CN1809353B - Medicine for prevention of and treatment for arteriosclerosis and hypertension. - Google Patents
Medicine for prevention of and treatment for arteriosclerosis and hypertension. Download PDFInfo
- Publication number
- CN1809353B CN1809353B CN200480008667.0A CN200480008667A CN1809353B CN 1809353 B CN1809353 B CN 1809353B CN 200480008667 A CN200480008667 A CN 200480008667A CN 1809353 B CN1809353 B CN 1809353B
- Authority
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- China
- Prior art keywords
- chemical compound
- methyl
- medicament
- calcium channel
- channel blocker
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 206010020772 Hypertension Diseases 0.000 title claims abstract description 30
- 208000011775 arteriosclerosis disease Diseases 0.000 title claims abstract description 14
- 206010003210 Arteriosclerosis Diseases 0.000 title claims abstract description 13
- 230000002265 prevention Effects 0.000 title description 22
- 229940079593 drug Drugs 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 239000000480 calcium channel blocker Substances 0.000 claims abstract description 48
- 229940127291 Calcium channel antagonist Drugs 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims abstract description 37
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 claims abstract description 37
- 150000002148 esters Chemical class 0.000 claims abstract description 22
- 239000000203 mixture Substances 0.000 claims abstract description 21
- -1 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl Chemical group 0.000 claims description 67
- ZKFQEACEUNWPMT-UHFFFAOYSA-N Azelnidipine Chemical compound CC(C)OC(=O)C1=C(C)NC(N)=C(C(=O)OC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZKFQEACEUNWPMT-UHFFFAOYSA-N 0.000 claims description 44
- 229950004646 azelnidipine Drugs 0.000 claims description 44
- 210000004204 blood vessel Anatomy 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
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- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 claims description 9
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- NSVFSAJIGAJDMR-UHFFFAOYSA-N 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate Chemical compound CC=1NC(C)=C(C(=O)OCCN(CC=2C=CC=CC=2)C=2C=CC=CC=2)C(C=2C=C(C=CC=2)[N+]([O-])=O)C=1P1(=O)OCC(C)(C)CO1 NSVFSAJIGAJDMR-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
Disclosed is the medicine used for preventing and treating arteriosclerosis, hypertension, heart disease or cerebrovascular disease. The composition of the medicine comprises (A) angiotensin II receptor antagonist which is selected from the compounds with the general formula (I) and is composed of ester which has pharmacological acceptance property and salt which has pharmacological acceptance property (such as olmesartan medoxomil) and (B) calcium channel blocker which is used as the active constituent and is selected from the dihydro-pyridine derivatives and is composed of salt which has which has pharmacological acceptance property.
Description
[technical field]
The present invention relates to a kind of arteriosclerotic medicament that prevents and/or treats.In addition, the present invention relates to a kind of prevention and/or therapeutic treatment disease, as hypertension, heart disease (angina pectoris, myocardial infarction, arrhythmia (comprising sudden death), heart failure or cardiac hypertrophy), the medicament of nephropathy (diabetic nephropathy, glomerulonephritis or nephrosclerosis) or cerebrovascular disease (cerebral infarction or cerebral hemorrhage).
[background technology]
At present, be extensive use of calcium channel blocker and rasied clinically and prevent and treat hypertension.Can use all kinds calcium channel blocker, in them 1,4-dihydrogen pyridine derivative such as Amlodipine, benidipine, nitrendipine, Manidipine, nicardipine, Nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine, nilvadipine, azelnidipine etc. are long lasting calcium channel blockers, and be widely-used clinically as the antihypertensive drug of first-selection.In addition; as rasied; it is more and more that the clinical practice of angiotensin ii receptor antagonist becomes gradually; this is because at first; angiotensin ii receptor antagonist is free from side effects as cough; it is a reason by the caused disease of angiotensin converting enzyme (ACE) inhibitor, and secondly, they have brought into play protective effect to cardiovascular and renal system.Yet, in many cases, only by a kind of blood pressure that can not control the hypertensive patient fully in these medicines.
Except vasorelaxation action, because calcium channel blocker is also brought into play short natruresis effect, they can also resist the hypertension (feritin dependent/non-dependent hypertension) that is caused by fluid retention effectively.On the other hand, angiotensin ii receptor antagonist antagonism renin dependent hypertension is effective especially, and in addition, they have brought into play fabulous protective effect in a plurality of organs.No matter therefore what hypertensive reason is, expectation is by reaching stable and significant resisting hypertension effect with calcium channel blocker and angiotensin ii receptor antagonist administering drug combinations.
Many composition of medicine that comprise calcium channel blocker and angiotensin ii receptor antagonist have been proposed (for example, No. 01/15674 patent gazette of international publication, No. 01/78699 patent gazette of international publication, No. 02/43807 patent gazette of international publication, No. 01/76632 patent gazette of international publication, No. 01/74390 patent gazette of international publication, Japanese patent gazette (Kohyo) 2002-524408 number, No. 92/10097 patent gazette of international publication, Japanese patent gazette (Kokoku) hei 7-035372, UK Patent Application discloses description No. 2268743, Japanese patent gazette (Kokai) hei 6-56789, Japanese patent gazette (Kokai) hei 5-155867, No. 2001/0004640 description of U.S. Patent Application Publication, the USP6204281 description, No. 3057471 communique of Japan Patent, No. 2930252 communique of Japan Patent, Japanese patent gazette (Kohyo) 2002-507213 number, Japanese patent gazette (Kohyo) 2001-513498 number, Japanese patent gazette (Kohyo) 2000-508632 number, Japanese patent gazette (Kokoku) hei 7-91299, Japanese patent gazette (Kokoku) hei 7-14939, Japanese patent gazette (Kokai) hei 6-65207, Japanese patent gazette (Kokai) hei 5-213894, Japanese patent gazette (Kohyo) 2002-518417 number, Japanese patent gazette (Kohyo) 2002-506010 number and Japanese patent gazette (Kohyo) 2001-522872 number), in more above-mentioned publications, disclose by specific calcium channel blocker and the nervous plain II receptor antagonist administering drug combinations of particular blood vessel have been reached best resisting hypertension effect.Yet the effect of angiotensin ii receptor antagonist that the present invention is specific and specific calcium channel blocker administering drug combinations is unknown.
On the other hand, the feature of the early stage pathological change of arteriosclerosis is medium-sized artery and aorticly thickens unusually, the early stage pathological change of arteriosclerosis damages with endothelial tissue, vascular smooth muscle cell (VSMC) is moved to tunica intima, vascular smooth muscle cell curing, the accumulation (foam cell) of the interior lipid of cell etc. is a feature. in addition, under the hypertension situation relevant with the arteriosclerosis process, knownly can change the vascular cell structure by reaction to various blood vessel load factors, vascular remodeling takes place. vascular remodeling refers to be changed by the blood vessel structure that hemodynamics variation such as blood flow and the tensile variation of blood vessel wall cause. except material as somatomedin and cytokine, think that also vaso-active substance also has contribution to this evolution. for example, known Angiotensin II, can promote propagation (the Medical Clinics of Japan of vascular smooth muscle cell, vol.21,1924,1995), also can promote reconstruct (the Joumal of Clinical andExperimental Medicine (IGAKUNO AYUMI) of blood vessel, Vol.193,361,2000).
