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

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.

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 a therapeutically effective amount of at least one compound of formula (I), or a salt thereof:

• wherein
• R1 and R2 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 R1 and R2 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;
• R3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR1R2, —C(O)OR1, acyl, or aryl;
• R4 is H, alkyl, or substituted alkyl;
• R5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —OR1, —NR1R2, —C(O)OR1, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic;
• or R3 and R5 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;
• R6 is H, alkyl, substituted alkyl or alkenyl;
• X is a bond, O or NR4;
• and,
• Y is N, CR6 or C;
• wherein:
• if Y is N or CR6, then bond b1 is nil and:
• (i) Z is H, bond b2 is a single bond, and A is CH;
• or,
• (ii) Z is nil, bond b2 is nil, and A is a single bond;
• and,
• if Y is C, then bond b1 is a single bond, and:
• (i) Z is CH2, bond b2 is a single bond, and A is CH;
• or,
• (ii) Z is CH, bond b2 is a double bond, and A is C.

A method of inhibiting the TASK-1 (KCNK3) channel 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 thereof:

• wherein
• R1 and R2 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 R1 and R2 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;
• R3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR1R2, —C(O)OR1, acyl, or aryl;
• R4 is H, alkyl, or substituted alkyl;
• R5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —OR1, —NR1R2, —C(O)OR1, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic;
• or R3 and R5 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;
• R6 is H, alkyl, substituted alkyl or alkenyl;
• X is a bond, O or NR4;
• and,
• Y is N, CR6 or C;
• wherein:
• if Y is N or CR6, then bond b1 is nil and:
• (i) Z is H, bond b2 is a single bond, and A is CH;
• or,
• (ii) Z is nil, bond b2 is nil, and A is a single bond;
• and,
• if Y is C, then bond b1 is a single bond, and:
• (i) Z is CH2, bond b2 is a single bond, and A is CH;
• or,
• (ii) Z is CH, bond b2 is a double bond, and A is C;
• or a salt thereof.

A method of increasing minute ventilation 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 thereof:

• wherein
• R1 and R2 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 R1 and R2 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;
• R3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR1R2, —C(O)OR1, acyl, or aryl;
• R4 is H, alkyl, or substituted alkyl;
• R5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —OR1, —NR1R2, —C(O)OR1, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic;
• or R3 and R5 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;
• R6 is H, alkyl, substituted alkyl or alkenyl;
• X is a bond, O or NR4;
• and,
• Y is N, CR6 or C;
• wherein:
• if Y is N or CR6, then bond b1 is nil and:
• (i) Z is H, bond b2 is a single bond, and A is CH;
• or,
• (ii) Z is nil, bond b2 is nil, and A is a single bond;
• and,
• if Y is C, then bond b1 is a single bond, and:
• (i) Z is CH2, bond b2 is a single bond, and A is CH;
• or,
• (ii) Z is CH, bond b2 is a double bond, and A is C.