AU2012203517B2

AU2012203517B2 - Salts of potassium ATP channel openers and uses thereof

Info

Publication number: AU2012203517B2
Application number: AU2012203517A
Authority: AU
Inventors: Neil M. Cowen; Kenneth B. Kashkin; Khaled A. Yamout
Original assignee: Essentialis Inc
Current assignee: Essentialis Inc
Priority date: 2006-01-05
Filing date: 2012-06-15
Publication date: 2014-04-24
Anticipated expiration: 2026-12-20
Also published as: AU2012203517A1

Abstract

Provided are immediate or prolonged administration of certain salts of KATp channel openers such as diazoxide to a subject to achieve novel pharmacodynamic, 5 pharmacokinetic, therapeutic, physiological, metabolic and compositional outcomes in the treatment of diseases or conditions involving KA-rP 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 10 to treat diseases of humans and animals.

Description

AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT ORIGINAL Name of Applicant: Essentialis, Inc. Actual Inventors: Neil M. Cowen and Kenneth B. Kashkin and Khaled A. Yamout Address for Service is: SHELSTON IP 60 Margaret Street Telephone No: (02) 9777 1111 SYDNEY NSW 2000 Facsimile No. (02) 9241 4666 CCN: 3710000352 Attorney Code: SW Invention Title: Salts of potassium ATP channel openers and uses thereof Details of Original Application No. 2006335153 dated 20 Dec 2006 The following statement is a full description of this invention, including the best method of performing it known to me/us: File: 58846AUP01 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF FIELD OF THE INVENTION [00011 The present invention relates to salts of potassium ATP (KAWr) channel openers, meti ods of preparing such salts, and methods of use thereof for treatment of a variety of diseases and conditions, including for example, diabetes and obesity. BACKGROUND OF THE INVENTION 10002] The following description of the background of the invention is provided'as an aid in understanding the invention and is not admitted to describe or constitute prior art to the invention.. [00031 ATP-sensitive potassium (KAW) channels play important roles in a variety of tissues by coupling cellular metabolism to electrical activity. The KATP channel has been identified as an octameric complex of two unrelated proteins, which assemble in a 4:4 stoichiometry The first is a pore forming subunit, Kir6.x, which forms an inwardly rectifying K' channel; the second is an ABC (ATF binding cassette) transporter, also known as the ulfonylurea receptor (SURx) (Babenko et al., Annu. Rev. Physiol, 60:667 687 (1998)). lhe Kir6.x pore forming subunit is common for many types of Kgrr channels, and bas two putative transmembrane domains (identified as TMI and TM2), which are linked by a pore loop (115). The subunit that comprises the SUR receptor includes multiple membrane-spanning domains and two nucleotide-binding folds. 100041 According to their tissue localization, KATI channels exist in different isoforms or subspecies resulting from the assembly of the SUR and Kir subunits in multiple combinations. The combination of the SUR] with the Kir6.2 subunits (SURI/Kir6.2) typically forms the adipocyte and pancreatic B-cell type KA-m channels, whereas the SUR2A/Kir6.2 and the SUR2B/Kir6.2 or Kir6.1 combinations typically form the cardiac la type and the mooth muscle type kATP channels, respectively (Babenko et al., Annu. Rev. Physiol., 60:667-687 (1998)). There is also evidence that the channel may include Kir2.x subunits. This class of potassium channels are inhibited by intracellular ATP and activated by intracellular nucleoside diphosphates. Such KATp channels link the metabolic status of the cells to the plasma membrane potential and in this way play a key role in regulating cellular activity. In most excitatory cells, KATp channels are closed under normal physiological conditions and open when the tissue is metabolically compromised (e.g. when the (ATP:ADP) ratio falls). This promotes K efflux and cell hyperpolarization, thereby preventing voltage-operated Ca2+ channels (VOCs) from opening. (Prog. Res Research, (2001) 31:77-80). [00051 Potassium channel openers (PCOs or KCOs; also referred to as channel activators or channel agonists), are a structurally diverse group of compounds with no apparent cornmon pharmacophore linking their ability to antagonize the inhibition of KArp channels by intracellular nucleotides. Diazoxide is a PCO that stimulates KAT? channels in pancreatic fl-cells (see Trube et al., Pfluegers Arch Eur JPhysiol, 407, 493-99 (1986)). Pinacidil and chromakalim are PCOs that activate sarcolemmal potassium channels (see Escande et al., Biochem Biophys Res Commun, 154, 620-625 (1988); Babenko et al., JBiol Chem, 275(2), 717-720 (2000)). Responsiveness to diazoxide has been shown to reside in the 6 * through I 11 predicted transmembrane domains (TMD6 11) and the first nucleotide-binding fold (NBF]) of the SURI subunit. 100061 Diazoxide, which is a nondiuretic benzothiadiazine derivative having the formula 7 -chloro-3-methyl-2H-1, 2 ,4-benzothiadiazine 1.1-dioxide (empirical formula CsH7C1N 2

O

2 S), is commercialized in three distinct formulations to treat two different disease indications: (1) hypertensive emergencies and (2) hyperinsulinemic hypoglycemic conditions. 1iypertensive emergencies are treated with Hyperstat IV, an aqueous formulation o'f diazoxide for-intravenous use, adjusted to pH 11.6 with sodium hydroxide. Hyperstat IV is administered as a bolus dose into a peripheral vein to treat malignant hypertension or sulfonylurea overdose. In this use, diazoxide acts to open potassium channels in vgscular smooth muscle, stabilizing the membrane potential at the resting level, resulting in vascular smooth muscle relaxation. 2 [00071 Hyperinsulinemic hypoglycemic conditions are treated with Proglycem@, an oral pharmaceutical version of diazoxide useful for administration to infants, children and adults. It is available as a chocolate mint flavored oral suspension, which includes 7.25% alcohol, sorbitol, chocolate cream flavor, propylene glycol, magnesium aluminum silicate, carboxymethylcellulose sodium, mint flavor, sodium benzoate, methylparaben, hydrochloric'acid to adjust the pH, poloxamer 188, propylparaben and water. Diazoxide is also available as a capsule with 50 or 100 mg of diazoxide including lactose and magnesium separate. [00081 S veral experimental formulations of diazoxide have been tested in humans and animals. ;These include an oral solution tested in pharmacodynamic and pharmacokingtic studies and a tablet formulation under development in the early 1960's as an anti-hypertensive, but never commercialized (see Calesnick et al., J. Pharm. Sci. 54:1277-128Q (1965); Reddy et al., AAPSPharm Sci Tech 4(4):1-98, 9 (2003); US Patent No. 6,361,795). [0009] Current oral formulations of diazoxide are labeled for dosing two or three times per day at 8 or 12 hour intervals. Most subjects receiving diazoxide are dosed three times per day, Commercial and experimental formulations of diazoxide are characterized by rapid drug release following ingestion with complete release in approximately 2 hours. Unless indicated differently, the term "approximately" when used in the context of a numeric value, refer to the stated numeric value +/- 10%. In the context of two-theta angles from XRPD studies, the term approximately refers to +/- 5% of the stated numeric value. [00101 Current oral formulations of diazoxide in therapeutic use result in a range of adverse side effects including dyspepsia, nausea, diarrhea, fluid retention, edema, reduced rates of excretion of sodium, chloride, and uric acid, hyperglycemia, vomiting, abdominal pain, ileus, tachycardia, palpitations, and headache. (See e.g., current packaging insert for the Proglycem@). Oral treatment with diazoxide is used in individuals experiencing serious disease where failure to treat results in significant morbidity and mortality. The adverse side effects from oral administration arc tolerated because the benefits of treatment are substantial. The adverse side effects profile of oral diazoxide limit the 3 utility of the drug in treating obese subjects at doses within the labeled range of 3 to 8 mg/kg per day. [00111 The effect of diazoxide in animal models of diabetes and obesity (e.g. obese and lean Zucker rats) has been previously reported. See e.g. Alemzadeh et al., Endocrinology 133:705-712(1993); Alemzadeh et al., Metabolism 45:334-341 (1996); Alemzadeh et al., Endocrinology 140:3197-3202 (1999); Stanridge et al., FASEB J 14:455-460 (2000); Alemzadeh et al., Med Sci Mpnit 10(3): BR53-60 (2004); Alemzadeh et al., Endocrfnology 145(12):3476-3484 (2004); Aizawa et al., JofPharma Exp Ther 275(1): 194-199 (1995); and Surwit et al., Endocrinology 141:3630-3637 (2000). [0012 .The effect of diazoxide in humans with obesity or diabetes has been previously reported. See e.g., Wigand et al., Diabetes 28(4):287-291 (1979), evaluation of diazoxide on insulin receptors; Ratzmann et al., Int J Obesity 7(5):453-458 (1983), glucose tolerance and insulin sensitivity in moderately obese patients; Marugo et al., Boll Spec It Biol Sper 53:1860-1866 (1977), moderate dose diazoxide treatment on weight loss in obese patients; Alernzadeh et al., JChn Endocr Metab 83:1911-1915 (1998), low dose diazoxide treainent on weight loss in obese hyperinsulinemic patients; Guldstrand et al., Diabetes and Metabolism 28:448-456 (2002), diazoxide in obese type [I diabetic patients; Ortqvist et al., Diabetes Care 27(9):2191-2197 (2004), beta-cell function measured by circulating C-peptide in children at clinical onset of type I diabetes; Bjork et al., Diabetes Care 21(3):427-430 (1998), effect of diazoxide on residual insulin secretion in adult type I diabetes patients; and Qvigstad et al., Diabetic Medicine 21:73-76 (2004). {0013] . U.S,. Patent No. 5,284,845 describes a method for normalizing blood glucose and insulin lev 1s in an individual exhibiting normal fasting blood glucose and insulin levels and exhibiting in an oral glucose tolerance test, elevated glucose levels and at least one insulin levpl abnormality selected from the group consisting of a delayed insulin peak, an exaggerated insulin peak and a secondary elevated insulin peak. According to this reference, the method includes administering diazoxide in an amount from about 0.4 to about 0.8 mg/kg body weight before each meal in an amount effective to normalize the blobd glucose 4nd insulin levels. 4 [00141 U.S. Patent No. 6,197,765 describes administration of diazoxide for treatment for syndrome-X, and resulting complications, that include hyperlipidemia, hypertension, central obesity, hyperinsulinemia and impaired glucose intolerance. According to this reference, diazoxide interferes with pancreatic islet function by ablating endogenous insulin secretion resulting in a state of insulin deficiency and high blood glucose levels equivalent to that of diabetic patients that depend on exogenous insulin administration for normalization of their blood glucose levels. I I fOO15] U.S. Patent No. 2,986,573 describes the preparation of diazoxide and its use for the treatment of hypertension. The patent asserts that alkali metal salts may be prepared by methods well-known in the art for the preparation of a salt of a strong base with a weak acid. It also alleges a specific method for making a sodium salt of diazoxide. This patent does not provide any evidence to support the formation of any salt of diazoxide. (00161 U.. Patent No. 5,629,045 describes diazoxide for topical ophthalmic administration. 100171 WO 98/10786 describes use of diazoxide in the treatment of X-syndrome including obesity associated therewith. 100181 U.S. Patent publication no. 2003/0035106 describes diazoxide containing compounds for reducing the consumption of fat-containing foods. 100191 U.S. Patent Publication No. 2004/0204472 describes the use of a Cox-2 inhibitor plus diazoxide in the treatment of obesity. Also described therein is the use of a Cox-2 inhibitor plus a pharmaceutically acceptable salt of diazoxide, wherein acceptable cations include alkali metals and alkaline earth metals. 100201 U.S. Patent Publication No. 2002/0035106 describes use of KATP channel agonists for reducing the consumption of fat containing food. This application mentions pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts and optionally alkylated ammonium salts, but does not disclose or describe how to prepare any such salts. This patent also does not provide any evidence to support the formation of any salt of a KATr channel agonist. 5 6 [0021] U.K. Patent GB982072 describes the preparation and use of diazoxide and derivatives for the treatment of hypertension and peripheral vascular disorders. This patent mentions non-toxic alkali metals salts but does not disclose or describe how to prepare any such salts. This patent does not provide any evidence to support the 5 formation of any salt of diazoxide or its derivatives. 10021a] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. [0021bi It is an object of the present invention to overcome or ameliorate at least one 10 of the disadvantages of the prior art, or to provide a useful alternative. SUMMARY OF THE INVENTION 10021c] According to a first aspect, the invention provides a salt comprising: an anion of a KATP channel opener selected from the group consisting of Formula I to IV and a cation selected from the group consisting of a sodium cation, a 15 potassium cation, choline, and hexamethyl hexamethylene diammonium, wherein if said cation is choline or hexamethyl hexamethylene diammonium, said anion is not within Formula III or IV;

R

2 b R R1 00 00 20 Formula I Formula II

R

2 b R 3 N R R3 N R S RR4) SN Was Formula III Formula IV wherein in Formula 1: 25 6a R' is selected from the group consisting of hydrogen, CI-C 6 alkyl, substituted Cj

C

6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R' is a substituted CI-C 6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; 5 R2a is hydrogen; X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, C 1

-C

6 alkyl, substituted CI-C 6 alkyl, C 1

-C

6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C 1

-C

6 alkoxy, provided however that when an atom of the chain is substituted with substituted Ci-C 6 alkyl, 10 substituted C 1

-C

6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; wherein in Formula II: 15 R' is selected from the group consisting of hydrogen, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R' is a substituted C 1

-C

6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group;

R

2 b is hydrogen; 20 X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, CI-C 6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted Ci-C 6 alkoxy, provided however that when an atom of the chain is substituted with substituted C 1

-C

6 alkyl, substituted C 1

-C

6 alkoxy or substituted cycloalkyl, then the substituent does not 25 include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; wherein in Formula III: R' is selected from the group consisting of hydrogen, CI-C 6 alkyl, 30 substituted C 1

-C

6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; R2a is hydrogen; 6b

R

3 is selected from the group consisting of hydrogen, halogen, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 3 is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; and 5 R 4 is selected from the group consisting of hydrogen, halogen, CI-C 6 alkyl, substituted C 1

-C

6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 4 is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; wherein in Formula IV: 10 R' is selected from the group consisting of hydrogen, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; R2b is hydrogen;

R

3 is selected from the group consisting of hydrogen, halogen, C I-C 6 alkyl, 15 substituted C 1

-C

6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R3 is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; and

R

4 is selected from the group consisting of hydrogen, halogen, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, cycloalkyl and substituted cycloalkyl provided however 20 that when R 4 is a substituted Ci-C 6 alkyl, then the substituent does not include an amino group. [0021d] ' According to a second aspect, the invention provides a polymorph of a salt, said salt comprising: diazoxide, and 25 a cation selected from the group consisting of choline and potassium cation. [0021e] According to a third aspect, the invention provides a pharmaceutical formulation comprising the salt according to the first and second aspects. [0021f] According to a fourth aspect, the invention provides use of a formulation according to the third aspect for the manufacture of a pharmaceutical for treating a 30 subject suffering from Prader Willi Syndrome. [0021g] According to a fifth aspect, the invention provides use of a formulation 6c according to the third aspect for the manufacture of a pharmaceutical for (i) inhibiting fasting insulin secretion, inhibiting glucose stimulated insulin secretion, elevating energy expenditure, elevating beta oxidation of fat, or inhibiting hyperphagia, in an obese, overweight or obesity prone subject, comprising administering 5 to said subject a therapeutically effective amount of said formulation; (ii) maintaining weight loss in an obese, overweight, or obesity prone subject, comprising administering to said subject a therapeutically effective amount of said formulation; (iii) preventing the transition to diabetes of a prediabetic subject comprising 10 administering to said subject a therapeutically effective amount of said formulation; (iv) preventing or treating weight gain, dyslipidemia, diabetes or impaired glucose tolerance in a subject treated with an anti-psychotic drug, comprising administering to said subject a therapeutically effective amount of said formulation; (v) treatment of a subject suffering from or at risk for Alzheimer's disease, 15 comprising administering to said subject a therapeutically effective amount of said formulation; (vi) treatment of a subject suffering from hypoglycemia, comprising administration to said subject a therapeutically effective amount of said formulation; or (vii) treating hyperlipoproteinemia characterized by elevated triglyceride 20 comprising administering said formulation. [0021h] According to a sixth aspect, the invention provides use of a pharmaceutical formulation comprising a salt comprising: an anion of a KATP channel opener selected from the group consisting of Formula I to IV and a cation selected from the group consisting of an alkali metal 25 cation and a compound comprising an ammonium comprising a tertiary amine group, Rab N R R S _ Formula I Formula II 30 R 3 N R d RI Fnr0u0a N Fnrmn~ II~ 6d wherein in Formula I:

R

1 is selected from the group consisting of hydrogen, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl or a substituted cycloalkyl, then the 5 substituent does not include an amino group; Ra is hydrogen; X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, CI-C 6 alkyl, substituted CI-C 6 alkyl, CI-C 6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C 1

-C

6 alkoxy, provided 10 however that when an atom of the chain is substituted with substituted C 1

-C

6 alkyl, substituted Ci-C 6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; 15 wherein in Formula II: R' is selected from the group consisting of hydrogen, C 1

-C

6 alkyl, substituted Ci-C 6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R' is a substituted Ci-C 6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; 20 R 2 b is hydrogen; X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, C I-C 6 alkyl, substituted CI-C 6 alkyl, C I-C 6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C,-C 6 alkoxy, provided however that when an atom of the chain is substituted with substituted CI-C 6 alkyl, 25 substituted C 1

-C

6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; wherein in Formula III: 30 R' is selected from the group consisting of hydrogen, Ci-C 6 alkyl, substituted C 1

-C

6 alkyl, and cycloalkyl provided however that when R 1 is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; 6e R2 is hydrogen;

R

3 is selected from the group consisting of hydrogen, halogen, CI-C 6 alkyl, substituted Ci-C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 3 is a substituted CI-C 6 alkyl, then the substituent does not include an 5 amino group; and

R

4 is selected from the group consisting of hydrogen, halogen, CI-C 6 alkyl, substituted CI-C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R4 is a substituted CI-C 6 alkyl, then the substituent does not include an amino group; 10 wherein in Formula IV:

R

1 is selected from the group consisting of hydrogen, C 1

-C

6 alkyl, substituted C1-C 6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; R 2 is hydrogen; 15 R 3 is selected from the group consisting of hydrogen, halogen, C 1

-C

6 alkyl, substituted Ci-C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R3 is a substituted CI-C 6 alkyl, then the substituent does not include an amino group; and

R

4 is selected from the group consisting of hydrogen, halogen, C 1

-C

6 alkyl, 20 substituted C 1

-C

6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 4 is a substituted CI -C 6 alkyl, then the substituent does not include an amino group. for the manufacture of a pharmaceutical for: (i) restoring normal glucose tolerance in a diabetic subject, comprising 25 administering to said subject a therapeutically effective amount of said formulation; (ii) delaying or preventing the progression of diabetes in a diabetic subject, comprising administering to said subject a therapeutically effective amount of said formulation; (iii) inducing beta-cell rest or improving insulin sensitivity or both in a subject 30 with type I diabetes, comprising administering to said subject a therapeutically effective amount of said formulation; and 6f (iv) preserving pancreatic function in a subject with type I diabetes, comprising administering to said subject a therapeutically effective amount of said formulation. [0021i] According to a seventh aspect, the invention provides use of a formulation 5 comprising a salt comprising anion of a KATP channel opener selected from the group consisting of Formula I to IV and a cation selected from the group consisting of an alkali metal cation and a compound comprising an ammonium comprising a tertiary amine group, R2b 10 X S'.NRN R1 0 00 Formula I Formula II R2b 15 R 3 N R R4R3K N~ R1 Formula III Formula IV 20 wherein in Formula I: R' is selected from the group consisting of hydrogen, Ci-C 6 alkyl, substituted C 1

-C

6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R 1 is a substituted C 1

-C

6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; 25 R 2 a is hydrogen; X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, C 1

-C

6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C 1

-C

6 alkoxy, provided however that when an atom of the chain is substituted with substituted C 1

-C

6 alkyl, 30 substituted C 1

-C

6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or 6g aromatic; wherein in Formula II: R' is selected from the group consisting of hydrogen, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, cycloalkyl, and substituted cycloalkyl provided however 5 that when R' is a substituted CI-C 6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; R 2 is hydrogen; X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, C 1

-C

6 alkyl, substituted C-C 6 alkyl, C 1

-C

6 10 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C-C 6 alkoxy, provided however that when an atom of the chain is substituted with substituted C 1

-C

6 alkyl, substituted C 1

-C

6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or 15 aromatic; wherein in Formula III: Ri is selected from the group consisting of hydrogen, C-C 6 alkyl, substituted C 1

-C

6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; 20 R 2 a is hydrogen; R3 is selected from the group consisting of hydrogen, halogen, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 3 is a substituted C-C 6 alkyl, then the substituent does not include an amino group; and 25 R4 is selected from the group consisting of hydrogen, halogen, C 1

-C

6 alkyl, substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; wherein in Formula IV: 30 R' is selected from the group consisting of hydrogen, CI-C 6 alkyl, substituted C 1

-C

6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group; 6h R2b is hydrogen;

R

4 is selected from the group consisting of hydrogen, halogen, C 1

-C

6 alkyl, substituted CI-C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 4 is a substituted C 1

-C

6 alkyl, then the substituent does not include an amino group. 10 for the manufacture of a pharmaceutical for treating a subject suffering from Prader Willi Syndrome comprising administering to said subject a therapeutically effective amount of said formulation. [0021j] According to an eighth aspect, the invention provides a method for the preparation of a salt of diazoxide comprising: 15 reacting one equivalent of a cation source selected from the group consisting of sodium hydroxide, potassium hydroxide, choline hydroxide, and hexamethyl hexamethylene diammonium dihydroxide with diazoxide, wherein said diazoxide is dissolved in a solvent selected from the group consisting of acetonitrile, methyl ethyl ketone (MEK), tetrahydrofurane (THF), and 2-methyltetrahydrofurane (2MeTHF), and 20 removing the solvent. [0021k] According to a ninth aspect the invention provides a method of treatment for (i) restoring normal glucose tolerance in a diabetic subject, comprising administering to said subject a therapeutically effective amount of said formulation; (ii) delaying or preventing the progression of diabetes in a diabetic subject, 25 comprising administering to said subject a therapeutically effective amount of said formulation; (iii) inducing beta-cell rest or improving insulin sensitivity or both in a subject with type I diabetes, comprising administering to said subject a therapeutically effective amount of said formulation; and 30 (iv) preserving pancreatic function in a subject with type I diabetes, comprising administering to a subject in need of said treatment a pharmaceutical formulation as used in the sixth aspect.

