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WO2009127251A1 - Combinations comprising a renin inhibitor - Google Patents

Combinations comprising a renin inhibitor Download PDF

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Publication number
WO2009127251A1
WO2009127251A1 PCT/EP2008/054586 EP2008054586W WO2009127251A1 WO 2009127251 A1 WO2009127251 A1 WO 2009127251A1 EP 2008054586 W EP2008054586 W EP 2008054586W WO 2009127251 A1 WO2009127251 A1 WO 2009127251A1
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Prior art keywords
acceptable salt
pharmaceutically acceptable
inhibitor
hypertension
receptor
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PCT/EP2008/054586
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French (fr)
Inventor
Christoph Schumacher
Christian Zaugg
Ovidiu Baltatu
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Novartis AG
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Combinations comprising a renin inhibitor
  • the invention 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.
  • renin inhibitors are therapeutic agents, in particular renin inhibitors.
  • WO2006/005741 describes in example 1 the preparation of said compounds.
  • the invention especially 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: (i) a diuretic or a pharmaceutically acceptable salt thereof
  • an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof
  • ACE/NEP angiotensin converting enzyme/neutral endopeptidase
  • an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof (v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof
  • glucagon-like peptide (GLP) analog respectively a GLP-1 receptor agonist, or a pharmaceutically acceptable salt thereof
  • a biguanidine analog or a pharmaceutically acceptable salt thereof a biguanidine analog or a pharmaceutically acceptable salt thereof.
  • 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 according to the present invention can be combined.
  • Renin inhibitors block the catalytic activity of the natural enzyme renin. Renin is released from the juxtaglomerular cells of the kidneys into the blood where it cleaves angiotensinogen to generate the decapeptide angiotensin I. Angiotensin I is further cleaved in the lungs, the kidneys and other organs by the enzyme angiotensin- converting enzyme to form the octapeptide angiotensinogen II. Angiotensin II, upon binding to angiotensin type I receptors, increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the salt- and flu id -retaining hormone aldosterone. Renin inhibitors, by inhibiting the processing of angiotensinogen and the formation of angiotensin II, mediate a reduction in blood pressure.
  • the preferred renin inhibitor is a salt of a compound of formula (I) with acetic acid, L-lactic acid, citric acid or fumaric acid, whereby the (L)-lactate salt is particularly preferred.
  • a diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide [58-94-6], hydrochlorothiazide [58-93-5], methylclothiazide [135-07- 9], and chlorthalidone [77-36-1]. The most preferred is hydrochlorothiazide.
  • ACE inhibitors comprises compounds having differing structural features.
  • ACE inhibitors are benazepril and enalapril.
  • Neutral endopeptidase mediate the degradation of natriuretic peptides such as atrial natriuretic peptide (ANP) and brain-derived natriuretic peptide (BNP). These peptides mediate diuretic and vasodilatatory effects. Therefore, compounds that inhibit neutral endopeptidase block the degration of the natriuretic peptides resulting in blood pressure reductions.
  • Preferred selective NEP inhibitors are for example phosphoramidon [36357-77-4], thiorphan [76721 -89-6], sinorphan [112573- 73-6], candoxatril [123122-55-4], candoxatrilat [123122-54-3], CGS25462 [147862- 03-1], , SQ28603 [100845-83-8], SQ29072 [122222-44-0] and SCH42495 [136511 - 43-8] or, if appropriate, a pharmaceutically acceptable salt thereof.
  • a preferred dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor is, for example, omapatrilate ([167305-00-2] cf. EP 629627), fasidotril [135038-57-2] or fasidotrilate [147841 -90-5], or Z13752A ([193420-09-6] cf. WO 97/24342) or, if appropriate, a pharmaceutically acceptable salt thereof.
  • Angiotensin Il type 1 AT1 receptor antagonists block the hypertensive and tissue- damaging effects of angiotensin II. As a consequence of these agents provide good blood pressure control and prevention of kidney or heart damage.
  • the class of AT1 receptor antagonists comprises compounds having differing structural features, essentially preferred are for example, valsartan ([137862-53-4] cf. EP 443983), losartan ([114798-26-4] cf. EP25331 0), candesartan ([139481 -59-7] cf. 459136), eprosartan ([133040-01-4] cf. EP403159), irbesartan ([138402-11 -6] cf.
  • EP454511 olmesartan ([144689-24-7] cf. EP 503785), tasosartan ([145733-36-4] cf. EP539086), telmisartan ([144701-48-4] cf. EP522314) and the compounds with the designations E-1477 [135070-05-2], SC-52458 [145216-43-9], ZD-8731 [135015-84-8] or, in each case, a pharmaceutically acceptable salt thereof.
  • a preferred AT1 -receptor antagonist is valsartan or a pharmaceutically acceptable salt thereof.
  • the class of calcium channel blockers essentially comprises dihydro- pyridines (DHPs) and non-DHPs such as diltiazem-type and verapamil-type CCBs.
  • a CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine [88150-42-9], felodipine [72509-76-3], ryosidine [89964-00-1], isradipine [75695-93-1], lacidipine [103890-78-4], nicardipine [55985- 32-5], nifedipine [21829-25-4], niguldipine [113165-32-5], niludipine [22609-73-0], nimodipine [66085-59-4], nisoldipine [63675-72-9], nitrendipine [39562-70-4], and nivaldipine [75530-68-6], or is preferably a DHP representative selected from
  • CCBs are therapeutically used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs.
  • Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof.
  • a DHP is amlodipine or a pharmaceutically acceptable salt, especially the besylate, thereof.
  • An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
  • Aldosterone mediates salt and water retention in the kidney and, in excessive amounts, hypertension and renal as well as cardiac fibrosis.
  • the pathologic effects of aldosterone can be therapeutically addressed with mineralocorticoid receptor blockers.
  • Preferred steroidal aldosterone antagonists are eplerenone ([107724-20-9] cf. EP 122232 A) and spironolactone [52-01 -7].
  • the enzyme aldosterone synthase converts in a three step reaction the substrate 11 -deoxycorticosterone to the product aldosterone by hydroxylating 11 -deoxycorticosterone to corticosterone, corticosterone to 18-OH-corticosterone and 18-OH-corticosterone to aldosterone.
  • the class of aldosterone synthase inhibitors can be applied for the treatment of hypertension and primary aldosteronism.
  • the class comprises both steroidal and non-steroidal aldosterone synthase inhibitors, the latter being most preferred.
  • aldosterone synthase inhibitors Preference is given to commercially available aldosterone synthase inhibitors or those aldosterone synthase inhibitors that have been approved by the health authorities.
  • the class of aldosterone synthase inhibitors comprises compounds having differing structural features. For example, mention may be made of the compounds which are selected from the group consisting of the non-steroidal aromatase inhibitors fadrozole [102676-47-1], including the (+)-enantiomer [102676-87-9] thereof, or in each case where applicable, a pharmaceutically acceptable salt thereof.
  • the most preferred non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole (US patents 4617307 and 4889861 ).
  • Endothelin is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists in three isoforms (ET-1 , ET-2 and ET-3). (ET shall mean any or all other isoforms of ET). Elevated levels of ET have been reported in plasma from patients with e.g. essential hypertension. Endothelin receptor antagonists can be used to inhibit the vasoconstrictive effects induced by ET.
  • a preferred endothelin antagonist is, for example, bosentan ([147536-97-8] cf. EP 526708 A), ambrisentan [177036-94-1], avosentan ([290815- 26-8] cf.
  • WO00/52007 enrasentan ([167256-08-8] cf.WO94/25013), atrasentan ([173937-91-2] cf. WO 96/06095), especially atrasentan hydrochloride [195733-43-8], darusentan ([171714-84-4] cf. EP 785926 A), BMS 193884 ([176960-47-7] cf. EP 702012 A), sitaxentan ([184036-34-8] cf. US 5594021 ), especially sitaxsentan sodium [210421-74-2], YM 598 ([342005-82-7] cf.
  • EP 882719 A S 0139 ([162117- 90-0] Cf. WO 97/27314), J 104132 ([198279-45-7] cf. EP 714897 A or WO 97/37665), furthermore, tezosentan ([180384-57-0] cf. WO 96/19459), or in each case, a pharmaceutically acceptable salt thereof.
  • Catecholamines such as noradrenalin and adrenalin are messengers of the sympathetic nervous system important in regulating organs such as the heart and peripheral vasculature. Noradrenalin and adrenalin mediate their physiological effects via alpha and beta adrenergic receptors. Beta-adrenoceptor antagonists are important drugs in the treatment of hypertension, angina, cardiac arrhythmias and glaucomas.
  • Preferred betai and beta2 adrenoceptor blockers are propranolol [525- 66-6], nadolol [42200-33-9], timolol [29023-48-1], oxprenolol [6452-71 -7], pindolol [13523-86-9], alprenolol [13655-52-2] or, where appropriate, a pharmaceutically acceptable salt thereof.
  • Preferred betai or cardioselective adrenoceptor blockers are metoprolol [51384-51-1], atenolol [29122-68-7] and acebutolol [37517-30-9] or, where appropriate, a pharmaceutically acceptable salt thereof.
  • Alpha-adrenoceptor blocker are clinically used in hypertension.
