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.

1 . A composition comprising at least one compound selected from the group consisting of: N-(2,4-bis-n-propylamino)-N-(6-methylamino)-[1,3,5]triazine (CLXXII), N-(2,4,6-tris-n-propylamino)-[1,3,5]triazine (CLXXIII), N-(2,4,6-tris-n-propylamino)-1,3-pyrimidine (CLXXIV), N-(2,4-bis-n-propylamino)-N-(6-i-propylamino)-1,3-pyrimidine (CLXXV), a salt thereof, and any combinations thereof. 
     
     
         2 . The composition of  claim 1 , wherein the salt is hydrogen sulfate, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate. 
     
     
         3 . The composition of  claim 1 , further comprising at least one pharmaceutically acceptable carrier. 
     
     
         4 . 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 an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N-(2,4-bis-n-propylamino)-N-(6-methylamino)-[1,3,5]triazine (CLXXII), N-(2,4,6-tris-n-propylamino)-[1,3,5]triazine (CLXXIII), N-(2,4,6-tris-n-propylamino)-1,3-pyrimidine (CLXXIV), N-(2,4-bis-n-propylamino)-N-(6-i-propylamino)-1,3-pyrimidine (CLXXV), a salt thereof, and any combinations thereof. 
     
     
         5 . The method of  claim 4 , 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, hypoxia, and hypercapnia. 
     
     
         6 . The method of  claim 5 , wherein the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic. 
     
     
         7 . The method of  claim 4 , wherein the subject is further administered a composition comprising at least one additional compound useful for treating the breathing control disorder or disease. 
     
     
         8 . The method of  claim 7 , wherein the at least one additional compound is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, a cannabinoid and an ampakine. 
     
     
         9 . The method of  claim 4 , wherein the formulation is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. 
     
     
         10 . The method of  claim 4 , wherein the subject is a mammal. 
     
     
         11 . The method of  claim 10 , wherein the mammal is a human. 
     
     
         12 . The method of  claim 4 , wherein the formulation is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, intraperitoneal, intrathoracic, intrapleural or intravenous route. 
     
     
         13 . A method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N-(2,4-bis-n-propylamino)-N-(6-methylamino)-[1,3,5]triazine (CLXXII), N-(2,4,6-tris-n-propylamino)-[1,3,5]triazine (CLXXIII), N-(2,4,6-tris-n-propylamino)-1,3-pyrimidine (CLXXIV), N-(2,4-bis-n-propylamino)-N-(6-i-propylamino)-1,3-pyrimidine (CLXXV), a salt thereof, and any combinations thereof. 
     
     
         14 . The method of  claim 13 , 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, hypoxia, and hypercapnia. 
     
     
         15 . The method of  claim 14 , wherein the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic. 
     
     
         16 . The method of  claim 15 , wherein the subject is further administered a composition comprising at least one additional compound useful for treating the breathing control disorder or disease. 
     
     
         17 . The method of  claim 16 , wherein the at least one additional compound is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, a cannabinoid and an ampakine. 
     
     
         18 . The method of  claim 13 , wherein the formulation is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. 
     
     
         19 . The method of  claim 13 , wherein the subject is a mammal. 
     
     
         20 . The method of  claim 19 , wherein the mammal is a human. 
     
     
         21 . The method of  claim 13 , wherein the formulation is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, intraperitoneal, intrathoracic, intrapleural or intravenous route. 
     
     
         22 . A composition comprising N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) or a salt thereof, wherein 4,6 bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 1% (w/w) with respect to (XXXV) or the salt thereof. 
     
     
         23 . The composition of  claim 22 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.5% (w/w) with respect to (XXXV) or the salt thereof. 
     
     
         24 . The composition of  claim 23 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.3% (w/w) with respect to (XXXV) or the salt thereof. 
     
     
         25 . The composition of  claim 24 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.2% (w/w) with respect to (XXXV) or the salt thereof. 
     
     
         26 . The composition of  claim 25 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.15% (w/w) with respect to (XXXV) or the salt thereof. 
     
     
         27 . The composition of  claim 26 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is present at a level equal to or lower than about 0.1% (w/w) with respect to (XXXV) or the salt thereof. 
     
