US 2008.0027082A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0027082 A1 Hocher et al. (43) Pub. Date: Jan. 31, 2008

(54) USE OF ADENOSINE A1 ANTAGONISTS IN Publication Classification RADIOCONTRAST MEDIA NDUCED NEPHROPATHY (51) Int. Cl. A 6LX 3/59 (2006.01) (76) Inventors: Berthold Hocher, Hannover (DE): A6IP I3/2 (2006.01) Yvan Fischer, Barsinghausen (DE); (52) U.S. Cl...... 51.4/265.1 Klaus Witte, Hannover (DE); Dieter Ziegler, Hemmingen (DE) (57) ABSTRACT Correspondence Address: MLAYER BROWN LLP Described herein are pharmaceutical combinations compris P.O. BOX2828 ing a therapeutically effective amount of a first selective CHICAGO, IL 60690 (US) adenosine A1 antagonist and a first radiocontrast media. In one embodiment the selective adenosine A1 antagonist (21) Appl. No.: 11/765,290 comprises 4-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4- yl)amino-trans-cyclohexanol methanesulfonate and/or (22) Filed: Jun. 19, 2007 (4S)-4-hydroxy-1-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4- Related U.S. Application Data yl)-L-prolinamide methanesulfonate. Also described are the use of a first selective adenosine A1 antagonist in the (60) Provisional application No. 60/805,173, filed on Jun. treatment of radiocontrast media induced nephropathy. Fur 19, 2006. Provisional application No. 60/805,168, thermore, a kit comprising a therapeutically effective filed on Jun. 19, 2006. Provisional application No. amount of a first selective adenosine A1 antagonist and a 60/871,062, filed on Dec. 20, 2006. first radiocontrast media is also described herein. Patent Application Publication Jan. 31, 2008 Sheet 1 of 4 US 2008/0027082 A1 Figure 1

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USE OF ADENOSINE A1 ANTAGONSTS IN of CIN. Along the renal tubular system, substances like RM RADIOCONTRAST MEDIA NDUCED that are not reabsorbed become increasingly concentrated. NEPHROPATHY Up to 99% of renal fluids are usually taken up by the action of manifold cellular and paracellular mechanisms. This CROSS REFERENCE TO RELATED means that the urine concentration of RM can increase by a APPLICATIONS factor of 100. Along with the continuous concentration process, tubular fluid containing RM will become increas 0001) This application claims the benefit of U.S. Provi ingly viscous and can lead to tubular obstruction (Ueda, sional Application Nos. 60/805,168 and 60/805,173 filed on 1993). Inevitably, intrarenal pressure increases as well, as Jun. 19, 2006 and U.S. Provisional Application No. 60/871, the kidney cannot expand due to the Surrounding capsule. As 062 filed on Dec. 20, 2006 and all three are hereby incor a consequence, renal perfusion pressure for the renal porated by reference in their entirety to the extent permitted medulla may no longer be sufficient to allow for sufficient by law. perfusion. FIELD 0006. In the kidney, activation of A1AR in afferent glom erular arterioles has been Suggested to contribute to tubulo 0002 Pharmaceutical combinations comprising a thera glomerular feedback (TGF) which is a strategic feedback peutically effective amount of a first selective adenosine A1 mechanism designed to control tubular flow and regional receptor antagonist and a first radiocontrast media (RM) are perfusion. The vasoconstriction elicited by elevations in described herein. Also described is the use of said combi NaCl) in the macula densa region of the nephron. A role of nations for the treatment of radiocontrast media induced adenosine in TGF response mediation is consistent with its nephropathy as well as kits comprising said combinations. effect to cause vasoconstriction. In addition to its vasocon strictor effect. A receptor stimulation contracts mesangial BACKGROUND cells in the glomerulus (Olivera, 1989). Acute renal failure 0003 Interventional techniques, fast multislice computer caused by the injection of RM has been recognized for many tomographies and new 3D reconstruction techniques have years as a complication in diagnostic and interventional increased the use of iodinated intravascular radiocontrast procedures. The incidence of acute renal failure directly media (RM). The majority of examinations require iodinated induced by RM lies at approximately 10-15%, while the RM for accurate and safe diagnosis and interventional incidence of CIN defined by clinically significant increases procedures. Today approximately 60 million doses are given in serum creatinine is as high as 22% (Porter, 1989). The every year world wide (Andrew, 2004). The use of radio peak creatinine concentration occurs within 3-5 days of contrast media can lead to a decline of excretory renal exposure to the contrast media and usually resolves satis function that starts soon after administration. The renal factorily. However, in about 10% of at-risk patients, dialysis dysfunction can be transient, persistent or even irreversible. is required. Preexisting renal insufficiency, reduced intra Hence, the use of radiocontrast media has been associated vascular volume and additional underlying diseases (e.g. with increased in-hospital morbidity, mortality, and cost of hypertension, diabetes mellitus) are thought to be some of medical care and long admissions, especially in patients the leading risk factors for radiocontrast media induced requiring dialysis. Radiocontrast media induced nephropa nephropathy. The osmolality, the measurement of the num thy (CIN) is therefore a clinically important problem. ber of molecules and particles in a solution per kilogram of water, of the RM is regarded to be of great importance in 0004 CIN is the structural damage of the kidney. The radiocontrast induced nephropathy. The incidence of neph definition of CIN varies. It can be defined as acute aggra ropathy induced by low-osmolar RM is low in the general vation of renal functionality after application of RM, population and has been calculated to be less than 2% induced as proximate cause to the exclusion of alternative (Nikolsky, 2003). etiologies. The most common definition of a minor effect is 0007 Adenosine production is one of the discussed an increase in serum creatinine greater than 25% or 44 mol/l mechanisms behind CIN. Adenosine is an endogenous neu (0.5 mg/dl) after the intravascular administration of a RM. A romodulator with predominantly inhibitory effects on the major effect is defined as increase in serum creatinine greater CNS, heart, kidneys and other organs. It is a naturally than 50% or 88 mmol/l (1 mg/dl). The pathogenesis of CIN occurring nucleoside, which exerts its biological effects by is not fully understood. It is believed that two main factors, interacting with a family of adenosine receptors known as hemodynamic as well as tubular effects, are involved. Appli A1, A2a, A2b, and A3, all of which modulate important cation of RM leads to a change in renal hemodynamics, physiological processes. Selective A1 adenosine receptor manifesting itself as a decrease in the glomerular filtration antagonists (AAR) have pronounced effects on the kidney rate (GFR). GFR is the rate of ultra filtration of plasma and have shown to be potent diuretics and natriuretics with across the walls of the glomerular capillaries and measure little effect on potassium excretion. Thus, they are renal ment of total GFR of both kidneys provides a sensitive index protective and useful for the treatment of renal failure, renal of overall renal excretory function. dysfunction, nephritis, hypertension, and edema. The kid 0005 The glomerular filtration rate is calculated by com neys produce adenosine constitutively to regulate glomeru paring urine creatinine levels with the blood test results. A lar filtration and electrolyte reabsorption mediated by the GFR value (see http://www.fpnotebook.com) in a range of adenosine A1 receptor system. The A1 adenosine receptor 97-137 ml/min/1.73 m is adequate for a male human and of has been found to govern the vasoconstriction response of 88-128 ml/min/1.73 m is adequate for a female human, the afferent glomerular arteriole. Adenosine causes a reduc whereas a GFR lower than 15 ml/min/1.73 m leads to tion in the blood flow to the kidney, and thus a reduction in kidney failure. A decrease in GFR induced by application of the glomerular filtration rate and the renal blood flow. RM is considered to be the main cause for the development Inhibition of the A1 receptor will heighten the glomerular US 2008/0027082 A1 Jan. 31, 2008

filtration rate and correspondingly increase the rate of urine effective amount of a first selective adenosine A1 receptor formation. The application of adenosine receptor antagonists antagonist and a radiocontrast media. has been implicated in protection from acute renal failure. The adenosine receptor antagonists aminophylline (combi 0011. A further embodiment described herein relates to a nation of theophylline and ethylenediamine 2:1) and theo kit comprising a therapeutically effective amount of a first phylline (which has been found to non-selectively antago selective adenosine A1 receptor antagonist and a radiocon nize adenosine receptors in the brain) were evaluated as trast media. potential agents to protect against radiocontrast media 0012. In an additional embodiment, the first AAR induced nephropathy (Shammas, 2001; Welch, 2002; Huber, antagonist may be selected from the compounds represented 2002). Aminophylline does not appear to add a protective by formula I role in preventing radiocontrast media induced nephropathy while theophylline was effective in preventing radiocontrast media induced nephropathy impaired renal excretory, endo crine and tubular function. R1 N1 R2 0008. These results suggest that adenosine may play a R5 role in the pathogenesis of CIN and that application of N1 N non-selective adenosine receptor antagonists has been impli cated in protection from acute renal failure associated with l 2 / R4 RM treatment. Erley (1994) investigated the influence of R3 N N the non-selective adenosine antagonist theophylline on the glomerular filtration rate after the application of RM and determined that adenosine plays a major role in CIN. Fur wherein thermore, Arakawa (1996) described the role of adenosine R1 and R2 are each independently selected from a hydrogen in the renal responses to the contrast medium iohexyl in dogs atom, an optionally Substituted alkyl, optionally Substituted with and without pre-existing renal insufficiency. Arakawa aryl, or optionally Substituted alkylaryl moiety or together indicated that in normal renal function, iohexyl elicits renal form an optionally substituted heterocyclic ring; vasodilation by activating mainly the adenosine A2 recep tors. Whereas in impaired renal function, iohexyl induces R3 is selected from a hydrogen atom or an optionally both A2 and A1 activation. Arakawa proposed that the substituted alkyl, optionally substituted aryl, or optionally adenosine A2 receptors were associated with the initial renal substituted alkylaryl moiety; vasodilation and that the adenosine A1 receptors were 0013 R4 and R5 are each independently selected from responsible for the Sustained aggravation of renal hemody a halogen atom, a hydrogen atom or an optionally namics. Yao (2000") investigated the influence of the Substituted alkyl, optionally Substituted aryl, or option selective adenosine A1 antagonist KW-3902 on radiocon ally substituted alkylaryl moiety, or R4 and R5 together trast media induced nephropathy in rats with chronic nitric form an optionally Substituted heterocyclic or option oxide deficiency. Yao Suggested adenosine influencing the ally substituted carbocyclic ring; pathogenesis of CIN via the activation of the A1 receptors. Greiner (2005') studied the influence on theophylline and and pharmaceutically acceptable salts of the foregoing, acetylcystein separately and in combination on radiocontrast pharmaceutically acceptable prodrugs of the foregoing, media induced nephropathy in intensive care patients and and pharmaceutically acceptable Solvates of the fore corroborated the prophylactic properties of theophylline in going. CIN. Lee (2006') concluded that renal A1 adenosine recep tors are only partially responsible in the pathogenesis of 0014) A further embodiment relates to a pharmaceutical radiocontrast nephropathy. In experiments with renal Al combination comprising a combination of 4-(2-phenyl-7H adenosine receptors knockout mice was found, that these pyrrolo2.3-opyrimidin-4-yl)amino-trans-cyclohexanol mice are protected from acute renal failure induced by RM methanesulfonate or (4S)-4-hydroxy-1-(2-phenyl-7H-pyr injection. Direct tubular toxicity seemed, however, not to be rolo2.3-opyrimidin-4-yl)-L-prolinamide methanesulfonate modulated by renal Al adenosine receptors. Patent applica with a first RM. tion EP 1 386 609 (CV Therapeutics') described methods 0015. In another embodiment the first RM may be an for restoring diuretic and renal function comprising adenos iodinated or gadolinium-based radiocontrast media selected ine A1 antagonist in combination with a diuretic. Patent from the group consisting of bunaiod, billigram, bilimiro, application WO99/31101 (Univ. South Florida) discloses bilopaque, cholimil, ethiodol, diatrast, dionosil, falignost, Xanthine derivatives as adenosine A1 receptor antagonists. gadobutrol, gadodiamide, gadopentetate dimeglumine, gas Additionally, radiolabelled derivatives and a method of trografin, hexabrix, hippodin, mangafodipir, amidotrizoate, imaging the adenosine A1 receptor antagonists for medical ethiodized oil, imagopaque, iodamide, iodipamide, iodix diagnostic purposes are mentioned. anol, iodophene, iophendylate, iomeron, iomeprol, iopami SUMMARY dol, iopanoic acid, iopiperidol, iophendylate, iopromide, iopydol, iosimenol, iothalamic acid, iotrolan, ioversol, iox 0009. Described herein is the use of a therapeutically ilan, ioxaglic acid, isopaque, ipodate, meglumine iothala effective amount of a first selective adenosine A1 receptor mate, meglumine acetrizoate, meglumine diatrizoate, metri antagonist for the treatment of nephropathy induced by a Zamide, myelotrast, omnipaque, osbil, optiray, optojod. first radiocontrast media. opacoron, perflutren, phenobutiodil, phentetiothalein 0010 Another embodiment described herein relates to a Sodium, priodax, propyliodone, skiodan, Sodium pharmaceutical combination comprising a therapeutically iodomethamate, sodium diatrizoate, telepaque, teridax, tet US 2008/0027082 A1 Jan. 31, 2008 rabrom, thorotrast, triognost, 1,3,5-Tri-n-hexyl-2,4,6-tri R4 and R5 are each independently selected from a halogen iodobenzene, tyropanoate, visipaque or xenetix, pharmaceu atom, a hydrogen atom or an optionally Substituted alkyl, tically acceptable salts of the foregoing prodrugs of the optionally substituted aryl, or optionally substituted alky foregoing, and a Solvate of the foregoing. laryl moiety, or R4 and R5 together form an optionally substituted heterocyclic or optionally substituted carbocy BRIEF DESCRIPTION OF THE FIGURES clic ring: 0016 FIG. 1: In volume restricted rats, hemodynamic and pharmaceutically acceptable salts of the foregoing, measurements are made, and the TGF response is assessed. pharmaceutically acceptable prodrugs of the foregoing, and 0017 FIG. 2: Experimental setting 2 is used for collect pharmaceutically acceptable Solvates of the foregoing, ing urine. Diuresis, urine osmolality and urine viscosity are for the prevention of nephropathy induced by a first radio determined. contrast media in mammals or humans. 0018 FIG. 3: Effects of Visipaque and substance 1 on 0022. One embodiment described herein relates to the use renal cortical blood flow with measurements over a 20 min of a therapeutically effective amount of a first selective period following injection of Visipaque or vehicle (control) adenosine A1 antagonist for the prevention of an increase in at time 0. Shown are means SEM (n=9), expressed as serum creatinine levels induced by a first radiocontrast relative values compared to cortical flow rates recorded media in mammals or humans. A further embodiment before Visipaque (or vehicle) challenge. *: P-0.05 Visipaque described herein is the use of a therapeutically effective vs. Control; +: P-0.05 substance 1+Visipaque vs. Visipaque. amount of a first selective adenosine A1 antagonist of 0.019 FIG. 4: Effects of Visipaque and substance 1 on formula I for the prevention of increase in serum creatinine renal cortical vascular conductance with measurements over levels induced by a first radiocontrast media in a transient, 20 min period following injection of Visipaque or vehicle persistent or irreversible increase in serum creatinine levels (control) at time 0. Shown are means SEM (n=9), induced by radiocontrast media in mammals or humans. expressed as relative values compared to cortical flow rates 0023. A further embodiment described herein relates to recorded before Visipaque (or vehicle) challenge. *: P-0.05 the use of a therapeutically effective amount of a first Visipaque vs. Control; +: P-0.05 substance 1+Visipaque vs. selective adenosine A1 antagonist for the prevention of Visipaque. decrease in renal blood flow induced by a first radiocontrast 0020 FIG. 5: Effects of Visipaque and substance 1 on media. A further embodiment described herein is the use of renal cortical oxygenation (PO) with measurements over 20 a therapeutically effective amount of a first selective adenos min period following injection of Visipaque or vehicle ine A1 antagonist of formula I for the prevention of decrease (control) at time 0. Shown are means SEM (n=9), in renal blood flow induced by a first radiocontrast media in expressed as relative values compared to cortical flow rates a transient, persistent or irreversible decrease in renal blood recorded before Visipaque (or vehicle) challenge. *: P-0.05 flow induced by radiocontrast media in mammals or Visipaque vs. Control; +: P-0.05 substance 1+Visipaque vs. humans. Visipaque. 0024. A further embodiment described herein relates to the use of a therapeutically effective amount of a first DESCRIPTION selective adenosine A1 antagonist for preventing or reducing 0021 Described herein is the use of a therapeutically the risk or need of dialysis caused by radiocontrast media effective amount of a first selective adenosine A1 antagonist induced nephropathy which may be transient, persistent or for the prevention of nephropathy induced by a first radio irreversible, in mammals or humans. A further embodiment contrast media in mammals or humans. Also described relates to the use of a therapeutically effective amount of a herein is the use of a therapeutically effective amount of a first selective adenosine A1 antagonist of formula I for first selective adenosine A1 antagonist of formula I preventing or reducing the risk or need of dialysis in a human or mammalian patient receiving radiocontrast media. In a further embodiment the need for dialysis is transient, persistent or irreversible. R1 N1 R2 R5 0025 A further embodiment relates to a pharmaceutical combination of a therapeutically effective amount of a first N1 N selective adenosine A1 antagonist and a first radiocontrast media, wherein the pharmaceutical combination is Suitable us 2 A R4 R3 N N for simultaneous, separate or step-wise administration to humans or mammals. 0026. Another embodiment described herein relates to a wherein kit comprising a therapeutically effective amount of a first R1 and R2 are each independently selected from a hydrogen selective adenosine A1 antagonist and a first radiocontrast atom, an optionally Substituted alkyl, optionally Substituted media, wherein the pharmaceutical combination is Suitable aryl, or optionally Substituted alkylaryl moiety or together for simultaneous, separate or step-wise administration to form an optionally substituted heterocyclic ring; humans or mammals. R3 is selected from a hydrogen atom or an optionally 0027. An A1AR which can be used with the various substituted alkyl, optionally substituted aryl, or optionally embodiments described herein may be selected from for substituted alkylaryl moiety; mula I US 2008/0027082 A1 Jan. 31, 2008

