CN101472593A

CN101472593A - Use of adenosine A1 antagonist in radiocontrast media induced nephropathy

Info

Publication number: CN101472593A
Application number: CNA2007800227051A
Authority: CN
Inventors: D·奇格勒; K·维特; B·霍赫; Y·菲舍尔
Original assignee: Solvay Pharmaceuticals GmbH
Current assignee: Abbott Products GmbH
Priority date: 2006-06-19
Filing date: 2007-06-18
Publication date: 2009-07-01

Abstract

The present invention relates to pharmaceutical combinations comprising a therapeutically effective amount of at least one selective adenosine A1 antagonist and at least one radiocontrast media. In particular, the present invention relates to pharmaceutical combinations comprising 4-[(2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-trans-cyclohexanol methanesulfonate and/or (4S)-4-hydroxy-1-(2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-L- prolinamide methanesulfonate as selective adenosine A1 antagonists and at least one radiocontrast media. The invention also relates to the use of said combinations in the manufacture of a medicament for the treatment of radiocontrast media induced nephropathy. Furthermore, the invention is relating to a kit comprising a therapeutically effective amount of said combination of at least one selective adenosine A1 antagonist and at least one radiocontrast media.

Description

The purposes of adenosine A 1 antagonist in the media induced nephropathy of pneumoradiography

Technical field

The present invention relates to drug regimen, it comprises at least a selective adenosine A1 receptor antagonist and at least a pneumoradiography medium (radiocontrast media, RM also claim the radiocontrast media) for the treatment of effective dose.The present invention also relates to the described purposes that is combined in the preparation medicine, this medicine is used for the treatment of the media induced nephropathy of pneumoradiography.In addition, the present invention relates to comprise the kit of described combination.

Background technology

Interventional technique, quick multi-disc computed tomography (CT) and new 3D reconstruction technique enlarged the purposes of pneumoradiography medium (RM) in the iodate blood vessel in the past in 10 years.For accurate and safe diagnosis and intervention program, great majority inspection needs iodate RM.Now, about 60,000,000 (Andrew, 2004 of annual in the world medication ¹).The pneumoradiography medium can cause the decline of renal excretion function, and it starts from after the administration soon.Renal dysfunction can be of short duration, persistent or even not reversible.Therefore, the use of pneumoradiography medium is relevant with the increase of the sickness rate of being admitted to hospital, mortality rate and medical treatment and nursing and the long-term cost of being in hospital, especially in the patient of needs dialysis.Therefore, the media induced nephropathy (CIN) of pneumoradiography is an important problem clinically.CIN is a kind of structural damage of kidney.The definition of CIN has nothing in common with each other.It can be defined as using the functional acute exacerbation of RM metanephros, and it is induced to getting rid of the approximate reason of the alternative cause of disease.The most common definition of secondary efficacy is that the increase of serum creatinine behind the intravascular administration of RM is greater than 25% or 44mol/l (0.5mg/dl).The increase that main effects is defined as serum creatinine is greater than 50% or 88mmol/l (1mg/dl).The pathogeny of CIN is not fully understood as yet.It is believed that and relate to two kinds of principal elements, haemodynamic effect and little tube effect.The application of RM causes the reduction of kidney hemodynamic variation, especially glomerular filtration rate (GFR).GFR is the ultrafiltration rate that blood plasma is crossed over the glomerule capillary wall, and the total GFR that measures two kidneys will provide the sensitivity index of overall renal excretion function.By comparing urine creatine acid anhydride level and blood test result, calculate glomerular filtration rate.Suitable GFR value is (referring to http://www.fpnotebook.com ²) with regard to the male, be 97-137ml/min/1.73m ², with regard to the women, be 88-128ml/min/1.73m, and GFR is lower than 15ml/min/1.73m ²Can cause renal failure.The GFR reduction of being brought out by the application of RM is considered to the main cause that CIN forms.Along the renal tubules system, do not become concentrated gradually by resorbent material (as RM).Kidney fluid up to 99% is absorbed by the effect of manifold (manifold) cell and secondary celelular mechanism usually.The urine concentration that this means RM can increase by 100 times.Along with the carrying out of continuous centralized procedure, the tubule fluid that the contains RM thickness gradually that will become can cause little pipe choking (Ueda, 1993 ³).Inevitably, intrarenal pressure also increases, because kidney is owing to the existence of tunicle on every side can not be expanded.Consequently, the renal perfusion pressure of renal medulla may no longer enough guarantee sufficient perfusion.In kidney, the activation of A1AR has been prompted to helping tubule bead feedback (TGF) in the Introduced cases glomerule small artery, and this is a kind of strategic feedback mechanism, and it is designed to control tubule and flows and regional perfusion.The rising of [NaCl] causes vasoconstriction in nephron macula densa (macula densa) district.Adenosine causes vasoconstrictive effect consistent in the effect that TGF replys in the mediation with it.Except its vasoconstriction effect, A ₁Receptor for stimulating makes mesangial cell shrinkage (Olivera, 1989 in the glomerule ⁴).The acute renal failure that is caused by RM injection be considered to for many years to diagnose always and the intervention program in complication.Directly the incidence rate of the acute renal failure of being brought out by RM is about 10-15%, and increases the incidence rate of defined CIN up to 22% (Porter, 1989 by significant serum kreatinin clinically ⁵).Peak kreatinin concentration occurs in 3-5 days that are exposed to contrast media, can eliminate satisfactorily usually, but in 10% dangerous patient nearly, need dialysis.Existing renal insufficiency, the minimizing of blood vessel inner capacities and other basic diseases (for example hypertension, diabetes) be it is said some leading risk factors of the media induced nephropathy of pneumoradiography.Osmolality is the measuring of molecule and amounts of particles in every kg water solution, and the osmolality of RM is considered to be of great importance in the media induced nephropathy of pneumoradiography.The incidence rate of the nephropathy of being brought out by the RM of hyposmosis is lower in general crowd, through calculating less than 2% (Nikolsky, 2003 ⁶).

The generation of adenosine is one of existing CIN mechanism of discussing.Adenosine is a kind of endogenous neuromodulator, has main depression effect for CNS, heart, kidney and other organs.It is a kind of naturally occurring nucleoside, brings into play its biological effect by interacting with adenosine receptor family, and this family is known A1, A2a, A2b and A3, and they all regulate and control the important physical process.Selectivity A1 adenosine receptor antagonists (A ₁AR) have outstanding kidney effect, shown it is powerful diuretic and short natruresis agent, do not have what effect for the drainage of potassium.Thereby they are kidney protectiveness, can be used for treating renal failure, renal dysfunction, nephritis, hypertension and edema.Kidney composition ground produces adenosine, absorbs with glomerular filtration and the electrolyte of regulating by the mediation of adenosine A 1 receptor system again.The A1 adenosine receptor has been found the arteriolar vasoconstriction of domination Introduced cases glomerule and has replied.Adenosine causes reducing to the blood flow of kidney, thereby reduces glomerular filtration rate and kidney blood flow.The inhibition of A1 receptor will improve glomerular filtration rate, correspondingly increase the urine generating rate.The application of adenosine receptor antagonists has been used to protect acute renal failure.Adenosine receptor antagonists aminophylline (combination of theophylline and ethylenediamine 2:1) and theophylline (being found the adenosine receptor in the antagonism brain non-selectively) are be evaluated as the potential drug (Shammas, 2001 that are protected from the media induced nephropathy of pneumoradiography; Welch, 2002; Huber, 2002 ⁷).As if aminophylline does not add the protectiveness role in the media induced nephropathy of prevention pneumoradiography, and theophylline is effective in the media induced nephropathy of prevention pneumoradiography, renal excretion, endocrine and tubule hypofunction.These results suggest, adenosine may play a role in the pathogeny of CIN, and the application of non-selective adenosine receptor antagonists that the acute renal failure relevant with RM treatment does not take place is relevant with protection.Erley (1994 ⁸) studied at RM and used the influence of the non-selective adenosine antagonist theophylline in back to glomerular filtration rate, and specified the important function of adenosine in CIN.In addition, Arakawa (1996 ⁹) adenosine has been described in existing effect in replying for the kidney of contrast media iohexol with the Canis familiaris L. that does not have renal insufficiency.Arakawa points out that in normal renal function, iohexol mainly causes the kidney vasodilation by activating adenosine A 2 receptors.And in the renal function that has gone down, iohexol induces the activation of A2 and A1.It is relevant with initial kidney vasodilation that Arakawa proposes adenosine A 2 receptors, and adenosine A 1 receptor is responsible for the hemodynamic persistence deterioration of kidney.Yao (2000 ¹⁰) studied the influence of the media induced nephropathy of pneumoradiography in the rat that selective adenosine A1 antagonist KW-3902 lacks for eremacausis nitrogen.The Yao prompting, adenosine influences the morbidity of CIN via the activation of A1 receptor.Greiner (2005 ¹¹) studied theophylline and acetylcysteine separately and combination to the influence of the media induced nephropathy of pneumoradiography of intensive care patient, proved conclusively the prevention character of theophylline in CIN.Lee (2006 ¹²) reach a conclusion, kidney A1 adenosine receptor is only born the part responsibility in the morbidity of radiographic contrast agent nephropathy.Find that these mices are protected to avoid the acute renal failure of being brought out by the RM injection utilizing kidney A1 adenosine receptor to reject in the experiment that mice carries out.But, as if direct tubule toxicity is not subjected to the regulation and control of kidney A1 adenosine receptor.Patent application EP 1 386 609 (CV Therapeutics ¹³) method of recovering diuresis and renal function has been described, it comprises the combination of adenosine A 1 antagonist and diuretic.Patent application WO 99/31101 (Univ.South Florida ¹⁴) xanthine derivative as adenosine A 1 receptor antagonists disclosed.And then, mentioned the radiolabeled derivant and the adenosine A 1 receptor antagonists imaging method that are used for the medical diagnosis purpose.

Summary of the invention

A ₁AR had been displayed in the nephrotoxicity model of some acute renal failures in the past possesses protective effect.It is main cause in the formation of the media induced acute renal failure of pneumoradiography that the release increase of kidney adenosine and the stimulation of kidney adenosine receptor have been suggested.We are surprised to find now, and the administration of formula I selectivity A1 receptor antagonist especially is of value to the needs of the dangerous and/or dialysis that prevention CIN forms in the patient who accepts the pneumoradiography medium.We are surprised to find now, and the administration of formula I selectivity A1 receptor antagonist especially is of value to the needs of danger and the end-organ damage (forming as CIN) and/or the dialysis of prevention side effect in the patient who accepts the pneumoradiography medium.

Prior art proposed with one group of specific severe case who suffers from some long-term renal insufficiency of selective adenosine A1 antagonist for treating, and purpose is healing or improves these renal insufficiency (for example referring to WO 2004/094428 ¹⁵).We are surprised to find now, the administration of formula I selectivity A1 receptor antagonist especially is of value to the needs of accepting the dangerous and/or dialysis that prevention CIN forms among the patient of pneumoradiography medium at all, these patients comprise healthy patients and have suffered from renal insufficiency, for example the patient of renal failure and other renal insufficiency.

Therefore, an object of the present invention is to treat the purposes of at least a selective adenosine A1 receptor antagonist in the preparation medicine of effective dose, this medicine is used for treating by the media induced nephropathy of at least a pneumoradiography the mammal and the mankind, be used to increase serum creatinine level, be used to reduce the kidney blood flow, and be used to prevent the dialysis demand that caused by the media induced nephropathy of pneumoradiography.

Another object of the present invention relates to drug regimen, and it comprises at least a selective adenosine A1 receptor antagonist and the pneumoradiography medium for the treatment of effective dose.

Another object of the present invention relates to kit, and it comprises at least a selective adenosine A1 receptor antagonist and the pneumoradiography medium for the treatment of effective dose.

At least a A that can use according to the present invention ₁The AR antagonist can select the group of free style I chemical compound and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate composition,

Wherein

R1 and R2 are selected from hydrogen atom, optional substituted alkyl, optional substituted aryl or optional substituted alkylaryl part independently of one another, perhaps constitute optional substituted heterocycle together;

R3 is selected from hydrogen atom or optional substituted alkyl, optional substituted aryl or optional substituted alkylaryl part;

R4 and R5 are selected from halogen atom, hydrogen atom or optional substituted alkyl, optional substituted aryl or optional substituted alkylaryl part independently of one another, and perhaps R4 and R5 constitute optional substituted heterocycle or optional substituted carbocyclic ring together;

Be used to prepare medicine, this medicine is used for the nephropathy of being brought out by at least a RM in mammal or mankind prevention.

And/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

Particularly, the present invention relates to drug regimen, it is by 4-[(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino]-the fixed combination composition of anti--Hexalin mesylate or (4S)-4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-L-prolineamide mesylate and at least a RM.