     
         28 . The composition of  claim 27 , wherein 4,6-bis-(n-propylamino)-1,3,5-triazin-2-ol (CLXXVIII) is essentially absent from the composition. 
     
     
         29 . A composition comprising N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) or a salt thereof, further comprising a buffer and a liquid carrier. 
     
     
         30 . The composition of  claim 29 , wherein the salt of (XXXV) is the hydrogen sulfate salt (XXXVI). 
     
     
         31 . The composition of  claim 29 , further comprising citric acid. 
     
     
         32 . The composition of  claim 29 , wherein the pH of the composition is adjusted with a base. 
     
     
         33 . The composition of  claim 32 , wherein the base comprises sodium hydroxide. 
     
     
         34 . The composition of  claim 29 , wherein the liquid carrier comprises water. 
     
     
         35 . The composition of  claim 29 , wherein the pH of the composition ranges from about 2.5 to about 6. 
     
     
         36 . The composition of  claim 35 , wherein the pH of the composition ranges from about 2.5 to about 5. 
     
     
         37 . The composition of  claim 36 , wherein the pH of the composition ranges from about 3 to about 4. 
     
     
         38 . The composition of  claim 29 , wherein the concentration of (XXXV) or the salt thereof in the composition is about 1-10 mg/mL. 
     
     
         39 . The composition of  claim 38 , wherein the concentration of (XXXV) or the salt thereof in the composition is about 5-10 mg/mL. 
     
     
         40 . The composition of  claim 39 , wherein the concentration of (XXXV) or the salt thereof in the composition is about 10 mg/mL. 
     
     
         41 . The composition of  claim 29 , comprising less than 0.5% (w/w) (CLXXVIII) with respect to (XXXV). 
     
     
         42 . The composition of  claim 41 , wherein less than 0.5% (w/w) of N-(4,6-Bis-n-propylamino)-[1,3,5]-triazin-2-ol (CLXXVIII) with respect to (XXXV) forms over a six-month period of storage of the composition at 2-8° C. 
     
     
         43 . The composition of  claim 42 , wherein less than 0.5% (w/w) of N-(4,6-Bis-n-propylamino)-[1,3,5]-triazin-2-ol (CLXXVIII) with respect to (XXXV) forms over a twelve-month period of storage of the composition at 2-8° C. 
     
     
         44 . The composition of  claim 43 , wherein less than 0.5% (w/w) of N-(4,6-Bis-n-propylamino)-[1,3,5]-triazin-2-ol (CLXXVIII) with respect to (XXXV) forms over an eighteen-month period of storage of the composition at 2-8° C. 
     
     
         45 . The composition of  claim 44 , wherein less than 0.5% (w/w) of N-(4,6-Bis-n-propylamino)-[1,3,5]-triazin-2-ol (CLXXVIII) with respect to (XXXV) forms over a twenty-four-month period of storage of the composition at 2-8° C. 
     
     
         46 . A crystalline free base of N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXV), Form A, with a XRPD spectrum as per  FIG. 22 . 
     
     
         47 . At least one crystalline salt of N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N.O-dimethyl-hydroxylamine (XXXV) selected from the group consisting of:
 (i) crystalline hydrogen sulfate salt (XXXVI) Form A, with a XRPD spectrum as per  FIG. 14 ;   (ii) crystalline hydrogen sulfate salt (XXXVI) comprising a mixture of Form A and Form B, with a XRPD spectrum as per  FIG. 23 ;   (iii) crystalline hydrogen sulfate salt (XXXVI) Form C, with a XRPD spectrum as per  FIG. 24 ;   (iv) crystalline hydrogen sulfate salt (XXXVI) Form D, with a XRPD spectrum as per  FIG. 25 ;   (v) crystalline hydrogen sulfate salt (XXXVI) comprising a mixture of Form A and Form D, with a XRPD spectrum as per  FIG. 26 ;   (vi) crystalline phosphoric acid salt (CLXXX) Form A, with a XRPD spectrum as per  FIG. 27 ;   (vii) crystalline phosphoric acid salt (CLXXX) Form C, with a XRPD spectrum as per  FIG. 28 ;   (viii) crystalline phosphoric acid salt (CLXXX) comprising a mixture of Form A and Form B, with a XRPD spectrum as per  FIG. 29 ;   (ix) crystalline phosphoric acid salt (CLXXX) comprising a mixture of Form C and Form D, with a XRPD spectrum as per  FIG. 30 ;   (x) crystalline phosphoric acid salt (CLXXX) comprising a mixture of Form C and Form E, with a XRPD spectrum as per  FIG. 31 ;   and any mixtures thereof.   
     