ide, iodixanol, iodophene, iophendylate, iomeron, iomeprol, iopamidol, iopanoic acid, iopiperidol, iophendylate, iopro mide, iopydol, iosimenol, iothalamic acid, iotrolan, ioversol, R1 N1 R2 ioXilan, ioxaglic acid, isopaque, ipodate, meglumine iothala R5 mate, meglumine acetrizoate, meglumine diatrizoate, metri Zamide, myelotrast, omnipaque, osbil, optiray, optojod. opa N1 N coron, perflutren, phenobutiodil, phentetiothalein Sodium, l 2 A R4 priodax, propyliodone, skiodan, Sodium iodomethamate, R3 N N Sodium diatrizoate, telepaque, teridax, tetrabrom, thorotrast, triognost, 1.3.5-Tri-n-hexyl-2,4,6-triiodobenzene, tyro panoate, visipaque, Xenetix, pharmaceutically acceptable wherein salts, prodrugs and Solvates of the foregoing. R1 and R2 are each independently selected from a hydrogen 0031. In an embodiment the RM includes xenetix, atom, an optionally Substituted alkyl, optionally Substituted omnipaque or visipaque. aryl, or optionally Substituted alkylaryl moiety or together form an optionally substituted heterocyclic ring; R3 is 0032 Some examples (Schering, Bracco Industria selected from a hydrogen atom or an optionally Substituted Chimica, Univ. California, Nyegaard, Cook Imaging Cor alkyl, optionally substituted aryl, or optionally substituted poration, Mallinckrodt, Eprova, Nycomed and Savag') of alkylaryl moiety; R4 and R5 are each independently selected additional RM suitable for use herein are described in EP 0 from a halogen atom, a hydrogen atom or an optionally 022 744, EP 0023992, EP 0026 281, EP 0 033 426, EP 0 substituted alkyl, optionally substituted aryl, or optionally 108 638, EP 0317 492, WO 87/00757, WO 89/08101, U.S. substituted alkylaryl moiety, or R4 and R5 together form an Pat. No. 2,776,241, U.S. Pat. No. 3,290,366, U.S. Pat. No. optionally substituted heterocyclic or optionally substituted 3.360,436, U.S. Pat. No. 5,349,085, GB 1321591, DE 2547 carbocyclic ring; in one embodiment 789, DE 2 726 196 and DE 2 909 439. The foregoing examples of suitable RM are meant to be illustrative and not R1 and R2 are each independently selected from a hydrogen to limit the group of suitable RM. atom, an optionally substituted alkyl or together form an optionally Substituted heterocyclic ring; R3 is a hydrogen 0033 Fore ease of reference, 4-(2-phenyl-7H-pyrrolo2, atom or an optionally substituted aryl; R4 and R5 are each 3-opyrimidin-4-yl)amino-trans-cyclohexanol methane independently selected from a halogen atom or a hydrogen sulfonate will hereafter be referred to as substance 1 and atom; (4S)-4-hydroxy-1-(2-phenyl-7H-pyrrolo2,3-alpyrimidin-4- yl)-L-prolinamide methanesulfonate will be referred to as in a further embodiment Substance 2. R1 is a hydrogen and R2 is an optionally substituted 0034. A further embodiment described herein relates to a cyclohexyl ring, or R1 and R2 together form an optionally use of Substance 1 and bunaiod, or Substance 1 and billigram, substituted pyrrolidine ring; R3 is a phenyl ring; R4 and R5 or Substance 1 and bilimiro, or Substance 1 and bilopaque, or are each a hydrogen atom; Substance 1 and cholimil, or Substance 1 and ethiodol, or In a further embodiment, the compounds of formula can be Substance 1 and diatrast, or Substance 1 and dionosil, or in the form of pharmaceutically acceptable salts of the Substance 1 and falignost, or Substance 1 and gadobutrol, or foregoing, pharmaceutically acceptable prodrugs of the fore Substance 1 and gadodiamide, or Substance 1 and gadopen going, and pharmaceutically acceptable Solvates of the fore tetate dimeglumine, or Substance 1 and gastrografin, or going. Substance 1 and hexabrix, or Substance 1 and hippodin, or Substance 1 and mangafodipir, or Substance 1 and amidot 0028. In a further embodiment, A1ARs described herein rizoate, or Substance 1 and ethiodized oil, or Substance 1 and may be selected from 4-(2-phenyl-7H-pyrrolo2,3-alpyri imagopaque, or Substance 1 and iodamide, or Substance 1 midin-4-yl)amino-trans-cyclohexanol methanesulfonate or and iodipamide, or Substance 1 and iodixanol, or Substance (4S)-4-hydroxy-1-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4- 1 and iodophene, or Substance 1 and iophendylate, or yl)-L-prolinamide methanesulfonate as well as pharmaceu Substance 1 and iomeron, or Substance 1 and iomeprol, or tically acceptable salts of the foregoing, pharmaceutically Substance 1 and iopamidol, or Substance 1 and iopanoic acid, acceptable prodrugs of the foregoing, and pharmaceutically or Substance 1 and iopiperidol, or Substance 1 and iophendy acceptable Solvates of the foregoing. late, or Substance 1 and iopromide, or Substance 1 and 0029. Additional A1ARs suitable for use herein are iopydol, or Substance 1 and iosimenol, or Substance 1 and described within the international patent applications WO iothalamic acid, or substance 1 and iotrolan, or Substance 1 and ioversol, or Substance 1 and ioxilan, or Substance 1 and 99/62518, WO 01/39777, WO 02/057267 and WO 2004/ ioxaglic acid, or Substance 1 and isopaque, or Substance 1 094428 (Osi Pharmaceuticals and Solvay Pharmaceuti and ipodate, or substance 1 and meglumine iothalamate, or cals'). Substance 1 and meglumine acetrizoate, or Substance 1 and 0030) Suitable RM which can be used as described herein meglumine diatrizoate, or Substance 1 and metrizamide, or include iodinated or gadolinium-based radiocontrast media Substance 1 and myelotrast, or Substance 1 and omnipaque, selected from the group consisting of bunaiod, billigram, or Substance 1 and Osbil, or Substance 1 and optiray, or bilimiro, bilopaque, cholimil, ethiodol, diatrast, dionosil, Substance 1 and optojod, or Substance 1 and opacoron, or falignost, gadobutrol, gadodiamide, gadopentetate dimeglu Substance 1 and perflutren, or Substance 1 and phenobu mine, gastrografin, hexabrix, hippodin, mangafodipir, ami tiodil, or Substance 1 and phentetiothalein Sodium, or Sub dotrizoate, ethiodized oil, imagopaque, iodamide, iodipam stance 1 and priodax, or Substance 1 and propyliodone, or US 2008/0027082 A1 Jan. 31, 2008

Substance 1 and skiodan, or Substance 1 and sodium iosimenol, or Substance 1 and iothalamic acid, or Substance iodomethamate, or Substance 1 and sodium diatrizoate, or 1 and iotrolan, or Substance 1 and ioversol, or Substance 1 Substance 1 and telepaque, or Substance 1 and teridax, or and iOXilan, or Substance 1 and ioxaglic acid, or Substance 1 Substance 1 and tetrabrom, or Substance 1 and thorotrast, or and isopaque, or Substance 1 and ipodate, or Substance 1 and Substance 1 and triognost, or Substance 1 and 1.3.5-Tri-n- meglumine iothalamate, or Substance 1 and meglumine hexyl-2,4,6-triiodobenzene, or Substance 1 and tyropanoate, acetrizoate, or Substance 1 and meglumine diatrizoate, or or Substance 1 and visipaque, or Substance 1 and Xenetix. A Substance 1 and metrizamide, or Substance 1 and myelotrast, or Substance 1 and omnipaque, or substance 1 and osbil, or further embodiment described herein relates to a pharma Substance 1 and optiray, or Substance 1 and optojod, or ceutical combination of Substance 1 and bunaiod, or Sub Substance 1 and opacoron, or Substance 1 and perflutren, or stance 1 and billigram, or Substance 1 and bilimiro, or Substance 1 and phenobutiodil, or Substance 1 and phen Substance 1 and bilopaque, or Substance 1 and cholimil, or tetiothalein Sodium, or Substance 1 and priodax, or Substance Substance 1 and ethiodol, or Substance 1 and diatrast, or 1 and propyliodone, or Substance 1 and skiodan, or Sub Substance 1 and dionosil, or Substance 1 and falignost, or stance 1 and Sodium iodomethamate, or Substance 1 and Substance 1 and gadobutrol, or Substance 1 and gadodia Sodium diatrizoate, or Substance 1 and telepaque, or Sub mide, or Substance 1 and gadopentetate dimeglumine, or stance 1 and teridax, or Substance 1 and tetrabrom, or Substance 1 and gastrografin, or Substance 1 and hexabrix, or Substance 1 and thorotrast, or Substance 1 and triognost, or Substance 1 and hippodin, or Substance 1 and mangafodipir, substance 1 and 1,3,5-Tri-n-hexyl-2,4,6-triiodobenzene, or or Substance 1 and amidotrizoate, or Substance 1 and Substance 1 and tyropanoate, or Substance 1 and visipaque, ethiodized oil, or Substance 1 and imagopaque, or Substance or Substance 1 and XenetiX. 1 and iodamide, or Substance 1 and iodipamide, or Substance 1 and iodixanol, or Substance 1 and iodophene, or Substance 0035 A further embodiment described herein relates to a 1 and iophendylate, or Substance 1 and iomeron, or Sub use of Substance 2 and bunaiod, or Substance 2 and billigram, stance 1 and iomeprol, or Substance 1 and iopamidol, or or Substance 2 and bilimiro, or Substance 2 and bilopaque, or Substance 1 and iopanoic acid, or Substance 1 and iopiperi Substance 2 and cholimil, or Substance 2 and ethiodol, or dol, or Substance 1 and iophendylate, or Substance 1 and Substance 2 and diatrast, or Substance 2 and dionosil, or iopromide, or Substance 1 and iopydol, or Substance 1 and Substance 2 and falignost, or Substance 2 and gadobutrol, or iosimenol, or Substance 1 and iothalamic acid, or Substance Substance 2 and gadodiamide, or Substance 2 and gadopen 1 and iotrolan, or Substance 1 and ioversol, or Substance 1 tetate dimeglumine, or Substance 2 and gastrografin, or and ioxilan, or substance 1 and ioxaglic acid, or substance 1 substance 2 and hexabrix, or substance 2 and hippodin, or and isopaque, or Substance 1 and ipodate, or Substance 1 and Substance 2 and mangafodipir, or Substance 2 and amidot meglumine iothalamate, or Substance 1 and meglumine rizoate, or Substance 2 and ethiodized oil, or Substance 2 and acetrizoate, or Substance 1 and meglumine diatrizoate, or imagopaque, or Substance 2 and iodamide, or Substance 2 Substance 1 and metrizamide, or Substance 1 and myelotrast, and iodipamide, or Substance 2 and iodixanol, or Substance or Substance 1 and omnipaque, or Substance 1 and osbil, or 2 and iodophene, or Substance 2 and iophendylate, or Substance 1 and optiray, or Substance 1 and optojod, or Substance 2 and iomeron, or Substance 2 and iomeprol, or Substance 1 and opacoron, or Substance 1 and perflutren, or Substance 2 and iopamidol, or Substance 2 and iopanoic acid, Substance 1 and phenobutiodil, or Substance 1 and phen or Substance 2 and iopiperidol, or Substance 2 and iophendy tetiothalein sodium, or Substance 1 and priodax, or Substance late, or Substance 2 and iopromide, or Substance 2 and 1 and propyliodone, or Substance 1 and skiodan, or Sub iopydol, or Substance 2 and iosimenol, or Substance 2 and stance 1 and sodium iodomethamate, or Substance 1 and iothalamic acid, or substance 2 and iotrolan, or Substance 2 Sodium diatrizoate, or Substance 1 and telepaque, or Sub and ioversol, or Substance 2 and ioxilan, or Substance 2 and stance 1 and teridax, or Substance 1 and tetrabrom, or loxaglic acid, or Substance 2 and isopaque, or Substance 2 Substance 1 and thorotrast, or Substance 1 and triognost, or and ipodate, or substance 2 and megiumine iothalamate, or substance 1 and 1,3,5-Tri-n-hexyl-2,4,6-triiodobenzene, or Substance 2 and meglumine acetrizoate, or Substance 2 and Substance 1 and tyropanoate, or Substance 1 and visipaque, meglumine diatrizoate, or Substance 2 and metrizamide, or or substance 1 and xenetix. A further embodiment described Substance 2 and myelotrast, or Substance 2 and omnipaque, herein relates to a kit comprising Substance 1 and bunaiod, or Substance 2 and Osbil, or Substance 2 and optiray, or or Substance 1 and billigram, or Substance 1 and bilimiro, or Substance 2 and optojod, or Substance 2 and opacoron, or Substance 1 and bilopaque, or Substance 1 and cholimil, or Substance 2 and perflutren, or Substance 2 and phenobu Substance 1 and ethiodol, or Substance 1 and diatrast, or tiodil, or Substance 2 and phentetiothalein Sodium, or Sub Substance 1 and dionosil, or Substance 1 and falignost, or stance 2 and priodax, or Substance 2 and propyliodone, or Substance 1 and gadobutrol, or Substance 1 and gadodia Substance 2 and skiodan, or Substance 2 and Sodium mide, or Substance 1 and gadopentetate dimeglumine, or iodomethamate, or Substance 2 and Sodium diatrizoate, or Substance 1 and gastrografin, or Substance 1 and hexabrix, or Substance 2 and telepaque, or Substance 2 and teridax, or Substance 1 and hippodin, or Substance 1 and mangafodipir, Substance 2 and tetrabrom, or Substance 2 and thorotrast, or or Substance 1 and amidotrizoate, or Substance 1 and Substance 2 and triognost, or Substance 2 and 1,3,5-Tri-n- ethiodized oil, or Substance 1 and imagopaque, or Substance hexyl-2,4,6-triiodobenzene, or Substance 2 and tyropanoate, 1 and iodamide, or Substance 1 and iodipamide, or Substance or Substance 2 and visipaque, or Substance 2 and XenetiX. A 1 and iodixanol, or Substance 1 and iodophene, or Substance further embodiment described herein relates to a pharma 1 and iophendylate, or Substance 1 and iomeron, or Sub ceutical combination of Substance 2 and bunaiod, or Sub stance 1 and iomeprol, or Substance 1 and iopamidol, or stance 2 and billigram, or Substance 2 and bilimiro, or Substance 1 and iopanoic acid, or Substance 1 and iopiperi Substance 2 and bilopaque, or Substance 2 and cholimil, or dol, or Substance 1 and iophendylate, or Substance 1 and Substance 2 and ethiodol, or Substance 2 and diatrast, or iopromide, or Substance 1 and iopydol, or Substance 1 and Substance 2 and dionosil, or Substance 2 and falignost, or US 2008/0027082 A1 Jan. 31, 2008

