Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists

Abstract

The present invention relates to urotensin II receptor antagonists, pharmaceutical compositions containing them and their use.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
       wherein Ar is selected from the group consisting of aryl, heteroaryl, benzoheteroaryl, pyridone, pyridazinone, and pyrimidone;  
       R 1  and R 2  are independently H, alkyl, cycloalkyl, bicyclic alkyl, adamantyl, aralkyl, aryl, R 7 CO, or R 8 OCO or R 1  and R 2  along with N can form a cyclic or bicyclic heterocyclic ring system or R 1  and L 1  or R 1  and one carbon of (CH 2 ) n  can form a 5, 6, or 7 membered ring;  
       R 3  is H, alkyl or aralkyl;  
       X and Y are independently C or N;  
       R 4 , R 5 , and R 6  are independently selected from the group consisting of H, alkyl, aralkyl, aryl, heteroaryl, benzoheteroaryl, hydroxyl, halo, haloalkyl, alkoxy, aminocarbonyl and aminosulfonyl or R 5  and R 6  together can form a 5-6 membered aromatic ring or a 5-7 membered aliphatic ring;  
       L 1  is selected from the group consisting of a single bond, O, NR 9 , CO, COO, OCO, SO 2 , NR 10 CO, NR 11 SO 2 , NR 12 CONR 13 , NR 14 SO 2 NR 15 , CH 2 CHOHCH 2 , arene heteroarene, pyridine, pyrimidone and pyridazinone;  
       L 2  and L 3  are independently selected from the group consisting of a single bond, CH 2 , NR 16 , CO and SO 2 ;  
       L 4  is (Z) n  where each Z is independently CH 2 , CR 17 R 18 , CO, NR 19 , CONR 20  or NR 21 CO, any two adjacent Zs may be replaced with a double or triple bond or R 17 , R 18  or two R 17 s can form a 5-8 membered aliphatic ring or R 17  and Ar can form a fused 5-8 membered aliphatic ring; n is an integer from 0 to 6; and  
       R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20  and R 21  are independently selected from the group consisting of H, alkyl, aryl and aralkyl, R 16  is also alkylsulfonyl or alkylcarbonyl or R 10  and CO and Ar can form pyridone, pyridazinone, and pyrimidone, and the pharmaceutically acceptable salts thereof.  
     
   
   
       2 . A compound of  claim 1  of the formula  
     
       
         
         
             
             
         
       
       wherein each R 15  is independently H, alkyl, aralkyl, haloalkyl, aryl, heteroaryl, benzoheteroaryl, alkoxy, aminocarbonyl or aminosulfonyl and two of R 15  can form a 5-6 membered aromatic ring or a 5-7 membered aliphatic ring;  
       m is 0-3; and  
       R 1 , R 2 , R 4 , R 5 , R 6 , n, X and Y are as defined in  claim 1 , and the pharmaceutically acceptable salts thereof.  
     
   
   
       3 . A compound of  claim 1  of the formula:  
     
       
         
         
             
             
         
       
       wherein each R 15  is independently H, alkyl, aralkyl, haloalkyl, aryl, heteroaryl, benzoheteroaryl, alkoxy, aminocarbonyl or aminosulfonyl and two of R 15  can form a 5-6 membered aromatic ring or a 5-7 member aliphatic ring;  
       M is 0-3; and  
       R 1 , R 2 , R 4 , R 5 , R 6 , n and X are as defined in  claim 1 , and the pharmaceutically acceptable salts thereof.  
     
   
   
