Bicyclically substituted uracils and the use thereof

Abstract

The present application relates to novel bicyclically substituted uracil derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases.

1 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         R 1  is hydrogen or (C 1 -C 4 )-alkyl, 
         R 2  is a group of the formula 
       
       
         
           
           
               
               
           
         
         where 
         * is the attachment site to the uracil nitrogen atom, 
         A is —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 -## or oxygen, 
         in which 
         ## is the attachment site to the phenyl ring, 
         m is a number 0, 1 or 2, 
         R 4  is halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 )-alkoxy, 
         R 5A  is hydrogen or deuterium, 
         R 5B  is hydrogen, deuterium or (C 1 -C 4 )-alkyl, 
         R 6  is hydrogen or fluorine, 
         R 7  is hydrogen or fluorine, 
         R 8  is halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl or nitro, 
         R 9  is hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, nitro or (C 1 -C 4 )-alkylthio, 
         R 3  is a group of the formula 
       
       
         
           
           
               
               
           
         
         where 
         # is the attachment site to the uracil nitrogen atom, 
         the ring Q is 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, 
         in which 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl may be substituted by 1 to 4 substituents independently selected from the group of halogen, difluoromethyl, trifluoromethyl, trideuteromethyl, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 4 )alkylcarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl and (C 1 -C 4 )-alkylsulphonyl, 
         in which (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl may in turn be substituted by 1 to 3 substituents independently selected from the group of halogen, cyano, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy and 4- to 7-membered heterocyclyl,
 and 
 
         in which two (C 1 -C 6 )-alkyl radicals bonded to a carbon atom of 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, together with the carbon atom to which they are bonded, may form a 3- to 6-membered carbocycle, 
         R 24  is halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy, 
         n is a number 0, 1, 2 or 3, 
         or a salt, a solvate, or a solvate of the salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein
 R 1  is hydrogen, methyl or ethyl,   R 2  is a group of the formula   
       
         
           
           
               
               
           
         
         where 
         * is the attachment site to the uracil nitrogen atom, 
         A is —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 -## or oxygen, 
         in which 
         ## is the attachment site to the phenyl ring, 
         R 4A  is hydrogen, fluorine, chlorine, trifluoromethyl or methyl, 
         R 4B  is hydrogen, fluorine, chlorine, trifluoromethyl or methyl, 
         with the proviso that at least one of the R 4A  and R 4B  radicals is not hydrogen, 
         R 5A  is hydrogen, 
         R 5B  is hydrogen, 
         R 6  is hydrogen, 
         R 7  is hydrogen, 
         R 8  is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl, 
         R 9  is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl, 
         R 3  is a group of the formula 
       
       
         
           
           
               
               
           
         
         where 
         # is the attachment site to the uracil nitrogen atom, 
         E 1  is CR 11  or N, 
         in which 
         R 11  is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl or aminocarbonyl, 
         E 2  is CR 12  or N, 
         in which 
         R 12  is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl, 
         E 3  is NR 14  or S, 
         in which 
         R 14  is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl, 
         G 1  is C═O or SO 2 , 
         G 2  is CR 16A R 16B , NR 17 , O or S, 
         in which 
         R 16A  is hydrogen, fluorine, (C 1 -C 4 )-alkyl or hydroxyl, 
         R 16B  is hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or trifluoromethyl, 
         or 
         R 16A  and R 16B  together with the carbon atom to which they are bonded form a 3- to 6-membered carbocycle, 
         R 17  is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkoxycarbonyl, 
         in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, cyano, (C 3 -C 7 )-cycloalkyl, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, 
         G 3  is CR 18A R 18B , NR 19 , O or S, 
         in which 
         R 18A  is hydrogen, fluorine, (C 1 -C 4 )-alkyl or hydroxyl, 
         R 18B  is hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or trifluoromethyl, 
         or 
         R 18A  and R 18B  together with the carbon atom to which they are bonded form a 3- to 6-membered carbocycle, 
         R 19  is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkoxycarbonyl, 
         in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, cyano, (C 3 -C 7 )-cycloalkyl, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, 
         G 4  is CH 2 , C═O or SO 2 , 
         K 1  is CH 2  or O, 
         K 2  is CH 2  or O, 
         with the proviso that only one of the K 1  and K 2  groups is O, 
         D 1 , D 2 , D 3  and D 4  are each independently CR 23  or N, 
         in which 
         R 23  is hydrogen, halogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl, 
         with the proviso that not more than 2 of the D 1 , D 2 , D 3  and D 4  groups are N, 
         R 24  is fluorine or methyl, 
         n is a number 0 or 1, 
         R 10  is (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl, 
         in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, 
         R 13  is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl, 
         R 15  is hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl, 
         in which (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, 
         R 20  is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkylcarbonyl, 
         in which (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, 
         R 21  is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkylsulphonyl, 
         R 22A  is hydrogen or (C 1 -C 4 )-alkyl, 
         R 22B  is hydrogen or (C 1 -C 4 )-alkyl, 
         or 
         R 22A  and R 22B  together with the carbon atom to which they are bonded form a carbonyl group, or a salt, a solvate, or a solvate of the salt thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein
 R 1  is hydrogen,   R 2  is a group of the formula   
       