Substance 2 and gadobutrol, or Substance 2 and gadodia stance 2 and Sodium iodomethamate, or Substance 2 and mide, or Substance 2 and gadopentetate dimeglumine, or Sodium diatrizoate, or Substance 2 and telepaque, or Sub Substance 2 and gastrografin, or Substance 2 and hexabrix, or stance 2 and teridax, or Substance 2 and tetrabrom, or Substance 2 and hippodin, or Substance 2 and mangafodipir, Substance 2 and thorotrast, or Substance 2 and triognost, or or Substance 2 and amidotrizoate, or Substance 2 and substance 2 and 1,3,5-Tri-n-hexyl-2,4,6-triiodobenzene, or ethiodized oil, or Substance 2 and imagopaque, or Substance Substance 2 and tyropanoate, or Substance 2 and visipaque, 2 and iodamide, or Substance 2 and iodipamide, or Substance or Substance 2 and XenetiX. 2 and iodixanol, or Substance 2 and iodophene, or Substance 0036) The term “therapeutically effective amount” of a 2 and iophendylate, or Substance 2 and iomeron, or Sub drug or pharmacologically active agent means a nontoxic stance 2 and iomeprol, or Substance 2 and iopamidol, or but Sufficient amount of the drug or active agent needed to Substance 2 and iopanoic acid, or Substance 2 and iopiperi provide the desired effect. In the combination therapy dol, or Substance 2 and iophendylate, or Substance 2 and described herein, a “therapeutically effective amount of one iopromide, or Substance 2 and iopydol, or Substance 2 and component of the combination is the amount of that com iosimenol, or Substance 2 and iothalamic acid, or Substance pound that is effective to provide the desired effect when 2 and iotrolan, or Substance 2 and ioVersol, or Substance 2 used in combination with the other components of the and ioxilan, or Substance 2 and ioxaglic acid, or Substance 2 combination. The amount that is “effective' will vary from and isopaque, or Substance 2 and ipodate, or Substance 2 and Subject to Subject, depending on the species, age, general meglumine iothalamate, or Substance 2 and meglumine condition of the individual, the particular active agent or acetrizoate, or Substance 2 and meglumine diatrizoate, or agents, and the like. It thus is not always possible to specify Substance 2 and metrizamide, or Substance 2 and myelotrast, an exact “therapeutically effective amount. However, an or Substance 2 and omnipaque, or Substance 2 and osbil, or appropriate “therapeutically effective amount” in any indi Substance 2 and optiray, or Substance 2 and optojod, or vidual case may be determined by a person of ordinary skill Substance 2 and opacoron, or Substance 2 and perflutren, or in the art. Substance 2 and phenobutiodil, or Substance 2 and phen 0037. In general, the first RM is not administered until the tetiothalein sodium, or Substance 2 and priodax, or Substance plasma level of the first selective adenosine A1 receptor 2 and propyliodone, or Substance 2 and skiodan, or Sub antagonist has reached a concentration of about 10 ng/ml to stance 2 and sodium iodomethamate, or Substance 2 and about 500 ng/ml. Also described herein are all concentration Sodium diatrizoate, or Substance 2 and telepaque, or Sub or concentration ranges, which lie within the range of 10 stance 2 and teridax, or substance 2 and tetrabrom, or ng/ml to 500 ng/ml. In one embodiment, the first selective Substance 2 and thorotrast, or Substance 2 and triognost, or adenosine A1 antagonist has a concentration of about 10, substance 2 and 1,3,5-Tri-n-hexyl-2,4,6-triiodobenzene, or about 20, about 30, about 40, about 50, about 60, about 70, Substance 2 and tyropanoate, or Substance 2 and visipaque, about 80, about 90, about 100, about 110, about 120, about or substance 2 and xenetix. A further embodiment described 130, about 140, about 150, about 160, about 170, about 180, herein relates to a kit comprising Substance 2 and bunaiod, about 190, about 200, about 210, about 220, about 230, or Substance 2 and billigram, or Substance 2 and bilimiro, or about 240, about 250, about 260, about 270, about 280, Substance 2 and bilopaque, or Substance 2 and cholimil, or about 290, about 300, about 310, about 320, about 330, Substance 2 and ethiodol, or Substance 2 and diatrast, or about 340, about 350, about 360, about 370, about 380, Substance 2 and dionosil, or Substance 2 and falignost, or about 390, about 400, about 410, about 420, about 430, Substance 2 and gadobutrol, or Substance 2 and gadodia about 440, about 450, about 460, about 470, about 480, mide, or Substance 2 and gadopentetate dimeglumine, or about 490, and about 500 ng/ml, and any other concentration Substance 2 and gastrografin, or Substance 2 and hexabrix, or or concentration ranges, which lie within in any ranges Substance 2 and hippodin, or Substance 2 and mangafodipir, defined by two of the previously mentioned concentration or Substance 2 and amidotrizoate, or Substance 2 and values, where the lower limit of said range is defined by the ethiodized oil, or Substance 2 and imagopaque, or Substance lower value and the upper limit of said range by the higher 2 and iodamide, or Substance 2 and iodipamide, or Substance value, e.g. a range of about 110 to about 180 ng/ml, about 2 and iodixanol, or Substance 2 and iodophene, or Substance 370 to about 390 ng/ml, about 10 to about 150 ng/ml, etc. A 2 and iophendylate, or Substance 2 and iomeron, or Sub further embodiment described herein includes the use of a stance 2 and iomeprol, or Substance 2 and iopamidol, or first radiocontrast media which is not administered until the Substance 2 and iopanoic acid, or Substance 2 and iopiperi therapeutically effective amount of the first selective adenos dol, or Substance 2 and iophendylate, or Substance 2 and ine A1 receptor antagonist is Sufficient to provide a plasma iopromide, or Substance 2 and iopydol, or Substance 2 and level concentration of about 10 ng/ml to about 500 ng/ml, iosimenol, or Substance 2 and iothalamic acid, or Substance about 20 ng/ml to about 400 ng/ml or about 30 ng/ml to 2 and iotrolan, or Substance 2 and ioVersol, or Substance 2 about 300 ng/ml. A further embodiment includes a pharma and ioxilan, or Substance 2 and ioxaglic acid, or Substance 2 ceutical combination comprising the first radiocontrast and isopaque, or Substance 2 and ipodate, or Substance 2 and media which is not administered until the therapeutically meglumine iothalamate, or Substance 2 and meglumine effective amount of the first selective adenosine A1 receptor acetrizoate, or Substance 2 and meglumine diatrizoate, or antagonist is sufficient to provide a plasma level concentra Substance 2 and metrizamide, or Substance 2 and myelotrast, tion of about 10 ng/ml to about 500 ng/ml, about 20 ng/ml or Substance 2 and omnipaque, or Substance 2 and osbil, or to about 400 ng/ml or about 30 ng/ml to about 300 ng/ml. A Substance 2 and optiray, or Substance 2 and optojod, or further embodiment includes using the first radiocontrast Substance 2 and opacoron, or Substance 2 and perflutren, or media which is not administered until the therapeutically Substance 2 and phenobutiodil, or Substance 2 and phen effective amount of the first selective adenosine A1 receptor tetiothalein sodium, or Substance 2 and priodax, or Substance antagonist is sufficient to provide a plasma level concentra 2 and propyliodone, or Substance 2 and skiodan, or Sub tion of about 10 ng/ml to about 500 ng/ml, about 20 ng/ml US 2008/0027082 A1 Jan. 31, 2008