       4 . A compound of  claim 1  selected from the group consisting of: 
 {4-Chloro-3-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;    {3-[2-(4-Benzyl-piperidin-1-yl)ethoxy]phenyl)-(2-methylquinolin-4-yl)amine;    {4-Chloro-3-[2-(4-phenylpiperidin-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;    {3-[2-(4-Benzylpiperazin-1-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;    {3-[2-(Benzylmethylamino)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;    {3-[2-(4-Benzylpiperidin-1-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine;    {3-[3-(4-Benzylpiperidin-1-yl)propoxy]phenyl}-(2-methylquinolin-4-yl)amine;    {3-[2-(1-Methyl-1-phenylethylamino)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;    [3-(2-Benzylaminoethoxy)phenyl]-(2-methylquinolin-4-yl)amine;    1-(1-{2-[3-(2-Methylquinolin-4-ylamino)phenoxy]ethyl}-4-phenylpiperidin-4-yl)ethanone;    [3-(3-Benzylaminopropoxy)phenyl]-(2-methylquinolin-4-yl)amine;    {3-[2-(2-Benzylimidazol-1-yl)ethoxy]phenyl)-(2-methylquinolin-4-yl)amine;    1-{2-[3-(2-Methylquinolin-4-ylamino)phenoxy]ethyl}piperidin-4-yl)diphenylmethanol;    4-Benzyl-1-{2-[3-(2-tert-butylquinolin-4-ylamino)phenoxy]ethyl)piperidin-4-ol;    4-Benzyl-1-{2-[3-(2-methylquinolin-4-ylamino)-5-trifluoromethylphenoxy]ethyl}piperidin-4-ol;    {3-[2-(4-Benzylpiperidin-1-yl)ethoxy]phenyl}-(2,6-dimethylpyrimidin-4-yl)amine;    {3-[2-(5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy]phenyl}-(2-methylquinolin-4-yl)amine;    {3-[2-(4-Benzylpiperazin-1-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine;    (2-Methylquinolin-4-yl)-{3-[2-(4-phenylpiperidin-1-yl)ethoxy]-5-trifluoromethyl phenyl}amine;    {3-[3-(1-Methyl-1-phenylethylamino)propoxy]phenyl}-(2-methylquinolin-4-yl)amine.    {3-[2-(5-Benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy]-5-trifluoromethylphenyl}-(2-methylquinolin-4-yl)amine;    N-(2-{1-[2-(3-Fluorophenyl)ethyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}ethyl)-3-(2-methylquinolin-4-ylamino)benzamide;    N-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide;    N-[2-(1,3-Dihydroisoindol-2-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide;    N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2-methyl-5-(2-methylquinolin-4-ylamino)benzamide;    N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2-hydroxy-5-(2-methylquinolin-4-ylamino)benzamide;    N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-3-(2-trifluoromethylquinolin-4-ylamino)benzamide;    N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2,4,6-trimethyl-3-(2-methylquinolin-4-ylamino)benzamide;    2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-4-(2-methylquinolin-4-ylamino)-2,3-dihydroisoindol-1-one;    3-(2-Methylquinolin-4-ylamino)-N-[2-(1,3,4,5-tetrahydrobenzo[c]azepin-2-yl)ethyl]benzamide;    N-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-2,5-bis(2-methylquinolin-4-ylamino)benzamide;    3-(2-Methylquinolin-4-ylamino)-N-[2-(octahydro-cis-isoquinolin-2-yl)ethyl]benzamide;    N-(2-Azepan-1-ylethyl)-3-(2-methylquinolin-4-ylamino)benzamide;    N-(2-Benzylaminoethyl)-3-(2-methylquinolin-4-ylamino)benzamide;    4-({2-[3-(2-Methylquinolin-4-ylamino)-benzoylamino]ethylamino}methyl)benzoic acid;    N-[2-(2,2-Dimethylpropylamino)ethyl]-3-(2-methylquinolin-4-ylamino)benzamide;    N-[2-(4-Benzylpiperazin-1-yl)ethyl]-3-(2-methylquinolin-4-ylamino)benzenesulfonamide;    (3-[5-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)isoxazol-3-yl]phenyl}-(2-methylquinolin-4-yl)amine;    {3-[3-(3,4-Dihydro-1H-isoquinolin-2-yl)propyl]-4-methylphenyl}-(2-methylquinolin-4yl)amine;    N 1 -[2-(3,4-Dihydro-1H-isoquinolin-2-yl)ethyl]-N 7 -(2-methylquinolin-4-yl)-1,2,3,4-tetrahydronaphthalene-1,7-diamine;    [3′-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-yl]-(2-methylquinolin-4-yl)amine;    {3-[2-(4-Benzylpiperidin-1-yl)ethanesulfonyl]phenyl}-(2-methylquinolin-4-yl)amine;    N-[2-(4-Benzylpiperidin-1-yl)ethyl]-N′-(2-methylquinolin-4-yl)pyrimidine-4,6-diamine; and    3-(4-Benzylpiperidin-1-yl)-1-[3-(2-methylquinolin-4-ylamino)phenyl]propan-1-one oxime.    
   
   
       5 . A compound of the formula  
     
       
         
         
             
             
         
       
       wherein A is a negatively ionizable group under physiological conditions;  
       X 1 —Y 1 -Z 1  is C, C(R) q C or C(R) q N;  
       L 4  is L 5 Ar′L 6  or X 2 Y 2 Z 2 ;  
       Ar′ and Ar″ are each independently aryl or heteroaryl;  
       L 5  and L 6  are each independently a bond, N, O, S, or X 2 Y 2 Z 2  where  
       X 2  and Z 2  are each independently C, N or O and  
       Y 2  is CO, SO, or SO 2 ;  
       R is CR 17 R 18 ;  
       m, n, p and q are independently an integer from (0 to 6) provided that m and n cannot both be 0; and  
       R 16 , R 17  and R 18  are each independently H, alkyl, arakyl, aryl, heteroaryl, hydroxyl, alkoxy, aryloxy, amino, aminocarbonyl, aminosulfonyl provided that when A is CO 2 H and X 1 —Y 1 -2 is C, then X 2 Y 2 2 is not NCON; and the pharmaceutically acceptable salts thereof.  
     
   
   
       6 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier or excipient.  
   
   
       7 . A pharmaceutical composition comprising a compound of  claim 5  and a pharmaceutically acceptable carrier or excipient.  
   
   
       8 . A method of treating conditions associated with urotensin-II imbalance by antagonizing the urotensin-II receptor which comprises administering to a patient in need thereof, a compound of  claim 5 .  
   
   
       9 . A method of treating conditions associated with urotensin-II imbalance by antagonizing the urotensin-II receptor which comprises administering to a patient in need thereof, a compound of  claim 1 .  
   
   
       10 . A method of treating conditions associated with urotensin-II imbalance by antagonizing the urotensin-II receptor which comprises administering to a patient in need thereof, a compound of  claim 5 .  
   
   
       11 . A method according to  claim 9  wherein the condition is selected from the group consisting of congestive heart failure, stroke, ischemic heart disease, angina, myocardial ischemia, cardiac arrhythmia, essential and pulmonary hypertension, renal disease, acute and chronic renal failure, end stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease, ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis, pulmonary fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders, Alzheimers disease, impulsivity, anxiety, stress, depression, Parkinsons, movement disorders, sleep-wake cycle, inventive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.  
   
   
       12 . A method according to  claim 10  wherein the condition is selected from the group consisting of congestive heart failure, stroke, ischemic heart disease, angina, myocardial ischemia, cardiac arrhythmia, essential and pulmonary hypertension, renal disease, acute and chronic renal failure, end stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease, ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis, pulmonary fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders, Alzheimers disease, impulsivity, anxiety, stress, depression, Parkinsons, movement disorders, sleep-wake cycle, inventive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.