At least a RM that can use according to the present invention is selected from following iodate or gadolinio (gadolinium-based) pneumoradiography medium: bunaiod (bunaiod), biligram (biligram), iopronic acid (bilimiro), pyrrole sieve piperazine gram (bilopaque), iocetamic acid (cholimil), ethiodized Oil, diodone (diatrast), propyliodone (dionosil), iomeglamic acid (falignost), gadobutrol, gadodiamide, Dimeglumine Gadopentetate (gadopentetate dimeglumine), Gastrografin, Hai Saixian, sodium iodohippurate (hippodin), mangafodipir, Diatrizoate, ethiodized Oil, iopentol (imagopaque), iodamide, adipiodone, iodixanol, iodophthalein, iofendylate, iomeprol, iomeprol, iopamidol, iopanoic acid, iopiperidol, iofendylate, iopromide, iopydol, the U.S. alcohol of iodine, iotalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, Acidum Metrizoicum (isopaque), Ipodate, iodine draws sour meglumine, meglumine acetrizoate, cardiografin, metrizamide, dimer-x (myelotrast), Omnipaque, iobenzamic acid, MP-328, iodine phenol sulfonic acid (optojod), vasurix (opacoron), perfluoropropane, phenobutiodil, phentetiothalein sodium, pheniodol, propyliodone, sodium iodomethanesulfonate (skiodan), iodoxyl, sodium amidotrizoate, iopanoic acid (telepaque), Teridax (teridax), tetrabromophenolphthalein sodium (tetrabrom), thorium oxygen glue, thypaque sodium (triognost), 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, cheese dissolves hydrochlorate (tyropanoate), prestige is looked Parker (visipaque) or Xenetix., and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

Detailed description of the invention

The present invention relates to treat the purposes of at least a selective adenosine A1 antagonist in the preparation medicine of effective dose, this medicine is used for preventing by the media induced nephropathy of at least a pneumoradiography the mammal or the mankind.The present invention thereby relate to the selective adenosine A1 antagonist of at least a formula I that treats effective dose and/or its pharmaceutically acceptable salt and/or prodrug and/or the purposes of solvate in the preparation medicine:

Wherein

Described medicine is used for preventing by the media induced nephropathy of at least a pneumoradiography the mammal or the mankind.

In addition, the present invention relates to treat the purposes of at least a selective adenosine A1 antagonist in the preparation medicine of effective dose, this medicine is used for being increased by the media induced serum creatinine level of at least a pneumoradiography mammal or mankind's prevention.The present invention thereby the purposes of selective adenosine A1 antagonist in the preparation medicine that relates at least a I of formula as defined above that treats effective dose, this medicine is used for being increased by the media induced serum creatinine level of at least a pneumoradiography in mammal or mankind prevention, preferably by of short duration, the lasting or irreversible increase of the media induced serum creatinine level of pneumoradiography.

In addition, the present invention relates to treat the purposes of at least a selective adenosine A1 antagonist in the preparation medicine of effective dose, this medicine is used to prevent reduced by the media induced renal blood flow of at least a pneumoradiography.The present invention thereby the selective adenosine A1 antagonist that relates at least a I of formula as defined above that treats effective dose prepare the purposes of medicine, this medicine is used for being reduced by the media induced renal blood flow of at least a pneumoradiography in mammal or mankind prevention, preferably by of short duration, the lasting or irreversible minimizing of the media induced renal blood flow of pneumoradiography.

In addition, at least a selective adenosine A1 antagonist that the present invention relates to treat effective dose prepares the purposes of medicine, this medicine is used for the dialysis demand that caused by the media induced nephropathy of pneumoradiography in mammal or mankind prevention, and described CIN can be of short duration, persistent or irreversible.The present invention thereby the selective adenosine A1 antagonist that relates at least a I of formula as defined above that treats effective dose prepare the purposes of medicine, this medicine is used for the dangerous or needs in people or mammalian subject prevention dialysis, preferably of short duration, lasting or irreversible dialysis, described patient is the experimenter who accepts the pneumoradiography medium.

The invention further relates to the treatment at least a selective adenosine A1 antagonist of effective dose and the drug regimen of at least a pneumoradiography medium, wherein this drug regimen be suitable for simultaneously, separately or segmentation to people or mammal administration.

In addition, the present invention relates to kit, it comprises at least a selective adenosine A1 antagonist and at least a pneumoradiography medium of effective dose at least, wherein this drug regimen be suitable for simultaneously, separately or segmentation to people or mammal administration.

The A1AR that can use according to the present invention can be selected from chemical compound and/or its pharmaceutically acceptable salt and/or prodrug and/or the solvate of formula I,

Wherein

R1 and R2 are selected from hydrogen atom, optional substituted alkyl, optional substituted aryl or optional substituted alkylaryl part independently of one another, perhaps constitute optional substituted heterocycle together; R3 is selected from hydrogen atom or optional substituted alkyl, optional substituted aryl or optional substituted alkylaryl part; R4 and R5 are selected from halogen atom, hydrogen atom or optional substituted alkyl, optional substituted aryl or optional substituted alkylaryl part independently of one another, and perhaps R4 and R5 constitute optional substituted heterocycle or optional substituted carbocyclic ring together;

Preferably, wherein

R1 and R2 are selected from hydrogen atom, optional substituted alkyl independently of one another or constitute optional substituted heterocycle together; R3 is selected from hydrogen atom or optional substituted aryl; R4 and R5 are selected from halogen atom or hydrogen atom independently of one another;

More preferably, wherein

R1 is that hydrogen atom and R2 are optional substituted cyclohexyl rings, and perhaps R1 and R2 constitute optional substituted pyrrolidine ring together; R3 is a benzyl ring; Each hydrogen atom naturally of R4 and R5.

In preferred embodiment, can be selected from 4-[(2-phenyl-7H-pyrrolo-[2 according to A1AR of the present invention, 3-d] pyrimidine-4-yl) amino]-anti--Hexalin mesylate or (4S)-4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-L-prolineamide mesylate, and/or its prodrug and/or solvate.

The A1AR that is suitable for this paper is described in the following international patent application: WO99/62518, WO 01/39777, WO 02/057267 and WO 2004/094428 (OsiPharmaceuticals and Solvay Pharmaceuticals ¹⁵).

The RM that can use according to the present invention can be iodate pneumoradiography medium or gadolinio pneumoradiography medium, it is selected from bunaiod (bunaiod), biligram (biligram), iopronic acid (bilimiro), pyrrole sieve Parker (bilopaque), iocetamic acid (cholimil), ethiodized Oil, diodone (diatrast), propyliodone (dionosil), iomeglamic acid (falignost), gadobutrol, gadodiamide, Dimeglumine Gadopentetate (gadopentetatedimeglumine), Gastrografin, Hai Saixian, sodium iodohippurate (hippodin), mangafodipir, Diatrizoate, ethiodized Oil, iopentol (imagopaque), iodamide, adipiodone, iodixanol, iodophthalein, iofendylate, iomeprol, iomeprol, iopamidol, iopanoic acid, iopiperidol, iofendylate, iopromide, iopydol, the U.S. alcohol of iodine, iotalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, Acidum Metrizoicum (isopaque), Ipodate, iodine draws sour meglumine, meglumine acetrizoate, cardiografin, metrizamide, dimer-x (myelotrast), Omnipaque, iobenzamic acid, MP-328, iodine phenol sulfonic acid (optojod), vasurix (opacoron), perfluoropropane, phenobutiodil, phentetiothalein sodium, pheniodol, propyliodone, sodium iodomethanesulfonate (skiodan), iodoxyl, sodium amidotrizoate, iopanoic acid, iophenoic acid (teridax), tetrabromophenolphthalein sodium (tetrabrom), thorium oxygen glue, thypaque sodium (triognost), 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, cheese dissolves hydrochlorate, prestige is looked Parker (visipaque) or Xenetix., and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

Preferred RM comprises that Xenetix., Omnipaque or prestige look Parker.

Be suitable for some examples (Schering, Bracco IndustriaChimica, Univ.California, Nyegaard, Cook Imaging Corporation, Mallinckrodt, Eprova, Nycomed and the Savag of the RM of this paper ¹⁶) be described in the following document: European patent application EP 0 022 744, EP 0 023 992, EP 0 026 281, EP 0 033 426, EP 0 108 638 and EP 0 317 492, International Application No. WO 87/00757 and WO89/08101, U.S. Pat 2,776,241, US 3,290,366, US 3,360,436 and US5,349,085, Britain application GB 1 321 591, and German patent DE 2 547 789, DE2 726 196 and DE 2 909 439, but be not limited to these RM.

4-[(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino]-anti--also will abbreviate material 1 as below the Hexalin mesylate, (4S)-and 4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-also will abbreviate material 2 as below the L-prolineamide mesylate.

In preferred embodiment, the present invention relates to the purposes of following combination: material 1 and bunaiod, perhaps material 1 and biligram, perhaps material 1 and iopronic acid, perhaps material 1 and pyrrole sieve Parker, perhaps material 1 and iocetamic acid, perhaps material 1 and ethiodized Oil, perhaps material 1 and diodone, perhaps material 1 and propyliodone, perhaps material 1 and iomeglamic acid, perhaps material 1 and gadobutrol, perhaps material 1 and gadodiamide, perhaps material 1 and Dimeglumine Gadopentetate, perhaps material 1 and Gastrografin, perhaps material 1 shows with the sea match, perhaps material 1 and sodium iodohippurate, perhaps material 1 and mangafodipir, perhaps material 1 and Diatrizoate, perhaps material 1 and ethiodized Oil, perhaps material 1 and iopentol, perhaps material 1 and iodamide, perhaps material 1 and adipiodone, perhaps material 1 and iodixanol, perhaps material 1 and iodophthalein, perhaps material 1 and iofendylate, perhaps material 1 and iomeprol, perhaps material 1 and iomeprol, perhaps material 1 and iopamidol, perhaps material 1 and iopanoic acid, perhaps material 1 and iopiperidol, perhaps material 1 and iofendylate, perhaps material 1 and iopromide, perhaps material 1 and iopydol, perhaps material 1 is U.S. pure with iodine, perhaps material 1 and iotalamic acid, perhaps material 1 and iotrolan, perhaps material 1 and ioversol, perhaps material 1 and ioxilan, perhaps material 1 and ioxaglic acid, perhaps material 1 and Acidum Metrizoicum, perhaps material 1 and Ipodate, perhaps material 1 draws sour meglumine with iodine, perhaps material 1 and meglumine acetrizoate, perhaps material 1 and cardiografin, perhaps material 1 and metrizamide, perhaps material 1 and dimer-x, perhaps material 1 and Omnipaque, perhaps material 1 and iobenzamic acid, perhaps material 1 and MP-328, perhaps material 1 and iodine phenol sulfonic acid, perhaps material 1 and vasurix, perhaps material 1 and perfluoropropane, perhaps material 1 and phenobutiodil, perhaps material 1 and phentetiothalein sodium, perhaps material 1 and pheniodol, perhaps material 1 and propyliodone, perhaps material 1 and sodium iodomethanesulfonate, perhaps material 1 and iodoxyl, perhaps material 1 and sodium amidotrizoate, perhaps material 1 and iopanoic acid, perhaps material 1 and iophenoic acid, perhaps material 1 and tetrabromophenolphthalein sodium, perhaps material 1 and thorium oxygen glue, perhaps material 1 and thypaque sodium, perhaps