6i [002111 According to a tenth aspect, the invention provides a method for the treatment for Prader Willi Syndrome comprising administering to a subject in need thereof a pharmaceutical formulation as used in the sixth or seventh aspects. [0021m] According to an eleventh aspect, the invention provides a method of 5 treatment for: (i) inhibiting fasting insulin secretion, inhibiting glucose stimulated insulin secretion, elevating energy expenditure, elevating beta oxidation of fat, or inhibiting hyperphagia, in an obese, overweight or obesity prone subject, comprising administering to said subject a therapeutically effective amount of said formulation; 10 (ii) maintaining weight loss in an obese, overweight, or obesity prone subject, comprising administering to said subject a therapeutically effective amount of said formulation; (iii) preventing the transition to diabetes of a prediabetic subject comprising administering to said subject a therapeutically effective amount of said formulation; 15 (iv) preventing or treating weight gain, dyslipidemia, diabetes or impaired glucose tolerance in a subject treated with an anti-psychotic drug, comprising administering to said subject a therapeutically effective amount of said formulation; (v) treatment of a subject suffering from or at risk for Alzheimer's disease, comprising administering to said subject a therapeutically effective amount of said 20 formulation; (vi) treatment of a subject suffering from hypoglycemia, comprising administration to said subject a therapeutically effective amount of said formulation; or (vii) treating hyperlipoproteinemia characterized by elevated triglyceride comprising administering said formulation 25 comprising the step of administering to a subject in need of said treatment a pharmaceutical formulation according to the third aspect. [0021n] According to a twelfth aspect, the invention provides a method for the treatment of Prader Willi Syndrome comprising administering to a subject in need thereof a pharmaceutical formulation according to the third, fourth or fifth aspects.

6j [0021o] According to a thirteenth aspect, the invention provides a salt of a diazoxide prepared by the method according to the eighth aspect. [0021p] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an 5 inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to". [0022] The current invention relates to methods of preparation and use of alkali metal, tertiary, amine and ammonium salts of diazoxide and diazoxide derivatives. It has been surprisingly found that it is difficult to produce salts of diazoxide and derivatives. 10 In particular, the inventors have been unable to reproduce formation of a diazoxide salt using the method asserted in U.S. Patent No. 2,986,573. Contrary to what is reported in the literature, salt formation with diazoxide and derivatives depends on a proper selection of solvent and counter-ion. [00231 Provided herein are pharmaceutical formulations of KATpe channel openers 15 and their use for treatment of various diseases and conditions including diabetes and obesity. Such formulations are characterized as being bioavailable. A KATP channel opener as used herein has any one or more of the following properties: (1) opening SURx/Kir6.y potassium channels, where x = 1, 2A or 2B and y- 1 or 2; (2) binding to the SURx subunit of KATP channels; and (3) inhibiting glucose induced release of insulin 20 following administration of the compound in vivo. Preferably, KATP channel openers are KATp channel openers with all three properties. KATP channel openers as defined herein are preferably salts prepared from the compounds of Formulae I-VIII, as set forth below. [00241 The present invention also provides salts of the compounds defined by Formulae I - VIII. Salts of Formulae I - IV provided herein include monovalent alkali 25 metal salts and, monovalent and divalent salts of organic compounds, preferably organic compounds which include an ammonium moiety. Salts of Formulae V - VIII are also provided herein, preferably prepared with monovalent and divalent counter-ions.

[00251 KATp channel openers defined by Formula I are as follows: XN R1 0 0 Formula I wherein:

R

1 is selected from the group consisting of hydrogen, lower alkyl, substituted . lower alkyl, cycloalkyl, and substituted cycloalkyl provided however that .when R' is a substituted lower alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; R2a is hydrogen; X is a l, 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, 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 3 is saturated, monounsaturated, polyunsaturated or aromatic; and all bioequivalents including salts, prodrugs and isomers thereof. [00261 In particular embodiments of Formula I, X is C(Ra)C(Rb), wherein Rs and Rb are independently selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, sulfonyl, and the like. In further embodiments, Ra and Rb are independently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted sulfonylalkylsuifinyl, alkylsulfbnyl, and the like. In a preferred embodiment, Ring B does not include any hetero atoms. (00271 Salts of embodiments of the channel openers defined by Formula I may be prepared from the following: (a) metal hydroxides, preferably alkali metal hydroxides (e.g., NaOH and KOH) and (b) organic hydroxides , preferably organic compounds which 7 include at least one tertiary amine or at least one quaternary ammonium ion (e.g., diethylamin ethanol, triethylamine, hydroxyethylpyrrolidine, choline and hexamethylhexamethylenediammonium, and the like). [0028] IQ-rp channel openers defined by Formula II are as follows:

R

2 b N R Formula II wherein:

R

1 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R' is a substituted lower alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; 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, 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 cycloalkyl or substituted lower alkoxy, then the substituent does not include an amino group; wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; and all bioequivalents including salts, prodrugs and isomers thereof. 10029] In articular embodiments of Formula II, X is C(Ra)C(Rb), wherein Ra and Rb are independently selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, sulfonyl, and the like. In further embodiments, Ra and Rb are independently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted 8 sulfonyl, alkylsulfinyl, alkylsulfonyl, nitro and the like. In preferred embodiment, Ring B does not include any heteroatoms. f0030] Salts of embodiments of the channel openers defined by Formula 11 may be prepared from the following: (a) metal hydroxides, preferably alkali metal hydroxides (e.&, NaOH and KOH) and (b) organic hydroxides , preferably organic compounds which include at least one tertiary amine or at least one quaternary ammonium ion (eg., diethylamine-ethanol, triethylamine, hydroxyethylpyrrolidine, choline and hexamethylhexamethylenediammonium, and the like). [00311 K',P channel openers defined by Formula III are as follows: R3 ItNY R' R "aS 'RE Formula III wherein:

R

1 is elected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, and cycloalkyl provided however that when R' 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? 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; and all bioequivalents including salts, prodrugs and isomers thereof. [00321 In particular embodiments of Formula III, R 1 is a lower alkyl, (preferably ethyl or meth 1); R 2 a is hydrogen; and R 3 and R 4 are each independently halogen. 9 100331 In another embodiment of Fornnula II, RI is methyl; R2a is hydrogen; R 3 is selected froni the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, and substituted cycloalkyl; and R 4 is chlorine. 10034} Slts of embodiments of the channel openers defined by Formula III may be prepared frorp the following: (a) metal hydroxides, preferably alkali metal hydroxides (e.g., NaOH ond KOH) and (b) organic hydroxides, preferably organic compounds which include at least one tertiary amine or at least one quaternary amnmonium ion (e.g., diethylamine ethanol, triethylamine, hydroxyethylpyrrolidine, choline and hexamethylhexamethylenediammonium, and the like). (00351 KATp channel openers defined by Formula IV are as follows: R3 N RI * 00 Formula IV wherein:

R

1 is selected from the group consisting of hydrogen. lower alkyl, substituted lower alkyl, and cycloalkyl provided however that when R' is a substituted ' lower alkyl, then the substituent does not include an amino group; R2b is hydrogen;

R

3 is ;elected 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; and all bioequivalents including salts, prodrugs and isomers thereof. 10036] In particular embodiments of Formula IV, RI is a lower alkyl, (preferably vthyl or methyl); R2b is hydrogen; and R 3 and R 4 are each independently halogen. 10 [0037] In another embodiment of Formula IV, R 3 is methyl; R2b is hydrogen; R 3 is selected froni the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloaikyl, and substituted cycloalkyl; and R 4 is chlorine. (0038] -Salts of embodiments of the channel openers defined by Formula IV may be prepared from the following: (a) metal hydroxides, preferably alkali metal hydroxides (e.g., NaOH and KOH) and (b) organic hydroxides, preferably organic compounds which include at least one tertiary amine or at least one quaternary ammonium ion (e.g., diethylamine'ethanol, triethylamine, hydroxyethylpyrrolidine, choline and hexamethylhexamethylenedianimonium, and the like). [00391 KArP channel openers defined by Formula V are as follows:' XN Ri 'RI Formula V wherein: RI is elected from the group consisting of optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R2a is selected from the group consisting ofhydrogen, and lower alkyl: 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, optionally substituted lower alkyl, optionally 'substituted lower alkoxy, optionally substituted cycloalkyl, or optionally substituted amino; wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; wherein at least one of R' or a substituent of X includes an amino group; and all bioequivalents including salts, prodrugs and isomers thereof. 11 [00401 Ii particular embodiments of Formula V, X is C(Ra)C(Rb), wherein Ra and Rb are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkoxy, amino, sulfonylamino, aminosulfonyl, sulfonyl, and the like. Preferably R' includes at lest one substituent containing an amino group. In further embodiments, Ra and Rb are independently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted silfonyl, substituted sulfonylamino, substituted amino, substituted amine, alkylsulfinyl,.alkylsulfonyl, alkylsulfonylamino, and the like. In a preferred embodiment, Ring B does not include any heteroatoms. 100411 KjTP channel openers defined by Formula VI are as follows: q2b xN R Formula VI wherein: RI is elected from the group consisting of optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R2b is selected from the group consisting of hydrogen and lower alkyl; 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, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, or optionally substituted amino; wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; wherein at least one of R' or a substituent of X includes an amino group; and ali bioequivalents including salts, prodmgs and isomers thereof. 12 [00421 Iri particular embodiments of Formula VI, X is C(Ra)C(Rb), wherein Ra and Rb are independently selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, amino, sulfonylamino, aminosulfonyl, sulfonyl, and the like. In further embodiments Ra and Rb are independently selected from the group consisting of hydroxyl, substituted oxy, substituted thiol, alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl, substituted sulfonyl, substituted sulfonylamino, substituted amino, substituted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, and-the like. Preferably R' includes at least one substituent containing an amino group. In a preferred embodiment, Ring B does not include any heteroatons. 100431 KATp channel openers defined by Formula VII are as follows: R3 NR R4 S 'R28 Formula VII wherein: Ri is selected from the group consisting of optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R2a is'selected from the group consisting of hydrogen, lower alkyl, and substituted 'lower alkyl;

R

3 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted amino, optionally ' substituted cycloalkyl and optionally substituted aryl;

R

4 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted amino, optionally substituted cycloalkyl and optionally substituted aryl; wherein at least one of R', R 3 and R 4 includes a substituent containing an amino group; 13 and all bioequivalents including salts, prodrugs and isomers thereof. [0044] Preferably, R 1 includes a substituent containing an amino group. In particular embodiments of Formula VII; R' includes an amino substituent, R 2 a is hydrogen; and R 3 and R 4 are edch independently halogen. 100451 In another embodiment of Formula VII, R 2 a is hydrogen; R 3 is selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, substituted auino, cycloalkyl, and substituted cycloalkyl; and R 4 is chlorine. [00461 KA-n. channel openers defined by Formula VHI are as follows: R2b 00 Formula VIII wherein: RI is $elected from the group consisting of optionally substituted amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; R2b is selected from the group consisting of hydrogen, lower alkyl, and substituted lower alkyl;

R

3 is selected from the group consisting of hydrogen, halogen, optionally 'substituted lower alkyl, optionally substituted amino, optionally ' substituted cycloalkyl and optionally substituted aryl;