  • Preferred alphal -adrenoceptor blockers are prazosin [19216-56-9] and doxazosin [74191 -85-8] or, where appropriate, a pharmaceutically acceptable salt thereof.
  • a preferred beta1/beta2/alpha1 adrenoceptor blocker is carvedilol [72956-09-3].
  • Centrally acting adrenoceptor modifiers are methyldopa [55-40-3] and clonidine [4205-90-7].
  • a reference to these compounds is to be understood as a reference to the racemate and, preferably, a reference to the active enantiomer.
  • HMG-Co-A reductase inhibitors also called hydroxy-methylglutaryl-co-enzyme-A reductase inhibitors
  • HMG-Co-A reductase inhibitors are understood to be those active agents that may be used to lower the lipid levels including cholesterol in blood.
  • the class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features.
  • atorvastatin for example, mention may be made of the compounds that are selected from the group consisting of atorvastatin [134523-00-5], cerivastatin [145599-86-6], compactin [73573-88-3], dalvastatin [132100-55-1], dihydrocompactin [78366-44-6], fluindostatin [93957-55-2], fluvastatin [93957-54-1], lovastatin [75330-75-5], pravastatin [147511 - 69-1], mevastatin (compactin)[73573-88-3], pravastatin [81093-37-0], rivastatin [143201-11 -0], rosuvastatin [287714-41 -4] and simvastatin (velostatin) [79902-63-9], or, in each case, a pharmaceutically acceptable salt thereof.
  • Preferred HMG-Co-A reductase inhibitors are fluvastatin and pitavastat
  • PPAR activators of the peroxysome proliferator activated receptor induce metabolic changes that affect both the lipid and glucose metabolism and therefore are useful to treat cardiovascular and metabolic pathologies such as atherosclerosis, chronic kidney disease and diabetes.
  • PPAR activators may be derived from different chemical classes.
  • Examples may include rosiglitazone [122320-73-4], pioglitazone [111025-46-8], R483 [213411 -83-7], isaglitazone [161600-01 -7], CS-011 [524675-01 - 2], FK-614 [193012-35-0], AVE8134 [ ], AMG131 [315223-08-6], metaglidasen [4687- 08-5], reglitazar [170861 -63-9], LY510929 [471854-50-9], GSK677954 [884324-15- 6], netoglitazone [161600-01-7], GFT505 [ ], PLX204 [884324-33-8], fenofibrate [49562-28-9], gemfibrozol [25812-30-0], clofibrate [637-07-0] and LY674 [425671 -29- 0] or, in each case, a pharmaceutically acceptable salt thereof.
  • Cyclooxygenase is an enzyme that is responsible for formation of prostanoids including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Selective inhibition of the COX-2 enzyme isoform may reduce the risk of renal failure associated with unselective COX-1/2 inhibitors. Examples of selective COX-2 inhibitors may include celecoxib [169590-42-5], rofecoxib [162011 -90-7], lumiracoxib [220991-20-8] and etohcoxib [202409-33-4], or in each case, a pharmaceutically acceptable salt thereof.
  • Examples of unselective COX-1/2 inhibitors may include acetyl salicylic acid [50-78-2], ibuprofen [15687-27-1], diclofenac [15307-86-5], paracetamol [103-90-2], mefenamic acid [61 -68-7], indometacin [53-86-1], piroxicam [36322-90-4], dexibuprofen [51146-56-6], dexketoprofen [22161 -81 -5], flurbiprofen [5104-49-4], naproxen [22204-53-1] and glucocorticoids such as cortisone [53-06-5], hydrocortisone [50-23-7], prednisone [53-03-2], betamethasone [378-44-9], triamcinolone [124-94-7] and dexamethasone [50-02-2], or in each case, a pharmaceutically acceptable salt thereof.
  • Nicotinic acid and nicotinic acid analogs induce plasma lipoprotein changes and triglyceride reductions and are therefore useful to treat cardiovascular pathologies such as atherosclerosis.
  • nicotinic acid niacin [59-67-6] and its pharmaceutical formulations.
  • Sulphonylurea receptor 1 binding agents induce the release of insulin from beta- cells and are therefore useful for the treatment of diabetes.
  • examples may include glyburide [10238-21 -8], glimepiride [93479-97-1], glipizide [29094-61-9], repaglinide [135062-02-1], nateglinide [105816-04-4], mitiglinide [145375-43-5] or a pharmaceutically acceptable salt thereof.
  • Alpha-glucosidase inhibitors reduce and slow-down the uptake of dietary carbohydrates and are therefore useful for the treatment of diabetes.
  • Examples may include acarbose [56180-94-0], miglitol [72432-03-2], voglibose [83480-29-9] and emigilate [ ] or a pharmaceutically acceptable salt thereof.
  • Preferred are acarbose, miglitol and voglibose or, in each case, a pharmaceutically acceptable salt thereof. .
  • Glucagon-like peptide and analogs stimulate the GLP-1 receptor and thus the release of insulin and preserve the beta cell function useful for the treatment of non insulin-dependent diabetes.
  • Examples may include exenatide [141758-74-9], liraglutide [204656-20-2], PC-DAC (exendin-4) [141732-76-5]:GLP-1 [89750-14-1], BIM-51077 [870151 -88-5], CS-872 [ ], LY548806 [898546-79-7], albugon [782500- 75-8] or a pharmaceutically acceptable salt thereof.
  • exenatide or a pharmaceutically acceptable salt thereof is exenatide or a pharmaceutically acceptable salt thereof.
  • Dipeptidyl protease inhibitors prevent the degradation of glucagon-like peptide and therefore enhance food-mediated insulin release from the beta-cell that is useful for the treatment of non insulin-dependent diabetes.
  • Examples may include sitagliptin [486460-32-6], vildagliptin [274901 -16-5], denagliptin [483369-58-0], SYR322 [850649-62-6], BMS477118 [361442-04-8], GRC8200, PSN-9301 , T666/815541 , SSR162369 [865720-53-2], KF-81364 and ST189428 or a pharmaceutically acceptable salt thereof.
  • Preferred are sitagliptin and vildagliptin or a pharmaceutically acceptable salt thereof.
  • Phosphodiesterase inhibitors modulate intracellular signaling and thus increase myocardial contractility and mediate vasodilatation useful for several cardiovascular pathologies such as heart failure, erectile dysfunction, pulmonary and essential hypertension.
  • Examples may include milrinone [78415-72-2], sildenafil [139755-83- 2] or a pharmaceutically acceptable salt thereof.
  • Biguanidine analogs alleviate insulin resistance by reducing hepatic glucose production and by also enhancing peripheral glucose uptake.
  • examples are metformin [657-24-9] and fenformin [114-86-3], preferred being metformin and if appropriate a pharmaceutically acceptable salt thereof.
  • the structure of the active agents identified by generic or tradenames may be taken from the current edition of the standard compendium "The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
  • corresponding active ingredients or pharmaceutically acceptable salts thereof may also be used in the form of a solvate, such as a hydrate or including other solvents used for crystallization.
  • the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
  • the compounds having an acid group for example COOH can also form salts with bases.
  • the combination according to the present invention comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by various routes of administration but are tested in this example using a continuous infusion via subcutaneously-implanted osmotic minipumps.
  • Each agent can be tested over a wide range of dosages to determine the optimal drug level for each agent in combination to elicit the maximal response.
  • treatment groups consisting of at least 6 animals per group.
  • Each study is best performed in which the effects of the combination treatment group are determined at the same time as the individual components are evaluated.
  • drug effects may be observed with acute administration (such as 1 day), it is preferable to observe responses in a chronic setting as shown below in which experiments are done over a three to seven week observation period.
  • the long-term study is of sufficient duration to allow for the full development of compensatory responses to occur and therefore, the observed effect will most likely depict the actual responses of the test system representing sustained or persistent effects.
  • An animal model for spontaneously malignant hypertension with renal and cardiac complications is represented by double transgenic rats over-expressing both the gene for human renin and the gene for human angiotensinogen.
  • This double transgenic rat strain is produced by crossbreeding two transgenic strains, one for human angiotensinogen with the endogenous promoter and one for human renin with the endogenous promoter. Neither single transgenic rat strain is hypertensive.
  • the double transgenic rats both males and females, develop severe hypertension with a mean systolic blood pressure of approximately 200 mm Hg and die after a mean of 55 days if untreated (Luft et al., Hypertension 1999; 33:212-218).
  • the fact that human renin orthologous gene can be studied in the rat is a unique feature of this model and allows the extrapolation to clinical high renin hypertension.
  • (xiv) naproxen or, if appropriate, a pharmaceutically acceptable salt thereof can be administered by various routes of administration but are tested in this example orally by gavage.
  • Each agent can be tested over a wide range of dosages to determine the optimal drug level for each agent in combination to elicit the maximal response.
  • Each study group is best performed in a parallel study design i.e. the effects of the combination treatment group are determined at the same time as the individual components are evaluated.
  • Blood pressure and the blood flow-mediated pathological effects on blood pressure sensitive organs such as the heart and kidney can be synergistically modified with combination therapy in comparison to the respective monotherapies.
  • blood pressure may be reduced to a similar degree with a low-dose component combination therapy as with a high-dose component monotherapy.
