Europaisches Patentamt 19 European Patent Office Office europeen des brevets (fj) Publication number: 0 336 950 B1 EUROPEAN PATENT SPECIFICATION @ Date of publication of patent specification © int. ci.5 : A61 K 45/06, A61 K 37/64, 22.01.92 Bulletin 92/04 A61K 31/55, A61K 31/44, A61K 31/40 (21) Application number: 88909317.5 (22) Date of filing : 11.10.88 @ International application number: PCT/EP88/00909 @ International publication number: WO 89/03691 05.05.89 Gazette 89/10 (54) POTENTIATION OF ANTIHYPERTENSIVE EFFECT OF ACE INHIBITORS. The file contains technical information (§) References cited : submitted after the application was filed and US-A- 4 591 598 not included in this specification US-A- 4 600 534 US-A- 4 666 901 CHEMICAL ABSTRACTS, Vol. 107, no. 13, 28 (§) Priority: 19.10.87 US 109965 September 1987 (Columbus, Ohio, US) Bitter- man Haim et al.: "Potentiation of the protec- tive effects of inhibitor (43) Date of publication of application : a converting enzyme 18.10.89 Bulletin 89/42 and a tromboxane synthetase inhibitor in hemorrhagic shock", see page 44, abstract 109110q, & J. Pharmacol. Exp. Ther. 1987, (45) Publication of the grant of the patent : 242(1), 8-14 (Eng). 22.01.92 Bulletin 92/04 @ Proprietor : CIBA-GEIGY AG @ Designated Contracting States : Klybeckstrasse 141 AT BE CH DE FR GB IT LI LU NL SE CH-4002 Basel (CH) (56) References cited : (72) Inventor : KSANDER, Gary, M. EP-A- 0 219 782 342 Woolf Road US-A- 4 473 575 Milford, NJ 08848 (US) US-A- 4 511 573 Inventor : ZIMMERMAN, Mark, B. US-A- 4 575 503 4310 Swarthmore Road Durham, NC 27707 (US) CO o If) o> CO CO CO Note : Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been LU filed until the opposition fee has been paid (Art. 99(1) European patent convention). Jouve, 18, rue Saint-Denis, 75001 PARIS EP 0 336 950 B1 Description In the European Patent Application No. 219782 the use of ACE-inhibitors separately or in combination with compounds which could have some influence on the prostaglandine-metabolism for the treatment of 5 atherosclerosis, thrombosis and other cardiovascular diseases has been described. The US Patent No. 4,511,573 solely discloses thromboxane synthetase inhibitors e.g. 1-methyl-2-(3-pyri- dyl)-3-(5-Carboxypentyl)-5-chloroindole and the US-Patent No. 4,473,575 discloses solely ACE-inhibitors, e.g. benazepril, benazeprilat and libenzapril. In the present invention it has been found that the 2-(3-pyridyl)-indole derivative 1-methyl-2-(3-pyridyl)-3- w (5-carboxypentyl)-5-chloroindole or pharmaceutical^ acceptable salts thereof surprisingly potentiate the anti- hypertensive effect of ACE (angiotensin converting enzyme) inhibitor antihypertensive agents. Object of the invention is to provide pharmaceutical compositions containing a combination of an effective antihypertensive amount of an angiotensin converting enzyme inhibitor and an amount effective for potentiating the antihypertensive effect of said angiotensin converting enzyme inhibitor of 1-methyl-2-(3-pyridyl)-3-(5-car- 15 boxypentyl)-5-chloroindole or a pharmaceutical^ acceptable salt thereof, in combination with one or more phar- maceutical^ acceptable carriers or the use of such pharmaceutical compositions for the manufacture of medicaments for the treatment of hypertension. The angiotensin converting enzyme inhibitors in the pharmaceutical compositions used as antihypertensive agents, the effect of which is potentiated, are those known in the art, captopril, enalapril, enalaprilat, quinapril, 20 ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, lisinopril, perindopril, spirapril, pentopril, pivopril, benazepril, benazeprilat, libenzapril and known pharmaceutical^ acceptable salts thereof. The names indi- cated are USAN (United States Adopted Names) or INN (International Non-Proprietary Names) adopted names. As to benazepril, benazeprilat, libenzapril (as yet unpublished names), such compounds are also known 25 in the art as CGS 14824, CGS 14831 and CGS 16617, respectively, and are 2,3,4,5-tetrahydro-1H-1-ben- zazepin-2-one derivatives of formula I. 30 35 Benazepril (CGS 14824) is the compound of formula I wherein R1 represents 2-phenylethyl, R2 represents ethoxy, and R3 represents hydroxy. Benazeprilat (CGS 14831) is the compound of formula I wherein R1 represents 2-phenylethyl, R2 and R3 represent hydroxy. Libenzapril (CGS 16617) is the compound of formula I wherein R1 represents 4-aminobutyl, and R2 and 40 R3 represent hydroxy. Said compounds are described e.g. in U.S. Patent No. 4,600,534, U.S. Patent No. 4,575,503 and U.S. Patent No. 4,473,575. 