Potentiation of Antihypertensive Effect of Ace Inhibitors

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-pyridyl)-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 antihypertensive 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 pharmaceutical^ 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 indicated 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.

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 pharmaceutical 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 pharmaceutically 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 compositions 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 advantageously 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 dosage 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 derivative as defined above, may be 35 administered preferably prior to or simultaneously with the ACE inhibitor antihypertensive agent to be potentiated. Effective antihypertensive doses of the known ACE inhibitors are reported in the art or can be readily determined. The use of the lowest effective dose is preferred. More particularly, the antihypertensive potentiating effect can be determined in male spontaneous hypertensive rats and the mean arterial pressure is measured in conscious fully ambulatory animals at intervals for 40 24 hours after administration of the 2-(3-pyridyl)-indole derivative. The blood pressure lowering effect after administration of the ACE inhibitor antihypertensive is compared to animals treated with the ACE inhibitor alone, the 2-(3-pyridyl)-indole derivative alone and vehicle alone. Illustrative of the invention, 1-methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chloroindole administered at a dose of 1 0 mg/kg p.o. significantly potentiates the blood pressure lowering effect of libenzepril also administered 45 at a dose of 1 0 mg/kg p.o. to spontaneously hypertensive rats. For example at 5 hours post administration, the blood pressure is reduced by about 35 mm in animals administered both compounds. In contrast thereto, the blood pressure is reduced by only about 22 mmHg in animals administered libenzapril alone at the same dose of 10 mg/kg p.o., and no blood pressure lowering effect is observed in animals administered CGS 15435 alone at the same dose of 10 mg/kg p.o.. so Further illustrative of the invention, potentiation of the blood pressure lowering effect of benazepril hydrochloride and captopril, administered intraarterially to spontaneous hypertensive rats at 0.1 mg/kg/min and 0.2 mg/kg/min, respectively is also observed after prior administration of 10 mg/kg p.o of CGS 15435. A significant aspect of the invention is the finding that the 2-(3-pyridyl)-indole derivative as defined above enhance the antihypertensive effectiveness of angiotensin converting enzyme inhibitors at doses which are 55 essentially devoid of antihypertensive activity. The 2-(3-pyridyl)-indole derivative as defined above is thus particularly useful as adjuvants to enhance the antihypertensive effectiveness of angiotensin converting enzyme inhibitor antihypertensive agents in mammals. 3 EP 0 336 950 B1

The effective dosage for achieving said potentiation or adjuvant effect is dependant on the species, weight, age and individual condition of the mammal host and on the form of administration. A unit dosage for oral administration to a mammal of 50 to 70 kg may contain between about 25 and 200 mg of a said 2-(3-pyridyl)-indole derivative as the adjuvant active ingredient to be used in combination with a suitable amount of the angiotensin 5 converting enzyme inhibitor to be potentiated. A unit dosage of the angiotensin converting enzyme inhibitor ranges between 2.5 and 50 mg, such being dependant on the effective antihypertensive dose of the particular angiotensin converting enzyme inhibitor to be potentiated. The following examples are intended to illustrate compositions useful in the new method according to this w invention.

Example 1

A) 10,000 Capsules each containing the following : 15

25C.O g Libenzapril -3- (5-carb- l-methyl-2- (3-pyridyl) 20 500.0500 O gcr oxypentyl) -5-chloroindoIe 1150.0 g Lactose 100.0 g Talcum powaer 25

B) 10,000 Capsules each containing the following :

•LUU100.0 • *g so Benazepril Hydrochloride l-methyl-2- (3-pyridyl) -3- (5-carb- 250.0 g oxypentyl)-5-chloroindole 1550.0 g 35 Lactose 100.0 g Talcum powaer

Procedure : 40 All the powders are passed through a screen with openings of 0.6 mm. Then the drug substances are placed in a suitable mixer and mixed first with the talcum, then with the lactose until homogenous. No. 3 capsules are filled with 200 mg, using a capsule filling machine.