to about 400 ng/ml or about 30 ng/ml to about 300 ng/ml. A 45, about 45.5, about 46, about 46.5, about 47, about 47.5 further embodiment also includes a pharmaceutical combi and about 48 hours, and every time period which lies in any nation comprising the first radiocontrast media which is not ranges defined by two of the before mentioned values, where administered until the therapeutically effective amount of the lower limit of said range is defined by the minor value said a first selective adenosine A1 receptor antagonist is and the upper limit of said range by the higher value, e.g. a sufficient to provide a plasma level concentration of about 10 range of about 1 to about 2 hours, about 0.1 to about 10 ng/ml to about 500 ng/ml, about 20 ng/ml to about 400 ng/ml hours, about 0.2 to about 6 hours, about 2 hours to about 45 or about 30 ng/ml to about 300 ng/ml. hours, about 9.5 to about 35 hours, etc. 0038. The duration of administration of the maintenance 0040. The first selective adenosine A1 receptor antago dosage of the first selective A1 adenosine antagonist is that nist may be administered intravenously in a loading dose which is sufficient to maintain the plasma level of the first followed by one or more maintenance doses. The first selective A1 adenosine antagonist at a concentration of selective adenosine A1 receptor antagonist loading dose is between about 10 ng/ml and about 500 ng/ml. The amount administered at a time period of between about 5 and about of the first selective A1 adenosine antagonist to be admin 25 minutes prior to the administration of the first radiocon istered to reach and maintain a specific plasma level of the trast media and the maintenance dosage of the first selective first selective A1 adenosine antagonist corresponds to spe adenosine A1 receptor antagonist is administered over a cific dosages to be administered to a patient. The skilled period of up to 48 hours subsequent to administration of the artisan is able to select an appropriate dosage for a specific loading dose of the first selective A1 receptor antagonist. In patient. A further embodiment also includes every concen a further embodiment the maintenance dose is administered tration or concentration range which lies within the range of over a period of up to about 0.1, about 0.3, about 0.5, about between 10 ng/ml to 500 ng/ml. In a further embodiment, the 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, first selective adenosine A1 antagonist has a concentration of about 4.5, about 5, about 5.5 about 6, about 6.5, about 7, about 10, about 20, about 30, about 40, about 50, about 60, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 70, about 80, about 90, about 100, about 110, about about 10.5, about 11, about 11.5, about 12, about 12.5, about 120, about 130, about 140, about 150, about 160, about 170, 13, about 13.5, about 14, about 14.5, about 15, about 15.5, about 180, about 190, about 200, about 210, about 220, about 16, about 16.5, about 17, about 17.5, about 18, about about 230, about 240, about 250, about 260, about 270, 18.5, about 19, about 19.5, about 20, about 20.5, about 21, about 280, about 290, about 300, about 310, about 320, about 21.5, about 22, about 22.5, about 23, about 23.5, about about 330, about 340, about 350, about 360, about 370, 24, about 24.5, about 25, about 25.5, about 26, about 26.5, about 380, about 390, about 400, about 410, about 420, about 27, about 27.5, about 28, about 28.5, about 29, about about 430, about 440, about 450, about 460, about 470, 29.5, about 30, about 30.5, about 31, about 31.5, about 32, about 480, about 490, and about 500 ng/ml, and every about 32.5, about 33, about 33.5, about 34, about 34.5, about concentration or concentration range which lies in any 35, about 35.5, about 36, about 36.5, about 37, about 37.5, ranges defined by two of the before mentioned concentration about 38, about 38.5, about 39, about 39.5, about 40, about values, where the lower limit of said range is defined by the 40.5, about 41, about 41.5, about 42, about 42.5, about 43, minor value and the upper limit of said range by the higher about 43.5, about 44, about 44.5, about 45, about 45.5, about value, e.g. a range of about 10 ng/ml to about 80 ng/ml. 46, about 46.5, about 47, about 47.5 and about 48 hours. A about 320 ng/ml to about 390 ng/ml, about 100 ng/ml to further embodiment includes every time interval which lies about 50 ng/ml, etc. within time period of about 5 minutes to 25 minutes prior to 0.039 The duration of administration of the maintenance the administration of the first radiocontrast media and the dosage of the first selective A1 adenosine antagonist lies maintenance dose of the first selective adenosine A1 recep between about 0.1 hours and about 48 hours to maintain the tor antagonist is administered over a period of up to about 48 plasma level of the first selective A1 adenosine at a con hours Subsequent to administration of the loading dose of the centration of between about 10 ng/ml to about 500 ng/ml. A first selective A1 receptor antagonist. In a further embodi further embodiment also includes every time interval which ment the maintenance dose is administered over a period of lies within the time period of about 0.1 hours and about 48 up to about 0.1, about 0.3, about 0.5, about 1, about 1.5, hours. In a further embodiment, the time period of admin about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, istration of the maintenance dosage is about 0.1, about 0.3. about 5, about 5.5 about 6, about 6.5, about 7, about 7.5, about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 3.5, about 4, about 4.5, about 5, about 5.5 about 6, about 11, about 11.5, about 12, about 12.5, about 13, about about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, 13.5, about 14, about 14.5, about 15, about 15.5, about 16, about 9.5, about 10, about 10.5, about 11, about 11.5, about about 16.5, about 17, about 17.5, about 18, about 18.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, 19, about 19.5, about 20, about 20.5, about 21, about 21.5, about 15, about 15.5, about 16, about 16.5, about 17, about about 22, about 22.5, about 23, about 23.5, about 24, about 17.5, about 18, about 18.5, about 19, about 19.5, about 20, 24.5, about 25, about 25.5, about 26, about 26.5, about 27, about 20.5, about 21, about 21.5, about 22, about 22.5, about about 27.5, about 28, about 28.5, about 29, about 29.5, about 23, about 23.5, about 24, about 24.5, about 25, about 25.5, 30, about 30.5, about 31, about 31.5, about 32, about 32.5, about 26, about 26.5, about 27, about 27.5, about 28, about about 33, about 33.5, about 34, about 34.5, about 35, about 28.5, about 29, about 29.5, about 30, about 30.5, about 31, 35.5, about 36, about 36.5, about 37, about 37.5, about 38, about 31.5, about 32, about 32.5, about 33, about 33.5, about about 38.5, about 39, about 39.5, about 40, about 40.5, about 34, about 34.5, about 35, about 35.5, about 36, about 36.5, 41, about 41.5, about 42, about 42.5, about 43, about 43.5, about 37, about 37.5, about 38, about 38.5, about 39, about about 44, about 44.5, about 45, about 45.5, about 46, about 39.5, about 40, about 40.5, about 41, about 41.5, about 42, 46.5, about 47, about 47.5 and about 48 hours. In a further about 42.5, about 43, about 43.5, about 44, about 44.5, about embodiment the first selective adenosine A1 receptor US 2008/0027082 A1 Jan. 31, 2008 antagonist may be administered intravenously at about 5. selective adenosine A1 receptor antagonist in a loading dose about 6, about 7, about 8, about 9, about 10, about 11, about to be administered intravenously followed by a maintenance 12, about 13, about 14, about 15, about 16, about 17, about dose where the first selective adenosine A1 receptor antago 18, about 19, about 20, about 21, about 22, about 23, about nist loading dose is administered at a time period of between 24 and about 25 minutes, and every period which lies in any about 5 and about 25 minutes, between about 10 and about ranges defined by two of the before mentioned values, where 20 minutes, between about 13 and about 17 minutes, or the lower limit of said range is defined by the minor value about 15 minutes prior to the administration of the first and the upper limit of said range by the upper value, e.g. a radiocontrast media. The maintenance dose of the first range of about 10 minutes to about 18 minutes, about 20 selective adenosine A1 receptor antagonist is administered minutes to about 25 minutes, about 12 minutes to about 15 over a period of up to about 48 hours subsequent to minutes, etc., prior to the administration of the first radio administration of the loading dose of the first selective A1 contrast media, and the maintenance dosage of the first receptor antagonist. The kit may also include a first radio selective adenosine A1 receptor antagonist is administered contrast media. over a period of up to about 48 hours subsequent to administration of the loading dose of the first selective A1 0043. The embodiments described herein are not limited receptor antagonist. In a further embodiment the mainte to specific dosage forms, carriers, excipients, or the like, as nance dose is administered over a period of up to about 0.1. such may vary. It is also to be understood that the termi about 0.3, about 0.5, about 1, about 1.5, about 2, about 2.5, nology used herein is for the purpose of describing particular about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, embodiments only, and is not intended to be limiting. about 6, about 6.5, about 7.5, about 8, about 8.5, about 9, 0044) It must be noted that as used in this specification about 9.5, about 10, about 10.5, about 11, about 11.5, about and the appended claims, the singular forms 'a', 'an, and 12, about 12.5, about 13, about 13.5, about 14, about 14.5, “the include plural referents unless the context clearly about 15, about 15.5, about 16, about 16.5, about 17, about dictates otherwise. Thus, for example, reference to “a thera 17.5, about 18, about 18.5, about 19, about 19.5, about 20, peutically effective agent includes a single agent as well as about 20.5, about 21, about 21.5, about 22, about 22.5, about two or more different agents in combination, and reference 23, about 23.5, about 24, about 24.5, about 25, about 25.5, to “a carrier includes mixtures of two or more carriers as about 26, about 26.5, about 27, about 27.5, about 28, about well as a single carrier, and the like. 28.5, about 29, about 29.5, about 30, about 30.5, about 31, about 31.5, about 32, about 32.5, about 33, about 33.5, about 0045. The terms “A1AR”, “selective adenosine A1 34, about 34.5, about 35, about 35.5, about 36, about 36.5, antagonist' and “selective adenosine A1 receptor antago about 37, about 37.5, about 38, about 38.5, about 39, about nist are used interchangeably herein to refer to a chemical 39.5, about 40, about 40.5, about 41, about 41.5, about 42, compound that induces a desired pharmacological and about 42.5, about 43, about 43.5, about 44, about 44.5, about physiological effect. 45, about 45.5, about 46, about 46.5, about 47, about 47.5 0046) The first selective adenosine A1 antagonist may be and about 48 hours. administered orally and/or intravenously. One embodiment 0041. A further embodiment includes a use comprising included here is the use of a therapeutically effective amount the therapeutically effective amount of the first selective of the first selective adenosine A1 receptor antagonist to be adenosine A1 receptor antagonist in a loading dose to be administered orally, Such as an extended release formula administered intravenously followed by a maintenance dose. tion, prior to the administration of the first radiocontrast The loading does of the first selective adenosine A1 receptor agent. A further embodiment included herein is the use of a antagonist is to be administered at a time period of between therapeutically effective amount of the first selective adenos about 5 and about 25 minutes, between about 10 and about ine A1 receptor antagonist in a loading dose which is 20 minutes, between about 13 and about 17 minutes, or administered intravenously followed by a maintenance dose about 15 minutes prior to the administration of the first where the first selective adenosine A1 receptor antagonist radiocontrast media. The maintenance dose of the first loading dose is administered at a time period of between selective adenosine A1 receptor antagonist is administered about 5 and about 25 minutes, between about 10 and about over a period of up to about 48 hours subsequent to 20 minutes, between about 13 and about 17 minutes, or administration of the loading dose of the first selective A1 about 15 minutes prior to the administration of the first receptor antagonist. A further embodiment includes a phar radiocontrast media. The maintenance dose of the first maceutical combination comprising the therapeutically selective adenosine A1 receptor antagonist is administered effective amount of the first selective adenosine A1 receptor over a period of up to about 48 hours subsequent to antagonist in a loading dose which is administered intrave administration of the loading dose of the first selective A1 nously followed by a maintenance dose, where the first receptor antagonist. selective adenosine A1 receptor antagonist loading dose is administered at a time period of about 5 to about 25 minutes, 0047 A further embodiment includes a pharmaceutical about 10 to about 20 minutes, about 13 to about 17 minutes, combination comprising a therapeutically effective amount or about 15 minutes prior to the administration of the first of the first selective adenosine A1 receptor antagonist to be radiocontrast media. The maintenance dose of the first administered orally, such as in an extended release formu selective adenosine A1 receptor antagonist is administered lation, prior to the administration of the first radiocontrast over a period of up to 48 hours Subsequent to administration agent. The pharmaceutical combination may also include a of the loading dosage of the first selective A1 receptor first radiocontrast media. antagonist. 0048. A further embodiment includes a pharmaceutical 0.042 A further embodiment described herein is a kit combination comprising a therapeutically effective amount comprising the therapeutically effective amount of the first of the first selective adenosine A1 receptor antagonist in a US 2008/0027082 A1 Jan. 31, 2008 loading dose which is administered intravenously followed istered to a patient without causing any undesirable biologi by a maintenance dose where the first selective adenosine cal effects or interacting in a deleterious manner with any of A1 receptor antagonist loading dose is administered at a the other components of the combination in which it is time period of about 5 to about 25 minutes, between about contained. "Pharmacologically active', as in a “pharmaco 10 and about 20 minutes, between about 13 and about 17 logically active' derivative or metabolite, refers to a deriva minutes, or about 15 minutes prior to the administration of tive or metabolite having the same type of pharmacological the first radiocontrast media. The maintenance dose of the activity as the parent compound and approximately equiva first selective adenosine A1 receptor antagonist is adminis lent in degree. When the term “pharmaceutically accept tered over a period of up to about 48 hours subsequent to able' is used to refer to a derivative of an active agent, it is administration of the loading dose of the first selective A1 to be understood that the compound is pharmacologically receptor antagonist. The pharmaceutical combination may active as well, i.e., therapeutically effective for the treatment also include a first radiocontrast media. of radiocontrast media induced nephropathy. 0049. A further embodiment disclosed herein also 0057 "Carriers' or “pharmaceutically acceptable auxil includes a kit comprising the therapeutically effective iary” as used herein refer to conventional pharmaceutically amount of the first selective adenosine A1 receptor antago acceptable excipient materials Suitable for drug administra nist to be administered orally, Such as in an extended release tion and include any such materials known to a person of formulation, prior to the administration of the first radio skill in the art that are nontoxic and do not interact with other contrast agent. The pharmaceutical combination may also components of a pharmaceutical combination or drug deliv include a first radiocontrast media. ery system in a deleterious manner. 0050. A further embodiment includes a kit comprising the 0058 As used herein, the terms “comprising and therapeutically effective amount of the first selective adenos “including are used herein in their open, non-limiting ine A1 receptor antagonist in a loading dose to be admin SS. istered intravenously followed by a maintenance dose where the first selective adenosine A1 receptor antagonist loading 0059. The term “prodrug” as used herein, represents dose is administered at a time period of between 5 and about derivatives of the compounds disclosed herein that are drug 25 minutes, between about 10 and about 20 minutes, precursors which, following administration to a patient, between about 13 and about 17 minutes, or about 15 minutes release or alter the drug in vivo via a chemical or physi prior to the administration of the first radiocontrast media. ological process. As used herein, the term “prodrug The maintenance dose of the first selective adenosine A1 includes metabolic precursors. In particular, prodrugs are receptor antagonist is administered over a period of up to derivatives of the compounds disclosed herein in which about 48 hours Subsequent to administration of the loading functional groups carry additional constituents which may dose of the first selective A1 receptor antagonist. The be cleaved under physiological conditions in vivo and pharmaceutical combination may also include a first radio thereby releasing the active principle of the compound (e.g., contrast media. a prodrug on being brought to a physiological pH or through an enzyme action is converted to the desired drug form). 0051. The term “intravenously relates to parenteral Prodrugs are bioreversible derivatives of drug molecules application and includes injection or infusion into a vein or used to overcome some barriers to the utility of the parent an artery, without limiting the group of parenteral applica drug molecule. These barriers include, but are not limited to, tion forms. solubility, permeability, stability, presystemic metabolism 0.052 The term "orally’ relates to enteral application and targeting limitations (Bundgaard, 1985'7). Prodrugs, i.e. which includes application of e.g. tablets, drops, pills, cap compounds that when administered to humans by any Sules, pellets, granules, etc. by mouth, without limiting the known route, are metabolised to compounds having formula group of enteral application forms. I are included within the scope of the present disclosure. 0060. The term “pharmaceutically acceptable salts' 0053 “Extended release' refers to a pharmaceutical dos refers to Salt forms that are pharmacologically acceptable age form. The term “extended includes e.g. “prolonged’. and Substantially non-toxic to the Subject being administered “retarded”, “controlled”, “retentive” and “delayed dosage the compounds described herein. In one embodiment the forms, without limiting. pharmaceutically acceptable salts is the mesylate salt. 0054) The term “container” refers to a hermetically sealed storage box for pharmaceuticals. It includes storage 0061 The term “solvates' pertains to the association of boxes for fluid pharmaceuticals as e.g. ampoules, vials, Suitable organic solvent molecules with molecules or ions of flask, dispensers, Syringes, etc. as well as storage boxes for an A1AR. As used herein, the term "solvates' refers both to Solid pharmaceuticals as e.g. blisters, capsules, etc. without stable Solvates, containing a defined number of solvent limiting the group of storage boxes. molecules per molecule of a compound of formula I, and inclusion complexes, which are less stable and contain a 0055. The term “irreversible” as used herein can be used variable number of solvent molecules per molecule of a interchangeably with the term “permanent'. A1AR. 0056 By “pharmaceutically acceptable' such as in the 0062) The term “treatment as used herein refers to recitation of a “pharmaceutically acceptable carrier, a reduction in severity and/or frequency of symptoms, elimi “pharmaceutically acceptable auxiliary” or a “pharmaceuti nation of symptoms and/or underlying cause, prevention of cally acceptable salt' is meant herein a material that is not the occurrence of symptoms and/or their underlying cause, biologically or otherwise undesirable, i.e., the material may and improvement or remediation of damage. Thus, for be incorporated into a pharmaceutical combination admin example, “treatment of a patient involves prevention of a US 2008/0027082 A1 Jan. 31, 2008 particular disorder or adverse physiological event in a sus those skilled in the art of synthetic organic chemistry and ceptible individual as well as treatment of a clinically described, for example, by J. March (1992). symptomatic individual. 0067. A further embodiment herein is a kit comprising in 0063. The “increase in serum creatinine level induced separate or the same containers in a single package phar by radiocontrast media can be transient, persistent or irre maceutical dosage forms for use in combination, compris versible. Reference values for serum creatinine levels (see ing, in one container a pharmaceutical dosage form com http://www.mceus.com/renal/renalcreat.html) in adult prising a first A1AR and in a second container a males lies between about 0.8 mg/dl and about 1.4 mg/dl., in pharmaceutical dosage form comprising a first RM. The kit adult females between about 0.6 mg/dl and about 1.1 mg/dl form is particularly advantageous but not limited to the case and in children between about 0.2 mg/dl and about 1.0 when the separate components must be administered in mg/dl. A range of values of between about 25% to about different dosage forms or are administered at different dos 50% or even higher increase in serum creatinine levels from age intervals. The selective adenosine A1 dosage forms may reference values defines CIN. An "increase in serum crea be injectable formulations like solutions and Suspensions. tinine level” as a measurable physiological parameter The kit may further comprise instructions which will typi defines a disease condition well understood by the skilled cally be written instructions on a package insert, a label, artisan. An increase of any value within in the range of about and/or on other components of the kit, and the intravenous 25% to about 70% in serum creatinine levels defines CIN. In dosage forms are as described herein. Each dosage form may a further embodiment, an increase of about 25, about 30, be individually housed. The present kits will also typically about 35, about 40, about 45, about 50, about 55, about 60, include means for packaging the individual kit components, about 65 and about 70%, and every range which lies in any i.e., the dosage forms, the container, and the written instruc ranges defined by two of the before mentioned values, where tions for use. the lower limit of said range is defined by the minor value 0068. In an embodiment, the therapeutically effective and the upper limit of said range by the higher value, e.g. a amount of A1AR is administered in a form as set forth range of about 25% to about 30%, about 25% to about 35%, above. However, in some cases, a patient may be given each, about 30% to about 60%, etc., defines CIN. This definition the therapeutically effective amount of A1AR and the RM, may in part account for the transient, persistent or irrevers in its own separate dosage form, or a combination of ible elevation of serum creatinine levels. individual “combination' dosage forms containing two or 0064. The “decrease in renal blood flow” induced by more of the present therapeutically effective A1ARs. When radiocontrast media can be transient, persistent or irrevers separate dosage forms are used, the A1AR and the RM can ible. Reference value for blood flow in the kidney is approxi be administered at essentially the same time (concurrently), mately 20% of the cardiac output per minute, thus lies at or at separately staggered times (sequentially). Optimum about 1000 ml/min in a healthy human. A range of values of beneficial effects are achieved when the active blood plasma between about 20% and about 80% or even larger decrease level concentrations of the A1AR agent is maintained during in renal blood flow from reference value defines CIN. A administration of the RM. These optimal beneficial effects “decrease in renal blood flow” as a measurable hemody can be achieved by application of a loading dose following namic parameter defines a disease condition well understood by one or more maintenance doses. The loading dose will by the skilled artisan. A decrease in value or value range rapidly increase the blood plasma level while the mainte within in the range of about 20% to about 80% in renal blood nance dose(s) will then serve to retain the desired blood flow defines CIN. In a further embodiment, a decrease of plasma concentration. A form comprising the A1AR and the about 20, about 25, about 30, about 35, about 40, about 45, RM constitutes, however, a further embodiment. Such a about 50, about 55, about 60, about 65, about 70, about 75, dosage form provides convenience and simplicity for the about 80, about 85 and about 90%, and every value or value patient, thus increasing the chances for patient compliance. range which lies in any ranges defined by two of the before Since two or even more active agents are being used together mentioned values, where the lower limit of said range is in combination, the potency of each of the agents and the defined by the minor value and the upper limit of said range interactive effects achieved by combining them together by the higher value, e.g. a range of about 25% to about 30%, must also be taken into account. A consideration of these about 20% to about 35%, about 30%, about 60%, etc., factors is well within the purview of the ordinarily skilled defines CIN. This definition may in part account for the clinician for the purpose of determining the therapeutically transient, persistent and irreversible decrease in renal blood effective or prophylactically effective dosage amounts. flow. 0069. The term “alkyl refers to the radical of saturated 0065. The renal blood flow can be measured using MRI aliphatic groups, including straight-chain alkyl groups, (magnetic resonance imaging) techniques to determine renal branched-chain alkyl groups, cycloalkyl (alicyclic) groups, blood flow and renal vascular resistance as well as PAH alkyl Substituted cycloalkyl groups, and cycloalkyl Substi (para amino hipuric acid) infusion techniques. tuted alkyl groups. The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, Sulfur 0.066 Any of the foregoing A1AR may be administered or phosphorous atoms replacing one or more carbons of the in the form of a salt, ester, amide, prodrug, active metabolite, hydrocarbon backbone, e.g., oxygen, nitrogen, Sulfur or analog, Solvate or the like, provided that the salt, ester, phosphorous atoms. In further embodiments, a straight chain amide, prodrug, active metabolite, analog, or Solvate is or branched chain alkyl has 30 or fewer carbon atoms in its pharmaceutically acceptable and pharmacologically active backbone (e.g., C-Clso for straight chain, C-Clso for in the present context. Salts, esters, amides, prodrugs, branched chain), and in an embodiment 20 or fewer, e.g. in metabolites, analogs, Solvates and other derivatives of the an embodiment “alkyl may be C-C or in a further embodi active agents may be prepared using procedures known to ment C-C. Likewise, in an embodiment cycloalkyls have US 2008/0027082 A1 Jan. 31, 2008

