CN1753661A - Adenosine a1 receptor antagonist for the treatment of cardiac and renal diseases - Google Patents
Adenosine a1 receptor antagonist for the treatment of cardiac and renal diseases Download PDFInfo
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- CN1753661A CN1753661A CN 200480004903 CN200480004903A CN1753661A CN 1753661 A CN1753661 A CN 1753661A CN 200480004903 CN200480004903 CN 200480004903 CN 200480004903 A CN200480004903 A CN 200480004903A CN 1753661 A CN1753661 A CN 1753661A
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Abstract
Disclosed are pharmaceutical composition comprising a beta-blocker and an adenosine A1 receptor antagonist (AA1RA), an angiotensin converting enzyme (ACE) inhibitor and an adenosine A1 receptor antagonist (AA1RA), and an angiotensin II receptor blocker (ARB) and an adenosine A1 receptor antagonist (AA1RA). Also disclosed are methods of treating cardiovascular disease, renal disease, alkalosis, or diabetic nephropathy comprising identifying a patient in need of such treatment, and administering a pharmaceutical composition disclosed herein to said patient.
Description
Related application
The 60/449th, No. 953 U.S. Provisional Patent Application of " using the method for angiotensin-convertion enzyme inhibitor or angiotensin-ii receptor blockers and adenosine A 1 receptor antagonists and beta blocker treatment disease " (METHOD OF TREATMENT OF DISEASE USING AN ANGIOTENSINCONVERTING ENZYME INHIBITOR OR AN ANGIOTENSIN II RECEPTOR BLOCKERAND AN ADENOSINE A1RECEPTOR ANTAGONIST AND A BETA-BLOCKER) by name that people such as present patent application requirement Dittrich applied on February 24th, 2003; The 60/450th, No. 499 U.S. Provisional Patent Application of " using the method for adenosine A 1 receptor antagonists and beta blocker treatment disease " (METHOD OF TREATMENT OFDISEASE USING AN ADENOSINE A1 RECEPTOR ANTAGONIST AND ABETA-BLOCKER) by name that people such as Dittrich applied on February 25th, 2003; The 60/450th, No. 500 U.S. Provisional Patent Application of " using adenosine A 1 receptor antagonists with the prevent diabetes nephropathy in pro-sugar futures urine patient and the early diabetes " (USE OF ADENOSINE A1 RECEPTOR ANTAGONISTS IN PRE-DIABETICPATIENTS AND EARLY DIABETES MELLITUS FOR THE PREVENTION OF DIABETICNEPHORPATHY) by name that people such as Dittrich applied on February 25th, 2003; The 60/451st, No. 326 U.S. Provisional Patent Application of " using adenosine A 1 receptor antagonists to treat alkalotic method " (METHOD OF TREATINGALKALOSIS USING ADENOSINE A1 RECEPTOR ANTAGONISTS) by name that people such as Dittrich applied on February 28th, 2003; The 60/464th, No. 811 U.S. Provisional Patent Application of " using adenosine A 1 receptor antagonists to treat alkalotic method " (METHOD OF TREATING ALKALOSIS USING ADENOSINE A1RECEPTORANTAGONISTS) by name that people such as Dittrich applied on April 21st, 2003; The 60/464th, No. 812 U.S. Provisional Patent Application of " using the method for angiotensin-convertion enzyme inhibitor or angiotensin-ii receptor blockers and adenosine A 1 receptor antagonists and beta blocker treatment disease " (METHOD OF TREATMENT OFDISEASE USING AN ANGIOTENSIN CONVERTING ENZYME INHIBITOR OR ANANGIOTENSIN II RECEPTOR BLOCKER AND AN ADENOSINE A1 RECEPTORANTAGONIST AND A BETA-BLOCKER) by name that people such as Dittrich applied on April 21st, 2003; The 60/464th, No. 813 U.S. Provisional Patent Application of " purposes that is used for the prevent diabetes nephropathy in adenosine A 1 receptor antagonists pro-sugar futures urine patient and the early diabetes " (USE OF ADENOSINE A1 RECEPTORANTAGONISTS IN PRE-DIABETIC PATIENTS AND EARLY DIABETES MELLITUSFOR THE PREVENTION OF DIABETIC NEPHORPATHY) by name that people such as Dittrich applied on April 21st, 2003; And the priority of people's such as Dittrich " using adenosine A 1 receptor antagonists and beta blocker to treat the method for disease " (the METHOD OF TREATMENT OF DISEASE USING ANADENOSINE A1 RECEPTOR ANTAGONIST AND A BETA-BLOCKER) by name that apply on April 21st, 2003 the 60/464th, No. 815 U.S. Provisional Patent Application; The full text of all temporary patent applications is incorporated herein by reference.
Technical field
The present invention relates to medical composition, its comprise one separately or with the adenosine A 1 receptor antagonists of other medicines combinations, and the method for suffering from the patient of heart disease and/or renal failure with described combination treatment.
Background technology
Summary of the invention
The present invention discloses a kind of medical composition, and it comprises a beta blocker (beta-blocker) and an adenosine A
1Receptor antagonist (adenosine A
1Receptor antagonist, AA
1RA).
In addition, the present invention discloses a kind of medical composition, and it comprises an angiotensin converting enzyme (angiotensinconverting enzyme, ACE) inhibitor and an adenosine A
1Receptor antagonist (AA
1RA).
In addition, the present invention discloses a kind of medical composition, and it comprises an angiotensin-ii receptor blockers, and (angiotensinII receptor blocker is ARB) with an adenosine A
1Receptor antagonist (AA
1RA).
The present invention also discloses a kind of method for the treatment of cardiovascular disease or kidney disease, and it comprises determines the described treatment of a needs of patients, and gives the medical composition that described patient this paper discloses.
This paper discloses the alkalotic method of treatment, and it comprises determines the described treatment of a needs of patients, and gives described patient's adenosine A
1Receptor antagonist (AA
1RA).The present invention also discloses and comprises AA
1The medical composition of RA.
This paper discloses the method for treatment of diabetic nephropathy, and it comprises determines the described treatment of a needs of patients, and gives described patient's adenosine A
1Receptor antagonist (AA
1RA).The present invention also discloses and comprises AA
1The medical composition of RA.
The specific embodiment
AA
1RA
The aspect of this disclosure relates to separately or makes up with one or more other medicines uses AA
1The method of RA treatment various diseases.Although current many AA
iRA can not buy as therapeutic agent, but its in this technology for known to us.AA
1RA optionally resists the A of adenosine
1Receptor.Most of known AA
1RA is xanthic derivant and comprises as 1,3-dipropyl-8-{3-oxatricyclo [3.1.2.0.
2,4] hot-6 (7)-yl } xanthine (1,3-dipropyl-8-{3-oxatricyclo[3.1.2.0.
2,4] oct-6 (7)-yl}xanthine) (is also referred to as 1,3-dipropyl-8-[5, outside the 6--and epoxy-2 (S) norborny] xanthine (1,3-dipropyl-8-[5,6-exo-epoxy-2 (S) norbornyl] xanthine), ENX, CVT-124 and BG9719), 8-(3-noradamantyl)-1, (8-(3-noradamantyl)-1 3-dipropylxanthine) (is also referred to as KW-3902), the chemical compound of theophylline and caffeine to 3-dipropyl xanthine.The 5th, 446,046,5,631,260 and 5,668, disclosed other AA in No. 139 United States Patent (USP)s
1RA, the full text of the description of all patents (comprising institute's drawings attached) is incorporated herein by reference.Category of the present invention comprises the present known AA of all that
1The AA that RA and all that are in the future to be found
1RA.
