CN1655820A - Pharmaceutical combination of PDE5 inhibitors with ace inhibitors - Google Patents
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- CN1655820A CN1655820A CNA038118262A CN03811826A CN1655820A CN 1655820 A CN1655820 A CN 1655820A CN A038118262 A CNA038118262 A CN A038118262A CN 03811826 A CN03811826 A CN 03811826A CN 1655820 A CN1655820 A CN 1655820A
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Abstract
Combinations comprising a) an inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) inhibitor and b) an inhibitor of angiotensin converting enzyme (ACE) are useful for treating hypertension.
Description
The present invention relates to a) cyclic guanosine monophosphate (cGMP) specific phosphodiesterase enzyme 5 types (PDE5) inhibitor and b) combination of angiotensin converting enzyme (ACE) inhibitor is used for the treatment of cardiovascular and metabolic disease, particularly hypertensive purposes.
Blood pressure (BP) is limited with independent or bonded form by many hemodynamic parameters.Systolic pressure (SBP) is the arterial hypertension that obtains when heart contraction.Diastolic pressure is the minimum arterial pressure that obtains when diastole.Difference between SBP and the DBP is defined as pulse pressure (PP).
Hypertension or BP raise and are defined as the SBP of 140mmHg at least and/or the DBP of 90mmHg at least.Utilize this definition, the hypertensive universality of developed country is about 20% adult crowd, and the crowd at 60 years old or higher age rises to about 60-70%, though when measuring in non-clinical setting, the major part among these hyperpietics all has normal BP.About 60% of the Hypertensive Population that these are older has isolated systolic hypertension (ISH), that is, they have the SBP and the normal DBP of rising.Hypertension increases relevant (Fagard, RH with the danger of apoplexy, myocardial infarction, auricular fibrillation, heart failure, peripheral blood vessel and renal damage; Am.J.Geriatric Cardiology 11 (1), 23-28,2002; Brown, MJ and Haycock, S; Drugs 59 (Suppl 2), 1-12,2000).
Hypertensive pathophysiology is the theme that continues arguement.Though it has been generally acknowledged that hypertension is unbalanced result between cardiac output and the peripheral vascular resistance, and most hyperpietics have the unusual cardiac output and the Peripheral resistance of increase, but still uncertain which parameter at first changes (Beevers, people such as G; BMJ 322,912-916,2001).
Although in various pharmacology's categories, used high amount of drug, comprise diuretic, alpha-adrenergic antagonist, beta-adrenergic antagonist, calcium channel blocker, angiotensin converting enzyme inhibitor and angiotensin receptor antagonist, but still can not satisfy the hypertensive needs of effective treatment.
The ACE inhibitor of the vasoconstriction effect of blocking-up renin-angiotensin peptide-aldosterone system is proposed as a hypertensive gamma therapy.They are effectively, and are considered to usually and can be tolerated well.The most general side effect is reported in the patient of 10-20%, is cough.The side effect of other less report comprises erythra, angioedema, hyperkalemia and functional renal failure.
5 type phosphodiesterases are cyclic guanosine monophosphate-specific phosphodiesterase enzyme.The inhibitor of PDE5 can reduce the hydrolysis rate of cGMP, thereby strengthens The Effect of Nitric Oxide.It has been found that they can be used for treating male erectile dysfunction.
According to first aspect, the invention provides comprise a) PDE5 inhibitor and b) ACE inhibitor be combined in the preparation be used for the treatment of disease, particularly cardiovascular and metabolic disease, more specifically be the purposes in the hypertensive medicine.
Term used herein " treatment " and " treatment " comprise retentivity, healing property and prophylactic treatment.Term " hypertension " comprises all diseases that are characterised in that blood pressure is extraordinary, as essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, the hypertension relevant, hypertension and the renovascular hypertension relevant, and extend further to the situation that hypertension is the known danger factor with atherosclerosis with diabetes.Therefore, term " hypertensive treatment " comprises the complication that is caused by hypertension, and the merging disease relevant with other comprises congestive heart failure, angor, apoplexy and impaired renal function, comprises the treatment or the prevention of renal failure.Metabolic disease comprises, metabolic syndrome (also being known as syndrome X) particularly, and diabetes and impaired glucose tolerance comprise its complication, as diabetic retinopathy and diabetic neuropathy.
Hereinafter, the combination of PDE5 inhibitor and ACE inhibitor comprises the combination of specific PDE 5 inhibitor and specificity ACE inhibitor, will be known as combination of the present invention.
Combination of the present invention uses hypertensive PDE5 inhibitor of treatment or ACE inhibitor to have more effective, stronger, less toxic advantage than separating, or has other preferable character.
Hereinafter, term " PDE5 inhibitor " is meant the PDE5 inhibitor that is used for the present invention, comprises all pharmaceutically acceptable salts, solvate and the polymorph of PDE5 inhibitor.Equally, term " ACE inhibitor " is meant the ACE inhibitor that is used for the present invention, comprises all pharmaceutically acceptable salts, solvate and the polymorph of ACE inhibitor.
