Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disordersB

Abstract

The present invention relates to multifunctional β-agonist compounds comprising a reactive oxygen species scavenger group and a nitric oxide donor, and to methods of treating chronic obstructive airway diseases, such as asthma and chronic bronchitis.

1 - 38 . (canceled) 
   
   
       39 . A method of treating or preventing a chronic obstructive airway disease in a mammal in need thereof comprising administering to said mammal an effective amount of a multifunctional β-agonist compound being ROS scavenger and NO donor of Formula 1: 
     
       
         
         
             
             
         
       
     
     or a salt thereof or a solvate thereof or an optical isomer thereof, wherein R 1  is selected from the group consisting of —OH, —ONO, —ONO 2 , —SNO, and —NONOate;
 R 2  is ROS scavenger group or a NO donor group connected to the —NH group via a linker made of C 5 -C 8  cyclic alkyl, or straight or branched C 1 -C 15  alkyl in which one carbon atom is optionally replaced by oxygen or nitrogen, wherein said ROS scavenger group is selected from a nitroxide free radical, alkenyl, sulfhydryl or dithiol moiety in oxidized or reduced form, and aryl, and wherein said NO donor group is selected from —ONO, —ONO 2 , —SNO, and —NONOate or R 2  is C 5 -C 8  cyclic alkyl, or straight or branched C 1 -C 15  alkyl; 
 R 3  and R 4  are independently selected from the group consisting of —OH, —CH 2 OH, —NH 2 , —NHCHO, or R 3  and R 4  together form a substituted 5 to 7-membered saturated heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, and oxygen, and sulfur, or R 3  and R 4  together form amino or hydroxy protecting groups selected from N-formyl, acetal, and ketal; 
 R 5  is selected from the group consisting of —H, —OH, —CH 2 OH, —NH 2 , —NHCHO, straight or branched chain C 1 -C 15  alkyl, and straight or branched chain C 1 -C 15  alkoxy; 
 whereas said ROS scavenger moieties are optionally substituted with one or more C 1 -C 15  alkyl groups, C 1 -C 15  alkoxy groups, phenyl, —NH 2 , —NHCHO, —OH, —CH 2 OH, and groups capable of donating NO in a charged or neutral form; and 
 whereas any of said alkyl groups is optionally substituted with one or more functional groups selected from hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, aryl, carboxyl, carbalkoyl, alkenyl, nitro, amino, alkoxyl, amido; 
 wherein at least one of R 1 , R 2 , R 3  and R 4  comprises at least one ROS scavenger selected from the group of moieties consisting of a nitroxide free radical, alkenyl, sulfhydryl or dithiol in oxidized or reduced form, and aryl; and 
 wherein at least one of R 1 , R 2 , R 3  and R 4  comprises at least one NO donor selected from —ONO, —ONO 2 , and —SNO. 
 
   
   
       40 . A method according to  claim 39 , wherein said saturated heterocycle is selected from the group consisting of pyrrolidine, oxazolidine, thiazolidine, tetrahydro-1,3-oxazine, 1,3-dioxane, piperidine, 3-thiapiperidine, and 1,3-thiazine. 
   
   
       41 . A method according to  claim 39 , wherein said saturated heterocycle comprises a substituted nitroxide free radical. 
   
   
       42 . A method according to  claim 39 , wherein the nitroxide free radical is a heterocyclyl moiety having the nitrogen atom within a 5-, 6- or 7-membered ring which optionally contains another heteroatom selected from oxygen and sulfur at position beta to the nitrogen, and which is substituted with methyl or ethyl at positions alpha to the nitrogen. 
   
   
       43 . A method according to  claim 42 , wherein said heterocyclyl moiety is linked to the β-agonist moiety via sharing of 1 to 2 atoms, or via a linker. 
   
   
       44 . A method according to  claim 39 , wherein said ROS scavenger group is selected from the group consisting of the following moieties: 
     
       
         
         
             
             
         
       
     
     wherein X is selected from carbon, oxygen, and sulfur, and n is an integer from 1 to 15. 
   
   
       45 . A method according to  claim 39 , wherein R 2  is selected from the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein m is 1-6 and R 8  and R 9  are independently C 1 -C 3  alkyl or —H. 
     
   
   
       46 . A method according to  claim 39 , wherein said multifunctional β-agonist compound has the formula: 
     
       
         
         
             
             
         
       
       or its salt; wherein R 1  is selected from the group consisting of —OH, —ONO, —ONO 2 , and —SNO; 
       R 5  is hydrogen; 
       and R 2  is a moiety selected from a nitroxide free radical having the nitrogen atom within a 5-, 6- or 7-membered saturated ring and which is substituted by up to four methyl groups at positions alpha to the nitrogen, sulfhydryl or dithiol moiety in oxidized or reduced form, —ONO, —ONO 2 , and —SNO, wherein said moiety is connected to the —NH group directly or via a linker made of C 1 -C 6  alkyl, and which linker is optionally substituted by one or more phenyl groups. 
     
   
   
       47 . A method according to  claim 39 , wherein said multifunctional β-agonist compound has one of the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       48 . A method according to  claim 39 , wherein said chronic obstructive airway disease is selected from the group consisting of asthma and chronic obstructive pulmonary disease. 
   
