STIMULATORS AND/OR ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE (SGC) IN COMBINATION WITH AN INHIBITOR OF NEUTRAL ENDOPEPTIDASE (NEP INHIBITOR) AND/OR AN ANGIOTENSIN AII ANTAGONIST AND THE USE THEREOF

Abstract

The present invention relates to stimulators and activators of soluble guanylate cyclase in combination with an inhibitor of neutral endopeptidase and/or angiotensin AII antagonists and the use thereof for the treatment and/or prophylaxis of cardiovascular disorders, for example heart failure with preserved ejection fraction or heart failure with reduced ejection fraction, renal disorders, for example chronic kidney failure, urological disorders, lung disorders, disorders of the central nervous system, for regulation of cerebral perfusion, for example in the event of vascular cerebral states of dementia, for the treatment and/or prophylaxis of fibrotic disorders and other disease symptoms (e.g. end organ damage affecting the brain, kidney or heart).

Claims

1. A combination comprising an sGC stimulator, sacubitril and/or an angiotensin AII antagonist and also in each case the salts, solvates and solvates of the salts thereof

2. The combination as claimed in claim 1 comprising an sGC stimulator, sacubitril and/or valsartan and also in each case the salts, solvates and solvates of the salts thereof

3. The combination as claimed in claim 1 comprising an sGC stimulator and LCZ696 and also in each case the salts, solvates and solvates of the salts thereof.

4. The combination as claimed in claim 1 for preparing a medicament for the treatment and/or prophylaxis of cardiovascular disorders, renal disorders, lung disorders, and also for the treatment and/or prophylaxis of fibrotic disorders.

5. A medicament comprising a combination as claimed in claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

6. The medicament comprising a combination as claimed in claim 1 in combination with one or more further active ingredients selected from the group consisting of ACE inhibitors, renin inhibitors, beta blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis (digoxin) derivatives, calcium sensitizers, nitrates and antithrombotics.

7. The medicament comprising a combination as claimed in claim 1 for the treatment and/or prophylaxis of cardiovascular disorders, renal disorders, lung disorders, and also for the treatment and/or prophylaxis of fibrotic disorders.

8. A method for the treatment and/or prophylaxis of cardiovascular disorders, renal disorders, lung disorders, and also for the treatment and/or prophylaxis of fibrotic disorders, in humans and animals comprising administering a therapeutically effective amount of the combination of claim 1 to a human or animal in need thereof.

9. A kit comprising a pharmaceutical composition comprising an sGC stimulator and a pharmaceutical composition comprising an angiotensin AII antagonist and N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenyl methyl)-4-amino-2R-methylbutanoic acid or the esters thereof.

10. The kit as claimed in claim 9 comprising a pharmaceutical composition comprising an sGC stimulator and a pharmaceutical composition comprising valsartan and N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid or an ester thereof.

11. The kit as claimed in claim 9 comprising a pharmaceutical composition comprising an sGC stimulator and a pharmaceutical composition comprising trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl {2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate.

Description

EXPERIMENTAL SECTION

[0194] The working examples which follow illustrate the invention. The invention is not restricted to the examples.

[0195] Unless stated otherwise, the percentages in the tests and examples which follow are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are based in each case on volume.

Assessment of Physiological Efficacy

[0196] The suitability of the combinations according to the invention for treating cardiovascular disorders can be demonstrated in the following assay systems:

Radiotelemetric Measurement of Blood Pressure and Heart Rate of Conscious Rats

[0197] A commercially available telemetry system from Data Sciences International DSI, USA, was employed for the measurements on conscious rats (Wistar strain Unilever/WU or Spontaneous Hypertensive Rat/SHR) described below. The system consists of 3 main components: (1) implantable transmitters (PhysioTel® telemetry transmitter), (2) receivers (PhysioTel® receiver), which are linked via a multiplexer (DSI Data Exchange Matrix) to a (3) data acquisition computer. The telemetry system makes it possible to continuously record blood pressure, heart rate and body motion of conscious animals in their usual habitat.

[0198] The studies are conducted on adult female rats with a body weight of >200 g. After transmitter implantation, the experimental animals are housed singly in type III Makrolon® cages. They have free access to standard feed and water. The day/night rhythm in the test laboratory is set by changing the illumination of the room.

Transmitter Implantation

[0199] The telemetry transmitters used (e.g. PA-C40 HD-S10, DSI) are surgically implanted under aseptic conditions in the experimental animals at least 14 days before the first experimental use.