45 Claims

1 . An antihypertensive pharmaceutical composition suitable for administration to a mammal comprising a) an antihypertensive effective amount of an angiotensin converting enzyme inhibitor selected from cap- so topril, enalapril, enalaprilat, quinapril, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolanril, 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-chloroindole or a pharmaceutically acceptable salt thereof, in an amount effective for potentiating the antihypertensive effect of said angiotensin-converting enzyme 55 inhibitor ; in combination with one or more pharmaceutically acceptable carriers. 2. An antihypertensive pharmaceutical composition according to claim 1 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 4 EP 0 336 950 B1 thereof. 3. An antihypertensive pharmaceutical composition according to claim 1 wherein the angiotensin converting enzyme inhibitor is benazepril, benazeprilat, libenzapril, or a pharmaceutically acceptable salt thereof. 4. An antihypertensive pharmaceutical composition according to claim 1 suitable for administration to a mammal comprising (a) an antihypertensive effective amount of the angiotensin converting enzyme inhibitor benazepril or a pharmaceutically 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. 5. An antihypertensive pharmaceutical composition according to claim 1 suitable for administration to a mammal comprising (a) an antihypertensive effective amount of the angiotensin converting enzyme inhibitor libenzapril or a pharmaceutically 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. 6. Use of a composition according to any of claims 1 to 5 for the manufacture of a medicament for the treatment of hypertension.

Patentanspruche

1 . Antihypertensive pharmazeutische Zusammensetzung, die sich fur die Verabreichung an einen Sauger eignet, umfassend a) eine antihypertensiv wirksame Menge eines Angiotensin-Converting-Enzyme-Hemmers, der ausge- wahlt wird aus Captopril, Enalapril, Enalaprilat, Quinapril, Pramipril, Cilazapril, Delapril, Fosenopril, Zofe- nopril, Indolapril, Lisinopril, Perindopril, Spirapril, Pentopril, Pivopril, Benazepril, Benazeprilat und Libenzapril odereinem pharmazeutisch annehmbaren Salz davon, und b) 1-Methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chlorindol oder ein pharmazeutisch annehmbares Salz davon in einer Menge, die zum Potenzieren der antihypertensiven Wirkung des Angiotensin-Converting- Enzyme-Hemmers wirksam ist ; in Kombination mit einem oder mehreren pharmazeutisch annehmbaren Tragern. 2. Antihypertensive pharmazeutische Zusammensetzung nach Anspruch 1 , worin der Angiotensin-Conver- ting-Enzyme-Hemmerausgewahlt wird aus Enalapril, Enalaprilat, Quinapril, Ramipril, Cilazapril, Delapril, Indo- lapril, Perindopril, Lisinopril, Spirapril, Benazepril, Benazeprilat und Libenzapril oder einem pharmazeutisch annehmbaren Salz davon. 3. Antihypertensive pharmazeutische Zusammensetzung nach Anspruch 1 , worin der Angiotensin-Conver- ting-Enzyme-Hemmer Benazepril, Benazeprilat, Libenzapril oder ein pharmazeutisch annehmbares Salz davon ist. 4. Antihypertensive pharmazeutische Zusammensetzung nach Anspruch 1 , die sich fur die Verabreichung an einen Sauger eignet, umfassend (a) eine antihypertensiv wirksame Menge des Angiotensin-Converting-Enzyme-Hemmers Benazepril oder eines pharmazeutisch annehmbaren Salzes davon und (b) 1-Methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chlorindol oder ein pharmazeutisch annehmbares Salz davon in einer Menge, die zum Potenzieren der antihypertensiven Wirkung des Angiotensin-Converting- Enzyme-Hemmers wirksam ist ; in Kombination mit einem oder mehreren pharmazeutisch annehmbaren Tragern. 5. Antihypertensive pharmazeutische Zusammensetzung nach Anspruch 1 , die sich fur die Verabreichung an einen Sauger eignet, umfassend (a) eine antihypertensiv wirksame Menge des Angiotensin-Converting-Enzyme-Hemmers Libenzapril oder eines pharmazeutisch annehmbaren Salzes davon und (b) 1-Methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chlorindol oder ein pharmazeutisch annehmbares Salz davon in einer Menge, die zum Potenzieren der antihypertensiven Wirkung des Angiotensin-Converting- Enzyme-Hemmers wirksam ist ; in Kombination mit einem oder mehreren pharmazeutisch annehmbaren Tragern. 6. Verwendung einer Zusammensetzung nach irgendeinem der Anspruche 1 bis 5 zur Herstellung eines Medikaments zur Behandlung von Hypertonic. EP 0 336 950 B1

