under vacuum to provide a solid which was Suspended in 2',3'-Isopropylidene-2-chloro-N'-cyclopentyladenosine hexane (250 mL), filtered, washed with hexane and dried 5'-nitrate (0.435 g, as prepared in the previous step) was 55 under vacuum to provide 2',3'-isopropylidene-N'-cyclopen diluted with TFA (20 mL) and water (5 mL) and the resulting tyladenosine (43 g). solution was allowed to stir for 30 minutes. The resulting reaction mixture was concentrated in vacuo and the resulting 2',3'-isopropylidene-N-cyclopentyladenosine-5'- residue was diluted with water (10 mL) and the resulting nitrate Solution was concentrated in vacuo. The crude residue 60 obtained was diluted with ethyl acetate, transferred to a sepa Acetic anhydride (22 eq) was slowly added to a stirred ratory funnel, washed with Saturated aqueous sodium bicar solution of nitric acid (5 eq., 63%) at -10°C. (acetonitrile bonate, dried over Sodium sulfate and concentrated in vacuo. CO, bath used for cooling) over a period of 4 hours with the The crude residue obtained was purified using flash column reaction temperature maintained at -5 to 5° C. during the chromatography on silica gel (using 10% methanol-dichlo 65 addition. The resultant solution was cooled to -20° C. and a romethane as eluent) to provide Compound 16 (0.250 g). "H solution of 2',3'-isopropylidene-N-cyclopentyladenosine NMR (DMSO-d,300 MHz): 81.52-1.95 (m, 9H), 4.13-4.24 (18.250 gm, 0.048 mol) in acetic anhydride (37 mL, 8 eq.) US 8,609,833 B2 93 94 was added slowly. The resultant reaction was allowed to stir at 1H), 4.59 (d. J=4.8 Hz, 1H), 4.74-4.85 (m, 2H), 5.49-5.52 (m, -15 to -5°C. for 1 hour and the resultant reaction mixture was 1H), 5.51 (d. J=5.1 Hz, 1H), 5.84 (d. J=5.1 Hz, 1H), 7.85 (s, slowly poured slowly into an ice-cold Solution of aqueous 2H), 8.33 (s, 1H). MS m/z 347.11 M+H". NaHCO, (168 gm in 800 mL water) and ethyl acetate (350 2',3'-Isopropylidene-adenosine-5'-nitrate mL) and the resultant solution was allowed to stir for 5 min utes. The organic layer was separated and the aqueous layer A solution of nitric acid (19.8 mL, 60%) was added slowly was extracted using ethyl acetate (350 mL). The combined over a period of 30 minutes to acetic anhydride (100 mL) at organic layers were washed with water, and dried over -10 to 10°C. (using acetonitrile-CO cooling bath) and the Sodium sulfate, concentrated in vacuo and purified using flash reaction mixture was allowed to stir at -10 to 10° C. for 10 10 minutes. The reaction mixture was then cooled to -30°C. and column chromatograpy on silica gel using 70% ethyl acetate then a solution of 2',3'-Isopropylidene-adenosine (5.945 g, as hexane as eluent to provide 2',3'-isopropylidene-N-cyclo prepared in the previous step) in acetic anhydride (49.3 mL) pentyladenosine-5'-nitrate (14.9 g). was added slowly. When addition was complete, the resulting Compound 17 reaction was allowed to warm to -5°C. and monitored using 15 TLC (solvent 5% MeOH-CHC1 or 70% EtOAc-hexane). When the reaction was complete, the reaction mixture was 2',3'-isopropylidene-N'-cyclopentyladenosine-5'-nitrate poured slowly into an ice cold mixture of Saturated aqueous (4.8 g) was diluted with a mixture of TFA (20 mL) and water NaHCOs (300 equivalent in 500 mL water) and ethyl acetate (5 mL) and the resultant reaction was allowed to stir for 30 (250 mL). The organic layer was separated and the aqueous minutes at room temperature. The resultant reaction mixture layer was back extracted with ethyl acetate. The combined was concentrated in vacuo and the resultant residue was organic layers were washed with water, dried over sodium diluted with water (10 mL) and concentrated in vacuo. The Sulfate, and concentrated in vacuo to provide a crude residue. resultant residue was diluted with ethyl acetate and washed The crude residue was purified using flash column (5% with Saturated aqueous Sodium bicarbonate, and the organic methanol-dichloromethane as eluent) to provide 2',3'-Isopro layer was dried over Sodium Sulfate and concentrated in vacuo pylidene-adenosine-5'-nitrate (4.850 g). "H NMR (DMSO to provide a white solid residue which was dried under 25 d,300 MHz): 81.31 (s.3H), 1.52 (s.3H), 1.53-1.96 (m, 9H), vacuum and then recrystallized from cold ethanol to provide 4.41-4.43 (m. 1H), 4.68-4.74 (m. 1H), 4.80-4.86 (m. 1H), Compound 17 (3.1 gm). 'H-NMR (DMSO-d): & 1.49-1.58 5.14-5.16 (m, 1H), 5.41 (d. J–6 Hz, 1H), 6.23 (s, 1H), 7.80 (s, (m, 4H), 1.66-1.72 (m. 2H), 1.89-1.94 (m. 2H), 4.12-4.17 (m, 1H), 8.21 (s, 1H), 8.29 (s, 1H). MS m/z 421.09 M+H". 