Sulfonamides as potassium channel blockers

A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and a compound having the formula:

• 23
• wherein
• ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted C5-C7 carbocycle, substituted and unsubstituted heteroaryl and substituted or unsubstituted 5-7-membered heterocycloalkyl;
• A is a member selected from —NHS(O)2—, —S(O)2NH—, —C(R4R5)S(O)n—, —S(O)nC(R4R5)—, —C(R4R5)NHS(O)n—, —S(O)nNHC(R4R5)—, —C(R4R5)S(O)nNH—, and —HNS(O)nC(R4R5)—
• wherein
• n is selected from the integers from 0 to 2;
• R1 is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted (C5-C7)carbocycle, substituted or unsubstituted heteroaryl and substituted or unsubstituted 5-7-membered heterocycloalkyl;
• R2 is a member selected from COOR3, substituted or unsubstituted 2-furan, substituted or unsubstituted 2-thiazole and
• 24
• wherein
• R3 is a member selected from the group consisting of substituted or unsubstituted C1-C4 alkyl and —CF3;
• X is selected from the group consisting of —N═N—, —N═C(R4)—, —C(R4)═N—, —C(R4R5)—C(R4R5)— and —C(R4)═C(R5)—,
• wherein
• R4 and R5 are members independently selected from the group consisting of hydrogen, substituted and unsubstituted lower alkyl, —OR6 and —CF3
• wherein
• R6 is a member selected from hydrogen, and substituted or unsubstituted lower alkyl;
• Y is a member selected from O, NR11 or S, in which R11 is a member selected from lower alkyl and —CF3.

A method of inhibiting potassium flux of a cell, said method comprising contacting said cell with an effective amount of a compound having the formula:

• 25
• wherein
• ring system Z is a member selected from the group consisting of substituted or unsubstituted C5-C7 carbocycle, substituted or unsubstituted aryl, substituted and unsubstituted membered heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;
• A is a member selected from —NHS(O)2—, —S(O)2NH—, —C(R4R5)S(O)n—, —S(O)nC(R4R5)—, —C(R4R5)NHS(O)n—, —S(O)nNHC(R4R5)—, —C(R4R5)S(O)nNH—, and —HNS(O)nC(R4R5)—
• wherein
• n is selected from the integers from 0 to 2;
• and
• R1 is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C5-C7)carbocycle, and substituted or unsubstituted 5-7-membered heterocycloalkyl,
• in an amount effective to inhibit said flux.

A method for reducing intraocular pressure in a subject in need thereof by decreasing potassium ion flow through intermediate conductance potassium channels in a cell, the method comprising the step of administering to the subject a compound having the formula:

• 26
• wherein
• ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted C5-C7 carbocycle, substituted and unsubstituted heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;
• A is a member selected from —NHS(O)2—, —S(O)2NH—, —C(R4R5)S(O)n—, —S(O)nC(R4R5)—, —C(R4R5)NHS(O)n—, —S(O)NHC(R4R5)—, —C(R4R5)S(O)nNH—, and —HNS(O)nC(R4R5)—
• wherein
• n is selected from the integers from 0 to 2;
• and
• R1 is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C5-C7)carbocycle, and substituted or unsubstituted 5-7-membered heterocycloalkyl,
• in an amount sufficient to decrease potassium ion flow through intermediate conductance, calcium activated potassium channels, thereby reducing intraocular pressure.

A method of preventing or retarding dehydration of erythrocytes comprising contacting said erythrocyte with a compound having the formula:

• 27
• wherein
• ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted and unsubstituted heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;
• A is a member selected from —NHS(O)2—, —S(O)2NH—, —C(R4R5)S(O)n—, —S(O)nC(R4R5)—, —C(R4R5)NHS(O)n—, —S(O)nNHC(R4R5)—, —C(R4R5)S(O)nNH—, and —HNS(O)nC(R4R5)—
• wherein
• n is selected from the integers from 0 to 2;
• and
• R1 is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C5-C7)carbocycle, and substituted or unsubstituted 5-7-membered heterocycloalkyl, in an amount effective to prevent or retard said dehydration.

A method for treating or preventing sickle cell disease comprising administering to a subject suffering sickle cell disease a therapeutically effective amount of a compound having the formula:

• 28
• wherein
• ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted C5-C7 carbocycle, substituted and unsubstituted heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;
• A is a member selected from —NHS(O)2—, —S(O)2NH—, —C(R4R5)S(O)n—, —S(O)nC(R4R5)—, —C(R4R5)NHS(O)n—, —S(O)nNHC(R4R5)—, —C(R4R5)S(O)nNH—, and —HNS(O)nC(R4R5)—
• wherein
• n is selected from the integers from 0 to 2;
• and
• R1 is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C5-C7)carbocycle, and substituted or unsubstituted 5-7-membered heterocycloalkyl.

A method of treating or preventing a disease state which is a member selected from inflammation and abnormal cell proliferation in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound having the formula:

• 29
• wherein
• ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted C5-C7 carbocycle, substituted and unsubstituted heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;
• A is a member selected from —NHS(O)2—, —S(O)2NH—, —C(R4R5)S(O)n—, —S(O)nC(R4R5)—, —C(R4R5)NHS(O)n—, —S(O)nNHC(R4R5)—, —C(R4R5)S(O)nNH—, and —HNS(O)nC(R4R5)—
• wherein
• n is selected from the integers from 0 to 2;
• and
• R1 is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C5-C7)carbocycle, and substituted or unsubstituted (C5-C7)heterocycloalkyl.