The fitness of PDE5 inhibitor and ACE inhibitor can wait and measure according to standard drug operation assessment their toxicity, pharmacokinetics (absorption, metabolism, distribution and elimination) then at an easy rate by using literature method assessment their usefulness and selectivity.Suitable compounds be effectively and optionally those, they do not have tangible toxic action when therapeutic dose, and preferably are biological available behind oral administration.
Effect can be defined as IC
50Value promptly suppresses the required compound concentration of 50% enzymatic activity.The IC of PDE5 inhibitor
50Value can use following PDE5 algoscopy to measure.Preferably, the PDE5 inhibitor has less than 100nM the PDE5 enzyme, is more preferably less than the IC of 50nM
50
Selectivity ratios can be at an easy rate by the corresponding IC of those skilled in the art by related certain enzyme
50The mensuration recently of value.The IC of PDE3 and PDE4 enzyme
50Value can be used definite literature method to learn and measure, and sees people such as Ballard SA; Journal of Urology 159,2164-2171,1998.
Preferably, the PDE5 inhibitor is optionally to the PDE5 enzyme.Preferred they to the selectivity of PDE5 than high by 100 to the selectivity of PDE3, more preferably high 300.More preferably, PDE5 has higher by 100 than PDE3 and PDE4, more preferably high 300 selectivity.
Preferably, the PDE5 inhibitor is to the IC of PDE5
50Value is less than 100nM, and has the selectivity higher 100 times than PDE3.
Oral bioavailability is meant the drug ratios that arrives body circulation oral administration.The factor of decision drug oral bioavailability is dissolving, membrane permeability and hepatic clearance.Usually, at first in external screening of carrying out and body subsequently technology can be used for measuring oral bioavailability.
Dissolving, promptly medicine can be tested by the dissolution in vitro degree that carries out under the appropriate pH of simulation GIT and predict by the moisture contents melting of gastrointestinal tract (GIT).Preferably, the PDE5 inhibitor has the minimal solubility of 50 μ g/ml.Dissolubility can be measured by standard procedure known in the art, as people such as Lipinski CA, and Adv.Drug Deliv.Rev.23 (1-3), 3-25, described in 1997.
Membrane permeability is meant the circulation of chemical compound via the GIT cell.Lipophile is the key property of prediction this point, and is by with an organic solvent carrying out external Log D with buffer
7.4Measure and determine.Preferably, the PDE5 inhibitor has-2-+4, more preferably-and the Log D of 1-+3
7.4Log D can measure by standard procedure known in the art, as at Stopher, and D and McClean, S; J.Pharm.Pharmacol.42 (2), described in 144,1990.
The cell monolayer algoscopy as in that the outflow transport protein is arranged, as the P-glycoprotein, is also referred to as under the condition of Caco2 stream existence, predicts favourable membrane permeability thereby add Caco2 in a large number.Preferably, the PDE5 inhibitor has greater than 2 * 10
-6Cm.s
-1, more preferably greater than 5 * 10
-6Cm.s
-1Caco2 stream.The value of Caco2 stream can be by standard procedure mensuration known in the art, as at Artursson, and P and Magnusson, C; J.Pharm.Sci, 79 (7), 595-600, described in 1990.
Metabolic stability is meant the ability of GIT metabolic compounds in the absorption process or absorbs the back liver ability of metabolic compounds immediately: first pass effect.The mensuration system is as measurable metabolism unstability such as microsome, hepatocyte.Preferably, the PDE5 inhibitor shows metabolic stability in the mensuration system, and it is equivalent to leach less than 0.5 liver.The example of mensuration system and date processing is at Obach, RS; Curr.Opin.Drug Disc.Devel.4 (1), 36-44,2001 and Shibata, people such as Y; Drug Met.Disp.28 (12), 1518-1523 describes in 2000.
Whether because influencing each other of said process, further having supported medicine to be that oral biology is available in human body can obtain by carrying out testing in the body in animal.Absolute bioavailability is that by oral route is separated or mixing gives chemical compound and mensuration in these researchs.For absolute determination (the oral biology of % is available), also can use intravenous route.The example of oral bioavailability can be at Ward in the assessment animal, people such as KW; Drug Met.Disp.29 (1), 82-87,2001; Berman, people such as J; J.Med.Chem.40 (6), 827-829,1997 and Han KS and Lee, MG; Drug Met.Disp.27 (2), 221-226 finds in 1999.