1H), 4.28-4.33 (m. 1H), 4.48 (bs, 1H), 4.65-4.87(m,3H), 5.5 Compound 18 (d. J=5.1 Hz, 1H), 5.63 (d. J=5.7 Hz, 1H), 5.91 (d. J=5.1 Hz, 30 1H), 7.75 (d. J=7.5 Hz, 1H), 8.17 (bs, 1H), 8.30 (s, 1H); MS 2',3'-Isopropylidene-adenosine-5'-nitrate (4.8 g. as pre (ES"): m/z 381.35 (M+1); Anal. Calcd for CHNO: C, pared in the previous step) was diluted with 4:1 mixture of 47.37; H, 5.30; N, 22.10. Found: C, 47.49; H, 5.12: N, 21.96. TFA (20 mL) and water (5 mL) and the resulting solution was allowed to stir at rt for 30 minutes. The resulting reaction 6.3 Example 3 35 mixture was concentrated in vacuo and the resulting residue was diluted with water (10 mL) and concentrated in vacuo to Synthesis of Compound 18 provide a residue which was diluted with ethyl acetate (20 mL). The resulting solution was washed with Saturated aque ous Sodium bicarbonate, dried over Sodium sulfate and con 40 centrated in vacuo to provide a white solid residue which was further dried in vacuo and then recrystallized from ethanol to 18 provide Compound 18 (3.1 g). "H NMR (DMSO-de, 300 MHz): 81.53-1.96 (m,9H), 4.12-4.17 (m. 1H), 428-4.33 (m, 1H), 4.65-4.70 (m, 1H), 4.74-4.87(m, 1H), 5.50 (d. J=5.1 Hz, 1H), 5.62 (d. J=5.7 Hz, 1H), 5.90 (d. J=5.1 Hz, 1H), 7.74 (d. 45 J=7.5 Hz, 1H), 8.17 (s, 1H), 8.30 (s, 1H). MS m/z 381.04 M+H". 6.4 Example 4 Synthesis of Compound 19 50

2',3'-Isopropylidene-adenosine 19 55 A Solution of adenosine (43 g) and 2,2-dimethoxypropane (5 eq.) in acetone (75 eq.) was treated with D-camphorsul phonic acid (1 eq) at and the resulting reaction was allowed to stir for 3 hr. The reaction mixture was concentrated in vacuo and diluted with a mixture of saturated aqueous NaHCO (250 mL) and ethyl acetate (250 mL). The resulting solution was transferred to a separatory funnel and the organic layer was separated, dried over sodium Sulfate, and concentrated in vacuo to provide a solid residue. The solid residue was sus pended in hexane, filtered, washed with hexane and dried to 65 Using the method described in Example 3 and using com provide 2',3'-Isopropylidene-adenosine (43 g). "H NMR mercially available 2-chloroadenosine in place of adenosine (DMSO-de, 300 MHz): 84.12-4.17 (m, 1H), 4.22-4.26 (m, in step 1, Compound 19 was prepared. US 8,609,833 B2 95 96 6.5 Example 5 Compound 22 Synthesis of Compound 21 A mixture of 2,6-dihydrazinoadenosine (60 mg, prepared as described in the previous step) and cyclopentanaldehyde (0.1 mL) in methanol (5 mL) was heated at reflux for 15 minutes. The reaction mixture was then cooled to room tem 21 perature and concentrated in vacuo to provide a crude residue NH-N=CH(cyclopentyl) which was purified using silica gel flash chromatography (10% methanol/dichloromethane eluent) to provide com N NN 10 pound 22 (48 mg). MS m/z 473.25 M+H". 6.7 Example 7 Synthesis of Compound 23 (Sodium Salt)

15

23 N-Hydrazinoadenosine A mixture of 6-chloroadenosine (1 g, 3.5 mmol) and hydra zine monohydrate (5 mL) in MeCH (10 mL) was stirred at 50° C. for 1 hr. The reaction mixture was allowed to cool to room temperature and was then concentrated in vacuo to provide a crude residue which was suspended in MeOH and (10 mL) and stirred at room temperature. The Solid product that sepa 25 rated out from the suspension was filtered, washed with MeOH and dried in vacuo to provide N'-hydrazinoadenosine (970 mg) which was used without further purification. Compound 21 HG OH A suspension of N'-hydrazinoadenosine (50 mg, prepared 30 (sodium salt) as described in the previous step) and cyclopentanealdehyde (0.26 mmol) in methanol (5 mL) was heated at reflux for 15 A mixture of 2',3'-isopropylidene-N'-cyclopentyladenos minutes and the reaction mixture was cooled to room tem ine (1 g, 0.0026 mol, prepared as set forth in Example 1) and perature, then concentrated in vacuo to provide a crude resi sulfur trioxide-pyridine complex (0.0039 mol) in DMF (17 due which was purified using silica gel flash chromatography 35 mL) was stirred at room temperature for about 18 hours. The (10% methanol/dichloromethane eluent) to provide com DMF was removed in vacuo and the resulting residue was pound 21 (52 mg). MS m/z. 363.11 M+H". dried in vacuo. The dried residue was diluted with water (25 6.6 Example 6 mL), neutralized to pH 7.0 using NaOH (1N) and concen trated in vacuo to provide a crude residue which was diluted Synthesis of Compound 22 40 with an solution of TFA (80% solution in water, 50 mL). The resulting solution was allowed to stir at 25°C. for 30 minutes and the reaction mixture was concentrated in vacuo to afford a crude residue which was diluted with water (10 mL) and 22 concentrated in vacuo. The crude compound obtained was 45 recrystallized from acetone-water to provide compound 23 NH-N=CH(cyclopentyl) (sodium salt) (805 mg). HMNR (DMSO-de, 300 MHz): 1.53-1.96 (m, 9H), 3.78-4.10 (m, 4H), 4.43-4.54 (m, 2H), N n N 5.90 (d. J=5.1 Hz, 1H), 8.23 (s, 1H), 8.46 (s, 1H). MS m/z 416.20 M+H". 2 O {llN N NH-H=CH(cyclopentyl) 50 6.8 Example 8 -ny Synthesis of Compound 24 (Sodium Salt)