[0200] For the implantation, the fasted animals are anesthetized with isoflurane (IsoFlo®, Abbott, initiation 5%, maintenance 2%) and shaved and disinfected over a large area of their abdomens. After the abdominal cavity has been opened along the linea alba, the liquid-filled measuring catheter of the system is inserted into the descending aorta in the cranial direction above the bifurcation and fixed with tissue glue (Vetbond™, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall muscle, and the wound is closed layer by layer. Post-operatively, an antibiotic (Ursocyclin® 10%, 60 mg/kg s.c., 0.06 ml/100 g body weight, Serumwerk Bernburg AG, Germany) for infection prophylaxis and an analgesic (Rimadyl®, 4 mg/kg s.c., Pfizer, Germany) are administered.

Substances and Solutions

[0201] Unless stated otherwise, the substances to be studied are administered orally to a group of animals in each case (n=6). In accordance with an administration volume of 2 ml/kg of body weight, the test substances are dissolved in suitable solvent mixtures. A solvent-treated group of animals is used as control.

Experimental Outline

[0202] The telemetry measuring system is configured for 24 animals.

[0203] Each of the instrumented rats living in the system is assigned a separate receiving antenna (RPC-1 Receiver, DSI). The implanted senders can be activated externally via an installed magnetic switch and are switched to transmission during the pre-run of the experiment. The signals emitted can be detected online by a data acquisition system (Dataquest™ A.R.T. for Windows, DSI or Ponemah, DSI) and processed accordingly.

[0204] In the standard procedure, the following are measured for 10-second periods in each case: (1) systolic blood pressure (SBP), (2) diastolic blood pressure (DBP), (3) mean arterial pressure (MAP), (4) heart rate (HR) and (5) activity (ACT). These parameters are measured over 24 hours after administration.

[0205] The acquisition of measurements is repeated under computer control at 5-minute intervals. The source data obtained as absolute values are corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1, DSI).

Evaluation

[0206] After the end of the experiment, the acquired individual data are sorted using the analysis software (Dataquest™ A.R.T. 4.1 Analysis or Ponemah, DSI). The 2 hour time point before substance administration is assumed as the blank value.

[0207] The data are smoothed over a presettable period by determination of the means (30 minute mean).

Literature

[0208] K. Witte, K. Hu, J. Swiatek, C. MUssig, G. Ertl and B. Lemmer, Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial (3-adrenergic signaling, Cardiovasc. Res. 47 (2): 203-405, 2000.

Long-Term Study in Ren-2 Transgenic Rats Treated With L-NAME

[0209] The cardiovascular effect after administration of an sGC modulator, neprilysin inhibitor, angiotensin AII antagonist and double and triple combinations thereof are demonstrated by determining the long-term effects on hemodynamic and hormonal parameters in a high renin, low-NO blood pressure model in rats.

[0210] Male transgenic Ren-2 rats (TGR(mRen2)27) are raised on-site and kept under controlled light and temperature conditions. From an age of 10 to 20 weeks the animals are randomized into different groups. The control group receive a placebo, the test groups sGC modulators, neprilysin inhibitors, angiotensin AII antagonists and double and triple combinations thereof for 4-10 weeks. The rats of the placebo and treatment groups also receive 30-100 mg/l L-NAME via drinking water. The test substances are administered p.o. as a suspension in a mixture of transcutol/cremophor/water (10/20/70=v/v/v) or as a tylose suspension. Systolic blood pressure and heart rate are measured weekly using the “tail-cuff” method in conscious animals in cages at a constant temperature of 37° C. Urine collections occur on day 0, during and at the end of the experiment in metabolism cages and proteinuria, urinary electrolyte excretion are determined. At the end of the studies, left ventricular pressure and cardiac contraction are measured under anesthesia. Finally, the animals are sacrificed by decapitation and blood samples withdrawn. Plasma and urine parameters are biochemically determined, e.g. ANP (RIA Kit RK 005-24, Phoenix Pharmaceuticals, Inc., USA), cGMP (RIA Kit RE29075, IBL International GmbH, Germany), renin, angiotensin I (RIA Kit CA-1533, DiaSorin S.p.A., Italy) and aldosterone (P2714, DiaSorin S.p.A., Italy). Organs, e.g. kidney, heart, lungs etc. are taken and gene expression profiles and histopathological data are collected.