The example that is used for PDE5 inhibitor of the present invention is:
Disclosed pyrazolo [4,3-d] pyrimidin-7-ones in EP-A-0463756, EP-A-0526004 and disclosed International Patent Application WO 93/06104, WO 98/49166, WO 99/54333, WO 00/24745, WO 01/27112 and WO 01/27113; Disclosed pyrazolo in EP-A-0995750, EP-A-0995751 and disclosed International Patent Application WO 93/07149 [3,4-d] pyrimidin-4-one; Disclosed pyrazolo in disclosed International Patent Application WO 01/18004, WO 02/00660 and WO 02/59126 [4,3-d] pyrimidine; Disclosed quinazoline-4-one in disclosed International Patent Application WO 93/12095; Disclosed pyrido in disclosed International Patent Application WO 94/05661 [3,2-d] pyrimidin-4-one; Disclosed purine-6-one in EP-A-1092718 and disclosed International Patent Application WO 94/00453; In disclosed International Application No. WO 95/19978 disclosed hexahydropyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1, the 4-diketone; Disclosed imidazo in EP-A-1092719 and disclosed International Application No. WO 99/24433 [5,1-f] [1,2,4] triazine-ketone; Disclosed dicyclic compound and in disclosed International Application No. WO 93/07124 people such as Rotella DP; J.Med.Chem.43 (7), 1257-1263, disclosed Imidazoquinazoline ketone in 2000.
The general formula of therapeutical active compound and wherein illustrational chemical compound are all introduced herein as a reference in the content of disclosed patent application and magazine article, particularly claim.
Other example that is used for PDE5 inhibitor of the present invention comprises: 4-bromo-5-(pyridine radicals methylamino)-6-[3-(4-chlorphenyl)-propoxyl group]-3 (2H)-2H-Pyridazin-3-ones; 1-[4-[(1,3-benzo dioxo (dioxol)-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-4-piperidines-carboxylic acid, a sodium salt; (+)-suitable-5,6a, 7,9,9,9a-six hydrogen-2-[4-(trifluoromethyl)-benzyl-5-methyl-ring penta-4,5] imidazo [2,1-b] purine-4 (3H) ketone; Fuzlocillin; Suitable-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydro ring penta [4,5]-imidazo [2,1-b] purine-4-ketone; 3-acetyl group-1-(2-chlorophenylmethyl)-2-propyl indole-6-carboxylate; 3-acetyl group-1-(2-chlorophenylmethyl)-2-propyl indole-6-carboxylate; 4-bromo-5-(3-pyridine radicals methylamino)-6-(3-(4-chlorphenyl) propoxyl group)-3-(2H) 2H-Pyridazin-3-one; 1-methyl-5-(5-morpholino acetyl group-2-just-propoxyl group phenyl)-3-just-propyl group-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones; 1-[4-[(1,3-benzo dioxo (dioxol)-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-the 4-piperidine carboxylic acid, a sodium salt; Pharmaprojects No.4516 (Glaxo Welcome); Pharmaprojects No.5051 (Bayer); Pharmaprojects No.5064 (KyowaHakko; See WO 96/26940); Pharmaprojects No.5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045﹠amp; 38-9456 (Bayer) and Sch-51866.
Being used for preferred PDE5 inhibitor of the present invention comprises:
5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-just-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil), be also referred to as 1-[[3-(6,7-dihydro-1-methyl-7-oxygen-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and the 4-ethoxyl phenenyl] sulfonyl]-4-methyl piperazine (seeing EP-A-0463756);
5-(2-ethyoxyl-5-morpholino acetylphenyl)-1-methyl-3-just-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (seeing EP-A-0526004);
3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-just-the propoxyl group phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (seeing WO 98/49166);
3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (seeing WO 99/54333);
(+)-3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfonyl)-2-(2-methoxyl group-1 (R)-methyl ethoxy) pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, be also referred to as 3-ethyl-5-{5-[4-ethyl piperazidine-1-base sulfonyl]-2-([(1R)-and 2-methoxyl group-1-Methylethyl] oxygen) pyridin-3-yl }-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (seeing WO 99/54333);
5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, be also referred to as 1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-the 3-pyridyl sulfonyl }-4-ethyl piperazidine (see WO01/27113, embodiment 8);
5-[2-is different-butoxy-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-(1-methyl piperidine-4-yl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (see WO01/27113, embodiment 15);
5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (see WO 01/27113, embodiment 66);
5-(5-acetyl group-2-propoxyl group-3-pyridine radicals)-3-ethyl-2-(1-isopropyl-3-azelidinyl)-2,6-dihydro-7H pyrazolo [4,3-d] pyrimidin-7-ones (see WO 01/27112, embodiment 124);
5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (see WO 01/27112, embodiment 132);
(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1,4-diketone (tadalafil, IC-351), that is, the embodiment 78 of disclosed International Application No. WO 95/19978 and 95 chemical compound, and the chemical compound of embodiment 1,3,7 and 8;
2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (vardenafil), be also referred to as 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f]-as-triazine-2-yl also)-the 4-ethoxyl phenenyl] sulfonyl]-the 4-ethyl piperazidine, the embodiment 20,19,337 of promptly disclosed International Application No. WO 99/24433 and 336 chemical compound;
[7-(3-chloro-4-mehtoxybenzyl amino)-1-methyl-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-ylmethoxy] acetic acid (see WO 02/59126, embodiment 1);
4-(4-chlorophenylmethyl) amino-6,7,8-trimethoxy quinazoline (embodiment 11 of disclosed International Application No. WO 93/07124 (EISAI)); With
7,8-dihydro-8-oxo-6-[2-propoxyl group phenyl]-1H-imidazo [4,5-g] quinazoline and 1-[3-[1-[(4-fluorophenyl) methyl]-7,8-dihydro-8-oxo-1H-imidazo [4,5-g] quinazoline-6-yl]-4-propoxyl group phenyl] Methanamide (derives from people such as Rotella DP, J.Med.Chem.43 (7), 1257-1263,2000 chemical compound 3 and 14).