55 24 2,6-Dihydrazinoadenosine A mixture of 2.6-chloro-2',3'5'-triacetyladenosine (0.150 gm, 0.33 mmol) and hydrazine monohydrate (2 mL) in MeOH (5 mL) was heated at reflux for about 8 hours. The 60 reaction mixture was cooled to room temperature and con centrated in vacuo, and the resulting residue was suspended in MeOH (5 mL) and stirred at room temperature for 1 hour. The e Solid product which separated out from the Suspension was HG eOH filtered, washed with MeOH and dried in vacuo to provide 65 2,6-dihydrazinoadenosine (65 mg), which was used without (sodium salt) further purification. US 8,609,833 B2 97 98 Using the method described in Example 8 and substituting determined in the presence of 100 uM R-PIA and 1 mM 2',3'-isopropylidene-adenosine (prepared as set forth in theophylline, respectively. For details see Klotz et al., Nau Example 3) for 2',3'-isopropylidene-N-cyclopentyladenos ine, Compound 24 (sodium salt) was prepared. 'HMNR myn-Schmiedeberg's Arch. Pharmacol., 357: 1-9, 1998. All (DMSO-d 300 MHz): 3.83-3.99 (m. 2H), 4.10-4.14 (m, binding data were calculated by non-linear curve fitting using 2H), 4.50-4.54 (m, 1H), 5.94 (d. J=6 Hz, 1H),8.5 (s, 1H), 8.73 the program SCTFIT (De Lean et al. Mol. Pharm. 1982, (s, 1H), 9.50 (bs, 2H). MS m/z 348.05 M+H". 21:5-16). 6.9 Example 9 10 Results are presented in Table 1 below and show that Com Cell Culture and Membrane Preparation pounds 16, 17, 18, 19, 23 (sodium salt), and 25, illustrative Purine Derivatives, are selective for the adenosine A receptor CHO cells stably transfected with human adenosine A and accordingly, are useful for treating a Condition, slowing receptor were grown and maintained in Dulbecco's Modified Eagles Medium with nutrient mixture F12 (DMEM/F12) 15 an animal's metabolic rate, or protecting an animals heart without nucleosides, containing 10% fetal calf serum, peni against myocardial damage during cardioplegia. TABLE 1. Affinities of illustrative Purine Derivatives for human A1, A2 and As adenosine receptors Compound Ki(A) (nM) Ki(A24) (nM) Ki(A) (nM) CCPA 0.83 (0.55-1.25) 2,270 (1950-2,660) 42.3 (32.1-55.8) 16 2.63 (2.04-3.38) 4,190 (2.440-7,200) 513 (367-715) 17 0.97 (0.80-1.17) 4,692 (2,300-9,560) 704 (400-1,240) 18 5.79 (4.73-7.10) 951 (530-1,708) 216 (132-350) 19 7 (5.14-9.23) 10,000 (5,790-15,760) 900 (445-1890) 23 4.05 (3.54-4.63) 9,113 (5,510-15,100) 1,020 (470-2,220) (sodium salt) 25 10.6 (6.77-16.70) >100,000 2020 (837-4870) Displacement of specific HCCPA binding in CHO cells stably transfected with human recombinant A1 adenosine receptor, expressed as Ki (nM), Displacement of specific HINECA binding in CHO cells stably transfected with human recombinant A2 adenosine receptor, expressed as Ki (nM), TDisplacement of specific HINECA binding in H EK cells stably transfected with human recombinant As adenosine receptor, expressed as Ki (nM), All data are geometric means with 95% confidence intervals in parantheses, 35 cillin (100U/mL), streptomycin (100 ug/mL), L-glutamine (2 6.11 Example 11 mM) and Geneticin (G-418, 0.2 mg/mL, A, 0.5 mg/mL) at 37°C. in 5% CO/95% air. Cells were then split 2 or 3 times Effects of Compound 17 on Septic Shock weekly at a ratio of between 1:5 and 1:20. 40 Membranes for radioligand binding experiments were pre Male BALB/c mice (6-8 weeks of age) were used in studies pared from fresh or frozen cells as described in Klotz et al., investigating lipopolysaccharide-induced cytokine produc Naunyn-Schmiedeberg's Arch. Pharmacol., 357: 1-9 (1998). tion and survival. For cytokine production the mice were The cell Suspension was then homogenized in ice-cold hypo treated with compound 17 (Oral administration of 0.03 tonic buffer (5 mM Tris/HCl, 2 mM EDTA, pH 7.4) and the 45 mg/kg) orally by gavage 30 min before being Subjected to homogenate was spun for 10 minutes (4°C.) at 1,000 g. The lipopolysaccharide (1 mg/kg i.p.) for 90 minutes, after this membranes were then sedimented from the supernatant for 30 period