R

4 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted amino, optionally substituted cycloalkyl and optionally substituted aryl; wherein at least one of R', R 3 and R 4 includes a substituent containing an amino group; and all bioequivalents including salts, prodrugs and isomers thereof, 14 100471 Pireferably R' includes a substituent containing an amino group. In particular embodiments of Formula VIII, R2b is hydrogen; and R 3 and R 4 are each independently halogen. 10048) In another embodiment of Formula VIII R2b is hydrogen; R 3 is selected from the group consisting of hydrogen, halogen, lower alkyl, optionally substituted lower alkyl, optionally substituted amino, and optionally substituted cycloalkyl; and R 4 is chlorine. 10049] Unless otherwise indicated, reference in this application to KATp channel openers should be understood to refer to KATp channel openers based upon a salt of one of the compounds described by Formulae I-VIII and having one or more, and preferably all three, of the following properties: (1) opening SURx/Kir6.y potassium channels, wherein x - 1, 2A or 2B and y = I or 2; (2) binding to the SURx subunit of K&rp channels; and (3) inhibiting glucose induced release of insulin following administration of the compound in vivo. Such KArp channel openers preferably have the structure of any of the compounds of Formula I-VfI, or more preferably Formula I1-IV where ring B or its equivalent does not include a4y heteroatoms. More preferably, the structure is diazoxide. Structural variants or bigequivalents of any of the compounds defined by Formulae I-VIII, such as derivatives, salts, prodrugs or isomers, are also contemplated herein. Specifically, salts of compounds of Formula I-IV wherein the cation is selected from a cation of an alkali metal or an organic compound which includes a tertiary amine or a quaternary ammonium ion. Preferably, when the salt includes an anion of diazoxide and a sodium cation, the salt is not in a form suitable for intravenous use. In other embodiments, when the anion is diazoxide in a solution suitable for intravenous use, the cation is not sodium. In alternate embodiments, in solutions suitable for intravenous use, when the cation is sodium, the anion is not an anion of diazoxide. In certain embodiments, when the salt includes an an~ion of diazoxide and a sodium cation, the salt is not in liquid form. More preferably, KATp channel openers contemplated herein are salts of compounds of Formulae HI a'nd IV wherein the cation is selected from sodium, potassium, choline or hexamethyl hexamethylene diammonium. Other KATp channel openers that are contemplated for use herein include BPDZ 62, BPDZ 73, NN414, BPDZ 154. 10050] Also provided herein are salts of compounds of Formula V - VII, wherein at least one substituent of the compound of Formulae V - VIT Includes an amino group. In 15 another embodiment, the compound of Formula V-VIII forms the anion of the salt and a monovalent 6r divalent metal forms the cation. In other embodiments, the cation includes a tertiary amino or quaternary ammonium group. 10051] In vitro analysis of glucose induced release of insulin via KArP channel openers can be determined using rat islets as provided by De Tullio et al., J. Med. Chem., 46:3342-3353 (2003), or by using human islets as provided by Bjorklund et al., Diabetes, 49:1840-1848 (2000). [00521 Provided herein are formulations, such as controlled release pharmaceutical formulations,of KATp channel openers and bioequivalents thereof, which include salts of the compounds of Formulae I-- VIII. In one embodiment, the salt can be formulated for controlled release following oral administration. Such formulations contain in a single administration dosage between 10 and 100 mg, between 25 and 100 mg, between 100 and 200 mg, between 200 and 300 mg, between 300 and 500 mg or between 500 and 2000 mg of the salt of the KATP channel openers provided in Formulae I - VIII. In certain embodiments, the dosage of the KATp channel openers contained in a formulation may be determined based on the weight of the subject for which it is to be administered, i.e., the formulation may contain in a single administration dosage between 0.1-20 mg of the KATp channel opener per kg of the subject's body weight, or between 0.1-0.5 mg of the KATP channel opener per kg of the subject's body weight; or between 0.5-1 mg of the KAW, channel opener per kg of the subject's body weight; or between 1-2 Ing of the KATe channel opener per kg of the subject's body weight, or between 2-5 mg of the KA-p channel opened; per kg of the subject's body weight, or between 5-10 mg of the KAT? channel opener per kg of the subject's body weight, or between 10-15 mg of the KATp channel opened per kg of the subject's body weight, or between 15-20 mg of the KATp channel opener per kg of the subject's body weight. [00531 Alsp provided herein are controlled release pharmaceutical formulations containing KAip channel openers selected from salts of Formulae I -VIII, which can be obtained by at least one of the following: (a) particle size reduction involving comminution, spray drying, or other rnicronising techniques, (b) use of an ion exchange resin, (c) use of inclusion complexes, for example cyclodextrin, (d) compaction of the KATP channel opener with a solubilizing agent including a low viscosity hypromellose, 16 low viscosity methylcellulose or similarly functioning excipient or combinations thereof, (e) associating the KAT? channel opener with a salt prior to formulation, (f) use of a solid dispersion of the KATp channel opener, (g) use of a self emulsifying system, (h) addition of one or more surfactants to the formulation, (i) use of nanoparticles, or (j) combinations of these approaches. [00541 Farther provided herein are controlled release pharmaceutical formulations containing KAw channel openers selected from salts of the compounds defined by Formulae I VII. which include at least one component that substantially inhibits release of the KA-rP channel activator from the formulation until after gastric transit. As used herein, "substantially inhibits" means less than 15% release, more preferably at least less than 10% release, or even more preferably at least less than 5% release of the drug from the formulation during gastric transport. Release can be measured in a standard USP based in-vitro gastric dissolution assay in a calibrated dissolution apparatus. See e.g., U.S. Pharmacppeia, Chapter 711 (2005). 100551 Also provided are oral pharmaceutical formulations of the KAWn channel openers selected from the salts of the compounds of Formulae I - VIII, which include at least one component that substantially inhibits release of the KAwp channel opener from the formulation until after gastric transit. Substantial inhibition of drug release during gastric transit is achieved by inclusion of a component in the formulation selected from the group consisting of: (a) a pH sensitive polymer or co-polymer applied as a compression coating on a tablet, (b) a pH sensitive polymer or co-polymer applied as a thin film on a tablet, (c) a pH sensitive polymer or co-polymer applied as a thin film to an encapsulation }ystem, (d) a pH sensitive polymer or co-polymer applied to encapsulated microparticlesi (e) a non-aqueous-soluble polymer or copolymer applied as a compression coating on a taplet, (f) a non-aqueous-soluble polymer or co-polymer applied as a thin film on a tables, (g) a non-aqueous soluble polymer applied as a thin film to an encapsulation system, and (h) a non-aqueous soluble polymer applied to microparticles, wherein the pH sensitive polymer or co-polymer is resistant to degradation under acid conditions. Alternatively, substantial inhibition of drug release during gastric transport can also be achieved by incorporation of the formulation in an osmotic pump system, by 17 use of systenis controlled by ion exchange resins, or by combinations of any of the above approaches., [0056] Also provided herein are controlled release pharmaceutical formulations of KArP channel openers selected from salts of the compounds of Formulae I - VIII, wherein the formulating includes at least one component that contributes to sustained release of a KATP channel'opener over an extended period, e.g., over a period of 2-24 hours following administration, or over a period of 2-4 hours following administration, or over a period of 4-8 hours following administration, or over a period of more than 8-24 hours following administration. These formulations are characterized in having one of the following components: -(a) a pH sensitive polymeric coating, (b) a hydrogel coating, (c) a film coating that controls the rate of diffusion of the drug from a coated matrix, (d) an erodable matrix that controls rate of drug release, (e) polymer coated pellets, granules or microparticle4 of drug which can be further encapsulated or compressed into a tablet, (f) an osmotic pump system containing the drug, (g) a compression coated tablet form of the drug, or (h) combinations of any of the approaches of(a) - (f) above. 100571 Asiused herein, an erodable matrix is the core of a tablet formulation that, upon exposure to a suitable aqueous environment, begins a process of disintegration which facilitaies the release of drug from the matrix. The rate of release of drug from the tablet is controlled both by the solubility of the drug and the rate of disintegration of the matrix. 100581 The above formulations may further comprise one or more additional pharmaceutically active agents (other than KATe channel openers selected from the salts of the compounds of Formulae I -VIII) useful for the treatment of a condition selected from the group consisting of obesity, prediabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention, other obesity associated co-morbidities, ischemic and reperfusion injury, epilepsy, cognitive impairment, schizophrenia, mania, other psychotic diseases, and the like. [00591 Further provided is a controlled release pharmaceutical formulation of a KATP channel opene selected from -the salts of the compounds of Formulae I - VIII wherein administration to an obese, overweight or obesity prone subject results in at least one of 18 the following: (a) inhibition of fasting insulin secretion, (b) inhibition of stimulated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, or (e) initibition of hyperphagia for about 24 hours. [0060] Additionally provided is a controlled release pharmaceutical formulation of a KATp channel opener selected from the salts of the compounds of Formulae I - VIII wherein administration to an obese, overweight or obesity prone subject results in at least one of the following: (a) inhibition of fasting insulin secretion, (b) inhibition of glucose stimulated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, or (e) inhibition of hyperphagia for about 18 hours. (0061] Still further provided is a controlled release pharmaceutical formulation of a KAy, channel opener selected from the salts of the compounds of Formulae I - VIII which upon administration to an obese, overweight or obesity prone subject results in at least one of the following: (a) inhibition of fasting insulin secretion, (b) inhibition of glucose stimulated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fht, or (e) inhibition of hyperphagia for about 24 hours. [00621 Additionally provided is a controlled release pharmaceutical formulation of a KAT channel pener selected from the salts of the compounds of Formulae I - VIII that upon administration to an obese, overweight or obesity prone subject results in at least one of the following: (a) inhibition of fasting insulin secretion, (b) inhibition of glucose stimulated insulin secretion, (c) elevation of energy expenditure, (d) elevation of beta oxidation of fat, or (e) inhibition of hyperphagia for about 18 hours. [0063] Prodvided herein is a method of treating hypoglycemia, the method comprising orally administering to a subject in need thereof, a controlled release formulation of a KATn channel opener selected from the salts of the compounds of Formulae I - VIII. 100641 Further provided herein is a method of treating obesity associated co morbidities in an obese, overweight or obesity prone subject, the method comprising administering a therapeutically effective amount of a solid oral dosage form of a KATp channel opener selected from the salts of the compounds of Formulae I - VIII, or controlled release pharmaceutical formulation of a KATP channel opener selected from the 19 salts of the compounds of Formulae I- VIII. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. 100651 Y1t further provided herein is a method of achieving weight loss in an obese overweight, or obesity prone subject, the method comprising administering a therapeutically effective amount of a solid oral dosage form of a KATp channel opener selected from' the salts of the compounds of Formulae I - VIII or controlled release pharmaccuticpl formulation of a KAW channel opener selected from the salts of the compounds of Fonnulae I- VIH. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. The daily dosage administered is preferably between 50 and 180 mg. In certain embodiments, the obese subject has a body mass index heater than 30 kg/r 2 , or greater than 35 kg/m 2 , or greater than 40 kg/M 2 , or greater than 5' kg/m 2 , or greater than 60 kg/M 2 at the time the method commences. 100661 Also provided is a method of maintaining a weight loss in an obese overweight, o- obesity prone subject, the method comprising administering a therapeuticall effective amount of a solid oral dosage form of a KArp channel opener selected from the salts of the compounds of Formulae I- VIII or controlled release pharmaceutical formulation of a KArP channel opener selected from the salts of the compounds ofFormulae I -VIH. It is preferable to maintain weight in an obese subject once some weight loss has occurred when the alternative is to regain weight. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. 10067] Further provided is a method of elevating energy expenditure in an overweight, oliese or obesity prone subject, the method comprising administering an effective amount of a solid oral dosage form of a KATp channel opener selected from the salts of the compounds of Formulae I - VIII or controlled release pharmaceutical formulation ofa KATp channel opener selected from the salts of the compounds of Formulae I - N4ll. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. In certain embodiments, the subject has a body mass index greater than 20 kg/m 2 , or greater than 25 kg/m 2 , or greater than 30 kg/m 2 , or greater than 35 kg/m2,|or greater than 40 kg/n2, or greater than 50 kg/m 2 , or greater than 60 kg/m 2 at the time the method commences. 20 100681 Additionally provided is a method of elevating beta oxidation of fat In an overweight, obese or obesity prone subject, the method comprising administering an effective amount of a solid oral dosage form of a KATP channel opener selected from the salts of the compounds of Formulae I - VIII or controlled release pharmaceutical formulation of a KAT channel opener selected from the salts of the compounds of Formulae I - VIIL In a preferred embodiment, administration is no more than two times per 24 hours,.or once per 24 hours. In certain embodiments, the subject has a body mass index greater'than 20 kg/m 2 , or greater than 25 kg/rm 2 , or greater than 30 kg/m 2 . or greater than 35 kg/mZ, or greater than 40 kg/n 2 , or greater than 50 kg/m 2 , or greater than 60 kg/rn 2 at the time the method commences. [00691 Yet further provided is a method of reducing visceral fat in an overweight, obese or obesity prone subject, the method comprising administering an effective amount of a solid oral dosage form of a KA-P channel opener selected from the salts of the compounds of Formulae I - VIII or controlled release pharmaceutical formulation of a KATP channel opener selected from the salts of the compounds of Formulae I - VIII. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. 10070] Still further provided is a method of delaying or preventing the transition to diabetes of a prediabetic subject comprising administering an effective amount of a KATP channel opener selected from the salts of the compounds of Formulae I -VIII or controlled release pharmaceutical formulation of a KA-rP channel opener selected from the salts of the co)npounds of Formulae I - VIII. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. [0071] Additionally provided is a method of restoring normal glucose tolerance in a prediabetic subject comprising administering an effective amount of a KATP channel opener selected from the salts of the compounds of Formulae I - VIII or controlled release pharmaceutical formulation of a KA-P channel opener selected from the salts of the compounds of Formulae I - VIII. In a preferred embodiment, administration is no more than two times per 24 ho-urs, or once per 24 hours. 21 100721 Further provided is a method of restoring normal glucose tolerance in a diabetic subject comprising administering an effective amount of a KATp channel opener selected from the salts of the compounds of Formulae I - VIII or controlled release phannaceutidal formulation of a KAI? channel opener selected from the salts of the compounds df Formulae I - VIII. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. [0073] Still further provided is a method of delaying or preventing progression of diabetes in as subject comprising administering an effective amount of a KATP channel opener selected from the salts of the compounds of Formulae I - VIII or controlled release pharmaceutical formulation of a KATp channel opener selected from the salts of the compounds of Formulae I - VIII. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. 100741 Also provided is a method to prevent or treat weight gain, impaired glucose tolerance or dyslipidemia associated with the administration of anti-psychotics to a subject, said gnethod including the co-administration of an effective amount of a KA-r channel open r selected from the salts of the compounds of Formulae I - VIII or controlled release pharmaceutical formulation of a KArp channel opener selected from the salts of the compounds of Formulae I - VIU. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. 10075J F,4rther provided is a method to treat obesity, or hyperphagia in a Prader-Willi Syndrome patient, a Froelich's Syndrome patient, in a Cohen Syndrome patient, in a Summit Syndrome patient, in an Alstrom Syndrome patient, in a Borjeson Syndrome patient or in a Bardet-Biedl Syndrome patient comprising the administration of an effective amount of a KATp channel opener selected from the salts of the compounds of Formulae I - VIII or controlled release pharmaceutical formulation of a KATp channel opener selected from the salts of the compounds of Formulae I - VIII. In a preferred embodiment, administrationn is no more than two times per 24 hours, or once per 24 hours. (00761 Sti.ll further provided is a method to treat obesity or elevated triglycerides in a patient suffering hyperlipoproteinemia type I, type 11, type III or type IV comprising administering:an effective amount of a KATp channel opener selected from the salts of the 22 compounds of Formulae I - VIII or controlled release pharmaceutical formulation of a KATP channel opener selected from the salts of the compounds of Formulae I - VIII. In a preferred embodiment, administration is no more than two times per 24 hours, or once per 24 hours. [0077] Also provided is a method of reducing the incidence of adverse effects from administration of a KATp channel opener selected from the salts of the compounds of Formulae I -VIII in the treatment of diseases of a subject achieved by any of the fallowing: (4) use of a dosage form that on administration reduces C, relative to the current Proglycem@ oral suspension or capsule products in order to reduce the incidence of adverse side effects that are associated with peak drug levels, (b) use of a dosage form that delays release until gastric transit is complete in order to reduce the incidence of adverse side effects that are associated with the release of drug in the stomach, (c) initiating dosing at subtherapeutic levels and in a stepwise manner increasing dose daily until the therapeutic dose is achieved wherein the number of steps is 2 to 10 to reduce the incidence of adverse side effects that occur transiently at the initiation of treatment, (d) use of the lovjest effective dose to achieve the desired therapeutic effect in order to reduce the incidence of adverse side effects that are dose dependent, or (e) optimizing the timing of administration of dose within the day and relative to meals. 10078] Ftrther provided is a method of preventing weight gain, dyslipidemia or impaired glu&se tolerance in a subject treated with an anti-psychotic drug, the method comprising administering a pharmaceutical formulation of a KAW channel opener selected from the salts of the compounds of Formulae I - VIII. [00791 Yet further provided is a method of treating weight gain, dyslipidemia or impaired glucpse tolerance in a subject treated with an anti-psychotic drug, the method comprising administering a pharmaceutical formulation of a KAr channel opener selected from the salts rof the compounds of Formulae I - VIII. 10080] Alpo provided is a method of treating diseases characterized by obesity, hyperphagia, dyslipidemia, or decreased energy expenditure including (a) Prader-Willi Syndrome, (b) Froelich's syndrome, (c) Cohen syndrome, (d) Summit Syndrome, (e) Alstrom Syndrome, (f) Borjesen Syndrome, (g) Bardet-Biedl Syndrome, or (h) 23 hyperlipoproteinemia type 1, 11, 111, and IV comprising administering a pharmaceutical formulation 6f a KAW channel opener selected from the salts of the compounds of Formulae I -VIH. 10081] Further provided is a pharmaceutical formulation of a KAW channel opener selected from the salts of the compounds of Formulae I-- VIII further comprising a pharmaceutically active agent other than the KATP channel opener. In this formulation, the other pharmaceutically active agent is an agent useful for the treatment of a condition selected frorr the group consisting of obesity, prediabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention, or other obesity associated co morbidities, ischemic and reperfusion injury, epilepsy, cognitive impairment, schizophrenia, mania, and other psychotic condition. 100821 like fbrmulations containing KATP channel openers selected from the salts of the compouna1s of Formulae I - VIII described herein provide for improved compliance, efficacy and safety, and for co-formulations with other agents. Included are co formulations 'of KAW channel openers selected from the salts of the compounds of Formulae I - VII1 with one or more additional pharmaceutically active agents that have complementary or similar activities or targets. Other pharmaceutically active agents that can be combined with KA-p channel openers selected from the salts of the compounds of Formulae I - VHII to treat obesity or to maintain weight loss in an obesity prone subject include, but are not limited to: sibutramine, orlistat, phentermine, rimonabant, a diuretic, an antiepileptic, or other pharmaceutical active whose therapeutic utility Includes weight loss. It is preferable to maintain weight in an obese subject once some weight loss has occurred when the alternative is to regain weight. Other pharmaceutically active agents that may be combined with KATp channel openers selected from the salts of the compounds of Formulae I - VIII to treat type H1 diabetes, or prediabetes include acarbose, miglitol, metformin, repaglinide, nateglinide, rosiglitizone, proglitizone, ramipril, metaglidasen, or any other pharmaceutical active that improves insulin sensitivity or glucose utilization or glycemic control where the mode of action is not enhanced insulin secretion. Other pharmaceutical active agent that can be combined with KArP channel openers selected from the salts of the compounds of Formulae I - VIII to treat obesity associated comorbiditics include a drug active used tolower cholesterol, a drug active 24 used to lower blood pressure, an anti-inflammatory drug that is not a cox-2 inhibitor, a drug that is an antidepressant, a drug used to treat urinary incontinence, or other drug routinely used to treat disease conditions the incidence of which is elevated in overweight or obese patients as compared to normal weight subjects including, but not limited to, drugs to treat atherosclerosis, osteoarthritis, disc herniation, degeneration of knees and hips, breast, endometrium, cervical, colon, leukemia and prostate cancers, hyperlipidemia, asthma/reactive airway disease, gallstones, GERD, obstructive sleep apnea, obesity hypoventilation syndrome, recurrent ventral hernias, menstrual irregularity and infertility. [0083] Also provided herein are methods for treating obesity or obesity associated co morbidities or other diseases or conditions involving KArP channels by co-administration to a subject in need thereof of an effective amount of any of the compounds according to Formulae I-Vm, or a salt of any of the compounds according to Formulae I-VIII or pharmaceutical formulation thereof, and a drug selected from the group consisting of an amphetamine or amphetamine mixture, Sibutranine, Orlistat, Rimonabant, a CB-1 agonist, a 5HT 2 , receptor agonist, a drug used to treat addiction, a beta adrenergic receptor agonist, an ACC inhibitor, leptin, a leptin analogue, a leptin agonist, a somatostatin agonist, an adiponectin agonist or secretagogue, Anylin, PYY or a PYY analogue, a glirelin antagonist, a drug that inhibits gastrointestinal lipases or other digestive enzymes, a de-novo lipogenesis inhibitor, a drug that blocks absorption of dietary fat, growth hormone or a growth hormone analogue, a growth hormone secretagogue, a CCK agonist, an oleoylethanolanine receptor agonist, a fatty acid synthase inhibitor, a thyroid receptor agonist, a selective androgen receptor modulator, a PPAR agonist, oxyntomodulin, oleoylestrone, a NPY2 receptor antagonist, a NPY5 receptor antagonist, a NPY agonist, a monoamine uptake inhibitor, a MTP inhibitor, a MC4 receptor agonist, a MCHI receptor antagonist a 5HT-6 antagonist, a histamine-3 antagonist, a 'gycine analog, a fgfl inhibitor, a DGAT-I inhibitor, a carboxypeptidase inhibitor, an appetite suppressant, a non-thiazide diuretic, a drug that lowers cholesterol, a drug that raises HDL cholesterol, a drug that lowers LDL cholesterol, a drug that lowers blood pressure, a drug that is an anti-depressant, a drug that improves insulin sensitivity, a drug that improves glucose utilization or uptake, a drug that is an anti-epileptic, a drug that is an anti-inflammatory, a drug that is an appetite suppressant, a drug that lowers 25 circulating triglycerides, a drug that is used to induce weight loss in an overweight or obese individual, and pharmaceutically acceptable salts thereof. [00841 Also provided herein are polymorphic forms (i.e., polymorphss") of the compounds df Formulae I - VIII, as exemplified by the X-ray Power Diffraction (XRPD) patterns shown in any of the figures. [0085] A)so provided are polymorphs of salts of diazoxide which include diazoxide and a cation selected from the group consisting of an alkali metal and a compound comprising a.tertiary amine or quaternary ammonium group. [00861 Also provided herein are methods for producing a diazoxide choline salt, which includes suspending diazoxide in a solvent and mixing with a choline salt, adding a co-solvent to 'the suspension under conditions sufficient to cause formation and precipitation of the diazoxide choline salt, and harvesting the precipitate to provide the diazoxide choline salt. 100871 Also provided herein are methods of treating obesity or obesity-related co morbidity in an obese subject, wherein the method comprising administering to a subject in need theredf an effective amount of a compound of Formula V-VIII. 10088] Also provided herein are methods for treatment of a subject suffering from or at risk fbr Alzheimer's disease (AD), which methods include administration to a subject a therapeutically effective amount of a pharmaceutical formulation comprising a compound of any of Forrhulae 1-VIII as provided herein. In some embodiments, the compound is diazoxide. Also provided herein are methods for treatment of a subject suffering from or at risk fbr AD, which methods include administration to a subject a therapeutically effective amount of a salt of a compound according to any of Formulae I-VIII. In some embodiments,: the compound is a salt of diazoxide. [0089] In another embodiment, the invention provides a method for treating hypoglycemia-by administration of an effective amount of a pharmaceutical formulation comprising-a salt selected from the group consisting of a) a salt comprising an anion of a KArp channel opener selected from the group consisting of Formula I, Formula II, Formula III arid Formula IV, and a cation selected from the group consisting of an alkali 26 metal and a compound comprising a tertiary amine or ammonium group; b) a salt comprising an anion of a Kxn, channel opener selected from the group consisting of Formula V, Formula VI, Formula VII and Formula VUII; and c) a salt comprising a cation of a KATp channel opener selected from the group consisting of Formula V, Formula VL Formula VII and Formula VIH, wherein at least one substituent comprises an amino group. [0090] In further embodiments, the hypoglycemia is selected from the group consisting of s) nighttime hypoglycemia, b) hypoglycemia attributable to a defect in insulin secreti.on, c) attributable to an insulin secreting tumor, and d) drug-induced hypoglycemia. 10091] In the present context, the term "therapeutically effective" or "effective amount" indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated. 100921 Th term pharmaceuticallyy acceptable" indicates that the identified material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectibles. [00931 As used herein, the term "composition" refers to a formulation suitable for administration'to an intended animal subject for therapeutic purposes that contains at least one pharmaceditically active compound and at least one pharmaceutically acceptable carrier or excipient. Other terms as used herein are defined below. 10094) Adipocyte: An animal connective tissue cell specialized for the synthesis and storage of fat. [00951 Agonist: A chemical compound that has affinity for and stimulates physiological activity at cell receptors normally stimulated by naturally occurring substances, triggering a biochemical response. An agonist of a receptor can also be considered an activator of the receptor. 27 [0096] About: is used herein to mean in quantitative terms plus or minus 10%. 100971 Adipose tissue: Tissue comprised principally of adipocytes. [00981 Adolescent: A person between 10 and 19 years of age. 101001 A'diponectin; A protein hormone produced and secreted exclusively by adipocytes that regulates the metabolism of lipids and glucose. Adiponectin influences the body's response to insulin. Adiponectin also has anti-inflammatory effects on the cells lining the walls of blood vessels. [01011 Aikali metal: refers to elements included in Group I of the periodic table, such as, lithium, sodium, potassium, rubidium, cesium and francium. [01021 A el oration of the symptoms of a particular disorder by administration of a particular ph naceutical composition: refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition. [01031 Arialog: a compound that resembles another in structure but differs by at least one atom. [0104) Antagonist: A substance that tends to nullify the action of another, as a drug that binds to a cell receptor without eliciting a biological response when confronted with an agonist for the receptor. 101051 Atherosclerotic Plaque: A buildup of cholesterol and fatty material within a blood vessel due to the effects of atherosclerosis [01061 Baliatric Surgery: A range of surgical procedures which are designed to aid in the management or treatment of obesity and allied diseases. [01071 Beta cell rest: Temporarily placing beta cells in a condition in which there is reduced metabolic stress due to suppressed secretion of insulin. 101081 Bilaminate: A component of a pharmaceutical dosage form that consists of the lamination .of two distinct materials. 28 [01091 Bjoavailability: Refers to the amount or extent of therapeutically active substance thdt is released from the drug product and becomes available in the body at the Intended site:of drug action. The amount or extent of drug released can be established by the phannacqkinetic-paraneters, such as the area under the blood or plasma drug concentration'-time curve (AUC) and the peak blood or plasma concentration (C .) of the drug. 101101 B(oequivalent: Two formulations of the same active substance are bioequivalenj when there is no significant difference in the rate and extent to which the active substarlce becomes available at the site of drug action when administered at the same molar dose under similar conditions. "Formulation" in this definition may include the free base 6f the active substance or different salts of the active substance. Bioequivalence may be demonstrated through several in vivo and in vitro methods. These methods, in descending order of preference, include pharmacokinetic, pharmacodynamic, clinical and in vitro studies. In particular, bioequivalence is demonstrated using pharmacokinetic measures such as the area under the blood or plasma drug concentrytion-time curve (AUC) and the peak blood or plasma concentration (Cmax) of the; drug, using statistical criteria. [0111} Capabinoid Receptor: Receptors in the endocannabinoid (BC) system associated with the intake of food and tobacco dependency. Blocking the cannabinoid receptor may reduce dependence on tobacco and the craving for food. 10112 Capsule: refers to a softgel, caplet, or any other encapsulated dosage form known to practitioners in the art, or a portion thereof. Sofigel refers a soft gelatin capsule, in agreement with the accepted nomenclature adopted by the SoftGel Association. A softgel is a one-piece, sealed, soft gelatin (or other film-forming material) shell that contains a solution, a suspension, or a semi-solid paste. [01131 Coyjbination: Refers to any association between or among two or more items. The combination can be two or more separate items, such as two compositions or two collections. It 6n be a mixture thereof, such as a single mixture of the two or more items, or any variation thereof. 29 (0114] Cpmposition: Refers to any mixture. It can be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof. [01151 C mpression tablet: Tablet formed by the exertion of pressure to a volume of tablet matrix 'in a die. (0116] C impression coated tablet: A tablet formed by the addition of a coating by compression to a compressed core containing the pharmaceutical active. As used herein the term "tablet" is intended to mean the same as a compression tablet unless indicated otherwise. 101171 Drivative: A chemical substance derived from another substance by modification or substitution. 101181 D~ily dosage: The total amount of a drug taken in a 24 hour period whether taken as a single dose or taken in multiple doses. 10119] Diazoxide: 7-chloro-3-methyl-2-H-1,2,4-benzothiadiazine 1,1 dioxide (shown below with it4 tautomer) with the empirical formula CgH7ClN 2