But the detailed mechanism of arteriosclerosis terminal illness from falling ill to developing into does not also throw a flood of light on.In addition, the detailed mechanism of vascular remodeling also is unknown.Though some report has been described the relation (Circulation, 104,2716,2001) of angiotensin ii receptor antagonist and vascular remodeling, and calcium channel blocker is known little about it to the effect and the mechanism thereof of the pathological change in arteriosclerosis and the blood vessel injury.And, for calcium channel blocker with the angiotensin ii receptor antagonist administering drug combinations resists arteriosclerotic prevention and therapeutic effect also seldom has report.Especially, although, calcium channel blocker is known little about it to the effect of renin-angiotensin system and the synergism of calcium channel blocker and angiotensin ii receptor antagonist in fact in that they are important problem aspect the arteriosclerosis treatment.
In addition, owing to comprise that the percutaneous coronary of percutaneous tranluminal coronary angioplasty (PTCA) is got involved (PCI) and the support implantation has lower aggressivity, they have occupied middle cardiac status in current antagonism ischemic heart disease therapeutic strategy.But the restenosis that occurs in the postoperative some months in the patient that 30-45% treats through these surgical methods is a main problem.For the mechanism of restenosis behind the PCI, behind PCI late period whole blood vessels the minimizing (being exactly reconstruct) of diameter be considered to important, except the neointima hyperplasia and hypertrophy that cause by smooth muscle cell proliferation, (coronary Intervention, vol.1,12; Medical clinics of Japan, Vol.21,1924,1995).In these cases, development is new can prevent effectively that the medicament of vascular restenosis is necessary behind the PCI.But, up to the present also untappedly go out medicament efficiently.
[of the present invention open]
Theme of the present invention provides and prevents and/or treats arteriosclerotic medicament.More specifically, theme of the present invention provides the medicament of the formation of neointima in prevention or inhibition vascular smooth muscle hypertrophy and the blood vessel.In addition, another theme of the present invention provides the medicament of vascular restenosis behind effective inhibition vascular remodeling and prevention of arterial sclerosis development and the PCI.
In addition, another theme of the present invention provides prevention or treatment hypertension or because the medicament of the disease that hypertension causes.More specifically, this theme provides and prevents and/or treats hypertension, heart disease [angina pectoris, myocardial infarction, arrhythmia (comprising sudden death), myocardial failure or cardiac hypertrophy], the medicament of nephropathy (diabetic nephropathy, glomerulonephritis or nephrosclerosis) or cerebrovascular (cerebral infarction or cerebral hemorrhage) (particularly prevent or treat hypertensive medicament).
The inventor has scrutinized above-mentioned theme, the administering drug combinations of finding the nervous plain II receptor antagonist of specific calcium channel blocker and particular blood vessel can effectively prevent the formation of neointima in the hypertrophy of vascular smooth muscle and the blood vessel, and the inhibitory action of finding the administering drug combinations of two kinds of medicaments is a synergism, but also finds that the lower dosage of effective dose when more individually dosed than them can observe effective inhibitory action.In addition, the inventor finds that administering drug combinations as indicated above can significantly prevent vascular remodeling, and finds that above-mentioned medicament can effectively suppress restenosis behind the PCI.
In addition, the inventor finds that the administering drug combinations of specific calcium channel blocker mentioned above and the nervous plain II receptor antagonist of particular blood vessel can obtain fabulous hypotensive effect. in addition, the inventor finds that medicament of the present invention is for preventing and/or treating hypertension, heart disease [angina pectoris, myocardial infarction, arrhythmia (comprising sudden death), myocardial failure or cardiac hypertrophy], nephropathy (diabetic nephropathy, glomerulonephritis or nephrosclerosis) or cerebrovascular (cerebral infarction or cerebral hemorrhage) are very effective. therefore on the basis of these discoveries described above, finish the present invention.
The invention provides a kind of angiosclerotic medicament that prevents and/or treats, comprise following component:
(A) be selected from by chemical compound the angiotensin ii receptor antagonist of the group that last acceptable ester of its pharmacology and the last acceptable salt of pharmacology thereof are formed with general formula (I); With
(B) be selected from by 1, the calcium channel blocker of the group that the last acceptable salt of 4-dihydrogen pyridine derivative and pharmacology thereof is formed is as active component.
In addition, from another aspect of the present invention, provide a kind of medicament that suppresses vascular smooth muscle cell proliferation, this medicament contains chemical compound (A) and chemical compound (B) is done active composition; A kind of medicament that neointima forms in the blood vessel that suppresses is provided, and this medicament contains chemical compound (A) and chemical compound (B) is done active composition; And a kind of medicament that suppresses vascular remodeling, this medicament contains chemical compound (A) and chemical compound (B) is done active composition.These medicaments can be used as for example percutaneous coronary intervention preventive of restenosis afterwards.From this respect, after the crown intervention of percutaneous, the invention provides a kind of percutaneous coronary that prevents and get involved the medicament of restenosis afterwards, this medicament comprises chemical compound (A) and chemical compound (B).
In addition, the invention provides a kind of medicament of the disease that prevents and/or treats hypertension or cause by hypertension, contain following compounds and do active composition:
(A) be selected from by chemical compound the angiotensin ii receptor antagonist of the group that last acceptable ester of its pharmacology and the last acceptable salt of pharmacology thereof are formed with the above general formula (I); With
(B) be selected from by 1 the calcium channel blocker of the group that the last acceptable salt of 4-dihydrogen pyridine derivative and pharmacology thereof is formed; And provide a kind of heart disease [angina pectoris that prevents and/or treats, myocardial infarction, arrhythmia (comprising sudden death), myocardial failure or cardiac hypertrophy], nephropathy (diabetic nephropathy, glomerulonephritis or nephrosclerosis) or the medicament of cerebrovascular (cerebral infarction or cerebral hemorrhage) etc., comprise that following compounds does active composition:
(A) be selected from by chemical compound the angiotensin ii receptor antagonist of the group that last acceptable ester of its pharmacology and the last acceptable salt of pharmacology thereof are formed with the above general formula (I); With
(B) be selected from by 1 the calcium channel blocker of the group that the last acceptable salt of 4-dihydrogen pyridine derivative and pharmacology thereof is formed.
Embodiment preferred according to the present invention, the medicament mentioned above that is provided is for containing the pharmaceutical composition of doing active composition of chemical compound (A) and chemical compound (B). this pharmaceutical composition can comprise one or more excipient that is used for preparation. another embodiment preferred according to the present invention, the medicament mentioned above that is provided can be simultaneously to drug compound (A) and chemical compound (B) or through proper spacing respectively to drug compound (A) and chemical compound (B).
In addition, embodiment preferred more according to the present invention, the medicament mentioned above that is provided is the pharmaceutical composition that contains angiotensin ii receptor antagonist and calcium channel blocker, wherein said angiotensin receptor II antagonist is (5-a methyl-2-oxo-1, the 3-Dioxol-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-l-[[2 '-(1H-tetrazolium-5-yl) phenylbenzene-4-yl] methyl] imidazole-5-carboxylic acid ester (following some part in this description is called " olmesartan medoxomil "), above-mentioned calcium channel blocker is selected from any one of calcium channel blocker, comprise (±)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrobenzophenone)-3,5-pyridine-dicarboxylic ester-3-(1-diphenyl methyl azetidine-3-yl) ester 5-isopropyl esters (following some part in this description is called " azelnidipine "); Amlodipine, benidipine, nitrendipine, Manidipine, nicardipine, Nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine and nilvadipine; Preferred calcium channel blocker is an azelnidipine.