         
           
           
               
               
           
         
         where 
         * is the attachment site to the uracil nitrogen atom, 
         A is —CH 2 —, 
         R 4A  is chlorine or trifluoromethyl, 
         R 4B  is hydrogen, 
         R 3  is a group of the formula 
       
       
         
           
           
               
               
           
         
         where 
         # is the attachment site to the uracil nitrogen atom, 
         E 1  is CR 11    
         in which 
         R 11  is hydrogen, 
         E 2  is N, 
         G 1  is C═O, 
         G 2  is CR 16A R 16B , NR 17 , O or S, 
         in which 
         R 16A  is hydrogen, fluorine, methyl or hydroxyl, 
         R 16B  is hydrogen, fluorine, methyl or trifluoromethyl, 
         or 
         R 16A  and R 16B  together with the carbon atom to which they are bonded form a cyclopropyl ring, 
         R 17  is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 5 )-cycloalkyl, 
         in which (C 1 -C 4 )-alkyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, cyano, cyclopropyl, cyclobutyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, 
         R 24  is hydrogen or fluorine, 
         R 10  is (C 1 -C 4 )-alkyl, 
         R 15  is hydrogen, methyl or ethyl, 
         in which methyl and ethyl may be substituted by 1 substituent selected from the group of fluorine, trifluoromethyl and cyclopropyl, 
         or a solvate of the salt thereof. 
       
     
     
         4 . The compound of  claim 1 , wherein
 R 1  is hydrogen,   R 2  is a group of the formula   
       
         
           
           
               
               
           
         
         where 
         * is the attachment site to the uracil nitrogen atom, 
         R 5A  is hydrogen, 
         R 5B  is hydrogen, 
         R 6  is hydrogen, 
         R 7  is hydrogen, 
         R 8  is fluorine, chlorine or trifluoromethyl, 
         R 9  is fluorine, chlorine, trifluoromethyl or methyl, 
         R 3  is a group of the formula 
       
       
         
           
           
               
               
           
         
         where 
         # is the attachment site to the uracil nitrogen atom, 
         E 1  is CR 11    
         in which 
         R 11  is hydrogen, 
         E 2  is N, 
         G 1  is C═O, 
         G 2  is CR 16A R 16 B, NR 17 , O or S, 
         in which 
         R 16A  is hydrogen, fluorine, methyl or hydroxyl, 
         R 16B  is hydrogen, fluorine, methyl or trifluoromethyl, 
         or 
         R 16A  and R 16B  together with the carbon atom to which they are bonded form a cyclopropyl ring, 
         R 17  is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 5 )-cycloalkyl, 
         in which (C 1 -C 4 )-alkyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, cyano, cyclopropyl, cyclobutyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, 
         R 24  is hydrogen or fluorine, 
         R 10  is (C 1 -C 4 )-alkyl, 
         R 15  is hydrogen, methyl or ethyl, 
         in which methyl and ethyl may be substituted by 1 substituent selected from the group of fluorine, trifluoromethyl and cyclopropyl, 
         or a salt, a solvate, or a solvate of the salt thereof. 
       