The AA that uses in medical composition that this paper discloses or the method
1RA can be the xanthine derivative chemical compound.Described xanthine derivative chemical compound can be chemical compound or its pharmaceutically acceptable salt of formula I,
Wherein
X
1With X
2Independent separately expression oxygen or sulfur;
Q represents:
Wherein Y represents a singly-bound or has the alkylene of 1 to 4 carbon atom, and n represents 0 or 1;
R
1With R
2Independent separately expression hydrogen, low-carbon alkyl, pi-allyl, propargyl or hydroxyl replacement, oxygen replace or unsubstituted low-carbon alkyl, and R
3Expression hydrogen or low-carbon alkyl, perhaps
R
4With R
5Identical or different and represent hydrogen or hydroxyl separately, and work as R
4With R
5When being hydrogen, R
1With R
2In at least one is the low-carbon alkyl that hydroxyl replaces or oxygen replaces,
But when Q is
The time, R then
1, R
2With R
3Be not methyl simultaneously.
In certain embodiments, the R in the formula I chemical compound
1With R
2Be low-carbon alkyl and R
3Be hydrogen; And X
1With X
2Be oxygen.In other embodiments, R
1, R
2And R
3Independent expression hydrogen or low-carbon alkyl.In other other embodiment, R
1With R
2Independent separately expression pi-allyl or propargyl and R
3Expression hydrogen or low-carbon alkyl.In certain embodiments, X
1With X
2Being oxygen and n is 0.
In certain embodiments, R
1For hydroxyl replaces, oxygen replaces or unsubstituted propyl group; R
2For hydroxyl replaces or unsubstituted propyl group; And Y is a singly-bound.In other embodiments, R
1Be propyl group, 2-hydroxypropyl, 2-oxopropyl or 3-oxopropyl; R
2Be propyl group, 2-hydroxypropyl or 3-hydroxypropyl.
In certain embodiments, Q is
And in other embodiments, Q is
In other embodiments, Q is that 9-hydroxyl, 9-oxo or 6-hydroxyl replace 3-three ring [3.3.1.0
3,7] nonyl (3tricyclo[3.3.1.0
3,7] nonyl) or 3-hydroxyl-1-three ring [3.3.1.1
3,7] decyl (3-hydroxy-ltricyclo[3.3.1.1
3,7] decyl).
In certain embodiments, described AA
1RA is selected from the group that is made up of following each thing: 8-(falling diamantane (obsolete)-3-yl)-1,3-dipropyl xanthine (8-(noradamantan-3-yl)-1,3-dipropylxanthine), 1, (3-allyl-8-(3-noradamantyl)-1-propargylxanthine), 8-are (anti--9-hydroxyl-3-three ring [3.3.1.0 for 3-diallyl-8-(3-noradamantyl) xanthine (1,3-Diallyl-8-(3-noradamantyl) xanthine), 3-pi-allyl-8-(3-noradamantyl)-1-propargyl xanthine
3,7] nonyl)-1,3-dipropyl xanthine (8-(trans-9-hydroxy-3-tricyclo[3.3.1.0
3,7] nonyl)-1,3-dipropylxanthine), 8-is (suitable-9-hydroxyl-3-three ring [3.3.1.0
3,7] nonyl)-1,3-dipropyl xanthine (8-(cis-9-hydroxy-3-tricyclo[3.3.1.0
3,7] nonyl)-1,3-dipropylxanthine), 8-is (anti--9-hydroxyl-3-three ring [3.3.1.0
3,7] nonyl)-1-(2-oxopropyl)-3-propyl group xanthine (8-(trans-9-hydroxy-3-tricyclo[3.3.1.0
3,7] nonyl-1-(2-oxopropyl)-3-propylxanthine) and 1-(2-hydroxypropyl)-8-be (anti--9-hydroxyl-3-three ring [3.3.1.0
3,7] nonyl)-3-propyl group xanthine (1-(2-hydroxypropyl)-8-(trans-9-hydroxy-3-tricyclo[3.3.1.0
3,7] nonyl)-3-propylxanthine), or its pharmaceutically acceptable salt.
In other embodiments, described AA
1RA is the xanthine epoxides chemical compound of formula II or formula III, or its pharmaceutically acceptable salt,
R wherein
6With R
7Identical or different, and can be hydrogen or one group of 1 alkyl, R to 4 carbon atoms
8Be oxygen or (CH
2)
1-4, and n=0-4.
Described xanthine epoxides chemical compound can be
Combination with beta blocker
Aspect of the present invention relates to uses beta blocker and adenosine A
1Receptor antagonist (or AA
1RA) combined therapy cardiovascular disease.In the treatment as the cardiovascular disease of congestive heart failure, hypertension, silent left ventricular dysfunction or coronary artery disease, each in these chemical compounds all demonstrates some effect a little separately.
Many beta blockers can be buied.These chemical compounds include, but is not limited to Acebutolol (acebutololhydrochloride), atenolol (atenolol), betaxolol hydrochloride (betaxolol hydrochloride), bisoprolol fumarate (bisoprolol fumarate), carteolol hydrochloride (carteolol hydrochloride), esmolol hydrochloride (esmolol hydrochloride), metoprolol (metoprolol), spectinomycin hydrochloride (metoprolol tartrate), nadolol (nadolol), penbutolol sulfate (penbutolol sulfate), pindolol (pindolol), propranolol hydrochloride (propranolol hydrochloride), succinate and timolol maleate (timolol maleate).Beta blocker is generally β
1And/or β
2The adrenoceptor blocker, it reduces positive chronotropic action, positive inotropic action, bronchiectasis and the vasodilation reaction that is caused by the beta-2 adrenoceptor agonist.Category of the present invention comprises present known beta blocker of all that and all that beta blocker in the future to be found.
Can run into a major issue with some disease of independent Drug therapy the time, the patient becomes after the treatment of a period of time and is difficult to treatment, and promptly the patient begins the fewer and feweri reaction of medicine until not reaction.This problem is suffering from for example congestive heart failure, and very general among the patient who treats with diuretic.
Independent diuretic works to a specific part of nephron, as proximal tubule, henle's loop (loop of henle) or distal tubule.The mechanism that diuretic increases the urine amount flows through the sodium of nephron for its inhibition and the absorption again of the water followed.Thereby for example, loop diuretic (loop diuretic) can suppress the resorption in the henle's loop.As a result, the sodium of higher concentration flow to distal tubule downwards.Initial this can cause more urine amount, therefore has diuresis.Yet increase and kidney that the distal portions of tubule identifies na concn react in two ways: a kind of is the absorption again that increases sodium in the nephron elsewhere; Another kind is to pass through adenosine A
1Receptor feeds back to afferent arteriole, and vasoconstriction takes place there.This feedback mechanism be known as pipe ball feedback (tubuloglomerular feedback, TGF).This vasoconstriction causes minimizing and glomerular filtration rate (glomerular filtration rate, minimizing GFR) of renal blood flow.As time goes on, these two mechanism cause the reduction of diuresis and the deterioration of renal function.The order of these some phenomenons promotes advancing of disease.
The present inventor has been found that AA
1The combination of RA and beta blocker be of value to congestive heart failure (congestiveheart failure, CHF) or hypertension, or other any signs as herein described.Known beta blocker has antihypertensive effect.Really cutter system is also unknown although they act on, and has proposed possible mechanism, as reducing cardiac output, reducing plasma renin activity and the anti-sympathetic nerve effect of central nervous system.According to various clinical researches, give hyperpietic's beta blocker and obviously can cause kinemic minimizing, very little blood pressure to change immediately at first and the increase of the Peripheral resistance that calculates.Along with continuing administration, blood pressure reduced in several days, and cardiac output still reduces and Peripheral resistance is reduced to the preceding level of treatment.Hyperpietic's plasma renin activity also obviously reduces, and this will have an inhibitory action to renin-angiotensin system, thereby reduces afterload and the feasible cardiac function that more effectively promotes.The use of these chemical compounds has demonstrated can increase the survival rate of suffering from CHF or hypertensive patient.Described chemical compound is now for treating the part of CHF and hypertensive standard drug.
