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(19) TZZ__¥_T (11) EP 1 915 993 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: A61K 31/165 (2006.01) A61P 9/00 (2006.01) of the grant of the patent: A61K 31/4422 (2006.01) 10.07.2013 Bulletin 2013/28 (21) Application number: 08002401.1 (22) Date of filing: 15.11.2001 (54) Synergistic combinations comprising a renin inhibitor for cardiovascular diseases Synergistische Kombinationen enthaltend einen Renininhibitor für Kardiovaskulären Erkrankungen Mélange synergique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires (84) Designated Contracting States: • Webb, Randy Lee AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Flemington MC NL PT SE TR NJ 08822 (US) Designated Extension States: RO SI (74) Representative: Dietel-Manske, Anja Novartis Pharma AG (30) Priority: 17.11.2000 GB 0028151 Patent Department 4002 Basel (CH) (43) Date of publication of application: 30.04.2008 Bulletin 2008/18 (56) References cited: EP-A- 0 678 503 WO-A-91/17771 (60) Divisional application: WO-A-92/10097 10179101.0 / 2 305 231 10179109.3 / 2 305 232 • VAN DER VRING JAN A ET AL: "T-Channel- 10179116.8 / 2 305 233 selective calcium channel blockade: A review of published data and therapeutic potential", (62) Document number(s) of the earlier application(s) in CURRENT THERAPEUTIC RESEARCH, vol. 59, accordance with Art. 76 EPC: no. 11, November 1998 (1998-11), pages 754-761, 05015603.3 / 1 602 370 ISSN: 0011-393X 01996377.6 / 1 341 533 • RAHUEL J ET AL: "Structure- based drug design: the discovery of novel nonpeptide orally active (73) Proprietor: Novartis AG inhibitors of human renin", CHEMISTRY AND 4056 Basel (CH) BIOLOGY, CURRENT BIOLOGY, LONDON, GB, vol. 7, no. 7, 1 July 2000 (2000-07-01), pages (72) Inventors: 493-504, XP002254255, ISSN: 1074-5521, DOI: • Hewitt, William 10.1016/S1074-5521(00)00134-4 Pottstown PA 19465 (US) Remarks: • Vasella, Daniel Lucius Thefile contains technical information submitted after 4056 Basel (CH) the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 915 993 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 915 993 B1 Description [0001] The invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising the renin inhibitor of formula (I) 5 10 15 20 or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof, and a carier. [0002] The disclosure relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutic agent selected from the group consisting of 25 (i) an AT1-receptor antagonist or a pharmaceutically acceptable salt thereof, (ii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, (iii) an angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof, (iv) an Calcium channel blocker or a pharmaceutically acceptable salt thereof, (v) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof, 30 (vi) an aldosterone antagonist or a pharmaceutically acceptable salt thereof, (vii) an dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof, (viii) an endothelin antagonist or a pharmaceutically acceptable salt thereof, and (ix) a diuretic or a pharmaceutically acceptable salt thereof. 35 [0003] The term "at least one therapeutic agent" shall mean that in addition to the compound of formula (I) one or more, for example two, furthermore three, active ingredients as specified can be combined. [0004] Renin inhibit the action of the natural enzyme renin. The latter passes from the kidneys into the blood where it effects the cleavage of angiotensinogen, releasing the decapeptide angiotensin I which is then cleaved in the lungs, the 40 kidneys and other organs to form the octapeptide angiotensinogen II. The octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium- ionretaining hormone aldosterone, accompanied by an increase in extracellular fluid volume. That increase can be attributed to the action of angiotensin II. Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I. As a result a smaller amount of angiotensin I I is produced. The reduced concentration of that active peptide hormone is the 45 direct cause of e.g. the hypotensive effect of renin inhibitors. [0005] The renin inhibitor of formula (I), chemically defined as 2 (S),4(S),5(S),7(S)-N-(3-amino-2,2-dimethy)-3-oxopro- pyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-octanamide, is specifically disclosed in EP 678503 A. Especially preferred is the hemi-fumarate salt thereof. [0006] Van der Vring et al. (Current Therapeutic Research, 59, 1998, 754-761) discloses the effect of the renin inhibitor 50 of formula (I), aliskiren. [0007] AT1-receptor antagonists (also called angiotensin II receptor antagonists) are understood to be those active ingredients that bind to the AT 1-receptor subtype of angiotensin II receptor but do not result in activation of the receptor. As a consequence of the inhibition of the AT 1 receptor, these antagonists can, for example, be employed as antihyper- tensives or for treating congestive heart failure. 55 [0008] The class of AT1 receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones. For example, mention may be made of the compounds that are selected from the group consisting of valsartan (cf. EP 443983), losartan (cf. EP253310), candesartan (cf. 459136), eprosartan (cf. EP 403159), irbesartan (cf. EP454511), olmesartan (cf. EP 503785), tasosartan (cf. EP539086), telmisartan (cf. EP 522314), 2 EP 1 915 993 B1 the compound with the designation E-1477 of the following formula 5 10 15 the compound with the designation SC-52458 of the following formula 20 25 30 and the compound with the designation the compound ZD-8731 of the following formula 35 40 45 or, in each case, a pharmaceutically acceptable salt thereof. [0009] Preferred AT1-receptor antagonist are those agents that have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof. HMG-Co-A reductase inhibitors (also called β-hydroxy-β-methylglutaryl-co- enzyme-A reductase inhibitors) are understood to be those active agents that may be used to lower the lipid levels including cholesterol in blood. 50 [0010] The class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features. For example, mention may be made of the compounds that are selected from the group consisting of atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, ri- vastatin, simvastatin, and velostatin, or, in each case, a pharmaceutically acceptable salt thereof. [0011] Preferred HMG-Co-A reductase inhibitors are those agents which have been marketed, most preferred is 55 fluvastatin and pitavastatin and also atorvastatin or, in each case, a pharmaceutically acceptable salt thereof. [0012] The interruption of the enzymatic degradation of angiotensin I to angiotensin II with so-called ACE-inhibitors (also called angiotensin converting enzyme inhibitors) is a successful variant for the regulation of blood pressure and thus also makes available a therapeutic method for the treatment of congestive heart failure. 3 EP 1 915 993 B1 [0013] The class of ACE inhibitors comprises compounds having differing structural features. For example, mention maybe made ofthe compounds whichare selected fromthe groupconsisting alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or, in each case, a pharmaceutically acceptable salt thereof. 5 [0014] Preferred ACE inhibitors are those agents that have been marketed, most preferred are benazepril and enalapril. [0015] The class of CCBs essentially comprises dihydropyridines (DHPs) and non- DHPs such as diltiazem-type and verapamil-type CCBs. [0016] A CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisol- 10 dipine, nitrendipine, and nivaldipine, and is preferably a non- DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, a pharmaceutically acceptable salt thereof. All these CCBs are therapeutically used, e.g. as anti-hypertensive, anti- angina pectoris or anti-arrhythmic drugs. Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine,

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