  • the combination formula may result in greater blood pressure reductions as expected by simply adding the effects of individual monotherapy components.
  • the combination therapy can be compared to that of the respective monotherapies by determining the maximum change in mean arterial blood pressure, 24 hour urinary protein content or changes in echocardiographic recordings at a given day. All values are represented as the group mean ⁇ standard error of the mean (SEM). Statistical significance is obtained when p ⁇ 0.05.
  • the albuminuria values for each of the treatment groups can be compared statistically using a one-way ANOVA followed by the appropriate post-hoc analysis, for example by performing a Bonferoni test. Studv design
  • echocardiographic recordings are generated in narcotized rats allowing the determination of left ventricular end diastolic area (LVEDA), end systolic area (LVESA) fractional shortening (FS), and changes in posterior wall (PW) thickness.
  • LVEDA left ventricular end diastolic area
  • FS end systolic area
  • PW posterior wall
  • isolated hearts are fixed in situ, by retrograde perfusion with buffered 4% formaldehyde after arrest in diastole by i.v. injection of 0.5 M KCI. After fixation, the left ventricle (LV) and the free wall of the right ventricle are separately weighed; LV longer diameter is measured with a caliper.
  • LV histological sections are stained with hematoxylin and eosin for qualitative examination and to quantify cardiomyocytes cross-sectional area with a semi- automated image analysis routine. Interstitial collagen deposition in LV is evaluated on Sirius red stained sections with a semi-automated image analysis routine (Masson et al., 1998).
  • LV chamber volume is determined in hearts arrested in diastole (KCI) and fixed in formalin under a hydrostatic pressure equivalent to the measured LV end-diastolic pressure. A metric rod is inserted into the LV to measure LV inner length.
  • the transverse diameters of the LV chamber are measured in two 1 -mm thick transverse sections near to the base and the apex of the ventricle (Jeremic et al., 1996).
  • the chamber volume is computed from an equation integrating transverse diameters and inner length.
  • the administration of a combination of the renin inhibitor of formula (I) L-lactate with avosentan had a superior anti-albuminuric effect than either drug alone.
  • the combination therapy was statistically superior to each monotherapy with a probability level of p ⁇ 0.5 using a one-way ANOVA and a Bonferoni test.
  • a synergistic effect on the development of albuminuria in this animal model for malignant hypertension with renal complications can be shown by the administration of a renin inhibitor of formula (I) L-lactate and avosentan in combination in comparison to the administration of the individual drugs.
  • An animal of non-insulin dependent diabetes with abnormal glucose tolerance that progresses to kidney disease is represented in the male Zucker diabetic rat model (Peterson in Lessons from Animal Diabetes V, edited by E. Shafrir, London Smith- Gordon, 225-230, 1994).
  • the characteristics of the model are hyperglycemia that develops between 7 and 10 weeks of age, early hypehnsulinemia that falls upon beta cell failure, hyperlipidemia and mild hypertension.
  • As the model expresses rat renin higher doses of a human renin inhibitor need to be applied in order to compensate for a lower drug binding affinity.
  • a pharmaceutically acceptable salt thereof can be administered by various routes of administration but are tested in this example orally by gavage.
  • Each agent can be tested over a wide range of dosages to determine the optimal drug level for each agent in combination to elicit the maximal response.
  • Each study group is best performed in which the effects of the combination treatment group are determined at the same time as the individual components are evaluated. Although drug effects may be observed upon short term treatment, it is preferable to observe responses in a chronic setting as shown below in which experiments are done over a three to seven week observation period. The long-term study is thus of sufficient duration to allow for the full development of compensatory responses to occur and therefore, the observed effect will most likely depict sustained pharmacological responses.
  • the combination therapy can be compared to that of the respective monotherapies by determining the maximum change in fasting glycemia, insulinemia and triglycehdemia, plasma lipoprotein particle concentrations and hemoglobin A1 C (HbAI C) levels, 24 hour urinary protein content or changes in the area under the glucose and insulin concentration curves, respectively, during oral glucose tolerance tests (OGTT) at a given day. All values are represented as the group mean ⁇ standard error of the mean (SEM). Statistical significance is obtained when p ⁇ 0.05.
  • the values for each of the treatment groups can be compared statistically using a one-way ANOVA followed by the appropriate post-hoc analysis, for example by performing a Bonferoni test. Studv design
  • ZDF (fa/fa) Male Zucker diabetic rats (ZDF (fa/fa) weighing between 370 and 430 g are studied at 13 weeks of age after the onset of diabetes (as determined by fasting blood glucose between 8.3 and 12.5 mmol/l). They are maintained on rat chow and subjected for four weeks to daily treatment by oral gavage with the renin inhibitor of formula (I) at a dose of 100 mg/kg, a therapeutic agent selected from the group consisting of (ii) to (ix) and (xii) to (xxi) at doses of 10 and 30 mg/kg and combinations of the renin inhibitor of formula (I) with a therapeutic agent selected from the group consisting of (ii) to (ix) and (xii) to (xxi) at the same doses.
  • the applied doses of renin inhibitor are increased in order to compensate for the weaker affinity of compounds of formula (I) to the rodent renin protein sequence.
  • Weekly plasma samples are collected in fasted states in order to determine glucose, insulin, hemoglobin A1 C, triglyceride and lipoprotein particle concentrations.
  • a blood sample is taken 4 hours after compound dosing via exteriorized cannula in the femoral vein.
  • the oral glucose challenge (1 g/kg) is then administered and blood samples are collected after 10, 20, 30, 60, 90 and 120 minutes for measurement of plasma and glucose levels.
  • 24 hour urine samples are collected using metabolic cages.
  • the urinary albumin content is measured by ELISA using a commercial kit (Celltrend GmbH, Luckenwalde, Germany).
  • kidney sections are analyzed immunohistochemically for biomarkers of kidney function such as TGFbeta, MCP-1 , nephrin and collagen.
  • the combination therapy was statistically superior to each monotherapy with a probability level of p ⁇ 0.5 using a one-way ANOVA and a Bonferoni test.
  • a synergistic effect on the development of albuminuria in this animal model for non insulin-dependent diabetes with renal complications can be shown by the administration of a renin inhibitor of formula (I) L-lactate and avosentan in combination in comparison to the administration of the individual drugs.
  • an improvement of regression of artherosclerosis without affecting the serum lipid levels can, for example, be demonstrated by using the animal model as disclosed by H. Kano et al. in Biochemical and Biophysical Research Communications 259, 414-419 (1999).
  • compositions of the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
  • composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
  • the invention furthermore relates to a method for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, angina pectoris, stroke, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery;
  • Atherosclerosis insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, IgA nephropathy, glomerulosclerosis, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
  • hyperlipidemia hyperthglceridemia, hyperinsulinemia, hyperglycemia, insulin resistance, impaired glucose tolerance, mature onset diabetes of the young (MODY), hyperlipoproteinemia, atherosclerosis and hypercholesterolemia,
  • peripheral vascular disease comprising administering to a warm-blooded animal, including man, in need thereof a jointly effective amount of a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent selected from the group consisting of
  • an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof
  • ACE/NEP angiotensin converting enzyme/neutral endopeptidase
  • an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof (v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof, (vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
  • the present inveniton relates to the use of a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent selected from the group consisting of
  • an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof
  • ACE/NEP angiotensin converting enzyme/neutral endopeptidase
  • AT1 angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof
  • a medicament for the manufacture of a medicament for the prevention of, delay of progression of, or treatment of a disease or condition selected from the group consisting of
  • Atherosclerosis insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, IgA nephropathy, glomerulosclerosis, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiprol iterative effect of the combination), all these diseases or conditions associated with or without hypertension;
  • hyperlipidemia hyperthglceridemia, hyperinsulinemia, hyperglycemia, insulin resistance, impaired glucose tolerance, mature onset diabetes of the young (MODY), hyperlipoproteinemia, atherosclerosis and hypercholesterolemia,
  • the invention furthermore relates to a pharmaceutical composition for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of
  • Atherosclerosis insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, IgA nephropathy, glomerulosclerosis, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
  • hyperlipidemia hyperthglceridemia, hyperinsulinemia, hyperglycemia, insulin resistance, impaired glucose tolerance, mature onset diabetes of the young (MODY), hyperlipoproteinemia, atherosclerosis and hypercholesterolemia,
  • peripheral vascular disease comprising a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent selected from the group consisting of
  • an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof
  • ACE/NEP angiotensin converting enzyme/neutral endopeptidase
  • an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof (v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof
  • compositions of the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
  • composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
  • a further aspect of the present invention is a kit for the prevention of, delay of progression of, treatment of a disease or condition according to the present invention comprising
  • the present invention likewise relates to a "kit-of-parts", for example, in the sense that the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points.
  • the parts of the kit of parts can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components.
  • the invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use.
  • These pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances.
  • the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compound.
  • Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules.
  • compositions for oral use can be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commercially available. Normally, in the case of oral administration, an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 70 kg in weight.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • the pharmaceutical preparation will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising an amount, being together with the further component(s) jointly effective, e.g. in lowering blood pressure by inhibition of renin and in reducing proteinuria by blockade of endothelin subtype A receptors.