Revendications

1. Composition pharmaceutique antihypertensive appropriee pour I'administration a un mammifere, comprenant a) une quantite efficace pourl'antihypertension d'un inhibiteurde I'enzyme de conversion de I'angiotensine choisi parmi les captopril, enalapril, enalaprilat, quinapril, ramipril, cilazapril, delapril, fosenopril, zofenopril, indolapril, lisinopril, perindopril, spirapril, pentopril, pivopril, benazepril, benazeprilat et libenzapril, ou un sel pharmaceutiquement acceptable de celui-ci ; et b) du 1-methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chloroindole, ou un sel pharmaceutiquement acceptable de celui-ci, en une quantite efficace pour la potential isation de I'effet antihypertenseur dudit inhibiteur de I'enzyme de conversion de I'angiotensine ; en combinaison avec un ou plusieurs supports ou vehicules pharmaceutiquement acceptables. 2. Composition pharmaceutique antihypertensive selon la revendication 1, dans laquelle I'inhibiteur de I'enzyme de conversion de I'angiotensine est choisi parmi les enalapril, enalaprilat, quinapril, ramipril, cilazapril, delapril, indolapril, perindopril, lisinopril, spirapril, benazepril, benazeprilat et libenzapril, ou un sel pharmaceutiquement acceptable de celui-ci. 3. Composition pharmaceutique antihypertensive selon la revendication 1, dans laquelle I'inhibiteur de I'enzyme de conversion de I'angiotensine est le benazepril, le benazeprilat, le libenzapril, ou un sel pharmaceutiquement acceptable de celui-ci. 4. Composition pharmaceutique antihypertensive selon la revendication 1, appropriee pour une administration a un mammifere, comprenant (a) une quantite efficace pourl'antihypertension de I'inhibiteur de I'enzyme de conversion de I'angiotensine, le benzapril ou un sel pharmaceutiquement acceptable de celui-ci ; et (b) du 1-methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chloroindole ou un sel pharmaceutiquement acceptable de celui- ci en une quantite efficace pour la potential isation de I'effet antihypertenseur dudit inhibiteur de I'enzyme de conversion de I'angiotensine ; en combinaison avec un ou plusieurs supports ou vehicules pharmaceutiquement acceptables. 5. Composition pharmaceutique antihypertensive selon la revendication 1, appropriee pour une administration a un mammifere, comprenant (a) une quantite efficace pourl'antihypertension de I'inhibiteur de I'enzyme de conversion de I'angiotensine, le libenzapril ou un sel pharmaceutiquement acceptable de celui-ci ; et (b) du 1-methyl-2-(3-pyridyl)-3-(5-carboxypentyl)-5-chloroindole ou un sel pharmaceutiquement acceptable de celui- ci, en une quantite efficace pour la potential isation de I'effet antihypertenseur dudit inhibiteur de I'enzyme de conversion de I'angiotensine ; en combinaison avec un ou plusieurs supports ou vehicules pharmaceutiquement acceptables. 6. Utilisation d'une composition selon I'une quelconque des revendications 1 a 5 pour la production d'un medicament pour le traitement de I'hypertension.