O

2 S and a molecular weight of 23(-7. N C or [01201 Encapsulation system: A structural feature that contains drug within such as a pharmaceutical capsule. A gel into which drug is incorporated also is considered an encapsulation'system. [0121] Equivalent amount: An amount of a derivative of a drug that in assays or upon administration to a subject produces an equal effect to a defined amount of the non derivatized dryg. 101221 Faity acid synthase: The central enzyme of a multienzyme complex that catalyses the formation of palmitate from acetylcoenzyme A, malonylcoenzyme A, and NADPH. 30 [01231 Gastric Lipase: An enzyme secreted into the gastrointestinal tract that catalyzes the'hydrolysis of dietary triglycerides. [0124] Glidant: An inactive component of a pharmaceutical formulation that prevents caking of the matrix during processing steps. [01251 Hyperinsulinemia: Excessively high blood insulin levels, which is differentiated from hyperinsulinism, excessive secretion of insulin by the pancreatic islets. Hyperinsulinernia may be the result of a variety of conditions, such as obesity and pregnancy. [0126] Hyperinsulinism: Excessive secretion of insulin by the pancreatic islets. 10127] Hyperlipidemia: A general term for elevated concentrations of any or all of the lipids in the plasma, such as cholesterol, triglycerides and lipoproteins. 101281 Hyperphagia: Ingestion of a greater than optimal quantity of food. 101291 Ingredient of a pharmaceutical composition: Ftefers to one or more materials used in the manufacture of a pharmaceutical composition. Ingredient can refer to an active ingredient (an agent) or to other materials in the compositions. Ingredients can include water and other solvents, salts, buffers. surfactants, non-aqueous solvents, and flavorings. [0130] In "in resistance: A condition in which the tissues of the body are diminished in their ability to respond to insulin. (01311 Isc emic injury: Injury to tissue that results from a low oxygen state usually due to obstruction of the arterial blood supply or inadequate blood flow leading to hypoxia in the tissue. [01321 Ketoacidosis: Acidosis accompanied by the accumulation of ketone bodies (ketosis) in the body tissue and fluids, as in diabetic acidosis. 10133] Kit: Refers to a packaged combination. A packaged combination can optionally include a label or labels, instructions and/or reagents for use with the combination. 31 [01341 Kir: Pore forming subunit of the KArp channel. Also known as the inwardly rectifying subunit of the KATP channel. Typically existing as Kir6.x and infrequently as Kir2.x subspecies. [0135] KArP channel; An ATP sensitive potassium ion channel across the cell membrane formed by the association of 4 copies of a sulfonylurea receptor and 4 copies of a pore foring subunit Kir. Agonizing the channel can lead to membrane hyperpolariza.tion. [01361 KATP channel opener: As used herein refers to a compound of any of Formulae I - VIII, or a derivative, salt or prodrug thereof, having one or more or preferably all of the followingthree properties: (1) opening SURx/Kir6.y potassium channels, where x = 1, 2A or 2B and y = 1 or 2; (2) binding to the SURx subunit of KATP channels; and (3) inhibiting glucose induced release of insulin following administration of the compound in vivo. [01371 Leptin: Product (16 kD) of the ob (obesity) locus. It is found in plasma of mammals and exerts a hormonal action, which reduces food uptake and increases energy expenditure. (01381 Lipogenesis: The generation of new lipids, primarily tiacylglycerides. It is dependent on the action of multiple distinct enzymes and transport molecules. 101391 Lipolysis: The breakdown of fat by the coordinated action of multiple enzymes. 101401 Lipoprotein lipase: An enzyme of the hydrolase class that catalyses the reaction of triacyglycerol and water to yield diacylglycerol and a fatty acid anion. The enzyme hydro~yses triacylglycerols in chylomicrons, very-low-density lipoproteins, low density lipopr teins, and diacylglycerols. 101411 Lubricant: An inactive component of a pharmaceutical formulation that provides for tle flow of materials in various processing steps, particularly tableting. [01421 Miroparticle: A small particulate formed in the process of developing pharmaceutical formulations that may be coated prior to producing the final dosage from. 32 [0143] Obesity: An increase in body weight beyond the limitation of skeletal and physical requirement, as the result of an excessive accumulation of fat in the body. Formally defined as having a body mass index greater than 30 kghn2. [0144] Obesity Prone: Subjects who because of genetic predisposition or prior history of obesity are at above average risk of becoming obese. [0145] Obesity related co-morbidities: Any disease or condition of animals or humans that Are increased incidence in obese or overweight subjects. Examples of such conditions in lude hypertension, prediabetes, type 2 diabetes, osteoarthritis and cardiovascular conditions. [0146] Omiotically controlled release: A pharmaceutical dosage form in which the release of the' active drug is principally achieved by the hydration of a swellable component of the formulation. 10147] Overweight: An subject whose weight is above that which is ideal for their height but who fails to meet the criteria for classification as obese. In humans using Body Mass Index ('g/m2) an overweight subjects has a BMI between 25 and 30. f01481 Oxidation of Fat: A series of reactions involving acyl-coenzyme A compounds, $hereby these undergo beta oxidation and thioclastic cleavage, with the formation of dcetyl-coenzyme A; the major pathway of fatty acid catabolism in living tissue. [01491 Pharmaceutical composition: Refers to a composition that contains an agent and one or more other ingredients that is formulated for administration to a subject. An agent refers to, an active ingredient of a pharmaceutical composition. Typically active ingredients are active for treatment of a disease or condition. For example, agents that can be included in pharmaceutical compositions include agents for treating obesity or diabetes. Thepharmaceutically active agent can be referred to as "a pharmaceutical active." 33 [01501 Pharmaceutical effect: Refers to an effect observed upon administration of an agent intended for treatment of a disease or disorder or for amelioration of the symptoms thereof. [01511 P armacodynamic: An effect mediated by drug action. [01521 Piarmacokinetic: Relating to the absorption, distribution, metabolism and elimination of the drug in the body. [0153] P41ymorph: A crystalline form of a compound that exists in at least two crystalline fotns. Polymorphic forms of any given compound are defined by the same chemical fon ila and/or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds. Such compounds may differ in packing origeometrical arrangement of respective crystalline lattices. The chemical and/or physical properties or characteristics of the various polymorphs may vary with each distinct polymorphic form, and may include, but are not limited to, variations in solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, and stability. 101541 Prpadipocyte: A progenitor cell to adipocytes. [0155] Prediabetic: A condition that precedes diagnosis of type U diabetes. Type II diabetes is a form of diabetes mellitus which is characterized by insulin insensitivity or resistance. 101561 Prodrug: Refers to a compound which, when metabolized, yields the desired active compound. Typically, the prodrug is inactive, or less active than the active compound, bdt may provide advantageous handling, administration, or metabolic properties. F& example, some prodrugs are esters of the active compound; during metabolysis, the ester group is cleaved to yield the active drug. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. [01571 Prolonged Administration (prolonged basis): Administration of a pharmaceutically acceptable formulation of a drug for 7 or more days. Typically, 34 prolonged administration is for at least two weeks, preferably at least one month, and even more preferably at least two months (i.e. at least 8 weeks). [01581 Quick dissolving formulation: A pharmaceutical formulation which upon oral administration may release substantially all of the drug active from the formulation within 10 minutes. [01591 Release formulation (sustained), (or "sustained release formulation"): A formulation if pharmaceutical product that, upon administration to animals, provides for release of the active pharmaceutical over an extended period of time than provided by fbrmulationsof the same pharmaceutical active that result in rapid uptake. Similar terms are extendedrelease, prolonged-release, and slow-release. In all cases, the preparation, by definition, has a reduced rate of release of active substance. [01601 Release fbrmulation (delayed), (or "delayed release formulation"): Delayed release products are modified-release, but are not extended-release. They involve the release of discrete amount(s) of drug some time after drug administration, e.g. enteric coated products, and exhibit a lag time during which little or no absorption occurs. [0161] Release formulation (controlled), (or "controlled release formulation"): A formulation of pharmaceutical product that may include both delay of release of pharmaceutical active upon administration and control of release in the manner described for sustained release. [01621 Salt: The neutral, basic or acid compound formed by the union of an acid or an acid radical and a base or basic radical. Used generally to describe any ionic compound not containing an oxide or hydroxide ion. [0163] Solid oral dosage form: Pharmaceutical formulations designed for oral administration including capsules and tablets. [01641 Subject: Refers to animals, including mammals, such as human beings, domesticated animals, and animals of commercial value. 35 [01651 Swifonylurea receptor: A component of the KArP channel responsible for interaction with sulfonylurea, other KATP channel antagonists, diazoxide and other KATe channel agonists. 101661 Thblet; Pharmaceutical dosage form that is produced by forming a volume of a matrix containing pharmaceutical active and excipients into a size and shape suitable for oral administration. 101671 Thermogenesis: The physiological process of heat production in the body. 101681 Threshold Concentration: The minimum circulating concentration of a drug required to exert a specific metabolic, physiological or compositional change in the body of a treated h an or animal. [0169] Treatment: Any manner in which the symptoms of a condition, disorder or disease or other indication, are ameliorated or otherwise beneficially altered. [0170] Triglyceride: Storage fats of animal and human adipose tissue principally consisting of glycerol esters of saturated fatty acids. 10171] Tvpe I diabetes: A chronic condition in which the pancreas makes little or no insulin because the beta cells have been destroyed. 101721 Urcoupling protein: A family of proteins that allow oxidation in mitochondria to proceed without the usual concomitant phosphorylation to produce ATP. 10173] Visceral fat: Human adipose tissues principally found below the subcutaneous fat and muscle layer in the body. ' BRIEF DESCRIPTION OF THE FIGURES [01741 Figure I shows UV spectra of the free form diazoxide and the sodium and potassium salts of diazoxide in acetonitrile. 101751 Figure 2 shows UV spectra of the free form diazoxide at varying pH. 101761 Figure 3 shows UV spectra of the free fbrm diazoxide and sodium and potassium salts of diazoxide in methanol. 36 101771 Figure 4A-D show X-Ray Powder Diffraction patterns for (a) free form diazoxide, (b) potassium salt of diazoxide from THF, (c) lysine salt of diazoxide from MEK, and (d) sodium salt of diazoxide from acetonitrile, respectively. [01781 Figures 5A-C show NMR spectra (DMSO-d6 solvent) for (a) free form diazoxide, (b) potassium salt, and (c) sodium salt, respectively. [0179] Figures 6A-C show X-Ray Powder Diffraction patterns for (a) sodium salt of diazoxide, (b) sodium salt of diazoxide after slurrying in water, and (c) free form diazoxide, respectively. [0180] Figure 7 shows DSC spectra for the free form diazoxide (top) and potassium salt of diazoxide (bottom). Description: "a" (Integral = -317.56 mJ; normalized = -84.82 Jg'1; Peak = 121.29*C); "b" (Integral = -1170.43 mJ; normalized = -154.64 Jg' 1 ; Peak = 329.2 1C); "c" (Extrap. Peak = 355.01*C; Peak Value = -4.58 mW; normalized = -1.22 Wg-'; Peak = 353.53"C). [01811 Figure 8 shows TGA spectra for the free form diazoxide (top) and potassium salt of diazoxide (bottom). [0182] Figures 9A-C show X-Ray Powder Diffraction patterns for (a) potassium salt of diazoxide, (b) potassium salt of diazoxide after slurrying in toluene, and (c) potassium salt of diazoxide after slurrying in toluene for 14 days, respectively. [01831 Figures 1OA-C show X-Ray Powder Diffraction patterns for (a) free form diazoxide, (b) choline salt of diazoxide, and (c) hexamethyl hexamethylene diammonium hydroxide salt of diazoxide, respectively. 10184] Figure 11 shows DSC spectra for the free form diazoxide (top) and choline salt of diazoxide (bottom). Description: "a" (Integral = -41.24 mJ; normalized = -8.05 Jg-'; Peak = I 19.29*C); "b" (Integral = -497.37 mJ; normalized = -97.10 Jg-'; Onset - 166.03"C; Peak = 167.27"C); "c" (Integral = -1167.83 mJ; normalized = -154.29 Jg''; Peak = 329.21*C). [01851 Figure 12 shows TGA spectra for the free form diazoxide (top) and choline salt of diazoxide (bottom). .MR_324092.1 37 [01861 Figures 13A-C show X-Ray Powder Diffraction patterns for (a) choline salt of diazoxide, (b) choline salt of diazoxide after slurrying in dichloromethane for 7 days, and (c) choline salt of diazoxide after moisture sorption analysis, respectively. [01871 Figures 14A-C show NMR spectra (DMSO-d6 solvent) for (a) free form diazoxide, (b) choline salt, and (c) hexamethyl hexamethylene diammonium hydroxide salt of diazoxide, respectively. [0188] Figure 15A shows overlay XRPD patterns of free form diazoxide, the product of potassium methoxide in methanol, and the product of sodium methoxide in methanol. Figures 15B-D show the XRPD patterns for (b) product of potassium methoxide reaction with diazoxide in methoanol, (c) product of sodium methoxide reaction with diazoxide in methanol, and (d) freeform diazoxide, respectively. 101891 Figures 16A-B show XRPD patterns of (a) polymorphic Form A of the choline salt of diazoxide, and (b) a mixture of polymorphic forms A and B of the choline salt of diazoxide. 101901 Figures 17A-B show the NMR spectra (DMSO-d6 solvent) for (a) polymorphic Form A of the choline salt of diazoxide, and (b) polymorphic Form B of the choline salt of diazoxide, respectively. [0191] Figures 18A-C show XRPD patterns of (a) polymorphic Form A of the potassium salt of diazoxide, (b) polymorphic Form B of the potassium salt of diazoxide, and (c) polymorphic Form C of the potassium salt of diazoxide, respectively. [0192] Figures 19A-D show XRPD patterns of (a) polymorphic Form D of the potassium salt of diazoxide, (b) polymorphic Form E of the potassium salt of diazoxide, (c) polymorphic Form F of the potassium salt of diazoxide, and (d) polymorphic Form G of the potassium salt of diazoxide, respectively. 101931 Figure 20 shows the DSC spectra of diazoxide choline salt Form A. Description: "a" (Extrap. Peak = 120.44"C; Peak Value = -1.02 mW; normalized = -0.20 Wg '; Peak = 118.63*C); "b" (Extrap. Peak = 167.94*C; Peak Value = -19.39 mW; normalized = -3.79 Wg'; Peak = 167.27"C). MR_324092.1 38 101941 Figure 21 shows the DSC spectra of diazoxide choline salt Form B. Description: "a" (Extrap. Peak = 165.05*C; Peak Value = -3.85 mW; normalized,- -0.86 Wg~'; Peak = 162.66*C). [01951 Figure 22 provides systolic blood pressure (SBP) and diastolic blood pressure (DBP) for Proglycem Oral Suspension (Proglycem) and Diazoxide Choline Controlled Release Tablets (DCCRT) at various times following dose administration (mean±SEM). 10196] Figure 23 provides pulse rate for Proglycem Oral Suspension (Proglycem) and Diazoxide Choline Controlled-Release Tablets (DCCRT) at various times following dose administration (mean SEM). [01971 Figure 24 provides mean plasma diazoxide (±SD) concentrations after a 200 mg dose of diazoxide (linear coordinates). [01981 Figure 25 provides mean plasma diazoxide (±SD) concentrations after a 200 mg dose of diazoxide (semilog coordinates). 10199] Figure 26 provides simulations to steady-state of once daily dosing with 200 mg diazoxide. DETAILED DESCRIPTION OF THE INVENTION [0200] The present invention provides salts of compounds of Formulae I - VIII and methods for their preparation. Salts of compounds of Formulae I - IV may be prepared using monovalent alkali metal cations and compounds which include one or more of a tertiary amine or quaternary ammonium moiety. In such salts, the compounds of Formulae I - IV exist in their anionic form. Furthermore, it has been discovered that the selection of a solvent for the preparation of these salts plays an important role in salt formation. Also described herein is the failure to obtain a salt of diazoxide from an alkali metal alkoxide using the method described in U.S. Pat. No. 2,986,573. 102011 Compounds of Formulae V - VIII can form both anions and cations, and thus salts can be prepared using a variety of counter ions, including both anions and cations. Cations of the compounds of Formulae V - VIII can be formed at an amino group, and anions of the compounds of Formulae V - VIII can be formed at either an amino group or AR_324092.1 39 Atty. Dkt. No.: 05959& Replacement Sheet at the sulfonyl group. The formation of salts based on compounds of Formulae V - VIII can be done in a variety of solvents, preferably organic solvents. 102021 As discussed herein, two polymorphic forms (i.e., Forms A and B) of the choline salt of diazoxide have been identified. In summary, both Forms A and B are anhydrous crystals of diazoxide choline salt. Diazoxide choline salt Form A can be formed using fast cooling procedures as provided herein, whereas slow cooling procedures generally favor formation of Form B. Slurry studies shows that Form A readily converts to Form B. Without wishing to be bound by theory, the slurry studies indicate that Form B of diazoxide choline salt is the thermodynamically more stable form. MR_324092.1 39-A 102031 1 regarding the potassium salt of diazoxide, seven polymorphic forms have been identified (i.e., Forms A-G). Diazoxide potassium salt Forms C, D, and F were observed be An acetone solvent, a hemihydrate, and a dioxane solvent, respectively. Forms A, B, E, and 0 were not commonly observed during screening, and elemental analysis suggests that Forms A, B, E and G may be mixtures, have residual solvent present, and/ r not be a potassium salt, at least in part. Without wishing to be bound by theory, slurry studies suggest that Form D is the thermodynamically most stable polymorph of the diazoxide potassium salt polymorphs. 10204) F rther provided are pharmaceutical formulations of particular KAip channel openers of salts of compounds of Formulae I - VIII that when administered to subjects achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, and metabolic outcomes. Yet further provided are pharmaceutical formulations, methods of administration and dosing of particular KATp channel openers selected from salts of the compounds defined by Formulae I - VHI that achieve therapeutic outcomes while reducing the incidence of adverse effects. 102051 Inparticular, pharmaceutical formulations selected from salts of compounds defined by Formulae i- VIII and formulated for oral administration exhibit advantageous properties including: facilitating consistency of absorption, pharmnacokinetic and pharmacodynamic responses across treated patients, contributing to patient compliance and improving the safety profile of the product, such as by reducing the frequency of serious advere effects. Method of treatment of metabolic and other diseases of humans and animals by administering the formulations are also provided. 102061 As shown below, diazoxide and derivatives thereof can exist as proton tautomers. Piton tautomers are isomers that differ from each other only in the location of a hydrogen atom and a double bond. The hydrogen atom and double bond switch locations between a carbon atom and a heteroatom, such as for example N. Thus, when the substituent on the nitrogen is hydrogen, the two isomeric chemical structures may be used interchangeably. 40) N 00 00 [02071 The particular KArP channel openers that can be used in the invention formulations include salts of any of the compounds within Formulae I to VIII. Exemplary compounds which have been previously reported include diazoxide, BPDZ 62, BPDZ 73- NN414 and BPDZ 154 (see, for example, Schou et al., Bioorg. Med. Chem., 13, 141-155 (2005)). Compound B3PDZ 154 also is an effective KArP channel activator in patients with hyperinsulinism and in patients with pancreatic insulinoma. The synthesis of BPDZ compound is provided in Cosgrove et al., J. Clin. EndocrinoL Metab., 87, 4860-486k (2002). 102081 Channel openers demonstrating decreased activity in the inhibition of insulin release and increased activity in vascular smooth muscle tissue have been previously reported and include analogs of diazoxide such as, for example, 3-isopropylamino-7 nethoxy-4H-l,2,4,-benzothiadiazine 1,1-dioxide, (a selective Kir6.2/SURl channel opener; see Dabrowski et al., Diabetes, 51, 1896-1906 (2002), and 2-alkyl substituted diazoxides (see, for example, Ouedraogo et al., Biol Chen., 383, 1759-1768 (2002)). The 2-alkyl si.tbstituted diazoxides generally do not function as traditional potassium channel activators, but instead show potential as Ca 2 + blockers. [02091 Other diazoxide analogs which have been previously reported include described in Schou et al., Bioorg. Med. Chem., 13, 141-155 (2005), are shown below. Rt R

R

2 QA R', R 2 and R 3 are: a) H, Cl, NHCH(CH 3

)

2 b) CF 3 , H, NHCH(CH3)2 c) H, Cl, NHCH 2

CH

2

CH(CH

3

)

2 d) H, Cl, NH-cyclobutyl 41 [02101 Diazoxide analogs having different alkyl substituents at the 3 position of the molecule (identified as R 3 shown below) are described in Bertolino et al., Receptors and Channels, 1,,267-278 (1993). H Rs N YIR3 RT 00

R

3 , R 6 and R7 are: i) nC7H I 1 , H, Cl a) H, H, CH 3 j) nC 3

H

7 , Cl, H b) H, H, Cl k) nC4H 9 , Cl, H c) CH l, CH 1) nC 5 H 1 , Cl, H d) CH 2 Cl, H, Cl m) nC 7 HisCIH e) NHz, H, H n) nC 3

H

7 , Cl, Cl f) CH 2 Ci 2 Cl, H, C g) nC 4

H

9 , H, Cl q) nC 7

H

1 1, Cl, Cl h) nC 5 i 11 , H, CI r) H, Cl, H 10211] KArp channel activity of salts of the compounds of Formulae I - VIII and related compounds can be measured by membrane potential studies as described in Schou et al., Bloorg. Med. Chem., 13, 141-155 (2005) and Dabrowski, et al., Diabetes, 51, 1896 1906 (2002). 10212] Masurement of the inhibition of glucose-stimulated insulin release from #TC6 cells is :described in Schou et al., Bioorg. Med. Chem., 13, 141-155 (2005). The ability of particular KA-rP channel openers to inhibit release of insulin from incubated rat pancreatic islets can be performed as described by Ouedraogo et al., BioL Chem., 383, 1759-1768 (2002). [0213] Activation of recombinant KATp channels by KATP channel openers can be examined by monitoring macroscopic currents of inside-out membrane patches from Xenopus oocytes co-expressing Kir6.2 and either SURI, SUR2A or SUR2B. SUR expressing me;nbranes can be prepared by known methods. See, for example, Dabrowski eta., Diabetc, 51, 1896-1906 (2002). 42 [0214] Binding experiments can be used to determine the ability of KAn, channel openers to bind SURi, SUR2A and SUR2B. See, for example, Schwanstecher et al., EMBO J., 17, 5529-5535 (1998). 102151 P separation of SURI and SUR2A chimeras, as described by Babenko et al., allows for comparison of pharmacologic profiles (i.e. sulfonyl sensitivity and responsivenees to diazoxide or other potassium channel openers) of the SURI/Kir6.2 and SUR2A/Kir6.2 potassium channels. See Babenko et al., J. Biol. Chem., 275(2), 717-720 (2000). The cloning of a sulfonylurea receptor and an inwardly rectifying K+ channel is described by lsomoto et al., J. Biol. Chem., 271 (40), 24321-24324 (1996); D'hahan et al., PNAS, 90(21), 12162-12167 (1999). 10216) Differences between the human SUR1 and human SUR2 genes are described and shown in'Aguilar-Bryan et al., Physiological Review, 78(1):227-245 (1998). [02171 "Aalo" and "halogen" refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), dr iodo (I). 102381 "l4ydroxyl" and "hydroxy" refer to the group -OH. [0219] "Substituted oxy" refers to the group -OR" , where R" can be alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl. [02201 "Substituted thiol" refers to the group -SReo, where Rbb can be alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl. [02211 " Ikyl" refers to an alkane-derived radical containing from I to 10, preferably I to 6, more preferably 1-4, yet more preferably 1-2, carbon atoms. Alkyl includes straight chain alkyl, branched alkyl and cycloalkyl, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. The alkyl group can be attached at any available point to produce a stable compound. An "alkylene" is a divalent alkyl. 43 [02221 A "substituted alkyl" is an alkyl group independently substituted with 1 or more, e.g., 1; 2, or 3, groups or substituents such as halo, hydroxy, optionally substituted alkoxy, optio'nally substituted alkylthio, alkylsulfiny, alkylsulfonyl, optionally substituted amino, optionally substituted amido, amidino, urea optionally substituted with alkyl, aminoqulfonyl optionally N-mono- or NN-di-substituted with alkyl, alkylsulfonyllamino, carboxyl, heterocycle, substituted heterocycle, nitro, cyano, thiol, sulfonylamin'o or the like attached at any available point to produce a stable compound. In particular, "fluoro substituted" refers to substitution by 1 or more, e.g., 1, 2, or 3 fluorine atonis. "Optionally fluoro substituted" means that substitution, if present, is fluoro. The thrm "optionally substituted" as used herein means that substitution may, but need not, be present. 102231 "iGower alkyl" refers to an alkyl group having 1-6 carbon atoms. [0224] A '"substituted lower alkyl" is a lower alkyl which is substituted with I or more, e.g., 1,'2, or 3, groups or substituents, as defined above, attached at any available point to produce a stable compound. [02251 "Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like. "Cycloalkylene" is a divalent cycloalkyl. [0226] "Spbstituted cycloalky1" refers to saturated or unsaturated, non-aromatic monocyclic, hicyclic or tricyclic carbon ring systems of 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like independently substituted with 1 or more, e.g., 1, 2, or 3, groups or substituents such as halo, hydroxy; optionally substituted alkoxy, optionally substituted alkylthio, alkylsulfinyl, Wlkylsulfonyl, optionally substituted amino, optionally substituted amido, amidino, ureaioptionally substituted with alkyl, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle, nitro, cyano, thiol, sulfonylamino or the like attached at any available point to produce a stable compound. 44 102271 "Aryl" alone or in combination means phenyl or naphthyl optionally carbocyclic fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members. 102281 "Substituted aryl" refers to an aryl group as defined above independently substituted with 1 or more, e.g., 1, 2, or 3, groups or substituents such as halo, hydroxy, optionally substituted alkoxy, optionally substituted alkylthio, alkylsulfinyl, alkylsulfony, optionally substituted amino, optionally substituted amido, amidino, urea optionally substituted with alkyl, aminosulfony optionally N-mono- or NN-di substituted with alkyl, alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle, nitro, cyano, thiol, sulfonylamino or the like attached at any available point to produce a stable compound. [0229] "Akoxy" denotes the group -OR*, where R* is alkyl. "Lower alkoxy" denotes the group -OR"*, where R' is lower alkyl 10230] "Substituted alkoxy" denotes the group -ORd, where R' is substituted alkyl. "Substituted lower alkoxy" denotes the group -ORad, where R is substituted lower alkyl. [0231] "AIkylthio" or "thioalkoxy" refers to the group -S-R**, here R" is alkyl. [02321 "Substituted alkylthio" or "substituted thioalkoxy" refers to the group -S-R, where R is substituted alkyl. [02331 "Siulfinyl" denotes the group -S(O)-. [02341 "Sulfonyl" denotes the group -S(O) 2