  • the doses of the renin inhibitor of formula (I) to be administered to warm-blooded animals, for example human beings, of, for example, approximately 70 kg body weight, especially the doses effective in the inhibition of the enzyme renin are from approximately 3 mg to approximately 3 g, preferably from approximately 10 mg to approximately 1 g, for example approximately from 20 mg to 200 mg, per person per day, divided preferably into 1 to 4 single doses which may, for example, be of the same size. Usually, children receive about half of the adult dose.
  • the dose necessary for each individual can be monitored, for example by measuring the serum concentration of the active ingredient, and adjusted to an optimum level.
  • Single doses comprise, for example, 10, 40 or 100 mg per adult patient.

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Abstract

The invention relates to drug combinations comprising the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with specific cardiovascular treatment agents of complementary pharmacological mechanism to generate a synergistic therapeutic effect.

Description

Combinations comprising a renin inhibitor
Field of the Invention
The invention 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.
Background of the Invention
4-{4-[1 -(3-Fluorophenyl)-pyrrolidin-3-yloxy]-phenyl}-5-[4-(3-methoxypropyl)-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-piperidin-3-ol, preferably as the (3S,4S,5R)-4-{4-[(S)-1-(3-fluoro-phenyl)-pyrrolidin-3-yloxy]-phenyl}-5-[4-(3-methoxy- propyl)-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-piperidin-3-ol diastereomer corresponding to formula I
Figure imgf000002_0001
and pharmaceutically acceptable salts thereof are therapeutic agents, in particular renin inhibitors. WO2006/005741 describes in example 1 the preparation of said compounds.
Objects of the Invention
The invention especially 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: (i) a diuretic or a pharmaceutically acceptable salt thereof
(ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof,
(vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof,
(x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof,
(xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof,
(xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof,
(xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof,
(xvi) a sulphonylurea receptor 1 binding agent or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof,
(xviii) a glucagon-like peptide (GLP) analog, respectively a GLP-1 receptor agonist, or a pharmaceutically acceptable salt thereof,
(xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof,
(xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof and
(xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof. 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 according to the present invention can be combined.
The numbers in square brackets following a chemical compound name refer to the Chemical Abstract's number of said compound. The content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the compounds and, based on these references, likewise enabled to synthesize the compounds.
Renin inhibitors block the catalytic activity of the natural enzyme renin. Renin is released from the juxtaglomerular cells of the kidneys into the blood where it cleaves angiotensinogen to generate the decapeptide angiotensin I. Angiotensin I is further cleaved in the lungs, the kidneys and other organs by the enzyme angiotensin- converting enzyme to form the octapeptide angiotensinogen II. Angiotensin II, upon binding to angiotensin type I receptors, increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the salt- and flu id -retaining hormone aldosterone. Renin inhibitors, by inhibiting the processing of angiotensinogen and the formation of angiotensin II, mediate a reduction in blood pressure.
The preferred renin inhibitor is a salt of a compound of formula (I) with acetic acid, L-lactic acid, citric acid or fumaric acid, whereby the (L)-lactate salt is particularly preferred.
(i) A diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide [58-94-6], hydrochlorothiazide [58-93-5], methylclothiazide [135-07- 9], and chlorthalidone [77-36-1]. The most preferred is hydrochlorothiazide.
(ii) The interruption of the enzymatic degradation of angiotensin I to angiotensin Il with angiotensin converting enzyme (ACE) inhibitors results in blood pressure reductions and protection of target organs such as kidney and heart. The class of - A -
ACE inhibitors comprises compounds having differing structural features. For example, mention may be made of the compounds which are selected from the group consisting of alacephl [74258-86-9], benazepril [86541 -75-5], benazephlat [86541 -78-8], captopril [62571 -86-2], ceronapril [111223-26-8], cilazapril [88768-40- 5], delapril [83435-66-9], enalapril [75847-73-3], enalaprilat [76420-72-9], fosinopril [98048-97-6], imidapril [89371 -37-9], lisinopril [76547-98-3], moveltopril [cf. BE 893553], perindopril [82834-16-0], quinapril [85441 -61 -8], ramipril [87333-19-5], spirapril [83647-97-6], temocapril [111902-57-9], and trandolapril [87679-37-6], or, in each case, a pharmaceutically acceptable salt thereof. Preferred ACE inhibitors are benazepril and enalapril.
(iii) Neutral endopeptidase (NEP) mediate the degradation of natriuretic peptides such as atrial natriuretic peptide (ANP) and brain-derived natriuretic peptide (BNP). These peptides mediate diuretic and vasodilatatory effects. Therefore, compounds that inhibit neutral endopeptidase block the degration of the natriuretic peptides resulting in blood pressure reductions. Preferred selective NEP inhibitors are for example phosphoramidon [36357-77-4], thiorphan [76721 -89-6], sinorphan [112573- 73-6], candoxatril [123122-55-4], candoxatrilat [123122-54-3], CGS25462 [147862- 03-1], , SQ28603 [100845-83-8], SQ29072 [122222-44-0] and SCH42495 [136511 - 43-8] or, if appropriate, a pharmaceutically acceptable salt thereof.
(iv) Compounds having an inhibitory effect on both angiotensin converting enzyme and neutral endopeptidase, so-called dual ACE/NEP inhibitors, have been generated as potent blood pressure reducing therapies. A preferred dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor is, for example, omapatrilate ([167305-00-2] cf. EP 629627), fasidotril [135038-57-2] or fasidotrilate [147841 -90-5], or Z13752A ([193420-09-6] cf. WO 97/24342) or, if appropriate, a pharmaceutically acceptable salt thereof.
(v) Angiotensin Il type 1 AT1 ) receptor antagonists block the hypertensive and tissue- damaging effects of angiotensin II. As a consequence of these agents provide good blood pressure control and prevention of kidney or heart damage. The class of AT1 receptor antagonists comprises compounds having differing structural features, essentially preferred are for example, valsartan ([137862-53-4] cf. EP 443983), losartan ([114798-26-4] cf. EP25331 0), candesartan ([139481 -59-7] cf. 459136), eprosartan ([133040-01-4] cf. EP403159), irbesartan ([138402-11 -6] cf. EP454511 ), olmesartan ([144689-24-7] cf. EP 503785), tasosartan ([145733-36-4] cf. EP539086), telmisartan ([144701-48-4] cf. EP522314) and the compounds with the designations E-1477 [135070-05-2], SC-52458 [145216-43-9], ZD-8731 [135015-84-8] or, in each case, a pharmaceutically acceptable salt thereof. A preferred AT1 -receptor antagonist is valsartan or a pharmaceutically acceptable salt thereof.
(vi) The class of calcium channel blockers (CCBs) essentially comprises dihydro- pyridines (DHPs) and non-DHPs such as diltiazem-type and verapamil-type CCBs. A CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine [88150-42-9], felodipine [72509-76-3], ryosidine [89964-00-1], isradipine [75695-93-1], lacidipine [103890-78-4], nicardipine [55985- 32-5], nifedipine [21829-25-4], niguldipine [113165-32-5], niludipine [22609-73-0], nimodipine [66085-59-4], nisoldipine [63675-72-9], nitrendipine [39562-70-4], and nivaldipine [75530-68-6], or is preferably a non-DHP representative selected from the group consisting of flunarizine [52468-60-7], prenylamine [390-64-7], diltiazem [42399-41 -7], fendiline [13042-18-7], gallopamil [16662-47-8], mibefradil [116644-53- 2], anipamil [83200-10-6], tiapamil [57010-31 -8] and verapamil [52-53-9], 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, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof. Especially preferred as a DHP is amlodipine or a pharmaceutically acceptable salt, especially the besylate, thereof. An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
(vii) Aldosterone mediates salt and water retention in the kidney and, in excessive amounts, hypertension and renal as well as cardiac fibrosis. The pathologic effects of aldosterone can be therapeutically addressed with mineralocorticoid receptor blockers. Preferred steroidal aldosterone antagonists are eplerenone ([107724-20-9] cf. EP 122232 A) and spironolactone [52-01 -7].
(viii) The enzyme aldosterone synthase converts in a three step reaction the substrate 11 -deoxycorticosterone to the product aldosterone by hydroxylating 11 -deoxycorticosterone to corticosterone, corticosterone to 18-OH-corticosterone and 18-OH-corticosterone to aldosterone. The class of aldosterone synthase inhibitors can be applied for the treatment of hypertension and primary aldosteronism. The class comprises both steroidal and non-steroidal aldosterone synthase inhibitors, the latter being most preferred. Preference is given to commercially available aldosterone synthase inhibitors or those aldosterone synthase inhibitors that have been approved by the health authorities. The class of aldosterone synthase inhibitors comprises compounds having differing structural features. For example, mention may be made of the compounds which are selected from the group consisting of the non-steroidal aromatase inhibitors fadrozole [102676-47-1], including the (+)-enantiomer [102676-87-9] thereof, or in each case where applicable, a pharmaceutically acceptable salt thereof. The most preferred non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole (US patents 4617307 and 4889861 ).