material

1 and 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, perhaps material 1 dissolves hydrochlorate with cheese, and perhaps material 1 is looked Parker with prestige, perhaps material 1 and Xenetix..In preferred embodiments, the present invention relates to following drug regimen: material 1 and bunaiod, perhaps material 1 and biligram, perhaps material 1 and iopronic acid, perhaps material 1 and pyrrole sieve Parker, perhaps material 1 and iocetamic acid, perhaps material 1 and ethiodized Oil, perhaps material 1 and diodone, perhaps material 1 and propyliodone, perhaps material 1 and iomeglamic acid, perhaps material 1 and gadobutrol, perhaps material 1 and gadodiamide, perhaps material 1 and Dimeglumine Gadopentetate, perhaps material 1 and Gastrografin, perhaps material 1 shows with the sea match, perhaps material 1 and sodium iodohippurate, perhaps material 1 and mangafodipir, perhaps material 1 and Diatrizoate, perhaps material 1 and ethiodized Oil, perhaps material 1 and iopentol, perhaps material 1 and iodamide, perhaps material 1 and adipiodone, perhaps material 1 and iodixanol, perhaps material 1 and iodophthalein, perhaps material 1 and iofendylate, perhaps material 1 and iomeprol, perhaps material 1 and iomeprol, perhaps material 1 and iopamidol, perhaps material 1 and iopanoic acid, perhaps material 1 and iopiperidol, perhaps material 1 and iofendylate, perhaps material 1 and iopromide, perhaps material 1 and iopydol, perhaps material 1 is U.S. pure with iodine, perhaps material 1 and iotalamic acid, perhaps material 1 and iotrolan, perhaps material 1 and ioversol, perhaps material 1 and ioxilan, perhaps material 1 and ioxaglic acid, perhaps material 1 and Acidum Metrizoicum, perhaps material 1 and Ipodate, perhaps material 1 draws sour meglumine with iodine, perhaps material 1 and meglumine acetrizoate, perhaps material 1 and cardiografin, perhaps material 1 and metrizamide, perhaps material 1 and dimer-x, perhaps material 1 and Omnipaque, perhaps material 1 and iobenzamic acid, perhaps material 1 and MP-328, perhaps material 1 and iodine phenol sulfonic acid, perhaps material 1 and vasurix, perhaps material 1 and perfluoropropane, perhaps material 1 and phenobutiodil, perhaps material 1 and phentetiothalein sodium, perhaps material 1 and pheniodol, perhaps material 1 and propyliodone, perhaps material 1 and sodium iodomethanesulfonate, perhaps material 1 and iodoxyl, perhaps material 1 and sodium amidotrizoate, perhaps material 1 and iopanoic acid, perhaps material 1 and iophenoic acid, perhaps material 1 and tetrabromophenolphthalein sodium, perhaps material 1 and thorium oxygen glue, perhaps material 1 and thypaque sodium, perhaps

material

1 and 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, perhaps material 1 dissolves hydrochlorate with cheese, and perhaps material 1 is looked Parker with prestige, perhaps material 1 and Xenetix..In preferred embodiments, the present invention relates to kit, it comprises: material 1 and bunaiod, perhaps material 1 and biligram, perhaps material 1 and iopronic acid, perhaps material 1 and pyrrole sieve Parker, perhaps material 1 and iocetamic acid, perhaps material 1 and ethiodized Oil, perhaps material 1 and diodone, perhaps material 1 and propyliodone, perhaps material 1 and iomeglamic acid, perhaps material 1 and gadobutrol, perhaps material 1 and gadodiamide, perhaps material 1 and Dimeglumine Gadopentetate, perhaps material 1 and Gastrografin, perhaps material 1 shows with the sea match, perhaps material 1 and sodium iodohippurate, perhaps material 1 and mangafodipir, perhaps material 1 and Diatrizoate, perhaps material 1 and ethiodized Oil, perhaps material 1 and iopentol, perhaps material 1 and iodamide, perhaps material 1 and adipiodone, perhaps material 1 and iodixanol, perhaps material 1 and iodophthalein, perhaps material 1 and iofendylate, perhaps material 1 and iomeprol, perhaps material 1 and iomeprol, perhaps material 1 and iopamidol, perhaps material 1 and iopanoic acid, perhaps material 1 and iopiperidol, perhaps material 1 and iofendylate, perhaps material 1 and iopromide, perhaps material 1 and iopydol, perhaps material 1 and the U.S. alcohol of iodine, perhaps material 1 and iotalamic acid, perhaps material 1 and iotrolan, perhaps material 1 and ioversol, perhaps material 1 and ioxilan, perhaps material 1 and ioxaglic acid, perhaps material 1 and Acidum Metrizoicum, perhaps material 1 and Ipodate, perhaps material 1 draws sour meglumine with iodine, perhaps material 1 and meglumine acetrizoate, perhaps material 1 and cardiografin, perhaps material 1 and metrizamide, perhaps material 1 and dimer-x, perhaps material 1 and Omnipaque, perhaps material 1 and iobenzamic acid, perhaps material 1 and MP-328, perhaps material 1 and iodine phenol sulfonic acid, perhaps material 1 and vasurix, perhaps material 1 and perfluoropropane, perhaps material 1 and phenobutiodil, perhaps material 1 and phentetiothalein sodium, perhaps material 1 and pheniodol, perhaps material 1 and propyliodone, perhaps material 1 and sodium iodomethanesulfonate, perhaps material 1 and iodoxyl, perhaps material 1 and sodium amidotrizoate, perhaps material 1 and iopanoic acid, perhaps material 1 and iophenoic acid, perhaps material 1 and tetrabromophenolphthalein sodium, perhaps material 1 and thorium oxygen glue, perhaps material 1 and thypaque sodium, perhaps

material

1 and 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, perhaps material 1 dissolves hydrochlorate with cheese, perhaps material 1 is looked Parker with prestige, perhaps material 1 and Xenetix..

In preferred embodiment, the present invention relates to the purposes of following combination: material 2 and bunaiod, perhaps material 2 and biligram, perhaps material 2 and iopronic acid, perhaps material 2 and pyrrole sieve Parker, perhaps material 2 and iocetamic acid, perhaps material 2 and ethiodized Oil, perhaps material 2 and diodone, perhaps material 2 and propyliodone, perhaps material 2 and iomeglamic acid, perhaps material 2 and gadobutrol, perhaps material 2 and gadodiamide, perhaps material 2 and Dimeglumine Gadopentetate, perhaps material 2 and Gastrografin, perhaps material 2 shows with the sea match, perhaps material 2 and sodium iodohippurate, perhaps material 2 and mangafodipir, perhaps material 2 and Diatrizoate, perhaps material 2 and ethiodized Oil, perhaps material 2 and iopentol, perhaps material 2 and iodamide, perhaps material 2 and adipiodone, perhaps material 2 and iodixanol, perhaps material 2 and iodophthalein, perhaps material 2 and iofendylate, perhaps material 2 and iomeprol, perhaps material 2 and iomeprol, perhaps material 2 and iopamidol, perhaps material 2 and iopanoic acid, perhaps material 2 and iopiperidol, perhaps material 2 and iofendylate, perhaps material 2 and iopromide, perhaps material 2 and iopydol, perhaps material 2 is U.S. pure with iodine, perhaps material 2 and iotalamic acid, perhaps material 2 and iotrolan, perhaps material 2 and ioversol, perhaps material 2 and ioxilan, perhaps material 2 and ioxaglic acid, perhaps material 2 and Acidum Metrizoicum, perhaps material 2 and Ipodate, perhaps material 2 draws sour meglumine with iodine, perhaps material 2 and meglumine acetrizoate, perhaps material 2 and cardiografin, perhaps material 2 and metrizamide, perhaps material 2 and dimer-x, perhaps material 2 and Omnipaque, perhaps material 2 and iobenzamic acid, perhaps material 2 and MP-328, perhaps material 2 and iodine phenol sulfonic acid, perhaps material 2 and vasurix, perhaps material 2 and perfluoropropane, perhaps material 2 and phenobutiodil, perhaps material 2 and phentetiothalein sodium, perhaps material 2 and pheniodol, perhaps material 2 and propyliodone, perhaps material 2 and sodium iodomethanesulfonate, perhaps material 2 and iodoxyl, perhaps material 2 and sodium amidotrizoate, perhaps material 2 and iopanoic acid, perhaps material 2 and iophenoic acid, perhaps material 2 and tetrabromophenolphthalein sodium, perhaps material 2 and thorium oxygen glue, perhaps material 2 and thypaque sodium, perhaps material 2 and 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, perhaps material 2 dissolves hydrochlorate with cheese, and perhaps material 2 is looked Parker with prestige, perhaps material 2 and Xenetix..In preferred embodiments, the present invention relates to following drug regimen: material 2 and bunaiod, perhaps material 2 and biligram, perhaps material 2 and iopronic acid, perhaps material 2 and pyrrole sieve Parker, perhaps material 2 and iocetamic acid, perhaps material 2 and ethiodized Oil, perhaps material 2 and diodone, perhaps material 2 and propyliodone, perhaps material 2 and iomeglamic acid, perhaps material 2 and gadobutrol, perhaps material 2 and gadodiamide, perhaps material 2 and Dimeglumine Gadopentetate, perhaps material 2 and Gastrografin, perhaps material 2 shows with the sea match, perhaps material 2 and sodium iodohippurate, perhaps material 2 and mangafodipir, perhaps material 2 and Diatrizoate, perhaps material 2 and ethiodized Oil, perhaps material 2 and iopentol, perhaps material 2 and iodamide, perhaps material 2 and adipiodone, perhaps material 2 and iodixanol, perhaps material 2 and iodophthalein, perhaps material 2 and iofendylate, perhaps material 2 and iomeprol, perhaps material 2 and iomeprol, perhaps material 2 and iopamidol, perhaps material 2 and iopanoic acid, perhaps material 2 and iopiperidol, perhaps material 2 and iofendylate, perhaps material 2 and iopromide, perhaps material 2 and iopydol, perhaps material 2 is U.S. pure with iodine, perhaps material 2 and iotalamic acid, perhaps material 2 and iotrolan, perhaps material 2 and ioversol, perhaps material 2 and ioxilan, perhaps material 2 and ioxaglic acid, perhaps material 2 and Acidum Metrizoicum, perhaps material 2 and Ipodate, perhaps material 2 draws sour meglumine with iodine, perhaps material 2 and meglumine acetrizoate, perhaps material 2 and cardiografin, perhaps material 2 and metrizamide, perhaps material 2 and dimer-x, perhaps material 2 and Omnipaque, perhaps material 2 and iobenzamic acid, perhaps material 2 and MP-328, perhaps material 2 and iodine phenol sulfonic acid, perhaps material 2 and vasurix, perhaps material 2 and perfluoropropane, perhaps material 2 and phenobutiodil, perhaps material 2 and phentetiothalein sodium, perhaps material 2 and pheniodol, perhaps material 2 and propyliodone, perhaps material 2 and sodium iodomethanesulfonate, perhaps material 2 and iodoxyl, perhaps material 2 and sodium amidotrizoate, perhaps material 2 and iopanoic acid, perhaps material 2 and iophenoic acid, perhaps material 2 and tetrabromophenolphthalein sodium, perhaps material 2 and thorium oxygen glue, perhaps material 2 and thypaque sodium, perhaps material 2 and 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, perhaps material 2 dissolves hydrochlorate with cheese, and perhaps material 2 is looked Parker with prestige, perhaps material 2 and Xenetix..In preferred embodiments, the present invention relates to kit, it comprises: material 2 and bunaiod, perhaps material 2 and biligram, perhaps material 2 and iopronic acid, perhaps material 2 and pyrrole sieve Parker, perhaps material 2 and iocetamic acid, perhaps material 2 and ethiodized Oil, perhaps material 2 and diodone, perhaps material 2 and propyliodone, perhaps material 2 and iomeglamic acid, perhaps material 2 and gadobutrol, perhaps material 2 and gadodiamide, perhaps material 2 and Dimeglumine Gadopentetate, perhaps material 2 and Gastrografin, perhaps material 2 shows with the sea match, perhaps material 2 and sodium iodohippurate, perhaps material 2 and mangafodipir, perhaps material 2 and Diatrizoate, perhaps material 2 and ethiodized Oil, perhaps material 2 and iopentol, perhaps material 2 and iodamide, perhaps material 2 and adipiodone, perhaps material 2 and iodixanol, perhaps material 2 and iodophthalein, perhaps material 2 and iofendylate, perhaps material 2 and iomeprol, perhaps material 2 and iomeprol, perhaps material 2 and iopamidol, perhaps material 2 and iopanoic acid, perhaps material 2 and iopiperidol, perhaps material 2 and iofendylate, perhaps material 2 and iopromide, perhaps material 2 and iopydol, perhaps material 2 and the U.S. alcohol of iodine, perhaps material 2 and iotalamic acid, perhaps material 2 and iotrolan, perhaps material 2 and ioversol, perhaps material 2 and ioxilan, perhaps material 2 and ioxaglic acid, perhaps material 2 and Acidum Metrizoicum, perhaps material 2 and Ipodate, perhaps material 2 draws sour meglumine with iodine, perhaps material 2 and meglumine acetrizoate, perhaps material 2 and cardiografin, perhaps material 2 and metrizamide, perhaps material 2 and dimer-x, perhaps material 2 and Omnipaque, perhaps material 2 and iobenzamic acid, perhaps material 2 and MP-328, perhaps material 2 and iodine phenol sulfonic acid, perhaps material 2 and vasurix, perhaps material 2 and perfluoropropane, perhaps material 2 and phenobutiodil, perhaps material 2 and phentetiothalein sodium, perhaps material 2 and pheniodol, perhaps material 2 and propyliodone, perhaps material 2 and sodium iodomethanesulfonate, perhaps material 2 and iodoxyl, perhaps material 2 and sodium amidotrizoate, perhaps material 2 and iopanoic acid, perhaps material 2 and iophenoic acid, perhaps material 2 and tetrabromophenolphthalein sodium, perhaps material 2 and thorium oxygen glue, perhaps material 2 and thypaque sodium, perhaps material 2 and 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, perhaps material 2 dissolves hydrochlorate with cheese, perhaps material 2 is looked Parker with prestige, perhaps material 2 and Xenetix..