     
     
         5 . A process for preparing a compound of formula (I) according to  claim 1 , wherein
 [A] a compound of the formula (II)   
       
         
           
           
               
               
           
         
         in which 
         R 1A  is (C 1 -C 4 )-alkyl, 
         T 1  is (C 1 -C 4 )-alkyl, 
         T 2  is (C 1 -C 4 )-alkyl, 
         is reacted in an inert solvent, optionally in the presence of a suitable base, with a compound of the formula (III)
   H 2 N—R 3   (III)
 
 
         in which R 3  is as defined in  claim 1 , 
         to give a compound of the formula (IV) 
       
       
         
           
           
               
               
           
         
         in which R 1A  and R 3  are each as defined above, 
         this is then reacted in an inert solvent, in the presence of a suitable base, with a compound of the formula (V)
   X 1 —R 2   (V)
 
 
         in which R 2  is as defined in  claim 1 , and 
         X 1  is hydroxyl or a suitable leaving group, especially chlorine, bromine or iodine 
         to give a compound of the formula (I-1) 
       
       
         
           
           
               
               
           
         
         in which R 1A , R 2  and R 3  are each as defined above, 
         or 
         [B] a compound of the formula (VI) 
       
       
         
           
           
               
               
           
         
         in which R 1A  and T 1  are each as defined above, 
         and 
         T 3  is (C 1 -C 4 )-alkyl 
         is converted in an inert solvent or else without solvent with a compound of the formula (III) to a compound of the formula (VII) 
       
       
         
           
           
               
               
           
         
         in which R 1A , R 3  and T 3  are each as defined above, 
         this is subsequently reacted in an inert solvent with chlorosulphonyl isocyanate to give a compound of the formula (IV) and this is subsequently converted analogously to process [A] to a compound of the formula (I-1), 
         or 
         [C] a compound of the formula (VIII) 
       
       
         
           
           
               
               
           
         
         in which R 2  is as defined in  claim 1 , 
         is reacted in an inert solvent with a compound of the formula (IX) 
       
       
         
           
           
               
               
           
         
         in which R 1A  and T 1  are each as defined above and 
         T 5  is (C 1 -C 4 )-alkyl 
         and cyclized in the presence of a suitable base to give a compound of the formula (X) 
       
       
         
           
           
               
               
           
         
         in which R 1A  and R 2  are each as defined above, 
         and this is then reacted in an inert solvent, in the presence of a suitable catalyst and a suitable base, with a compound of the formula (XI) 
       
       
         
           
           
               
               
           
         
         in which R 3  is as defined above 
         and 
         T 6  is hydrogen, (C 1 -C 4 )-alkyl, or the two T 6  radicals together form a —C(CH 3 ) 2 —C(CH 3 ) 2 — bridge to give a compound of the formula (I-1), 
         or 
         [D] a compound of the formula (I-1) is hydrolysed in an inert solvent in the presence of a suitable acid or base to give a compound of the formula (I-2) 
       
       
         
           
           
               
               
           
         
         in which R 2  and R 3  are each as defined in  claim 1 , and 
         R 1B  is hydrogen, 
         any protecting groups are detached and/or the compounds of the formulae (I-1) and (I-2) are, where appropriate, converted with the appropriate (i) solvents and/or (ii) bases or acids to a solvate, a salt, or a solvate of the salt thereof. 
       
     
     
         6 . A method for treatment and/or prophylaxis of a disease in a human or animal in need thereof, comprising administering an effective amount of a compound according to  claim 1  to the human or animal. 
     
     
         7 . A method for treatment and/or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, kidney failure, nephropathy, fibrotic disorders of the internal organs and dermatological fibroses in a human or animal in need thereof, comprising administering an effective amount of a compound according to  claim 1  to the human or animal. 
     
     
         8 . A pharmaceutical composition comprising a compound according to  claim 1  in combination with one or more inert nontoxic pharmaceutically suitable excipients. 
     
     
         9 . A pharmaceutical combination comprising a compound according to  claim 1  in combination with one or more further active ingredients selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, diuretics, kinase inhibitors, matrix metalloprotease inhibitors, stimulators and activators of soluble guanylate cyclase and phosphodiesterase inhibitors. 
     