AA
1RA works to CHF patient's kidney afferent arteriole, produces vasodilation and therefore improves renal blood flow.They are also blocked by above-mentioned adenosine and (pass through A
1Receptor) Jie Dao TGF mechanism.This finally makes GFR increase and renal function improves.In addition, AA
1RA suppresses the absorption again (and thereby suppress the absorption again of water) of sodium in the proximal tubule, and it causes diuresis.
Combination acts synergistically of the present invention described herein is with the further disease of improving hypertension or CHF patient.Especially in the salt-sensitive hypertension patient, AA
1The diuresis of RA brings high blood pressure down by two kinds of different mechanism together with the blocking-up of Beta-3 adrenergic receptor, and their effect is based upon over each other.In addition, most of CHF patient also needs extra diuretic.By improving renal blood flow and renal function, described combination makes more how far other hold the bigger effect of the diuretic that works to prepare.
Beta blocker is very definite in hypertensive treatment.AA
1The interpolation of RA will further be treated hypertension by the resorbent diuresis that the sodium of proximal tubule is flow through in its inhibition.In addition, because many hyperpietics are sodium sensitivity, so add AA
1RA will cause further blood pressure to reduce to beta blocker.AA
1RA acts on pipe ball feedback (tubuloglomerular feedback) thereby can further improve renal function causes stronger diuresis and lower blood pressure.
Thereby, this disclosure relate in one aspect to an a kind of beta blocker and adenosine A of comprising
1Receptor antagonist (AA
1RA) medical composition.The group that following each thing of the optional freedom of described beta blocker is formed: Acebutolol, atenolol, betaxolol hydrochloride, bisoprolol fumarate, carteolol hydrochloride, esmolol hydrochloride, metoprolol, spectinomycin hydrochloride, nadolol, penbutolol sulfate, pindolol, propranolol hydrochloride, succinate and timolol maleate, or its pharmaceutically acceptable salt, prodrug, ester or amide.Yet, comprise other beta blockers also within category of the present invention.
This disclosure relate to a kind of method for the treatment of cardiovascular disease or kidney disease on the other hand, it comprises determines the described treatment of a needs of patients, and gives described patient medical composition described herein.In certain embodiments, described patient may be a mammal, the group that following each animal of the optional freedom of described mammal is formed: little muroid, rat kind, Lagomorpha, Cavia porcellus class, dog class, cat class, sheep class, goat class, cow class, primates (as monkey, chimpanzee and ape) and the mankind.In certain embodiments, described patient is human.
In certain embodiments, dosing step comprises and almost gives described beta blocker and described AA simultaneously
1RA.These embodiment comprise AA
1RA and the embodiment of beta blocker in the identical compositions that gives promptly contain a single tablet, pill or the capsule of two kinds of chemical compounds, or injection solution in the azygos vein, or a single drinkable solution, or a single sugar-coat prescription or an ointment.Described embodiment also comprises the embodiment of each chemical compound in the compositions that can separately give, but instruct the patient almost to take described compositions of separating simultaneously, promptly after taking a pill, take another pill at once or behind a kind of chemical compound of injection, inject another kind of chemical compound etc. at once.
In other embodiments, dosing step comprises and at first gives beta blocker and AA
1A kind of among the RA also then gives beta blocker and AA
1Another kind among the RA.In these embodiments, can give patient one and comprise a kind of compositions in the described chemical compound, and then give another afterwards and comprise alternative compositions in the described chemical compound in certain period (a few minutes or several hours).Comprise also among these embodiment that with conventional or serve as that the basis gives patient one and comprises a kind of compositions in the described chemical compound continuously acceptance comprises the embodiment of another kind of compound compositions once in a while simultaneously.
The inventive method is desirable to provide the treatment for cardiovascular disease, and it can comprise arrhythmia, recurrent ventricular tachycardia, recurrent ventricular fibrillation, coronary artery disease or acute myocardial infarction that congestive heart failure, hypertension, silent left ventricular dysfunction, auricular fibrillation, other modalities (modality) are difficult to treat.In some cases, the needs of patients of suffering from cardiovascular disease reduces afterload.The inventive method also is suitable for these patients treatment is provided.
The present invention relates to a kind of medical composition on the other hand, and it comprises a kind of aforesaid AA
1The combination of RA and beta blocker, and the physiology goes up acceptable supporting agent, diluent or excipient or its combination.
Combination with angiotensin-convertion enzyme inhibitor or angiotensin-ii receptor blockers
Aspect of the present invention relates to the use adenosine A
1Receptor antagonist (or AA
1RA) treat kidney and/or heart disease with the combination of angiotensin converting enzyme (ACE) inhibitor or angiotensin-ii receptor blockers (ARB).In as the heart disease of congestive heart failure, hypertension, silent left ventricular dysfunction or acute myocardial infarction or the treatment as the kidney disease of the nephropathy of the kidney injury of the nephropathy of diabetic nephropathy, contrast agent mediation, toxin-induced or Mediated by Free Radicals, each in these chemical compounds all demonstrates some effect a little separately.
Many ACE inhibitor can be buied.The similar a bit chemical compound of these chemical constitutions comprises lisinopril (lisinopril), enalapril (enalapril), quinapril (quinapril), ramipril (ramipril), benazepril (benazepril), captopril (captopril), fosinopril (fosinopril), moexipril (moexipril), trandolapril (trandolapril) and perindopril (perindopril).ACE inhibitor is generally the chemical compound of the effect that suppresses angiotensin converting enzyme, and this angiotensin converting enzyme can be converted into Angiotensin II with angiotensin I.Category of the present invention comprises present known ACE inhibitor of all that and all that ACE inhibitor in the future to be found.
Many ARB also can buy or be known in this technology.These chemical compounds comprise losartan (losartan), irbesartan (irbesartan), Candesartan (candesartan), telmisartan (telmisartan), Ai Poshatan (eposartan) and valsartan (valsartan).ARB brings high blood pressure down by lax blood vessel.This makes blood flow better.The function of ARB comes from the bonded ability of its blocking-up Angiotensin II, and this is in conjunction with causing vasoconstriction usually.Category of the present invention comprises present known ARB of all that and all that ARB in the future to be found.
The present inventor has been found that AA
1The combination of RA and ACE inhibitor or ARB is of value to congestive heart failure (CHF) or hypertension.ACE inhibitor and the ARB use in CHF depends on the inhibition of renin-angiotensin system.These chemical compounds can reduce afterload, thereby the feasible cardiac function that more effectively promotes.In addition, renal function be " normalization " or improve, make the patient can more effectively eliminate excessive liquid.The use of these chemical compounds has demonstrated can increase the survival rate of suffering from CHF or hypertensive patient.Described chemical compound is now for treating the part of CHF and hypertensive standard drug.
Combination acts synergistically of the present invention described herein is with the further renal function that improves, in order to continue diuresis.In addition, most of CHF patient also needs extra diuretic.Described combination makes by improving renal blood flow and renal function more how far other hold the diuretic that works to produce more large effect.
ACE inhibitor and ARB are very definite in the hypertensive treatment of working by renin-angiotensin system.AA
1The interpolation of RA will further be treated hypertension by the resorbent diuresis that the sodium of proximal tubule is flow through in its inhibition.In addition, because many hyperpietics are sodium sensitivity, so add AA
1RA can cause further blood pressure to reduce to ACE inhibitor or ARB.AA
1Can further improve renal function and cause stronger diuresis and lower blood pressure thereby RA acts on pipe ball feedback.
ACE inhibitor and ARB are also by preventing by immunosuppressant, the inductive injury of kidney of cyclosporin A known to us.Although yet they all can use, still have the injury of kidney effect.The present inventor has been found that ACE inhibitor and ARB and AA
1RA combination is the inductive nephrotoxicity of prophylactic agent more effectively, as by cyclosporin A, (iodinating) contrast agent and the inductive nephrotoxicity of aminoglycoside antibiotics.Existing under this background can be by two kinds of minimized kidney vasoconstriction of chemical compound.In addition, in adenosine A
1Under the background that receptor antagonist exists, cyclosporin is more not remarkable for the direct negative effects of renal cells, A in this blocking-up
1Receptor reduces initiatively process.In addition, exist still less to the deleterious oxidized byproduct of renal cells.In addition, under the background that the nephrotoxicity medicine exists, AA
1The blocking-up of RA helps to keep function for the inhibitory action of pipe ball feedback mechanism.