from 4-10 carbon atoms in their ring structure, and in a 0074 The selective adenosine A1 antagonists described further embodiment cycloalkyls have from 5-7 carbon atoms herein have low lipophilic properties and therewith high in their ring structure, e.g. 5, 6 or 7 carbons in the ring hydrophilic properties resulting in good water solubility. The structure. Moreover, the term “optionally substituted alkyl significantly lower lipophilic properties of the compounds as used throughout the specification and claims is intended described herein distinguish said compounds over other to include both “unsubstituted alkyls' and “substituted known selective A1 antagonists; exemplary data is depicted alkyls', the latter of which refers to alkyl moieties having in the table below. Substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, TABLE 1. for example, halogen, hydroxyl, alkylcarbonyloxy, arylcar bonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, car lipophilic properties of selective adenosine Al antagonists boxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, PGP-factor Permeability (%) LogP (ACD v9.05) alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phos Substance 1 1.5 37.4 1.6 phinato, cyano, amino (including alkylamino, dialkylamino, Substance 2 10.1 27.0 -1.4 arylamino, diarylamino, and alkylarylamino), acylamino KW3902 1.4 31.1 4.2 (including alkylcarbonylamino, arylcarbonylamino, car bamoyl and ureido), amidino, imino, Sulfhydryl, alkylthio. arylthio, thiocarboxylate, Sulfates, Sulfonato, Sulfamoyl, Sul 0075 From the receptor binding and enzyme profiling of fonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, Substance 1 in a wide range of assays, it was concluded that alkylaryl, or an aromatic or heteroaromatic moiety. It will be Substance 1 behaved as a selective adenosine A1 receptor understood by those skilled in the art that the moieties ligand with some phosphodiesterase PDE4 inhibiting activ substituted on the hydrocarbon chain can themselves be ity. The displacement of rolipram by substance 1 from substituted, if appropriate. Cycloalkyls can be further sub phosphodiesterase PDE4 sites correlated with the relative stituted, e.g., with the substituents described above. potency of substance 1 to inhibit this enzyme; the calculated pKi of the PDE4 inhibition was 750 nM; the activities on 0070 An “alkylaryl moiety is an alkyl substituted with other phosphodiesterases (PDE 1, 2, 3, 5 and 6) were at least an aryl (e.g., phenylmethyl (benzyl)). The term “alkyl also 25 fold lower. The phosphodiesterase PDE4 inhibiting activ includes unsaturated aliphatic groups analogous in length ity may be used for titration purposes of patients. The and possible substitution to the alkyls described above, but phosphodiesterase PDE4 inhibiting activity of the com that contain a first double or triple bond respectively. pounds described herein prevents overdosage of the selec 0071. The term “aryl” as used herein, refers to the radical tive A1 antagonist by alarming the patients with self of aryl groups, including 5- and 6-membered single-ring evident, non-serious signals like e.g. headache before aromatic groups that may include from Zero to four heteroa serious events like e.g. CNS convulsion can occur. toms, for example, benzene, pyrrole, furan, thiophene, imi 0.076 Study Protocol dazole, benZOxazole, benzothiazole, triazole, tetrazole, pyra Zole, pyridine, pyrazine, pyridazine and pyrimidine, and the 0077 Study 1 like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. 0078 Animal studies were performed in 60 anesthetized Those aryl groups having heteroatoms in the ring structure rats. Renal hemodynamics were assessed and oxygen ten may also be referred to as "heterocyclic ring”. The aromatic sion within the kidney is measured after application of RM. ring can be substituted at one or more ring positions with Total blood flow to the kidney was quantified by the transit Such substituents as described above, as for example, halo time method and local hemodynamics by laser-Doppler gen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, Flux. In addition, regional oxygen tension of the kidney was alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alky assessed and urine collected to determine urine osmolarity, lcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbo Viscosity and diuresis. Using a recently established tech nyl, phosphate, phosphonato, phosphinato, cyano, amino nique (Wronski, 2003), it is possibly to assess the TGF (including alkylamino, dialkylamino, arylamino, diary response in this setting. The RM significantly reduces renal lamino, and alkylarylamino), acylamino (including alkylcar blood flow and perturbs regional kidney oxygenation. This bonylamino, arylcarbonylamino, carbamoyl and ureido), effect is most likely due to viscous properties, as seen by an amidino, imino, Sulfhydryl, alkylthio, arylthio, thiocarboxy increase in urine viscosity. These RM effects on renal late, Sulfates, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif hemodynamics (renal blood flow and hypoxia) were allevi luoromethyl, cyano, azido, heterocyclyl alkylaryl, or an ated or even reversed by prior administration of the A1AR aromatic or heteroaromatic moiety. Aryl groups can also be antagonists. fused or bridged with alicyclic or heterocyclic rings which 0079. Two protocols were undertaken. In Protocol 1, fluid are not aromatic So as to form a polycycle (e.g., tetralin). restriction took place 24 h before experiments. This led to 0072 The term "heteroatom' as used herein means an augmented concentration of RM in the tubular system. atom of any element other than carbon or hydrogen. In one Catheters, transit-time flowmeters, laser-Doppler probes and embodiment the heteroatom is nitrogen. Sounds for assessing absolute pC) were implanted. Control measurements were recorded, and then the RM was admin 0073. It will be noted that the structure of some of the istered. In Protocol 2, measurements were repeated. In the compounds disclosed herein include asymmetric carbon fluid replete animal, urine Volume, osmolarity and Viscosity atoms. It is to be understood accordingly, that the isomers arising from Such asymmetry (e.g., all enantiomers and were determined. Control measurements were recorded, diastereomers) are included within the scope of the disclo then, the RM was administered. Sure, unless indicated otherwise. Some isomers can be 0080 Renal blood flow, oxygen tension and regional obtained in Substantially pure form by classical separation blood flows and the TGF response in rats was assessed after techniques and by Stereochemically controlled synthesis. water restriction took place. Reduced plasma Volume is a US 2008/0027082 A1 Jan. 31, 2008 generally recognized risk factor, since CM is concentrated in When required, modifications were made to the protocols. the tubules during antidiuresis. Total and regional RBF and oxygen tension in the renal medulla and cortex were assessed according to prior studies 0081 FIG. 1 depicts the protocols. In the top panel, the (Flemming, 2000 and 2001') by measuring laser-Doppler RM was given after control measurements (N=15). The fluxes and direct assessment of pC). After the calculation of bottom panel depicts the series where the A1AR is given individual mean values of every parameter, these mean prior to the RM (N=15). values of every animal were used to calculate group aver 0082 In order to collect sufficient urine, volume repleted ages and Standard errors of each controvintervention group. rats were used. Diuresis, urine osmolality and Viscosity were The latter were used to test differences for statistical sig assessed for control and the RM (N=15, Error! Reference nificance, in an embodiment levels of less than 0.05 are Source not found. top panel), and for control, the A1AR and considered to indicate significance. The test methods used the A1AR--the RM (N=15, Error! Reference source not were chosen with respect to the parameters of the underlying found. bottom panel). All experiments were performed on data. adult, male Wistar rats obtained from the animal facility of the institute. The rats were housed in groups. All animals 0083) Study 2 were randomly distributed between the protocols. The ani (984 A study analogous to the one described by Yao mals were identified by cage number. A standard rat diet (2000") with selected variations in the protocol was per (Altromin 1324. Altromin GmbH, D-32791 Lage) served as formed. In contrast to the Yao study, chronic as well as acute chow. Feeding and drinking was discontinued approx. 12 experiments were carried out. Indometacine is used in hours before the surgery for protocol 1. In protocol 2, addition to L-name (N-(p-nitro-L-arginine methyl ester) in drinking was allowed ad libitum. Drinking water was offered this study. ad libitum, except for a time period of 12 h before CM application. Thus, the animals were water deprived. In protocol 2, water was offered ad libitum until immediately EXPERIMENTAL before the experiment. Granulated textured wood (Granulat 0085 1. Effects of Acute Application of Substance 1 on A2, J. Brandenburg, D-49424 Goldenstedt) was used as bedding material for the cages. The cages were changed and Diuresis and Natriuresis Following Radiocontrast Media cleaned every day between 6:00 and 8:00 a.m. During the (Diatrizoate) in Anesthetized Rats acclimatization, the animals were kept in groups of 3-5 0086) The radiocontrast media-dependent acute kidney animals in MAKROLON cages each (type 4) at a room failure was induced using an experimental protocol based on temperature of 22° C.it3° C. and a relative humidity of that published by the group of Osswald.’ Male Sprague 60%+20%. Deviation may be caused, for example, during Dawley rats of approximately 300 g body weight were the cleaning procedures. Anesthesia was introduced and acclimatized for at least 1 week before the start of the maintained by urethane. Rats were placed on a heated table chronic pretreatment with the nitric oxide synthase inhibitor to maintain body temperature at 37° C. throughout the N-nitro-L-arginine methyl ester (L-NAME for 7-9 weeks at Surgery. The body temperature was controlled during the a daily dose of 5 mg/kg). For the experiments, the overnight study. After an incision in the left groin, the femoral artery fasted rats (which had continued free access to drinking was carefully prepared and cannulated with a polypropylene water) were anesthetized with Inactin (80 mg/kg, given i.p. catheter (PP 10) to measure the renal perfusion pressure as a bolus). Catheters were placed (i) in the trachea, (ii) in (RPP). Another catheter (PP50) of the same material was one jugular vein (for radiocontrast medium administration, placed into the carotid artery to measure systemic blood and background saline infusion; see below), (iii) in the other pressure (BP) and heart rate (HR). Finally, an inflatable cuff jugular vein for vehicle or Sunstance 1 administration, (iv) in was placed around the abdominal aorta; one above and the the carotid artery for blood sampling, and part of the other below the origin of the renal arteries. A servo con background Saline infusion; see below), and (v) in the trolled inflation of the proximal cuff allowed it to reduce and bladder for urine collection. The rats were kept on a heated maintain renal perfusion pressure at a preset level. Two 500 table to maintain their body temperature at 37° C. After um diameter optical fibers (Moore instruments, GB) were collecting urine samples for 60-90 min for baseline mea implanted into the cortex and the medulla of left kidney, and Surements, the animals received vehicle or Substance 1 as an ultrasound transit time flow probe (1RB, Transonic Sys follows: a loading bolus of 0.15, or 1.5 mg substance 1 per tems inc, USA) was placed around the renal artery of the kg, or vehicle, in a Volume of 1 mukg, was applied intra same kidney to determine local blood flows (LFC and LFM venously, followed by a continuous intravenous infusion at respectively) and total kidney blood flow (RBF). pC) was a rate of 1.5, and 15 pg. Substance 1 per kg per min, or likewise locally determined. Local blood flow was measured vehicle, in a volume of 11 uL/kg min until the end of the and processed by a laser-Doppler flowmeter (Moore Instru experiment. With these dose regimens steady-state plasma ments, GB). The arterial catheter was connected to the levels of substance 1 were 59-23, and 314+36 ng/mL, calibrated pressure transducer. The inflatable cuff was con respectively. Ten minutes after the start of the substance 1 nected to an extracorporal servo control system and the flow (or vehicle) treatment, diatrizoate (meglumine salt, Urolux, probes were connected via extension cables to the Flowme 0.61 g diatrizoate/mL, corresponding to a total iodine con ters. Oxygen partial pressure sensing probes were positioned tent of 290 mg/mL, Sanochemia Diagnostics, Neuss, Ger in a corresponding manner. After analog to digital conver many), prewarmed at body temperature, was infused iv over sion all data (BP RPP. RBF, LFC, LFM, local oxygen 3 min at a dose of 2.55 mL/kg, corresponding to 740 mg tension) were stored on-line in ASCII format by a computer iodine/kg (the timepoint of contrast medium administration system (IBM compatible AT). After implantation and stabi was defined as to). A background saline solution was infused lization, the experiment was started. The test solutions were from the beginning and maintained at a rate of ~1.2 mL/h per infused. After 5 min equilibrium, measurements of RBF, 100 g until the end of the experiments (0.24 mL/h via the local fluxes and local pO was commenced. Then, a 5 min arterial catheter, and 0.96 mL/h via the venous line). This step response was obtained to assess TGF. Urine was col infusion was required to compensate for the Volume loss due lected 35 minto evaluate diuresis, osmolality and viscosity. to the operation, and the Subsequent blood sampling, but US 2008/0027082 A1 Jan. 31, 2008

also to insure the patency of the arterial catheter between the formed using adult male 3-4 months old Wistar rats. Body blood sampling timepoints. Urine samples were collected weight ranged from 250 to 400 g. The rats received a according to the following schedule: baseline (60-90 min standard chow diet. Feeding and drinking was discontinued preceding the start of Substance 1, or vehicle, administra approx. 12 hours before the Surgery. The animals were tion), to-30 min (0.5 h timepoint), 30-60 min (1 h timepoint), 60-120 min (2 h timepoint), and 120-180 min (3 h time anesthetized by intraperitoneal injection ofurethane Solution point). Plasma samples were taken at the end of each of the (2% in water, 6 ml per kg), and placed on a heated table to above periods. The measured values of urine volume, and maintain body temperature at 37°C. throughout Surgery and urine levels of Na" were used to calculate the rates of Subsequent experiments. After an incision in the left groin diuresis and natriuresis over the time intervals mentioned the femoral artery was carefully prepared and cannulated to above. measure the mean arterial blood pressure. Another catheter 0087 As shown in Table 2, substance 1 treatment pro was placed into the carotid artery for administration of duced a large and significant increase in urine production in contrast medium. Finally, an inflatable cuff was placed the first 30 min following contrast medium administration, around the abdominal aorta above the origin of the renal as compared to the vehicle control group; in spite of the fact arteries. A servo controlled inflation of the cuff allowed for that the rate of diuresis then returned towards lower values the reduction and maintenance of the renal perfusion pres in all groups, a stimulating effect of Substance 1 persisted for sure at a preset levels. Two 500 um diameter optical fibers at least 3 h. Because radiocontrast media are eliminated via were implanted into the cortex and the outer medulla of left the urine, this diuretic effect of substance 1 is likely to kidney to determine local laser-Doppler fluxes and an ultra strongly promote their elimination and thus to limit their sound transit time flow probe was placed around the renal toxicity. artery of the same kidney to determine total kidney blood

TABLE 2 Effects of substance 1 on diuresis following diatrizoate administration in anesthetized in rats, Values are expressed in mL per kg body weight per h, and represent means it SEM (n = 14 - 24). Statistical significance was evaluated using one-way analysis of variance followed by a Bonferroni test. n.s.: non significant: * : P < 0.05; **: P & 0.01 and ***: P & 0.001 wS. vehicle controls.

Time after Vehicle Substance 1 Substance 1 CM control Low dose P vs. vehicle high dose P wS. vehicle

O.S 17.10 - 142 27.31 - 236 ::::::::: 28.01 - 2.02 ::::::::: 1 h 3.76 O.31 3.87 0.40 l.S. 4.97 O.30 2h 1.96 - 0.15 3.34 - 0.42 :::::: 3.13 - 0.27 3 h 2.14 - 0.40 3.54 OSO l.S. 3.11 - 0.36 l.S.

0088. Likewise, substance 1 caused a pronounced and flow (RBF). Renal oxygen levels (oxygen partial pressure= Sustained increase in Sodium excretion over values seen in pO) was likewise determined locally (cortical and medul the vehicle control group (Table 3). Chloride excretion was lary pC, respectively: OxyLite, Oxford Optronics). After stimulated by Substance 1 in a similar way, whereas potas implantation and stabilization, the experiment was started by sium excretion was not relevantly affected by the compound measuring hemodynamic and oxygenation parameters under throughout eh experiment (not shown). baseline conditions. Vehicle or Substance 1 (5 mg/kg as an

TABLE 3 Effects of Substance 1 on Sodium excretion following diatrizoate administration in anesthetized in rats, Values are expressed in Imol per kg body weight per h, and represent means it SEM (n = 14 - 24). Statistical significance was evaluated using one-way analysis of variance followed by a Bonferroni test. n.s.: non significant: *: P < 0.05; **: P < 0.01; and ***: P & 0.001 vs. vehicle controls.