   
       49 . A method according to  claim 48 , comprising symptoms selected from the group consisting of emphysema, chronic bronchitis, recurrent obstruction to air flow within the lung, increased resistance to air flow, narrowing or restriction of an airway, inflammation, bronchial hyperreactivity, airway hyperresponsiveness, mucosal edema, mucus plugging and hypersecretion, and reduced expansion of respiratory parenchyma. 
   
   
       50 . A method according to  claim 48 , wherein said asthma is selected from the group consisting of atopic, extrinsic, and intrinsic. 
   
   
       51 . A method according to  claim 39 , wherein said administration is selected from the group consisting of systemic administration and topical administration. 
   
   
       52 . A method according to  claim 39 , wherein said β-agonist compound is administered by a route selected from the group consisting of oral, parenteral, intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, implant, buccal, inhalation spray, nasal, vaginal, rectal, and sublingual route. 
   
   
       53 . A method of  claim 39 , wherein said mammal is human. 
   
   
       54 . A method according to  claim 39 , wherein said β-agonist compound, or a salt thereof or a solvate thereof or an optical isomer thereof is administered in a pharmaceutical composition comprising carriers, adjuvants, and excipients. 
   
   
       55 . A method according to  claim 54 , said composition further comprising an active agent selected from the group consisting of mucolytic, bronchodilator, muscle relaxant, decongestant, respiratory stimulant, vasodilator, β-agonist, anti allergic, antiasthmatics, analgesic, anti-inflammatory, antibiotic, antifungal, antiprotozoal, and antiviral agent. 
   
   
       56 . A method according to  claim 52 , wherein said administration is via an inhalation device. 
   
   
       57 . An inhalation device for administering a multifunctional β-agonist compound according to the method of  claim 39 , said compound being ROS scavenger and NO donor of Formula 1: 
     
       
         
         
             
             
         
       
       or its salt, wherein R 1  is selected from the group consisting of —OH, —ONO, —ONO 2 , and —SNO; 
       R 2  is ROS scavenger group or a NO donor group connected to the —NH group via a linker made of C 5 -C 8  cyclic alkyl or straight or branched C 1 -C 15  alkyl in which one carbon atom is optionally replaced by oxygen or nitrogen, wherein said ROS scavenger group is selected from a nitroxide free radical, alkenyl, sulfhydryl or dithiol moiety in oxidized or reduced form, and aryl, and wherein said NO donor group is selected from —ONO, —ONO 2 , and —SNO, or R 2  is C 5 -C 8  cyclic alkyl, or straight or branched C 1 -C 15  alkyl; 
       R 3  and R 4  are independently selected from the group consisting of —OH, —CH 2 OH, —NH 2 , —NHCHO, or R 3  and R 4  together form a substituted 5 to 7-membered saturated heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, and oxygen, and sulfur, or R 3  and R 4  together form amino or hydroxy protecting groups selected from N-formyl, acetal, and ketal; 
       R 5  is selected from the group consisting of —H, —OH, —CH 2 OH, —NH 2 , —NHCHO, straight or branched chain C 1 -C 15  alkyl, and straight or branched chain C 1 -C 15  alkoxy; 
       whereas said ROS scavenger moieties are optionally substituted with one or more C 1 -C 15  alkyl groups, C 1 -C 15  alkoxy groups, phenyl, —NH 2 , —NHCHO, —OH, —CH 2 OH, and groups capable of donating NO in a charged or neutral form; and 
       whereas any of said alkyl groups is optionally substituted with one or more functional groups selected from hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, aryl, carboxyl, carbalkoyl, alkenyl, nitro, amino, alkoxyl, amido; 
       wherein at least one of R 1 , R 2 , R 3  and R 4  comprises at least one ROS scavenger selected from the group of moieties consisting of a nitroxide free radical, alkenyl, sulfhydryl or dithiol in oxidized or reduced form, and aryl; and 
       wherein at least one of R 1 , R 2 , R 3  and R 4  comprises at least one NO donor selected from —ONO, —ONO 2 , and —SNO; 
       which device comprises an element selected from the group consisting of metered dose inhaler, liquid nebulizer, dry powder inhaler, sprayer, and thermal vaporizer. 
     
   
   
       58 . A kit comprising an inhalation device according to  claim 57 , wherein said multifunctional β-agonist is in the form of fine power or solution or suspension, wherein said powder or solution or suspension optionally contains other components selected from bulking agent, buffer, carrier, excipient, additive, antioxidant, stabilizer, surfactant, odorant, and a second pharmaceutically active agent. 
   
   
       59 . A method of treating or preventing a respiratory disorder in a mammal in need thereof comprising administering to said mammal an effective amount of a multifunctional β-agonist compound as described in  claim 39 , or a salt thereof or a solvate thereof or an optical isomer thereof. 
   
   
       60 . A method according to  claim 59 , wherein said disorder is selected from the group consisting of asthma, chronic bronchitis, bronchiectasis, emphysema, chronic obstructive pulmonary disease, chronic obstructive airway disease, acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) in child or adult, pneumonia, pneumonitis, and restrictive diseases of the lungs.