From another aspect of the present invention, the invention provides the chemical compound that is selected from by having formula mentioned above (I), its pharmacology go up acceptable ester with and the pharmacology go up group that acceptable salt is formed Angiotensin II receptor antagonist and be selected from by 1, the calcium channel blocker of the group that acceptable salt is formed on 4-dihydrogen pyridine derivative and the pharmacology thereof prepares the purposes of medicament mentioned above.
In addition, the invention provides and prevent and/or treat arteriosclerotic method, comprise that chemical compound (A) and the chemical compound (B) with effective dose delivers medicine to any method that mammal comprises the people; The method that suppresses vascular smooth muscle cell proliferation is provided, comprises that chemical compound (A) and the chemical compound (B) with effective dose delivers medicine to any method that mammal comprises the people; Film formed method in the angiogenesis inhibiting is provided, comprises that chemical compound (A) and the chemical compound (B) with effective dose delivers medicine to any method that mammal comprises the people; The method that suppresses vascular remodeling is provided, comprises that chemical compound (A) and the chemical compound (B) with effective dose delivers medicine to any method that mammal comprises the people; Provide and suppress the percutaneous coronary intervention method of restenosis afterwards, comprise that chemical compound (A) and the chemical compound (B) with effective dose delivers medicine to any method that mammal comprises the people.Preferably, in the present invention, near the minimum of the chemical compound (A) that contains of every kind of compositions and the effective dose of chemical compound (B) effective dose when individually dosed chemical compound (A) or chemical compound (B) or below minimum.
In addition, the invention provides and prevent and/or treat hypertension or, comprise that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people by the method for the caused disease of hypertension; Prevention is provided or treats hypertensive method, comprise that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; Prevention is provided or treats cardiopathic method, comprise that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; Prevention is provided or treats anginal method, comprise that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; The method of prevention or treatment myocardial infarction is provided, comprises that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; Prevention is provided or treats ARR method, comprise that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; The method of prevention or treatment sudden death is provided, comprises that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; The method of prevention or treatment heart failure is provided, comprises that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; The method of prevention or treatment cardiac hypertrophy is provided, comprises that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; The method of prevention or treatment nephropathy is provided, comprises that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; The method of prevention or treatment diabetic nephropathy is provided, comprises that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; Prevention is provided or treats brightic method, comprise that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; Prevention is provided or treats nephrosclerotic method, comprise that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; The method of prevention or treatment cerebrovascular is provided, comprises that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; The method of prevention or treatment cerebral infarction is provided, comprises that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people; And/or the method for preventing or treating cerebral hemorrhage is provided, comprise that above-claimed cpd (A) and the above-claimed cpd (B) with effective dose delivers medicine to any method that mammal comprises the people.
[Short Description of accompanying drawing]
Fig. 1 is illustrated in 0.1 to 1.0mg/kg/ day dosage range and uses the calcium channel blocker azelnidipine to suppress the synthetic result of DNA in the vascular smooth muscle cell.
Fig. 2 is illustrated in 0.1 to 1.0mg/kg/ day dosage range and uses the calcium channel blocker azelnidipine to suppress the result that neointima forms in the blood vessel.
Fig. 3 is illustrated in 0.5 to 3.0mg/kg/ day dosage range and uses the angiotensin ii receptor antagonist Olmesartan to suppress the synthetic result of DNA in the vascular smooth muscle cell.
Fig. 4 is illustrated in 0.5 to 3.0mg/kg/ day dosage range and uses the angiotensin ii receptor antagonist Olmesartan to suppress the result that neointima forms in the blood vessel.
Fig. 5 is illustrated in 0.1mg/kg/ days to 0.5mg/kg/ days dosage range and (uses any of these medicines separately with this dosage, they can not produce any remarkable result) simultaneously, administration azelnidipine and Olmesartan suppress the synthetic result of DNA in the vascular smooth muscle cell respectively.
Fig. 6 is illustrated in 0.1mg/kg/ days to 0.5mg/kg/ days dosage range and (uses any of these medicines separately with this dosage, they can not produce any remarkable result) simultaneously, administration azelnidipine and Olmesartan suppress the result that neointima forms in the blood vessel respectively.
Fig. 7 is illustrated in stimulates the synthetic result of enhanced DNA in the Mus vascular smooth muscle cell that azelnidipine relies on concentration behind the angiotensin-ii receptor mode suppresses to cultivate.
The synthetic result of DNA in the vascular smooth muscle cell that Fig. 8 represents significantly to suppress to cultivate by co-administered azelnidipine and Olmesartan with low concentration uses any of these medicines separately with this concentration, and they can not produce any remarkable result
[implementing best mode of the present invention]
Medicament of the present invention is characterised in that containing (A) is selected from by the chemical compound with general formula mentioned above (I), the angiotensin ii receptor antagonist of the group that last acceptable ester of its pharmacology and the last acceptable salt of pharmacology thereof are formed, (B) be selected from by 1, the calcium channel blocker of the group that the last acceptable salt of 4-dihydrogen pyridine derivative and pharmacology thereof is formed is made active component.
Chemical compound with formula (I) mentioned above, [4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[[2 '-(1H-tetrazolium-5-yl) phenylbenzene-4-yl] methyl] imidazole-5-carboxylic acid] be known compound, for example can easily use Japanese patent gazette (Kokai) hei 5-78328 (USP5,616,599 description) etc. the disclosed method method obtains in. and the chemical compound pharmacology with formula (I) mentioned above goes up acceptable salt and is not particularly limited, those of ordinary skills can select these salt. and the pharmacology as the chemical compound with formula mentioned above (I) goes up acceptable salt, such salt is for example alkali metal salt such as sodium salt, potassium salt or lithium salts; Alkali salt such as calcium salt or magnesium salt; Slaine such as aluminum salt, iron salt, zinc salt, mantoquita, nickel salt or cobalt salt, amine salt such as ammonium salt, the t-octylamine salt, the dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum (morpholine salt), glucosamine salt (glucosaminesalt), phenylglycine alkyl ester salt (phenylglycine alkyl ester salt), ethylenediamine salt (ethylenediamine salt), N-cardiografin salt (methylglucamine salt), guanidinesalt, the diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt (dibenzylethylenediamine salt), chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethyl ammonium salt or three (methylol) aminomethane salt, but be not limited to these salt.The preferred alkali metal salt that uses especially preferably uses sodium salt.