(ix) Endothelin (ET) is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists in three isoforms (ET-1 , ET-2 and ET-3). (ET shall mean any or all other isoforms of ET). Elevated levels of ET have been reported in plasma from patients with e.g. essential hypertension. Endothelin receptor antagonists can be used to inhibit the vasoconstrictive effects induced by ET. A preferred endothelin antagonist is, for example, bosentan ([147536-97-8] cf. EP 526708 A), ambrisentan [177036-94-1], avosentan ([290815- 26-8] cf. WO00/52007), enrasentan ([167256-08-8] cf.WO94/25013), atrasentan ([173937-91-2] cf. WO 96/06095), especially atrasentan hydrochloride [195733-43-8], darusentan ([171714-84-4] cf. EP 785926 A), BMS 193884 ([176960-47-7] cf. EP 702012 A), sitaxentan ([184036-34-8] cf. US 5594021 ), especially sitaxsentan sodium [210421-74-2], YM 598 ([342005-82-7] cf. EP 882719 A), S 0139 ([162117- 90-0] Cf. WO 97/27314), J 104132 ([198279-45-7] cf. EP 714897 A or WO 97/37665), furthermore, tezosentan ([180384-57-0] cf. WO 96/19459), or in each case, a pharmaceutically acceptable salt thereof.
(x) Catecholamines, such as noradrenalin and adrenalin are messengers of the sympathetic nervous system important in regulating organs such as the heart and peripheral vasculature. Noradrenalin and adrenalin mediate their physiological effects via alpha and beta adrenergic receptors. Beta-adrenoceptor antagonists are important drugs in the treatment of hypertension, angina, cardiac arrhythmias and glaucomas. Preferred betai and beta2 adrenoceptor blockers are propranolol [525- 66-6], nadolol [42200-33-9], timolol [29023-48-1], oxprenolol [6452-71 -7], pindolol [13523-86-9], alprenolol [13655-52-2] or, where appropriate, a pharmaceutically acceptable salt thereof. Preferred betai or cardioselective adrenoceptor blockers are metoprolol [51384-51-1], atenolol [29122-68-7] and acebutolol [37517-30-9] or, where appropriate, a pharmaceutically acceptable salt thereof. Alpha-adrenoceptor blocker are clinically used in hypertension. Preferred alphal -adrenoceptor blockers are prazosin [19216-56-9] and doxazosin [74191 -85-8] or, where appropriate, a pharmaceutically acceptable salt thereof. A preferred beta1/beta2/alpha1 adrenoceptor blocker is carvedilol [72956-09-3]. Centrally acting adrenoceptor modifiers are methyldopa [55-40-3] and clonidine [4205-90-7]. As most of above compounds exist as racemates whereby only one enantiomer is predominantly active, a reference to these compounds is to be understood as a reference to the racemate and, preferably, a reference to the active enantiomer.
(xi) By inhibiting cardiac sodium/potassium ATPase, the force of cardiac contraction in the failing heart is increased and the cardiac oxygen consumption is reduced. The sodium/potassium ATPase regulates the sodium/potassium exchange across the muscle cell membrane. The inhibition of the ATPase increases intracellular calcium which increases the force of myocardial contraction and reduces the arrhythmogenic substrate. A preferred sodium/potassium ATPase inhibitor is digoxin [20830-75-5]. Digoxin is used in conditions of heart failure and atrial fibrillation. (xii) HMG-Co-A reductase inhibitors (also called hydroxy-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. 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 [134523-00-5], cerivastatin [145599-86-6], compactin [73573-88-3], dalvastatin [132100-55-1], dihydrocompactin [78366-44-6], fluindostatin [93957-55-2], fluvastatin [93957-54-1], lovastatin [75330-75-5], pravastatin [147511 - 69-1], mevastatin (compactin)[73573-88-3], pravastatin [81093-37-0], rivastatin [143201-11 -0], rosuvastatin [287714-41 -4] and simvastatin (velostatin) [79902-63-9], or, in each case, a pharmaceutically acceptable salt thereof. Preferred HMG-Co-A reductase inhibitors are fluvastatin and pitavastatin and also atorvastatin or, in each case, a pharmaceutically acceptable salt thereof.
(xiii) Activators of the peroxysome proliferator activated receptor (PPAR) induce metabolic changes that affect both the lipid and glucose metabolism and therefore are useful to treat cardiovascular and metabolic pathologies such as atherosclerosis, chronic kidney disease and diabetes. PPAR activators may be derived from different chemical classes. Examples may include rosiglitazone [122320-73-4], pioglitazone [111025-46-8], R483 [213411 -83-7], isaglitazone [161600-01 -7], CS-011 [524675-01 - 2], FK-614 [193012-35-0], AVE8134 [ ], AMG131 [315223-08-6], metaglidasen [4687- 08-5], reglitazar [170861 -63-9], LY510929 [471854-50-9], GSK677954 [884324-15- 6], netoglitazone [161600-01-7], GFT505 [ ], PLX204 [884324-33-8], fenofibrate [49562-28-9], gemfibrozol [25812-30-0], clofibrate [637-07-0] and LY674 [425671 -29- 0] or, in each case, a pharmaceutically acceptable salt thereof. Preferred PPAR activators are rosiglitazone, pioglitazone, fenofibrate, gemfibrozil and clofibrate. or in each case, a pharmaceutically acceptable salt thereof.
(xiv) Cyclooxygenase (COX) is an enzyme that is responsible for formation of prostanoids including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Selective inhibition of the COX-2 enzyme isoform may reduce the risk of renal failure associated with unselective COX-1/2 inhibitors. Examples of selective COX-2 inhibitors may include celecoxib [169590-42-5], rofecoxib [162011 -90-7], lumiracoxib [220991-20-8] and etohcoxib [202409-33-4], or in each case, a pharmaceutically acceptable salt thereof. Examples of unselective COX-1/2 inhibitors may include acetyl salicylic acid [50-78-2], ibuprofen [15687-27-1], diclofenac [15307-86-5], paracetamol [103-90-2], mefenamic acid [61 -68-7], indometacin [53-86-1], piroxicam [36322-90-4], dexibuprofen [51146-56-6], dexketoprofen [22161 -81 -5], flurbiprofen [5104-49-4], naproxen [22204-53-1] and glucocorticoids such as cortisone [53-06-5], hydrocortisone [50-23-7], prednisone [53-03-2], betamethasone [378-44-9], triamcinolone [124-94-7] and dexamethasone [50-02-2], or in each case, a pharmaceutically acceptable salt thereof.
(xv) Nicotinic acid and nicotinic acid analogs induce plasma lipoprotein changes and triglyceride reductions and are therefore useful to treat cardiovascular pathologies such as atherosclerosis. For example, mention may be made of nicotinic acid (niacin) [59-67-6] and its pharmaceutical formulations.
(xvi) Sulphonylurea receptor 1 binding agents induce the release of insulin from beta- cells and are therefore useful for the treatment of diabetes. Examples may include glyburide [10238-21 -8], glimepiride [93479-97-1], glipizide [29094-61-9], repaglinide [135062-02-1], nateglinide [105816-04-4], mitiglinide [145375-43-5] or a pharmaceutically acceptable salt thereof.
(xvii) Alpha-glucosidase inhibitors reduce and slow-down the uptake of dietary carbohydrates and are therefore useful for the treatment of diabetes. Examples may include acarbose [56180-94-0], miglitol [72432-03-2], voglibose [83480-29-9] and emigilate [ ] or a pharmaceutically acceptable salt thereof. Preferred are acarbose, miglitol and voglibose or, in each case, a pharmaceutically acceptable salt thereof. .
(xviii) Glucagon-like peptide and analogs stimulate the GLP-1 receptor and thus the release of insulin and preserve the beta cell function useful for the treatment of non insulin-dependent diabetes. Examples may include exenatide [141758-74-9], liraglutide [204656-20-2], PC-DAC (exendin-4) [141732-76-5]:GLP-1 [89750-14-1], BIM-51077 [870151 -88-5], CS-872 [ ], LY548806 [898546-79-7], albugon [782500- 75-8] or a pharmaceutically acceptable salt thereof. Preferred is exenatide or a pharmaceutically acceptable salt thereof.
(xix) Dipeptidyl protease inhibitors prevent the degradation of glucagon-like peptide and therefore enhance food-mediated insulin release from the beta-cell that is useful for the treatment of non insulin-dependent diabetes. Examples may include sitagliptin [486460-32-6], vildagliptin [274901 -16-5], denagliptin [483369-58-0], SYR322 [850649-62-6], BMS477118 [361442-04-8], GRC8200, PSN-9301 , T666/815541 , SSR162369 [865720-53-2], KF-81364 and ST189428 or a pharmaceutically acceptable salt thereof. Preferred are sitagliptin and vildagliptin or a pharmaceutically acceptable salt thereof.
(xx) Phosphodiesterase inhibitors modulate intracellular signaling and thus increase myocardial contractility and mediate vasodilatation useful for several cardiovascular pathologies such as heart failure, erectile dysfunction, pulmonary and essential hypertension. Examples may include milrinone [78415-72-2], sildenafil [139755-83- 2] or a pharmaceutically acceptable salt thereof.
(xxi) Biguanidine analogs alleviate insulin resistance by reducing hepatic glucose production and by also enhancing peripheral glucose uptake. Examples are metformin [657-24-9] and fenformin [114-86-3], preferred being metformin and if appropriate a pharmaceutically acceptable salt thereof.