" the treatment effective dose " of medicine or pharmacological component but represent the nontoxic amount that required effect enough is provided of this medicine or composition.In conjoint therapy of the present invention, " the treatment effective dose " of a kind of component of this combination is that this chemical compound is making up other components are united effectively provides required effect when using amount with this.The amount of " effectively " will be different because of the curee, depend on individual age and general situation, specific active ingredient etc.Thereby not necessarily may specify accurate " treatment effective dose ".But, those of ordinary skills utilize normal experiment can determine " treatment effective dose " suitable in any individual case.

At least a RM is earlier administration not, has reached the concentration of 10～500ng/ml up to the blood plasma level of at least a selective adenosine A1 receptor antagonist.The present invention also relates to any any concentration or concentration range that is positioned at 10～500ng/ml scope.In preferred embodiment, at least a selective adenosine A1 antagonist has following concentration: 10,20,30,40,50,60,70,80,90,100,110,120,130,140,150,160,170,180,190,200,210,220,230,240,250,260,270,280,290,300,310,320,330,340,350,360,370,380,390,400,410,420,430,440,450,460,470,480,490 and 500ng/ml, and be positioned at any concentration or concentration range by two any scopes that above-mentioned concentration value limited, the lower limit of wherein said scope is by being limited than fractional value, the upper limit of described scope is limited by bigger numerical, for example 110-180ng/ml, 370-390ng/ml, scopes such as 10-150ng/ml.The present invention thereby relate to following purposes, it comprises the not earlier administration of at least a pneumoradiography medium, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.The present invention thereby further relate to drug regimen, it comprises the not earlier administration of at least a pneumoradiography medium, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.The invention further relates to following purposes, it comprises the not earlier administration of at least a pneumoradiography medium, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.The invention further relates to drug regimen, it comprises the not earlier administration of at least a pneumoradiography medium, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.

The application time period of the maintenance dose of at least a selectivity A1 adenosine antagonist is enough to keep the concentration of the blood plasma level of this at least a selectivity A1 adenosine antagonist at 10～500ng/ml.At least a selectivity A1 adenosine antagonist that gives with the amount that reaches and keep the concrete blood plasma level of at least a selectivity A1 adenosine antagonist be equivalent to the concrete dosage that will give the patient.The technical staff can select to be suitable for concrete patient's dosage.The present invention also relates to any any concentration or concentration range that is positioned at 10～500ng/ml scope.In preferred embodiment, at least a selective adenosine A1 antagonist has following concentration: 10,20,30,40,50,60,70,80,90,100,110,120,130,140,150,160,170,180,190,200,210,220,230,240,250,260,270,280,290,300,310,320,330,340,350,360,370,380,390,400,410,420,430,440,450,460,470,480,490 and 500ng/ml, and be positioned at any concentration or concentration range by two any scopes that above-mentioned concentration value limited, the lower limit of wherein said scope is by being limited than fractional value, the upper limit of described scope is limited by bigger numerical, for example 10-180ng/ml, 320-390ng/ml, scopes such as 100-150ng/ml.

The application time period of the maintenance dose of at least a selectivity A1 adenosine antagonist is between 0.1-48 hour, with the blood plasma level of the keeping at least a selectivity A1 adenosine antagonist concentration at 10～500ng/ml.The invention further relates to the arbitrary time span phase of little period of any 0.1-48 of being positioned at.In preferred embodiment, the administration time section of maintenance dose is 0.1,0.3,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5,14,14.5,15,15.5,16,16.5,17,17.5,18,18.5,19,19.5,20,20.5,21,21.5,22,22.5,23,23.5,24,24.5,25,25.5,26,26.5,27,27.5,28,28.5,29,29.5,30,30.5,31,31.5,32,32.5,33,33.5,34,34.5,35,35.5,36,36.5,37,37.5,38,38.5,39,39.5,40,40.5,41,41.5,42,42.5,43,43.5,44,44.5,45,45.5,46,46.5,47,47.5 and 48 hours, and any arbitrary period that is positioned at by two any scopes that above-mentioned one hour value limited, the lower limit of wherein said scope is by being limited than fractional value, the upper limit of described scope is limited by bigger numerical, for example 1-2 hour, 0.1-10 hour, 0.2-6 hour, 2-45 hour, 9.3-35 hour etc. scope.

At least a selective adenosine A1 receptor antagonist can give loading dose by intravenous, that continues gives maintenance dose, 5～25 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist before giving described at least a pneumoradiography medium, and after the administration of described at least a selectivity A1 receptor antagonist loading dose the longest 48 hours period, give the maintenance dose of at least a selective adenosine A1 receptor antagonist, in preferred embodiment, go through the following period: at the most 0.1,0.3,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5,14,14.5,15,15.5,16,16.5,17,17.5,18,18.5,19,19.5,20,20.5,21,21.5,22,22.5,23,23.5,24,24.5,25,25.5,26,26.5,27,27.5,28,28.5,29,29.5,30,30.5,31,31.5,32,32.5,33,33.5,34,34.5,35,35.5,36,36.5,37,37.5,38,38.5,39,39.5,40,40.5,41,41.5,42,42.5,43,43.5,44,44.5,45,45.5,46,46.5,47,47.5 and 48 hours.The present invention relates to any being located at and give the arbitrary time span section of described at least a pneumoradiography medium in 5～25 minute time period before, and after the administration of described at least a selectivity A1 receptor antagonist loading dose the longest 48 hours period, give the maintenance dose of at least a selective adenosine A1 receptor antagonist, in preferred embodiment, go through the following period: at the most 0.1,0.3,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5,14,14.5,15,15.5,16,16.5,17,17.5,18,18.5,19,19.5,20,20.5,21,21.5,22,22.5,23,23.5,24,24.5,25,25.5,26,26.5,27,27.5,28,28.5,29,29.5,30,30.5,31,31.5,32,32.5,33,33.5,34,34.5,35,35.5,36,36.5,37,37.5,38,38.5,39,39.5,40,40.5,41,41.5,42,42.5,43,43.5,44,44.5,45,45.5,46,46.5,47,47.5 and 48 hours.In preferred embodiment, can be before giving described at least a

pneumoradiography medium

5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 and 25 minutes, give at least a selective adenosine A1 receptor antagonist with any arbitrary period intravenous that is positioned at by two above-mentioned minute any scopes that value limited, the lower limit of wherein said scope is by being limited than fractional value, the upper limit of described scope is limited by bigger numerical, for example 10-18 minute, 20-25 minute, scope such as 12-15 minute, and after the administration of described at least a selectivity A1 receptor antagonist loading dose the longest 48 hours period, give the maintenance dose of at least a selective adenosine A1 receptor antagonist, in preferred embodiment, go through: at the most 0.1 as the next stage, 0.3,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5,14,14.5,15,15.5,16,16.5,17,17.5,18,18.5,19,19.5,20,20.5,21,21.5,22,22.5,23,23.5,24,24.5,25,25.5,26,26.5,27,27.5,28,28.5,29,29.5,30,30.5,31,31.5,32,32.5,33,33.5,34,34.5,35,35.5,36,36.5,37,37.5,38,38.5,39,39.5,40,40.5,41,41.5,42,42.5,43,43.5,44,44.5,45,45.5,46,46.5,47,47.5 and 48 hours.The present invention thereby relate to following purposes, it comprises the loading dose that intravenous is treated at least a selective adenosine A1 receptor antagonist of effective dose, that continues gives maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and be included in and give the longest 48 hours period after the described at least a selectivity A1 receptor antagonist loading dose, give the maintenance dose of at least a selective adenosine A1 receptor antagonist.The present invention thereby further relate to drug regimen, it comprises the loading dose that intravenous is treated at least a selective adenosine A1 receptor antagonist of effective dose, that continues gives maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and be included in and give the longest 48 hours period after the described at least a selectivity A1 receptor antagonist loading dose, give the maintenance dose of at least a selective adenosine A1 receptor antagonist.The present invention thereby further relate to kit, it comprises the loading dose that intravenous is treated at least a selective adenosine A1 receptor antagonist of effective dose, that continues gives maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and be included in and give the longest 48 hours period after the described at least a selectivity A1 receptor antagonist loading dose, give the maintenance dose of at least a selective adenosine A1 receptor antagonist.

The present invention is not limited to concrete dosage form, carrier, excipient etc. in its broad scope, they can have nothing in common with each other.Be appreciated that also term used herein only supplies to describe the purpose of the specific embodiment, does not plan to be limited.

Must be noted that be used in this description and singulative " ", " a kind of " and " being somebody's turn to do " of enclosing in claims comprise that plural number refers to thing, context has except the clearly appointment in addition.Thereby for example,, comprise the mixture and the single carrier of two or more carriers for the appellation of " carrier " for the appellation single component of " treatment effective ingredient " and the combination of two or more heterogeneities, or the like.

Term " A1AR ", " selective adenosine A1 antagonist " and " selective adenosine A1 receptor antagonist " are used interchangeably in this article, and the chemical compound of required pharmacology, physiological effect is induced in expression.

At least a selective adenosine A1 antagonist can pass through oral and/or intravenous administration.The present invention thereby relate to following purposes, it is included in and gives to give at oral formulations before at least a radiopaque contrast medium, preferably the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose in the time-delay delivery formulations.

The present invention thereby relate to following purposes, it comprises the loading dose that intravenous is treated the described at least a selective adenosine A1 receptor antagonist of effective dose, that continues gives maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and be included in and give the longest 48 hours period after the described at least a selectivity A1 receptor antagonist loading dose, give the maintenance dose of at least a selective adenosine A1 receptor antagonist.

The present invention thereby relate to drug regimen, it is included in and gives to give at oral formulations before at least a radiopaque contrast medium, preferably the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose in the time-delay delivery formulations.

The present invention thereby relate to drug regimen, it comprises the loading dose that intravenous is treated the described at least a selective adenosine A1 receptor antagonist of effective dose, that continues gives maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and comprise and go through the longest 48 hours period after the administration of described at least a selectivity A1 receptor antagonist loading dose, give the maintenance dose of at least a selective adenosine A1 receptor antagonist.

The present invention thereby relate to kit, it is included in and gives to give at oral formulations before at least a radiopaque contrast medium, preferably the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose in the time-delay delivery formulations.

The present invention thereby relate to kit, it comprises the loading dose that intravenous is treated the described at least a selective adenosine A1 receptor antagonist of effective dose, that continues gives maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and comprise and go through the longest 48 hours period after the administration of described at least a selectivity A1 receptor antagonist loading dose, give the maintenance dose of at least a selective adenosine A1 receptor antagonist.

Term " intravenous " relates to the parenteral medication, and it comprises injection or be infused into vein and intra-arterial, but is not limited to the form of above-mentioned parenteral medication.

Term " oral " relates to the enteral medication, and it comprises oral administration for example tablet, drop, pill, capsule, powder, granule etc., but is not limited to the form of above-mentioned enteral medication.

" time-delay discharges " expression pharmaceutical dosage form.Term " time-delay " for example includes but not limited to the dosage form of " prolongation ", " delaying ", " delay " and " delay ".

The medicinal storage box of term " container " expression sealing.It comprises the storage box of liquid medicine, for example ampoule, bottle, flask, disperser, syringe etc., and the storage box of solid drugs, and for example blister, capsule etc., but be not limited to above-mentioned storage box.

Term used herein " irreversible " can exchange with term " forever " and use.

" pharmaceutically acceptable " among the application for example in the narration of " pharmaceutically acceptable carrier ", " pharmaceutically acceptable auxiliary agent " or " pharmaceutically acceptable salt " expression be not biology or undesirable material aspect other, that is to say, this material can be incorporated in the drug regimen to patient's administration, any other component interaction that can not cause any undesirable biological effect or be contained with harmful mode and its combination." pharmacologically active " in " pharmacologically active " derivant or metabolite expression has derivant or the metabolite with the pharmacologically active of parent compound same type and about degree of equal value.When term " pharmaceutically acceptable " is used to represent the derivant of active component, it should be interpreted as that this chemical compound also is a pharmacologically active, it is effective for treatment promptly to be used for the treatment of the media induced nephropathy of pneumoradiography.

" carrier " used herein or " pharmaceutically acceptable auxiliary agent " expression is suitable for acceptable excipient materials on the conventional pharmaceutical of drug administration, comprise any this class material known in the art, they are nontoxic, not to be harmful to other component interactions of mode and drug regimen or drug delivery system.