The acceptable ester of chemical compound pharmacology with formula mentioned above (I) comprises the chemical compound of the formula (I) of the carboxy moiety with esterification.The last acceptable ester of pharmacology is not particularly limited, and those of ordinary skills can select these esters.With regard to above-mentioned ester, the preferred ester that can rupture by biological process such as hydrolysis in vivo.Form above-mentioned ester group (when this ester be expressed as-during COOR, group is represented with R) can be C for example
1-C
4Alkoxy C
1-C
4Alkyl such as methoxy ethyl, 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl, 1-(isopropoxy) ethyl, the 2-methoxy ethyl, 2-ethoxyethyl group, 1,1-dimethyl-1-methoxy, ethoxyl methyl, propoxyl group methyl, isopropoxy methyl, butoxymethyl or tert-butoxy methyl; C
1-C
4Alkoxylate C
1-C
4Alkoxy C
1-C
4Alkyl such as 2-methoxy ethoxy methyl; C
6-C
10Aryloxy group C
1-C
4Alkyl such as phenoxymethyl; Halo C
1-C
4Alkoxy C
1-C
4Alkyl is as 2,2,2-trichlorine ethoxyl methyl or two (2-chloroethoxy) methyl; C
1-C
4Alkoxy carbonyl C
1-C
4Alkyl is the methoxycarbonyl methyl for example; Cyano group C
1-C
4Alkyl such as cyano methyl or 2-cyano ethyl; C
1-C
4Alkyl sulfide methyl such as methyl sulfidomethyl or ethyl sulfidomethyl; C
6-C
10Virtue sulfidomethyl such as phenyl sulfidomethyl or naphthyl sulfidomethyl; C
1-C
4Alkyl sulphonyl C
1-C
4Low alkyl group is chosen wantonly by the halogen atom replacement as 2-methyl sulphonyl ethyl or 2-trifluoromethyl sulfonyl ethyl; C
6-C
10Aryl sulfonyl C
1-C
4Alkyl such as 2-benzenesulfonyl ethyl or 2-tosyl ethyl; C
1-C
7Aliphatic series acyloxy C
1-C
4Alkyl is the formyloxy methyl for example, acetoxy-methyl, propionyloxy methyl, butyryl acyloxy methyl, oxy acid methyl neopentyl, valeryl oxygen ylmethyl, isoamyl acyl-oxygen ylmethyl, hexylyloxy methyl, 1-formyloxy ethyl, 1-acetoxyl group ethyl, 1-propionyloxy ethyl, 1-butyryl acyloxy ethyl, 1-new pentane acyloxy ethyl, 1-penta acyloxy ethyl, 1-isoamyl acyloxy ethyl, 1-hexylyloxy ethyl, 2-formyloxy ethyl, 2-acetoxyl group ethyl, 2-propionyloxy propyl group, 2-butyryl acyloxy ethyl, 2-new pentane acyloxy ethyl, 2-penta acyloxy ethyl, 2-isoamyl acyloxy ethyl, 2-hexylyloxy ethyl, 1-formyloxy propyl group, 1-acetoxyl group propyl group, 1-propionyloxy propyl group, 1-butyryl acyloxy propyl group, 1-new pentane acyloxy propyl group, 1-penta acyloxy propyl group, 1-isoamyl acyloxy propyl group, 1-hexylyloxy propyl group, 1-acetoxyl group butyl, 1-propionyloxy butyl, 1-butyryl acyloxy butyl, 1-new pentane acyloxy butyl, 1-acetoxyl group amyl group, 1-propionyloxy amyl group, 1-butyryl acyloxy amyl group, 1-new pentane acyloxy amyl group or 1-new pentane acyloxy hexyl; C
5-C
6Naphthene base carbonyl oxygen base C
1-C
4Alkyl such as cyclopentylcarbonyl oxygen ylmethyl, cyclohexyl-carbonyl oxygen ylmethyl, 1-cyclopentylcarbonyl oxygen base ethyl, 1-cyclohexyl-carbonyl oxygen base ethyl, 1-cyclopentylcarbonyl oxygen base propyl group, 1-cyclohexyl-carbonyl oxygen base propyl group, 1-cyclopentylcarbonyl oxygen Ji Dingji or 1-cyclohexyl-carbonyl oxygen Ji Dingji; C
6-C
10Aryl carbonyl oxygen base C1-C
4Alkyl such as benzoyloxy group methyl; C
1-C
6Alkoxy-carbonyl oxy C1-C
4Alkyl such as methoxycarbonyl oxygen ylmethyl, 1-(methoxycarbonyl oxygen base) ethyl, 1-(methoxycarbonyl oxygen base) propyl group, 1-(methoxycarbonyl oxygen base) butyl, 1-(methoxycarbonyl oxygen base) amyl group, 1-(methoxycarbonyl oxygen base) hexyl, ethoxy carbonyl oxygen ylmethyl, 1-(ethoxy carbonyl oxygen base) ethyl, 1-((ethoxy carbonyl oxygen base) propyl group, 1-(ethoxy carbonyl oxygen base) butyl, 1-(ethoxy carbonyl oxygen base) amyl group, 1-(ethoxy carbonyl oxygen base) hexyl, propoxycarbonyl oxygen ylmethyl, 1-(propoxycarbonyl oxygen base) ethyl, 1-(propoxycarbonyl oxygen base) propyl group 1-(propoxycarbonyl oxygen base) butyl, isopropoxy carbonyl oxygen ylmethyl, 1-(isopropoxy carbonyl oxygen base) ethyl, 1-(isopropoxy carbonyl oxygen base) butyl, butoxy carbonyl oxygen ylmethyl, 1-(butoxy carbonyl oxygen base) ethyl, 1-(butoxy carbonyl oxygen base) propyl group, 1-(butoxy carbonyl oxygen base) butyl, isobutoxy carbonyl oxygen ylmethyl, 1-(isobutoxy carbonyl oxygen base) ethyl, 1-(isobutoxy carbonyl oxygen base) propyl group, 1-(isobutoxy carbonyl oxygen base) butyl, tert-butoxycarbonyl oxygen ylmethyl, 1-(tert-butoxycarbonyl oxygen base) ethyl, pentyloxy carbonyl oxygen ylmethyl, 1-(pentyloxy carbonyl oxygen base) ethyl, 1-(pentyloxy carbonyl oxygen base) propyl group, hexyloxy carbonyl oxygen ylmethyl, 1-(hexyloxy carbonyl oxygen base) ethyl or 1-(hexyloxy carbonyl oxygen base) propyl group; C
5-C
6Cyclo alkoxy carbonyl oxygen base C
1-C
4Alkyl is cyclopentyloxy ketonic oxygen ylmethyl for example, 1-(cyclopentyloxy ketonic oxygen base) ethyl, 1-(cyclopentyloxy ketonic oxygen base) propyl group, 1-(cyclopentyloxy ketonic oxygen base) butyl, cyclohexyloxy carbonyl oxygen ylmethyl, 1-(cyclohexyloxy carbonyl oxygen base) ethyl, 1-(cyclohexyloxy carbonyl oxygen base) propyl group or 1-(cyclohexyloxy carbonyl oxygen base) butyl; [5-(C
1-C
4Alkyl)-the 2-Oxy-1, the 3-Dioxol-4-yl] methyl (5-methyl-2-Oxy-1 for example, the 3-Dioxol-4-yl) methyl, (5-ethyl-2-Oxy-1,3-Dioxol-4-yl) methyl, (5-propyl group-2-Oxy-1, the 3-Dioxol-4-yl) methyl, (5-isopropyl-2-Oxy-1,3-Dioxol-4-yl) methyl or (5-butyl-2-Oxy-1,3-Dioxol-4-yl) methyl; [(phenyl is randomly used C to 5-
1-C
4Alkyl, C
1-C
4Alkoxyl or halogen atom replace) the 2-Oxy-1, the 3-Dioxol-4-yl] methyl (5-phenyl-2-Oxy-1 for example, the 3-Dioxol-4-yl) methyl, [5-(4-tolyl)-2-Oxy-1, the 3-Dioxol-4-yl] methyl, [5-(4-methoxyphenyl)-2-Oxy-1, the 3-Dioxol-4-yl] methyl, [5-(4-fluorophenyl)-2-Oxy-1, the 3-Dioxol-4-yl] methyl or [5-(4-chlorphenyl)-2-Oxy-1,3-Dioxol-4-yl] methyl; Or phthalidyl, the optional C that uses
1-C
4Alkyl, C
1-C
4Alkoxyl, phthalidyl for example, dimethyl phthalidyl or dimethoxy phthalidyl, preferred oxy acid methyl neopentyl, phthalidyl or (5-methyl-2-Oxy-1,3-Dioxol-4-yl) methyl, and more preferably (5-methyl-2-Oxy-1,3-Dioxol-4-yl) methyl.