Being used for preferred PDE5 inhibitor of the present invention is selected from following and pharmaceutically acceptable salt:
5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-just-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil);
(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazine also [2 ', 1 ': 6,1]] pyrido [3,4-b] indole-1, the 4-diketone (tadalafil, IC-351);
2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (vardenafil);
5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl] 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; With
5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones.
Particularly preferred PDE5 inhibitor is 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-just-propyl group-1; 6-dihydro-7H-pyrazolo [4; 3-d] pyrimidin-7-ones (sldenafil) (is also referred to as 1-[[3-(6; 7-dihydro-1-methyl-7-oxygen-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and the 4-ethoxyl phenenyl] sulfonyl]-the 4-methyl piperazine) and pharmaceutically acceptable salt.The sldenafil citrate is preferred salt.
The example that is used for ACE inhibitor of the present invention comprises direct acting ACE inhibitor and prodrug thereof, comprises alacepril, alindapril, moveltipril, benazepril, benazeprilat, captopril, Ceronapril, cilazapril, cilazaprilat, delapril, enalapril, enalaprilat, fosinopril, Imidapril, indole Na Puli, in benzene Zepu profit, lisinopril, moexipril, Moveltipril, pentopril, perindopril, quinapril, quinaprilat, ramipril, Puli is passed in human relations, spirapril, temocapril, teprotide, trandolapril and Zofenopril.In addition, ACE inhibitor can be " a dual ACE/NEP inhibitor ", promptly, the chemical compound that suppresses ACE and neutral endopeptidase (NEP) simultaneously, as, for example, omapatrilat, fasidotril, mixanpril, sampatrilat, BMS-189921, MDL-100240 and Z13752A.
The preferred compositions that is used for the treatment of hypertensive PDE5 inhibitor and ACE inhibitor is:
Sldenafil and quinapril hydrochloride;
Sldenafil and benazepril hydrochlorate;
Sldenafil and captopril;
Sldenafil and enalapril maleate;
Sldenafil and fosinopril;
Sldenafil and lisinopril;
Sldenafil and moexipril;
Sldenafil and ramipril;
Sldenafil and trandolapril;
Tadalafil and quinapril hydrochloride;
Tadalafil and benazepril hydrochlorate;
Tadalafil and captopril;
Tadalafil and enalapril maleate;
Tadalafil and fosinopril;
Tadalafil and lisinopril;
Tadalafil and moexipril;
Tadalafil and ramipril;
Tadalafil and trandolapril;
Vardenafil and quinapril hydrochloride;
Vardenafil and benazepril hydrochlorate;
Vardenafil and captopril;
Vardenafil and enalapril maleate;
Vardenafil and fosinopril;
Vardenafil and lisinopril;
Vardenafil and moexipril;
Vardenafil and ramipril; With
Vardenafil and trandolapril.
Drug regimen of the present invention is used to comprise the treatment of diseases of cardiovascular and metabolic disease, and they also can be used for other disease, as thrombotic treatment, and be used to carry out the saturating lumen shape of percutaneous postangioplasty patient (" patient's behind the PTCA-") processing.
Preferably, the cardiovascular disease that treat is hypertension, congestive heart failure, angor, apoplexy or renal failure.More preferably described cardiovascular disease is essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, the hypertension relevant with diabetes, hypertension and renovascular hypertension, congestive heart failure, angor, apoplexy or the renal failure relevant with atherosclerosis.In particularly preferred embodiments, the disease that treat is an essential hypertension.In another particularly preferred embodiment, the disease that treat is a pulmonary hypertension.In another particularly preferred embodiment, the disease that treat is a secondary hypertension.In another particularly preferred embodiment, the disease that treat is an isolated systolic hypertension.In another particularly preferred embodiment, the disease that treat is the hypertension relevant with diabetes.In another particularly preferred embodiment, the disease that treat is the hypertension relevant with atherosclerosis.In another particularly preferred embodiment, the disease that treat is a renovascular hypertension.
Preferably, the metabolic disease that treat is impaired glucose tolerance or diabetes, comprises its complication, as diabetic retinopathy and diabetic neuropathy.More preferably, described metabolic disease is an impaired glucose tolerance, 1-type diabetes, non--insulin-dependent type 2 diabetes mellitus or insulin-dependent type 2 diabetes mellitus.
Combination of the present invention can be individually dosed, but normally with according to target route of administration and standard drug operate suitable drugs excipient, the diluent or carrier mixing administration of selecting.
For example, combination of the present invention can tablet, the form of capsule, many-microgranule, gel, thin film, ovule, elixir, solution or suspension is oral, oral cavity or sublingual administration, it can comprise seasoning or coloring agent, be used for instant-, postpone-, change-, continue-, pulsation-or control-release application.Combination of the present invention can also be fast-disperses or fast-dissolved form of medication or with the dispersive form of high energy or with the form administration of coated granule.As required, Shi Yi preparation can be the coating or the form of coating not.
