1,2,3,4-tetrahydroisoquinolines derivatives

Abstract

The invention relates to novel 1,2,3,4-tetrahydroisoquinoline derivatives and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as neurohormonal antagonists.

1 . A pharmaceutical composition comprising a compound of general formula 1,  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents —CH 2 —, —CH 2 CH 2 —, —C(CH 3 ) 2 —;  
 Y represents oxygen, NH;  
 n represents the numbers 1 or 2;  
 Z represents quinolin-4-yl which may be mono-substituted with lower alkyl in the positions 2, 6, or 8, or di-substituted with lower alkyl in the positions 2,6 or 2,8; [1,8]naphthyridin-4-yl which may be substituted in position 7 with lower alkyl; pyridin-4-yl which may be substituted in position 2 with R 7 R 8 N— and additionally in position 6 with hydrogen or lower alkyl;  
 R 1  represents naphthalen-1-yl; naphthalen-2-yl; benzo[1,3]dioxol-5-yl; benzyl, or mono-, di-, or tri-substituted benzyl substituted in the phenyl ring independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano; phenyl, or mono-, di- or tri-substituted phenyl, substituted independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano;  
 R 2  represents hydrogen, lower alkyl, aryl or forms with R 1  a styryl group of E or Z geometry, whereby the phenyl ring in the styryl group may be mono-, di- or tri-substituted phenyl, substituted independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano;  
 R 3 , R 4 , R 5  and R 6  independently represent hydrogen, cyano, hydroxy, lower alkyloxy, aralkyloxy, lower alkenyloxy, and R 5  additionally represents R 7 R 8 NCO;  
 R 4  and R 5  together may form with the phenyl ring a five- or a six-membered ring containing one or two oxygen atoms;  
 R7 and R8 independently represent hydrogen, lower alkyl, aryl, aralkyl, or together with the N form a pyrrolidine, piperidine, or morpholine ring;  
 and optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates; and their pharmaceutically acceptable salts, solvent complexes, and morphological forms, and  
 a pharmaceutically acceptable carrier and optionally an adjuvant, said pharmaceutical composition further comprising an additional pharmaceutically active compound.  
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the additional pharmaceutically active compound is selected from the group consisting of an ACE inhibitor, an angiotensin II receptor antagonist, an endothelin receptor antagonist, a vasopressin antagonist, a beta-adrenergic antagonist, an alpha-adrenergic antagonist, a TNF-alpha antagonist, and a modulator for peroxisome proliferators activator receptor.  
     
     
         3 . A method for preventing or treating a disorder or disease which is associated with a dysregulation of urotensin II or urotensin II receptors comprising administering a prophylactically or therapeutically effective amount of a compound of general formula 1,  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents —CH 2 —, —CH 2 CH 2 —, —C(CH 3 ) 2 —;  
 Y represents oxygen, NH;  
 n represents the numbers 1 or 2;  
 Z represents quinolin-4-yl which may be mono-substituted with lower alkyl in the positions 2, 6, or 8, or di-substituted with lower alkyl in the positions 2,6 or 2,8; [1,8]naphthyridin-4-yl which may be substituted in position 7 with lower alkyl; pyridin-4-yl which may be substituted in position 2 with R 7 R 8 N— and additionally in position 6 with hydrogen or lower alkyl;  
 R 1  represents naphthalen-1-yl; naphthalen-2-yl; benzo[1,3]dioxol-5-yl; benzyl, or mono-, di-, or tri-substituted benzyl substituted in the phenyl ring independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano; phenyl, or mono-, di- or tri-substituted phenyl, substituted independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano;  
 R 2  represents hydrogen, lower alkyl, aryl or forms with R 1  a styryl group of E or Z geometry, whereby the phenyl ring in the styryl group may be mono-, di- or tri-substituted phenyl, substituted independently with lower alkyl, lower alkyloxy, trifluoromethyl, halogen, cyano;  
 R 3 , R 4 , R 5  and R 6  independently represent hydrogen, cyano, hydroxy, lower alkyloxy, aralkyloxy, lower alkenyloxy, and R 5  additionally represents R 7 R 8 NCO;  
 R 4  and R 5  together may form with the phenyl ring a five- or a six-membered ring containing one or two oxygen atoms;  
 R7 and R8 independently represent hydrogen, lower alkyl, aryl, aralkyl, or together with the N form a pyrrolidine, piperidine, or morpholine ring;  
 and optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates; and their pharmaceutically acceptable salts, solvent complexes, and morphological forms.  
 
     
     
         4 . The method of  claim 3 , wherein wherein a disorder or disease is associated with restenosis after balloon or stent angioplasty.  
     
     
         5 . The method of  claim 3 , wherein the disorder or disease is associated with vascular or myocardial dysfunction.  
     
     
         6 . The method of  claim 5 , wherein the disorder or disease is hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, asthma, chronic obstructive pulmonary disease, high-altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or pulmonary fibrosis.  
     
     
         7 . The method of  claim 3 , wherein the disorder or disease is cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, addiction, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, seizures, stress, or depression.  
     
     
         8 . A method for preventing or treating a disorder or disease which is associated with a dysregulation of urotensin II or urotensin II receptors comprising administering a prophylactically or therapeutically effective amount of the pharmaceutical composition of  claim 1 .  
     
     
         9 . The method of  claim 8 , wherein a disorder or disease is associated with restenosis after balloon or stent angioplasty.  
     
     
         10 . The method of  claim 8 , wherein the disorder or disease is associated with vascular or myocardial dysfunction.  
     
     
         11 . The method of  claim 10 , wherein the disorder or disease is hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, asthma, chronic obstructive pulmonary disease, high-altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or pulmonary fibrosis.  
     
     
         12 . The method of  claim 8 , wherein the disorder or disease is cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, addiction, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, seizures, stress, or depression.  
     
     
         13 . A method for preventing or treating a disorder or disease which is associated with a dysregulation of urotensin II or urotensin II receptors comprising administering a prophylactically or therapeutically effective amount of the pharmaceutical composition of  claim 2 .  
     
     
         14 . The method of  claim 13 , wherein a disorder or disease is associated with restenosis after balloon or stent angioplasty.  
     
     
         15 . The method of  claim 13 , wherein the disorder or disease is associated with vascular or myocardial dysfunction.  
     
     
         16 . The method of  claim 15 , wherein the disorder or disease is hypertension, atherosclerosis, angina or myocardial ischemia, congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, asthma, chronic obstructive pulmonary disease, high-altitude pulmonary edema, Raynaud's syndrome, portal hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or pulmonary fibrosis.  
     
     
         17 . The method of  claim 13 , wherein the disorder or disease is cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, addiction, schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior, seizures, stress, or depression.