blood was taken and serum obtained for analysis. minutes at 100,000 g and resuspended in 50 mM Tris/HCl Serum was diluted 1:5 prior to being assayed for cytokines buffer pH 7.4 (for A. adenosine receptors: 50 mM Tris/HCl, using species-specific ELISA kits (R& D Systems) for the 10 mM MgCl, 1 mM EDTA, pH 8.25), frozen in liquid 50 chemokine MIP-1C. and the cytokine TNF-C. levels, which nitrogen at a protein concentration of 1-3 mg/mL and stored were expressed as pg/mL. For Survival studies mice were at 80° C. treated with compound 17 (Oral administration of 0.03 mg/kg) starting 30 mins prior to the mice being Subjected to 6.10 Example 10 lipopolysaccharide (55 mg/kg i.p.). The Survival of the mice 55 was followed over 72 h and expressed as a percentage of Adenosine Receptor Binding Studies surviving mice at each time point. Oral administration of 0.03 mg/kg compound 17 delays lipopolysaccharide (60 mg/kg) The affinities of selected Purine Derivatives for the adenos induced mortality in conscious mice. N=12-14 per group. ine A receptor were determined by measuring the displace FIG. 1 shows that Compound 17, administered orally to ment of specific H 2-chloro-N'-cyclopentyl adenosine 60 BALB/c mice at a dose of 0.03 mg/kg, reduces lipopolysac binding in CHO cells stably transfected with human recom charide-induced plasma TNF-C. and MIP-1C. production in binant A adenosine receptor expressed as Ki (nM). the BALB/c mouse model. Dissociation constants of unlabeled compounds (K-val FIG. 2 shows that Compound 17, administered orally to ues) were determined in competition experiments in 96-well BALB/c mice at a dose of 0.03 mg/kg, reduces lipopolysac microplates using the A selective agonist 2-chloro-N-H 65 charide-induced mortality in the BALB/c mouse model. cyclopentyladenosine (HICCPA, 1 nM) for the character The above example shows that Compound 17, an illustra ization of A receptor binding. Nonspecific binding was tive Purine Derivative, reduces lipopolysaccharide-induced US 8,609,833 B2 99 100 plasma levels of TNF-C. and MIP-1C, and delays lipopolysac 6.13 Example 13 charide-induced mortality in mice. Accordingly, Compound 17 is useful for treating septic Effect of Compound 17 on Function Recovery after shock. Global Ischemia/Reperfusion Effect of Compound 17 on Function Recovery after Ischemia/ 6.12 Example 12 Reperfusion Rathearts were initially perfused at a constant pressure of 70 mm Hg using the procedure described above in section Anti-Arrhythmia Effects of Compound 17 10 6.12.1. After a 20 minutes stabilization period, hearts were subjected to 30 minute no-flow ischemia followed by 40 Heart Perfusion minute reperfusion. In treated hearts, Compound 17 was Male Sprague-Dawley rats (having a body weight of 250 to infused for 10 minutes prior to induction of ischemia. Com 300 g) were heparinized using sodium heparin (1,000 U/kg pound 17 significantly improved +dp/dt after 30 minutes 15 ischemia followed by 40 minutes of reperfusion at the con i.p.), followed 10 minutes later by introduction of anesthesia centration of 1 nM. Thus, the A1 agonist compound was not via intraperitoneal administration of Sodium pentobarbital only effective in reducing fibrillations but was also effective (40 mg/kg). Once the animal was anesthetized, the thorax was in improving myocardial contractility (dp/dt) in a myocardial opened, and the heart was rapidly removed and perfused ischemia-reperfusion model in the perfused heart. This obser through the ascending aorta using Krebs-Ringer buffer con Vation is in line with data indicating the cardioprotective sisting of NaCl (118 mmol/liter), KC1 (4.75 mmol/liter), effect of A1 agonism in various models of ischemia and KHPO (1.18 mmol/liter), MgSO (1.18 mmol/liter), CaCl reperfusion (e.g. Roscoe et al., 2000; Jacobson et al., 2000; (2.5 mmol/liter), NaHCO, (25 mmol/liter), and glucose (11 Lee et al., 2003), and the cardioprotective effect of A1 ago mmol/liter). A mixture of 95% O, and 5% CO, at 37°C. was nists in vitro (Goldenberg et al., 2003) and in vivo (Baxter et bubbled through the perfusate. The heart was initially per 25 al., 2001; Donato et al., 2003: Kopecky et al., 2003; Kehl et fused at a constant pressure of 70 mm Hg. About 10 min after al., 2003: Arora et al., 2003; Regan et al., 2003; Yang et al., the constant pressure perfusion, perfusion was switched to 2003). Effect of compound 12 (1 nM) on maximal rates of constant flow perfusion achieved using a microtube pump. development of left ventricular pressure (+dP/dt) after 30 The perfusion pressure was maintained at the same level of minutes of ischemia followed by 40 minutes of reperfusion. constant pressure perfusion by adjusting flow rate. Once the 30 *P<0.05 when compared with the value of control. flow rate was determined, it was maintained throughout the FIG. 4 shows that Compound 17 is useful in exerting a experiment. The hearts were stimulated by rectangular pulses cardioprotective effect following ischemia and reperfusion. at a rate of 5 Hz and 2-millisecond duration and twice the The above example shows that Compound 17, an illustra diastolic threshold, delivered from a stimulus isolation unit tive Purine Derivative, is effective for reducing fibrillations 35 and improving myocardial contractility following ischemia (ADInstruments Ltd, Australia). and reperfusion, and accordingly, is useful in treating an Effect of Compound 17 on Ischemia-Induced Arrhythmias ischemic condition or a reperfusion injury. Rathearts were perfused at constant pressure of 70 mmHg without pacing as described above. Bipolar epicardial elec 6.14 Example 14 trocardiogram (ECG) was recorded by placing two electrodes 40 on the Surface of right appendage and apex. A stainless steel Synthesis of Compound 25 cannula was used as indifferent electrode. The ECG and heart rate were continuously monitored and data were recorded using a PowerLab data acquisition system (ADInstruments Ltd, Australia) in conjunction with a Macintosh computer, 45 25 and analyzed using Chart.3 computer package. After a 20-minute equilibration period, regional ischemia was induced by ligation of the left anterior descending (LAD) coronary artery, and the ligature was released 30 minutes after occlusion. Compound 17 was applied interperfusate 10 min 50 utes before LAD ligation and was present during LAD liga tion. Compound 17 was tested in this model at 10, 30 and 100 pM concentrations. The incidences of ventriculartachycardia (VT) were almost same in control non-treated (12/12) and in treated hearts (20/22). Incidence of ventricular fibrillation 55 (VF) was 58% (7/12) in non-treated hearts, and 9% (2/22) in treated hearts. The total duration of both VT and VF were significantly shortened by compound 17 at concentrations of 30 and 100 pM. 60 2',3'-Isopropylidene-N (R)-(3-tetrahydrofuranyl) FIG. 3 shows that Compound 17 reduces the duration of adenosine ischemia-induced arrhythmias in isolated perfused rat hearts relative to a non-treated control group. 2',3'-isopropylidene-6-chloroadenosine (0.750gm, 0.0023 The above example shows that Compound 17, an illustra mol) was diluted with ethanol (20 mL) and to the resultant tive Purine Derivative, reduces the incidence of ventricular 65 solution was added R-(3-aminotetrahydrofuranylamine. fibrillation and accordingly, is useful for treating a cardiac MeSOH (0.630gm, 0.0035 mol), followed by triethylamine arrhythmia. (0.9 mL). The resultant reaction was heated at refluxed for 2 US 8,609,833 B2 101 102 days, then cooled to room temperature and the resultant reac gesia (% MPE). '% MPE was calculated using the following tion mixture was concentrated in vacuo, diluted with water formula:% MPE=(post-drug value-baseline)/(cut-off time (25 mL) and ethyl acetate (25 mL), and transferred to a baseline)x100. separatory funnel. The organic layer was separated, dried FIG. 5 shows that Compound 17 is useful in exerting an over Sodium sulfate and concentrated in vacuo to provide a analgesic effect in an animal. crude residue which was recrystallized from EtOAc-hexane The results show that Compound 17, an illustrative Purine to provide 2',3'-Isopropylidene-N (R)-(3-tetrahydrofura Derivative, exertsa analgesic effect in an animal, and, accord nyl)adenosine (0.680 gm). ingly, is useful for the treatment of pain. N (R)-(3-Tetrahydrofuranyl)adenosine 10 6.16 Example 16 Acetic anhydride (4.6 mL, 30 eq.) was slowly added over a Effect of Compound 17 on Pain period of about 20 minutes to a stifling solution of nitric acid (0.8 mL, 63% purchased from ACROS) which had been pre Male mice (each having a body weight of 20-30 g) were cooled to about -5°C. using an acetonitrile-CO bath. The 15 subcutaneously administered 20 ul of a 1% formalin solution initial reaction is vigorous and addition should be done very in formaldehyde (prepared by diluting a commercial 4% w/v stock formalin solution) into the dorsal region of their carefully to avoid the increase in temperature. After addition left hind paw. The mice were assigned to either a control