This solid composite medicament, for example, tablet, can comprise excipient, as microcrystalline Cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine and starch (preferred corn, Rhizoma Solani tuber osi or tapioca), disintegrating agent such as sodium glycollate starch, croscarmellose sodium and specific complex silicate, and granulation binding agent such as polyvinylpyrrolidone, hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and arabic gum.In addition, also can comprise lubricant such as magnesium stearate, stearic acid, docosane acid glyceride and Pulvis Talci.Following example of formulations only illustrates, rather than limitation of the scope of the invention.Active component is meant combination of the present invention.
Preparation 1:
Tablet is to use the following ingredients preparation: active component (50mg) is mixed, and mixture is pressed into tablet with cellulose (crystallite), silicon dioxide, stearic acid (smoldering).
Preparation 2:
Iv formulation can be by oozing normal saline (1000ml) combined preparation with active component (100mg) and grade.
Tablet is made by standard method, for example, and direct compression or wet method or dry granulation.The core of tablet can be wrapped up with suitable coating.
The solid composite of similar type also can be used as the implant in gelatin or the HPMC capsule.In this, preferred excipient comprises lactose, starch, cellulose, lactose or high-molecular weight Polyethylene Glycol.For aqueous suspension and/or elixir, can be with PDE5 and ACE inhibitor and various sweeting agent or flavoring agent, coloring material or dyestuff, emulsifying and/or suspensoid and diluent such as water, ethanol, propylene glycol and glycerol, and combined hybrid.
Change to discharge and form of medication that pulsation discharges can comprise excipient, as with respect to the form of medication of instant-free described those, and change other excipient that agent is worked as rate of release, these are wrapped on the device body and/or are included in wherein.Rate of release changes agent and comprises, but is not limited only to hydroxypropyl emthylcellulose, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, poly-titanium dioxide ethylene, xanthan gum, Carbomer, ammonium-methacrylate copolymers, castor oil hydrogenated, Brazil wax, paraffin, cellulose acetate phthalate, Hydroxypropyl Methylcellulose Phathalate, methacrylic acid copolymer and composition thereof.The form of medication that changes release and pulsation release can comprise wherein a kind of or its combination of the excipient that changes rate of release.The excipient that changes rate of release can be present in the form of medication simultaneously, promptly is present in the substrate, and/or is present on the form of medication, promptly is present on surface or the coating.
The drug-delivery preparation that disperses or dissolves fast (FDDF) can comprise following ingredients: aspartame, acesulfame-K, citric acid, croscarmellose sodium, crospovidone, two ascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropyl emthylcellulose, magnesium stearate, mannitol, methylmethacrylate, the Herba Menthae flavoring agent, Polyethylene Glycol, the silicon dioxide of smoldering, silicon dioxide, sodium glycollate starch, the Fumaric acid sodium stearyl, Sorbitol, xylitol.Term used herein disperses or dissolves has described the dissolubility that FDDF depends on used medicine, if promptly medicine is insoluble, then can prepare quick dispersion form of medication, if medicine is soluble, then can prepare quick dissolving form of medication.
Combination of the present invention also can non-intestinal, for example in the spongy body, in interior, indoor, the urethra of intravenous, intra-arterial, intraperitoneal, sheath, interior, the intracranial of breastbone, intramuscular or subcutaneous administration, or they can pass through infusion or the administration of needleless (needleless) injection technique.For this parenterai administration, they preferably use with the form of sterile aqueous solution, wherein can comprise other material, for example, the salt of capacity or glucose, thus solution and blood etc. are oozed.If desired, aqueous solution suitably should be cushioned (preferred) to the pH of 3-9.The suitable preparation of parenteral formulation under aseptic condition can be finished at an easy rate by the standard pharmaceutical technology that those skilled in the art know.
Following administration level and other administration level herein are for the general human patients with about 65-70kg body weight.The technical staff can be easy to determine that body weight drops on this scope patient in addition, as child and the required administration level of old people.
The present invention's combination is depended on its effect with the administration of this dosage form, but can be contemplated to 1-500mg PDE5 inhibitor and 1-100mg ACE inhibitor, is administered three times in one day.Preferred dose is 10-100mg (for example, 10,25,50 and 100mg) PDE5 inhibitor and 5-50mg (for example, 5,10,25 an and 50mg) ACE inhibitor, and they can be administered once in one day, twice or three times (preferably once).Yet accurate dose can be determined by the prescriber, and depend on the order of severity of patient's age and body weight and symptom.
When oral and non-intestinal gave human patients, the administration every day level of the present invention combination was generally 5-500mg/kg (single or separate dosage).