By albuminuretic measurement, ACE inhibitor and ARB are of value to the handicapped deterioration of prevent diabetes patient middle kidney for known to us.In case diabetes begin, glycosuria forms gradually and kidney begins initiatively to absorb glucose again, especially passes through proximal convoluted tubule.The disease process that this active process can cause oxidative stress and begin diabetic nephropathy.This process show as kidney plumpness and renal hypertrophy in early days.At last, kidney begins to show other symptom, as the renal function of Microalbuminuria and decline.Suppose to pass through adenosine A
1The active that glucose is regulated on acceptor portion ground absorbs again.Pass through AA
1This process of blocking RA can limit or the prevent diabetes patient in the early stage infringement that shows.
As AA disclosed herein
1The combinations of RA and ACE inhibitor or ARB is with the infringement of the early stage and secondary of kidney in the restriction diabetics.The combination or the glycosuria in detecting dangerous patient (metabolic syndrome) that give the present invention's announcement when being diagnosed as diabetes give the combination that the present invention discloses.Use the long-term treatment of the present invention's combination to comprise and give medical composition as herein described every day.
Thereby one aspect of the present invention relates to a kind of angiotensin converting enzyme (ACE) inhibitor and adenosine A of comprising
1Receptor antagonist (AA
1RA) medical composition.The group that following each thing of the optional freedom of described ACE inhibitor is formed: lisinopril, enalapril, quinapril, ramipril, benazepril, captopril, fosinopril, moexipril, trandolapril and perindopril, or its pharmaceutically acceptable salt, prodrug, ester or amide.Yet, comprise other ACE inhibitor also within category of the present invention.
The present invention relates to a kind of angiotensin-ii receptor blockers (ARB) and adenosine A of comprising on the other hand
1Receptor antagonist (AA
1RA) medical composition.The group that following each thing of the optional freedom of described ARB is formed: losartan, irbesartan, Candesartan, telmisartan, Ai Poshatan and valsartan, or its pharmaceutically acceptable salt, prodrug, ester or amide.Yet, comprise other ARB also within category of the present invention.
The present invention relates to a kind of ACE inhibitor, ARB and adenosine A of comprising on the other hand
1Receptor antagonist (AA
1RA) medical composition.
The present invention relates to a kind of method for the treatment of cardiovascular disease or kidney disease on the other hand, and it comprises determines the described treatment of a needs of patients, and gives described patient medical composition described herein.In certain embodiments, described patient may be a mammal, the group that following each animal of the optional freedom of described mammal is formed: little muroid, rat kind, Lagomorpha, Cavia porcellus class, dog class, cat class, sheep class, goat class, cow class, primates (as monkey, chimpanzee and ape) and the mankind.In certain embodiments, described patient is human.
In certain embodiments, dosing step comprises and almost gives described ACE inhibitor or described ARB and described AA simultaneously
1RA.These embodiment comprise AA
1RA is the embodiment in identical given compositions with ACE inhibitor or ARB, promptly contains a single tablet, pill or the capsule of two kinds of chemical compounds, or injection solution in the azygos vein, or a single drinkable solution, or a single sugar-coat prescription or an ointment.Described embodiment also comprises the embodiment of each chemical compound in the compositions that can separately give, but instruct the patient almost to take described compositions of separating simultaneously, promptly after taking a pill, take another pill at once or behind a kind of chemical compound of injection, inject another kind of chemical compound etc. at once.
In other embodiments, dosing step comprises and at first gives ACE inhibitor or ARB and AA
1A kind of among the RA also then gives ACE inhibitor or ARB and AA
1Another kind among the RA.In these embodiments, can give patient one and comprise a kind of compositions in the described chemical compound, and then give another afterwards and comprise alternative compositions in the described chemical compound in certain period (a few minutes or several hours).Comprise also among these embodiment that with conventional or serve as that the basis gives patient one and comprises a kind of compositions in the described chemical compound continuously the while is accepted an embodiment who comprises another kind of compound compositions once in a while.
The inventive method is desirable to provide the treatment for cardiovascular disease, and it can comprise congestive heart failure, hypertension, silent left ventricular dysfunction or acute myocardial infarction.In some cases, the needs of patients of suffering from cardiovascular disease reduces afterload.The inventive method also is suitable for these patients treatment is provided.
The inventive method also is desirable to provide the treatment for kidney disease, and it can comprise nephropathy, hypertensive nephropathy, the diabetic nephropathy of the kidney injury of nephropathy, toxin-induced of kidney hypertrophy, kidney hypertrophy, Microalbuminuria, albuminuria, diabetic nephropathy, contrast agent mediation or Mediated by Free Radicals, nephropathy, the kidney injury of toxin-induced or the nephropathy of Mediated by Free Radicals of contrast agent mediation.
The present invention relates to a kind of medical composition on the other hand, and it comprises an AA as indicated above
1The combination of RA and ACE inhibitor or ARB, and the physiology goes up acceptable supporting agent, diluent or excipient or its combination.
Alkalotic treatment
Alkalosis is a kind of by blood plasma bicarbonate (HCO
3 -) the concentration Acid-Base balance disorder that raises and to cause.It is a constitutional Pathophysiology incident, it is characterized in that obtaining bicarbonate or loss fixed acid from extracellular fluid.Kidney keeps normal Acid-Base balance by two kinds of mechanism: the recovery of main bicarbonate in proximal tubule, and the generation of main bicarbonate in far-end kidney unit.The recovery of bicarbonate is mainly by Na
+-H
+Antiporter (antiporter) is regulated, on less degree by adenosinetriphosphataes (H
+-ATPase) regulate.Influence HCO
3 -Resorbent principal element comprises effective tremulous pulse blood volume, glomerular filtration rate, potassium, and the dividing potential drop of carbon dioxide.The regeneration of bicarbonate mainly is subjected to far-end Na
+Transmitting the pH value, the ammonium that reach absorption again, aldosterone, whole body drains and the excretory influence of titratable acid.
There are many dissimilar alkalosis, for example metabolic alkalosis and respiratory alkalosis.Respiratory alkalosis is a kind of disease that influences the climber under high height above sea level situation.
Produce metabolic alkalosis, the acquisition of alkali or the loss of acid must take place.The loss of acid can or be passed through kidney by upper gastrointestinal.Excess base can give HCO through intestinal by oral or non-
3 -Obtain, or obtain by giving lactate, acetate or citrate.
The factor that metabolic alkalosis is kept in help comprises glomerular filtration rate reduction, volume contraction, hypokalemia, and aldosterone is excessive.The clinical state relevant with metabolic alkalosis for vomiting, excessive, the adrenal gland's gonad syndrome of mineralocorticoid, take in Radix Glycyrrhizae, give diuretic and Bart and Ji Teman syndrome (Bartter ' s and Gitelman ' s syndromes).
Two types (being chloride response type, chloride opposing type) of metabolic alkalosis are to classify according to the content of urine chloride.Chloride response type metabolic alkalosis relates to the urine chloride level and is lower than 10 equivalent parts per millions (mEq/L), and it is characterized in that extracellular fluid (ECF) volume reduces and low serum chloride, as taking place with vomiting.This type responds to giving chloride salt.Chloride opposing type metabolic alkalosis relates to the urine chloride level and is higher than 20mEq/L, and it is characterized in that ECF is volume gain.Hint that as title this type resisted giving of chloride salt.Oral alkali of excess intake (be generally milk and add calcium carbonate) and the concurrent primary aldosteronism of alkalosis are the alkalotic example of chloride opposing type.