     
         48 . A salt of N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XXXV), comprising approximately one mole equivalent of sulfuric acid. 
     
     
         49 . The salt of  claim 48 , further comprising one mole equivalent of water. 
     
     
         50 . A salt of N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N.O-dimethyl-hydroxylamine (XXXV), comprising at least one mole equivalent of phosphoric acid. 
     
     
         51 . The salt of  claim 50 , comprising about one mole equivalent of phosphoric acid. 
     
     
         52 . A method of reducing or minimizing the open channel fraction of the potassium maxi-K or BK channel in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are independently H, 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. 
     
     
         53 . The method of  claim 52 , 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, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine, O-Allyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine, 6-(Methoxy(methyl)amino)-N 2 -propyl-1,3,5-triazine-2,4-diamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine, O-Benzyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine, 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, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-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, N-(2,4-Bis-n-propylamino)-N-(6-methylamino)-[1,3,5]triazine, N-(2,4,6-Tris-n-propylamino)-[1,3,5]triazine, N-(2,4,6-Tris-n-propylamino)-1,3-pyrimidine, N-(2,4-Bis-n-propylamino)-N-(6-i-propylamino)-1,3-pyrimidine, a salt thereof and mixtures thereof. 
     
     
         54 . The method of  claim 52 , wherein the subject is a mammal. 
     
     
         55 . The method of  claim 54 , wherein the mammal is human. 
     
     
         56 . A method of inhibiting the TASK-1 (KCNK3) channel in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are independently H, 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. 
     
     
         57 . The method of  claim 56 , 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, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine, O-Allyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine, 6-(Methoxy(methyl)amino)-N 2 -propyl-1,3,5-triazine-2,4-diamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine, O-Benzyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine, 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, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-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, N-(2,4-Bis-n-propylamino)-N-(6-methylamino)-[1,3,5]triazine, N-(2,4,6-Tris-n-propylamino)-[1,3,5]triazine, N-(2,4,6-Tris-n-propylamino)-1,3-pyrimidine, N-(2,4-Bis-n-propylamino)-N-(6-i-propylamino)-1,3-pyrimidine, a salt thereof and mixtures thereof. 
     
     
         58 . The method of  claim 57 , wherein the compound of formula (I) is selected from the group consisting of: N-(4,6-Bis-n-propylamino-1,3,5]triazin-2-yl)-O-methyl-hydroxylamine; N-(4,6-Bis-n-propylamino-1,3,5]triazin-2-yl)-N′,N′-dimethylhydrazine; N-(2,4-Bis-n-propylamino)-N-(6-methylamino)-[1,3,5]triazine; N-[(2,6-Bis-n-propylamino)-pyrimidin-4-yl]-N,O-dimethyl-hydroxylamine; N,N-Dimethyl-N′-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine; a salt thereof and mixtures thereof. 
     
     
         59 . The method of  claim 56 , wherein the subject is a mammal. 
     
     
         60 . The method of  claim 59 , wherein the mammal is human. 
     
     
         61 . A method of increasing minute ventilation in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are independently H, 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, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine, O-Allyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine, 6-(Methoxy(methyl)amino)-N 2 -propyl-1,3,5-triazine-2,4-diamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine, O-Benzyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine, 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, N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-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, N-(2,4-Bis-n-propylamino)-N-(6-methylamino)-[1,3,5]triazine, N-(2,4,6-Tris-n-propylamino)-[1,3,5]triazine, N-(2,4,6-Tris-n-propylamino)-1,3-pyrimidine, N-(2,4-Bis-n-propylamino)-N-(6-i-propylamino)-1,3-pyrimidine, 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. 
     
     
         66 . The method of  claim 65 , wherein the infusion dose of the pharmaceutical formulation is about 0.016 mg/kg/min. 
     
     
         67 . The method of  claim 61 , wherein the infusion dose of the pharmaceutical composition produce plasma concentrations of at least about 726 ng/mL 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.