Hypertensive Heart Failure Model in Dogs

[0211] The cardiovascular effect after administration of an sGC modulator (sGC stimulator or sGC activator), neprilysin inhibitor, angiotensin AII antagonist, and double and triple combinations thereof are evaluated in a dog model of “mild” systolic heart failure caused by angiotensin AII antagonist-induced acute hypertension. An experimental animal model of left ventricular dysfunction is triggered by right ventricular “tachypacing” at 180 bpm for 10 days. The experimental implementation of this model has been described in detail. [Redfield et al., Circulation 1993;87:2016-2022]

Hypertensive “Renal Wrap” Dogs

[0212] The effect of an sGC modulator (sGC stimulator or sGC activator), neprilysin inhibitor, angiotensin AII antagonist, and double and triple combinations thereof on blood pressure and heart rate are tested in the hypertensive “renal wrap” dog model. In the model a kidney is wrapped with silk, while the second kidney is subjected to an occlusion of the main kidney artery. [Page et al., Science 1939; 89: 2307-2308; Goldblatt et al., Proc Natl Acad Sci 1976; 73: 1722-1724]. About 4 weeks after the operation, the dogs develop stable high blood pressure.

Results

[0213] Results are shown in FIGS. 1 and 2 for the compound of the formula (6) in a triple combination with a neprilysin inhibitor and an angiotensin AII antagonist compared to the single administration of the compound of the formula (6) and a double combination of a neprilysin inhibitor and an angiotensin AII antagonist.

[0214] The compound of the formula (6) shows no hemodynamic effects (blood pressure, heart rate) at an oral dose of 0.1 mg/kg; at 0.3 mg/kg a decrease in the mean arterial blood pressure of ca. −10% and a transient increase in heart rate was observed. The comparative substances, which are administered orally as a double combination, show a decrease in the mean arterial blood pressure of ca. −20% with associated reflex tachycardia at the dose investigated. The addition of 0.1 mg/kg of the compound of the formula (6) to the double combination leads, compared with the double combination alone, to a reduced reflexive increase in the heart rate with the same decrease in the mean arterial blood pressure. The combination of the compound of the formula (6) at a dose of 0.3 mg/kg with a neprilysin inhibitor and an angiotensin AII antagonist shows an additional effect on the blood pressure decrease. Surprisingly, a non-additive effect on the heart rate was observed in the triple-combination trial (no additive compensatory effect or reflex tachycardia). In the double and triple combination, 30 mg/kg sacubitril and 10 mg/kg valsartan is used.

[0215] Results are shown in FIGS. 3, 4 and 5 for the compound of the formula (29) in a triple combination with a neprilysin inhibitor and an angiotensin AII antagonist compared to the single administration of the compound of the formula (29) and a double combination of a neprilysin inhibitor and an angiotensin AII antagonist.

[0216] The compound of the formula (29) shows a decrease in the mean arterial blood pressure of ca. −10% or 15% and an associated reflex tachycardia at an oral dose of 3 mg/kg and 10 mg/kg. The compound of the formula (29) shows reflex tachycardia at an oral dose of 1 mg/kg. The comparative substances, which are administered orally as a double combination, show a decrease in the mean arterial blood pressure of ca. −15% at the dose investigated. The triple combination of the compound of the formula (29) with a neprilysin inhibitor and an angiotensin AII antagonist shows an effect on the blood pressure decrease. In the double and triple combination, 30 mg/kg sacubitril and 10 mg/kg valsartan is used.

Description of the Figures

[0217] FIG. 1: B-x) mean arterial blood pressure and heart rate as % deviation versus time [h] after substance administration; compound of the formula (6), 0.3 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10 mg/kg valsartan p.o., triple combination: compound of the formula (6), 0.3 mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

[0218] FIG. 2: B-x) mean arterial blood pressure and heart rate as % deviation versus time [h] after substance administration; compound of the formula (6), 0.1 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10 mg/kg valsartan p.o., triple combination: compound of the formula (6), 0.1 mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

[0219] FIG. 3: B-x) mean arterial blood pressure and heart rate as % deviation versus time [h] after substance administration; compound of the formula (29), 10 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10 mg/kg valsartan p.o., triple combination: compound of the formula (29), 10 mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

[0220] FIG. 4: B-x) mean arterial blood pressure and heart rate as % deviation versus time [h] after substance administration; compound of the formula (29), 3 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10 mg/kg valsartan p.o., triple combination: compound of the formula (29), 3 mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.

[0221] FIG. 5: B-x) mean arterial blood pressure and heart rate as % deviation versus time [h] after substance administration; compound of the formula (29), 1 mg/kg p.o.; double combination: 30 mg/kg sacubitril and 10 mg/kg valsartan p.o., triple combination: compound of the formula (29), 1 mg/kg, 30 mg/kg sacubitril and 10 mg/kg valsartan p.o.