Many have the patient of edematous condition with diuretic therapy.Unfortunately, along with successive treatment, patient's bicarbonate level increases and carrying out property alkalosis thereupon.Diuretic causes metabolic alkalosis by some mechanism, comprises that the volumetrical acute contraction of (1) extracellular fluid (ECF) (drains NaCl and do not drain HCO
3 -), thereby increase HCO among the ECF
3 -Concentration; (2) inductive potassium of diuretic and chloride loss; And (3) secondary aldosteronism.Any that continues in use diuretic or the latter two factors all can be kept alkalosis.
AA
1The interpolation of RA makes and can continue diuresis and keep renal function and alkalosis is worsened.AA
1RA suppresses to flow through the HCO of kidney proximal tubule
3 -Active absorb again.
Thereby one aspect of the present invention relates to a kind of method for the treatment of metabolic alkalosis, and it comprises determines the described treatment of a needs of patients, and gives described patient's adenosine A
1Receptor antagonist (AA
1RA).In certain embodiments, the patient suffers from high mountain disease (high altitudemountain sickness).In certain embodiments, the patient has edema.In the middle of in these embodiments some, the patient may be in the diuretic therapy.Described diuretic can be loop diuretic, near-end diuretic or far-end diuretic.In other embodiments, the patient stands the upper gastrointestinal acid loss by described patient, for example the acid loss that produces by excessive vomiting.In other other embodiment, the oral alkali of patient's excess intake.The inventive method can be with any antagonism adenosine A
1The chemical compound of receptor is put into practice.
The present invention relates to a kind of medical composition on the other hand, and it comprises AA as indicated above
1The RA combination, and the physiology goes up acceptable supporting agent, diluent or excipient or its combination.
The treatment of diabetic nephropathy
Uncontrolled diabetes can cause the infringement of the many tissues of health.The kidney damage that is caused by diabetes often relates to thickening of inner kidney structure, particularly glomerule (kidney thin film) mostly and hardens.Ji Manersidi-hepatolenticular degeneration (Kimmelstiel-Wilson disease) is unique microscopic feature of diabetic nephropathy, and the sclerosis of its mesonephric glomerulus is with nature of glass nodositas deposit.
Glomerule is filtering blood and the place that forms urine.It serves as an optional membrane, allows some materials to drain to enter in the urine and allows other materials to keep in vivo.Along with the diabetic nephropathy development, the glomerule of more and more numbers is destroyed, causes renal function to weaken.Filtration is slowed down and is normally remained on intravital protein (being albumin) and may infiltrate in the urine.Before other symptom development, albumin can occur 5 to 10 years in urine.Diabetic nephropathy is often with hypertension.
Diabetic nephropathy can finally cause the nephrotic syndrome (syndrome is characterized in that protein excessive loss in the urine) and chronic renal failure.Along with the development of kidney disease in latter stage, disease can continue development usually in occurring with 2 to 6 years after the albuminuretic renal insufficiency.
The mechanism that causes diabetic nephropathy is also unknown.It may be incorporated into irrelevantly in the structure of the basement membrane of glomerule and tissue by glucose molecule and cause.The ultra-filtration relevant with the hyperglycemia level (urine generates to be increased) may be the additional mechanism of disease progression.
In the U.S., diabetic nephropathy be chronic renal failure and latter stage kidney disease common reason.About 40% insulin-dependent diabetics is developed the kidney disease in latter stage the most at last.Because 80% among the diabetic nephropathy patient due to the insulin dependent diabetes mellitus (IDDM) (IDDM) suffers from these diabetes more than 18 years or 18 years.At least 20% non-insulin-dependent diabetes mellitus (NIDDM) patient will be developed diabetic nephropathy, but the time-histories of disease development is than more variable many among the IDDM.Risk relates to the control of blood sugar level.If glucose control is bad, then risk is controlled when good greater than glucose level.
Diabetic nephropathy comprises that generally with other diabetic complications hypertension, retinopathy and blood vessel change, although may be also not obvious in early stage these complication of nephropathy.Before the nephrotic syndrome or chronic renal failure development, can there be many years in nephropathy.When in the routine urinalysis demonstration urine protein being arranged, normal diagnosable is nephropathy.
Give angiotensin-convertion enzyme inhibitor (ACE inhibitor) the more late period that the treatment of current diabetic nephropathy is included in described disease.Because ACE inhibitor is possible invalid when described disease asymptomatic (being that the patient only shows albuminuria), so currently also do not have a more early stage treatment of disease.
Although involving the mechanism of the early stage kidney disease of diabetics is hyperglycemia, a potential mechanism may relate to that the active of glucose absorbs again in the proximal tubule.This resorption depends in part on adenosine A
1Receptor.
AA
1The afferent arteriole that RA acts on kidney produces the kidney blood flow that therefore vasodilation also improves diabetics.This finally makes GFR increase and improve renal function.In addition, AA
1RA suppresses newly to be diagnosed as the absorption again of glucose in the patient of diabetes or symptom (metabolic syndrome) the patient's on the line proximal tubule.
Thereby one aspect of the present invention relates to a kind of method of treatment of diabetic nephropathy, and it comprises determines the described treatment of a needs of patients, and gives described patient's adenosine A
1Receptor antagonist (AA
1RA).In certain embodiments, the patient is a pre-diabetes, and in other embodiments, the patient is an early diabetes.In certain embodiments, the patient suffers from insulin dependent diabetes mellitus (IDDM) (IDDM), and in other embodiments, the patient suffers from non-insulin-dependent diabetes mellitus (NIDDM).
In certain embodiments, use the inventive method to prevent or reverse the kidney hypertrophy.In other embodiments, use the inventive method to prevent or reverse the kidney hypertrophy.In other other embodiment, use the inventive method to improve Microalbuminuria or albuminuria.
It is preceding to develop type ii diabetes (being NIDDM) the patient, and it almost always has " pre-diabetes ".The pre-diabetes patient has and is higher than normal value but enough high as yet so that be diagnosed as the blood sugar level of diabetes.For example, when using fasting plasma glucose (FPG) to detect, pre-diabetes patient's blood sugar level is between 110-126 milligram/decilitre (mg/dL), or when using oral glucose tolerance detection (OGTT), blood sugar level is between 140-200mg/dL.When using FPG or OGTT, blood sugar level is lower than 110 or 140 respectively and is considered to normal, and when using FPG or OGTT, and blood sugar level is higher than 126 or 200 individuality respectively and is considered to diabetes.The inventive method can be with any antagonism adenosine A
1The chemical compound of receptor is put into practice.
Some aspect of the inventive method can use a kind of combined therapy to put into practice, AA promptly of the present invention
1RA chemical compound and the combination of one second chemical compound give described patient.In certain embodiments, second chemical compound can be selected from inhibitors of protein kinase C, hamartoplasia inhibitor, antioxidant, glycosylation inhibitor and Endothelin B acceptor inhibitor.
Medical composition
Term " medical composition " refers to a kind of The compounds of this invention and mixture as other chemical constituents of diluent or supporting agent.Described medical composition helps giving an organism described chemical compound.Have the multiple technology that gives chemical compound in this technology, it includes, but is not limited to oral, injection, aerosol, non-through intestinal and topical.Medical composition also can obtain by the inorganic or organic acid reaction with chemical compound and example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid and analog thereof.
Term " supporting agent " definition is a kind of to be helped a chemical compound and is incorporated into chemical compound in the cell or tissue.Dimethyl sulfoxide (DMSO) for example is because it helps absorbing in the cell or tissue that many organic compound enter organism, so be a kind of generally supporting agent of utilization.
Term " diluent " is defined in the compounds that dilutes in the water, chemical compound that its dissolving is correlated with and the biologic activity form of stablizing described chemical compound.In this technology, utilize the salt that is dissolved in the buffer solution as diluent.Because the salt environment of phosphate buffer salt simulating human blood, so it is a kind of buffer solution that generally uses.Because buffer salt can be controlled the pH value of solution under low concentration, so the buffering diluent seldom changes the biologic activity of chemical compound.