Term used herein " comprises " and uses " comprising " their open, non-limiting implication.

The derivant of The compounds of this invention represented in term used herein " prodrug ", and they are the prodrugs that discharge medicine after to patient's administration in the body via chemistry or physiological processes.Term used herein " prodrug " comprises metabolic precursor thereof.Definite, prodrug is the derivant of The compounds of this invention, thereby wherein functional group carry can be in the physiological condition lower body cracked other composition discharge this compound activity key element (for example, prodrug under physiological pH or the effect by enzyme be converted into required medicament forms).Prodrug is the biorebersible derivative of drug molecule, is used to overcome some barriers of parent drug molecular application.These barriers include but not limited to dissolubility, permeability, stability, the preceding metabolism of body circulation and targeting restriction (Bundgaard, 1985 ¹⁷).Prodrug (just at the chemical compound that is metabolised to the chemical compound with formula I by any known approach during to people's administration) belongs to the present invention.

The form of term " pharmaceutically acceptable salt " expression salt, they are that the pharmacology is upward acceptable, and are nontoxic basically concerning the experimenter who accepts the The compounds of this invention administration.Preferably, pharmaceutically acceptable salt is a mesylate.

Term " solvate " relates to suitable organic solvent molecule and A1AR molecule or ionic association.The solvate that term used herein " solvate " expression is stable, wherein the formula I chemical compound of per molecule contains the solvent molecule of fixed qty; Also represent inclusion complex, they are more unsettled, and per molecule A1AR contains the solvent molecule of variable number.

The minimizing of term used herein " treatment " expression serious symptom and/or frequency, the elimination of symptom and/or basic reason, the prevention of the generation of symptom and/or their basic reasons, and the improvement of damage or remedy.Thereby for example, patient's " treatment " comprises the prevention of susceptible individual particular obstacle or bad physiological event and the treatment that the individuality of clinical symptoms is arranged.

By pneumoradiography medium inductive " serum creatinine level increase " may be of short duration, persistent or irreversible, preferred of short duration.The reference value of serum creatinine level (referring to Http:// www.rnceus.com/renal/renalcreat.html ¹⁸), in adult male, be positioned at about 0.8-1.4mg/dl, in the adult female, be 0.6-1.1mg/dl, in the child 0.2-1.0mg/dl.Serum creatinine level from reference value increase 25%-50% or even higher any range defined CIN.Any (arbitrarily) at random numerical value that serum creatinine level increases in the 25-70% scope has defined CIN." serum creatinine level increase " as measurable physiologic parameters defined the disease degree that the technical staff fully understands.In preferred embodiment, increase by 25,30,35,40,45,50,55,60,65 and 70% and any number or the numerical range that are positioned at by any two any scopes that above-mentioned numerical value limited defined CIN, the lower limit of wherein said scope is limited by less numerical value, the upper limit of described scope is limited by bigger numerical, for example scopes such as 25-30%, 25-35%, 30-60%.This definition can be explained of short duration, the lasting or irreversible rising of serum creatinine level on the part degree.

By pneumoradiography medium inductive " reduction of kidney blood flow " may be of short duration, persistent or irreversible, preferred of short duration.Healthy people's renal blood flow reference value is kinemic about 20% per minute, thereby is positioned at 1000ml/min.Than kidney blood flow reference value reduce between the 20%-80% or even higher any range defined CIN.Any number or numerical range that the kidney blood flow reduces in the 20-80% scope have defined CIN." reduction of kidney blood flow " as measurable hemodynamic parameter defined the disease degree that the technical staff fully understands.In preferred embodiment, reduce by 20,25,30,35,40,45,50,55,60,65,70,75,80,85 and 90% and any number or the numerical range that are positioned at by any two any scopes that above-mentioned numerical value limited defined CIN, the lower limit of wherein said scope is limited by less numerical value, the upper limit of described scope is limited by bigger numerical, for example scopes such as 25-30%, 20-35%, 30-60%.This definition can be explained of short duration, the lasting and irreversible inhibition of kidney blood flow on the part degree.

Can utilize MRI (nuclear magnetic resonance) technology and PAH (P-aminophippuric acid) infusion techniques to measure the kidney blood flow, to measure kidney blood flow and kidney blood vessel resistance.

Any described A1AR can be with form administrations such as salt, ester, amide, prodrug, active metabolite, analog, solvates, as long as this salt, ester, amide, prodrug, active metabolite, analog or solvate in the context are pharmaceutically acceptable and pharmacologically active.The salt of active component, ester, amide, prodrug, metabolite, analog, solvate and other derivants can utilize the known standard technology of synthetic organic chemistry those skilled in the art to be prepared, for example as J.March (1992 ¹⁹) described.

In concrete embodiment, the present invention also relates to kit, it is included in the unitary package pharmaceutical dosage form that is used to the associating use in the container separately, be included in the pharmaceutical dosage form that comprises at least a A1AR in the container that separates, be included in the pharmaceutical dosage form that comprises at least a RM in the container of opening in second minute.The kit form is particularly conducive to but the situation that is not limited to that separately component must give or gives at different dosing intervals in different dosage forms.Selective adenosine A1 dosage form can advantageously injectable preparation, as solution and suspension.Kit can further comprise description, and it will be that intravenous dosage form is as described herein in packing plug, label and/or the printed instructions on other components of kit usually.Every kind of dosage form can be stored separately.Kit of the present invention also comprises the device of packing independent kit component usually, just dosage form, case and written operation instruction.

Preferably, the A1AR of treatment effective dose is with the mode administration as above emphasized.But in some cases, the patient can be treated the A1AR and the RM of effective dose separately, in the dosage form of separating separately, perhaps in the combination that contains two or more independent " combination " dosage forms for the treatment of effective A1AR.When using the dosage form of separating, A1AR and RM can be in the substantially the same times (walking abreast) or in separately staggered time (successively) administration.When in the RM administration time, keeping the active blood plasma levels concentration of A1AR composition, reach best beneficial effect.Can reach these best beneficial effects by application load dosage succeeded by maintenance dose.Loading dose will be very apace increase blood plasma level, and maintenance dose will keep the blood plasma level that reached.But, the form that comprises whole A1AR and RM is preferred.A kind of like this dosage form is provided convenience for the patient and is oversimplified, thereby increases the probability of patient's compliance.Because two kinds or even the various active composition be to unite use together, the effectiveness of every kind of composition and also must take in by merge the interaction that they are reached together.Within ordinary skill clinicist's authority, purpose is to determine that treatment is gone up effectively or effective dosage is gone up in prevention fully in the consideration of these factors.

Term " alkyl " expression radical of saturated aliphatic group comprises straight chained alkyl, branched alkyl, cycloalkyl (alcyl), the cycloalkyl of alkyl replacement and the alkyl of cycloalkyl substituted.The term alkyl also further comprises oxygen, nitrogen, sulfur or the phosphorus atoms that may further include the one or more carbon that replace hydrocarbon skeleton, for example alkyl of oxygen, nitrogen, sulfur or phosphorus atoms.In preferred embodiment, the straight or branched alkyl has 30 or following carbon atom in its skeleton (for example straight chain is C ₁-C ₃₀, side chain is C ₃-C ₃₀), more preferably 20 or below, for example in one embodiment, " alkyl " can be C ₁-C ₆The perhaps C in further embodiment ₁-C ₄Equally, in one embodiment, cycloalkyl has 4-10 carbon atom in their ring structure, and in further embodiment, cycloalkyl has 5-7 carbon atom in their ring structure, for example have 5,6 or 7 carbon in ring structure.And, spread all over the employed term of description and claims " optional substituted alkyl " and be intended to comprise that " unsubstituted alkyl " and " alkyl of replacement ", the latter represent to have the substituent moieties of the hydrogen on one or more carbon of replacement hydrocarbon skeleton.This class substituent group can for example comprise halogen; hydroxyl; alkyl carbon acyloxy; aryl-carbonyl oxygen; alkoxy carbonyl oxygen base; aryloxy group carbon acyloxy; carboxylate radical; alkyl-carbonyl; alkoxy carbonyl; amino carbonyl; the alkylthio group carbonyl; alkoxyl; phosphate radical; phosphate radical closes (phosphonato); phosphonate radical closes (phosphinato); cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises the alkyl carbon acylamino; the aryl carbon aroylamino base; carbamyl and urea groups); amidino groups; imino group; sulfydryl; alkylthio group; arylthio; the thiocarboxylic acid root; sulfate radical; sulfonate radical closes (sulfonato); sulfamoyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; alkylaryl or aromatics or heteroaromatic moiety.Itself it will be understood by those skilled in the art that if suitably, can be substituted the part that replaces on hydrocarbon chain.Cycloalkyl can further be substituted, and is for example replaced by above-mentioned substituent group.

The alkyl (for example phenyl methyl (benzyl)) that " alkylaryl " part is replaced by aryl.Term " alkyl " also comprises undersaturated aliphatic group, is similar to abovementioned alkyl in length and possible replacement, but contains at least one two keys or three key respectively.

Term used herein " aryl " expression aryl, comprise 5 and 6 yuan of mono-cyclic aromatic group, it can comprise zero to four hetero atoms, for example benzene, pyrroles, furan, thiophene, imidazoles, benzoxazole, benzothiazole, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyridazine and pyrimidine etc.Aryl also comprises multi-ring condensed aromatic group, for example naphthyl, quinolyl, indyl etc.In ring structure, have heteroatomic those aryl and also can be called as " heterocycle ".Aromatic ring can be replaced by above-mentioned substituent group at one or more ring positions, for example halogen; hydroxyl; alkoxyl; alkyl carbon acyloxy; aryl-carbonyl oxygen; alkoxy carbonyl oxygen base; aryloxy group carbon acyloxy; carboxylate radical; alkyl-carbonyl; alkoxy carbonyl; amino carbonyl; the alkylthio group carbonyl; phosphate radical; phosphoryl; phosphono; cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises the alkyl carbon acylamino; the aryl carbon aroylamino base; carbamyl and urea groups); amidino groups; imino group; sulfydryl; alkylthio group; arylthio; the thiocarboxylic acid root; sulfate radical; sulfonyl; sulfamoyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; alkylaryl or aromatics or heteroaromatic moiety.Aryl also can not be the aliphatic series ring or the heterocyclic fused or bridging of aromatics, multi-ring to constitute (for example naphthane).

Atoms of elements beyond term used herein " hetero atom " any de-carbon of expression or the hydrogen, preferred hetero atom is a nitrogen.

To notice that the structure of some The compounds of this invention comprises asymmetric carbon atoms.Correspondingly understand, the isomer (for example whole enantiomer and diastereomer) that is produced by this class unsymmetry comprises all that within the scope of the invention other has except the appointment.By the isolation technics of classics and the synthetic pure basically form that can obtain this class isomer of spatial chemistry control.

Selective adenosine A1 antagonist of the present invention has low lipophilic character and with its high-hydrophilic matter, causes good water-soluble.Remarkable lower lipophilic character district office with compound used therefor of the present invention states chemical compound in other known selectivity A1 antagonisies; At following table (table 1: describe exemplary data the lipophilic character of selective adenosine A1 antagonist).

	The PGP-factor	Permeability (%)	LogP(ACD?v9.05)
	The PGP-factor	Permeability (%)	LogP(ACD?v9.05)	Material 1	1，5	37，4	1，6
Material 2	10，1	27，0	-1，4	Material 1	1，5	37，4	1，6
Material 2	10，1	27，0	-1，4	KW3902	1，4	31，1	4，2

Table 1: the lipophilic character of selective adenosine A1 antagonist

Reach a conclusion in receptors bind and enzyme behavior the algoscopy widely from material 1, material 1 shows as selective adenosine A1 receptors ligand, has certain phosphodiesterase PDE4 and suppresses active.Material 1 is replaced from the relative effectivenes of the rolipram in phosphodiesterase PDE4 site and material 1 inhibition this kind of enzyme relevant; The pKi that suppresses PDE4 is through being calculated as 750nM; Activity to other phosphodiesterases (

PDE

1,2,3,5 and 6) is hanged down at least 25 times.Phosphodiesterase PDE4 suppresses active titration (titration) purpose that can be used for the patient.The phosphodiesterase PDE4 of compound used therefor of the present invention suppresses active for example matters of aggravation may take place by point out self evident non-seriousness signal to the patient, and the headache before for example CNS faints from fear can prevent the overdosage of selectivity A1 antagonist.

Description of drawings

Fig. 1: in the limited rat of volume, carry out hematodinamics and measure, assessment TGF replys.

Fig. 2: experiment is provided with 2 and is used to collect urine.Measure diuresis, urine osmolality and urine viscosity.