of acetic anhydride is complete, the resultant Solution was group and administered vehicle, or to a treatment group and cooled to -20° C. and 2',3'-isopropylidene-N R-(3-tet intraperitoneally administered Compound 17 (1.0 mg/kg). rahydrofuranyl)-adenosine (0.605, 0.0016 mol) was added. Both groups of animals were monitored for a reaction for 30 The resultant reaction was monitored using thin-layer chro minutes post-treatment to determine how much time each matography (solvent 5% MeOH CHC1 or 70% EtOAc animal spends licking the treated paw. The licking time in hexane). When the reaction was complete, the reaction mix control group (vehicle pretreated animals) was then com ture was poured slowly into a cold solution of NaHCO (100 25 pared to the licking time in the treatment group in order to mL) and the resultatint solution was diluted with ethyl acetate calculate the analgesic effect. The 30 minute reaction period (100 mL), allowed to stir for 5 minutes, then transferred to a was divided into two phases: an early phase which lasts from separatory funnel. The organic layer was collected and the 0-5 minutes post-treatment, and a late phase which lasts from aqueous layer was extracted with ethyl acetate (50 mL). The 10-30 minutes post-treatment. combined organic layers were then washed with water, dried 30 FIG. 6 shows that Compound 17 is useful in exerting an over Sodium sulfate, and concentrated in vacuo to afford a analgesic effect in an animal. crude residue. The crude residue was diluted with TFA (16 The results indicate that Compound 17, an illustrative mL) and water (4 mL) and the resultant solution was allowed Purine Derivative, exhibits an analgesic effect during the late to stir at room temperature for 30 minutes, then concentrated phase of the response and, accordingly, is useful for treating in vacuo. The resultant residue was diluted with water and 35 pa1n. concentrated in vivo to afford a crude product which was purified using flash column chromatograpy on silica gel using 6.17 Example 17 10% methanol-dichloromethane to provide Compound 25 (265 mg). "H-NMR (DMSO-d): 8 1.97-2.10 (m. 1H), 2.12 Effect of Compound 17 on Pain 2.20 (m, 1H), 3.57-3.61 (dd, J–4.8 and 4.5 Hz, 1H), 3.67-3.74 40 (dd, J=8.1 and 8.1 Hz, 1H), 3.81-3.92 (m, 2H), 4.12-4.17 (m, BALB/C mice (6-8 weeks of age) were intraperitoneally 1H), 4.30 (s, 1H), 4.679s, 1H), 4.74-4.87 (n, 3H), 5.489s, administered streptozotocin (40 mg/kg, once per day for 5 1H), 5.61 (s, 1H), 5.91 (d. J=5.1 Hz, 1H), 7.99 (d. J=4.8 Hz, consecutive days) to induce diabetes (blood glucose levels 1H), 8.20 (s, 1H), 8.34 (s, 1H); MS (ES"): m/z383.06 (M+1). were greater than 200 mg/mL). Three weeks after the first 45 streptozotocin injection, the animals were intraperitoneally 6.15 Example 15 administered Compound 17 (1 mg/kg) into a rear paw and post-treatment allodynia was measured using an ElectroVon Effect of Compound 17 on Pain frey anesthesiometer (IITC Inc., Woodland Hills Calif. 91367). The analgesic activity of Compound 17 was mea Male mice (body weight of 25-35 grams) were put in 50 sured at 0 minutes (control), 15 minutes, 30 minutes and 60 groups as follows: a first group which was intreperitoneally minutes time point after administration of Compound 17. administered buprenorphine (0.3 mg/kg), a second group FIG. 7 shows that Compound 17 is useful in exerting an which was intreperitoneally administered buprenorphine (1 analgesic effect in a animal. mg/kg), a third group which was intreperitoneally adminis The results indicate that Compound 17, an illustrative tered Compound 17 (3 mg/kg), a fourth group which was 55 Purine Derviative, produces a marked and lasting analgesic intreperitoneally co-administered Compound 17 (3 mg/kg) effect, and, accordingly, is useful for treating pain in an ani and buprenorphine (1.0 mg/kg), and a fifth group which was mal. intreperitoneally co-administered Compound 17 (3 mg/kg) and buprenorphine (0.3 mg/kg). The analgesic effects in mice 6.18 Example 18 was measured using an IITC model 33 tail-flick analgesia 60 meter (IITC Inc., Woodland Hills, Calif.) at 0 minutes (base Effect of Compound 17 on Pain line control), 5 minutes, 15 minutes, 30 minutes and 60 min utes (in some cases also 90 and 120 minutes) post-treatment. Male Wistar rats (each weighing between 200-250 g, kept compound or vehicle treatment. Average recoding value of under pathogen-free conditions at 24-25° C. and provided two readings was used for each time point. A baseline for 65 with standard