Preferred are combinations, such as a combined preparation or pharmaceutical compositions, respectively, comprising the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and, as a second active agent, an active agent selected from the group consisting of hydrochlorothiazide, chlorthalidone, benazepril, enalapril, lisinopril, ramipril, candoxatril, valsartan, losartan, candesartan, irbesartan, olmesartan, telmisartan, amlodipine, especially the besylate salt thereof, eplerenone, spironolactone, fadrozole, including the (+)-enantiomer thereof, bosentan, ambrisentan, avosentan, darusentan, sitaxentan, propranolol, metoprolol, atenolol, carvedilol, clonidine, digoxin, atorvastatin, fluvastatin, rosuvastatin, simvastatin, rosiglitazone, pioglitazone, celecoxib, diclofenac, acetyl salicylic acid, naproxene, dexamethasone, fenofibrate, nicotinic acid, glyburide, glimepiride, glipizide, nateglinide, repaglinide, acarbose, miglitol, voglibose, exenatide, sitagliptin, vildagliptin, milrinone, sildenafil and metformin.
The structure of the active agents identified by generic or tradenames may be taken from the current edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
The corresponding active ingredients or pharmaceutically acceptable salts thereof may also be used in the form of a solvate, such as a hydrate or including other solvents used for crystallization.
The compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having an acid group (for example COOH) can also form salts with bases.
All the more surprising is the experimental finding that the combined administration of the renin inhibitor of formula (I) or a salt thereof with a therapeutic agent selected from the group consisting of (i) to (xxi) results not only in a beneficial, especially a synergistic, therapeutic effect, but also in additional benefits resulting from the combined treatment and further surprising beneficial effects compared to a monotherapy applying only one of the pharmaceutically active compounds used in the combinations disclosed herein. In particular, all the more surprising is the experimental finding that the combination of the present invention results not only in a beneficial, especially a synergistic, therapeutic effect but also in additional benefits resulting from combined treatment such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions as specified hereinafter.
It can be shown by established test models and especially those test models described herein that the combination of the renin inhibitor of formula (I) with a therapeutic agent selected from the group consisting of (i) to (xxi) results in a more effective prevention or preferably treatment of diseases specified in the following. In particular, it can be shown by established test models and especially those test models described herein that the combination of the present invention results in a more effective prevention or preferably treatment of diseases specified hereinafter.
If taken simultaneously, this results not only in a further enhanced beneficial, especially a synergistic, therapeutic effect, but also in additional benefits resulting from the simultaneous treatment such as a surprising prolongation of efficacy, a broader variety of therapeutic effects and surprising beneficial effects, e.g. in addition to blood pressure reductions, improvement of metabolic conditions such as lipid or glycemic profiles and better protection of organs for a number of combinations as described herein. Moreover, for a human patient, especially for elderly people, it is more convenient and easier to remember to take two tablets at the same time, e.g. before a meal, than staggered in time, i.e. according to a more complicated treatment schedule. More preferably, both active ingredients are administered as a fixed combination, i.e. as a single tablet, in all cases described herein. Taking a single tablet is even easier to handle than taking two tablets at the same time. Furthermore, the packaging can be accomplished with less effort.
The term "synergistic" as used herein means that the effect achieved with the methods and compositions of the present invention is greater than the sum of the effects that result from methods and compositions comprising the active ingredients of this invention separately.
The person skilled in the pertinent art is fully enabled to select a relevant and standard animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.
The pharmaceutical activities as effected by administration of representatives of the class of renin inhibitors or of the combination of active agents used according to the present invention can be demonstrated e.g. by using corresponding pharmacological models known in the pertinent art. The person skilled in the pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.
The combination according to the present invention comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by various routes of administration but are tested in this example using a continuous infusion via subcutaneously-implanted osmotic minipumps. Each agent can be tested over a wide range of dosages to determine the optimal drug level for each agent in combination to elicit the maximal response. For these studies, it is preferred to use treatment groups consisting of at least 6 animals per group. Each study is best performed in which the effects of the combination treatment group are determined at the same time as the individual components are evaluated. Although drug effects may be observed with acute administration (such as 1 day), it is preferable to observe responses in a chronic setting as shown below in which experiments are done over a three to seven week observation period. The long-term study is of sufficient duration to allow for the full development of compensatory responses to occur and therefore, the observed effect will most likely depict the actual responses of the test system representing sustained or persistent effects.
The beneficial effects on blood pressure as well as heart and kidney function can, for example, be demonstrated in the following test model: Method
An animal model for spontaneously malignant hypertension with renal and cardiac complications is represented by double transgenic rats over-expressing both the gene for human renin and the gene for human angiotensinogen. This double transgenic rat strain is produced by crossbreeding two transgenic strains, one for human angiotensinogen with the endogenous promoter and one for human renin with the endogenous promoter. Neither single transgenic rat strain is hypertensive. In contrast, the double transgenic rats, both males and females, develop severe hypertension with a mean systolic blood pressure of approximately 200 mm Hg and die after a mean of 55 days if untreated (Luft et al., Hypertension 1999; 33:212-218). The fact that human renin orthologous gene can be studied in the rat is a unique feature of this model and allows the extrapolation to clinical high renin hypertension.
The combination according to the present invention comprising the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof together with
(i) hydrochlorothiazide,
(ii) benazepril,
(iii) candoxathl,
(iv) omapatrilat
(v) valsartan,
(vi) amlodipine
(vii) spironolactone,
(viii) fadrozole,
(ix) avosentan,
(x) propranolol
(xi) digoxin,
(xii) atorvastatin
(xiii) rosiglitazone
(xiv) naproxen or, if appropriate, a pharmaceutically acceptable salt thereof can be administered by various routes of administration but are tested in this example orally by gavage. Each agent can be tested over a wide range of dosages to determine the optimal drug level for each agent in combination to elicit the maximal response. Each study group is best performed in a parallel study design i.e. the effects of the combination treatment group are determined at the same time as the individual components are evaluated.
Although drug effects may be observed upon short term treatment, it is preferable to observe responses in a chronic setting as shown below in which experiments are done over a three to seven week observation period. The long-term study is thus of sufficient duration to allow for the full development of compensatory responses to occur and therefore, the observed effect will most likely depict sustained pharmacological responses.
Blood pressure and the blood flow-mediated pathological effects on blood pressure sensitive organs such as the heart and kidney can be synergistically modified with combination therapy in comparison to the respective monotherapies. On one hand, blood pressure may be reduced to a similar degree with a low-dose component combination therapy as with a high-dose component monotherapy. On the other hand, the combination formula may result in greater blood pressure reductions as expected by simply adding the effects of individual monotherapy components.
Statistical Analysis
The combination therapy can be compared to that of the respective monotherapies by determining the maximum change in mean arterial blood pressure, 24 hour urinary protein content or changes in echocardiographic recordings at a given day. All values are represented as the group mean ± standard error of the mean (SEM). Statistical significance is obtained when p < 0.05. The albuminuria values for each of the treatment groups can be compared statistically using a one-way ANOVA followed by the appropriate post-hoc analysis, for example by performing a Bonferoni test. Studv design
Four week old double transgenic rats with telemetric transducer devices implanted in the abdominal aorta for blood pressure recordings are subjected to daily treatment by oral gavage with the renin inhibitor of formula (I) at a dose of 10 mg/kg, a therapeutic agent selected from the group consisting of (i) to (xiv) at doses of 10 and 30 mg/kg and combinations of the renin inhibitor of formula (I) with a therapeutic agent selected from the group consisting of (i) to (xiv) at the same doses. After three, five and seven weeks of drug treatment, 24 hour urine samples are collected using metabolic cages. The urinary albumin content is measured by ELISA using a commercial kit (Celltrend GmbH, Luckenwalde, Germany). In addition, echocardiographic recordings are generated in narcotized rats allowing the determination of left ventricular end diastolic area (LVEDA), end systolic area (LVESA) fractional shortening (FS), and changes in posterior wall (PW) thickness. After sacrifice of the animals, isolated hearts are fixed in situ, by retrograde perfusion with buffered 4% formaldehyde after arrest in diastole by i.v. injection of 0.5 M KCI. After fixation, the left ventricle (LV) and the free wall of the right ventricle are separately weighed; LV longer diameter is measured with a caliper. LV histological sections are stained with hematoxylin and eosin for qualitative examination and to quantify cardiomyocytes cross-sectional area with a semi- automated image analysis routine. Interstitial collagen deposition in LV is evaluated on Sirius red stained sections with a semi-automated image analysis routine (Masson et al., 1998). LV chamber volume is determined in hearts arrested in diastole (KCI) and fixed in formalin under a hydrostatic pressure equivalent to the measured LV end-diastolic pressure. A metric rod is inserted into the LV to measure LV inner length. The transverse diameters of the LV chamber are measured in two 1 -mm thick transverse sections near to the base and the apex of the ventricle (Jeremic et al., 1996). The chamber volume is computed from an equation integrating transverse diameters and inner length.