The pharmacology who forms with regard to the ester of above-mentioned formula (I) chemical compound goes up with regard to the acceptable salt, and those of ordinary skills can go up acceptable salt to the pharmacology and select, and are not particularly limited.Such salt for example can be, hydrohalide such as hydrofluoride, hydrochlorate, hydrobromate or hydriodide; Nitrate; Perchlorate; Sulfate; Phosphate; C
1-C
4Alkylsulfonate can be chosen wantonly by halogen atom and replaces for example metilsulfate, trifluoromethyl sulfonic acid or ethyl sulfonate; C
6-C
10Arylsulphonate can be chosen wantonly by C
1-C
4Alkyl replaces, for example benzene sulfonate or tosilate; C
1-C
6Soap such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalates or maleate; Or amino acid salts glycinate for example, lysinate, arginine salt, ornithine salt, glutamate, Glu or aspartate, preferred salt hydrochlorate, nitrate, sulfate or phosphate, special preferred salt hydrochlorate.
The angiotensin ii receptor antagonist that can be used as chemical compound (A), the chemical compound or its pharmacology that preferably have above-mentioned formula (I) go up acceptable ester, more preferably have above-mentioned formula (I) chemical compound pharmacology and go up acceptable ester, and the oxy acid methyl neopentyl ester that further more preferably has the chemical compound of formula (I), phthalidyl ester or (5-methyl-2-Oxy-1,3-Dioxol-4-yl) methyl ester.Most preferably use (5-methyl-2-Oxy-1,3-Dioxol-4-yl) 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl] the imidazole-5-carboxylic acid ester.
When from by chemical compound, when its pharmacology goes up the group selection chemical compound that acceptable salt is formed on acceptable ester and the pharmacology, can also use their hydrate or solvate with above-mentioned formula (I).The chemical compound pharmacology who has above-mentioned formula (I) in use goes up under the situation of acceptable ester, the chemical compound of some esterification has one or more asymmetric carbon atoms, but also can with based on the pure optical isomer of above-mentioned asymmetric carbon atom or stereoisomer for example any mixture of diastereomer or these stereoisomers or racemic compound as chemical compound (A).
The calcium channel blocker that can be used as chemical compound (B) comprises 1, the 4-dihydrogen pyridine derivative, it is to have 1 in molecule, 4-dihydropyridine part or have and 1, the calcium channel blocker of 4-dihydropyridine part chemical equivalence structure division. propose many medicines and can be used as and comprise 1, the channel blocker of 4-dihydrogen pyridine derivative calcium, and in fact in clinical use. those of ordinary skills can select any suitable chemical compound that produces effect of the present invention. as 1, the 4-dihydrogen pyridine derivative, for example can use azelnidipine, Amlodipine, benidipine, nitrendipine, Manidipine, nicardipine, Nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine or nilvadipine are as calcium channel blocker, but these calcium channel blockers that scope of the present invention is not limited to enumerate. in addition, according to Japanese patent gazette (Kokai) Sho 63-253082 (USP4,772,596 description) etc. disclosed method can easily prepare azelnidipine, USP4 in addition, 572,909 description or USP4,879,303 description disclosed methods can easily prepare Amlodipine.
Owing to be not particularly limited 1,4-dihydrogen pyridine derivative pharmacology goes up acceptable salt, and those of ordinary skills can select any salt.The last acceptable salt of pharmacology can be acid-addition salts or base addition salts.These salt can be for example to be alkali metal salt such as sodium salt, potassium salt or lithium salts; Alkali salt such as calcium salt or magnesium salt; Slaine such as aluminum salt, iron salt, zinc salt, mantoquita, nickel salt or cobalt salt; Or base addition salts, for example amine salt such as ammonium salt, t-octylamine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-cardiografin salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethyl ammonium salt or three (methylol) aminomethane salt; Or acid-addition salts, for example hydrohalide such as hydrofluoride, hydrochlorate, hydrobromate or hydriodide; Nitrate; Perchlorate; Sulfate; Phosphate; C
1-C
4Alkylsulfonate can be chosen wantonly by halogen atom and replaces for example metilsulfate, trifluoromethyl sulfonic acid or ethyl sulfonate; C
6-C
10Arylsulphonate can be chosen wantonly by C
1-C
4Alkyl replaces, for example benzene sulfonate or tosilate; C
1-C
6Soap such as acetate, malate, fumarate, succinate, citrate, tartrate oxalates or maleate; Or amino acid salts glycinate for example, lysinate, arginine salt, ornithine salt, glutamate, Glu or aspartate, but scope of the present invention is not limited to these above-mentioned salt.
As comprising 1, the calcium channel blocker of 4-dihydrogen pyridine derivative can use above-claimed cpd or its pharmacology to go up the hydrate or the solvate of acceptable salt.Some comprises 1 in addition, contains one or more asymmetric carbon atoms in the calcium channel blocking agent molecule of 4-dihydrogen pyridine derivative.In these situations, can with based on the pure optical isomer of above-mentioned asymmetric carbon atom or stereoisomer for example any mixture of diastereomer or these stereoisomers or racemic compound as chemical compound (B).As chemical compound (B), preferably (±)-2-amino-1,4-dihydro-6-methyl-4-(3-nitre phenyl)-3,5-dipicolinic acid 3-(1-benzhydryl azetidine-3-yl) ester 5-isopropyl esters, (R)-2-amino-1,4-dihydro-6-methyl-4-(3-nitre phenyl)-3,5-dipicolinic acid 3-(1-benzhydryl azetidine-3-yl) ester 5-isopropyl esters, Amlodipine benzene sulfonate or Amlodipine maleate.
Shown in the test of this description example is concrete, by the medicament co-action of the present invention that chemical compound (A) and chemical compound (B) are formed, the formation of angiogenesis inhibiting inner membrance and the propagation of vascular smooth muscle cell, thus suppressed vascular remodeling.Based on above-mentioned effect, except that prevention and or treatment arteriosclerosis, medicament of the present invention can be used for preventing the restenosis after the crown intervention of percutaneous.
