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WO2009127251A1 - Combinaisons renfermant un inhibiteur de la rénine - Google Patents

Combinaisons renfermant un inhibiteur de la rénine 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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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

La présente invention concerne des combinaisons médicamenteuses renfermant l’inhibiteur de la rénine de formule (I) ou l’un de ses sels pharmaceutiquement acceptables avec des agents thérapeutiques cardiovasculaires spécifiques de mécanisme pharmacologique complémentaire afin de générer un effet thérapeutique synergique.
PCT/EP2008/054586 2008-04-16 2008-04-16 Combinaisons renfermant un inhibiteur de la rénine Ceased WO2009127251A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002040007A1 (fr) * 2000-11-17 2002-05-23 Novartis Ag Complexes medicamenteux comportant un inhibiteur de la renine et servant au traitement de maladies cardiovasculaires
WO2003027091A1 (fr) * 2001-09-21 2003-04-03 Novartis Ag Derives du pyranne utilises comme inhibiteurs de ace et nep
WO2006005741A2 (fr) * 2004-07-09 2006-01-19 Speedel Experimenta Ag Composes organiques
WO2006103273A1 (fr) * 2005-03-31 2006-10-05 Speedel Experimenta Ag Piperidines substituees utiles en tant qu'inhibiteurs de renine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002040007A1 (fr) * 2000-11-17 2002-05-23 Novartis Ag Complexes medicamenteux comportant un inhibiteur de la renine et servant au traitement de maladies cardiovasculaires
WO2003027091A1 (fr) * 2001-09-21 2003-04-03 Novartis Ag Derives du pyranne utilises comme inhibiteurs de ace et nep
WO2006005741A2 (fr) * 2004-07-09 2006-01-19 Speedel Experimenta Ag Composes organiques
WO2006103273A1 (fr) * 2005-03-31 2006-10-05 Speedel Experimenta Ag Piperidines substituees utiles en tant qu'inhibiteurs de renine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MARKI H P ET AL: "Piperidine renin inhibitors: from leads to drug candidates", FARMACO, SOCIETA CHIMICA ITALIANA, PAVIA, IT, vol. 56, no. 1-2, 1 January 2001 (2001-01-01), pages 21 - 27, XP002317172, ISSN: 0014-827X *

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