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 method for the treatment of cardiovascular disorders, renal disorders, lung disorders, and fibrotic disorders in humans and animals comprising administering to a patient in need thereof a therapeutically effective amount of (1) an sGC modulator selected from the group consisting of sGC stimulators and sGC activators; (2) sacubitril; and (3) valsartan and also in each case the salts, solvates and solvates of the salts thereof.

2. The method of claim 1, wherein sacubitril and valsartan are administered as 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.

3. The method of claim 1, wherein the sGC modulator is an sGC stimulator selected from the group consisting of compounds of the formulae ##STR00015## ##STR00016## and salts, solvates and solvates of the salts of the compounds of formulae (3), (4), (6), (7) and (28), or is an sGC activator selected from the group consisting of a compound of the formula ##STR00017## and salts, solvates, and solvates of the salts thereof.

4. The method of claim 3, wherein sacubitril and valsartan are present as tri sodium [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.

5. The method of claim 1, wherein the sGC modulator is an sGC stimulator of the formula (6) or is an sGC activator of the formula (29) or a salt, solvate or solvate of a salt of the compound of formula (6) or of formula (29), and further wherein sacubitril and valsartan are present as 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.

6. The method of claim 5, wherein the sGC modulator is an sGC activator of the formula (29) or a salt, solvate, or solvate of a salt thereof.

7. The method of claim 1, wherein the sGC modulator is an sGC stimulator of the formula (6) or is an sGC activator of the formula (29) or a salt, solvate or solvate of a salt of the compound of formula (6) or of formula (29).

8. The method of claim 1, wherein the disorder being treated is a cardiovascular disorder selected from the group consisting of acute and chronic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diastolic heart failure, systolic heart failure, and acute phases of worsening of existing chronic heart failure, hypertension, and resistant hypertension; a renal disorder that is chronic kidney failure; or is diabetic retinopathy.

9. The method of claim 3, wherein the disorder being treated is a cardiovascular disorder selected from the group consisting of acute and chronic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diastolic heart failure, systolic heart failure, and acute phases of worsening of existing chronic heart failure, hypertension, and resistant hypertension; a renal disorder that is chronic kidney failure; or is diabetic retinopathy.

10. The method of claim 5, wherein the disorder being treated is a cardiovascular disorder selected from the group consisting of acute and chronic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diastolic heart failure, systolic heart failure, and acute phases of worsening of existing chronic heart failure, hypertension, and resistant hypertension; a renal disorder that is chronic kidney failure; or is diabetic retinopathy.

11. The method of claim 6, wherein the disorder being treated is a cardiovascular disorder selected from the group consisting of acute and chronic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diastolic heart failure, systolic heart failure, and acute phases of worsening of existing chronic heart failure, hypertension, and resistant hypertension; a renal disorder that is chronic kidney failure; or is diabetic retinopathy.

12. The method of claim 7, wherein the disorder being treated is a cardiovascular disorder selected from the group consisting of acute and chronic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diastolic heart failure, systolic heart failure, and acute phases of worsening of existing chronic heart failure, hypertension, and resistant hypertension; a renal disorder that is chronic kidney failure; or is diabetic retinopathy.

13. The method of claim 12, wherein the sGC modulator is an sGC stimulator of the formula (6) or a salt, solvate or solvate of a salt thereof and the disorder being treated is a cardiovascular disorder selected from the group consisting of acute and chronic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diastolic heart failure, systolic heart failure, and acute phases of worsening of existing chronic heart failure, hypertension, and resistant hypertension or the sGC modulator is an sGC activator of the formula (29) or a salt, solvate or solvate of a salt thereof and the disorder being treated is a renal disorder that is chronic kidney failure, or is diabetic retinopathy.

14. The method of claim 13, wherein the sGC modulator is an sGC activator of the formula (29) or a salt, solvate or solvate of a salt of the compound of formula (29), and the disorder being treated is a renal disorder that is chronic kidney failure, or is diabetic retinopathy.

15. The method of claim 5, wherein the sGC modulator is an sGC stimulator of the formula (6) and is administered at a dosage of 1.25-20 mg od and 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 is administered at a dosage of 100-200 mg or the sGC modulator is an sGC activator of the formula (29) or a salt, solvate or solvate of a salt of the compound of formula (29) and 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 is administered at a dosage of 100-200 mg bid.

16. The method of claim 15, wherein the disorder being treated is a cardiovascular disorder selected from the group consisting of acute and chronic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diastolic heart failure, systolic heart failure, and acute phases of worsening of existing chronic heart failure, hypertension, and resistant hypertension; a renal disorder that is chronic kidney failure; or is diabetic retinopathy.

Description

DESCRIPTION OF THE FIGURES

(1) 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.

(2) 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.

(3) 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.

(4) 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.

(5) 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.