Therefore, tablet or capsule can comprise 5mg-250mg (for example, 10-100mg) combination of the present invention, suitably, individually dosed or give two or more at every turn.In any case the doctor can determine the optimum accurate dosage of arbitrary individual patient, and it can change along with age, body weight and the reaction of particular patient.Above-mentioned dosage is giving an example of general case.Certainly, also exist the example that should accept higher or lower dosage range, these also fall within the scope of the present invention.Those skilled in the art will appreciate that combination of the present invention can be as required or expectation with the form picked-up of single dose (that is, prn).Will be appreciated that also the treatment that all lists of references herein relate to comprises acute treatment (carrying out as required) and chronic treatment (more secular continued treatment).
But combination of the present invention is intranasal or pass through inhalation also, and send from pressurizing vessel, pump, aerosol apparatus, nebulizer or sprinkler easily with the form that dry powder inhaler or aerosol spray are presented and to pass, wherein can use or not use suitable propellant, for example dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, hydrofluoroalkane, as 1,1,1, the 2-tetrafluoroethane (HFA 134A[trade mark]) or 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227EA[trade mark]), carbon dioxide or other suitable gas.In the situation of pressurized aerosol, thereby dosage unit can be determined by providing a valve to send to pass metered amount.Container, pump, aerosol apparatus, nebulizer or the sprinkler of pressurization can comprise the solution or the suspension of reactive compound, and for example, the mixture that uses ethanol and propellant is as solvent, and it also can comprise lubricant, for example, and sorbitan trioleate.The capsule and the cartridge case (for example, making with gelatin) that are used for inhaler or insufflator can be formulated into the powder substrate that comprises combination of the present invention and suit, as the mixture of powders of lactose or starch.
Preferably aerosol or dried powder preparation are handled, made each dosing or " one gas " comprise 1 μ g-50mg combination of the present invention, be used to send and pass the patient.Using aerocolloidal total dosage every day is 1 μ g-50mg, the form administration that it can single dose, or more generally, within one day with the separate dosage forms administration.
Optionally, combination of the present invention can suppository or the form administration of vaginal suppository, or with the form partial smearing of gel, hydrogel, lotion, solution, cream, ointment or powder puff.But combination of the present invention is skin or transdermal administration also, for example, and by using transdermal patches, storehouse or subcutaneous injection.They also can pass through lung or rectum administration.
Partial smearing is when skin, combination of the present invention can be formulated into suitable ointment, wherein comprise suspendible or be dissolved in, for example, has reactive compound in following one or more the mixture: mineral oil, Albolene, white vaseline, propylene glycol, polyethylene glycol oxide polypropylene oxide chemical compound, emulsifing wax and water.Optionally, they can be formulated into suitable lotion or cream, suspendible or be dissolved in following one or more the mixture: mineral oil, sorbitan monostearate, Polyethylene Glycol, liquid paraffin, polysorbate 60, hexadecane ester type waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Combination of the present invention also can be used in combination with cyclodextrin.Known cyclodextrin can form inclusion complex and the non-inclusion complex that contains the medicine molecule.The formation of drug-cyclodextrin complex can change dissolubility, rate of dissolution, bioavailability and/or the stability of drug molecule.The drug-cyclodextrin complex can be used for most form of medication and route of administration usually.As with a kind of selection of the direct complexation of medicine, cyclodextrin can be used as auxiliary additive, for example, as carrier, diluent or solubilizer.α-, β-and gamma-cyclodextrin be the most normal use, suitable example describes in disclosed International Patent Application WO 91/11172, WO 94/02518 and WO 98/55148.
The oral administration of the present invention's combination is preferred approach, most convenient.Under the situation that drug absorption reduces after receptor suffers from the disease of swallowing or suffers from oral administration, medicine can non-intestinal, Sublingual or oral administration.
Combination of the present invention can be used as triple therapy, that is, and and with the part of three kinds of pharmaceutical treatment patients' therapeutic scheme.The third medicament in the triple therapy can be second kind of PDE5 or ACE inhibitor, or it can be selected from the 3rd medicine group.For example, it can be neutral endopeptidase inhibitor, angiotensin II receptor antagonism, calcium channel blocker, and as Amlodipine, his spit of fland is cut down in Ta Ting such as holder, Beta receptor blockers (that is B-adrenergic receptor antagonist) or diuretic.
Will be appreciated that the present invention has covered following others, and the above embodiment that describes in detail with respect to first aspect extends to these aspects:
I) a kind of hypertensive drug regimen of the present invention (be used for simultaneously, separate or the order administration) that is used for the treatment of;
Ii) a kind ofly be used for the treatment of hypertensive test kit, this test kit comprises: first pharmaceutical composition that a) contains the PDE5 inhibitor; B) contain second pharmaceutical composition of ACE inhibitor; And c) container of described compositions;
Hypertensive method among iii) a kind of treatment patient comprises the described patient of combined therapy of the present invention with effective dose.
Algoscopy
Be suitable for preferred compounds of the invention are effectively and PDE5 inhibitor optionally.To 3 ', 5 '-the external PDE of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) phosphodiesterase suppress active can be by measuring their IC
50PH-value determination pH (enzymatic activity 50% suppresses required compound concentration).