     
         10 . A method for treatment and/or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, kidney failure, nephropathy, fibrotic disorders of the internal organs and dermatological fibroses in a human or animal in need thereof, comprising administering an effective amount of a pharmaceutical composition according to  claim 8  to the human or animal. 
     
     
         11 . A method for treatment and/or prophylaxis of heart failure, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, kidney failure, nephropathy, fibrotic disorders of the internal organs and dermatological fibroses in a human or animal in need thereof, comprising administering an effective amount of a pharmaceutical combination according to  claim 9  to the human or animal. 
     
     
         12 . The method of  claim 6 , wherein the disease is selected from the group consisting of a cardiovascular disorder, an inflammatory disorder, allergic disorder and a fibrotic disorder. 
     
     
         13 . The method of  claim 6 , wherein the disease is selected from the group consisting of acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischaemia, myocardial infarction, shock, atherosclerosis, cardiac hypertrophy, cardiac fibrosis, atrial and ventricular arrhythmias, transitory and ischaemic attacks, stroke, pre-eclampsia, inflammatory cardiovascular disorders, peripheral and cardiac vascular disorders, peripheral perfusion disorders, arterial pulmonary hypertension, spasms of the coronary arteries and peripheral arteries, thromboses, thromboembolic disorders, oedema development, for example pulmonary oedema, cerebral oedema, renal oedema or heart failure-related oedema, and restenoses such as after thrombolysis treatments, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplants and bypass operations, and micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thromboses, microalbuminuria, myocardial insufficiency, endothelial dysfunction, elevated levels of fibrinogen and of low-density LDL elevated concentrations of plasminogen activator/inhibitor 1 (PAI-1), acutely decompensated heart failure, right heart failure, left heart failure, global failure, ischaemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, and diastolic and systolic heart failure, polycystic kidney disease (PCKD) and of syndrome of inappropriate ADH secretion (SIADH), renal disorders, especially of acute and chronic renal insufficiency, and of acute and chronic kidney failure, acute renal insufficiency encompasses acute manifestations of kidney disease, of kidney failure and/or renal insufficiency with and without the need for dialysis, and also underlying or related renal disorders such as renal hypoperfusion, intradialytic hypotension, volume deficiency (e.g. dehydration, blood loss), shock, acute glomerulonephritis, haemolytic-uraemic syndrome (HUS), vascular catastrophe (arterial or venous thrombosis or embolism), cholesterol embolism, acute Bence-Jones kidney in the event of plasmacytoma, acute supravesicular or subvesicular efflux obstructions, immunological renal disorders such as kidney transplant rejection, immune complex-induced renal disorders, tubular dilatation, hyperphosphataemia and/or acute renal disorders characterized by the need for dialysis, including in the case of partial resections of the kidney, dehydration through forced diuresis, uncontrolled blood pressure rise with malignant hypertension, urinary tract obstruction and infection and amyloidosis, and systemic disorders with glomerular factors, such as rheumatological-immunological systemic disorders, for example lupus erythematodes, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, and x-ray contrast agent- and medicament-induced acute interstitial renal disorders, chronic renal insufficiency encompasses chronic manifestations of kidney disease, of kidney failure and/or renal insufficiency with and without the need for dialysis, and also underlying or related renal disorders such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerular and tubular proteinuria, renal oedema, haematuria, primary, secondary and chronic glomerulonephritis, membranous and membranoproliferative glomerulonephritis, Alport syndrome, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, renal inflammation, immunological renal disorders such as kidney transplant rejection, immune complex-induced renal disorders, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, abnormally reduced creatinine and/or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, hyperphosphataemia and/or the need for dialysis, and in the event of renal cell carcinoma, after partial resections of the kidney, dehydration through forced diuresis, uncontrolled blood pressure rise with malignant hypertension, urinary tract obstruction and infection and amyloidosis, and systemic disorders with glomerular factors, such as rheumatological-immunological systemic disorders, for example lupus erythematodes, and also