Because with minimum dosage or minimum dosage lower dosage administering drug combinations chemical compound (A) and the chemical compound (B) more individually dosed than each component, medicament characteristics of the present invention are that the new intima formation and the vascular smooth muscle cell proliferation of blood vessel have been brought into play good inhibition effect.The low dosage that especially, preferably can not cause effect with each component when individually dosed is given drug compound (A) and chemical compound (B) simultaneously.
Shown in this description test example is concrete, synergism medicament of the present invention by chemical compound (A) and chemical compound (B) has more effectively reduced blood pressure. based on above-mentioned effect, medicament of the present invention can be used in and prevents and/or treats hypertension, heart disease (angina pectoris, myocardial infarction, arrhythmia (comprising sudden death), heart failure or cardiac hypertrophy etc.), nephropathy (diabetic nephropathy, glomerulonephritis or nephrosclerosis etc.) or cerebrovascular disease (cerebral infarction, cerebral hemorrhage etc.), be preferred for treatment. by administering drug combinations angiotensin ii receptor antagonist and calcium channel blocker, comprise that the medicament of the present invention of angiotensin ii receptor antagonist and calcium channel blocker produces better effect than one of individually dosed these medicaments.
Preparation medicament of the present invention can be prepared into the pharmaceutical composition (i.e. the form of " combination drug ") that inclusion compound (A) and chemical compound (B) are done effective ingredient.For example, every kind of active component can be mixed and be prepared into the physics unitary agent then.In addition, chemical compound (A) and chemical compound (B) can be prepared into independently preparation respectively, provide with the form of the medicament of the combination that contains every kind of preparation.The medicament of back can be used as the medicament of giving drug compound (A) and chemical compound (B) simultaneously or giving drug compound (A) and chemical compound (B) at certain intervals respectively.
Described in this manual " simultaneously " comprises for drug compound (A) and chemical compound (B) and roughly gives drug compound (A) and chemical compound (B) simultaneously, and restriction is not accurate to the same time just.For the dosage form of while administration without limits; For example comprise the oral administration administration composition and in non-composition for oral administration any one.However, medicament of the present invention being prepared into single compositions, to take these two kinds of compositionss then simultaneously be favourable.
Described in this manual " at certain intervals " refers to take chemical compound of the present invention (A) and chemical compound (B) respectively at different time for respectively drug compound (A) and chemical compound (B).To certain intervals respectively administration mode without limits.For example, comprise at first administration angiotensin ii receptor antagonist, then behind the certain intervals, administration calcium channel blocker, or administration calcium channel blocker at first, then behind the certain intervals, the administration angiotensin ii receptor antagonist, but to dosage form without limits.
Except that effective ingredient chemical compound (A) and chemical compound (B), if necessary can be by using acceptable and suitable additive such as the excipient of pharmacology, lubricant, binding agent, disintegrating agent, demulsifier, stabilizing agent, flavoring agent, diluent etc. are prepared into suitable dosage form such as tablet, capsule by the method for previously known with medicament of the present invention, granule, the syrup of powder or oral administration, or the suppository of injection or parenterai administration, administration then.Because chemical compound (A) that contains in medicament of the present invention and chemical compound (B) be the chemical compound of oral administration normally, so oral administration medicament of the present invention is favourable.
As " excipient ", can enumerate the derivant such as the lactose that comprise sugar as organic excipient, sucrose, glucose, mannitol or sorbitol; Starch derivatives is corn starch for example, potato starch, alphalise starch or dextrin; Cellulose derivative is microcrystalline Cellulose for example; Arabic gum; Dextran; Or amylopectin; And inorganic excipients comprises for example light anhydrous silicic acid of silicate derivative, synthetic aluminium silicate, calcium silicates or Magnesiumaluminumsilicate; Phosphate is calcium hydrogen phosphate for example; Carbonate is calcium carbonate for example; Or sulfate calcium sulfate for example.
As " lubricant ", can enumerate for example stearic acid; Stearic slaine such as calcium stearate and magnesium stearate; Pulvis Talci; Silica sol; Wax is Cera Flava and spermaceti for example; Boric acid; Adipic acid; Sulfate is sodium sulfate for example; Ethylene glycol; Fumaric acid; Sodium benzoate; The DL-leucine; Lauryl sulfate is sodium lauryl sulphate or Stepanol MG for example; Silicic acid is silica anhydride or hydrate of silicic acid for example; Starch derivatives perhaps mentioned above.
As " binding agent ", can enumerate for example hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, Polyethylene Glycol or to those similar excipient mentioned above.
As " disintegrating agent ", can enumerate for example cellulose derivative such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylcellulose calcium or internal crosslinking Sodium Tvlose; And the starch/cellulose derivative of chemical modification for example carboxymethyl starch or carboxymethyl starch sodium.
As " demulsifier ", can enumerate as Colloidal Clay such as bentonite or aluminium-magnesium silicate; Metal hydroxides such as magnesium hydroxide or aluminium hydroxide; Anion surfactant is sodium lauryl sulphate or calcium stearate for example; Cationic surface active agent is benzalkonium chloride for example; Or non-ionic surface active agent such as polyoxyethylene sorbitan alcohol fatty acid ester or fatty acid cane sugar ester.
As " stabilizing agent ", can enumerate for example p-Hydroxybenzoate such as methyl parahydroxybenzoate or propyl parabene; Pure as chlorobutanol, benzyl alcohol or phenethanol; Benzalkonium chloride; Phenol is phenol or cresol for example; Thimerosal; Dehydroacetic acid; Or sorbic acid.
As " correctives ", for example can enumerate sweetener for example saccharin sodium or aspartame; Acidulant such as citric acid, malic acid or tartaric acid; Spice such as menthol, Fructus Citri Limoniae or orange.
As " diluent ", the conventional diluent that uses can be enumerated for example lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline Cellulose, water, ethanol, macrogol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, the mixture of Magnesiumaluminumsilicate or these chemical compounds.
The mode that can suit is to the dosage of active component angiotensin ii receptor antagonist and calcium channel blocker, and their dose ratio selects, and this depends on various factors for example pharmaceutically active and patient's symptom, age and body weight.Though dosage is with symptom, ages etc. and becoming are in case of oral administration, according to patient's symptom, the adult can be that lower limit and 1000mg (preferred 500mg) are that the upper limit is distinguished administration, every day one to six time simultaneously or at certain intervals with 0.1mg (preferred 0.5mg) at every turn.In the situation of parenterai administration, according to patient's symptom, the adult can be that lower limit and 100mg (preferred 50mg) are that the upper limit is distinguished administration, every day one to six time simultaneously or at certain intervals with 0.01mg (preferred 0.05mg) at every turn.For example, the dose ratio of chemical compound (A) and chemical compound (B) is in 1: 10000 to 10000: 1 weight ratio scope, preferably in 1: 1000 to 1000: 1 scope, more preferably in 1: 100 to 100: 1 scope.
When medicament of the present invention is used to prevent and/or treat arteriosclerosis, need suitably adjust the blood drug level of chemical compound (A) and chemical compound (B) after the administration usually so that it is near the minimum of individually dosed chemical compound (A) or chemical compound (B) or below minimum.