Required PDE enzyme can separate from multiple source, comprises platelet, people's ventricle, people's skeletal muscle and the bovine retina of people's spongy body, people and rabbit, mainly by Thompson, and people such as WJ; Biochemistry 18 (23), 5228-5237, and 1979, as people such as Ballard SA; J.Urology 159 (6), 2164-2171, and the improvement of 1998 described methods is carried out.Particularly, the cAMP PDE3 of cGMP-specific PDE 5 and cGMP-inhibition can obtain from people sponge soma, human blood platelets or rabbit platelet; The PDE2 that cGMP-stimulates obtains from people's spongy body; Calcium/calmodulin, CaM (Ca/CAM)-dependency PDE1 derives from people's ventricle; CAMP-specific PDE 4 derives from people's skeletal muscle; Photoreceptor PDE6 derives from bovine retina.The total length people recombinant clone of phosphodiesterase 7-11 can be from transfection to the SF9 cell produces.
Algoscopy can be used Thompson WJ and Appleman MM; Biochemistry 10 (2), 311-316, and 1971, mainly by people such as Ballard SA; J.Urology 159 (6), 2164-2171, under improvement of " in batch " method of 1998 or the use product code TRKQ7090/7100, by the improvement of Amersham plc institute description scheme, utilization is direct to be detected [
3H]-the flicker short range algoscopy of the AMP/GMP of labelling carries out.In a word, for flicker short range algoscopy, the effect of PDE inhibitor is by under the condition that has various inhibitor concentration and a small amount of substrate to exist, measure enzyme really quantitatively and research (cGMP or cAMP, 3: 1 ratio, unlabelled with [
3H]-labelling ,-1/3Km or littler concentration), IC like this
50=Ki.With measuring buffer [20mMTris-HCl pH7.4,5mM MgCl
2, the 1mg/ml bovine serum albumin] and additional final mensuration volume to 100 μ l.Use enzyme to begin reaction, cultivate 30-60min down for 30 ℃, produce＜30% substrate turnover, and stop with 50 μ l yttrium silicate SPA pearls (each the unlabelled cyclic nucleotide that contains 3mM PDE 9-11).The 20min of seal plate, and jolting once more afterwards, makes pearl sedimentation 30 minutes in the dark, then (Packard, Meriden, CT) counting on the TopCount flat bed reader.Acitivity unit is changed into the active % of unmarked contrast (100%), the IC that obtains with respect to inhibitor concentration and use ' Fit curve ' Microsoft Excel expansion
50Value is drawn.
Zooscopy
The effect of the present invention's combination is confirmed in the hypertensive animal model of people; wherein use enalapril as representational ACE inhibitor; and use 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-just-propyl group-1; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (chemical compound of the embodiment 4 of disclosed International Patent Application WO 99/54333) is as representational PDE5 inhibitor.
Animal
Spontaneous hypertensive rat (SHR) is widely used as the hypertensive model of people.According to disclosed method, with mesentery, back leg and the kidney blood flow of the male SHR of Doppler streaming probe measurement (20-22 week is big), aortic blood pressure and heart rate (Gardiner, people such as SM; Br.J.Pharmacol.132 (8), 1625-1629,2001).
Medicine
The solution of enalapril (7.5 μ g/mL), PDE5 inhibitor (200 μ g/mL) and enalapril and PDE5 inhibitor combination (7.5 μ g/mL+200 μ g/mL) is speed with 0.4mL/h infusion in experimental period.Control animals received either chemical compound excipient; The grade that is adjusted to pH4 with hydrochloric acid is oozed normal saline.
Scheme
Record baseline hemodynamic parameter.Then by treat animal (n=7 or 8/group) at random with drug solution continuous infusion 4 days.Every day monitoring of blood kinetic parameter in the research cycle of 7h change.Provide in following table with the generality result who represents with the difference of excipient reaction.
| Treatment | |||
| Enalapril | The PDE5 inhibitor | Combination | |
| Total change of average BP | ??-2.4 | ??-12.1 | ??-17.8 |
| The change (%) of mesentery conduction | ??+22.4 | ??+22.1 | ??+48.1 |
| The change (%) of kidney conduction | ??+14.2 | ??-0.8 | ??+34.2 |
| The change (%) of aorta conduction | ??+3.7 | ??+19.8 | ??+30.1 |
As a result, particularly for the kidney conduction, confirmed that the combination of two kinds of medicaments can produce than the bigger effect of the summation of their each self-applyings.
Claims (13)
1. the preparation that is combined in of cyclic guanosine monophosphate specific phosphodiesterase enzyme 5 types (PDE5) inhibitor and angiotensin converting enzyme (ACE) inhibitor is used to comprise essential hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, the hypertension relevant with diabetes, the hypertension relevant and the hypertension of renovascular hypertension with atherosclerosis, congestive heart failure, angor, apoplexy, the alleviation of diabetes and impaired glucose tolerance, purposes in healing property or the preventative-therapeutic medicine.
2. purposes according to claim 1, wherein said PDE5 inhibitor has the IC less than 100nM
50Value.
3. purposes according to claim 2, wherein said PDE5 inhibitor has the IC less than 50nM
50Value.