rat chow and water ad libitum) were anaesthe every mouse between 2-4 seconds of latency and a 10-second tized via intraperitoneal administration of pentobarbital (50 cut-off time was set for the maximum possible effect of anal mg/kg) and placed in a stereotaxic frame. The atlanto-occipi US 8,609,833 B2 103 104 tal membrane was exposed and a PE-10 catheter (7.5 cm) was pared for monitoring of blood pressure and heart rate. Com inserted through an incision into the Subarachnoidal space. pound 17 was then intravenously administered via the femo The external end of the catheter was then fixed to the skull, the ral vein at a dose of 1 ng/kg/minute, 10 ng/kg/minute, or 1000 wound was closed, and the rats were allowed to recover for 7 ng/kg/minute (n=2 animals per dosage size) for a total admin days post-Surgery. Animals without neurological deficits istration period of 20 minutes. were placed in a plexiglass observation chamber on a metal The results show that a 10 ng/kg/minute dose of lowered mesh Surface and mechanical thresholds of the plantar Surface of the paw were determined using a Dynamic Plantar Aesthe heart rate from 440 beats per minute to 370 beats per minute siometer (Ugo Basile, Italy) as follows: Following acclima and that the 1000 ng/kg/minute dose reduced heart rate from tion, the touch stimulator unit was placed under the animals 440 beats per minute to 150 beats per minute. Thus, Com paw Such that the filament was positioned under the target 10 pound 17, an illustrative Purine Deriviative is exerts a heart area of the paw. The filament was then lifted such that it rate lowering effect, and accordingly, a Purine Derivative is contacted the pad of the animal’s paw and continually exerted useful for lowering an animal’s ventricular rate to a rate of not an increasing upward force on the paw until the animal with less than about 40 beats per minute. drew the paw. The paw withdrawal threshold was measured 5 The present invention is not to be limited in scope by the times in this manner in turns and the mean of the 5 values was 15 specific embodiments disclosed in the examples which are calculated. After control threshold measurements were com intended as illustrations of a few aspects of the invention and plete, carrageenan (3%, 100 ul) was administered subcutane any embodiments that are functionally equivalent are within ously into a hindpaw, resulting in marked Swelling and red the scope of this invention. Indeed, various modifications of ness of the treated paw. Three hours after the carrageenan the invention in addition to those shown and described herein administration, the threshold values were measured again. will become apparent to those skilled in the art and are The animals were then divided into a control group (admin intended to fall within the scope of the appended claims. istered vehicle intrathecally) and a treatment group (admin All references cited herein are incorporated by reference in stered Compound 17 intrathecally at in a 10 ul injection their entirety. volume). Threshold determinations were repeated as describe What is claimed is: above at 15 minutes, 30 minutes, 60 minutes, 90 minutes and 25 120 minutes after the administration of vehicle or Compound 1. A compound having the formula 17. FIG. 8 shows that Compound 17 exerts an analgesic effect in a animal. (Ia) Results show that Compound 17, an illustrative Purine Derivative, is effective for raising the pain threshold in a rat 30 model of pain, and, accordingly, is useful for treating pain. 6.19 Example 19 Effect of Compound 17 on Pain 35 or a pharmaceutically acceptable salt thereof, wherein Male CD rats (each weighing from 220g to 250 g) were A is CHOSONH; prepared according to the procedure set forth in Z. Seltzer et B and C are –OH: al., Pain, 43:205-218 (1990). The rats were then anesthetized D is via intraperitoneal administration of Sodium pentobarbital 40 (50 mg/kg). A skin incision was made at the upper '/3 and 2/3 left thigh area of each rat and the left sciatic nerve was NHR exposed and freed from the Surrounding connective tissue. An 8-0 nylon suture was then used to tightly ligate the left sciatic nerve of each rat so that the dorsal /3 to /2 of the nerve thickness was trapped in the ligature. The incision was closed 45 'N1SN using 4-0 sterile Suture. Seven days post-Surgery, the animals were put into four groups: a first group that was administered . as vehicle (control group); a second group that was administered Compound 17 at 0.1 mg/kg, a third group that was adminis tered buprenorphine at 0.3 mg/kg, and a fourth group that was 50 co-administered Compound 17 at 0.1 mg/kg and buprenor A and B are trans with respect to each other; phine at 0.3 mg/kg. Animals in all four groups were assessed B and C are cis with respect to each other; for allodynia immediately prior to treatment and at 10, 20, 30 C and D are cis or trans with respect to each other; and 60 minutes post-treatment using the Von Frey Hair test R" is —C-C monocyclic cycloalkyl, -C-C mono (G. M. Pitcher et al., JNeurosci Methods, 87:185-93 (1999)). 