SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
Provided are immediate or prolonged administration of certain salts of K ATP 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 K ATP 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.
1 - 78 . (canceled)
79 . A method for the preparation of a salt of a compound of Formulae I-IV comprising:
reacting one equivalent of a cation source selected from the group consisting of an alkali metal hydroxide or an organic cation source comprising an ammonium comprising at least one tertiary amine group with a compound of Formulae I-IV,
wherein in Formula I:
R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R 1 is a substituted lower alkyl or a substituted cycloalkyl, then the substituent does not include an amino group;
R 2a is hydrogen;
X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, or substituted lower alkoxy, provided however that when an atom of the chain is substituted with substituted lower alkyl, substituted lower alkoxy or substituted cycloalkyl, then the substituent does not include an amino group;
wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic;
wherein in Formula II
R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R 1 is a substituted lower alkyl or a substituted cycloalkyl, then the substituent does not include an amino group;
R 2b is hydrogen;
X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, cycloalkyl, substituted cycloalkyl, or substituted lower alkoxy, provided however that when an atom of the chain is substituted with substituted lower alkyl, substituted lower alkoxy or substituted cycloalkyl, then the substituent does not include an amino group;
wherein ring B is saturated monounsaturated, polyunsaturated or aromatic;
wherein in Formula III:
R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, and cycloalkyl provided however that when R 1 is a substituted lower alkyl, then the substituent does not include an amino group;
R 2 a is hydrogen;
R 3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 3 is a substituted lower alkyl, then the substituent does not include an amino group;
R 4 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 4 is a substituted lower alkyl, then the substituent does not include an amino group;
wherein in Formula IV
R 1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, and cycloalkyl provided however that when R 1 is a substituted lower alkyl, then the substituent does not include an amino group;
R 2b is hydrogen;
R 3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 3 is a substituted lower alkyl, then the substituent does not include an amino group;
R 4 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 4 is a substituted lower alkyl, then the substituent does not include an amino group;
wherein said compound of Formulae I-IV is dissolved in a solvent selected from the group consisting of acetonitrile, low molecular weight ketones, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide and n-methyl pyrrolidinone, and
removing the solvent.
80 - 129 . (canceled)
130 . The method of claim 79 wherein said cation source is sodium hydroxide or potassium hydroxide.
131 . The method of claim 130 wherein said solvent is selected from the group consisting of acetonitrile, low molecular weight ketones, and tetrahydrofuran.
132 . The method of claim 79 wherein said cation source is choline hydroxide or hexamethyl hexamethylene diammonium dihydroxide.
133 . The method of claim 132 wherein said solvent is selected from the group consisting of acetonitrile, low molecular weight ketones, tetrahydrofuran, and 2-methyl tetrahydrofuran.
134 . The method of claim 132 wherein said cation source is choline hydroxide, and said solvent is selected from the group consisting of acetonitrile, low molecular weight ketones, tetrahydrofuran, and 2-methyl tetrahydrofuran.
135 . The method of claim 79 wherein said compound of Formulae I-IV is dissolved in a solvent at a ratio of about 1 g compound of Formulae I-IV to about 1 to 5 mL solvent.
136 . The method of claim 79 further comprising adding a co-solvent prior to the step of removing the solvent.
137 . The method of claim 136 wherein said co-solvent is selected from the group consisting of methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), isopropanol (IPA), c-Hexane, heptane, toluene, dichloromethane (CH 2 Cl 2 ), and dioxane.
138 . The method of claim 136 wherein said co-solvent is methyl tert-butyl ether (MTBE).
139 . The method of claim 136 wherein the ratio of said solvent to said co-solvent is about 3:12-16 (solvent:co-solvent).
140 . The method of claim 79 wherein said compound of Formulae I-IV is diazoxide.
141 . The method of claim 140 wherein said cation source is sodium hydroxide or potassium hydroxide.
142 . The method of claim 140 wherein said solvent is selected from the group consisting, of acetonitrile, low molecular weight ketones, and tetrahydrofuran.
143 . The method of claim 140 wherein said cation source is choline hydroxide or hexamethyl hexamethylene diammonium dihydroxide.
144 . The method of claim 143 wherein said solvent is selected from the group consisting of acetonitrile, low molecular weight ketones, tetrahydrofuran, and 2-methyl tetrahydrofuran.
145 . The method of claim 143 wherein said cation source is choline hydroxide.
146 . The method of claim 145 wherein said solvent is selected from the group consisting of acetonitrile, low molecular weight ketones, tetrahydrofuran, and 2-methyl tetrahydrofuran.
147 . The method of claim 140 wherein diazoxide is dissolved in a solvent at a ratio of about 1 g diazoxide to about 1 to 5 mL solvent.
148 . The method of claim 140 further comprising adding a co-solvent prior to the step of removing the solvent.
149 . The method of claim 148 wherein said co-solvent is selected from the group consisting of methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), isopropanol (IPA), c-Hexane, heptane, toluene, dichloromethane (CH 2 Cl 2 ), and dioxane.
150 . The method of claim 148 wherein said co-solvent is methyl tert-butyl ether (MTBE).
151 . The method of claim 148 wherein the ratio of said solvent to said co-solvent is about 3:12-16 (solvent:co-solvent).