4. according to the described purposes of any one aforementioned claim, wherein said PDE5 inhibitor is selected from
5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-just-propyl group-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil);
(6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1,4-diketone (tadalafil);
2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (vardenafil);
5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; With
5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azelidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones
And pharmaceutically acceptable salt.
5. purposes according to claim 4; wherein said PDE5 inhibitor is 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazinyl sulfonyl) phenyl]-1-methyl-3-just-propyl group-1; 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil) or its pharmaceutically acceptable salt.
6. purposes according to claim 5, wherein said PDE5 inhibitor is the sldenafil citrate.
7. according to the described purposes of any one aforementioned claim, wherein said ACE inhibitor is selected from benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril and pharmaceutically acceptable salt thereof.
8. purposes according to claim 7, wherein the combination of PDE 5 inhibitor and ACE inhibitor is selected from
Sldenafil citrate and quinapril hydrochloride;
Sldenafil citrate and benazepril hydrochlorate;
Sldenafil citrate and captopril;
Sldenafil citrate and enalapril maleate;
Sldenafil citrate and fosinopril;
Sldenafil citrate and lisinopril;
Sldenafil citrate and moexipril;
Sldenafil citrate and ramipril; With
Sldenafil citrate and trandolapril.
9. purposes according to claim 1, wherein said medicine is used for the treatment of hypertension.
10. pharmaceutical composition that comprises cyclic guanosine monophosphate specific phosphodiesterase enzyme 5 types (PDE5) inhibitor and angiotensin converting enzyme (ACE) inhibitor.
11. while, separately or order be administered for the hypertensive pharmaceutical composition of treatment, comprise cGMP specific phosphodiesterase enzyme 5 types (PDE5) inhibitor and angiotensin converting enzyme (ACE) inhibitor.
12. one kind is used for the treatment of hypertensive test kit, this test kit comprises: first pharmaceutical composition that a) contains the PDE5 inhibitor; B) contain second pharmaceutical composition of ACE inhibitor; And c) container of described compositions.
13. hypertensive method among the treatment patient comprises with the PDE5 inhibitor and the ACE inhibitor of effective dose and treats described patient simultaneously, separately or in proper order.
Applications Claiming Priority (4)
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| GB0211919A GB0211919D0 (en) | 2002-05-23 | 2002-05-23 | Novel combination |
| GB0211919.6 | 2002-05-23 | ||
| GB0229784A GB0229784D0 (en) | 2002-12-20 | 2002-12-20 | Novel combination |
| GB0229784.4 | 2002-12-20 |
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| CN1655820A true CN1655820A (en) | 2005-08-17 |
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| GB0318094D0 (en) * | 2003-08-01 | 2003-09-03 | Pfizer Ltd | Novel combination |
| DE102004011512B4 (en) | 2004-03-08 | 2022-01-13 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical preparation containing pimobendan |
| US8980894B2 (en) | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
| EP1579862A1 (en) | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
| FR2902009B1 (en) * | 2006-06-13 | 2012-12-07 | Bioprojet Soc Civ | USE OF A VASOPEPTIDASE INHIBITOR FOR THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION |
| JP2010501577A (en) | 2006-08-24 | 2010-01-21 | サーフェイス ロジックス，インコーポレイティド | Compounds with improved pharmacokinetics |
| EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
| EP2825159B1 (en) | 2012-03-15 | 2022-06-22 | Boehringer Ingelheim Vetmedica GmbH | Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof |
| ES2860526T3 (en) | 2013-07-19 | 2021-10-05 | Boehringer Ingelheim Vetmedica Gmbh | Preserved Etherified Cyclodextrin Derivatives Containing A Liquid Aqueous Pharmaceutical Composition |
| PL2925305T3 (en) | 2013-12-04 | 2017-07-31 | Boehringer Ingelheim Vetmedica Gmbh | Improved pharmaceutical compositions of pimobendan |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
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| GB9013750D0 (en) * | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
| US6143746A (en) * | 1994-01-21 | 2000-11-07 | Icos Corporation | Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use |
| GB9401090D0 (en) * | 1994-01-21 | 1994-03-16 | Glaxo Lab Sa | Chemical compounds |
| EP2295436A1 (en) * | 1997-11-12 | 2011-03-16 | Bayer Schering Pharma AG | 2-Phenyl-subsitituted Imidazotriazinones as Phosphodiesterase V inhibitors |
| TWI265925B (en) * | 1999-10-11 | 2006-11-11 | Pfizer | Pyrazolo[4,3-d]pyrimidin-7-ones useful in inhibiting type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases(cGMP PDE5), process and intermediates for their preparation, their uses and composition comprising them |
| CN1378547A (en) * | 1999-10-11 | 2002-11-06 | 辉瑞大药厂 | 5-(2-substituted-5-heterocyclylsulphenylpyrid-3-yl)-dihydropyrazolo [4,3-d] pyrimidin 7-ones as phosphodiesterase inhibitors |
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| EP1506015A2 (en) | 2005-02-16 |
| PE20040514A1 (en) | 2004-08-24 |
| IL164975A0 (en) | 2005-12-18 |
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