Fig. 3: prestige is looked the effect of Parker and 1 pair of renal cortex blood flow of material, looks Parker or carrier (contrast) is measured during back 20 minutes in 0 o'clock time injection prestige.Shown meansigma methods ± SEM (n=9), with look the relative value that cortex flow velocity that Parker (or carrier) write down before attacking compares in prestige and represent. ^*: P＜0.05 prestige is looked Parker vs. contrast; +: P＜0.05 material 1+ prestige is looked Parker vs. prestige and is looked Parker.

Fig. 4: prestige is looked the effect of Parker and 1 pair of renal cortex blood vessel of material electric conductance, looks Parker or carrier (contrast) is measured during back 20 minutes in 0 o'clock time injection prestige.Shown average ± SEM (n=9), with look the relative value that cortex flow velocity that Parker (or carrier) write down before attacking compares in prestige and represent. ^*: P＜0.05 prestige is looked Parker vs. contrast; +: P＜0.05 material 1+ prestige is looked Parker vs. prestige and is looked Parker.

Fig. 5: prestige is looked Parker and 1 pair of renal cortex Oxygenation of material (pO ₂) effect, look Parker or carrier (contrast) is measured during back 20 minutes in 0 o'clock time injection prestige.Shown average ± SEM (n=9), with look the relative value that cortex flow velocity that Parker (or carrier) write down before attacking compares in prestige and represent. ^*: P＜0.05 prestige is looked Parker vs. contrast; +: P＜0.05 material 1+ prestige is looked Parker vs. prestige and is looked Parker.

The specific embodiment

Experiment

Material 1 acute medication in anesthetized rat for diuresis of pneumoradiography medium (amidotrizoic acid) back and natriuretic effect

Utilization is based on by Osswald. ^10,20The experimental program that group announced is induced pneumoradiography medium-dependency acute renal depletion.Make the male Sprague-Dawley rat of the about 300g of body weight adapt to at least 1 week, begin then with the chronic pretreatment of inhibitors of nitric oxide synthase NG-nitro-L-arginine methyl ester (L-NAME 7-9 week, every day dosage 5mg/kg).With regard to experiment, the rat (continuing free near quoting water) of overnight fasting is anaesthetized (80mg/kg, i.p. inject) with 5-sec-butyl-5-ethyl-2-thiobarbituric acid.Conduit is placed (i) trachea, (ii) (be used for administration of pneumoradiography medium and background saline infusion in a jugular vein; As follows), (iii) (be used for carrier or material 1 administration) in another jugular vein, (iv) (be used for blood sampling and a part of background saline infusion in the carotid artery; As follows), and (v) (be used for urine collecting) in the bladder.Rat is remained on the heating platform, with the body temperature of keeping them at 37 ℃.After the urine sample that collection is used for base line measurement reaches 60-90 minute, animals received carrier or material 1 are as follows: 0.15 or 1.5mg material 1/kg that load is injected, perhaps carrier 1mL/kg, the intravenous medication, succeeded by continuous intravenous infusion, speed is 1.5 and 15 μ g material 1/kg/min, and perhaps carrier 11 μ L/kg/min finish up to experiment.Utilize these dosage regimens, the steady state blood plasma level of material 1 is respectively 59 ± 23 and 314 ± 36ng/mL.Material 1 (or carrier) is disposed back 10 minutes of beginning, go through the amidotrizoic acid (meglumine salt that 3 minutes intravenous infusions are warming up to body temperature in advance, Urolux, 0.61g amidotrizoic acid/mL is equivalent to total content of iodine 290mg/mL, Sanochemia Diagnostics, Neuss, Germany), dosage is 2.55mL/kg, and (contrast media time of administration point is defined as t to be equivalent to 740mg iodine/kg ₀).Just in time from beginning infusion background saline solution, speed maintains～1.2mL/h/100g, finishes (0.24mL/h is via ductus arteriosus, and 0.96mL/h is via duct of Arantius) up to experiment.Need this infusion with compensation because operation and subsequently the body fluid of blood sampling lose, but guarantee that also the ductus arteriosus between the blood sampling time point is open.Collect urine sample according to following arrangement: baseline (60-90min before material 1 or the carrier administration), t ₀-30min (0.5h time point), 30-60min (1h time point), 60-120min (2h time point) and 120-180min (3h time point).When finishing, gathers plasma sample in each above-mentioned stage.Utilize Na in measured volume of urine value and the urine ⁺Level calculation is gone through the diuresis and the natruresis speed of above-mentioned interval.

Material 1 is disposed and is compared with the vehicle Control group, produces big in the 30min before after the contrast media administration and significant urine produces increase; Although diuretic speed returns to lower numerical value then in all organizing, but the zest effect of material 1 continues 3h at least.Because the pneumoradiography medium is eliminated via urine, this diuresis effect of material 1 promotes their elimination probably consumingly, thereby limits their toxicity.

Behind the CM

Vehicle Control

Material 1

P is with carrier

Material 1

P is with carrier

Time		Low dosage	Relatively	High dose	Relatively
Time		Low dosage	Relatively	High dose	Relatively	0.5h	17.10±1.42	27.31±2.36	＊＊＊	28.01±2.02	＊＊＊
1h	3.76±0.31	3.87±0.40	n.s.	4.97±0.30	n.s.	0.5h	17.10±1.42	27.31±2.36	＊＊＊	28.01±2.02	＊＊＊
1h	3.76±0.31	3.87±0.40	n.s.	4.97±0.30	n.s.	2h	1.96±0.15	3.34±0.42	＊＊	3.13±0.27	＊＊
3h	2.14±0.40	3.54±0.50	n.s.	3.11±0.36	n.s.	2h	1.96±0.15	3.34±0.42	＊＊	3.13±0.27	＊＊

Table 2: material 1 in anesthetized rat for diuretic effect after the amidotrizoic acid administration.Numerical value is represented with mL/kg body weight/h, represents meansigma methods ± SEM (n=14-24).Utilize one factor analysis of variance succeeded by Bonferroni test evaluation significance,statistical.Compare n.s.: not remarkable with vehicle Control; ^*: P＜0.05; ^*: P＜0.01; With ^{* *}: P＜0.001.

Equally, material 1 is compared the sodium excretion that causes giving prominence to and continue with observed numerical value in the vehicle Control group increases.The drainage of chlorine is subjected to the stimulation of material 1 in a similar manner, and the drainage of potassium is not subjected to the relative influence (not shown) of this chemical compound at whole experimental session.

Time behind the CM	Vehicle Control	Material	1 low dosage	P compares with carrier	Material	1 high dose	P compares with carrier
Time behind the CM	Vehicle Control	Material	1 low dosage	P compares with carrier	Material	1 high dose	P compares with carrier	0.5h	1332±184	3039±354	＊＊＊	3301±306	＊＊＊
1h	185±39	338±81	n.s.	520±77	＊＊			0.5h	1332±184	3039±354	＊＊＊	3301±306	＊＊＊
1h	185±39	338±81	n.s.	520±77	＊＊	2h	153±40	613±121	＊＊	591±88	＊＊
3h	329±72	842±121	＊＊	830±91	＊＊	2h	153±40	613±121	＊＊	591±88	＊＊

Table 3: material 1 in anesthetized rat for the effect of sodium excretion after the amidotrizoic acid administration.Numerical value is represented with μ mol/kg body weight/h, represents meansigma methods ± SEM (n=14-24).Utilize one factor analysis of variance succeeded by Bonferroni test evaluation significance,statistical.Compare n.s.: not remarkable with vehicle Control; ^*: P＜0.05; ^*: P＜0.01; With ^{* *}: P＜0.001.

Material 1 acute medication in anesthetized rat for the effect of pneumoradiography medium (iodixanol) metanephros blood flow and Oxygenation

Experimental program is based on the method for former announcement ^21,22Use bull 3-4 months aged Wistar rats to experimentize.Body weight from 250 to 400g.Rat is accepted standard feed.Feed and drinking-water interrupted about 12 hours before operation.Peritoneal injection urethane solution (2% aqueous solution, 6ml/kg) anesthetized animal place animal on the heating platform, with whole surgery and subsequently experimental session keep body temperature at 37 ℃.After cutting the left side groin, prepare out femoral artery carefully, cannulate is to measure mean arterial blood pressure.Another conduit is placed carotid artery, be used for the administration of contrast media.At last, expandable cuff is placed on around the ventral aorta on the renal artery initial point.The cuff of servomechanism installation control expands and makes the renal perfusion pressure minimizing and maintain default level.The cortex of kidney and outside medullary substance are implanted the optical fiber of two diameter 500 μ m to the left, measuring local laser-Doppler's flux, ultrasonic time difference flow probe are placed on around the renal artery of identical kidney, to measure total renal blood flow (RBF).The same local kidney oxygen level (partial pressure of oxygen=pO that measures ₂) (be respectively cortex and medullary substance pO ₂, OxyLite, OxfordOptronics).After implantation and the stabilisation,, begin experiment by measuring hematodinamics and the oxygenate parameter under the base line condition.Give carrier or material 1 (5mg/kg, intravenous push) then.Carry out new measurement, (prestige is looked Parker 320 to 30 minutes application iodixanols after carrier or material 1 administration; 1.5mL i.a.; Amersham Buchler, Braunschweig, Germany) or carrier.After other 20 minutes, repeated measure (going through 20 minutes, shown in the following accompanying drawing).Experimental group thereby be: 1. carrier+carrier (' contrast '), carrier+prestige looks Parker and material 1+ prestige is looked Parker.

Material 1 does not change prestige and looks Parker attack hemodynamic parameter (arteriotony RBF) (not shown) before.After prestige is looked the Parker administration, observe powerful of short duration mean arterial blood pressure increase (～35mmHg), continue about 10min, prevented (not shown) by material 1 part.Compare with the vehicle Control group, look in the Parker group in carrier+prestige, the renal cortex blood flow shows of short duration initial increase, succeeded by carrying out property and significant reduce (Fig. 3).On the contrary, look the Parker group with carrier+prestige and compare, in the presence of material 1, the cortex blood flow shows lasting and significant increasing, and blood flow significantly raises always and finishes (Fig. 3) up to measuring phases.The cortical vessels conduction is looked Parker by prestige and is reduced rapidly and stably, and material 1 is kept the level (Fig. 4) of this parameter in the vehicle Control group.Medullary substance blood flow rising momently after prestige is looked the Parker injection similarly, (～3min), drop to below the control level then; Be attended by the conduction of medullary substance blood vessel and looked the rapid and inhibition stably of Parker by prestige; Material 1 is only disposed, and part (but significantly) prevents these effect (not shown)s.At last, material 1 causes cortex pO ₂Remarkable increase, continue to finish (Fig. 5) up to experiment.

In a word, these observed results show that material 1 improves kidney hematodinamics and Oxygenation, thus the potential ill-effect of antagonism pneumoradiography medium iodixanol at least in part.

Research approach

Research 1

In 60 anesthetized rats, carry out zooscopy.Assessment kidney hematodinamics is measured the oxygen tension in the kidney after the RM medication.By quantizing the total blood flow of kidney, quantize local blood kinetics by laser-Doppler's flux by the time method.In addition, the regional oxygen tension of assessment kidney is collected urine, to measure osmolality, viscosity and the diuresis of urine.Utilize technology (Wronski, 2003 of setting up recently ²¹), the TGF that might be evaluated in this environment replys.RM significantly reduces the kidney blood flow, upsets regional kidney Oxygenation.This effect is most possible because adhesion properties increases seen as urine viscosity.The administration formerly of A1AR antagonist alleviates or even reverses these RM effects for kidney hematodinamics (kidney blood flow and hypoxidosis).

Work out two kinds of schemes: scheme 1: the fluid restriction occurs in experiment 24h before.This causes that RM concentration increases in the little guard system.Implantation catheter, by time effusion meter, laser-Doppler's probe and sound source, be used to assess absolute pO ₂Record contrast measurement result gives RM then.Scheme 2: then with repeated measure.In the animal of full of liquid, measure volume of urine, osmolality and viscosity.Record contrast measurement result gives RM then.

After the moisture restriction, carry out the assessment that kidney of rats blood flow, oxygen tension and regional blood flow and TGF reply.It generally is the risk factor of generally acknowledging that plasma volume reduces, because CM concentrates in the tubule during diuresis.Fig. 1 describes these schemes.In the hurdle, top, after measuring, contrast gives RM (N=15).Hurdle, the end is depicted in the series (N=15) that RM gives A1AR before.