When medicament of the present invention is used to prevent and/or treat hypertension, the dosage of angiotensin ii receptor antagonist is lower than the dosage of the angiotensin ii receptor antagonist when angiotensin ii receptor antagonist is used alone as depressor (this is its original application), and the dosage of angiotensin ii receptor antagonist can greatly reduce, and this is because by angiotensin ii receptor antagonist and calcium channel blocker administering drug combinations can be reached fabulous resisting hypertension effect.
[embodiment]
Below, by embodiment hereinafter described the present invention has been carried out more detailed description, but scope of the present invention is not limited to these embodiment.In the test example, " olmesartanmedoxomil " is called simply " Olmesartan (olmesartan) ".
Test example 1: arteriosclerosis inhibitory action
(A) material and method
(1) the inductive blood vessel injury model of cover capsule (Cuff)
Use C57BL/6 mice in 10 age in week.In the part of this research, also use AT1a receptor gene damaged (ATlaKO) mice.The polyethylene tube that will vertically cut by loosely places struvite blood vessel injury in the inducing mouse around the mice femoral artery.In the blood vessel of damage, following data are measured.Use the former existing report of this blood vessel injury model analysis vascular remodeling (Physiol.Genomics., 2, pp.13-30,2000; Circulation, 104, pp.2716-2721,2001; Circulation, 106, pp.847-853,2002).
(2) formation of blood vessel neointima and DNA are synthetic
Prepare the specimens paraffin embedding slices of damaging tremulous pulse after 14 days at placement cover capsule, carry out Elasticavan Gieson dyeing, transverse section by image analysis software research tunica intima and middle film then. synthetic for quantitative DNA, after placing the cover capsule, give injected in mice bromodeoxyribouridine (BrdU) 7 days, calculate according to the BrdU index of sneaking into nuclear calculating then.
(3) give wild-type mice peritoneal injection AT1 receptor blocking agent Olmesartan by osmotic minipumps, then as the dose dependent of research Olmesartan as described in (2).After placing the cover capsule, begin to mice oral administration azelnidipine, then as the dose dependent of research azelnidipine as described in (2)
(4) give wild-type mice administration Olmesartan and azelnidipine simultaneously, then the effect of the effect of co-administered Olmesartan and azelnidipine with individually dosed Olmesartan or azelnidipine as described in (2) compared.Be not enough to cause the dose study Olmesartan of remarkable result and the effect of azelnidipine with the effective dose of independent Olmesartan or azelnidipine and by independent Olmesartan or azelnidipine, to determine the synergism of two kinds of medicaments.
(5) the Mus smooth muscle cell by use cultivating, studied use Angiotensin II stimulate the back (by sneak into [
3H] dT), the common processing of Olmesartan and azelnidipine promotes the synthetic effect of DNA.
(B) result
(1) in the inductive blood vessel injury model of the cover capsule of wild-type mice, the DNA of vascular smooth muscle cell is synthetic to be increased, and the formation of angiogenesis inner membrance is strengthened.By using azelnidipine in dosage dependence mode, can suppress these variations in the scope of 0.1 to 1.0mg/kg/ day dosage, but to blood pressure without any influence (Fig. 1 and Fig. 2).In addition, rely on mode with dosage, Olmesartan shows similar inhibition effect at 0.5 to 3.0mg/kg/ day dosage range, and to not influence (Fig. 3 and Fig. 4) of blood pressure.When the Olmesartan (can not cause any remarkable result) of 0.1mg/kg/ days azelnidipine of while administration and 0.5mg/kg/ days, significantly suppress the formation (Fig. 5 and Fig. 6) of synthetic increase of vascular smooth muscle cell DNA and angiogenesis inner membrance with these two kinds of medicines of these dosage.According to these results, clearly show co-administered azelnidipine and Olmesartan co-action in vivo, can suppress the propagation of vascular smooth muscle cell and improve vascular remodeling.
(2) in vitro study, studied the synergism of above-mentioned azelnidipine and Olmesartan.As shown in Figure 7, can suppress Angiotensin II by the mode administration azelnidipine that relies on concentration and stimulate the synthetic promotion of DNA in the Mus vascular smooth muscle cell that the back cultivates.When the azelnidipine of the low dosage that will be not enough to cause any effect separately and Olmesartan co-administered, synthetic (Fig. 8) of the DNA in the Mus smooth muscle cell that can significantly suppress to cultivate.
Test example 2: hypotensive effect
In the spontaneous hypertensive rat (SHRs, SPF level, Breeder:Hoshino Laboratory Animals) in 56 20 ages in week, carry out the pick off that surgical operation is implanted their blood pressures of record.After restoring, begin to monitor age their blood pressure in 24 weeks from surgical operation.By medicine-feeding canula continuous 7 days (once a day) oral administrations sodium carboxymethyl cellulose (CMC-Na) solution (2ml/kg).The 5th day and the blood pressure of measuring in the 6th day to begin from monitoring of blood pressure are divided into 7 groups (every group of 8 rats) by every group mean blood pressure with animal, (every group of formation sees Table 1).Then from 25 continuous 14 days of ages of week (once a day) give sodium carboxymethyl cellulose (CMC-Na) solution (2ml/kg: matched group) or trial drug be suspended in trial drug solution (2ml/kg) the 0.5%CMC-Na solution, observe blood pressure.The blood pressure of the 6th group and the 7th group sees Table 2 (numerical value in table is represented meansigma methods ± standard deviation).In the animal that gives the group that Olmesartan adds azelnidipine jointly, observe fabulous hypotensive effect.
Table 1.
The 1st group of matched group (0.5%CMC-Na solution)
The 2nd group of olmesartan medoxomil (0.2mg/kg)
The 3rd group of olmesartan medoxomil (1.0mg/kg)
The 4th group of azelnidipine (2.0mg/kg)
The 5th group of azelnidipine (5.0mg/kg)
The 6th group of olmesartan medoxomil (0.2mg/kg)+azelnidipine
(2.0mg/kg)
The 7th group of olmesartan medoxomil (1.0mg/kg)+azelnidipine
(5.0mg/kg)
Table 2
Test example 3: hypotensive effect
Be divided into 4 groups (every group of 15 mices) with the damaged mice of male apo E (ApoE) in 12 ages in week is following: matched group (giving the group of 0.5% carboxymethyl cellulose solution (CMC)), give olmesartan medoxomil the group of (3mg/kg), give the group of azelnidipine (3mg/kg), and give the group that and olmesartan medoxomil (3mg/kg) adds azelnidipine (3mdkg).Continuous 24 weeks are given animal orally give test compound or carrier (0.5%CMC solution).(12 week age) give food rich in fat (containing 0.15% cholesterol and 15% salt-free butter) to all animals of all groups after beginning to give test compound.After the 23rd all administrations, pass through non-preheating type blood pressure monitor (BP MONITOR FOR RATS﹠amp; MICE, Model MK-2000 ' Muromachi Kikai Co., Ltd.) systolic pressure of the whole mices of mensuration.The results are shown in Table 3 (numerical value in table is represented meansigma methods ± standard deviation).