Results
The administration of a combination of the renin inhibitor of formula (I) L-lactate with avosentan had a superior anti-albuminuric effect than either drug alone. The combination therapy was statistically superior to each monotherapy with a probability level of p<0.5 using a one-way ANOVA and a Bonferoni test. Thus, a synergistic effect on the development of albuminuria in this animal model for malignant hypertension with renal complications can be shown by the administration of a renin inhibitor of formula (I) L-lactate and avosentan in combination in comparison to the administration of the individual drugs.
The beneficial effects on metabolic parameters as well as heart and kidney function can, for example, be demonstrated in the following test model:
Method
An animal of non-insulin dependent diabetes with abnormal glucose tolerance that progresses to kidney disease is represented in the male Zucker diabetic rat model (Peterson in Lessons from Animal Diabetes V, edited by E. Shafrir, London Smith- Gordon, 225-230, 1994). The characteristics of the model are hyperglycemia that develops between 7 and 10 weeks of age, early hypehnsulinemia that falls upon beta cell failure, hyperlipidemia and mild hypertension. As the model expresses rat renin, higher doses of a human renin inhibitor need to be applied in order to compensate for a lower drug binding affinity.
The combination according to the present invention comprising the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof together with
(ii) benazepril,
(iii) candoxathl,
(iv) omapatrilat
(v) valsartan,
(vi) amlodipine
(vii) spironolactone,
(viii) fadrozole,
(ix) avosentan,
(xii) atorvastatin
(xiii) rosiglitazone,
(xiv) naproxen (xv) nicotinic acid,
(xvi) glyburide,
(xvii) acarbose,
(xviii) exenatide,
(xix) sitagliptin,
(xx) sildenafil,
(xxi) metformin.
or if appropriate a pharmaceutically acceptable salt thereof can be administered by various routes of administration but are tested in this example orally by gavage. Each agent can be tested over a wide range of dosages to determine the optimal drug level for each agent in combination to elicit the maximal response. Each study group is best performed in which the effects of the combination treatment group are determined at the same time as the individual components are evaluated. Although drug effects may be observed upon short term treatment, it is preferable to observe responses in a chronic setting as shown below in which experiments are done over a three to seven week observation period. The long-term study is thus of sufficient duration to allow for the full development of compensatory responses to occur and therefore, the observed effect will most likely depict sustained pharmacological responses.
Statistical Analysis
The combination therapy can be compared to that of the respective monotherapies by determining the maximum change in fasting glycemia, insulinemia and triglycehdemia, plasma lipoprotein particle concentrations and hemoglobin A1 C (HbAI C) levels, 24 hour urinary protein content or changes in the area under the glucose and insulin concentration curves, respectively, during oral glucose tolerance tests (OGTT) at a given day. All values are represented as the group mean ± standard error of the mean (SEM). Statistical significance is obtained when p < 0.05. The values for each of the treatment groups can be compared statistically using a one-way ANOVA followed by the appropriate post-hoc analysis, for example by performing a Bonferoni test. Studv design
Male Zucker diabetic rats (ZDF (fa/fa) weighing between 370 and 430 g are studied at 13 weeks of age after the onset of diabetes (as determined by fasting blood glucose between 8.3 and 12.5 mmol/l). They are maintained on rat chow and subjected for four weeks to daily treatment by oral gavage with the renin inhibitor of formula (I) at a dose of 100 mg/kg, a therapeutic agent selected from the group consisting of (ii) to (ix) and (xii) to (xxi) at doses of 10 and 30 mg/kg and combinations of the renin inhibitor of formula (I) with a therapeutic agent selected from the group consisting of (ii) to (ix) and (xii) to (xxi) at the same doses. The applied doses of renin inhibitor are increased in order to compensate for the weaker affinity of compounds of formula (I) to the rodent renin protein sequence. Weekly plasma samples are collected in fasted states in order to determine glucose, insulin, hemoglobin A1 C, triglyceride and lipoprotein particle concentrations. For the OGTT, a blood sample is taken 4 hours after compound dosing via exteriorized cannula in the femoral vein. The oral glucose challenge (1 g/kg) is then administered and blood samples are collected after 10, 20, 30, 60, 90 and 120 minutes for measurement of plasma and glucose levels. After four weeks of drug treatment, 24 hour urine samples are collected using metabolic cages. The urinary albumin content is measured by ELISA using a commercial kit (Celltrend GmbH, Luckenwalde, Germany). In addition, upon sacrifice of the animals, kidney sections are analyzed immunohistochemically for biomarkers of kidney function such as TGFbeta, MCP-1 , nephrin and collagen.
Results
The combination therapy was statistically superior to each monotherapy with a probability level of p<0.5 using a one-way ANOVA and a Bonferoni test. Thus, a synergistic effect on the development of albuminuria in this animal model for non insulin-dependent diabetes with renal complications can be shown by the administration of a renin inhibitor of formula (I) L-lactate and avosentan in combination in comparison to the administration of the individual drugs. Furthermore, an improvement of regression of artherosclerosis without affecting the serum lipid levels can, for example, be demonstrated by using the animal model as disclosed by H. Kano et al. in Biochemical and Biophysical Research Communications 259, 414-419 (1999).
That the compounds or combinations according to the present invention can be used for the regression of a cholesterol diet-induced atherosclerosis, can be demonstrated using the test model described, e.g., by C. Jiang et al. in Br. J. Pharmacol. (1991 ), 104, 1033-1037.
That the compounds or combinations according to the present invention can be used for the treatment of renal failure, especially chronic renal failure, can be demonstrated using the test model described, e.g., by D. Cohen et al. in Journal of Cardiovascular Pharmacology, 32: 87-95 (1998).
Further benefits when applying the composition of the present invention are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
Preferably, the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
The pharmaceutical composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
Accordingly, the invention furthermore relates to a method for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, angina pectoris, stroke, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery;
(b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, IgA nephropathy, glomerulosclerosis, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
(c) endothelial dysfunction with or without hypertension,
(d) hyperlipidemia, hyperthglceridemia, hyperinsulinemia, hyperglycemia, insulin resistance, impaired glucose tolerance, mature onset diabetes of the young (MODY), hyperlipoproteinemia, atherosclerosis and hypercholesterolemia,
(e) glaucoma, macular degeneration, cataracts,
(f) isolated systolic hypertension (ISH),
(g) diabetic retinopathy and
(h) peripheral vascular disease; foot ulcerations comprising administering to a warm-blooded animal, including man, in need thereof a jointly effective amount of a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent selected from the group consisting of
(i) a diuretic or a pharmaceutically acceptable salt thereof
(ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof, (vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof,
(x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof,
(xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof,
(xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof,
(xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof,
(xvi) a sulphonylurea receptor 1 binding agent or or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof,
(xviii) a glucagon-like peptide analog or a pharmaceutically acceptable salt thereof,
(xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof,
(xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof and
(xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof.
Furthermore, the present inveniton relates to the use of a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent selected from the group consisting of
(i) a diuretic or a pharmaceutically acceptable salt thereof
(ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable (v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof,
(vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof,
(x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof,
(xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof,
(xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof,
(xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof,
(xvi) a sulphonylurea receptor 1 binding agent or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof,
(xviii) a glucagon-like peptide analog or a pharmaceutically acceptable salt thereof,
(xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof,
(xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof and
(xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof.
for the manufacture of a medicament for the prevention of, delay of progression of, or treatment of a disease or condition selected from the group consisting of
(a) hypertension, congestive heart failure, angina pectoris, stroke, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery;
(b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, IgA nephropathy, glomerulosclerosis, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiprol iterative effect of the combination), all these diseases or conditions associated with or without hypertension;
(c) endothelial dysfunction with or without hypertension,
(d) hyperlipidemia, hyperthglceridemia, hyperinsulinemia, hyperglycemia, insulin resistance, impaired glucose tolerance, mature onset diabetes of the young (MODY), hyperlipoproteinemia, atherosclerosis and hypercholesterolemia,
(e) glaucoma, macular degeneration, cataracts,
(f) isolated systolic hypertension (ISH),
(g) diabetic retinopathy and
(h) peripheral vascular disease; foot ulcerations
The invention furthermore relates to a pharmaceutical composition for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of
(a) hypertension, congestive heart failure, angina pectoris, stroke, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery;
(b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, IgA nephropathy, glomerulosclerosis, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension;
(c) endothelial dysfunction with or without hypertension,
(d) hyperlipidemia, hyperthglceridemia, hyperinsulinemia, hyperglycemia, insulin resistance, impaired glucose tolerance, mature onset diabetes of the young (MODY), hyperlipoproteinemia, atherosclerosis and hypercholesterolemia,
(e) glaucoma, macular degeneration, cataracts,
(f) isolated systolic hypertension (ISH),
(g) diabetic retinopathy and
(h) peripheral vascular disease; foot ulcerations comprising a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent selected from the group consisting of
(i) a diuretic or a pharmaceutically acceptable salt thereof
(ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof,
(vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof,
(x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof,
(xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof,
(xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof,
(xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof,
(xvi) a sulphonylurea receptor 1 binding agent or or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof,
(xviii) a glucagon-like peptide analog or a pharmaceutically acceptable salt thereof,
(xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof,
(xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof and (xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Further benefits when applying the composition of the present invention are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
Preferably, the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
The pharmaceutical composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
A further aspect of the present invention is a kit for the prevention of, delay of progression of, treatment of a disease or condition according to the present invention comprising
(a) an amount of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form;
(b) an amount of at least one therapeutic agent selected from the group consisting of components (i) to (xxi), or, in each case, where appropriate, a pharmaceutically acceptable salt thereof in a second etc. unit dosage form; and
(c) a container for containing said first, second etc. unit forms.