Time after Vehicle Substance 1 Substance 1 CM control Low dose P vs. vehicle high dose P vs. vehicle

O.S 1332 184 3039 354 ::::::::: 3301 - 306 ::::::::: 1 h 185 - 39 338 81 l.S. S2O 77 :::::: 2h 153 - 40 613 121 :::::: 591 88 :::::: 3h 329 72 842 - 121 :::::: 830 - 91 ::::::

0089 2. Effects of Acute Application of Substance 1 on intravenous bolus) were then administered. New measure Renal Blood Flow and Oxygenation Following Radiocon ments were performed, and 30 min after vehicle or substance trast Media (Iodixanol) in Anesthetized Rats 1 administration, lodixanol (Visipaque 320; 1.5 mL i.a.: 0090 The experimental protocol was based on a previ Amersham Buchier, Braunschweig, Germany), or vehicle ously published methodology. The experiments were per was applied. After another 20 min, measurements were US 2008/0027082 A1 Jan. 31, 2008

repeated (over a period of 20 min, shown in figures below). variations of the disclosed embodiments will become appar The experimental groups were thus: 1. Vehicle+Vehicle ent to those of ordinary skill in the art upon reading the (control), Vehicle+Visipaque, and Sunstance 1+Visipaque. foregoing disclosure. The inventors expect skilled artisans to 0.091 Substance 1 did not modify hemodynamic param employ such variations as appropriate (e.g., altering or eters (arterial blood pressure, RBF) before the Visipaque combining features or embodiments), and the inventors challenge (not shown). Following Visipaque administration, intend for the invention to be practiced otherwise than as a strong, transient increase in mean arterial blood pressure specifically described herein. was observed (by ~35 mm Hg), which lasted for approxi mately 10 min, and was partially prevented by Sunstance 1 0097 Accordingly, this invention includes all modifica (not shown). In the Vehicle+Visipaque group, renal cortical tions and equivalents of the Subject matter recited in the blood flow showed a short initial increase which was fol claims appended hereto as permitted by applicable law. lowed by a progressive and significant decrease, as com Moreover, any combination of the above described elements pared to the vehicle control group (FIG.3). In contrast, in the in all possible variations thereof is encompassed by the presence of substance 1, cortical blood flow displayed a invention unless otherwise indicated herein or otherwise Sustained and significant increase, blood flow remaining clearly contradicted by context. significantly elevated until the end of the measurement period as compared to the Vehicle+Visipaque group (FIG. 0098. The use of individual numerical values are stated as 3). Cortical vascular conductance was rapidly and stably approximations as though the values were preceded by the lowered by Visipaque, whereas Substance 1 maintained this word “about or “approximately.” Similarly, the numerical parameter at levels seen in the vehicle control group (FIG. values in the various ranges specified in this application, 4). Similarly, medullary blood flow transiently rose (for ~3 unless expressly indicated otherwise, are stated as approxi min) after Visipaque injection, and then fell below control mations as though the minimum and maximum values levels; concomitantly, medullary vascular conductance was within the stated ranges were both preceded by the word rapidly and stably depressed by Visipaque; Substance 1 “about' or “approximately.” In this manner, variations treatment only partially (but significantly) prevented these above and below the stated ranges can be used to achieve effects (not shown). Finally, Substance 1 caused a significant Substantially the same results as values within the ranges. As increase in cortical pO, which persisted until the end of the used herein, the terms “about and “approximately' when experiment (FIG. 5). referring to a numerical value shall have their plain and 0092. Overall, these observations show that substance 1 ordinary meanings to a person of ordinary skill in the art to improves renal hemodynamics and oxygenation, thus at which the disclosed subject matter is most closely related or least partially antagonizing the potentially deleterious the art relevant to the range or limitation at issue. The effects of the radiocontrast medium iodixanol. amount of broadening from the strict numerical boundary depends upon many factors. For example, Some of the 0093 U.S. patent application Ser. No. filed on factors which may be considered include the criticality of Jun. 19, 2007 and claiming the benefit of U.S. Provisional the element and/or the effect a given amount of variation will Patent Application Nos. 60/805,168 and 60/805,173 filed on have on the performance of the claimed Subject matter, as Jun. 19, 2006 and U.S. Provisional Application No. 60/871, well as other considerations known to those of skill in the 062 filed on Dec. 20, 2006 is hereby incorporated by art. As used herein, the use of differing amounts of signifi reference in its entirety. cant digits for different numerical values is not meant to 0094 All references, including publications, patent appli limit how the use of the words “about' or “approximately cations, and patents, cited herein are hereby incorporated by will serve to broaden a particular numerical value or range. reference to the same extent as if each reference were Thus, as a general matter, “about' or “approximately individually and specifically indicated to be incorporated by broaden the numerical value. Also, the disclosure of ranges reference and were set forth in its entirety herein. is intended as a continuous range including every value 0.095 The use of the terms “a” and “an and “the' and between the minimum and maximum values plus the broad similar referents in the context of this disclosure (especially ening of the range afforded by the use of the term “about in the context of the following claims) are to be construed to or “approximately.” Thus, recitation of ranges of values cover both the singular and the plural, unless otherwise herein are merely intended to serve as a shorthand method indicated herein or clearly contradicted by context. All of referring individually to each separate value falling within methods described herein can be performed in any suitable the range, unless otherwise indicated herein, and each sepa order unless otherwise indicated herein or otherwise clearly rate value is incorporated into the specification as if it were contradicted by context. The use of any and all examples, or individually recited herein. exemplary language (e.g., Such as, preferred, preferably) provided herein, is intended merely to further illustrate the 0099] It is to be understood that any ranges, ratios and content of the disclosure and does not pose a limitation on ranges of ratios that can be formed by, or derived from, any the scope of the claims. No language in the specification of the data disclosed herein represent further embodiments should be construed as indicating any non-claimed element of the present disclosure and are included as part of the as essential to the practice of any aspect of the present disclosure as though they were explicitly set forth. This includes ranges that can be formed that do or do not include disclosure. a finite upper and/or lower boundary. Accordingly, a person 0.096 Alternative embodiments of the claimed disclosure of ordinary skill in the art most closely related to a particular are described herein, including the best mode known to the range, ratio or range of ratios will appreciate that such values inventors for practicing the claimed invention. Of these, are unambiguously derivable from the data presented herein. US 2008/0027082 A1 Jan. 31, 2008

CITED DOCUMENTS 0115 ' EP 0022 744 filed by Schering, EP 0023992 filed by Bracco Industria Chimica, EP 0026 281 filed by 0100 ' Andrew E. Berg KJ, “Nephrotoxic effects of Bracco Industria Chimica, EP 0 033 426 filed by Univ. X-ray contrast media, J Toxicol Clin Toxicol. 2004; California, EP 0108.638 filed by Nyegaard, EP 0317 492 42(3):325-32 filed by Schering, WO 87/00757 filed by Cook Imaging 0101 http://www.fpnotebook.com/REN70.htm and Corporation, WO 89/08101 filed by Mallinckrodt, U.S. http://www.fpnotebook.com/REN38.htm (15 Jun. 2006) Pat. No. 2,776,241 filed by Schering, U.S. Pat. No. 3.290,366 filed by Mallinckrodt, U.S. Pat. No. 3,360,436 0102) Ueda J, Nygren A. Hansell P. Ulfendahl H R. filed by Eprova, U.S. Pat. No. 5,349,085 filed by “Effect of intravenous contrast media on proximal and Nycomed, GB 1321 591 filed by Nyegaard, DE 2547789 distal tubular hydrostatic pressure in the rat kidney'. Acta filed by Savag, DE 2726 196 filed by Nyegaard, DE 2909 Radiol 1993: 34(1): 83-87 439 filed by Schering 0103) Olivera A. Lamas S. Rodriguez-Puyol D. Lopez 0116 '7 Bundgaard, H. (editor), “Design of Prodrugs, Novoa J M. “Adenosine induces mesangial cell contrac Elsevier, 1985 tion by an A1-type receptor. Kidney Int 1989; 35(6): 1300-1305 0117) http://www.mceus.com/renal/renalcreat.html (15 Jun. 2006) 0104) Porter, "Contrast-associated nephropathy” Am. J. 0118 ' Advanced Organic Chemistry: Reactions, Cardiol. (1989), 64(9), 22E-26E Mechanisms and Structure, 4th Edition, New York: Wiley 01.05) Nikolsky E, Aymong E. D. Dangas G, Mehran R. Interscience, 1992 "Radiocontrast nephropathy: identifying the high-risk 0119) Wronski T. Seeliger E. Persson P B, Former C, patient and the implications of exacerbating renal func Fichtner C. Scheller J et al. The step response: a method tion”, Rev Cardiovasc Med 2003; 4 Suppl 1:S7-S14 to characterize mechanisms of renal blood flow autoregu 0106) a) Shammas et al., “Aminophylline does protect lation. Am J Physiol Renal Physiol 2003; 285(4): F758 against radiocontrast nephropathy in patients undergoing F764 percutaneous angiographic procedures. J Invasive Car 0120 ° a) Flemming B, Arenz N. Seeliger E. Wronski T, diol (2001), 13(11), 738-40; b) Welch et al. “Adenosine A1 receptor antagonists in the kidney: effects in fluid Steer K. Persson P B. Time-dependent autoregulation of retaining disorders’. Curr Opin Pharmacol (2002), 2(2), renal blood flow in conscious rats. J Am Soc Nephrol 165-70; c) Huber et al. “Effect of theophylline on contrast 2001; 12(11):2253-2262 and b) Flemming B, Seeliger E. material-nephropathy in patients with chronic renal insuf Wronski T. Steer K, Arenz N. Persson P B. Oxygen and ficiency: controlled, randomized, double-blinded study’. renal hemodynamics in the conscious rat. J Am Soc Radiology (2002), 223(3), 772-9 Nephrol 2000: 11(1):18-24 0121 ° Erley C M, Heyne N, Burgert K, Langanke J, 01.07 Erley et al., “Adenosineantagonist theophylline Risler T. & Osswald H (1997): Prevention of Radiocon prevents the reduction of glomerularfiltration rate after trast-Induced Nephropathy by Adenosine Antagonists in contrast media application', Kidney Int. (1994), 45, 1425 Rats with Chronic Nitric Oxide Deficiency. J. Am. Soc. 31 Nephrol. 8:1125-1132 0108) K. Akawara et al., “Role of adenosine in the renal responses to contrast medium', Kidney Int. (1996), 49(5), We claim: 1199-2O6 1. A method of preventing radiocontrast media induced 0109) ' K. Yao et al., “The selective adenosine A1 nephropathy in mammals or humans comprising adminis receptor antagonist KW-3902 prevents radiocontrast tering a therapeutically effective amount of a first selective media-induced nephropathy in rats with chronic nitric adenosine A1 antagonist. oxide deficiency’. Europ J of Pharmacology (2001) 414, 2. The method of claim 1 wherein the first selective 99-104 adenosine A1 receptor antagonist is administered intrave nously in a loading dose followed by Subsequent adminis 0110 '' Greiner, Dissertation “Prophylaxis of Contrast tration as a maintenance dose, wherein the loading dose is Induced Nephropathy with Theophylline and Acetylcys administered between about five minutes and about twenty teine in ICU-Patients', TU München, 19 Oct. 2005 five minutes prior to the administration of a first radiocon 0111 ° H. Thomas Lee, Michael Jan, Soo Chan Bae, Jin trast media and wherein the maintenance dose is adminis Deok Joo, Farida R. Goubaeva, Jay Yang, and Mihwa tered over a period of less than about 48 hours subsequent Kim, “A adenosine receptor knockout mice are protected to administration of the loading dose. against acute radiocontrast nephropathy in Vivo”. Am J 3. The method of claim 2 wherein the maintenance dose Physiol Renal Physiol 290: F1367-F1375, 2006 is administered such that the plasma level of the first selective A1 adenosine antagonist is maintained between 0112 EP 1 386 609, filed by CV. Therapeutics about 10 ng/ml and about 500 ng/ml. 4. The method of claim 1 wherein the first adenosine A1 0113 '' WO99/31101, filed by Univ. South Florida receptor antagonist is administered orally prior to the admin 0114) WO99/62518, WO 01/39777, WO 02/057267, istration of a first radiocontrast media. all filed by Osi Pharmaceuticals and WO 2004/094428 5. The method of claim 1 wherein the first radiocontrast filed by Solvay Pharmaceuticals media is not administered until the plasma concentration US 2008/0027082 A1 Jan. 31, 2008 level of the first adenosine A1 receptor antagonist has and pharmaceutically acceptable salts of the foregoing, reached a concentration of between about 10 ng/ml and pharmaceutically acceptable prodrugs of the foregoing, about 500 ng/ml. and pharmaceutically acceptable Solvates of the fore 6. The method of claim 1 wherein the first selective going. adenosine A1 receptor antagonist is selected from pyrrolo 9. The method of claim 8 wherein the first selective 2.3dpyrimidine derivatives of formula I adenosine A1 receptor antagonist is selected from the group consisting of 4-(2-phenyl-7H-pyrrolo2.3-opyrimidin-4- yl)amino-trans-cyclohexanol methanesulfonate, (4S)-4-hy droxy-1-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4-yl)-L- R1 N1 R2 prolinamide methanesulfonate, pharmaceutically acceptable R5 prodrugs of the foregoing, and pharmaceutically acceptable Solvates of the foregoing. N1 n 10. The method of claim 9 wherein the first selective adenosine A1 receptor antagonist is 4-(2-phenyl-7H-pyr l 2 / R4 R3 N N rolo2,3-dipyrimidin-4-yl)amino-trans-cyclohexanol meth anesulfonate, pharmaceutically acceptable prodrugs of the foregoing, and pharmaceutically acceptable solvates of the wherein foregoing. i) R1 and R2 are each independently selected from a 11. The method of claim 9 wherein the first selective hydrogen atom, an optionally Substituted alkyl, option adenosine A1 receptor antagonist is (4S)-4-hydroxy-1-(2- ally substituted aryl, or optionally substituted alkylaryl phenyl-7H-pyrrolo2,3-dipyrimidin-4-yl)-L-prolinamide moiety or together form an optionally Substituted het methanesulfonate, pharmaceutically acceptable prodrugs of erocyclic ring; the foregoing, and pharmaceutically acceptable Solvates of the foregoing. ii) R3 is selected from a hydrogen atom or an optionally 12. The method of claim 2 wherein the first radiocontrast Substituted alkyl, optionally Substituted aryl, or option media is an iodinated or gadolinium-based radiocontrast ally substituted alkylaryl moiety; media selected from the group consisting of bunaiod, bili iii) R4 and R5 are each independently selected from a gram, bilimiro, bilopaque, cholimil, ethiodol, diatrast, halogen atom, a hydrogen atom or an optionally Sub dionosil, falignost, gadobutrol, gadodiamide, gadopentetate stituted alkyl, optionally substituted aryl, or optionally dimeglumine, gastrografin, hexabrix, hippodin, mangafo substituted alkylaryl moiety, or R4 and R5 together dipir, amidotrizoate, ethiodized oil, imagopaque, iodamide, form an optionally Substituted heterocyclic or option iodipamide, iodixanol, iodophene, iophendylate, iomeron, ally Substituted carbocyclic ring: iomeprol, iopamidol, iopanoic acid, iopiperidol, iophendy late, iopromide, iopydol, iosimenol, iothalamic acid, iotro and pharmaceutically acceptable salts of the foregoing, lan, ioversol, ioxilan, ioxaglic acid, isopaque, ipodate, pharmaceutically acceptable prodrugs of the foregoing, meglumine iothalamate, meglumine acetrizoate, meglumine and pharmaceutically acceptable Solvates of the fore diatrizoate, metrizamide, myelotrast, omnipaque, osbil, opti going. ray, optojod, opacoron, perflutren, phenobutiodil, phentetio 7. The method of claim 6 wherein the first selective thalein sodium, priodax, propyliodone, skiodan, Sodium adenosine A1 receptor antagonist is selected from pyrrolo iodomethamate, sodium diatrizoate, telepaque, teridax, tet 2.3dpyrimidine derivatives of formula I, wherein rabrom, thorotrast, triognost, 1.3.5-Tri-n-hexyl-2,4,6-tri iodobenzene, tyropanoate, visipaque or xenetix, pharmaceu i) R1 and R2 are each independently selected from a tically acceptable salts of any of the foregoing, prodrugs of hydrogen atom, an optionally Substituted alkyl or any of the foregoing, and Solvates of any of the foregoing. together form an optionally substituted heterocyclic 13. A method of preventing a radiocontrast media induced ring: increase in serum creatinine levels in mammals or humans ii) R3 is a hydrogenatom or an optionally Substituted aryl, comprising administering a therapeutically effective amount of a first selective adenosine A1 antagonist. iii) R4 and R5 are each independently selected from a 14. The method of claim 13 wherein the first selective halogen atom or a hydrogen atom; adenosine A1 receptor antagonist is administered intrave and pharmaceutically acceptable salts of the foregoing, nously in a loading dose followed by Subsequent adminis pharmaceutically acceptable prodrugs of the foregoing, tration as a maintenance dose, wherein the loading dose is and pharmaceutically acceptable Solvates of the fore administered between about five minutes and about twenty going. five minutes prior to the administration of a first radiocon 8. The method of claim 7 wherein the selective adenosine trast media and wherein the maintenance dose is adminis A1 receptor antagonist is selected from pyrrolo2.3dpyri tered over a period of less than about 48 hours subsequent midine derivatives of formula I, wherein to administration of the loading dose. 15. The method of claim 14 wherein the maintenance dose i) R1 is a hydrogen and R2 is an optionally substituted is administered such that the plasma level of the first cyclohexyl ring, or R1 and R2 together form an option selective A1 adenosine antagonist is maintained between ally Substituted pyrrolidine ring; about 10 ng/ml and about 500 ng/ml. ii) R3 is a phenyl ring, 16. The method of claim 13 wherein the first adenosine A1 receptor antagonist is administered orally prior to the admin iii) R4 and R5 are each a hydrogen atom; istration of a first radiocontrast media. US 2008/0027082 A1 Jan. 31, 2008

