Novel compounds and compositions for treatment of breathing control disorders or diseases

Abstract

The present invention includes compositions that are 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 formulation of the invention. The present invention further includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the invention.

What is claimed is:  
     
         1 - 60 . (canceled) 
     
     
         61 . A method of increasing minute ventilation in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein
 R 1  and R 2  are independently 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 or 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 H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 , —C(O)OR 1 , acyl, or aryl; 
 R 4  is H, alkyl, or substituted alkyl; 
 R 5  is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —OR 1 , —NR 1 R 2 , —C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or 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; 
 R 6  is H, alkyl, substituted alkyl or alkenyl; 
 X is a bond, O or NR 4 ; and, 
 Y is N, CR 6  or C; wherein:
 if Y is N or CR 6 , then bond b 1  is nil and:
 (i) Z is H, bond b 2  is a single bond, and A is CH; or, 
 (ii) Z is nil, bond b 2  is nil, and A is a single bond; 
 
 and, 
 if Y is C, then bond b 1  is a single bond, and:
 (i) Z is CH 2 , bond b 2  is a single bond, and A is CH; or, 
 (ii) Z is CH, bond b 2  is a double bond, and A is C; 
 
 or a salt thereof. 
 
 
       
     
     
         62 . The method of  claim 61 , wherein the compound of formula (I) is selected from the group consisting of:
 N-(4,6-Bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   N-(4,6-Bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   N-(4-Cyclopropylmethyl)-N-(6-n-propylamino)[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   N-(4-Ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   N-(Bis-4,6-(2-methylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   N-(Bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   N-(Bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   N-(4-(Methoxy(methyl)amino)-6-(n-propylamino)-1,3,5-triazin-2-yl)propionamide,   6-(Methoxy(methyl)amino)-N 2 -propyl-1,3,5-triazine-2,4-diamine,   6-[1,2]Oxazinan-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine,   O-Benzyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine,   6-((Benzyloxy)(isopropyl)amino)-N 2 ,N 4 -dipropyl-1,3,5-triazine-2,4-diamine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylamine,   6-(Methyl(thiophen-2-ylmethoxy)amino)-N 2 ,N 4 -dipropyl-1,3,5-triazine-2,4-diamine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxylamine,   4-N-(2-Dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   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,   4-N-(1-N-Methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   4,6-Bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   4,6-Bis-(N-(pyridin-4-yl-methyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   4,6-Bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   4,6-Bis-[N-(tetrahydropyran-4-yl-methyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine,   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,   2,6-Bis-(N-n-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N′,N′-dimethylhydrazine,   N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N′-methylhydrazine,   2-(n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,   2-(n-Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,   2-(n-Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine,   2-(n-Propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidine,   2,4-Bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine,   2-(n-Propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]pyrimidine,   8-(7-Methyl-2-(n-propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol,   N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine,   N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine,   N-(2-(Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine,   N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine,   N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine,   N-(2-n-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine,   N-Methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine,   N,N-Dimethyl-N′-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine,   
       a salt thereof and mixtures thereof. 
     
     
         63 . The method of  claim 62 , wherein the compound of formula (I) is N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine, or a salt thereof. 
     
     
         64 . The method of  claim 61 , wherein the pharmaceutical formulation is administered via intravenous infusion. 
     
     
         65 . The method of  claim 64 , wherein the infusion dose of the pharmaceutical formulation is at least about 0.016 mg/kg/min of compound (I). 
     
     
         66 . The method of  claim 65 , wherein the infusion dose of the pharmaceutical formulation is about 0.016 mg/kg/min of compound (I). 
     
     
         67 . The method of  claim 61 , wherein the infusion dose of the pharmaceutical composition produce plasma concentrations of at least about 726 ng/mL of compound (I) in the subject. 
     
     
         68 . The method of  claim 61 , wherein the subject is a mammal. 
     
     
         69 . The method of  claim 68 , wherein the mammal is human. 
     
     
         70 . The method of  claim 64 , wherein the infusion dose of the pharmaceutical formulation is about 0.012 mg/kg/min of compound (I).