-

10235] "Substituted sulfinyl" denotes the group -S(O) -R, where Rfis alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted hetereocyclylelkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl or substituted aralkyl. [0236) "Substituted sulfonyl" denotes the group -S(O) 2 R", where Ra is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted 45 cycloalkylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted hetereocyclyalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl or substituted aralkyl. 10237] "4ulfonylanino" denotes the group - S(O) 2 NR'*- where Rbh is hydrogen or alkyl. 10238) "Substituted sulfonylamino" denotes the group -S(O) 2 NR-RiJ, where R" is hydrogen or optionally substituted alkyl, and RY is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl or substituted aralkyl. 10239] "Amino" or "amine" denotes the group -NH 2 . A "divalent amine" denotes the group -NH-. A "substituted divalent amine" denotes the group -NRk- wherein Rak is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted ac, 4, sulfonyl or substituted sulfonyl. 10240] "Substituted amino" or "substituted amine" denotes the group -NRmnRm, wherein R""" and R" are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, substituted sulkfonyl, or cycloalkyl provided, however, that at least one of R"" and R" is not hydrogen. R""R"" in combination with the nitrogen may form an optionally substituted heterocyclic or heteroaryl ring: [0241J "A kylsulfinyl" denotes the group -S(O)R", wherein R* is optionally substituted alkyl. [0242] "AkylsuIfonyl" denotes the group -S(O) 2 R', wherein RP' is optionally substituted alkyl. 10243] "Alkylsulfonylamino" denotes the-group -NRT'S(O)2R", wherein R' is optionally substituted alkyl, and R"" Is hydrogen or alkyl. 102441 A "primary amino substituent" denotes the group -NH 2 . 46 10245] A "secondary amino substituenV' denotes the group -NHR", wherein R" is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, substituted sulfonyl, or cycloalkyl. [0246) A,"tertiary amino substituent" denotes the group -NR"R", wherein R" and RaI are independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, apyl, substituted acyl, sulfonyl, substituted sulfonyl, or cycloalkyl. 102471 "(uaternary ammonium substituent" denotes the group -N*RRtRu, wherein R", R and R " are independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, sulfonyl, substituted sulfonyl, or cycloalkyl. 102481 "Heteroaryl" means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group consisting of 0, S, and N. Heteroaryl is also intended to in lude oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is retained. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indoll, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazoly), isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofiuryl, indolyl, and the like. "Heteroarylene" means a divalent heteroaryl. [0249) "Heterocycle" or "heterocyclyl" means a saturated or unsaturated, non aromatic carbo'yclic group having a single ring or multiple condensed rings, e.g. a cycloalkyl groiUp having from 5 to 10 atoms in which from 1 to 3 carbon atoms in a ring are replaced by heteroatoms, such as 0, S, N, and are optionally fused with benzo or heteroaryl of 5-6 ring members and/or are optionally substituted. Heterocyclyl is intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Examples of heterocycle or heterocyclyl groups are morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyt, and the like. 47 [02501 "leterocyclylalkyl" refers to the group -R-Het where Het is a heterocycle group and R is an alkylene group. 102511 A "substituted heteroaryl," "substituted heterocyclyl," or "substituted heterocyclylalkyl" is a heteroaryl, heterocyclyl, or heterocyclylalkyl, respectively, independently substituted with I or more, e.g., 1, 2, or 3, groups or substituents such as halogen, hydoxy, optionally substituted alkoxy, optionally substituted alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted amino, optionally substituted amido, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl, aryl or heterolryl groups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkylcarbonylanino, arylcarbonylamino, heteroarylcarbonylarnino, carboxyl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfonylamino, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, attached at any available point to produce a stable compound. [02521 "Atnido" denotes the group -C(O)NHz. "Substituted amido" denotes the group -C(O)NAkRI, wherein Rk and R' are independently hydrogen, lower alkyl, substituted locker alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, provided, however, that at least one of Rk and R' is not hydrogen. RkR in combination with the nitrogen may form an optionally substituted heterocyclic or heteroaryl ring. [02531 "Anidino" denotes the group -C(=NR")NR"R*, wherein R"', R", and R* are independently hydrogen or optionally substituted lower alkyl. [02541 "Acyloxy" denotes the group -OC(O)Rh, where R" is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and the like. [02551 "Aryloxy" denotes the group -OAr, where Ar is an aryl, or substituted aryl, group. "Heteroaryloxy" denotes groups -OHet, wherein Het is an optionally substituted heteroaryl group. 48 [0256] "Arylsulfonylamino" denotes the group -NRqS(O)2R', wherein R! is optionally substituted aryl, and R is hydrogen or lower alkyl. "Heteroarylsulfonylanino" denotes the group -NKfS(O)2R, wherein R' is optionally substituted heteroaryl, and RI is hydrogen or lower alkyl. [02571 "Alkylcarbonylamino" denotes the group -NRqC(O)RP, wherein RP is optionally substituted alkyl, and RI is hydrogen or lower alkyl. 102581 "4rylcarbonylamino" denotes the group -NRqC(O)R', wherein R! is optionally substituted aryl, and R" is hydrogen or lower alkyl. 102591 "Heteroarylcarbonyl amino" denotes the group -NRqC(O)R, wherein R is optionally substituted aryl, and Rq is hydrogen or lower alkyl. 10260] Pharmaceutical formulations containing KA7p channel openers can include the free base of a compound defined by any of Formulae I - VIII, or a salt thereof. Salts of the compounds of Formulae I - VIII as provided herein may have one or more of the following cha acteristics: (1) stability in solution during synthesis and formulation, (2) stability in a solid state, (3) compatibility with excipients used in the manufacture of tablet formulations, (4) quantitatively yield the KATp channel opener upon exposure to simulated or actual gastric and duodenal conditions, (5) release KATP channel opener from sufficiently small particles that are readily dissolved and absorbed, (6) provide, when incorporated into a pharmaceutical formulation, for absorption of greater than 80% of the administered dose, (7) present no elevated toxicological risk as compared to the free base of the KATr chnneI opener, (8) can be formulated into acceptable pharmaceutical formulations t6 treat obesity and other diseases of humans, (9) are acceptable to the FDA as the basis of a drug product, (10) can be recrystallized to improve purity, (11) can be used to form cocrystals of two or more salts of the KATP channel opener, (12) have limited hygroscopicity to improve stability, (13) synthetic and crystallization conditions under which the salt is formed can be varied resulting in different crystal structures (polymorphs) can be controlled in the synthesis of the salt, or (14) have improved solubility as compared to the free base in aqueous systems at physiological pH values. 10261] The: KAT channel openers provided in Formulae I - VIII are preferably formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are 49 non-toxic salts in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal'administration and increasing the solubility to facilitate administering lower effective doses of the drug. 102621 Salts of the compounds of Formulae I - IV can include metal cations, preferably alltali metal cations, such as for example, sodium or potassium. Cations can be selected fromi any group I alkali metal. Divalent metals cations, such as alkaline earth metals (e.g., magnesium, calcium and the like), have not been found to be useful for salt formation with the compounds of Formulac I - IV. [0263] Salts of the compounds of Formulae I - IV which include alkali metal cations can be prepared by reacting the compounds of Formulae I-- IV with an alkali metal hydroxide or alkali metal alkoxide, such as for example, NaOH, KOH or NaOCH3, in a variety of solvents which may be selected from low molecular weight ketones (e.g., acetone, methyl ethyl ketone), tetrahydrofuran (THF), dimethylformamide (DMF), and n methyl pyrrolidinone, and the like. Surprisingly, salt formation with an alkali metal hydroxide or alkoxide is not observed when an alcohol, particularly a lower alcohol such as for example methanol or ethanol, is used as the solvent. This result was confirmed by both X-Ray Pbwder Diffraction and NMR, and is contrary to the disclosure of U.S. Pat. No. 2.986,573, which purports to describe formation of diazoxide salts in alcohol. [02641 The compounds of Formulae I - IV can also form salts with organic cations that include atleast one tertiary amine or ammonium cation. Organic cation compounds can be monovilent, divalent, trivalent and tetravalent by inclusion of one, two, three or four tertiary amine or ammonium ions within the compound, respectively. When a multivalent compound is used, the tertiary amine or quaternary ammonium moieties are preferably separated by a chain of at least 4 atoms, more preferably by a chain of at least 6 atoms, such es for example, hexamethyl hexamethylene diammonium dihydroxide, wherein the quaternary ammonium moieties are separated by--(CH 2

)

