Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-20
2001-12-11
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06329384
ABSTRACT:
This is a 371 of PCT/EP98/05773 filed Sep. 10, 1998.
The present invention relates to novel pharmaceutical combination products suitable for treating cardiovascular disorders and comprising an inhibitor of the renin-angiotensin system (RAS inhibitor) and an endothelin antagonist.
Combination products suitable for treating cardiovascular disorders and comprising an inhibitor of the renin-angiotensin system (RAS inhibitor) and an endothelin antagonist have been disclosed (EP-A-634,175, EP-A-617,001). However, the effect of these mixtures of active ingredients is unsatisfactory.
Combinations with improved properties have now been found.
The present invention relates to a combination of an endothelin antagonist of the formula I
in which the substituents have the following meanings:
R
1
C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy;
R
2
C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy;
R
3
C
1
-C
8
-alkyl which may be substituted by a phenyl radical which in turn may be substituted by one or two C
1
-C
4
-alkoxy radicals,
Zz oxygen or a single bond,
and an RAS inhibitor.
Preferred endothelin antagonists are those compounds of the formula I in which the substituents have the following meanings:
R
1
: C
1
-C
2
-alkyl, C
1
-C
2
-alkoxy
R
2
: C
1
-C
2
-alkyl, C
1
-C
2
-alkoxy
R
3
: C
1
-C
2
-alkyl which may be substituted by a phenyl radical which in turn may be substituted by one or two C
1
-C
2
-alkoxy radicals,
Z: oxygen or a single bond.
Particularly suitable endothelin antagonists are the following compounds:
Suitable inhibitors of the renin-angiotensin system are in particular angiotensin II antagonists and very particularly ACE inhibitors.
ACE inhibitors suitable for the purpose of the present invention are alacepril, benazepril, captopril, cilazapril, cilazaprilat, delapril, enalapril, enalaprilat, fosinopril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril and zofenopril. Among these, preference is given to ramipril and, in particular, to trandolapril.
Angiotensin II antagonists suitable for the purpose of the present invention are: losartan, the potassium salt of
2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]-methyl-1-H-imidazole-5-methanol; valsartan, N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl-4-yl]methyl-L-valine;
candesartan, 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)[1,1 -biphenyl]-4-yl]methyl]-1-H-benzimidazole-7-carboxylic acid;
4′-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid;
2-n-butyl-1-[4-(6-carboxy-2,5-dichlorobenzoylamino)benzyl]-6-N-(methylaminocarbonyl)-n-pentylaminobenzimidazole;
4′-[(1,4′-dimethyl-2′-propyl-[2,6′-bi-1-H-benzimidazol]-1′-yl)-methyl]-[1,1′-biphenyl]-2-carboxylic acid;
4-(pentafluoroethyl)-2-propyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1-H-imidazole-5-carboxylic acid;
4′-[[2-butyl-4-chloro-5-(hydroxymethyl)-1-H-imidazol-1-yl]methyl]-[1,1′-biphenyl]-2-carboxylic acid;
2-ethyl-5,6,7,8-tetrahydro-4-([2′-(-H-tetrazol-5-yl)biphenyl-4-yl]methoxy)quinoline;
2-ethyl-4-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride;
1-[[3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)-5-benzofuranyl]-methyl]-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid;
1-[[3-bromo-2-[2-[(trifluoromethyl)sulfonyl]amino]phenyl-5-benzofuranyl]methyl]-4-cyclopropyl-2-ethyl-1-H-imidazole-5-carboxamide;
5,7-dimethyl-2-ethyl-3-(2′-(1H-tetrazol-5-yl)(1,1′-biphenyl)-4-yl)-methyl)-3H-imidazo-(4,5-b)pyridine;
5-[4′-(3,5-dibutyl-1,2,4-triazol-1-ylmethyl)biphenyl-2-yl]-1H-tetrazole;
1,4-dibutyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2,3-dihydro-1H-imidazol-2-one;
2-n-butyl-4-spirocyclopentane-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one;
(E)-&agr;-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1-Himidazol-5-yl]-methylene]-2-thiophenepropanoic acid;
2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester;
2-propyl-4-[(3-trifluoroacetyl)pyrrol-1-yl]-1-[[2′-(2H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid; and the potassium salt of 2,7-diethyl-5-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]-triazole.
Disorders associated with vasoconstriction or other biological effects of endothelin and/or angiotensin II which may be particularly mentioned are the control or prevention of coronary disorders, cardiovascular disorders such as hypertension, heart failure, ischemia (in the heart, brain, gastrointestinal tract, liver and/or kidney) or vasospasms. Further examples of disorders which can be treated are renal insufficiency and renal failure, dialysis, subarachnoid hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension, and the treatment of gastric and duodenal ulcers and of leg ulcer in which vasoconstriction is involved. They can also be employed for atherosclerosis and for preventing restenosis after balloon-induced vasodilatation. Finally, the endothelin concentration is increased in the bronchial secretion of patients with asthma. Increased endothelin levels in blood plasma are also found during migraine attacks. The combination can therefore also be used in these two cases.
On administration of the combination according to the invention there is a considerable, more than additive, enhancement of the blood pressure-lowering properties and of the duration of action compared with the single substances. The doses of the individual active ingredients can thus be considerably reduced. This means that fewer side effects are to be expected on administration.
The ratio by weight of inhibitor of the renin-angiotensin system to endothelin antagonist is normally in the range from 50:1 to 1:500, preferably 10:1 to 1:100 and, in particular, 2:1 to 1:50.
The combinations according to the invention are generally administered orally, for example in the form of tablets, lacquered tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions. The active ingredients can be administered in the form of products which contain both active ingredients together, such as tablets or capsules, or separately as ad-hoc combination of single substances, which can be administered concurrently or sequentially.
To produce tablets, lacquered tablets, sugar-coated tablets and hard gelatin capsules it is possible to process a combination according to the invention with pharmaceutically inert, inorganic or organic excipients. Excipients which can be used for tablets, sugar-coated tablets and hard gelatin capsules are lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof. Excipients suitable for such gelatin capsules are vegetable oils, waxes, fats, semisolid and liquid polyols.
Excipients suitable for producing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Excipients suitable for injection solutions are water, alcohols, polyols, glycerol, vegetable oils. Excipients suitable for suppositories are natural or hardened oils, waxes, fats, semiliquid or liquid polyols and the like.
The pharmaceutical preparations may additionally contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts to alter
Kirchengast Michael
Korioth Horst
Munter Klaus
Abbott Laboratories
Henley III Raymond
Keil & Weinkauf
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