1-Methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chloroindole is a known thromboxane synthetase inhibitor e.g. as described in U.S. Patent 4,51 1,573. Pharmaceutical compositions thereof are described in said U.S. patents. 45 Pharmaceutical^ acceptable salts of the compounds cited herein represent particularly those known in the art for said compounds, including any pharmaceutically acceptable acid-addition salts for compounds having a basic amino group and pharmaceutically acceptable salts derived from pharmaceutically acceptable bases for acidic compounds having e.g. a free carboxy group. The compounds, including their salts, can also be used in the form of their hydrates. so Pharmaceutical compositions represent pharmaceutical acceptable compositions which are suitable for enteral such as oral, and parenteral such as intravenous administration to mammals, including man, and which comprise an effective amount of the active ingredients in combination with one or more pharmaceutically acceptable carriers, e.g. as aqueous solutions for parenteral administration, or as tablets or capsules for oral administration. Such pharmaceutical compositions are prepared according to methods generally known in the 55 art, e.g. as described in the above-cited patents. As already indicated above a particular aspect of the invention is directed to antihypertensive pharmaceuti- cal compositions suitable for administration to a mammal comprising (a) an antihypertensive effective amount of an angiotensin converting enzyme inhibitor selected from cap- 2 EP 0 336 950 B1 topril, enalapril, enalaprilat, quinapril, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, lisinopril, perindopril, spirapril, pentopril, pivopril, benazepril, benazeprilat and libenzapril, or a pharmaceutically acceptable salt thereof ; and (b) 1-methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chloro-indole, or a pharmaceutically acceptable salt 5 thereof, in an amount effective for potentiating the antihypertensive effect of said angiotensin-converting enzyme inhibitor ; in combination with one or more pharmaceutically acceptable carriers. Preferred are the above-cited compositions wherein the angiotensin converting enzyme inhibitor is selected from enalapril, enalaprilat, quinapril, ramipril, cilazapril, delapril, indolapril, perindopril, lisinopril, spirapril, benazepril, benazeprilat and libenzapril, or a pharmaceutically acceptable salt thereof. w Particular preferred are the above-cited compositions wherein the angiotensin converting enzyme inhibitor is benazepril, benazeprilat, libenzapril, or a pharmaceutically acceptable salt thereof. Particular embodiments of said compositions are directed to : 1. antihypertensive pharmaceutical compositions suitable for administration to a mammal comprising (a) an antihypertensive effective amount of the angiotensin converting enzyme inhibitor benazepril or a phar- 15 maceutically acceptable salt thereof ; and b) 1-methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chloroindole or a pharmaceutically acceptable salt thereof in an amount effective for potentiating the antihypertensive effect of said angiotensin converting enzyme inhibitor ; in combination with one or more pharmaceutically acceptable carriers ; 2. antihypertensive pharmaceutical compositions suitable for administration to a mammal comprising (a) 20 an antihypertensive effective amount of the angiotensin converting enzyme inhibitor libenzapril or a phar- maceutically acceptable salt thereof ; and (b) 1-methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chloroindole or a pharmaceutically acceptable salt thereof in an amount effective for potentiating the antihypertensive effect of said angiotensin converting enzyme inhibitor ; in combination with one or more pharmaceutically acceptable carriers. 25 A further specific aspect of the invention is directed to the use of above described pharmaceutical compo- sitions for the manufacture of medicaments for the treatment of hypertensions. The antihypertensive potentiating properties as defined above for the 2-(3-pyridyl)-indole derivative are demonstrated using test procedures standard in the art for determining antihypertensive activity using advan- tageously mammals, such as rats or dogs. The antihypertensive potentiating compound, the 2-(3-pyridyl)-indole 30 derivative as defined above, can be administered to the test animal enterally or parenterally, advantageously orally or intravenously, for example in the form of suspensions or aqueous solutions. For example, the oral dos- age may range between 0.1 and 25 mg/kg, preferably between 1 and 15 mg/kg, the dose depending on the compound and mammal involved. The antihypertensive potentiating compound, the 2-(3-pyridyl)-indole