Term " physiology is last to be accepted " definition one can not eliminated the supporting agent or the diluent of the biologic activity and the character of chemical compound.
Can itself give human patients with medical composition as herein described, or as in combined therapy, to give human patients with other active component or suitable supporting agent or the medical composition form of mixed with excipients.Can in " Lei Shi pharmacy complete works " (Remington ' s Pharmaceutical Sciences) that Pennsylvania, USA (PA) Easton city (Easton) Mike publishing company (Mack Publishing Co.) publishes nineteen ninety the 18th edition, find the preparation of the chemical compound used at once and give technology.
That suitable route of administration can comprise is for example oral, rectum, through mucous membrane or enteral administration; Non-through the intestinal transmission, comprise intramuscular, subcutaneous, intravenous, intramedullary injection, also comprise in the sheath, directly in the ventricle, intraperitoneal, intranasal or intraocular injection.
Perhaps, can a partial mode give chemical compound and the mode that is better than with whole body gives, for example enter kidney or heart area by the chemical compound direct injection that is generally long-acting or sustained release formulation.In addition, can in a targeted drug induction system, give medicine, for example be surrounded by in the liposome of tissue specificity antibody one.Liposome will be target spot with the organ and optionally be absorbed by organ.
Medical composition of the present invention can self known mode be made, for example by means of the mixing of routine, dissolving, granulation, sugaring clothing, porphyrize, emulsifying, encapsulated, hold back or the tabletting process.
Thereby, can use one or more physiologys to go up acceptable supporting agent and prepare medical composition used according to the invention in a usual manner, supporting agent includes and is beneficial to excipient and the auxiliary agent that reactive compound is processed into the preparation that pharmaceutically uses.Proper formula depends on selected route of administration.Can use in this technology any for us known technology, supporting agent and excipient suitable and that fully understood, for example described in " the Lei Shi pharmacy complete works " above.
For injection, can prepare medicament of the present invention in aqueous solution or in the liplid emulsions, preferable going up in the compatible buffers the physiology as Han Keshi solution (Hanks ' s solution), Ringer's mixture (Ringer ' s solution) or normal saline buffer solution prepared.For mucosal, in prescription, use the penetrating agent that is suitable for barrier to be infiltrated.Described penetrating agent is generally known in this technology.
For oral administration, can be by will easily preparing chemical compound for our known pharmaceutically acceptable supporting agent combination in reactive compound and this technology.Described supporting agent can be formulated into chemical compound of the present invention and be tablet, pill, dragee, capsule, liquid, gel, syrup, unguentum, suspension and analog thereof, is used for patient's to be treated oral absorption.The pharmaceutical preparation that is used to orally use can obtain as follows: with one or more solid excipients and medical combined hybrid of the present invention; in case of necessity after adding proper auxiliary agent, grind the mixture of gained and processing granular mixture according to circumstances to obtain the tablet or the dragee heart.Suitable excipient is in particular filler, as saccharide, comprises lactose, sucrose, mannitol or Sorbitol; The cellulose preparation class is as corn starch, wheaten starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone (PVP).In case of necessity, can add disintegrating agent, as crospolyvinylpyrrolidone, agar or alginic acid or its salt, as sodium alginate.
The dragee heart has suitable coating.For this purpose, can use spissated sugar juice, it can contain Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, carbomer gel (carbopol gel), Polyethylene Glycol and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture according to circumstances.Can add in tablet or dragee coating that dyestuff or pigment are used to differentiate or the various combination of characterization active compound doses.
The pharmaceutical preparation that can orally use comprises sucking fit (push-fit) capsule of being made by gelatin, also comprises by gelatin and the soft seal capsule of making just like the plasticizer of glycerol or Sorbitol.The sucking fit capsule can contain active component, and it is mixed with filler as lactose, as the binding agent of starch and/or as the lubricant of Talcum or magnesium stearate and stabilizing agent according to circumstances.In soft capsule, reactive compound can be dissolved or be suspended in the suitable liquid as fatty oil, liquid paraffin or liquid macrogol.In addition, can add stabilizing agent.In addition, prescription of the present invention can be surrounded by enteric polymer.The prescription of all oral administrations should be the dosage that is suitable for described administration.
For oral administration, compositions can be taked the tablet prepared in a usual manner or the form of lozenge.
For for inhalation, chemical compound used according to the invention is with the aerosol spray form and use a suitable propellant as dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide or other suitable gas to carry expediently from pressurized package or aerosol apparatus.Under the situation of a pressurised aerosol, can carry the quantity of a metering to determine dosage unit by a valve is provided.For example, can prepare be used for an inhaler or insufflator for example be the capsule of gelatin and cartridge case, it contains the mixture of powders of described chemical compound and suitable powder substrate (as lactose or starch).
Can prepare chemical compound and be used for non-by injection, for example by bullet formula injection or continuous infusion through enteral administration.The prescription that is used for injecting for example can unit dosage forms be present in ampoule or be present in the multi-dose container with an antiseptic that adds.Described compositions can be taked the form as suspension, solution or emulsion in oiliness or aqueous vehicles, and can contain the blender just like suspending agent, stabilizing agent and/or dispersant.
Be used for non-medicine prescription and comprise that reactive compound is the aqueous solution of water-soluble form through enteral administration.In addition, the suspension preparation of reactive compound can be become suitable oily injection suspensions.Suitable lipophilic solvent or mediator comprise the fatty oil as Oleum sesami, or as the Acrawax of ethyl oleate or triglyceride, or liposome.Water injection suspension liquid can contain the material that increases suspension viscosity, as sodium carboxymethyl cellulose, Sorbitol or dextran.Suspension also can contain suitable stabilizers according to circumstances or increase the medicament of compound dissolution degree, to prepare highly enriched solution.
Perhaps, active component can be powder type, is used for forming preparation with the suitable mediator just like aseptic apirogen water before use.
For example, also chemical compound can be mixed with the rectal compositions as suppository or enema,retention, it contains the conventional suppository bases just like cocoa butter or other glyceride.
Except that previously described prescription, chemical compound also can be mixed with-durative action preparation.Can be by implanting (for example subcutaneous or intramuscular) or giving described long term prescription by intramuscular injection.Thereby, for example can prepare described chemical compound, or described chemical compound is formulated as the slightly soluble derivant, for example slightly soluble salt with suitable polymerization or hydrophobic material (for example in the emulsion that can accept in the oil) or ion exchange resin.
The medical supporting agent that is used for hydrophobic compound of the present invention is a cosolvent system, and it comprises benzyl alcohol, an electrodeless surfactant, one and a miscible organic polymer and the water of water.Employed general cosolvent system is a VPD cosolvent system, and it is the electrodeless surfactant Polysorbate of benzyl alcohol, 8%w/v (Polysorbate) 80 of one 3% w/v (w/v)
TMAnd the solution of 65%w/v Liquid Macrogol, supply volume with dehydrated alcohol.Certainly, the ratio of cosolvent system can change greatly and can not destroy its dissolubility and toxic characteristic.In addition, itself can changing of cosolvent composition: for example, can use other hypotoxic electrodeless surfactants to replace POLYSORBATE 80
TMThe fragment of Polyethylene Glycol (fraction) size can change; The alternative Polyethylene Glycol of other biological compatible polymers is as polyvinylpyrrolidone; And other sugar or polysaccharide can replace dextrose.
Perhaps, can use other induction systems to be used for the hydrophobicity pharmaceutical compound.Liposome and emulsion are to be the conveying mediator of our known hydrophobic drug or the example of supporting agent.Also can use some organic solvent, although be cost with bigger toxicity usually as dimethyl sulfoxine.In addition, chemical compound can use a slow-released system to carry, as contains the semi permeability substrate of the solid hydrophobic polymer of therapeutic agent.Various slow-release materials are determined by the those skilled in the art and are known.The chemical property that depends on slow releasing capsule, it can discharge several Zhou Zhizhi of chemical compound more than 100 days.The chemical property and the biological stability that depend on therapeutic agent can use extra strategy to be used for stable protein.