renal artery stenosis, renal artery thrombosis, renal vein thrombosis, analgesic nephropathy and renal tubular acidosis, x-ray contrast agent- and medicament-induced chronic interstitial renal disorders, metabolic syndrome and dyslipidaemia, sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hypercalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), of chronic obstructive pulmonary disease (COPD), of acute respiratory distress syndrome (ARDS), of acute lung injury (ALI), of alpha-1-antitrypsin deficiency (AATD), of pulmonary fibrosis, of pulmonary emphysema (for example pulmonary emphysema caused by cigarette smoke), of cystic fibrosis (CF), of acute coronary syndrome (ACS), heart muscle inflammation (myocarditis) and other autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), cardiogenic shock, aneurysms, sepsis (SIRS), multiple organ failure (MODS, MOF), inflammation disorders of the kidney, chronic intestinal disorders (IBD, Crohn's Disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders, asthmatic disorders of varying severity with intermittent or persistent characteristics (refractive asthma, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, medicament- or dust-induced asthma), of various forms of bronchitis (chronic bronchitis, infectious bronchitis, eosinophilic bronchitis), of Bronchiolitis obliterans, bronchiectasis, pneumonia, idiopathic interstitial pneumonia, farmer's lung and related disorders, coughs and colds (chronic inflammatory cough, iatrogenic cough), inflammation of the nasal mucosa (including medicament-related rhinitis, vasomotoric rhinitis and seasonal allergic rhinitis, for example hay fever) and of polyps, fibrotic disorders of the internal organs, for example of the lung, the heart, the kidney, the bone marrow and in particular the liver, and also of dermatological fibroses and fibrotic eye disorders. In the context of the present invention, the term “fibrotic disorders” encompasses particularly the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, cardiomyopathy, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy and proliferative vitroretinopathy, postoperative scarring, for example resulting from glaucoma operations, ageing and hornifying skin, dyslipidaemias (hypercholesterolaemia, hypertriglyceridaemia, elevated concentrations of the postprandial plasma triglycerides, hypoalphalipoproteinaemia, combined hyperlipidaemias), nephropathy and neuropathy), cancers (skin cancer, brain tumours, breast cancer, bone marrow tumours, leukaemias, liposarcomas, carcinoma of the gastrointestinal tract, of the liver, pancreas, lung, kidney, urinary tract, prostate and genital tract, and also malignant tumours in the lymphoproliferative system, for example Hodgkin's and non-Hodgkin's lymphoma), of disorders of the gastrointestinal tract and of the abdomen (glossitis, gingivitis, periodontitis, oesophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis, proctitis, pruritus ani, diarrhoea, coeliac disease, hepatitis, chronic hepatitis, hepatic fibrosis, cirrhosis of the liver, pancreatitis and cholecystitis), skin disorders (allergic skin disorders, psoriasis, acne, eczema, neurodermitis, various forms of dermatitis, and also keratitis, bullosis, vasculitis, cellulitis, panniculitis, lupus erythematodes, erythema, lymphoma, skin cancer, Sweet's syndrome, Weber-Christian syndrome, scarring, warts, chillblains), of disorders of the skeletal bone and of the joints, and also of the skeletal muscle (various forms of arthritis, various forms of arthropathies, scleroderma and of further disorders with an inflammatory or immunological component, for example paraneoplastic syndrome, in the event of rejection reactions after organ transplants and for wound healing and angiogenesis, especially in the case of chronic wounds, ophthalmologic disorders, for example glaucoma, normotensive glaucoma, high intraocular pressure and combinations thereof, of age-related macular degeneration (AMD), of dry or non-exudative AMD, moist or exudative or neovascular AMD, choroidal neovascularization (CNV), detached retina, diabetic retinopathy, atrophic lesions to the retinal pigment epithelium (RPE), hypertrophic lesions to the retinal pigment epithelium (RPE), diabetic macular oedema, retinal vein occlusion, choroidal retinal vein occlusion, macular oedema, macular oedema due to retinal vein occlusion, angiogenesis at the front of the eye, for example corneal angiogenesis, for example following keratitis, cornea transplant or keratoplasty, corneal angiogenesis due to hypoxia (extensive wearing of contact lenses), pterygium conjunctiva, subretinal oedema and intraretinal oedema, elevated and high intraocular pressure resulting from traumatic hyphaema, periorbital oedema, postoperative viscoelastic retention, intraocular inflammation, use of corticosteroids, pupillary block or idiopathic causes, and of elevated intraocular pressure following trabeculectomy and due to pre-operative conditions.