Salts of potassium atp channel openers and uses thereof
OwnerNeil M. Coweninventor
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Abstract
Provided are immediate or prolonged administration of certain salts of KATP channel openers such as diazoxide to a subject to achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, metabolic and compositional outcomes in the treatment of diseases or conditions involving KATP channels. Also provided are pharmaceutical formulations, methods of administration and dosing of the salts that achieve these outcomes and reduce the incidence of adverse effects in treated individuals. Further provided are method of co-administering the salts with other drugs to treat diseases of humans and animals.
Claims61
A method for treating a dyslipidemia in a subject having a triglyceride level of at least about 500 mg/dL and an HDL-C level of about 40 mg/dL or less, the method comprising administering to the subject a therapeutically effective amount of a KATP channel opener, said KATP channel opener comprising an anion of a KATP channel opener selected from the group consisting of Formula I, Formula II, Formula III and Formula IV,
- wherein in Formulas I and II:
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R1 is a substituted C1-C6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group;
- R2a is hydrogen;
- R2b is hydrogen;
- X is a 1, 2 or 3 atom chain, wherein each atom is independently selected from carbon, sulfur and nitrogen, and each atom is optionally substituted with halogen, hydroxyl, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C1-C6 alkoxy, provided however that when an atom of the chain is substituted with substituted C1-C6 alkyl, substituted C1-C6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group;
- and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic, and
- wherein in Formulas III and IV:
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, and cycloalkyl provided however that when R1 is a substituted C1-C6 alkyl, then the substituent does not include an amino group;
- R2a is hydrogen;
- R2b is hydrogen;
- R3 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R3 is a substituted C1-C6 alkyl, then the substituent does not include an amino group;
- R4 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R4 is a substituted C1-C6 alkyl, then the substituent does not include an amino group, and
- a cation selected from the group consisting of an alkali metal and a compound comprising an ammonium group comprising at least one tertiary amine group.
A method for treating dyslipidemia in a subject having a triglyceride level of at least about 1000 mg/dL, the method comprising administering to the subject a therapeutically effective amount of a fibrate or a salt thereof and a therapeutically effective amount of a KATP channel opener, said KATP channel opener comprising an anion of a KATP channel opener selected from the group consisting of Formula I, Formula II, Formula III and Formula IV,
- wherein in Formulas I and II:
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R1 is a substituted C1-C6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group;
- R2a is hydrogen;
- R2b is hydrogen;
- X is a 1, 2 or 3 atom chain, wherein each atom is independently selected from carbon, sulfur and nitrogen, and each atom is optionally substituted with halogen, hydroxyl, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C1-C6 alkoxy, provided however that when an atom of the chain is substituted with substituted C1-C6 alkyl, substituted C1-C6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group;
- and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic, and
- wherein in Formulas III and IV:
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, and cycloalkyl provided however that when R1 is a substituted C1-C6 alkyl, then the substituent does not include an amino group;
- R2 is hydrogen;
- R2b is hydrogen;
- R3 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R3 is a substituted C1-C6 alkyl, then the substituent does not include an amino group;
- R4 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R4 is a substituted C1-C6 alkyl, then the substituent does not include an amino group, and
- a cation selected from the group consisting of an alkali metal and a compound comprising an ammonium group comprising at least one tertiary amine group.
A method for reducing elevated triglycerides in a subject undergoing statin therapy, the method comprising administering to the subject a therapeutically effective amount of a KATP channel opener, said KATP channel opener comprising an anion of a KATP channel opener selected from the group consisting of Formula I, Formula II, Formula III and Formula IV,
- wherein in Formulas I and II:
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R1 is a substituted C1-C6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group;
- R2a is hydrogen;
- R2b is hydrogen;
- X is a 1, 2 or 3 atom chain, wherein each atom is independently selected from carbon, sulfur and nitrogen, and each atom is optionally substituted with halogen, hydroxyl, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C1-C6 alkoxy, provided however that when an atom of the chain is substituted with substituted C1-C6 alkyl, substituted C1-C6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group;
- and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic, and
- wherein in Formulas III and IV:
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, and cycloalkyl provided however that when R1 is a substituted C1-C6 alkyl, then the substituent does not include an amino group;
- R2a is hydrogen;
- R2b is hydrogen;
- R3 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R3 is a substituted C1-C6 alkyl, then the substituent does not include an amino group;
- R4 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R4 is a substituted C1-C6 alkyl, then the substituent does not include an amino group, and
- a cation selected from the group consisting of an alkali metal and a compound comprising an ammonium group comprising at least one tertiary amine group.
A method for treating a subject with nonalcoholic steatohepatitis (NASH), the method comprising administering to the subject a therapeutically effective amount of a KATP channel opener, said KATP channel opener comprising an anion of a KATP channel opener selected from the group consisting of Formula I, Formula II, Formula III and Formula IV,
- wherein in Formulas I and II:
- R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R1 is a substituted C1-C6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group;
- R2a is hydrogen;
- R2b is hydrogen;
- X is a 1, 2 or 3 atom chain, wherein each atom is independently selected from carbon, sulfur and nitrogen, and each atom is optionally substituted with halogen, hydroxyl, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C1-C6 alkoxy, provided however that when an atom of the chain is substituted with substituted C1-C6 alkyl, substituted C1-C6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group;
- and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic, and
- wherein in Formulas III and IV:
- R1 is selected from the group consisting of hydrogen, C1-C6 al substituted C1-C6 alkyl, and cycloalkyl provided however that when R1 is a substituted C1-C6 alkyl, then the substituent does not include an amino group;
- R2a is hydrogen;
- R2b is hydrogen;
- R3 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R3 is a substituted C1-C6 alkyl, then the substituent does not include an amino group;
- R4 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R4 is a substituted C1-C6 alkyl, then the substituent does not include an amino group, and
- a cation selected from the group consisting of an alkali metal and a compound comprising an ammonium group comprising at least one tertiary amine group.
A pharmaceutical formulation comprising diazoxide choline, wherein oral administration of a 290 mg dose of diazoxide choline once daily to a subject results in steady state AUC0-24>500 μg*hr/mL.
A pharmaceutical formulation comprising a salt of diazoxide formulated for oral administration, wherein bioavailability of diazoxide is at least about 50%.
Dependencies are inferred from the claim text.