Table 3
| Organize | Systolic pressure (mmHg) |
| Matched group | 129±3 |
| Olmesartan medoxomil organizes | 121±4 |
| Azelnidipine is organized | 127±4 |
| Olm esartan medoxomil and azelnidipine are organized jointly | 112±3 |
As above shown in the result, organize jointly at olmesartan medoxomil and azelnidipine and to observe significant hypotensive effect (p=0.0063, the check of Dunnett ' s multiple comparisons), can not show any significant effect with any medicament of this dosage, by giving the effect that olmesartan medoxomil and azelnidipine cause jointly is (p=0.0065, the two-way analysis of variance) of working in coordination with.
(preparation embodiment)
Tablet (composition of medicine)
olmesartan medoxomil 10.0mg
Azelnidipine 10.0mg
Lactose 278.0mg
Corn starch 50.0mg
Magnesium stearate 2.0mg
With the powder mixes of above-mentioned prescription, contain the tablet of 350mg compositions then with the preparation of tablet machine tabletting, as needs, tablet can apply with sugar.
[industrial usability]
Medicament of the present invention can be used as artery sclerosis and hypertensive prophylactic and/or therapeutic agent.
Claims (21)
1. one kind prevents and/or treats hypertensive medicament, comprises following component:
(A) be selected from the have formula chemical compound of (I), its pharmacology goes up the angiotensin ii receptor antagonist that acceptable ester and pharmacology thereof go up acceptable salt;
With
(B) be selected from azelnidipine, Amlodipine, benidipine, nitrendipine, Manidipine, nicardipine, Nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine and nilvadipine and pharmacology thereof go up the calcium channel blocker of acceptable salt and make active component.
2. prevent and/or treat arteriosclerotic medicament, comprise that the chemical compound (A) and the chemical compound (B) of claim 1 definition made active component.
3. the medicament that suppresses vascular smooth muscle cell proliferation comprises that the chemical compound (A) and the chemical compound (B) of claim 1 definition done active composition.
4. suppress the medicament that the blood vessel neointima forms, comprise that the chemical compound (A) and the chemical compound (B) of claim 1 definition done active composition.
5. the medicament that suppresses vascular remodeling comprises that the chemical compound (A) and the chemical compound (B) of claim 1 definition done active composition.
6. any one medicament of claim 1 to 5, wherein angiotensin ii receptor antagonist is (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[[2 '-(1H-tetrazolium-5-yl) phenylbenzene-4-yl] methyl] the imidazole-5-carboxylic acid ester.
7. any one medicament of claim 1 to 5, wherein calcium channel blocker is an azelnidipine.
8. any one medicament of claim 1 to 5, wherein angiotensin ii receptor antagonist is (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[[2 '-(1H-tetrazolium-5-yl) phenylbenzene-4-yl] methyl] imidazole-5-carboxylic acid ester and calcium channel blocker be azelnidipine.
9. any one medicament of claim 1 to 5, wherein calcium channel blocker is an Amlodipine.
10. any one medicament of claim 1 to 5, wherein angiotensin ii receptor antagonist is (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[[2 '-(1H-tetrazolium-5-yl) phenylbenzene-4-yl] methyl] imidazole-5-carboxylic acid ester and calcium channel blocker be Amlodipine.
11. be selected from the have formula chemical compound of (I), its pharmacology goes up acceptable ester and the pharmacology goes up the angiotensin ii receptor antagonist (A) of acceptable salt and is selected from azelnidipine, Amlodipine, benidipine, nitrendipine, Manidipine, nicardipine, Nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, the calcium channel blocker (B) that felodipine and nilvadipine and pharmacology thereof go up acceptable salt prevents and/or treats purposes in the arteriosclerosis medicament in preparation
12. the chemical compound (A) of claim 11 definition and chemical compound (B) purposes in the medicament of preparation inhibition vascular smooth muscle cell proliferation.
13. the chemical compound (A) of claim 11 definition and chemical compound (B) purposes in the medicament that preparation inhibition blood vessel neointima forms.
14. the chemical compound (A) of claim 11 definition and chemical compound (B) purposes in the medicament of preparation inhibition vascular remodeling.
15. the chemical compound (A) of claim 11 definition and chemical compound (B) prevent and/or treat purposes in the hypertensive medicament in preparation.
16. each purposes of claim 11 to 15, wherein medicament is to comprise that chemical compound (A) and chemical compound (B) do the pharmaceutical composition of active composition.
17. each purposes of claim 11 to 15, wherein angiotensin ii receptor antagonist is (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[[2 '-(1H-tetrazolium-5-yl) phenylbenzene-4-yl] methyl] the imidazole-5-carboxylic acid ester.
18. each purposes of claim 11 to 15, wherein calcium channel blocker is an azelnidipine.
19. each purposes of claim 11 to 15, wherein angiotensin ii receptor antagonist is (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[[2 '-(1H-tetrazolium-5-yl) phenylbenzene-4-yl] methyl] imidazole-5-carboxylic acid ester and calcium channel blocker be azelnidipine.
20. any one medicament of claim 11 to 15, wherein calcium channel blocker is an Amlodipine.
21. each purposes of claim 11 to 15, wherein angiotensin ii receptor antagonist is (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 4-(1-hydroxyl-1-Methylethyl)-2-propyl group-1-[[2 '-(1H-tetrazolium-5-yl) phenylbenzene-4-yl] methyl] imidazole-5-carboxylic acid ester and calcium channel blocker be Amlodipine.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003022990 | 2003-01-31 | ||
| JP022990/2003 | 2003-01-31 | ||
| JP030830/2003 | 2003-02-07 | ||
| JP2003030830 | 2003-02-07 | ||
| PCT/JP2004/000861 WO2004067003A1 (en) | 2003-01-31 | 2004-01-29 | Medicine for prevention of and treatment for arteriosclerosis and hypertension |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1809353A CN1809353A (en) | 2006-07-26 |
| CN1809353B true CN1809353B (en) | 2010-05-05 |
Family
ID=36840895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200480008667.0A Expired - Lifetime CN1809353B (en) | 2003-01-31 | 2004-01-29 | Medicine for prevention of and treatment for arteriosclerosis and hypertension. |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1809353B (en) |
| NO (1) | NO334451B1 (en) |
| UA (1) | UA82216C2 (en) |
| ZA (1) | ZA200506076B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5492904A (en) * | 1991-05-15 | 1996-02-20 | E. I. Du Pont De Nemours And Company | Composition of angiotensin-II receptor antagonists and calcium channel blockers |
| US5616599A (en) * | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
-
2004
- 2004-01-29 CN CN200480008667.0A patent/CN1809353B/en not_active Expired - Lifetime
- 2004-01-29 UA UAA200507589A patent/UA82216C2/en unknown
-
2005
- 2005-07-28 ZA ZA200506076A patent/ZA200506076B/en unknown
- 2005-08-30 NO NO20054020A patent/NO334451B1/en not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5616599A (en) * | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
| US5492904A (en) * | 1991-05-15 | 1996-02-20 | E. I. Du Pont De Nemours And Company | Composition of angiotensin-II receptor antagonists and calcium channel blockers |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200506076B (en) | 2006-05-31 |
| CN1809353A (en) | 2006-07-26 |
| NO20054020L (en) | 2005-10-27 |
| NO334451B1 (en) | 2014-03-03 |
| NO20054020D0 (en) | 2005-08-30 |
| UA82216C2 (en) | 2008-03-25 |
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