6 -. Primary and secondary amihes do not to effectively form salts with the compounds of Formulae I - IV. 50 [0265] Silts of the compounds of Formulae I - IV can be prepared by reacting the compounds of Formulae I- IV with compounds that include at least one tertiary amine or quaternary aramonium ion (e.g., choline hydroxide, hexamethyihexamethylene diammonium dihydroxide) in a solvent selected from low molecular weight ketones (e.g., acetone, methyl ethyl ketone), tetrahydrofuran, dimethylformamide, and n-methyl pyrrolidinone. As with the preparation of salts from alkali metal hydroxides, amine and ammonium containing compounds do not form salts when the solvent is an alcohol. [02661 Pharmaceutically acceptable salts of the compounds of Formulae I - IV cin also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethylamino-ethanol, hydroxyethyl pyrrolidine, ammonium, tetrapropylanpmonium, tetrabutylphosphonium, hexamethyl diamrmonium, methyldiethanamine, triethylamine, meglumine, and procaine, and can be prepared using the appropriate corresponding bases. [02671 Pr'eferred basic addition salts of the compounds of Formulae I - IV can include those containing hexamethyl hexamethylene diammonium, choline, sodium, potassium, methyldiethyl amine, triethylamine, diethylamino-ethanol, hydroxyethyl pyrrolidine, tetrapropylammnonium and tetrabutylphosphonium ions. 102681 Preferred basic addition salts of the compounds of Formulae I - IV can be prepared using hexarnethyl hexamethylene diammonium dihydroxide, choline hydroxide, sodium hydroxide, sodium methoxide, potassium hydroxide, potassium methoxide, ammonium hydroxide, tetrapropylammonium hydroxide, and tetrabutylphosphonium hydroxide. The basic addition salts can be separated into inorganic salts (e.g., sodium, potassium and the like) and organic salts (e.g., choline, hexamethyl hexamethylene diammonium hydroxide, and the like). 102691 The compounds of Formulae V - VIII have the unique property of being able to form both a'nions and cations. In basic media, the compounds of Formulae V - VIII typically form. anions. Anions can be formed at either an amino or substituted amino substituent, or at the sulfonyl group. In acidic media, the compounds of Formulae V VIII generally form cations by protonation of an amino group, thereby forming an ammonium moiety. 51 [02701 Salts of the anions of compounds of Formulae V - VIII can include metal cations, inchjding monovalent metal cations of any group I alkali metal (e.g., sodium, potassium, and the like), divalent metal cations of any group II alkaline earth metal (e.g., calcium, magnesium, and the like), and aluminum cations. [02711 S41ts of the compounds of Formulae V - VIII which include metal cations can be prepared ljy reacting the compounds of Formulae V - VIII with a alkali or alkaline earth metal hydroxides or alkoxides, such as for example, sodium hydroxide or sodium methoxide, in an organic solvent, such as for example lower alcohols, low molecular weight ketones (e.g., acetone, methyl ethyl ketone, and the like), tetrahydrofuran, dimethylforniamide, and n-methyl pyrrolidinone, and the like. [0272 Salts of the compounds of Formulae V - VIII, may include organic or inorganic counter ions, including but not limited to, acetate, acetonide, acetyl, adipate, aspartate, besylate, biacetate, bitartrate, bromide, butoxide, butyrate, calcium, camsylate, caproate, carbonate, citrate cyprionate, decaroate, diacetate, dimegulumine, dinitrate, dipotassium, .dipropionate, disodium, disulfide, edisylate, enanthate, estolate, etabonate, ethylsuccinate, fumarate, furoate, gluceptate, gluconate, hexacetonide, hippurate, hyclate, hydrobromide, hydrochloride, isethionate, lactobionate, malate, maleate, meglumine, methylbromi~e, methylsulfate, metrizoate, nafate, napsylate, nitrate, oleate, palmitate, pamoate, pheppropionate, phosphate, pivalate, polistirex, polygalacturonate, probutate, propionate, saccharate, sodium glycinate, sodium phosphate, sodium succinate, stearate, succinate, sulfate, sulfonate, sulfosalicylate, tartrate, tebutate, terephalate, terephthalate, tosylate, triflutate, trihydrate, trisilicate, tromethamine, valerate, or xinafblate. Preferred organic catio)s include compounds having tertiary amines or quaternary ammonium groups. [02731 Other, pharmaceutically acceptable salts of the compounds of Formulae V VIII include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonatc, ethanesulfonate, benzenesulfonate, p-toluene sulfonate, cyclohexylsulfamate and quinate, Pharmaceutically acceptable salts of the compounds of Forrnulae V - VIII can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, Ohosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric 52 acid, malonid acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p toluenesulfoiic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid. [0274] Pharmaceutically acceptable salts of the compounds of Formulae V - VMI also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such',as carboxylic acid or phenol are present. For example, see Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995. Such .alts of the compounds of Formulae V - VTII can be prepared using the appropriate corresponding bases. 102751 Silts of the compounds of Formulae V - VIII can be prepared, for example, by dissolving the free-base form of a compound in a suitable solvent, such as an aqueous or aqueous-alcohol in solution containing the appropriate acid and then isolated by evaporating the solution. In another example, a salt is prepared by reacting the free base and acid in an organic solvent. [02761 The salts of the compounds of Formulae V - VIII may be present as a complex. Examples of complexes include 8-chlorotheophylline complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cclodextrin inclusion complexes. 10277] Solvents useful in the preparation of pharmaceutically acceptable salts of the compounds of Formulae V - VIII include organic solvents, such as for example, acetonitrile, as'etone, alcohols (e.g., methanol, ethanol and isopropanol), tetrahydrofuran, methyl ethyl l etone (MEK), ethers (e.g., diethyl ether), benzene, toluene, xylenes, dimethylfornanide (DMP), and N-methyl pyrrolidinone (NMP), and the like. Preferably, the solvents are selected from acetonitrile and MEK. 102781 The salts of compounds of Formulae V - VIf may be present as a complex. Examples of CEmplexes include 8-chlorotheophylline complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrin inclusion complexes. 53 (02791 Fmulations of salts of the compounds of Formulae I - VIII provided herein exhibit at least one, or preferably some or even more preferably, all the following characteristics: (1) they are stable at ambient temperatures for a minimum of one year; (2) they provide for ease of oral administration; (3) they facilitate patient compliance with dosing, (4) upon administration, they consistently facilitate high levels of absorption of the pharmaceutical active; (5) upon once or twice daily oral administration they allow release of thd KArP channel opener over a sustained time frame such that the circulating concentration of the KATp channel opener or its metabolically active metabolites does not fall below a therapeutically effective concentration; (6) they achieve these results independent f the pl of the gastrointestinal tract of treated subjects, and (7) they delay release until 1astric transit is complete or nearly complete. [0280] F4rmulations designed for oral administration of the salts of the compounds of Formulae I -;VHI can be provided, for example, as capsules, tablets, or as quick dissolve tablets or films. Capsule or tablet formulations include a number of distinguishing components. 'One is a component to improve absorption of the KATr channel opener. Another sustains release of the drug over more than 2 hours. A third delays substantial release of the drug until gastric transit is completed. [02811 Oral administration formulations of the salts of the compounds of Formulae I - VIII can also be provided, for example, as oral suspensions, oral solutions, encapsulated oral suspensions, and encapsulated oral solutions. Formulations can be designed fbr immediate release or controlled release. Preferably, such oral formulations are not produced frorp a liquid form of the sodium salt of diazoxide. [02821 Formulations of the salts of the compounds of Formulae I - VIII can also be prepared for transdermal, intranasal and intravenous (I.V.) administration, provided that when the anion is diazoxide and the cation is sodium, the formulation is not for intravenous use. [02831 In anotherr embodiment, formulations of the salts of the compounds of Formulae I - VMI are prepared for transdermal or intranasal ,administration, provided that when the aniop is diazoxide and the cation is sodium, the formulation is not produced using a liquid form of the salt of the compounds of Fornulae I - VIII. 54 [02841 In another embodiment, formulations of the salts of the compounds of Formulae I VIII are prepared for transdermal, intmnasal and intravenous (l.V.) administration excluding the sodium salt of diazoxide. [0285] F(rmulations of KATP channel openers prepared using salts of the compounds selected from Formulae I - Villi exhibit improved solubility and absorption compared to previous foribulations of these drugs. These advantageous properties are achieved by any one or more bf the following approaches: (1) reducing particle size of the formulation by comminutiort, spray drying, or other micronising techniques, (2) using an ion exchange resin in the formulation, (3) using inclusion complexes, for example using a cyclodextrin, (4) compaction of the salt of KATP channel opener with a solubilizing agent including low viscosity hypromellose, low viscosity methylcellulose or similarly functioning excipient and combinations thereof, (5) associating the salt of the KA-w channel opener with a distinct salt p.ior to formulation, (6) using a solid dispersion of the salt of the KATP channel open, (7) using a self emulsifying system, (8) adding one or more surfactants to the formulation, (9) using nanoparticles in the formulation, or (10) combinations of these approaches. [02861 Release of KArp channel opener selected from salts of the compounds of Formulae I - VIII over a sustained period of time (e.g., 2-30 hours) can be achieved by the use of one or more approaches including, but not limited to: (1) the use of pH sensitive polymeric coatings, (2) the use of a hydrogel, (3) the use of a film coating that controls the rite of diffusion of the drug from a coated matrix, (4) the use of an erodable matrix that controls rate of drug release, (5) the use of polymer coated pellets, granules, or microparticles which can be further encapsulated or compressed into a tablet, (6) the use of an osmuoticpump system, (7) the use of a compression coated tablet, or (8) combinations of these approaches. [02871 Delay of release of Krrp channel openers selected from the salts of the compounds of Formulae I - VIII from the formulation until gastric transit is complete can be achieved irk the formulations provided herein by any of several mechanisms. For example, pH sensitive polymer or co-polymer can be used which when applied around the drug matrix functions as an effective barrier to release of active at pH 3.0 or lower and is unstable at pH 5.5 and above. This provides for control of release of the active compound 55 in the stomach but rapidly allows release once the dosage form has passed into the small intestine. AA alternative to a pH sensitive polymer or co-polymer is a polymer or co polymer that'is non-aqueous-soluble. The extent of resistance to release in the gastric environment can be controlled by coating with a blend of the non-aqueous-soluble and a aqueous soluble polymer. In this approach neither of the blended polymers or co polymers are pH sensitive. One example of a pH sensitive co-polymer is the Budragit@ methacrylic co-polymers, including Eudragit@ L 100, S 100 or L 100-55 solids, L 30 D 55 or FS 3015 dispersions, or the L 12,5 or S 12.5 organic solutions. 10288] Polymers that delay release can be applied to a tablet either by spray coating (as a thin filni) or by compression coating. If a capsule is used, then the polymer(s) may be applied over the surface of the capsule or applied to microparticles of the drug, which may then be encapsulated such as in a capsule or gel. If the capsule is coated, then it will resist disintegration until after gastric transit. If microparticles are coated, then the capsule may disintegrate in the stomach but little to no drug will be released until after the free microparticles complete gastric transit. Finally, an osmotic pump system that uses e.g., a swellable hydrogel can be used to delay drug release in the stomach. The swellable hydrogel takes up moisture after administration. Swelling of the gel results in displacement of the drug from the system for absorption. The timing and rate of release of the drug depend on the gel used, and the rate at which moisture reaches the gel, which can be controlled by the size of the opening in the system through which fluid enters. See Drug Delivery Technologies online article Dong et al., "L-OROS@& SOFTCAP" for Controlled Release of Non-Aqueous Liquid Formulations." 102891 Accordingly, delay of release of formulations of KArp channel openers prepared as salts of the compounds of Formulae I - VIII until after gastric transit is complete can be achieved by any of several mechanisms, including, but not limited to: (a) a pH sensitive polymer or co-polymer applied as a compression coating on a tablet; (b) a pH sensi tive polymer or co-polymer applied as a thin film on a tablet; (c) a pH sensitive polyiner or co-polymer applied as a thin film to an encapsulation system; (d) a pH sensitive polymer or co-polymer applied to encapsulated microparticles, (e) a non aqueous-soludle polymer or copolymer applied as a compression coating on a tablet; (f) a non-aqueous-soluble polymer or co-polymer applied as a thin film on a tablet; (g) a non 56 aqueous soluble polymer applied as a thin film to an encapsulation system; (h) a non aqueous soluble polymer applied to microparticles; (i) incorporation of the formulation in an osmotic pbmp system, or (j) use of systems controlled by ion exchange resins, or (k) combinations of these approaches, wherein the pH sensitive polymer or co-polymer is resistant to degradation under acid conditions. [02901 Formulations are provided that are designed for administration once daily (i.e., once per 24 hours). These formulations can contain between 25 and 500 mg of KArp channel openers selected from salts of the compounds of Formulae I - VIII. Formulations'intended for administration twice daily (per 24 hours) may also be provided. These can contain between 25 and 250 mg of KArP channel openers. [02911 The formulations provided herein exhibit improved safety of the administered drug product.|This improvement in safety occurs by at least two mechanisms. First, delay of release of active drug until gastric transit is complete can reduce the incidence of a range of gastrointestinal adverse side effects including nausea, vomiting, dyspepsia, abdominal pain, diarrhea and ileus. Second, by sustaining release of the active drug over 2 or more hours up to as long as 24 hours, peak drug levels are reduced relative to the peak drug levels observed for the same administered dose using any oral formulation that does not have 'sustained or controlled release. This reduction in peak drug levels can contribute to reductions in adverse effects that are partially or completely determined by peak drug levels. These adverse effects include: fluid retention with the associated reduced rates df excretion of sodium, chloride and uric acid, edema, hyperglycemia and the associated potential for progression to ketoacidosis, cataracts and non-ketotic hyperosmolar coma, headaches, tachycardia and palpitations. [02921 Also provided herein are controlled release formulations of KArP channel openers prepared from salts of compounds of Formulae I - VIII, which have one feature from each of A-D as shown in Table 1. 57 Table 1: Controlled Release Formulation Characteristics and Properties A. Unit Form: Tablet or Capsule B. Dosage/unit: 10-100mg 100-200 mg 200-300 mg 300-500 mg 500-2000mg - C. Dosing Once daily (24 hours) Twice daily (24 hours) D. Release time: 2-4 hrs 4-8 hrs 8-24 hours [02931 For example, a controlled release composition can be a tablet containing 25 100 mg of a salt of a compound of Formulae I - VIII, wherein such tablet administered once daily to achieve a controlled release time of 2-4 hours. All of these formulations can further include the feature of substantially delaying pharmaceutical active release until after gastric t ansit is complete. [02941 In addition, any of the above formulations from Table 1 can include at least one feature thAt improves the solubility or absorption of the KATp channel opener. [02951 Exemplary controlled release formulations provided herein include the active compound (i. ., a KAW channel opener selected from a salt of a compound of any of Formulae I - VIll) and a matrix which includes a gelling agent that swells upon contact with aqueous Quid. The active compound entrapped within the gel is slowly released into the body upon dissolution of the gel. The active compound can be evenly dispersed within the matrix or can be present as pockets of drug in the matrix. For example, the drug can be fohnulated into small granules which are dispersed within the matrix. In addition, the granules of drug also can include a matrix, thus, providing a primary and a secondary matiix as described in U.S. Pat. No. 4,880,830 to Rhodes. 58 (02961 The gelling agent preferably is a polymeric material, which can include, for example, ang pharmaceutically acceptable water soluble or water insoluble slow releasing polymer suc6 as xantham gum, gelatin, cellulose ethers, gum arabic, locust bean gum, guar gum, ca'rboxyvinyl polymer, agar, acacia gum, tragacanth, veegum, sodium alginate or alginic acip, polyvinylpyrrolidone, polyvinyl alcohol, or film forming polymers such as methyl celluipse (MC), carboxymethyl cellulose (CMC), hydroxypropyl methylcellulose, hyroxypropy methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HFC), ethylcellulose (EC), acrylic resins or mixtures of the above (see e.g., U.S. Pat. No. 5,415,871). (0297] Tl e gelling agent of the matrix also can be a heterodisperse gum comprising a heteropolysaccharide component and a homopolysaccharide component which produces a fast-forming and rigid gel as described in U.S. Pat. No. 5,399,359. The matrix also can include a crogs-linking agent such as a monovalent or multivalent metal cations to further add rigidity atid decrease dissolution of the matrix, thus further slowing release of drug. The amount of crosslinking agent to add can be detenrined using methods routine to the ordinary skilled artisan. [02981 T1e matrix of the controlled release composition also can include one or more pharnaceutically acceptable recipients recognized by those skilled in the art, i.e. formulation recipients. Such recipients include, for example, binders. polyvinylpyrrblidone, gelatin, starch paste, microcrystalline cellulose; diluents (or fillers): starch, sucrose, dextrose, lactose, fructose, xylitol, sorbitol, sodium chloride, dextrins, calcium phosphate, calcium sulphate; and lubricants: stearic acid, magnesium stearate, calcium stearate, Precirol @ and flow aids for example talc or colloidal silicon dioxide. [02991 Thb matrix of the controlled release composition can further include a hydrophobic material which slows the hydration of the gelling agent without disrupting the hydrophilip nature of the matrix, as described in U.S. Pat. No. 5,399,359. The hydrophobic polymer can include, for example, alkylcellulose such as ethylcellulose, other hydroph bic cellulosic materials, polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, waxes, shellac, hydrogenated vegetable oils, waxes and waxy substances such as carnauba wax, spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol, beeswax, ceresin, 59 paraffin, mytistyl alcohol, stearyl alcohol, cetylalcohol and stearic acid, and any other pharmaceuti ally acceptable hydrophobic material known to those skilled in the art. [03001 The amount of hydrophobic material incorporated into the controlled release composition is that which is effective to slow the hydration of the gelling agent without disrupting thbh ydrophilic matrix forced upon exposure to an environmental fluid. In certain preferred embodiments, the hydrophobic material is included in the matrix in an amount from-about I to about 20 percent by weight and replaces a corresponding amount of the formulation excipient. A solvent for the hydrophobic material may be an aqueous or organic solvent, or mixtures thereof. [0301] Eanples of commercially available alkylcelluloses are Aquacoat @ (aqueous dispersion of iethylcellulose available from FMC) and Surelease @ (aqueous dispersion of ethylcellulosq available from Colorcon). Examples of commercially available acrylic polymers suitable for use as the hydrophobic material include Eudragit @ RS and RL (copolymers 4f acrylic and methacrylic acid esters having a low content (e.g., 1:20 or 1:40) of quaternary arnmonium compounds). 103021 The controlled release composition also can be coated to retard access of liquids to the Active compound and/or retard release of the active compound through the film-coating. 'The film-coating can provide characteristics of gastroresistance and enterosolubility by resisting rapid dissolution of the composition in the digestive tract. The filrn-coati g generally represents about 5-15% by weight of the controlled release composition. 'Preferably, the core by weight represents about 90% of the composition with the remaining 10% provided by the coating. Such coating can be a film-coating as is well known inithe art and include gels, waxes, fats, emulsifiers, combination of fats and emulsifiers, polymers, starch, and the like. 103031 Polymers and co-polymers are useful as thin film coatings. Solution coatings and dispersion'coatings can be used to coat the active compound, either alone or combined with a matrix. The coating is preferably applied to the drug or drug and matrix combination as a solid core of material as is well known in the art. 10304] A solution for coating can include polymers in both organic solvent and aqueous solvent systems, and typically further including one or more compounds that act 60 as a plasticizer. Polymers useful for coating compositions include, fbr example, methylcellulose (Methocel @ A; Dow Chemical Co.), hydroxypropylmethylcellulose with a molecular weight between 1,000 and 4,000,000 (Methocel @ E; Dow Chemical Co. or Pharmacoat @; Shin Etsu), hydroxypropyl cellulose with a molecular weight between 2,000 and 2,600,000, ethyl cellulose, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate ti-imellitate (Eastman Kodak), carboxymethylethyl cellulose (Duodcel @), hydroxypropyl methylcellulose phthalate, ethylcellulose, methylcellulose and, in general, cellulosic derivatives, olymethacrylic acid-methacrylic acid copolymer (Type A 1:1 Eudragit L100; Type B 1:2 Eudragit S100; and Type C 1:1 Eudragit LI 00-55, aqueous dispersion 30% solids, Eudragit L3OD), poly(meth)acryl ester: poly(ethyl acrylate, methyl methacrylate 2:1), Eudragit NE3OD aqueous dispersion 30% solids, polyaminomethacrylate Eudragit El 00, poly(trimcthylammonioethyl methacrylate chloride) ammoniomethacrylate copolymer, Eudragit RL3)D and Eudragit RS30D, carboxyvinyl polymers, polyvinylalcohols, glucans scleroglucans, mannans, and xanthans. 103051 Alueous polymeric dispersions include Budragit L30D and RS/RL3OD, and NE30D, AQTACOAT@ brand ethyl cellulose, Surelease brand ethyl cellulose, EC brand N-10F ethyl cellulose, Aquateric brand cellulose acetate phthalate, Coateric brand Poly(vinyl acetate phthalate), and Aqacoat brand hydroxypropyl methylcellulose acetate succinate. Most of these dispersions are latex, pseudolatex powder or micronized powder mediums. [03061 A plasticizing agent may be included in the coating to improve the elasticity and the stability of the polymer film and to prevent changes in the polymer permeability over prolonged storage. Such changes may affect the drug release rate. Suitable conventional pIasticizing agents include, for example, diethyl phthalate, glycerol triacetate, acetylated monoglycerides, acetyltributylcitrate, acetyltriethyl citrate, castor oil, citric acid esters, dibutyl phthalate, dibutyl sebacate, diethyloxalate, diethyl malate, diethylfumarate, diethylphthalate, diethylsuccinate, diethylmalonate, diethyltartarate, dimethylphthalate, glycerin, glycerol, glyceryl triacetate, glyceryltributyrate, mineral oil and lanolin alcohols, petrolatum and lanolin alcohols, phthalic acid esters, polyethylene glycols, propylene glycol, rape oil, sesame oil, triacetin, tributyl citrate, triethyl citrate, 61 and triethyl 4cetyl citrate, or a mixture of any two or more of the foregoing. Plasticizers which can bd used for aqueous coatings include, for example, propylene glycol, polyethylene glycol (PEG 400), triacetin, polysorbate 80, triethyl citrate, and dietbyl d tartrate. [0307] Ai coating solution comprising a mixture of hydroxypropylmethylcellulose and aqueous ethy)cellulose (e.g. Aquacoat brand) as the polymer and dibutyl sebacate as plasticizer ca be used for coating microparticles. (Aquacoat is an aqueous polymeric dispersion ofiethylcellulose and contains sodium lauryl sulfate and cetyl alcohol). Preferably, th e plasticizer represents about 1- 2 % of the composition. 103081 In: addition to the polymers, the coating layer can include an excipient to assist in formulatiooi of the coating solution. Such excipients may include a lubricant or a wetting agent. Suitable lubricants as excipients for the film coating include, for example, -talc, calcium Ntearate, colloidal silicon dioxide, glycerin, magnesium stearate, mineral oil, polyethylene glycol, and zinc stearate, aluminum stearate or a mixture of any two or more of the foregoing. Suitable wetting agents include, for example, sodium lauryl sulfate, acacia, benzalkonium chloride, cetomacrogol emulsifying wax, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolaninc, docusate sodium, sodium stearate, emulsifying wax, glyceryl monostearate, hydroxypropyl cellulose, lanolin alcohols, lecithin, mineral oil, onoethanolamine, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, pilyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, sorbitan esters, stearyl alcohol and triethanolamine, or a mixture of any two or more of the foregoing. [03091 Thg specified tablet or capsule formulations of Table 1 may include co formulation with an obesity treating drug (in addition to a KATP channel opener selected from a salt of a compound of Formulae I - VIII). Obesity treating drugs that may be used include, but are not limited to, sibutramine hydrochloride (5-30 mgtnIt), orlistat (50-360 mg/unit), pheritermine hydrochloride or resin complex (15 to 40 mg/unit), zonisamide (100 to 600 ne/unit), topiratnate (64 to 460 mg/unit), naltrexone hydrochloride (50 to 600 mg/unit), rimonabant (5 to 20 mg/unit), ADP356 (5 to 25 mg/unit), ATL962 (20 to 400 mg/unit), or AOD9604 (1 to 10 mg/unit). These formulations are preferably used once daily. For a twice daily dosing, the amount of KArP channel opener selected from a salt of 62 a compound of Formulae I-- VIT is one half the amount included in the once daily formulation and the co-formulated obesity treating drug is half of the amount specified. Alternative obesity treating drugs may include, but are not limited to: selective serotonin 2c receptor agonists, dopamine antagonists, cannabinoid-1 receptor antagonists, leptin analogues, leptin transport and/or leptin receptor promoters, neuropeptide Y and agouti related peptide antagonists, proopiomelanocortin and cocaine and amphetamine regulated transcript promoters, melanocyte-stimulating hormone analogues, melanocortin-4 receptor agonists, and agents that affect insulin metabolism/activity, which can include protein-tyrosine phosphatase-1B inhibitors, peroxisome proliferator activated receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin, astrointestinal-neural pathway agents, including those that increase cholecystokir in activity, increase glucagon-like peptide-1 activity (e.g., extendin 4, liraglutide, di'peptidyl peptidase IV inhibitors), and increase protein YY3-36 activity and those that decrease ghrelin activity, as well as anylin analogues, agents that may increase resting metabolic rate ("selective" P-3 stimulators/agonist, uncoupling protein homologues, 'and thyroid receptor agonists), melanin concentrating hormone antagonists, phytostanol analogues, amylase inhibitors, growth hormone fragments, synthetic analogues of dehydroepiandrosterone sulfate, antagonists of adipocyte 11 Bhydroxysteroid dehydrogenase type 1 activity, corticotropin releasing hormone agonists, inhibitors of fatty acid synthesis, carboxypeptidase inhibitors, indanones/indanols, aninosterols, and other gastrointestinal lipase inhibitors. [0310] The specified tablet or capsule formulations of Table I may include co formulation With a diabetes treating drug (in addition to a KA- channel opener selected from a salt ofla compound of Formulae I - VITT). Diabetes treating drugs that may be used include, .but are not limited to, acarbose (50 to 300 mg/unit), miglitol (25 to 300 mg/unit), metformin hydrochloride (300 to 2000 mg/unit), repaglinide (1-16 mg/unit), nateglinide (200 to 400 mg/unit), rosiglitizone (5 to 50 mg/unit), metaglidasen (100 to 400 mg/unit) or any drug that improves insulin sensitivity, or improves glucose utilization and uptake. These formulations are preferably used once daily. For a twice daily dosing, the amount of'the KArp channel opener selected from a salt of a compound of Formulae I - VIll is half the amount included in the once daily formulation and the co-formulated diabetes treating drug is half of the amount specified. 