In order to collect sufficient urine, use the full rat of Bladder Volume.Assessment contrast and RM (N=15, hurdle, Fig. 2 top), the diuresis of contrast, A1AR and A1AR+RM (N=15, hurdle at the bottom of Fig. 2), urine osmolality and viscosity.All experiments are all carried out at Thirty male rats, obtain this rat from the animal housing of institute.The rat grouping is raised in cages.Give various schemes with all animals random assortment.Divide animal with the cage numbering area.Standard rat diet (Altromin 1324, Altromin GmbH, D-32791 Lage) is served as feedstuff.With regard to scheme 1, before operation, interrupt taking food and drinking water about 12 hours.In scheme 2, can arbitrarily drink water.Drinking water is arbitrarily supply, before the CM medication except the 12h.Thereby animal is a hydropenia.In scheme 2, water is arbitrarily supply, up to experiment soon before.(Granulat A2, J.Brandenburg is D-49424Goldenstedt) as the base material of cage to use the graininess veined wood.Between 6:00 and 8:00a.m., change and clean cage every day.Between the laundering period, animal per 3-5 one group is maintained in the MAKROLON cage (4 type) 22 ℃ ± 3 ℃ of room temperatures, relative humidity 60% ± 20%.For example during cleaning procedure, may cause deviation.Introduce anesthesia, keep with urethane.Rat is placed on the heating platform, during whole surgery, keep body temperature at 37 ℃.During studying, control body temperature.After cutting left groin, prepare out femoral artery carefully, with polypropylene conduit (PP10) cannulate, to measure renal perfusion pressure (RPP).Another conduit (PP50) of same material is placed carotid artery, to measure systemic blood pressure (BP) and heart rate (HR).At last, expandable cuff is placed on around the ventral aorta; One on the renal artery initial point, another is beneath.The nearside cuff of servomechanism installation control expands and makes the renal perfusion pressure minimizing and maintain default level.The cortex of kidney and medullary substance are implanted the optical fiber (Mooreinstruments of two diameter 500 μ m to the left, GB), with the ultrasonic time flow probe (1RB that passes through, Transonic Systemsinc, USA) be placed on around the renal artery of identical kidney, to measure regional flow's (being respectively LFC and LFM) and total renal blood flow (RBF).PO ₂Be local mensuration equally.(Moore Instruments GB) measures and assesses regional flow by laser-Doppler flowmeter.Connect ductus arteriosus and pressure transducer through calibrating.Connect expandable cuff and external servo-control system, via prolonging cable connection traffic probe and effusion meter.With corresponding manner fixed oxygen dividing potential drop inducing probes.After analogue signal was converted into digital signal, total data (BP, RPP, RBF, LFC, LFM, local oxygen tension) was passed through computer system (IBM compatible AT) with the online storage of ASCII fromat.After implantation and the stabilisation, begin experiment.The infusion test solution.After the balance 5 minutes, start RBF, local flux and local pO ₂Measurement.Obtain stepping in 5 minutes then and reply, with assessment TGF.Collect urine and reach 35 minutes, to estimate diuresis, osmolality and viscosity.When needed, scheme is made amendment.According to former research (Flemming, 2000 and 2001 ²²) pass through Laser Measurement-Doppler's flux and directly assess pO ₂, total and regional RBF and oxygen tension in assessment renal medulla and the cortex.Calculate after the individual meansigma methods of every kind of parameter, utilize the cell mean and the standard error of each contrast/intervention group of these mean value calculation of every animal.The latter is used for test statistics and learns significant difference, preferably is considered to remarkable less than 0.05 level.According to the parameter of basic data, select the test method that is adopted.

Research 2

Research is similar to Yao (2000 ¹⁰) described, in scheme, select some variations.Different with the research of Yao, carry out chronic and acute experiment.In this research except L-name (N-

-nitro-L-arginine methyl esters) also uses indometacin in addition.

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²¹Wronski?T，Seeliger?E，Persson?PB，Forner?C，Fichtner?C，Scheller?J?et?al.The?step?response：a?method?to?characterizemechanisms?of?renal?blood?flow?autoregulation.Am?J?Physiol?RenalPhysiol?2003；285(4)：F758-F764

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Claims (according to the modification of the 19th of treaty)

1. treat selective adenosine A1 antagonist and/or its pharmaceutically acceptable salt and/or prodrug and/or the purposes of solvate in the preparation medicine of at least a formula I of effective dose,

Wherein

2. treat selective adenosine A1 antagonist and/or its pharmaceutically acceptable salt and/or prodrug and/or the purposes of solvate in the preparation medicine of at least a formula I as defined in claim 1 of effective dose,

Described medicine is used for being increased by the media induced serum creatinine level of at least a pneumoradiography mammal or mankind's prevention, and preferred prevention is by of short duration, the lasting or irreversible increase of the media induced serum creatinine level of pneumoradiography.

3. treat selective adenosine A1 antagonist and/or its pharmaceutically acceptable salt and/or prodrug and/or the purposes of solvate in the preparation medicine of at least a formula I as defined in claim 1 of effective dose,

Described medicine is used for being reduced by the media induced renal blood flow of at least a pneumoradiography mammal or mankind's prevention, and preferred prevention is by of short duration, the lasting or irreversible minimizing of the media induced renal blood flow of pneumoradiography.

4. treat selective adenosine A1 antagonist and/or its pharmaceutically acceptable salt and/or prodrug and/or the purposes of solvate in the preparation medicine of at least a formula I as defined in claim 1 of effective dose,

Described medicine is used for the dangerous or needs in people or mammalian subject prevention dialysis, preferably prevents of short duration, lasting or irreversible dialysis, and described patient accepts the pneumoradiography medium.

5. according to claim 1,2,3 or 4 any one purposes, wherein the time period of the described at least a selectivity A1 adenosine antagonist of application of treatment effective dose is enough to keep the blood plasma level of this at least a selectivity A1 adenosine antagonist at 10～500ng/ml, preferred 20～400ng/ml, the more preferably concentration of 30～300ng/ml.

6. according to

claim

1,2,3,4 or 5 any one purposes, it comprises the described at least a selective adenosine A1 receptor antagonist for the treatment of effective dose with the loading dose intravenous, and comprise maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and is included in the maintenance dose that gives to give during the longest 48 hours after the described at least a selectivity A1 receptor antagonist loading dose this at least a selective adenosine A1 receptor antagonist.

7. according to

claim

1,2,3,4 or 5 any one purposes, it is included in and gives to give at oral formulations before at least a radiopaque contrast medium, preferably the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose in the time-delay delivery formulations.

8. according to

claim

1,2,3,4,5,6 or 7 any one purposes, it comprises not and early to give at least a pneumoradiography medium, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.

9. according to

claim

1,2,3,4,5,6,7 or 8 any one purposes, it comprises maintenance dose a period of time of the described at least a selectivity A1 adenosine antagonist of application of treatment effective dose, this time period is enough to keep the blood plasma level of this at least a selectivity A1 adenosine antagonist at 10～500ng/ml, preferred 20～400ng/ml, the more preferably concentration of 30～300ng/ml.

10. according to

claim

1,2,3,4,5,6,7,8 or 9 any one purposes, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from the pyrrolo-[2 of formula I as defined in claim 1,3d] pyrimidine derivatives, and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

11. according to

claim

1,2,3,4,5,6,7,8,9 or 10 any one purposes, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from 4-[(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino]-anti--Hexalin mesylate or (4S)-4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-L-prolineamide mesylate, and/or its prodrug and/or solvate.

12. according to claim 1,2,3,4,5,6,7,8,9,10 or 11 any one purposes, wherein said at least a pneumoradiography medium is iodate pneumoradiography medium or gadolinio pneumoradiography medium, it is selected from bunaiod, biligram, iopronic acid, pyrrole sieve Parker, iocetamic acid, ethiodized Oil, diodone, propyliodone, iomeglamic acid, gadobutrol, gadodiamide, Dimeglumine Gadopentetate, Gastrografin, Hai Saixian, sodium iodohippurate, mangafodipir, Diatrizoate, ethiodized Oil, iopentol, iodamide, adipiodone, iodixanol, iodophthalein, iofendylate, iomeprol, iomeprol, iopamidol, iopanoic acid, iopiperidol, iofendylate, iopromide, iopydol, the U.S. alcohol of iodine, iotalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, Acidum Metrizoicum, Ipodate, iodine draws sour meglumine, meglumine acetrizoate, cardiografin, metrizamide, dimer-x, Omnipaque, iobenzamic acid, MP-328, iodine phenol sulfonic acid, vasurix, perfluoropropane, phenobutiodil, phentetiothalein sodium, pheniodol, propyliodone, sodium iodomethanesulfonate, iodoxyl, sodium amidotrizoate, iopanoic acid, iophenoic acid, tetrabromophenolphthalein sodium, thorium oxygen glue, thypaque sodium, 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, cheese dissolves hydrochlorate, prestige is looked Parker or Xenetix., and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

13. according to

claim

1,2,3,4,5,6,7,8,9,10,11 or 12 any one purposes, wherein said medicine is a kind of fixed combination.

14. a drug regimen, it comprises

A) selective adenosine A1 antagonist and/or its pharmaceutically acceptable salt and/or prodrug and/or the solvate of at least a formula I of treatment effective dose,

Wherein

R4 and R5 are selected from halogen atom, hydrogen atom or optional substituted alkyl, optional substituted aryl or optional substituted alkylaryl part independently of one another, and perhaps R4 and R5 constitute optional substituted heterocycle or optional substituted carbocyclic ring together; And

B) at least a pneumoradiography medium,

Wherein this drug regimen be suitable for simultaneously, separately or segmentation to people or mammal administration.

15. drug regimen according to claim 14, its selective adenosine A1 receptor antagonist that comprises at least a formula I that treats effective dose is selected from the pyrrolo-[2 of formula I, 3d] pyrimidine derivatives and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate

Wherein

R1 and R2 are selected from hydrogen atom, optional substituted alkyl independently of one another or constitute optional substituted heterocycle together;

R3 is selected from hydrogen atom or optional substituted aryl;

R4 and R5 are selected from halogen atom or hydrogen atom independently of one another;

Preferably, wherein

R1 is a hydrogen atom, and R2 is optional substituted cyclohexyl ring, and perhaps R1 and R2 constitute optional substituted pyrrolidine ring together;

R3 is a benzyl ring;

Each hydrogen atom naturally of R4 and R5;

A) at least a pneumoradiography medium,

16. according to the drug regimen of claim 15, it comprises

A) the described at least a selective adenosine A1 receptor antagonist of treatment effective dose, it is selected from 4-[(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino]-anti--Hexalin mesylate or (4S)-4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-L-prolineamide mesylate, and/or its prodrug and/or solvate; And

B) at least a pneumoradiography medium,

17. according to claim 14,15 or 16 drug regimen, it comprises the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose that gives with the loading dose intravenous, and comprise maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and is included in the maintenance dose that gives to give during the longest 48 hours after the described at least a selectivity A1 receptor antagonist loading dose this at least a selective adenosine A1 receptor antagonist.

18. according to claim 14,15,16 or 17 drug regimen, it is included in and gives to give at oral formulations before at least a pneumoradiography medicine, preferably the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose in the time-delay delivery formulations.

19. according to claim 14,15,16,17 or 18 any one drug regimens, it comprises not and early to give at least a pneumoradiography medium, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.

20. according to claim 14,15,16,17,18 or 19 any one drug regimens, the time period of wherein using at least a selectivity A1 adenosine antagonist is enough to keep the blood plasma level of this at least a selectivity A1 adenosine antagonist at 10～500ng/ml, preferred 20～400ng/ml, the more preferably concentration of 30～300ng/ml.