In a variation thereof, the present invention likewise relates to a "kit-of-parts", for example, in the sense that the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points. The parts of the kit of parts can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. Preferably, the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components.
The invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use. These pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances. For example, the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compound. Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
The dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition. Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commercially available. Normally, in the case of oral administration, an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 70 kg in weight. The dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition. The pharmaceutical preparation will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising an amount, being together with the further component(s) jointly effective, e.g. in lowering blood pressure by inhibition of renin and in reducing proteinuria by blockade of endothelin subtype A receptors.
The doses of the renin inhibitor of formula (I) to be administered to warm-blooded animals, for example human beings, of, for example, approximately 70 kg body weight, especially the doses effective in the inhibition of the enzyme renin are from approximately 3 mg to approximately 3 g, preferably from approximately 10 mg to approximately 1 g, for example approximately from 20 mg to 200 mg, per person per day, divided preferably into 1 to 4 single doses which may, for example, be of the same size. Usually, children receive about half of the adult dose. The dose necessary for each individual can be monitored, for example by measuring the serum concentration of the active ingredient, and adjusted to an optimum level. Single doses comprise, for example, 10, 40 or 100 mg per adult patient.

Claims

Claims
1. A pharmaceutical composition 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
(i) a diuretic or a pharmaceutically acceptable salt thereof
(ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof,
(vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof,
(x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof,
(xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof,
(xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof,
(xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof,
(xvi) a sulphonylurea receptor 1 binding agent or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof,
(xviii) a glucagon-like peptide analog or a pharmaceutically acceptable salt thereof, (xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof, (xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof and (xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof; and a carrier.
2. A composition according to claim 1 wherein the renin inhibitor is present in the form of the acetate, L-lactate, citrate or fumarate salt, preferably in the form of the L- lactate salt.
3. A composition according to claim 1 or 2 wherein, independent of one another, - said ATi-receptor antagonist is valsartan or a pharmaceutically acceptable salt thereof; -said HMG-Co-A reductase inhibitor is fluvastatin and pitavastatin, or or a pharmaceutical acceptable salt thereof; -said angiotensin converting enzyme (ACE) inhibitor is benazepril or enalapril, or a pharmaceutical acceptable salt thereof; -said Calcium channel blocker is amlodipine or a pharmaceutical acceptable salt thereof; - said aldosterone synthase inhibitor is fadrozole (including the (+)-enantiomer thereof or a pharmaceutical acceptable salt thereof; -said aldosterone antagonist is eplerenone ; -said dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitor is omapatrilate or a pharmaceutical acceptable salt thereof; -said endothelin antagonist is bosentan or a pharmaceutically acceptable salt thereof; and -said diuretic is hydrochlorothiazide.
4. A composition according to any one of claims 1 to 3 for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e. g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; and (c) endothelial dysfunction with or without hypertension, (d) hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypercholesterolemia ; and (e) glaucoma.
5. A composition according to any one of claims 1 to 3 for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (f) isolated systolic hypertension (ISH), (g) diabetic retinopathy, and (h) peripheral vascular disease.
6. A composition according to any one of claims 1 to 5 for simultaneous, separate or sequential use.
7. A kit for the prevention, delay of progression, or treatment according to claim 4 comprising (a) an amount of the renin inhibitor of formula (I) or a pharmaceutical acceptable salt thereof in a first unit dosage form; (b) an amount of at least one therapeutic agent selected from the group consisting of components (i) a diuretic or a pharmaceutically acceptable salt thereof
(ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof,
(vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof,
(x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof,
(xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof, (xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof,
(xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof,
(xvi) a sulphonylurea receptor 1 binding agent or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof,
(xviii) a glucagon-like peptide analog or a pharmaceutically acceptable salt thereof,
(xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof,
(xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof or
(xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof; in a second etc. unit dosage form; and (c) a container for containing said first, second etc. unit forms.
8. Use of a combination of the renin inhibitor of formula (I) or a pharmaceutical acceptable salt thereof with at least one therapeutic agent selected from the group consisting of (i) a diuretic or a pharmaceutically acceptable salt thereof
(ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof,
(vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof,
(x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof, (xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof,
(xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, (xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof, (xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof, (xvi) a sulphonylurea receptor 1 binding agent or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof, (xviii) a glucagon-like peptide analog or a pharmaceutically acceptable salt thereof, (xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof, (xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof and (xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the prevention of, delay of progression of, or treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e. g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; (c) endothelial dysfunction with or without hypertension, comprising administering the pharmaceutical composition of the present invention; and (d) hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypercholesterolemia; and (e) glaucoma.
9. Use of a combination of the renin inhibitor of formula (I) or a pharmaceutical acceptable salt thereof with at least one therapeutic agent selected from the group consisting of (i) a diuretic or a pharmaceutically acceptable salt thereof (ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof,
(vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof,
(x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof,
(xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof,
(xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof,
(xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof,
(xvi) a sulphonylurea receptor 1 binding agent or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof,
(xviii) a glucagon-like peptide analog or a pharmaceutically acceptable salt thereof,
(xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof,
(xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof and
(xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the prevention of, delay of progression of, or treatment of a disease or condition selected from the group consisting of (f) isolated systolic hypertension (ISH), (g) diabetic retinopathy, and (h) peripheral vascular disease.
10. A method for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of (a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous transluminal angioplasty, and restenosis after coronary artery bypass surgery; (b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e. g. chronic renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidemic hypertension, increase of formation of collagen, fibrosis, and remodeling following hypertension (antiproliferative effect of the combination), all these diseases or conditions associated with or without hypertension; (c) endothelial dysfunction with or without hypertension, (d) hyperlipidemia, hyperlipoproteinemia, atherosclerosis and hypercholesterolemia, (e) glaucoma ; furthermore (f) isolated systolic hypertension (ISH), (g) diabetic retinopathy, and (h) peripheral vascular disease; comprising administering to a warm-blooded animal, including man, in need thereof a jointly effective amount of a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent selected from the group consisting of (i) a diuretic or a pharmaceutically acceptable salt thereof
(ii) an angiotensin-converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof,
(iii) a neutral endopeptidase (NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(iv) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof,
(v) an angiotensin type I (AT1 )-receptor antagonist or a pharmaceutically acceptable salt thereof,
(vi) a calcium channel blocker or a pharmaceutically acceptable salt thereof,
(vii) an aldosterone antagonist or a pharmaceutically acceptable salt thereof,
(viii) an aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof,
(ix) an endothelin receptor antagonist or a pharmaceutically acceptable salt thereof, (x) an adrenergic receptor blocker or a pharmaceutically acceptable salt thereof,
(xi) a membrane sodium/potassium ATPase inhibitor or a pharmaceutically acceptable salt thereof,
(xii) a HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof,
(xiii) a peroxysome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt thereof,
(xiv) a cyclooxygenase inhibitor or a pharmaceutically acceptable salt thereof,
(xv) a nicotinic acid homologue or a pharmaceutically acceptable salt thereof,
(xvi) a sulphonylurea receptor 1 binding agent or a pharmaceutically acceptable salt thereof,
(xvii) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt thereof,
(xviii) a glucagon-like peptide analog or a pharmaceutically acceptable salt thereof,
(xix) a dipeptidyl protease inhibitor or a pharmaceutically acceptable salt thereof,
(xx) a phosphodiesterase inhibitor or a pharmaceutically acceptable salt thereof and
(xxi) a biguanidine analog or a pharmaceutically acceptable salt thereof.
PCT/EP2008/054586 2008-04-16 2008-04-16 Combinations comprising a renin inhibitor Ceased WO2009127251A1 (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2002040007A1 (en) * 2000-11-17 2002-05-23 Novartis Ag Synergistic combinations comprising a renin inhibitor for cardiovascular diseases
WO2003027091A1 (en) * 2001-09-21 2003-04-03 Novartis Ag Pyrane derivatives as both ace- and nep- inhibitors
WO2006005741A2 (en) * 2004-07-09 2006-01-19 Speedel Experimenta Ag Piperdine derivatives as renin inhibitors
WO2006103273A1 (en) * 2005-03-31 2006-10-05 Speedel Experimenta Ag Substituted piperidines as renin inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002040007A1 (en) * 2000-11-17 2002-05-23 Novartis Ag Synergistic combinations comprising a renin inhibitor for cardiovascular diseases
WO2003027091A1 (en) * 2001-09-21 2003-04-03 Novartis Ag Pyrane derivatives as both ace- and nep- inhibitors
WO2006005741A2 (en) * 2004-07-09 2006-01-19 Speedel Experimenta Ag Piperdine derivatives as renin inhibitors
WO2006103273A1 (en) * 2005-03-31 2006-10-05 Speedel Experimenta Ag Substituted piperidines as renin inhibitors

Non-Patent Citations (1)

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Title
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