63 [0311] The specified tablet or capsule formulations of Table 1 may include co formulation with a cholesterol lowering drug. Cholesterol lowering drugs that may be used include but are not limited to, pravastatin, simvastatin, atorvastatin, fluvastatin, rosuvastatin or lovastatin (all at 10 to 80 mg/unit). These formulations are preferably used once da ly. For a twice daily dosing, the amount of KArP channel opener selected from a salt of a compound of Formulae I - VIII is preferably 25 to 200 mg/unit and the co-formulate i cholesterol lowering drug is half of the amount specified. [0312] T e specified tablet or capsule formulations of Table I may include co formulation with a depression treating drug. Depression treating drugs that may be used include, but are not limited to, citalopram hydrobromide (10 to 80 mg/unit), escitalopram hydrobromidb (5 to 40 mg/unit), fluvoxamine maleate (25 to 300 mg/unit), paroxetine hydrochloride (12.5 to 75 mg/unit), fluoxetine hydrochloride (30 to 100 mg/unit), setraline hydrochloride (25 to 200 mg/unit), amitriptyline hydrochloride (10 to 200 mg/unit), desipramine hydrochloride (10 to 300 mg/unit), nortriptyline hydrochloride (10 to 150 mg/unit), duloxetine hydrochloride (20 to 210 mg/unit), venlafaxine hydrochloride (37.5 to 150 ing/unit), phenelzine sulfate (10 to 30 mg/unit), bupropion hydrochloride (200 to 400 nig/unit), or mirtazapine (7.5 to 90 mg/unit). These formulations are preferably uskd once daily. For a twice daily dosing, the amount of KAWn channel opener selected from, a salt of a compound of Formulae I - VIII is preferably half the amount included in the once daily formulation and the co-formulated depression treating drug is half of the anqount specified. [0313] The specified tablet or capsule formulations of Table 1 may include co formulation with a hypertension treating drug. Hypertension treating drugs that may be used include, but are not limited, to enalapril maleate (2.5 to 40 mg/unit), captopril (2.5 to 150 mg/unit), lisinopril (10 to 40 mg/unit), benzaepril hydrochloride (10 to 80 mg/unit), quinapril hydrochloride (10 to 80 mg/unit), peridopril erbumine (4 to 8 mg/unit), ramipril (1.25 to 20 n/unit), trandolapril (1 to 8 mg/unit), fosinopril sodium (10 to 80 mg/unit), moexipril hycrochloride (5 to 20 mg/unit), losartarr potassium (25 to 200 mg/unit), irbesartan (75 to 600 mg/unit), valsartan (40 to 600 mg/unit), candesartan cilexetil (4 to 64 mg/unit), olmesartan medoxamil (5 to 80 mg/unit), telmisartan (20 to 160 mg/unit), eprosartan nesylate (75 to 600 mg/unit), atenolol (25 to 200 mg/unit), propranolol 64 hydrochloride (10 to 180 mg/unit), metoprolol tartrate, succinate or fumarate (each at 25 to 400 mg/unit), nadolol (20 to 160 mg/unit), betaxolol hydrochloride (10 to 40 mg/unit), acebutolol hydrochloride (200 to 800 mg/unit), pindolol (5 to 20 mg/unit), bisoprolol fumarate (5 to 20 mg/unit), nifedipine (15 to 100 mg/unit), felodipine (2.5 to 20 mg/unit), amlodipine besylate (2.5 to 20 mg/unit), nicardipine (10 to 40 mg/unit), nisoldipine (10 to 80 mg/unit), terazosin hydrochloride (1 to 20 mg/unit), doxasoxin mesylate (4 to 16 mg/unit), prazosin hydrochloride (2.5 to 10 mg/unit), or alfuzosin hydrochloride (10 to 20 mg/unit). These formulations are preferably used once daily. For a twice daily dosing, the amount o4KAIrP channel opener is preferably half the amount included in the once daily formulation and the co-formulated hypertension treating drug is half of the amount specified. [03141 The specified tablet or capsule formulations of Table I may include co formulation *ith a diuretic to treat edema. Diuretics that may be used include, but are not limited to amiloride hydrochloride (1 to 10 mg/unit), spironolactone (10 to 100 mg/unit), triamterene (i5 to 200 mg/unit), bumetanide (0.5 to 4 mg/unit), furosemide (10 to 160 mg/unit), ethacrynic acid or ethacrynate sodium (each at 10 to 50 mg/unit), tosemide (5 to 100 mg/unit), chlorthalidone (10 to 200 mg/unit), indapamide (1 to 5 mg/unit), hydrochloroliiazide (10 to 100 mg/unit), chlorothiazide (50 to 500 mg/unit), bendroflumethiazide (5 to 25 mg/unit),hydroflumethiazide (10 to 50 mg/unit), mythyclothiazide (1 to 5 mg/unit), or polytbiazide (1 to 10 mg/unit). These formulations are preferably used once daily. For a twice daily dosing, the amount of KATP channel opener selected from a salt of a compound of Formulae I-- VIII is preferably half the amount included in the once daily formulation and the co-formulated diuretic is half of the amount specified. [03151 The specified tablet or capsule formulations of Table I may include co formulation w ith a drug to treat inflammation or pain. Drugs for treating inflammation or pain that may be used include, but are not limited to aspirin (100 to 1000 mg/unit), tramadol hydrochloride (25 to 150 mg/unit), gabapentin (100 to 800 mg/unit), acetominophep (100 to 1000 mg/unit), carbamazepine (100 to 400 mg/unit), ibuprofen (100 to 1600 rpg/unit), ketoprofen (12 to 200 mg/unit), fenprofen sodium (100 to 600 mg/unit), flur iprofen sodium or flurbiprofen (both at 50 to 200 mg/unit), or 65 combinations of any of these with a steroid or aspirin. These formulations are preferably used once daily. For a twice daily dosing, the amount of KArp channel opener selected from a salt of a compound of Formulae I - VII is preferably half the amount included in the once daily formulation and the co-formulated diuretic is half of the amount specified. [0316] The specified tablet or capsule formulations of Table 1 may include co formulation with a drug to treat obesity associated co-morbidities include those specified above for treating diabetes, cholesterol, depression, hypertension and edema, or drugs to treat atherosclerosis, osteoarthritis, disc herniation, degeneration of knees and hips, breast, endometrial, cervical, colon, leukemia and prostate cancers, hyperlipidemia, asthma/reactve airway disease, gallstones, GERD, obstructive sleep apnea, obesity hypoventilation syndrome, recurrent ventral hernias, menstrual irregularity and infertility. 103171 Tie specified tablet or capsule formulations of Table I may include co formulation With an anti-psychotic drug the combination used to treat the psychotic condition and to treat or prevent weight gain, dyslipidemia or impaired glucose tolerance in the treated subject. Drugs for treating various psychotic conditions that may be used include, but ae not limited to, lithium or a salt thereof (250 to 2500 mg/unit), carbamazepixie or a salt thereof (50 to 1200 mg/unit), valproate, valproic acid, or divalproex (1!5 to 2500 mg/unit), lamotrigine (12.5 to 200 mg/unit), olanzapine (5 to 20 mg/unit), clozapine (12.5 to 450 mg/unit), or risperidone (0.25 to 4 mg/unit). These coformulations are preferably intended for once per day administration. For a twice daily dosing, the arpount of KArp channel opener selected from a salt of a compound of Formulae I - VIII is preferably half the amount included in the once daily formulation and the co-for-mulated anti-psychotic is half of the amount specified. 10318] The specified tablet or capsule formulations of Table 1 may include co formulation Vwith a drug to treat or prevent ischemic or reperfusion irury. Drugs for treating or preventing ischemic-or reperflsion injury that may be used include, but are not limited to: low molecular weight heparins (e.g., dalteparin, enoxaparin, nadroparin, tinzaparin or danaparoid), ancrd, pentoxifylline, nimodipine, flunarizine, ebselen, tirilazad, clomethiazole, an AMPA agonist (e.g., GYKI 52466, NBQX, YM90K, zonampanel, orvWQX), SYM 2081, selfotel, Cerestat, CP-101,606, dextrophan, dextromethorphan, MK-801, NPS 1502, remacemide, ACEA 1-021, GV150526, eliprodil 66 ifenprodil, litbeluzole, naloxone, nalfemene citicoline, acetyl-l-carnitine, nifedipine, resveratrol, a nitrone derivative, clopidogrel, dabigatram, prasugrel, troxoprodil, AGY 94806, or KAI-9803. 103191 Provided are formulations administered once or twice daily to an obese or overweight sUbject continuously result in a circulating concentration of KATP channel opener selected from a salt of a compound of Formulae I - VIII sufficient to induce weight loss. Weight loss occurs by the preferential loss of body fat. Additional weight loss can occur when the formulation is administered in combination with a reduced calorie diet, [03201 Provided are formulations of KAxr channel openers selected from a salt of a compound of, Formulae I - VIII administered as a single dose to an obese, overweight or obesity-prond subject that result in the inhibition of fasting or glucose stimulated insulin secretion fbr about 24 hours or for about 18 hours. [03211 Prpvided are formulations of KArp channel openers selected from a salt of a compound of;Formulae I - VIII administered as a single dose to an obese, overweight or obesity-prone subject that result in the elevation of energy expenditure for about 24 hours or for about l hours. [0322] Provided are formulations of Kxrp channel openers selected from a salt of a compound of Fornulae I - ViII administered as a single dose to an obese, overweight or obesity-prone subject that result in the elevation of beta oxidation of fat for about 24 hours or for alout 18 hours. 10323) Provided are formulations of KArP channel openers selected from a salt of a compound of Formulae I - VTII administered as a single dose to an obese, overweight or obesity-prone hyperphagic subject that result in the inhibition of hyperphagia for about 24 hours or for alout 18 hours. [03241 Provided are fbrnulations suitable for continuous administration once or twice daily (per 24 hours) to a subject, resulting in a circulating concentration of KATp channel openers selected from a salt of a compound of Formulae I - VIII sufficient to induce either beta-cell. rest or improved insulin sensitivity or both. Such beta-cell rest and 67 improvements in insulin sensitivity can contribute to effective treatment of type I diabetes, typb II diabetes and prediabetes. Such beta-cell rest and improvements in insulin sensitivity can contribute to effective restoration of normal glucose tolerance in type 11 diabe ic and prediabetic subjects. (03251 The various pharmaceutical KATp channel opener formulations selected from a salt of a compound of Formulae I - VIII have a variety of applications, including, but not limited to: (1) treatment of obesity; (2) prevention of weight gain in subjects who are predisposed 1o obesity; (3) treatment of hyperinsulinemia or hyperinsulinism; (4) treatment of hypoglycemia; (5) treatment of hyperlipidemia, (6) treatment of type 11 diabetes, (7) 'Preservation of pancreatic function in type I diabetics; (8) treatment of metabolic syndrome (or syndrome X); (9) prevention of the transition from prediabetes to diabetes, (10) correction of the defects in insulin secretion and insulin sensitivity contributing fo prediabetes and type 11 diabetes, (11) treatment of polycystic ovary syndrome, (I)) prevention of ischemic or reperfusion injury, (13) treat weight gain, dyslipidemia, or impairment of glucose tolerance in subjects treated with antipsychotics drugs, (14) prevent weight gain, dyslipidemia, or impairment of glucose tolerance in subjects treated with antipsychotics drugs and (15) treatment of any disease where hyperlipidemia, byperinsulinemia. hyperinsulinism, hyperlipidemia, hyperphagia or obesity are cc~tributing factors to the severity or progression of the disease, including but not limited to, Prader Willi Syndrome, Froelich's syndrome, Cohen syndrome, Summit Syndrome, Alstrom Syndrome, Borjesen Syndrome, Bardet-Biedl Syndrome, or hyperlipoproteinemia type I, 1I, IH, and IV. (0326] In one embodiment, a KAp channel opener selected from a salt of a compound of Formulae I - VIII is administered to an overweight or obese subject as an oral dosage once per 24 hours to induce weight loss. In further embodiments, the subject (a) is not a type I diabetic, (b) is not a type 11 diabetic, (c) is not experiencing chronic, recurrent or drug-induced hypoglycemia, (d) does not have metabolic syndrome, or (e) is not experiencing malignant hypertension. [0327] In pOne embodiment, a KATp channel opener selected from a salt of a compound of Formulae I - VIII is administered to an overweight or obese subject as an oral dosage twice per 24 hours to induce weight loss. This treatment can be the sole treatment to 68 induce weight loss. In further embodiments, the overweight or obese subject (a) does not have an insulin secreting tumor, (b) is not suffering from Poly Cystic Ovary Syndrome, (c) is not a type I diabetic, (d) is not a type II diabetic, (e) does not have metabolic syndrome, (f) is not experiencing chronic recurrent or drug-induced hypoglycemia, (g) has not been'treated for schizophrenia with haloperidol, or (h) is not experiencing malignant hypertension. In further embodiments, the overweight or obese adolescent (a) has not been diagnosed as being type I or type II diabetic, (b) is not experiencing chronic, recurrent or drug-induced hypoglycemia, or (c) has not been diagnosed as having metabolic syndrome. [0328] In another embodiment, a KATp channel opener selected from a salt of a compound ofFormulae I - VIII is administered to an overweight or obese subject as an oral dosage form three times per 24 hours to induce weight loss. This treatment can be the sole treatment to induce weight loss. In further embodiments, the overweight or obese subject (a) does not have an insulin-secreting tumor, (b) is not suffering from Poly Cystic Ovary Syndrome, (c) is not a type I diabetic, (d) is not a type II diabetic, (e) does not have metabolic syndrome, or (f) is not experiencing chronic, recurrent or drug-induced hypoglycemiA. [03291 In another embodiment, a KATP channel opener selected from a salt of a compound of Formulae I - VIII is administered to an overweight or obese adolescent as an oral dosage form three times per 24 hours to induce weight loss. This treatment can be the sole treatrhent to induce weight loss. In further embodiments, the overweight or obese adolescent is (a) is not a type I or type I diabetic, (b) is not experiencing chronic, recurrent or diug-induced hypoglycemia or (c) does not have metabolic syndrome. [03301 In another embodiment, a KrP channel opener selected from a salt of a compound of Formulae I - VIII is administered as an oral dosage form three times per 24 hours to indude weight loss to an overweight or obese adult who (a) is not simultaneously receiving glucagon injections, triiodothyroxin or furosemide, (b) is not being treated for schizophrenia with haloperidol, or (c) is not experiencing malignant hypertension. 69 103311 In another embodiment, a KArp channel opener selected from a salt of a compound of Formulae I - VIII is administered to an overweight or obese subject as an oral dosage fprm four times per 24 hours to induce weight loss. 103321 I another embodiment, a KAT channel opener selected from a salt of a compound o Formulae I - VIII is administered to an overweight or obese subject as an oral dosage form administered from one, two, three or four times per 24 hours to induce weight loss af a daily dose of 50 to 700 mg. In a further embodiment, the overweight or obese subject (a) is not type I diabetic, (b) is not type 11 diabetic, (c) is not suffering chronic, recurent or drug-induced hypoglycemia, Or (d) does not have metabolic syndrome. 10333] In. another embodiment, a KArP channel opener selected from a salt of a compound of Formulae I - VIII is administered to an overweight or obese subject as an oral dosage form administered from one, two, three or four times per 24 hours to induce weight loss ai a daily dose of 130 to 400 mg. In a further embodiment, the overweight or obese subject (a) is not type I diabetic, (b) is not type 11 diabetic, (c) is not suffering chronic, recurrent or drug-induced hypoglycemia, or (d) does not have metabolic syndrome. [03341 In other embodiments, a KATP channel opener selected from a salt of a compound of.Formulae I - VIII is administered to an overweight or obesity prone subject as an oral dosage form one, two, three or four times per 24 hours to maintain a weight loss, as it is preferable to maintain weight in an obese subject once some weight loss has occurred when the alternative is to regain weight. In a further embodiment, the administered aaily dose of the KAr, channel opener is 50 to 275 mg. [0335) In other embodiments, a KA-rp channel opener selected from a salt of a compound of Pormulae I - VIII is-administered as an oral dosage form to an overweight, obese, or obesity prone subject to (a) elevate energy expenditure, (b) elevate beta oxidation of fat, or (c) reduce circulating triglyceride concentrations. [0336] In other embodiments, an oral dosage of a KATp channel opener selected from a salt of a corripound of Formulae I --VIII is administered to an subject in need thereof to induce the loss of 25%, 50%, or 75% of initial body fat. 70 [03371 Ii another embodiment, an oral dosage of a KArp channel opener selected from a salt of a coinpound of Formulae I - VI[ is administered to an subject in need thereof to induce (a) the preferential loss of body fat or (b) the preferential loss of visceral body fat. 103381 In' additional embodiments, an oral dosage of a KATP channel opener selected from a salt of a compound of Formulae I - VMI is administered one, two or three times per 24 hours at daily doses of 50 to 700 mg to an subject to (a) induce the loss of 25%, 50% or 75% bf initial body fat, (b) induce the preferential loss of body fat, or (c) induce the preferential loss of visceral fat. [0339] In, another embodiment, an oral dosage of a KArp channel opener selected from a salt of a compound of Formulae I - VII is administered to an subject to induce the preferential loss of body fat and to induce reduction in circulating triglycerides. [03401 In; another embodiment, an oral dosage of a KA-I channel opener selected from a salt of a compound of Formulae I - VIII is co-administered with sibutramine, orlistat, rimonabant, an appetite suppressant, an anti-depressant, an anti-epileptic, a diuretic, a drug that inddces weight loss by a mechanism that is distinct from a KATP channel opener, or a drug that'lowers blood pressure, to induce weight loss and/or treat obesity associated co-morbidities in an overweight, obese, or obesity prone subject. In further embodiments, the overweight, obese, or obesity prone subject (a) is a type I diabetic, (b) is not a type H diabetic, (c) is not suffering from chronic, recurrent or drug-induced hypoglycemia, or (d) does not havermetabolic syndrome. (03411 In another embodiment an oral dosage of a KAT channel opener selected from a salt of a compound of Fonnulae I -VIUI is co-administered with an anti-depressant, a drug that lowers blood pressure, a drug that lowers cholesterol, a drug that raises HDL, an anti-inflammatory that is not a Cox-2 inhibitor, a drug that lowers circulating triglycerides, to an overweight, obese, or obesity prone subject to induce weight loss and/or treat obesity associated co-morbidities. In further embodiments, the overweight, obese, or obesity prone subject (a) is not a type I diabetic, (b) is not a type II diabetic, (c) is not suffering from chronic, recurrent or drug-induced hypoglycemia, or (d) does not have metabolic syndrome. 71 [03421 hi another embodiment, an oral dosage of a KATP channel opener selected from a salt of a compound of Formulae I - VIII is co-administered with a drug that lowers blood pressure, a drug that lowers cholesterol, a drug that raises HDL, an anti inflammatori, that is not a Cox-2 inhibitor, a drug that lowers circulating triglycerides, to maintain weight and/or treat obesity associated co-morbidities in an overweight, obese, or obesity prone subject, as it is preferable to maintain weight in an obese subject once some weight loss has occurred when the alternative is to regain weight. In further embodiments, the overweight, obese, or obesity prone subject (a) is not a type I diabetic, (b) is not a type II diabetic, (c) is not suffering from chronic, recurrent or drug-induced hypoglycemia, or (d) does not have metabolic syndrome. [03431 In! additional embodiments, an oral dosage form of a KATP channel opener selected frong a salt of a compound of Formulae I- VIII is used to administer a therapeutically effective dose of a KATP channel opener to an obese, overweight or obesity prone subject in need thereof to treat obesity, to (a) provide beta cell rest, (b) treat type I or type II diabetes, or (c) prevent the occurrence of diabetes. [0344] In additional embodiments, an oral dosage form of a KArP channel opener selected from a salt of a compound of.Formulae I - VIII is co-administered with Phentermine or a derivative thereof to an obese adult or adolescent to induce weight loss and/or treat obesity and obesity-associated co-morbidities. In further embodiments, a solid oral dosage form or tablet formulation of a KATP channel opener is co-administered with Phenterrpine or a derivative thereof to an obese adult or adolescent to treat metabolic syndrome in a patient in need thereof. [03451 In further embodiments, a pharmaceutically acceptable formulation of a KATP channel open selected from a salt of a compound of Formulae I - VIII at doses of 50 to 700 mg/day is co-administered with Phentermine or a derivative thereof at daily doses of 15 to 37.5 mg to an overweight or obese subject to induce weight loss, to treat metabolic syndrome, or to induce weight loss and treat obesity-associated co-morbidities. [03461 In Another embodiment, a quick dissolving formulation of a KATP channel opener selected from a salt of a compound of Formulae I -VIII is used to provide a therapeutically effective dose to a patient-in need thereof. 72 [03471 In further embodiments, a KATP channel opener selected from a salt of a compound of Formulae I - VIII is administered once per 24 hours at doses of 50 mg to 700 mg to an overweight or obese subject. [0348] In further embodiments, a KATp channel opener selected from a salt of a compound ofFormulae I - VHI is formulated as a tablet or capsule for oral administratin. The tablet or capsule may be co-formulated with metformin. In another embodiment, a KArP channel opener selected from a salt of a compound of Formulae I VIII is formulated as an oral suspension or solution, and the oral suspension or solution may be further encapsulated in another embodiment. [0349]. In another embodiment, a pharmaceutical salt of a KArP channel opener selected from a salt of a compound of Formulae I - V111 is formulated as a tablet or capsule for oral administration, or as an oral suspension or as an oral solution, or as an oral suspension or solution that is encapsulated. 103501 In' another embodiment a KA7P channel opener selected from a salt of a compound of Formulae I - VI is co-formulated with hydro-chlorothiazide, chlorothiazide, cyclothiazide, benzthiazide, metyclothiazide, bendro-flumethiazide, hydroflumethiazide, trichlormethiazide, or polythiazide in a pharmaceutical formulation suitable for oral administration. 103511 Upon administration of formulations which include a salt of a compound of Formulae I - VIII provided herein to humans or animals, some or all of the following effects are observed: (1) the production of lipoprotein lipase by adipocytes is reduced; (2) enhanced lipolysis by adipocytes; (3) expression of fatty acid synthase by adipocytes is reduced; (4) yceraldehydes phosphate dehydrogenase activity of adipocytes is reduced; (5) little or no new triglycerides are synthesized and stored by adipocytes; (6) enhanced expression of-03 Adrenergic Receptor (B3AR) an improvement in the adrenergic function in adipocytes; (7) reduced glucose stimulated secretion of insulin by pancreatic B-cells; (8) decreased insulinemia; (9) enhanced blood glucose levels; (10) increased expression of Uncoupling Protein 1 in adipocytes; (11) enhanced thermogenesis in white and brown adipose tissue! (12) reduction of plasma triglyceride concentration; (13) decrease in circulating leptin concentrations; (14) up-regulation of insulin receptors; (15)enhanced 73 glucose uptake; (16) reduced adipocyte hyperplasia; (17) reduced adipocyte hypertrophy; (18) reducedrates of conversion of preadipocytes to adipocytes; (19) reduced rates of hyperphagia;' (20) increased protection of CNS, cardiac and other tissues from ischemic or reperfusio'n injury; (21) improved insulin sensitivity; (22) elevated CSF insulin concentrations; (23) elevated circulating adiponectin concentrations; (25) reduced circulating triglyceride concentrations; (26) enhancement of beta-cell rest. 103521 Theshold concentrations of the current invention include those circulating concentrations of KATp channel openers resulting from the administration of the selected from salts of compounds of Formulae I - VIII as an i.v. formulation, an immediate release oral formulation, a controlled release formulation, a transdermal fornulation, or an intranasal formulation to an overweight or obese subject which results in (1) measurable suppression qf fasting insulin levels, (2) suppression of fasting insulin levels by at least 20% from tho baseline measurement in the same subject prior to treatment with a KATp channel opener selected from a salt of a compound of Formulae I -VIII, (3) suppression of fasting insulin levels by at least 3 00 / from the baseline measurement in the same subject prior to treatment with a KATp channel opener selected from a salt of a compound of Formulae I - VIII, (4) suppression of fasting insulin levels by at least 40% from the baseline measurement in the same subject prior to treatment with a KATp channel opener selected from a salt of a compound of Formulae I - VIII, (5) suppression of fasting insulin levels-by at least 50% from the baseline measurement in the same subject-prior to treatment with a KAW channel opener selected from a salt of a compound of Formulae I VIII, (6) suppression of fasting insulin levels by at least 60% from the baseline measurement in the same subject prior to treatment with a KATp channel opener selected from a salt of a compound of Formulae 1 - VIII, (7) suppression of fasting insulin levels by at least 700(o from the baseline measurement in the same subject prior to treatment with a KA-rp channel opener selected from a salt of a compound of Formulae I - VIII, (8) suppression 'f fasting insulin levels by at least 80% from the baseline measurement in the same subject prior to treatment with a KA-P channel opener selected from a salt of a compound of Formulae I- VIII, (9) loss of weight, (10) elevation of resting energy expenditure, or (11) elevation of the oxidation of fat or fatty acids. Threshold effects of the current invention include those circulating concentrations of KATe channel openers selected from salts of compounds of Formulae I - VIII resulting from the administration 74 of an i.v. formulation of the drug, or an immediate release oral formulation of the drug, or a controlled release formulation of the drug, or a sustained release formulation, or a transdermal formulation, or an intranasal formulation of the drug to an obesity prone subject which result in (1) the loss of weight, and (2) the maintenance of weight. Threshold effects of the current invention include those circulating concentrations of KArp channel operjers selected from salts of compounds of Formulae I - VIl resulting from the administration of an i.v. formulation of the drug, or an immediate release oral formulation of the drug, dr a controlled release formulation of the drug, or a sustained release formulation, or a transdermal formulation, or an intranasal formulation of the drug to a prediabetic subject which result in prevention of the transition to diabetes. Threshold effects of the, current invention include those circulating concentrations of KATp channel openers resulting from the administration of selected from salts of compounds of Formulae I -,Vil as an i.v. formulation, or an immediate release oral formulation, or a controlled release formulation, or a sustained release formulation, or a transdermal formulation, or an intranasal formulation to a subject with type 1 diabetes which result in beta cell rest.; [0353] The mode of action by which weight is maintained or lost resulting from the prolonged administration of KAP channel openers selected from salts of compounds of Formulae I - VIII to overweight, obese or obesity prone subjects as provided herein includes, but is not limited to, one or more of (1) enhanced energy expenditure, (2) enhanced oxielation of fat and fatty acids, (3) enhancement of lipolysis in adipose tissue, (4) enhanced glucose uptake by tissues and enhanced insulin sensitivity, and (5) improved beta adrenergic response. The mode of action by which weight is maintained or lost resulting front the prolonged administration of KATp channel openers selected from salts of compound of Formulae I - VII to obese or obesity prone subjects as provided herein may also include the suppression of appetite. [03541 Prolonged administration of pharmaceutical formulations of Kxrp channel openers selected from salts of compounds of Formulae I - VIH to overweight or obese humans or animals results in substantial and sustained weight loss including some or all of the following effects: (1) preferential loss of body fat; (2) loss of greater than 25% of initial body fat mass; (3) loss of greater than 50% of initial body fat mass; (4) loss of 75 greater than 75% of initial body fat mass; (5) significant increase in resting energy expenditure;' (6) increase in the oxidation of fat and fatty acids; (7) reduction in blood pressure; (8) production of lipoprotein lipase by adipooytes is reduced; (9) enhanced lipolysis by Adipocytes; (10) expression of fatty acid synthase by adipocytes is reduced; (11) glyceraldehydes phosphate dehydrogenase activity of adipocytes is reduced; (12) little or no new triglycerides are synthesized and stored by adipocytes; (13) enhanced expression of B 3 Adrenergic Receptor (fbAR) and an improvement in the adrenergic function in adipocytes; (14) reduced glucose stimulated secretion of insulin by pancreatic B-cells; (1 S)decreased insulinemia; (16) enhanced blood glucose levels; (17) increased