21. according to claim 14,15,16,17,18,19 or 20 any one drug regimens, wherein said at least a pneumoradiography medium is iodate pneumoradiography medium or gadolinio pneumoradiography medium, it is selected from bunaiod, biligram, iopronic acid, pyrrole sieve Parker, iocetamic acid, ethiodized Oil, diodone, propyliodone, iomeglamic acid, gadobutrol, gadodiamide, Dimeglumine Gadopentetate, Gastrografin, Hai Saixian, sodium iodohippurate, mangafodipir, Diatrizoate, ethiodized Oil, iopentol, iodamide, adipiodone, iodixanol, iodophthalein, iofendylate, iomeprol, iomeprol, iopamidol, iopanoic acid, iopiperidol, iofendylate, iopromide, iopydol, the U.S. alcohol of iodine, iotalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, Acidum Metrizoicum, Ipodate, iodine draws sour meglumine, meglumine acetrizoate, cardiografin, metrizamide, dimer-x, Omnipaque, iobenzamic acid, MP-328, iodine phenol sulfonic acid, vasurix, perfluoropropane, phenobutiodil, phentetiothalein sodium, pheniodol, propyliodone, sodium iodomethanesulfonate, iodoxyl, sodium amidotrizoate, iopanoic acid, iophenoic acid, tetrabromophenolphthalein sodium, thorium oxygen glue, thypaque sodium, 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, cheese dissolves hydrochlorate, prestige is looked Parker or Xenetix., and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

22. a kit, it comprises

Wherein

B) at least a pneumoradiography medium,

23. according to the kit of claim 22, it comprises

(a) at least a selective adenosine A1 receptor antagonist and/or its pharmaceutically acceptable salt and/or prodrug and/or the solvate of the formula I of treatment effective dose,

Wherein

R3 is selected from hydrogen atom or optional substituted aryl;

Preferably, wherein

R3 is a benzyl ring;

Each hydrogen atom naturally of R4 and R5; And

B) at least a pneumoradiography medium,

24. the kit according to claim 23 wherein comprises

A) at least a selective adenosine A1 receptor antagonist of treatment effective dose, it is selected from 4-[(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino]-anti--Hexalin mesylate or (4S)-4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-L-prolineamide mesylate, and/or its prodrug and/or solvate, and

B) at least a pneumoradiography medium,

25. according to claim 22,23 or 24 any one kits, it comprises

A) the loading dose container of the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose that gives of intravenous,

B) the maintenance dose container of the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose that gives of intravenous,

C) at least a pneumoradiography medium,

It comprises with the loading dose intravenous and gives described at least a selective adenosine A1 receptor antagonist, and comprise maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and is included in the maintenance dose that gives to give during the longest 48 hours after the described at least a selectivity A1 receptor antagonist loading dose this at least a selective adenosine A1 receptor antagonist.

26. according to claim 22,23 or 24 any one kits, it comprises

A) contain the container of described at least a selective adenosine A1 receptor antagonist of the treatment effective dose of orally give,

B) at least a pneumoradiography medium,

It is included in and gives to give at oral formulations before at least a pneumoradiography medicine, preferably the described at least a selective adenosine A1 receptor antagonist in the time-delay delivery formulations.

27. according to claim 22,23,24,25 or 26 any one kits, it comprises the described at least a pneumoradiography medium of early not treating effective dose, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.

28. according to claim 22,23,24,25,26 or 27 any one kits, wherein the time period of the described at least a selectivity A1 adenosine antagonist of application of treatment effective dose is enough to keep the blood plasma level of this at least a selectivity A1 adenosine antagonist at 10～500ng/ml, preferred 20～400ng/ml, the more preferably concentration of 30～300ng/ml.

29. according to claim 22,23,24,25,26,27 or 28 any one kits, wherein said at least a pneumoradiography medium is iodate pneumoradiography medium or gadolinio pneumoradiography medium, it is selected from bunaiod, biligram, iopronic acid, pyrrole sieve Parker, iocetamic acid, ethiodized Oil, diodone, propyliodone, iomeglamic acid, gadobutrol, gadodiamide, Dimeglumine Gadopentetate, Gastrografin, Hai Saixian, sodium iodohippurate, mangafodipir, Diatrizoate, ethiodized Oil, iopentol, iodamide, adipiodone, iodixanol, iodophthalein, iofendylate, iomeprol, iomeprol, iopamidol, iopanoic acid, iopiperidol, iofendylate, iopromide, iopydol, the U.S. alcohol of iodine, iotalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, Acidum Metrizoicum, Ipodate, iodine draws sour meglumine, meglumine acetrizoate, cardiografin, metrizamide, dimer-x, Omnipaque, iobenzamic acid, MP-328, iodine phenol sulfonic acid, vasurix, perfluoropropane, phenobutiodil, phentetiothalein sodium, pheniodol, propyliodone, sodium iodomethanesulfonate, iodoxyl, sodium amidotrizoate, iopanoic acid, iophenoic acid, tetrabromophenolphthalein sodium, thorium oxygen glue, thypaque sodium, 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, cheese dissolves hydrochlorate, prestige is looked Parker or Xenetix., and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

Claims

Wherein

6. according to claim 1,2,3,4 or 5 any one purposes, it comprises the described at least a selective adenosine A1 receptor antagonist for the treatment of effective dose with the loading dose intravenous, and comprise maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and is included in the maintenance dose that gives to give during the longest 48 hours after the described at least a selectivity A1 receptor antagonist loading dose this at least a selective adenosine A1 receptor antagonist.

7. according to claim 1,2,3,4 or 5 any one purposes, it is included in and gives to give at oral formulations before at least a radiopaque contrast medium, preferably the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose in the time-delay delivery formulations.

8. according to claim 1,2,3,4,5,6 or 7 any one purposes, it comprises not and early to give at least a pneumoradiography medium, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.

9. according to claim 1,2,3,4,5,6,7 or 8 any one purposes, it comprises maintenance dose a period of time of the described at least a selectivity A1 adenosine antagonist of application of treatment effective dose, this time period is enough to keep the blood plasma level of this at least a selectivity A1 adenosine antagonist at 10～500ng/ml, preferred 20～400ng/ml, the more preferably concentration of 30～300ng/ml.

10. according to claim 1,2,3,4,5,6,7,8 or 9 any one purposes, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from the pyrrolo-[2 of formula I as defined in claim 1,3d] pyrimidine derivatives, and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

11. according to claim 1,2,3,4,5,6,7,8,9 or 10 any one purposes, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from 4-[(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino]-anti--Hexalin mesylate or (4S)-4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-L-prolineamide mesylate, and/or its prodrug and/or solvate.

13. according to claim 1,2,3,4,5,6,7,8,9,10,11 or 12 any one purposes, wherein said medicine is a kind of fixed combination.

14. a drug regimen, it comprises

A) at least a selective adenosine A1 antagonist of treatment effective dose, and

B) at least a pneumoradiography medium,

15. drug regimen according to claim 14, it comprises the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose that gives with the loading dose intravenous, and comprise maintenance dose, before giving described at least a pneumoradiography medium 5～25 minutes, preferred 10～20 minutes, more preferably 13～17 minutes, more preferably 15 minutes time period gives the loading dose of this at least a selective adenosine A1 receptor antagonist, and is included in the maintenance dose that gives to give during the longest 48 hours after the described at least a selectivity A1 receptor antagonist loading dose this at least a selective adenosine A1 receptor antagonist.

16. according to the drug regimen of claim 14, it is included in and gives to give at oral formulations before at least a pneumoradiography medicine, preferably the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose in the time-delay delivery formulations.

17. according to claim 14,15 or 16 any one drug regimens, it comprises not and early to give at least a pneumoradiography medium, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.

18. according to claim 14,15,16 or 17 any one drug regimens, the blood plasma level that the time period of wherein using at least a selectivity A1 adenosine antagonist is enough to keep this at least a selectivity A1 adenosine antagonist is at 10～500ng/ml, and preferred 20～400

Ng/ml, the more preferably concentration of 30～300ng/ml.

19. according to claim 14,15,16,17 or 18 any one drug regimens, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from the pyrrolo-[2 of formula I, 3d] pyrimidine derivatives and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate

Wherein

R4 and R5 are selected from halogen atom, hydrogen atom or optional substituted alkyl, optional substituted aryl or optional substituted alkylaryl part independently of one another, and perhaps R4 and R5 constitute optional substituted heterocycle or optional substituted carbocyclic ring together.

20. according to claim 14,15,16,17, any one drug regimen of 18 or 19, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from the pyrrolo-[2 of formula I, 3d] pyrimidine derivatives and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate

Wherein

R3 is selected from hydrogen atom or optional substituted aryl;

Preferably, wherein

R3 is a benzyl ring;

Each hydrogen atom naturally of R4 and R5.

21. according to claim 14,15,16,17,18,19 or 20 any one drug regimens, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from 4-[(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino]-anti--Hexalin mesylate or (4S)-4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-L-prolineamide mesylate, and/or its prodrug and/or solvate.

22. according to any claim 14,15,16,17,18,19,20 or 21 drug regimen, wherein said at least a pneumoradiography medium is iodate pneumoradiography medium or gadolinio pneumoradiography medium, it is selected from bunaiod, biligram, iopronic acid, pyrrole sieve Parker, iocetamic acid, ethiodized Oil, diodone, propyliodone, iomeglamic acid, gadobutrol, gadodiamide, Dimeglumine Gadopentetate, Gastrografin, Hai Saixian, sodium iodohippurate, mangafodipir, Diatrizoate, ethiodized Oil, iopentol, iodamide, adipiodone, iodixanol, iodophthalein, iofendylate, iomeprol, iomeprol, iopamidol, iopanoic acid, iopiperidol, iofendylate, iopromide, iopydol, the U.S. alcohol of iodine, iotalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, Acidum Metrizoicum, Ipodate, iodine draws sour meglumine, meglumine acetrizoate, cardiografin, metrizamide, dimer-x, Omnipaque, iobenzamic acid, MP-328, iodine phenol sulfonic acid, vasurix, perfluoropropane, phenobutiodil, phentetiothalein sodium, pheniodol, propyliodone, sodium iodomethanesulfonate, iodoxyl, sodium amidotrizoate, iopanoic acid, iophenoic acid, tetrabromophenolphthalein sodium, thorium oxygen glue, thypaque sodium, 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, cheese dissolves hydrochlorate, prestige is looked Parker or Xenetix., and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.

23. a kit, it comprises

B) at least a pneumoradiography medium,

24. according to the kit of claim 23, it comprises

C) at least a pneumoradiography medium,

25. according to the kit of claim 23, it comprises

B) at least a pneumoradiography medium,

It is included in and gives to give at oral formulations before at least a pneumoradiography medicine, preferably the described at least a selective adenosine A1 receptor antagonist of the treatment effective dose in the time-delay delivery formulations.

26. according to claim 23,24 or 25 any one kits, it comprises the described at least a pneumoradiography medium of early not treating effective dose, described at least a selective adenosine A1 receptor antagonist up to the treatment effective dose is enough to provide 10～500ng/ml, preferred 20～400ng/ml, more preferably the blood plasma level concentration of 30～300ng/ml.

27. according to claim 23,24,25 or 26 any one kits, wherein the time period of the described at least a selectivity A1 adenosine antagonist of application of treatment effective dose is enough to keep the blood plasma level of this at least a selectivity A1 adenosine antagonist at 10～500ng/ml, preferred 20～400ng/ml, the more preferably concentration of 30～300ng/ml.

28. according to claim 23,24,25,26 or 27 any one kits, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from the pyrrolo-[2 of formula I, 3d] pyrimidine derivatives and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate

Wherein

29. according to claim 23,24,25,26,27 or 28 any one kits, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from the pyrrolo-[2 of formula I, 3d] pyrimidine derivatives and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate

Wherein

R3 is selected from hydrogen atom or optional substituted aryl;

Preferably, wherein

R3 is a benzyl ring;

Each hydrogen atom naturally of R4 and R5.

30. according to claim 23,24,25,26,27,28 or 29 any one kits, the described at least a selective adenosine A1 receptor antagonist of wherein treating effective dose is selected from 4-[(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) amino]-anti--Hexalin mesylate or (4S)-4-hydroxyl-1-(2-phenyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-L-prolineamide mesylate, and/or its prodrug and/or solvate.

31. according to claim 23,24,25,26,27,28,29 or 30 any one kits, wherein said at least a pneumoradiography medium is iodate pneumoradiography medium or gadolinio pneumoradiography medium, it is selected from bunaiod, biligram, iopronic acid, pyrrole sieve Parker, iocetamic acid, ethiodized Oil, diodone, propyliodone, iomeglamic acid, gadobutrol, gadodiamide, Dimeglumine Gadopentetate, Gastrografin, Hai Saixian, sodium iodohippurate, mangafodipir, Diatrizoate, ethiodized Oil, iopentol, iodamide, adipiodone, iodixanol, iodophthalein, iofendylate, iomeprol, iomeprol, iopamidol, iopanoic acid, iopiperidol, iofendylate, iopromide, iopydol, the U.S. alcohol of iodine, iotalamic acid, iotrolan, ioversol, ioxilan, ioxaglic acid, Acidum Metrizoicum, Ipodate, iodine draws sour meglumine, meglumine acetrizoate, cardiografin, metrizamide, dimer-x, Omnipaque, iobenzamic acid, MP-328, iodine phenol sulfonic acid, vasurix, perfluoropropane, phenobutiodil, phentetiothalein sodium, pheniodol, propyliodone, sodium iodomethanesulfonate, iodoxyl, sodium amidotrizoate, iopanoic acid, iophenoic acid, tetrabromophenolphthalein sodium, thorium oxygen glue, thypaque sodium, 1,3,5-three n-hexyls-2,4, the 6-triiodo-benzene, cheese dissolves hydrochlorate, prestige is looked Parker or Xenetix., and/or its pharmaceutically acceptable salt and/or prodrug and/or solvate.