17. The method of claim 13 wherein the first radiocontrast ii) R3 is a phenyl ring, media is not administered until the plasma concentration level of the first adenosine A1 receptor antagonist has iii) R4 and R5 are each a hydrogen atom; reached a concentration of between about 10 ng/ml and and pharmaceutically acceptable salts of the foregoing, about 500 ng/ml. pharmaceutically acceptable prodrugs of the foregoing, 18. The method of claim 13 wherein the first selective and pharmaceutically acceptable Solvates of the fore adenosine A1 receptor antagonist is selected from pyrrolo going. 2.3dpyrimidine derivatives of formula I 21. The method of claim 20 wherein the first selective adenosine A1 receptor antagonist is selected from the group consisting of 4-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4- yl)amino-trans-cyclohexanol methanesulfonate, (4S)-4-hy R1 N1 R2 droxy-1-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4-yl)-L- R5 prolinamide methanesulfonate, pharmaceutically acceptable prodrugs of the foregoing, and pharmaceutically acceptable N1 N Solvates of the foregoing. l 2 M R4 22. The method of claim 21 wherein the first selective R3 N N adenosine A1 receptor antagonist is 4-(2-phenyl-7H-pyr rolo2.3-pyrimidin-4-yl)amino-trans-cyclohexanol meth anesulfonate, pharmaceutically acceptable prodrugs of the wherein foregoing, and pharmaceutically acceptable solvates of the i) R1 and R2 are each independently selected from a foregoing. hydrogen atom, an optionally Substituted alkyl, option 23. The method of claim 21 wherein the first selective ally substituted aryl, or optionally substituted alkylaryl adenosine A1 receptor antagonist is (4S)-4-hydroxy-1-(2- moiety or together form an optionally Substituted het phenyl-7H-pyrrolo2.3-opyrimidin-4-yl)-L-prolinamide erocyclic ring; methanesulfonate, pharmaceutically acceptable prodrugs of ii) R3 is selected from a hydrogen atom or an optionally the foregoing, and pharmaceutically acceptable Solvates of Substituted alkyl, optionally Substituted aryl, or option the foregoing. ally substituted alkylaryl moiety; 24. The method of claim 14 wherein the first radiocontrast media is an iodinated or gadolinium-based radiocontrast iii) R4 and R5 are each independently selected from a media selected from the group consisting of bunaiod, bili halogen atom, a hydrogen atom or an optionally Sub gram, bilimiro, bilopaque, cholimil, ethiodol, diatrast, stituted alkyl, optionally substituted aryl, or optionally dionosil, falignost, gadobutrol, gadodiamide, gadopentetate substituted alkylaryl moiety, or R4 and R5 together dimeglumine, gastrografin, hexabrix, hippodin, mangafo form an optionally Substituted heterocyclic or option dipir, amidotrizoate, ethiodized oil, imagopaque, iodamide, ally Substituted carbocyclic ring: iodipamide, iodixanol, iodophene, iophendylate, iomeron, iomeprol, iopamidol, iopanoic acid, iopiperidol, iophendy and pharmaceutically acceptable salts of the foregoing, late, iopromide, iopydol, iosimenol, iothalamic acid, iotro pharmaceutically acceptable prodrugs of the foregoing, lan, ioversol, ioxilan, ioxaglic acid, isopaque, ipodate, and pharmaceutically acceptable Solvates of the fore meglumine iothalamate, meglumine acetrizoate, meglumine going. diatrizoate, metrizamide, myelotrast, omnipaque, osbil, opti 19. The method of claim 18 wherein the first selective ray, optojod, opacoron, perflutren, phenobutiodil, phentetio adenosine A1 receptor antagonist is selected from pyrrolo thalein sodium, priodax, propyliodone, skiodan, Sodium 2.3dpyrimidine derivatives of formula I, wherein iodomethamate, sodium diatrizoate, telepaque, teridax, tet i) R1 and R2 are each independently selected from a rabrom, thorotrast, triognost, 1.3.5-Tri-n-hexyl-2,4,6-tri hydrogen atom, an optionally Substituted alkyl or iodobenzene, tyropanoate, visipaque or xenetix, pharmaceu together form an optionally substituted heterocyclic tically acceptable salts of any of the foregoing, prodrugs of ring: any of the foregoing, and Solvates of any of the foregoing. 25. A method of preventing a radiocontrast media induced ii) R3 is a hydrogenatom or an optionally Substituted aryl, decrease in renal blood flow in mammals or humans com iii) R4 and R5 are each independently selected from a prising administering a therapeutically effective amount of a halogen atom or a hydrogen atom; first selective adenosine A1 antagonist. 26. The method of claim 25 wherein the first selective and pharmaceutically acceptable salts of the foregoing, adenosine A1 receptor antagonist is administered intrave pharmaceutically acceptable prodrugs of the foregoing, nously in a loading dose followed by Subsequent adminis and pharmaceutically acceptable Solvates of the fore tration as a maintenance dose, wherein the loading dose is going. administered between about five minutes and about twenty 20. The method of claim 19 wherein the selective adenos five minutes prior to the administration of a first radiocon ine A1 receptor antagonist is selected from pyrrolo2.3d trast media and wherein the maintenance dose is adminis pyrimidine derivatives of formula I, wherein tered over a period of less than about 48 hours subsequent i) R1 is a hydrogen and R2 is an optionally substituted to administration of the loading dose. cyclohexyl ring, or R1 and 27. The method of claim 26 wherein the maintenance dose is administered such that the plasma level of the first R2 together form an optionally substituted pyrrolidine selective A1 adenosine antagonist is maintained between ring: about 10 ng/ml and about 500 ng/ml. US 2008/0027082 A1 Jan. 31, 2008

28. The method of claim 25 wherein the first adenosine A1 R2 together form an optionally substituted pyrrolidine receptor antagonist is administered orally prior to the admin ring: istration of a first radiocontrast media. 29. The method of claim 25 wherein the first radiocontrast ii) R3 is a phenyl ring, media is not administered until the plasma concentration iii) R4 and R5 are each a hydrogen atom; level of the first adenosine A1 receptor antagonist has reached a concentration of between about 10 ng/ml and and pharmaceutically acceptable salts of the foregoing, about 500 ng/ml. pharmaceutically acceptable prodrugs of the foregoing, 30. The method of claim 25 wherein the first selective and pharmaceutically acceptable Solvates of the fore adenosine A1 receptor antagonist is selected from pyrrolo going. 2.3dpyrimidine derivatives of formula I 33. The method of claim 32 wherein the first selective adenosine A1 receptor antagonist is selected from the group consisting of 4-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4- yl)amino-trans-cyclohexanol methanesulfonate, (4S)-4-hy droxy-1-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4-yl)-L- prolinamide methanesulfonate, pharmaceutically acceptable prodrugs of the foregoing, and pharmaceutically acceptable Solvates of the foregoing. 34. The method of claim 33 wherein the first selective adenosine A1 receptor antagonist is 4-(2-phenyl-7H-pyr rolo2.3-opyrimidin-4-yl)amino-trans-cyclohexanol meth anesulfonate, pharmaceutically acceptable prodrugs of the wherein foregoing, and pharmaceutically acceptable solvates of the i) R1 and R2 are each independently selected from a foregoing. hydrogen atom, an optionally Substituted alkyl, option 35. The method of claim 33 wherein the first selective ally substituted aryl, or optionally substituted alkylaryl adenosine A1 receptor antagonist is (4S)-4-hydroxy-1-(2- moiety or together form an optionally Substituted het phenyl-7H-pyrrolo2,3-dipyrimidin-4-yl)-L-prolinamide erocyclic ring; methanesulfonate, pharmaceutically acceptable prodrugs of ii) R3 is selected from a hydrogen atom or an optionally the foregoing, and pharmaceutically acceptable solvates of Substituted alkyl, optionally Substituted aryl, or option the foregoing. ally substituted alkylaryl moiety; 36. The method of claim 26 wherein the first radiocontrast media is an iodinated or gadolinium-based radiocontrast iii) R4 and R5 are each independently selected from a media selected from the group consisting of bunaiod, bili halogen atom, a hydrogen atom or an optionally Sub gram, bilimiro, bilopaque, cholimil, ethiodol, diatrast, stituted alkyl, optionally substituted aryl, or optionally dionosil, falignost, gadobutrol, gadodiamide, gadopentetate substituted alkylaryl moiety, or R4 and R5 together dimeglumine, gastrografin, hexabrix, hippodin, mangafo form an optionally Substituted heterocyclic or option dipir, amidotrizoate, ethiodized oil, imagopaque, iodamide, ally Substituted carbocyclic ring: iodipamide, iodixanol, iodophene, iophendylate, iomeron, and pharmaceutically acceptable salts of the foregoing, iomeprol, iopamidol, iopanoic acid, iopiperidol, iophendy pharmaceutically acceptable prodrugs of the foregoing, late, iopromide, iopydol, iosimenol, iothalamic acid, iotro and pharmaceutically acceptable Solvates of the fore lan, ioversol, ioxilan, ioxaglic acid, isopaque, ipodate, going. meglumine iothalamate, meglumine acetrizoate, meglumine diatrizoate, metrizamide, myelotrast, omnipaque, osbil, opti 31. The method of claim 30 wherein the first selective ray, optojod, opacoron, perflutren, phenobutiodil, phentetio adenosine A1 receptor antagonist is selected from pyrrolo thalein sodium, priodax, propyliodone, skiodan, Sodium 2.3dpyrimidine derivatives of formula I, wherein iodomethamate, sodium diatrizoate, telepaque, teridax, tet i) R1 and R2 are each independently selected from a rabrom, thorotrast, triognost, 1.3.5-Tri-n-hexyl-2,4,6-tri hydrogen atom, an optionally Substituted alkyl or iodobenzene, tyropanoate, visipaque or xenetix, pharmaceu together form an optionally substituted heterocyclic tically acceptable salts of any of the foregoing, prodrugs of ring: any of the foregoing, and Solvates of any of the foregoing. ii) R3 is a hydrogenatom or an optionally Substituted aryl, 37. A method of preventing or reducing the need of dialysis in a human or mammalian patient receiving a first iii) R4 and R5 are each independently selected from a radiocontrast media comprising administering a therapeuti halogen atom or a hydrogen atom; cally effective amount of a first selective adenosine A1 and pharmaceutically acceptable salts of the foregoing, antagonist. pharmaceutically acceptable prodrugs of the foregoing, 38. The method of claim 37 wherein the first selective and pharmaceutically acceptable Solvates of the fore adenosine A1 receptor antagonist is administered intrave going. nously in a loading dose followed by Subsequent adminis 32. The method of claim 31 wherein the selective adenos tration as a maintenance dose, wherein the loading dose is ine A1 receptor antagonist is selected from pyrrolo2.3d administered between about five minutes and about twenty five minutes prior to the administration of a first radiocon pyrimidine derivatives of formula I, wherein trast media and wherein the maintenance dose is adminis i) R1 is a hydrogen and R2 is an optionally substituted tered over a period of less than about 48 hours subsequent cyclohexyl ring, or R1 and to administration of the loading dose. US 2008/0027082 A1 Jan. 31, 2008