Some be used to dissolve and the Emulsion of carrying above-mentioned xanthine derivative at United States Patent (USP) the 6th, 210, discuss to some extent in No. 687, its mode of quoting in full is incorporated herein (comprising any graphic).
The salt form of available pharmaceutically compatible equilibrium ion provides employed chemical compound lot in the medicine combination of the present invention.Can form pharmaceutically compatible salt with many acid, include, but is not limited to hydrochloric acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid etc.Salt trends towards more solvable than corresponding free acid or alkali form in aqueous solvent or other protonic solvents.
Be applicable to that medical composition of the present invention comprises that the active component dosage that is contained can effectively reach the compositions of its intended purposes.More precisely, the treatment effective dose means the dosage that can effectively prevent, alleviate or improve disease symptoms or prolong the chemical compound that the patient that treats of institute survives.Be preferably in those skilled in the art's the limit of power, the detailed disclosure that especially considering this paper is provided can determine to treat effective dose.
Definite prescription, route of administration and the dosage of medical composition of the present invention can consider that patient's disease selects (for example, seeing people's' 1975 " therapeutic pharmacological basis " (" The PharmacologicalBasis of Therapeutics ") such as Fingl chapter 1 page 1) by individual doctor.Typically, the dosage range that gives patient's compositions generally can be about 0.5 to 1000 milligram of per kilogram weight in patients.It is required to look the patient, can give single dose or two or more a series of dosage in the process more than a day or a day.
Dosage every day of adult patient can be: for example, pressing free alkali calculates, the oral dose of medical composition of the present invention or its pharmaceutically acceptable salt between 0.1mg between the 500mg, preferable between 1mg between the 250mg, for example 5mg to 200mg or be intravenous, subcutaneous or intramuscular dosage between 0.01mg between the 100mg, preferable between 0.1mg between the 60mg, for example 1 to 40mg, gives described compositions 1 to 4 time every day.Perhaps can give compositions of the present invention, be preferably the dosage of every day one up to 400mg by continuous intravenous infusion.Thereby, oral administration every day accumulated dose should 1 in the 2000mg scope and non-through the every day of enteral administration accumulated dose should be in the 400mg scope 0.1.Suitably should give described chemical compound and reach one period continuous treatment time, week or more than the week for example, or some months or several years.
Can individually adjust dosage and spacing of doses time so that the blood plasma level or the minimum effective drug concentration (MEC) of the active part that is enough to keep regulating effect to be provided.For each chemical compound, MEC can change, but can estimate by vitro data.The essential dosage that reaches MEC should depend on individual characteristics and route of administration.Yet, can use HPLC check or bioassay to determine plasma concentration.
Also can use the MEC value to determine the spacing of doses time.Should use a scheme to give compositions, the 10-90% of time keeps blood plasma level on MEC in this scheme, and 30-90% and the best of being preferably the time are the 50-90% of time.
Under the situation of topical or selectivity picked-up, effective local concentration of medicine and plasma concentration are irrelevant.
The amount of the compositions that is given undoubtedly should depend on the patient that treated, patient's body weight, ailing seriousness, administering mode and prescriber's judgement.
In case of necessity, described compositions can be present in a packing or the packaging device, and it contains one or more unit dosage forms that contains described active component.For example, packing can comprise metal or plastic tab, as film blister package (blister pack).Described packing or packaging device can illustrate with administration.Described packing or dispenser also can be with the bulletins relevant with container, and this container has reflected the approval of office for the medicament forms that is used for the mankind or veterinary's administration for the specified form of government bodies of manufacturing, use or the sale of management medicine, this bulletin.For example, described bulletin can be U.S. food and drug administration's (U.S.Food andDrug Administration) labeling of being ratified that is used for prescription drugs or the product inset of being ratified.Also can prepare the compositions that is included in the The compounds of this invention of preparing in the compatible medical supporting agent, can be placed in the proper container and labelling indication treatment of conditions method.
Claims (25)
1. medical composition is characterized in that: described pharmaceutical composition comprises a beta blocker (beta-blocker) and an adenosine A
1Receptor antagonist (adenosine A
1Receptor antagonist, AA
1RA).
2. compositions according to claim 1, it is characterized in that: described beta blocker is selected from the group that is made up of following each thing: Acebutolol (acebutolol hydrochloride), atenolol (atenolol), betaxolol hydrochloride (betaxolol hydrochloride), bisoprolol fumarate (bisoprolol fumarate), carteolol hydrochloride (carteolol hydrochloride), esmolol hydrochloride (esmolol hydrochloride), metoprolol (metoprolol), spectinomycin hydrochloride (metoprolol tartrate), nadolol (nadolol), penbutolol sulfate (penbutololsulfate), pindolol (pindolol), propranolol hydrochloride (propranolol hydrochloride), succinate and timolol maleate (timolol maleate), or its pharmaceutically acceptable salt, prodrug (prodrug), ester or amide.
3. medical composition, it is characterized in that: described pharmaceutical composition comprises an angiotensin converting enzyme (angiotensin converting enzyme, ACE) inhibitor and an adenosine A
1Receptor antagonist (AA
1RA).
4. medical composition is characterized in that: described pharmaceutical composition comprises an angiotensin-ii receptor blockers, and (angiotensin II receptor blocker is ARB) with an adenosine A
1Receptor antagonist (AA
1RA).
5. medical composition is characterized in that: described medical composition comprises an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-ii receptor blockers (ARB) and an adenosine A
1Receptor antagonist (AA
1RA).
6. compositions according to claim 3, it is characterized in that: described ACE inhibitor is selected from the group that is made up of following each thing: lisinopril (lisinopril), enalapril (enalapril), quinapril (quinapril), ramipril (ramipril), benazepril (benazepril), captopril (captopril), fosinopril (fosinopril), moexipril (moexipril), trandolapril (trandolapril) and perindopril (perindopril), or its pharmaceutically acceptable salt, prodrug, ester or amide.
7. compositions according to claim 4 is characterized in that: described ARB is selected from the group that is made up of following each thing: losartan (losartan), irbesartan (irbesartan), Candesartan (candesartan), telmisartan (telmisartan), Ai Poshatan (eposartan) and valsartan (valsartan).
8. according to the described compositions of arbitrary claim in the claim 1,3 or 4, it is characterized in that: described AA
1RA is xanthine derivative chemical compound (xanthine-derivative compound) or its pharmaceutically acceptable salt of formula I,
Wherein
X
1With X
2Independent separately expression oxygen or sulfur;
Q represents:
Or
Wherein Y represents a singly-bound or has the alkylene of 1 to 4 carbon atom, and n represents 0 or 1;
R
1With R
2Independent separately expression hydrogen, low-carbon alkyl, pi-allyl, propargyl or hydroxyl replacement, oxygen replace or unsubstituted low-carbon alkyl, and R
3Expression hydrogen or low-carbon alkyl, perhaps
R
4With R
5Identical or different and represent hydrogen or hydroxyl separately, and work as R
4With R
5When being hydrogen, R
1With R
2In at least one is the low-carbon alkyl that hydroxyl replaces or oxygen replaces, but as Q be
The time, R then
1, R
2And R
3Be not methyl simultaneously, or wherein said AA
1RA is the xanthine epoxides chemical compound of formula II or formula III, or its pharmaceutically acceptable salt,
R wherein
6With R
7Identical or different, and can be the alkyl of hydrogen or one group of 1-4 carbon atom, R
8Be oxygen or (CH
2)
1-4, and n=0-4.
