Novel compounds as respiratory stimulants for treatment of breathing control disorders or diseases

Abstract

The present invention includes a composition comprising a compound, such as a 2,4,6-triamino-1,3,5-triazine, 2,4,6-triaminopyrimidine, 2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine or 2,4-diamino-7H-pyrrolo[2,3-d]pyrimidine, that is useful in the treatment of breathing control diseases or disorders in a subject in need thereof. The present invention also includes a method of treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the invention. The present invention further includes a method of preventing destabilizing or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the invention.

1 - 34 . (canceled) 
     
     
         35 . A compound of formula (I), or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein the compound of formula (I) is selected from the group consisting of:
 (i) Y is N, bond b 1  is nil, Z is H, bond b 2  is a single bond, A is CH, and the compound is a compound of formula (II-a): 
 
       
         
           
           
               
               
           
         
         (ii) Y is N, bond b 1  is nil, Z is nil, bond b 2  is nil, and A is a bond, and the compound is a compound of formula (II-b): 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl and substituted heteroaryl; 
 R 2  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl and substituted heteroaryl;
 or R 1  and R 2  combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; 
 
 R 3  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 , —C(O)OR 1 , and aryl; 
 R 4  is selected from the group consisting of H, alkyl, and substituted alkyl; 
 R 5  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 , —C(O)OR 1 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or R 3  and R 5  combine as to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; and 
 X is O. 
 
     
     
         36 . The compound of  claim 35 , wherein R 3  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl. 
     
     
         37 . The compound of  claim 35 , wherein R 5  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, and substituted alkenyl. 
     
     
         38 . The compound of  claim 35 , wherein the salt is selected from the group consisting of sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, phosphoric, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic. 
     
     
         39 . The compound of  claim 35 , wherein the salt is selected from the group consisting of hydrogen sulfate and hydrochloride. 
     
     
         40 . A pharmaceutical composition comprising at last one compound of  claim 35  and at least one pharmaceutically acceptable carrier. 
     
     
         41 . A method of preventing or treating a breathing control disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (I) or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein the compound of formula (I) is selected from the group consisting of:
 (i) Y is N, bond b 1  is nil, Z is H, bond b 2  is a single bond, A is CH, and the compound is a compound of formula (II-a): 
 
       
         
           
           
               
               
           
         
         (ii) Y is N, bond b 1  is nil, Z is nil, bond b 2  is nil, and A is a bond, and the compound is a compound of formula (II-b): 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl and substituted heteroaryl; 
 R 2  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl and substituted heteroaryl;
 or R 1  and R 2  combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; 
 
 R 3  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 , —C(O)OR 1 , and aryl; 
 R 4  is selected from the group consisting of H, alkyl, and substituted alkyl; 
 R 5  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 , —C(O)OR 1 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or R 3  and R 5  combine as to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; and 
 X is O. 
 
     
     
         42 . The method of  claim 41 , wherein the breathing control disorder or disease is selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity-hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and chronic obstructive pulmonary disease (COPD); wherein the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic. 
     
     
         43 . The method of  claim 41 , wherein the subject is further administered at least one additional agent useful for treating the breathing disorder or disease. 
     
     
         44 . The method of  claim 43 , wherein the at least one additional agent is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotonergic modulator, a cannabinoid and an ampakine. 
     
     
         45 . The method of  claim 41 , wherein the at least one compound is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. 
     
     
         46 . The method of  claim 41 , wherein the at least one compound is part of a pharmaceutically acceptable composition further comprising at least one pharmaceutically acceptable carrier. 
     
     
         47 . The method of  claim 41 , wherein the subject is a mammal. 
     
     
         48 . The method of  claim 47 , wherein the mammal is a human. 
     
     
         49 . The method of  claim 41 , wherein the at least one compound is administered to the subject by at least one route selected from the group consisting of inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal and intravenous. 
     
     
         50 . The method of  claim 41 , wherein the at least one compound is selected from the group consisting of:
 N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XX),   N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXII),   N-(4-Cyclopropylmethyl)-N-(6-n-propylamino) [1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV),   N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXVII),   N-(Bis-4,6-(2-methylpropylamino)) [1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX),   N-(Bis-4,6-(2,2-dimethylpropylamino)) [1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI),   N-(Bis-4,6-(cyclopropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXIII),   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXV),   O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII),   6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine (LVII),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV),   O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII),   6-((Benzyloxy)(isopropyl)amino)-N 2 ,N 4 -dipropyl-1,3,5-triazine-2,4-diamine (LXXII),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII),   6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCVI),   4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII),   4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV),   4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII),   4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX),   4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI),   4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXIII),   4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXV), and   N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII).   
     
     
         51 . A method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (I), or a salt or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein the compound of formula (I) is selected from the group consisting of:
 (i) Y is N, bond b 1  is nil, Z is H, bond b 2  is a single bond, A is CH, and the compound is a compound of formula (II-a): 
 
       
         
           
           
               
               
           
         
         (ii) Y is N, bond b 1  is nil, Z is nil, bond b 2  is nil, and A is a bond, and the compound is a compound of formula (II-b): 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl and substituted heteroaryl; 
 R 2  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl and substituted heteroaryl;
 or R 1  and R 2  combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; 
 
 R 3  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 , —C(O)OR 1 , and aryl; 
 R 4  is selected from the group consisting of H, alkyl, and substituted alkyl; 
 R 5  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 , —C(O)OR 1 , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; or R 3  and R 5  combine as to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; and 
 X is O. 
 
     
     
         52 . The method of  claim 51 , wherein the destabilization is associated with a breathing control disorder or disease selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity-hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and chronic obstructive pulmonary disease (COPD); wherein the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic. 
     
     
         53 . The method of  claim 51 , wherein the subject is further administered at least one additional agent useful for treating the breathing disorder or disease. 
     
     
         54 . The method of  claim 53 , wherein the at least one additional agent is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotonergic modulator, a cannabinoid and an ampakine. 
     
     
         55 . The method of  claim 51 , wherein the at least one compound is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. 
     
     
         56 . The method of  claim 51 , wherein the at least one compound is part of a pharmaceutically acceptable composition further comprising at least one pharmaceutically acceptable carrier. 
     
     
         57 . The method of  claim 51 , wherein the subject is a mammal. 
     
     
         58 . The method of  claim 57 , wherein the mammal is a human. 
     
     
         59 . The method of  claim 51 , wherein the at least one compound is administered to the subject by at least one route selected from the group consisting of inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal and intravenous route. 
     
     
         60 . The method of  claim 51 , wherein the at least one compound is selected from the group consisting of:
 N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XX),   N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXII),   N-(4-Cyclopropylmethyl)-N-(6-n-propylamino) [1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV),   N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXVII),   N-(Bis-4,6-(2-methylpropylamino)) [1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX),   N-(Bis-4,6-(2,2-dimethylpropylamino)) [1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI),   N-(Bis-4,6-(cyclopropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXIII),   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXV),   O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII),   6-[1,2]Oxazinan-2-yl-N,N-dipropyl-[1,3,5]triazine-2,4-diamine (LVII),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV),   O-Benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII),   6-((Benzyloxy)(isopropyl)amino)-N 2 ,N 4 -dipropyl-1,3,5-triazine-2,4-diamine (LXXII),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII),   6-(Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI),   N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCVI),   4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII),   4-N-(3-(1-N-Methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV),   4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII),   4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX),   4,6-Bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI),   4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXIII),   4,6-Bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXV), and   N-(5,8,11-Trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]nonadeca-1(18),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII).   
       a salt thereof and mixtures thereof.