39. The method of claim38 wherein the maintenance dose 44. The method of claim 43 wherein the selective adenos is administered such that the plasma level of the first ine A1 receptor antagonist is selected from pyrrolo2.3d selective A1 adenosine antagonist is maintained between pyrimidine derivatives of formula I, wherein about 10 ng/ml and about 500 ng/ml. i) R1 is a hydrogen and R2 is an optionally substituted 40. The method of claim 37 wherein the first adenosine A1 cyclohexyl ring, or R1 and receptor antagonist is administered orally prior to the admin istration of a first radiocontrast media. R2 together form an optionally substituted pyrrolidine 41. The method of claim 37 wherein the first radiocontrast ring: media is not administered until the plasma concentration ii) R3 is a phenyl ring, level of the first adenosine A1 receptor antagonist has reached a concentration of between about 10 ng/ml and iii) R4 and R5 are each a hydrogen atom; about 500 ng/ml. and pharmaceutically acceptable salts of the foregoing, 42. The method of claim 37 wherein the first selective pharmaceutically acceptable prodrugs of the foregoing, adenosine A1 receptor antagonist is selected from pyrrolo and pharmaceutically acceptable Solvates of the fore 2.3dpyrimidine derivatives of formula I going. 45. The method of claim 44 wherein the first selective adenosine A1 receptor antagonist is selected from the group consisting of 4-(2-phenyl-7H-pyrrolo2.3-opyrimidin-4- R1 N1 R2 yl)amino-trans-cyclohexanol methanesulfonate, (4S)-4-hy R5 droxy-1-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4-yl)-L- prolinamide methanesulfonate, pharmaceutically acceptable N1 N prodrugs of the foregoing, and pharmaceutically acceptable l 2 M R4 Solvates of the foregoing. R3 N N 46. The method of claim 45 wherein the first selective adenosine A1 receptor antagonist is 4-(2-phenyl-7H-pyr wherein rolo2,3-alpyrimidin-4-yl)amino-trans-cyclohexanol meth anesulfonate, pharmaceutically acceptable prodrugs of the i) R1 and R2 are each independently selected from a foregoing, and pharmaceutically acceptable solvates of the hydrogen atom, an optionally substituted alkyl, option foregoing. ally substituted aryl, or optionally substituted alkylaryl 47. The method of claim 45 wherein the first selective moiety or together form an optionally Substituted het adenosine A1 receptor antagonist is (4S)-4-hydroxy-1-(2- erocyclic ring; phenyl-7H-pyrrolo2,3-dipyrimidin-4-yl)-L-prolinamide methanesulfonate, pharmaceutically acceptable prodrugs of ii) R3 is selected from a hydrogen atom or an optionally the foregoing, and pharmaceutically acceptable Solvates of Substituted alkyl, optionally Substituted aryl, or option the foregoing. ally substituted alkylaryl moiety; 48. The method of claim 38 wherein the first radiocontrast iii) R4 and R5 are each independently selected from a media is an iodinated or gadolinium-based radiocontrast halogen atom, a hydrogen atom or an optionally Sub media selected from the group consisting of bunaiod, bili stituted alkyl, optionally substituted aryl, or optionally gram, bilimiro, bilopaque, cholimil, ethiodol, diatrast, substituted alkylaryl moiety, or R4 and R5 together dionosil, falignost, gadobutrol, gadodiamide, gadopentetate form an optionally Substituted heterocyclic or option dimeglumine, gastrografin, hexabrix, hippodin, mangafo ally Substituted carbocyclic ring: dipir, amidotrizoate, ethiodized oil, imagopaque, iodamide, iodipamide, iodixanol, iodophene, iophendylate, iomeron, and pharmaceutically acceptable salts of the foregoing, iomeprol, iopamidol, iopanoic acid, iopiperidol, iophendy pharmaceutically acceptable prodrugs of the foregoing, late, iopromide, iopydol, iosimenol, iothalamic acid, iotro and pharmaceutically acceptable Solvates of the fore lan, ioversol, ioxilan, ioxaglic acid, isopaque, ipodate, going. meglumine iothalamate, meglumine acetrizoate, meglumine 43. The method of claim 42 wherein the first selective diatrizoate, metrizamide, myelotrast, omnipaque, osbil, opti adenosine A1 receptor antagonist is selected from pyrrolo ray, optojod, opacoron, perflutren, phenobutiodil, phentetio 2.3dpyrimidine derivatives of formula I, wherein thalein sodium, priodax, propyliodone, skiodan, Sodium iodomethamate, sodium diatrizoate, telepaque, teridax, tet i) R1 and R2 are each independently selected from a rabrom, thorotrast, triognost, 1.3.5-Tri-n-hexyl-2,4,6-tri hydrogen atom, an optionally Substituted alkyl or iodobenzene, tyropanoate, visipaque or xenetix, pharmaceu together form an optionally substituted heterocyclic tically acceptable salts of any of the foregoing, prodrugs of ring: any of the foregoing, and Solvates of any of the foregoing. ii) R3 is a hydrogenatom or an optionally Substituted aryl, 49. A pharmaceutical combination comprising iii) R4 and R5 are each independently selected from a i) a therapeutically effective amount of a first selective halogen atom or a hydrogen atom; adenosine A1 antagonist, and and pharmaceutically acceptable salts of the foregoing, ii) a first radiocontrast media, pharmaceutically acceptable prodrugs of the foregoing, wherein the pharmaceutical combination is suitable for and pharmaceutically acceptable Solvates of the fore simultaneous, separate or step-wise administration to going. humans or mammals. US 2008/0027082 A1 Jan. 31, 2008 20

50. The pharmaceutical combination of claim 49 wherein i) R1 and R2 are each independently selected from a the first selective adenosine A1 receptor antagonist is admin hydrogen atom, an optionally substituted alkyl or istered intravenously in a loading dose followed by subse together form an optionally substituted heterocyclic quent administration as a maintenance dose, wherein the ring: loading dose is administered between about five minutes and about twenty-five minutes prior to the administration of a ii) R3 is a hydrogenatom or an optionally Substituted aryl, first radiocontrast media and wherein the maintenance dose iii) R4 and R5 are each independently selected from a is administered over a period of less than about 48 hours halogen atom or a hydrogen atom; Subsequent to administration of the loading dose. 51. The pharmaceutical combination of claim 50 wherein and pharmaceutically acceptable salts of the foregoing, the maintenance dose is administered such that the plasma pharmaceutically acceptable prodrugs of the foregoing, level of the first selective A1 adenosine antagonist is main and pharmaceutically acceptable Solvates of the fore tained between about 10 ng/ml and about 500 ng/ml. going. 52. The pharmaceutical combination of claim 49 wherein 56. The pharmaceutical combination of claim 55 wherein the first adenosine A1 receptor antagonist is administered the selective adenosine A1 receptor antagonist is selected orally prior to the administration of a first radiocontrast from pyrrolo2.3dpyrimidine derivatives of formula I, media. wherein 53. The pharmaceutical combination of claim 49 wherein i) R1 is a hydrogen and R2 is an optionally substituted the first radiocontrast media is not administered until the cyclohexyl ring, or R1 and plasma concentration level of the first adenosine A1 receptor antagonist has reached a concentration of between about 10 R2 together form an optionally substituted pyrrolidine ng/ml and about 500 ng/ml. ring: 54. The pharmaceutical combination of claim 49 wherein the first selective adenosine A1 receptor antagonist is ii) R3 is a phenyl ring, selected from pyrrolo2.3dpyrimidine derivatives of for iii) R4 and R5 are each a hydrogen atom; mula I and pharmaceutically acceptable salts of the foregoing, pharmaceutically acceptable prodrugs of the foregoing, I and pharmaceutically acceptable Solvates of the fore R1 N1 R2 going. R5 57. The pharmaceutical combination of claim 56 wherein the first selective adenosine A1 receptor antagonist is N1 N selected from the group consisting of 4-(2-phenyl-7H l 2 M R4 pyrrolo2,3-dipyrimidin-4-yl)amino-trans-cyclohexanol R3 N N methanesulfonate, (4S)-4-hydroxy-1-(2-phenyl-7H-pyrrolo 2.3-opyrimidin-4-yl)-L-prolinamide methanesulfonate, pharmaceutically acceptable prodrugs of the foregoing, and wherein pharmaceutically acceptable Solvates of the foregoing. i) R1 and R2 are each independently selected from a 58. The pharmaceutical combination of claim 57 wherein hydrogen atom, an optionally Substituted alkyl, option the first selective adenosine A1 receptor antagonist is 4-(2- ally substituted aryl, or optionally substituted alkylaryl phenyl-7H-pyrrolo2.3-dpyrimidin-4-yl)amino-trans-cy moiety or together form an optionally Substituted het clohexanol methanesulfonate, pharmaceutically acceptable erocyclic ring; prodrugs of the foregoing, and pharmaceutically acceptable Solvates of the foregoing. ii) R3 is selected from a hydrogen atom or an optionally 59. The pharmaceutical combination of claim 57 wherein Substituted alkyl, optionally Substituted aryl, or option the first selective adenosine A1 receptor antagonist is (4S)- ally substituted alkylaryl moiety; 4-hydroxy-1-(2-phenyl-7H-pyrrolo2.3-opyrimidin-4-yl)- iii) R4 and R5 are each independently selected from a L-prolinamide methanesulfonate, pharmaceutically accept halogen atom, a hydrogen atom or an optionally Sub able prodrugs of the foregoing, and pharmaceutically stituted alkyl, optionally substituted aryl, or optionally acceptable Solvates of the foregoing. substituted alkylaryl moiety, or R4 and R5 together 60. The pharmaceutical combination of claim 50 wherein form an optionally Substituted heterocyclic or option the first radiocontrast media is an iodinated or gadolinium ally Substituted carbocyclic ring: based radiocontrast media selected from the group consist ing of bunaiod, billigram, bilimiro, bilopaque, cholimil, and pharmaceutically acceptable salts of the foregoing, ethiodol, diatrast, dionosil, falignost, gadobutrol, gadodia pharmaceutically acceptable prodrugs of the foregoing, mide, gadopentetate dimeglumine, gastrografin, hexabrix, and pharmaceutically acceptable Solvates of the fore hippodin, mangafodipir, amidotrizoate, ethiodized oil, ima going. gopaque, iodamide, iodipamide, iodixanol, iodophene, 55. The pharmaceutical combination of claim 54 wherein iophendylate, iomeron, iomeprol, iopamidol, iopanoic acid, the first selective adenosine A1 receptor antagonist is iopiperidol, iophendylate, iopromide, iopydol, iosimenol, selected from pyrrolo2.3dpyrimidine derivatives of for iothalamic acid, iotrolan, ioversol, ioXilan, ioxaglic acid, mula I, wherein isopaque, ipodate, meglumine iothalamate, meglumine ace US 2008/0027082 A1 Jan. 31, 2008 trizoate, meglumine diatrizoate, metrizamide, myelotrast, omnipaque, osbil, optiray, optojod, opacoron, perflutren, phenobutiodil, phentetiothalein sodium, priodax, propyli R1 R2 odone, skiodan, Sodium iodomethamate, sodium diatrizoate, N1 telepaque, teridax, tetrabrom, thorotrast, triognost, 1.3.5-Tri R5 n-hexyl-2,4,6-triiodobenzene, tyropanoate, visipaque or N1 N Xenetix, pharmaceutically acceptable salts of any of the foregoing, prodrugs of any of the foregoing, and Solvates of l 2 M R4 any of the foregoing. R3 N N 61. A kit comprising wherein i) a therapeutically effective amount of a first selective i) R1 and R2 are each independently selected from a adenosine A1 antagonist, and hydrogen atom, an optionally Substituted alkyl, option ii) a first radiocontrast media, ally substituted aryl, or optionally substituted alkylaryl moiety or together form an optionally Substituted het wherein the pharmaceutical combination is suitable for erocyclic ring; simultaneous, separate or step-wise administration to ii) R3 is selected from a hydrogen atom or an optionally humans or mammals. Substituted alkyl, optionally Substituted aryl, or option 62. The kit of claim 61 further comprising ally substituted alkylaryl moiety; i) a loading dose of the first selective adenosine A1 iii) R4 and R5 are each independently selected from a receptor antagonist to be administered intravenously; halogen atom, a hydrogen atom or an optionally Sub stituted alkyl, optionally substituted aryl, or optionally and substituted alkylaryl moiety, or R4 and R5 together ii) a maintenance dose of the first selective adenosine A1 form an optionally Substituted heterocyclic or option receptor antagonist to be administered intravenously, ally substituted carbocyclic ring; and pharmaceutically acceptable salts of the foregoing, wherein the loading dose is administered intravenously pharmaceutically acceptable prodrugs of the foregoing, followed by subsequent intravenous administration of and pharmaceutically acceptable Solvates of the fore the maintenance dose, wherein the loading dose is going. administered between about five minutes and about 68. The kit of claim 67 wherein the first selective adenos twenty-five minutes prior to the administration of the ine A1 receptor antagonist is selected from pyrrolo2.3d first radiocontrast media and wherein the maintenance pyrimidine derivatives of formula i, wherein dose is administered over a period of less than about 48 i) R1 and R2 are each independently selected from a hours Subsequent to administration of the loading dose. hydrogen atom, an optionally substituted alkyl or 63. The kit of claim 61 wherein the first selective adenos together form an optionally substituted heterocyclic ine A1 receptor antagonist is administered intravenously in ring: a loading dose followed by Subsequent administration as a ii) R3 is a hydrogenatom or an optionally Substituted aryl, maintenance dose, wherein the loading dose is administered between about five minutes and about twenty-five minutes iii) R4 and R5 are each independently selected from a prior to the administration of the first radiocontrast media halogen atom or a hydrogen atom; and wherein the maintenance dose is administered over a and pharmaceutically acceptable salts of the foregoing, period of less than about 48 hours Subsequent to adminis pharmaceutically acceptable prodrugs of the foregoing, tration of the loading dose. and pharmaceutically acceptable Solvates of the fore 64. The kit of claim 63 wherein the maintenance dose is going. 69. The kit of claim 68 wherein the selective adenosine A1 administered such that the plasma level of the first selective receptor antagonist is selected from pyrrolo2.3dpyrimidine Al adenosine antagonist is maintained between about 10 ng/ml and about 500 ng/ml. derivatives of formula I, wherein 65. The kit of claim 61 wherein the first adenosine A1 i) R1 is a hydrogen and R2 is an optionally substituted receptor antagonist is administered orally prior to the admin cyclohexyl ring, or R1 and istration of a first radiocontrast media. R2 together form an optionally substituted pyrrolidine 66. The kit of claim 61 wherein the first radiocontrast ring: media is not administered until the plasma concentration ii) R3 is a phenyl ring, level of the first adenosine A1 receptor antagonist has reached a concentration of between about 10 ng/ml and iii) R4 and R5 are each a hydrogen atom; about 500 ng/ml. and pharmaceutically acceptable salts of the foregoing, 67. The kit of claim 61 wherein the first selective adenos pharmaceutically acceptable prodrugs of the foregoing, ine A1 receptor antagonist is selected from pyrrolo2.3d and pharmaceutically acceptable Solvates of the fore pyrimidine derivatives of formula I going. US 2008/0027082 A1 Jan. 31, 2008 22

70. The kit of claim 69 wherein the first selective adenos rabrom, thorotrast, triognost, 1.3.5-Tri-n-hexyl-2,4,6-tri ine A1 receptor antagonist is selected from the group con iodobenzene, tyropanoate, visipaque or xenetix, pharmaceu sisting of 4-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4- tically acceptable salts of any of the foregoing, prodrugs of yl)amino-trans-cyclohexanol methanesulfonate, (4S)-4- any of the foregoing, and Solvates of any of the foregoing. hydroxy-1-(2-phenyl-7H-pyrrolo2,3-dipyrimidin-4-yl)-L- 74. A method of using a selective adenosine A1 antagonist prolinamide methanesulfonate, pharmaceutically acceptable comprising: prodrugs of the foregoing, and pharmaceutically acceptable Solvates of the foregoing. creating a kit containing a therapeutically effective 71. The kit of claim 70 wherein the first selective adenos amount of a first selective adenosine A1 antagonist and ine A1 receptor antagonist is 4-(2-phenyl-7H-pyrrolo2.3- a first radiocontrast media. dpyrimidin-4-yl)amino-trans-cyclohexanol methane 75. A method of using a selective adenosine A1 antagonist Sulfonate, pharmaceutically acceptable prodrugs of the comprising: foregoing, and pharmaceutically acceptable solvates of the administering a therapeutically effective amount of a first foregoing. Selective adenosine A1 antagonist to prevent radiocon 72. The kit of claim 70 wherein the first selective adenos trast media induced nephropathy. ine A1 receptor antagonist is (4S)-4-hydroxy-1-(2-phenyl 76. A method of using a selective adenosine A1 antagonist 7H-pyrrolo2.3-opyrimidin-4-yl)-L-prolinamide methane comprising: Sulfonate, pharmaceutically acceptable prodrugs of the foregoing, and pharmaceutically acceptable solvates of the administering a therapeutically effective amount of a first foregoing. Selective adenosine A1 antagonist to prevent a radio 73. The kit of claim 61 wherein the first radiocontrast contrast media induced increase in serum creatinine media is an iodinated or gadolinium-based radiocontrast levels. media selected from the group consisting of bunaiod, bili 77. A method of using a selective adenosine A1 antagonist gram, bilimiro, bilopaque, cholimil, ethiodol, diatrast, comprising: dionosil, falignost, gadobutrol, gadodiamide, gadopentetate administering a therapeutically effective amount of a first dimeglumine, gastrografin, hexabrix, hippodin, mangafo Selective adenosine A1 antagonist to prevent a radio dipir, amidotrizoate, ethiodized oil, imagopaque, iodamide, contrast media induced decrease in renal blood flow. iodipamide, iodixanol, iodophene, iophendylate, iomeron, 78. A method of using a selective adenosine A1 antagonist iomeprol, iopamidol, iopanoic acid, iopiperidol, iophendy comprising: late, iopromide, iopydol, iosimenol, iothalamic acid, iotro lan, ioversol, ioxilan, ioxaglic acid, isopaque, ipodate, administering a therapeutically effective amount of a first meglumine iothalamate, meglumine acetrizoate, meglumine Selective adenosine A1 antagonist to prevent or reduce diatrizoate, metrizamide, myelotrast, omnipaque, osbil, opti the need of dialysis in a human or mammalian patient ray, optojod. opacoron, perflutren, phenobutiodil, phentetio receiving a first radiocontrast media. thalein Sodium, priodax, propyliodone, skiodan, Sodium iodomethamate, sodium diatrizoate, telepaque, teridax, tet k k k k k