55 cyclic cycloalkenyl, -(CH2), (C-C monocyclic FIG. 9 shows that Compound 17, alone or in combination cycloalkyl). —(CH), (C-Cs monocyclic with buprenorphine, exerts an analgesic effect in a animal. cycloalkenyl), —Cs-C bicyclic cycloalkyl, or—Cs The results show that Compound 17, an illustrative Purine C. bicyclic cycloalkenyl: Derivative, exerts an analgesic effect in an animal, and, Ris-halo, CN, NHR, OR, SR, NHC(O) accordingly, is useful for treating pain. 60 OR, NHC(O)R, NHC(O)NHR, NHNHC (O)R, NHNHC(O)OR, NHNHC(O)NHR, or 6.20 Example 20 NH N–C(R)R’; R" is -H, -C-Cls alkyl, -aryl, -(CH2)-aryl, Effect of Compound 17 on Heart Rate —(CH)-(3- to 7-membered monocyclic hetero 65 cycle), —(CH)-(8- to 12-membered bicyclic het Adult male Wistar rats (each weighing from about 350 g to erocycle), —(CH), (C-Cs monocyclic about 400 g) were anesthetized as in Example 19, then pre cycloalkyl). —(CH), (C-Cs monocyclic US 8,609,833 B2 105 106 cycloalkenyl), —(CH2)(-Cs-C bicyclic —(CH2), (C-C bicyclic cycloalkyl). —(CH), cycloalkyl). —(CH), (C-C bicyclic cycloalk —(C-C bicyclic cycloalkenyl), or —(CH), aryl; enyl), —C=C-(C-Co alkyl) or —C=C-aryl; R is NHR, OR, SR, NHC(O)R, NHC Ris-C-Cio alkyl, -aryl, -(CH2), aryl, -(CH2), (O)OR, NHC(O)NHR', NHNHC(O)R, 5 NHNHC(O)NHR, or NHNHC(O)OR; (C-C monocyclic cycloalkyl). —(CH), (C-Cs R" is —C-Cls alkyl, -aryl, -(CH2)-aryl, -(CH2)- monocyclic cycloalkenyl), —(CH2)—(C-C bicy (3- to 7-membered monocyclic heterocycle), clic cycloalkyl). —(CH), (C-C bicyclic —(CH)-(8- to 12-membered bicyclic heterocycle), cycloalkenyl). —(CH2)(3- to 7-membered monocy —(CH2), (C-Cs monocyclic cycloalkyl). clic heterocycle), —(CH2)(8- to 12-membered —(CH) —(C-C monocyclic cycloalkenyl), bicyclic heterocycle), -phenylene-(CH2)COOH, or 10 -(CH2), cs-C2 bicyclic cycloalkyl), -(CH2), -phenylene-(CH2)COO—(C-C alkyl); —(C-C bicyclic cycloalkenyl), —C=C-(C-Co R’ is -H, -C-Cio alkyl, -aryl, -(CH2)-aryl, alkyl) or —C=C-aryl; —(CH), (C-Cs monocyclic cycloalkyl). R is —C(O)O(C-C alkyl). —C(O)NH(C-Co —(CH2), —(C-C monocyclic cycloalkenyl), alkyl), —C(O)N(C-C alkyl). —C(O)NH-aryl, —(CH2), (C-C bicyclic cycloalkyl). —(CH), 15 -CH(NH)NH or -CH(NH)NH(C-C alkyl); —(C-C bicyclic cycloalkenyl), —(CH)-(3- to and 7-membered monocyclic heterocycle), or —(CH2)- each n is independently an integer ranging from 1 to 5. (8- to 12-membered bicyclic heterocycle); 3. A composition comprising an effective amount of a R is —C-Cls alkyl, -aryl, -(CH2)-aryl, -(CH2), compound or a pharmaceutically acceptable salt of the com (3- to 7-membered monocyclic heterocycle), pound of claim 1 and a physiologically acceptable carrier or —(CH)-(8- to 12-membered bicyclic heterocycle), vehicle. —(CH2), (C-Cs monocyclic cycloalkyl). 4. A composition comprising an effective amount of a —(CH), (C-C monocyclic cycloalkenyl), compound or a pharmaceutically acceptable salt of the com —(CH2), —(C-C bicyclic cycloalkyl). —(CH), pound of claim 2 and a physiologically acceptable carrier or —(C-C bicyclic cycloalkenyl), —C=C-(C-Co 25 vehicle. alkyl) or —C=C-aryl; and 5. A composition comprising a cardioplegia-inducing each n is independently an integer ranging from 1 to 5. agent, an effective amount of the compound or pharmaceuti 2. A compound having the formula cally acceptable salt of the compound of claim 1, and a physiologically acceptable carrier or vehicle. 30 6. A compound having the formula: (Ic)

35 or a pharmaceutically acceptable salt thereof, wherein A is CH-NHR: 40 B and C are –OH: D is

45

50

A and B are trans with respect to each other; B and C are cis with respect to each other; 55 C and Dare cis or trans with respect to each other; R" is —H. —C-C alkyl, -aryl, -3- to 7-membered monocyclic heterocycle, -8- to 12-membered bicyclic heterocycle. —C-C monocyclic cycloalkyl, —C- Cs monocyclic cycloalkenyl, -C-C bicyclic 60 cycloalkyl, —Cs-C bicyclic cycloalkenyl, —(CH) —(C-C monocyclic cycloalkyl). —(CH2), —(C-C monocyclic cycloalkenyl),