9. compositions according to claim 8 is characterized in that: described AA
1RA is selected from the group that is made up of following each thing: 8-(falling diamantane (obsolete)-3-yl)-1, and 3-dipropyl xanthine (8-(noradamantan-3-yl)-1,3-dipropylxanthine); 1, (3-allyl-8-(3-noradamantyl)-l-propargylxanthine), 8-are (anti--9-hydroxyl-3-three ring [3.3.1.0 for 3-diallyl-8-(3-noradamantyl) xanthine (1,3-Diallyl-8-(3-noradamantyl) xanthine), 3-pi-allyl-8-(3-noradamantyl)-1-propargyl xanthine
3,7] nonyl)-1,3-dipropyl xanthine (8-(trans-9-hydroxy-3-tricyclo[3.3.1.0
3,7] nonyl)-1,3-dipropylxanthine), 8-is (suitable-9-hydroxyl-3-three ring [3.3.1.0
3,7] nonyl)-1,3-dipropyl xanthine (8-(cis-9-hydroxy-3-tricyclo[3.3.1.0
3,7] nonyl)-1,3-dipropylxanthine), 8-is (anti--9-hydroxyl-3-three ring [3.3.1.0
3,7] nonyl)-1-(2-oxopropyl)-3-propyl group xanthine (8-(trans-9-hydroxy-3-tricyclo[3.3.1.0
3,7] nonyl)-1-(2-oxopropyl)-3-propylxanthine), 1-(2-hydroxypropyl)-8-is (anti--9-hydroxyl-3-three ring [3.3.1.0
3,7] nonyl)-3-propyl group xanthine (1-(2-hydroxypropyl)-8-(trans-9-hydroxy-3-tricyclo[3.3.1.0
3,7] nonyl)-3-propylxanthine),
And
Or its pharmaceutically acceptable salt.
10. a method for the treatment of cardiovascular disease is characterized in that: comprise and determine the described treatment of a needs of patients, and give described patient medical composition according to claim 1.
11. method according to claim 10 is characterized in that: described cardiovascular disease is congestive heart failure, hypertension, silent left ventricular dysfunction or coronary artery disease.
12. method according to claim 10 is characterized in that: described needs of patients reduces afterload (after-load).
13. method according to claim 10 is characterized in that: diuretic therapy that described needs of patients is extra or diuretic therapy are difficult to cure described patient.
14. a method for the treatment of cardiovascular disease or kidney disease is characterized in that: comprise and determine the described treatment of a needs of patients, and give described patient according to the described medical composition of arbitrary claim in the claim 3 to 5.
15. method according to claim 14, it is characterized in that: described patient suffers from the cardiovascular disease of the congestive heart failure of being selected from, hypertension, silent left ventricular dysfunction or acute myocardial infarction, or wherein said needs of patients reduction afterload, or wherein diuretic therapy is difficult to cure described patient.
16. method according to claim 14 is characterized in that: described kidney disease is nephropathy, the kidney injury of toxin-induced or the nephropathy of Mediated by Free Radicals of kidney hypertrophy, kidney hypertrophy, Microalbuminuria, albuminuria, diabetic nephropathy, contrast agent mediation.
17. the alkalotic method of treatment is characterized in that: comprise and determine the described treatment of a needs of patients, and give described patient's one adenosine A
1Receptor antagonist (AA
1RA).
18. method according to claim 17 is characterized in that: described alkalosis is metabolic alkalosis or respiratory alkalosis.
19. method according to claim 17 is characterized in that: described patient has edema, be in the diuretic therapy or suffer from upper gastrointestinal acid loss by described patient.
20. method according to claim 17 is characterized in that: described AA
1RA is xanthine derivative chemical compound or its pharmaceutically acceptable salt of formula I,
Wherein
X
1With X
2Independent separately expression oxygen or sulfur;
Q represents:
Wherein Y represents a singly-bound or has the alkylene of 1 to 4 carbon atom, and n represents 0 or 1;
R
1With R
2Independent separately expression hydrogen, low-carbon alkyl, pi-allyl, propargyl or hydroxyl replacement, oxygen replace or unsubstituted low-carbon alkyl, and R
3Expression hydrogen or low-carbon alkyl, perhaps
R
4With R
5Identical or different and represent hydrogen or hydroxyl separately, and work as R
4With R
5When being hydrogen, R
1With R
2In at least one is the low-carbon alkyl that hydroxyl replaces or oxygen replaces, but as Q be
The time, R then
1, R
2With R
3Be not methyl simultaneously,
Or wherein said AA
1RA is the xanthine epoxides chemical compound of formula II or formula III, or its pharmaceutically acceptable salt,
R wherein
6With R
7Identical or different, and can be hydrogen or one group of 1 alkyl, R to 4 carbon atoms
8Be oxygen or (CH
2)
1-4, and n=0-4.
21. the method for a treatment of diabetic nephropathy is characterized in that: comprise and determine the described treatment of a needs of patients, and give described patient's one adenosine A
1Receptor antagonist (AA
1RA).
22. method according to claim 21 is characterized in that: described patient is pre-diabetes or is early diabetes.
23. method according to claim 21 is characterized in that: described AA
1RA is xanthine derivative chemical compound or its pharmaceutically acceptable salt of formula I,
Wherein
X
1With X
2Independent separately expression oxygen or sulfur;
Q represents:
Or
Wherein Y represents a singly-bound or has the alkylene of 1 to 4 carbon atom, and n represents 0 or 1;
R
1With R
2Independent separately expression hydrogen, low-carbon alkyl, pi-allyl, propargyl or hydroxyl replacement, oxygen replace or unsubstituted low-carbon alkyl, and R
3Expression hydrogen or low-carbon alkyl, perhaps
R
4With R
5Identical or different and represent hydrogen or hydroxyl separately, and work as R
4With R
5When being hydrogen, R
1With R
2In at least one is the low-carbon alkyl that hydroxyl replaces or oxygen replaces, but as Q be
The time, R then
1, R
2With R
3Be not methyl simultaneously,
Or wherein said AA
1RA is the xanthine epoxides chemical compound of formula II or formula III, or its pharmaceutically acceptable salt,
R wherein
6With R
7Identical or different, and can be hydrogen or one group of 1 alkyl, R to 4 carbon atoms
8Be oxygen or (CH
2)
1-4, and n=0-4.
24. method according to claim 21 is characterized in that: further comprise and give a chemical compound that is selected from the group that forms by following each thing: inhibitors of protein kinase C, hamartoplasia inhibitor, antioxidant, glycosylation inhibitor and Endothelin B acceptor inhibitor.
25. method according to claim 21 is characterized in that: described treatment comprises prevention, reverses or improves the disease that is selected from by the following group that forms: kidney hypertrophy, kidney hypertrophy, Microalbuminuria and albuminuria.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US44995303P | 2003-02-24 | 2003-02-24 | |
| US60/449,953 | 2003-02-24 | ||
| US60/450,500 | 2003-02-25 | ||
| US60/450,499 | 2003-02-25 | ||
| US60/451,326 | 2003-02-28 | ||
| US60/464,815 | 2003-04-21 | ||
| US60/464,811 | 2003-04-21 | ||
| US60/464,813 | 2003-04-21 | ||
| US60/464,812 | 2003-04-21 |
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| Publication Number | Publication Date |
|---|---|
| CN1753661A true CN1753661A (en) | 2006-03-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480004903 Pending CN1753661A (en) | 2003-02-24 | 2004-02-24 | Adenosine a1 receptor antagonist for the treatment of cardiac and renal diseases |
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| Country | Link |
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| CN (1) | CN1753661A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101677943B (en) * | 2007-05-22 | 2013-10-23 | 巴克斯特国际公司 | Multi-dose concentrate esmolol with benzyl alcohol |
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2004
- 2004-02-24 CN CN 200480004903 patent/CN1753661A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101677943B (en) * | 2007-05-22 | 2013-10-23 | 巴克斯特国际公司 | Multi-dose concentrate esmolol with benzyl alcohol |
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