expression of Uncoupling Protein I in adipocytes; (18) enhanced thermogenesis in white and brown adipose tissue; (19) reduction of plasma triglyceride concentration; (20) decrease in circulating leptin concentrations; (21) up-regulation of insulin receptors; (22) enhanced glucose uptake; (23) reduced adipocyte hyperplasia; (24) reduced adipocyte hypertrophy;i(25) reduced rates of conversion of preadipocytes to adipocytes; (26) reduced rates'of hyperphagia; (27) the sequential loss first of the metabolically most active adipose tissue (visceral), followed by the loss of less metabolically active adipose tissue; (28) elevation of circulating adiponectin concentrations; (29) elevation of cerebrospinal fluid insulin levels; (30) enhanced islet insulin mRNA and insulin content; or (31) enhanced metabolic efficiency of insulin. (03551 Prolonged administration of formulations of KAr channel openers selected from salts of compounds of Formulae I -VIII to obesity prone humans or animals, including subjects who have undergone various types of bariatric surgery, results in sustained maintenance of weight including some or all of the following effects: (1) increased resting energy expenditure; (2) increase in the oxidation of fat and fatty acids; (3) reduction in blood pressure; (4) production of lipoprotein lipase by adipocytes is reduced; (5) enhanced lipolysis by adipocytes; (6) expression of fatty acid synthase by adipocytes is reduced; (7) glyceraldehyde phosphate dehydrogenase activity of adipocytes is reduced; (8) little or no new triglycerides are synthesized and stored by adipocytes; (9) enhanced expression of 63 Adrenergic Receptor (13 3 AR) and improvement in the adrenergic futIction in adipocytes; (10) reduced glucose stimulated secretion of insulin by pancreatic B-cells; (11) decreased insulinemia; (12) enhanced blood glucose levels; (13) increased expression of Uncoupling Protein 1 in adipocytes; (14) enhanced thermogenesis 76 in white and brown adipose tissue; (15) reduction of plasma triglyceride concentration; (16) decreased circulating leptin concentration; (17) up-regulation of insulin receptors; (18) enhanced glucose uptake; (19) reduced adipocyte hyperplasia; (20) reduced adipocyte hypertrophy; (21) reduced rates of conversion of preadipocytes to adipocytes; (22) reduced'rates of hyperphagia; (23) elevated circulating adiponectin concentration; (24) elevated cerebrospinal fluid insulin levels; (25) enhanced islet insulin mRNA and insulin content; or (26) enhanced metabolic efficiency of insulin. [0356] nhomediate or prolonged administration of formulations of KArP channel openers selected from salts of compounds of Formulae I - VIII to prediabetic or type I diabetic hum ns or animals results in the prevention of beta cell failure, improved glycemic control, and prevention of the transition from prediabetes to diabetes including some or all of the following effects: (1) increase in resting energy expenditure; (2) increase in the oxidation of fat and fatty acids; (3) reduction in blood pressure; (4) production of 1 lipoprotein lipase by adipocytes is reduced; (5) enhanced lipolysis by adipocytes; (d) expression of fatty acid synthase by adipocytes is reduced; (7) glyceraldehy4e phosphate dehydrogenase activity of adipocytes is reduced; (8) little or no new triglycerides are synthesized and stored by adipocytes; (9) enhanced expression of 133 Adrenergic Receptor (13 3 AR) and an improvement in the adrenergic function in adipocytes; (10) reduced glucose stimulated secretion of insulin by pancreatic B-cells; (11) decreased insulinemia; (12) enhanced blood glucose levels; (13) increased expression of Uncoupling Protein I in adipocytes; (14) enhanced thermogenesis in white and brown adipose tissue; (15) reduction of plasma triglyceride concentration; (16) decreased circulating leptin concentrations; (17) up-regulation of insulin receptors; (18) enhanced glucose uptake; (19) reduced adipocyte hyperplasia; (20) reduced adipocyte hypertrophy; (21) reduced rates of conversion of preadipocytes to adipocytes; (22) reduced rates cf hyperphagia; (23) elevated circulating adiponectin concentrations; (24) elevated cerebrospinal fluid insulin levels; (25) enhanced islet insulin mRNA and insulin content; or (26) enhanced metabolic efficiency of insulin. [0357] Immediate or prolonged administration of formulations of KATp channel openers selected from salts of compounds of Formulae I - VIII to humans or animals that are at risk for myocardial infarct, or stroke, or undergoing surgical procedure that restores 77 blood flow t6 heart or brain results in improved therapeutic outcomes post-surgically, or following the occurrence of myocardial infarct or stroke by improving the survival of tissue after blood flow is restored, reduced stunning of tissue, and altering the nature of the inflammatory responses. [03581 Pharmaceutical formulations as provided herein are designed to be used in the treatment of 'besity, hyperlipidemia, hypertension, weight maintenance, type I diabetes, prediabetes, type I diabetes, metabolic syndrome or any condition where weight loss, reduction in circulatingg triglycerides or beta cell rest contributes to therapeutic outcomes provide for atrange of critical changes in pharmacodynamic and pharmacokinetic responses to administered doses of Kmr channel openers selected from salts of compounds of Formulae I - VIII which changes include one or more of the following: (1) extending the pharmacodynamic effect of an administered dose to 24 hours or longer as measured 1 y the suppression of insulin secretion; (2) providing for substantial uptake of the active pharmaceuticall ingredient in the small intestine; (3) providing for substantial uptake of the active pharmaceutical ingredient in the large intestine; (4) result in lowered Cmax versus -urrent oral suspension or capsule products for the same administered dose of active phargnaceutical ingredient; (5) provide for circulating concentrations of unbound active pharm a ceutical ingredient above threshold concentrations for 24 or more hours from a single administered dose; and (6) provide for more consistent drug absorption by treated subjects as compared to existing capsule formulations. [03591 Pharmaceutical co-formulations of the current invention designed to treat a range of conditions in humans and animals include the combination of KArp channel openers selected frorn salts of compounds of Formulae I-VIII with: (1) a diuretic, (2) a drug that lowers blood pressure, (3) a drug that suppresses appetite, (4) a cannabinoid receptor antagonist, (5) a drug that suppresses that action of gastric lipases, (6) any drug that is used to induce weightloss, (7) a drug that lowers cholesterol, (8) a drug that lowers LDL bound cholesterol, (9) a drug that improves insulin sensitivity, (10) a drug that improves glucose utilization or uptake, (11) a drug that reduces incidence of atherosclerotic plaque, (12) a drug that reduces inflammation, (13) a drug that is antidepressant (14) a drug that is an anti-epileptic, or (15) a drug that is an anti-psychotic. 78 103601 Treatment of humans or animals using pharmaceutical formulations (which include KAF channel openers selected from salts of compounds of Formulae I - VHI) result in reduced incidence of adverse side effects including but not limited to edema, fluid retention, reduced rates of excretion of sodium, chloride, and uric acid, hyperglycemia, ketoacidosis, nausea, vomiting, dyspepsia, ileus and headaches. These reductions in, frequency of adverse side effects are achieved by: (1) initiating dosing of subjects at suhtherapeutic doses and in a step wise manner increasing the dose daily until the therapeutic dose is achieved where the number of days over which the step qp in dose is effected is 2 to 10, (2) use of the lowest effective dose to achieve the desired therapeutic effect, (3) use of a pharmaceutical formulation that delays release of active until gastric itansit is complete, (4) use of a pharmaceutical formulation that delays release of active until gastric transit is complete, (5) use of a pharmaceutical formulation that results inlower circulating peak drug levels as compared to an immediate release oral suspension or capsule formulation for the same administered dose, and (6) optimizing the timing of adn inistration of dose within the day and relative to meals. 103611 Tr atment of patients suffering from Prader Willi Syndrome, Froelich's Syndrome, Cohen Syndrome, Summit Syndrome, Alstrom Syndrome, Borjesen Syndrome, Bardet-Biedl Syndrome, and hyperlipoprotelnemia type I, II, 1UI, and IV with the current int mention using pharmaceutical formulations of KArP channel openers selected from salts of compounds of Formulae I - VIII result in some or all of the following therapeutic outcomes: (1) weight loss, (2) reduced rates of weight gain, (3) inhibition of hyperphagia, (4) reduced incidence of impaired glucose tolerance, prediabetes or diabetes, (5) reduced incidence of congestive heart failure, (6) reduced hypertension, and (7) reduced rates of all cause mortality. 10362] Trdatment of prediabetic subjects using invention pharmaceutical formulations of KArP channel openers selected from salts of compounds of Formulae I- VUI result in some or all of the following therapeutic outcomes: (1) weight loss, (2) restoration of normal glucose tolerance, (3) delayed rates of progression to diabetes, (4) reduced hypertension, and (5) reduced rates of all cause mortality. 10363] Treptment of diabetic subjects using invention pharmaceutical formulations of KArP channel openers selected from salts of compounds of Formulae I - VI1 result in 79 some or all < f the following therapeutic outcomes: (1) weight loss, (2) restoration of normal gluc6se tolerance, (3) delayed rates of progression of diabetes, (4) improvements in glucose tolerance, (5) reduced hypertension, and (6) reduced rates of all cause mortality. 10364] Co-administration of drags with formulations of KArp channel openers selected froni salts of compounds of Formulae I - VIII in the treatment of diseases of overweight, 9bese or obesity prone human and animal subjects involves the co administratio'n of a pharmaceutically acceptable formulation of KATP channel openers with an acceptable formulation of: (1) sibutramine, (2) orlistat, (3) rimonabant, (4) a drug that is an appetite suppressant, (5) any drug used to induce weight loss in an obese or overweight subject, (6) a non-thiazide diuretic, (7) a drug that lowers cholesterol, (8) a drug that raises HDL cholesterol, (9) a drug that lowers LDL cholesterol, (10) a drug that lowers blood pressure, (11) a drug that is an anti-depressant, (12) a drug that improves insulin sensitIvity, (13) a drug that improves glucose utilization and uptake (14) a drug that is an anti-epileptic, (15) a drug that is an anti-inflammatory, or (16) a drug that lowers circulating triglycerides. [03651 Co-administration of drugs with formulations of KA-p channel openers selected from salts of compounds of Formulae I - VIU in the treatment or prevention of weight gain, dyslipidemia, impaired glucose tolerance or diabetes in subjects treated with antipsychotics drugs involve the co-administration of a pharmaceutically acceptable formulation of KATP channel openers with an acceptable formulation of- lithium, carbamazepine, valproic acid and divalproex, and lamotrigine; antidepressants generally classified as nmonoamine oxidase inhibitors including isocarboxazid, phenelzine sulfate and tranylcyptomine sulfate; tricyclic antidepressants including doxepin, clomipramine, amitriptyline, maproiline, desipromine, nortryptyline, desipramine, doxepin, trimipramine, imipramine and protryptyline; tetracyclic antidepressants including mianserin, mittazapine, maprotiline, oxaprotline, delequanine, levoprotline, triflucarbine, setiptiline, lortalaline, azipramin, aptazapine maleate and pirlindole; and major tranquilizers ahd atypical antipsychotics including paloproxidol, perphenazine, thioridazine, risperidone, clozapine, olanzapine and chlorpromazine. 80 103661 16 one embodiment; a KAW channel opener selected from a salt of a compound of Formulae 1-VIII is administered to an overweight or obese subject as an oral, transdermal or intranasal formulation to reach and maintain the threshold concentration required to measurably reduce fasting insulin levels for a prolonged period. Preferably the KATp chanel opener formulation reduces fasting insulin levels by at least 20%, more preferably by at least 30%, more preferably by at least by 40%, more preferably by at least 50%, more preferably by at least by 60%, more preferably by at least by 70%, and more preferably by at least 80%. Fasting insulin levels are commonly measured using the glucose tolerance test (OGTT). After an overnight fast, a patient ingests a known amount of glucose. Initial glucose levels are determined by measuring pre-test glucose levels in blood and urine. Blood insulin levels are measured by a blood is draw every hour after the glucose is consumed for up to three hours. In a fasting glucose assay, subjects with plasma gluooge values greater than 200 mg/dl at 2 hours post-glucose load indicate an impaired glucose tolerance. [0367] In another embodiment, a KATp channel opener selected from a salt of a compound of Formulae I - VIII is administered to an overweight or obese subject as an oral, transdenpral or intranasal formulation to reach and maintain the threshold concentrationrequired to induce weight loss for a prolonged period. [03681 In another embodiment, a KATp channel opener selected from a salt of a compound of Vormulae I - Vm is administered to an overweight or obese subject as an oral, transderial or intranasal fbrmulation to reach and maintain the threshold concentration required to elevate resting energy expenditure for a prolonged period. 103691 In another embodiment, a KATP channel opener selected from a salt of a compound of ormulae I - VIII is administered to an overweight or obese subject as an oral, transdermal or intranasal formulation to reach and maintain the threshold concentration rquired to elevate fat and fatty acid oxidation for a prolonged period. [03701 In another embodiment, a KArp channel opener selected from a salt of a compound of formulae I - VIII is administered to an obesity prone subject as an oral, transdermal or intranasal formulation to reach and maintain the threshold concentration required to induce weight loss for a prolonged period. 81 [6371] In another ernbodinient, a KAW channel opener selected from a salt of a compound of Formulae I - VIII is administered to an obesity prone subject as an oral, transdermal or intranasal formulation to reach and maintain the threshold concentration required to maintain weight fbr a prolonged period. [0372] Irl another embodiment, a KArp channel opener selected from a salt of a compound oi Formulae I - VIII is administered to an overweight or obese subject as an oral, transdeAnal or intranasal formulation to reach and maintain a drug concentration above the threshold concentration required to induce weight loss for a prolonged period. 103731 In another embodiment, a KA,- channel opener selected from a salt of a compound ofFormulae I - VIII is administered to an overweight or obese subject as an oral, transdermal or intianasal formulation for a prolonged period of time to reduce body fat by more than 25%, more preferably by at least 50%, and more preferably by at least 75%. (03741 In another embodiment, a KATP channel opener selected from a salt of a compound of Formulae I - VIII is administered to an overweight or obese subject as an oral, transdermal or intranasal formulation for a prolonged period of time to preferentially reduce visceral fat deposits. 10375] Inlanother embodiment, a KArp channel opener selected from a salt of a compound ofFormulae I - VIII is administered to an overweight or obese subject as an oral, transdennal or intranasal formulation for a prolonged period of time to reduce visceral fat depots and other fat deposits. 103761 In another embodiment, a KATp channel opener selected from a salt of a compound of formulae I - VIII is administered to a normoinsulinemic overweight or obese subject as an oral, transdermal or intranasal formulation to reach and maintain a drug concentration above the threshold concentration required to induce weight loss for a prolonged period. 10377] In another embodiment, a KA-p channel opener selected from a salt of a compound of Formulae I - ViII is administered to a prediabetic subject as an oral, transdermal or intranasal formulation to reach and maintain a drug concentration above 82 the threshold concentration required to prevent the transition to diabetes fbr a prolonged period. [03781 In another embodiment, a K&Ir channel opener selected from a salt of a compound of Formulae I -VIII is administered to a type I diabetic subject as an oral, transdermal er intranasal formulation to reach and maintain a drug concentration above the threshold concentration required to induce beta cell rest for a prolonged period. 103791 hx another embodiment, a single dose of a pharmaceutically acceptable formulation of a KATp channel opener selected -from a salt of a compound of Formulae I VIII is administered to an subject in need thereof that results in circulating concentration of active dru sufficient to diminish the secretion of insulin for 24 or more hours. [0380] In another embodiment, a pharmaceutically acceptable formulation of a KATP channel opener selected from a salt of a compound of Formulae I - VIII is administered over a prolonged basis to an subject in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to diminish the secretion of insulin on a continuous basis. 103811 In another embodiment, a single dose of a pharmaceutically acceptable formulation o' a KATP channel opener selected from a salt of a compound of Formulae I VIII is administered to an subject in need thereof that results in circulating concentration of active drug sufficient to elevate non-esterified fatty acids in circulation for 24 or more hours. (03821 In another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener selected from a salt of a compound of Formulae I - VIII is administered over a prolonged basis to an subject in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to elevate non-esterified fatty acids in circulation on a continuous basis. 103831 In another embodiment, a single dose of a pharmaceutically acceptable formulation of a KATp channel opener selected from a salt of a compound of Formulae 1 VIN is administered to an subject in need thereof that results in circulating concentration of active drug sufficient to treat hypoglycemia in circulation for 24 or more hours. 83 [03841 h another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener selected from a salt of a compound of Formulae I- VIII is administered over a prolonged basis to an subject in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to treat hypoglycemia on a continuous basis. 10385] 1In another embodiment, a pharmaceutically acceptable formulation of a KAy, channel opener selected from a salt of a compound of Formulae I - VIII is administered over a prolonged basis to an subject in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to induce weight loss on a continuous basis. 10386] In' another embodiment, a pharmaceutically acceptable formulation of a KATP channel opener selected from a salt of a compound of Formulae I - VIII is administered over a prolonged basis to an subject in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to maintain weight on a continuous b4sis, as it is preferable to maintain weight in an obese subject once some weight loss h6 occurred when the alternative is to regain weight. [0387] Inianother embodiment, a pharmaceutically acceptable formulation of a KAT, channel opener selected from a salt of a compound of Formulae I - VI is administered over a prolonged basis to an subject in need thereof no more than once per 24 hours that results in circulating concentration of active drug sufficient to reduce circulating triglyceride levels on a continuous basis. [0388] In'another embodiment, a single dose of a pharmaceutically acceptable formulation of a KArp channel opener selected from a salt of a compound of Formulae I VIII is administered to an subject in need thereof that results in circulating concentration of active drug sufficient to reduce or prevent ischemic or reperfusion injury in circulation for 24 or more hours. [03891 In another embodiment, a pharmaceutically acceptable formulation of a KAW channel opener selected from a salt of a compound of-Formulae I - VIII is administered over a prolonged basis to an subject in need thereof no more than-once per 24 hours that 84 results in circulating concentration of active drug sufficient reduce or prevent ischemic or reperfusion injury on a continuous basis. [0390] Ir another embodiment, the frequency of adverse effects caused by treatment with a KATp channel opener selected from a salt of a compound of Formulae I - VIII is reduced using a pharmaceutically acceptable formulation of diazoxide or its derivatives that is administered to an subject in need thereof on a daily basis in which the first dose is known to be 'subtherapeutic and daily dose is subsequently increased stepwise until the therapeutic dose is reached. [03911 1n another embodiment, the frequency of adverse effects caused by treatment with a KATp channel opener selected from a salt of a compound of Formulae I - VIII is reduced using a pharmaceutically acceptable formulation that is administered to an subject in need thereof on a daily basis in which the active ingredient is not released from the formulation until gastric transit is complete. [03921 In,another embodiment, the frequency of adverse effects caused by treatment with a KA-p channel opener selected from a salt of a compound of Formulae I - VIII is reduced using a pharmaceutically acceptable formulation that is administered to an subject in need thereof on a daily basis in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oral suspension or capsule formulation of Proglycem@V. 10393]' In another embodiment, the frequency of adverse effects caused by treatment with a KATp channel opener selected from a salt of a compound of Formulae I - VIII is reduced using, a pharmaceutically acceptable formulation that is administered to an subject in neeaI thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently increased stepwise until the therapeutic dose is reached, the active ingredient is not release from the formulation until gastric transit is complete and in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oral suspension or capsule formulation of Proglycem@, 103941 In another embodiment, the frequency of adverse effects caused by treatment with a KA-p channel opener selected from a salt of a compound of Formulae I - VIII is 85 reduced using a pharmaceutically acceptable formulation that is administered to an overweight or obese subject in need thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently increased stepwise until the therapeutic d'ose is reached, the active ingredient is not release from the formulation until gastric transit is complete, in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oralsuspension or capsule formulation of Proglycem@, and in which the maximum dose is less than 5 mg/kg/day. [0395] In another embodiment, the frequency of adverse effects caused by treatment with a KATp channel opener selected from a salt of a compound of Formulae I- VIII is reduced using a pharmaceutically acceptable formulation that is administered to an overweight or obese subject in need thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently increased stepwise until the therapeutic dose is reached, the active ingredient is not release from the formulation until gastric transit; is complete, in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oral suspension or capsule formulation, and in which the maximum dose is less than 2.5 mg/k'g/day. [0396] In.another embodiment, the treatment of an overweight or obese subject is optimized for weight loss by administration of a pharmaceutically acceptable formulation of a KATp cha nel opener selected from a salt of a compound of Formulae I -- VIII once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide continuous release for at least 6 hours. [03971 In another embodiment, the treatment of an overweight or obese subject is optimized for.weight loss by administration of a pharmaceutically acceptable formulation of a KATp channel opener selected from a salt of a compound of Formulae I - VIII once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide continuous release for at least 12 hours. 10398) In another embodiment, the treatment of an overweight or obese subject is optimized for iveight loss by administration of a pharmaceutically acceptable formulation 86 of a KATP channel opener selected from a salt of a cornpound of Formulae I -VIII once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide a rising drug concentration in circulation for at least 8 hours. [0399] In another embodiment, the treatment of an overweight or obese subject is optimized for weight loss by administration of a pharmaceutically acceptable formulation of a KArP channel opener selected from a salt of a compound of Fonnulae I -VIII once per 24 hours )n which the release of the active ingredient from the formulation has been modified to provide a rising drug concentration in circulation for at least 12 hours. [04001 In another embodiment, the treatment of an overweight or obese subject is optimized for weight loss by administration of a pharmaceutically acceptable formulation of a KAT channel opener selected from a salt of a compound of Formulae I - VIII once per 24 hours in which the release of the active ingredient from the formulation has been modified to natch the pattern of basal insulin secretion. [0401] In, another embodiment, the frequency of adverse effects caused by treatment with a KATP channel opener selected from a salt of a compound of Formulae I - VIII is reduced using a pharmaceutically acceptable formulation that is administered to an obesity prone subject in need thereof on a daily basis in which the first dose is known to be subtherapeutic and daily dose is subsequently increased stepwise until the therapeutic dose is reached, the active ingredient is not release from the fbrmulation until gastric transit is complete, in which the maximum circulating concentration of active ingredient is lower than what would be realized by the administration of the same dose using an oral suspension or'capsule formulation, and in which the maximum dose is less than 5 mg/kg/day. 10402) In another embodiment, the frequency of adverse effects caused by treatment with a KATp channel opener selected from a salt of a compound of Formulae I -VIII is reduced using'a pharmaceutically acceptable formulation that is administered to an obesity prone subject in need thereof on a daily basis in which the first dose is known to be subtherapeutic and.daily dose is subsequently increased stepwise until the therapeutic dose is reached, the active ingredient is not release from the formulation until gastric transit is complete, in which the maximum circulating concentration of active ingredient 87 is lower thar what would be realized by the administration of the same dose using an oral suspension or capsule formulation, and in which the maximum dose is less than 2.5 mg/kg/day. 10403] IA another embodiment, the treatment of an obesity prone subject is optimized for weight maintenance by administration of a pharmaceutically acceptable formulation of a KATP channel opener selected from a salt of a compound of Formulae I- VIII once per 24 hours in which the release of the active ingredient from the formulation has been modified to iirovide continuous release for at least 6 hours. 104041 In' another embodiment, the treatment of an obesity prone subject is optimized fbr weight maintenance by administration of a pharmaceutically acceptable formulation of a KATp channel opener selected from a salt of a compound of Formulae I - VIII once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide continuous release for at least 12 hours. 104051 In' another embodiment, the treatment of an obesity prone subject is optimized for weight maintenance by administration of a pharmaceutically acceptable formulation of a KArp chainel opener selected from a salt of a compound of Formulae I - VIII once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide a rising drug concentration in circulation for at least 8 hours. (04061 In another embodiment, the treatment of an obesity prone subject is optimized for weight maintenance by administration of a pharmaceutically acceptable formulation of a KATP channel opener selected from a salt of a compound of Formulae I - VIH once per 24 hours in which the release of the active ingredient from the formulation has been modified to provide a rising drug concentration in circulation for at least 12 hours. [0407] In another embodiment, the treatment of an obesity prone subject is optimized for weight maintenance by administration of a pharmaceutically acceptable formulation of a KArp charinel opener selected from a salt of a compound of Formulae I- VIII once per 24 hours in which the release of the active ingredient from the formulation has been modified to match the pattern of basal insulin secretion. 88 [04081 In another embodiment, a pharmaceutically acceptable formulation of a KAW channel opener selected from a salt of a compound of Formulae I - VfI is co administered with sibutramine to an overweight or obese subject to induce weight loss. 10409] I another embodiment, a pharmaceutically acceptable formulation of a KAT? channel opener selected from a salt of a compound of Formulae I - VIII is co administered' with orlistat to an overweight or obese subject to induce weight loss. [0410] Id another embodiment, a pharmaceutically acceptable formulation of a KAT? channel opener selected from a salt of a compound of Formulae I - VIII is co administered with rimonabant to an overweight or obese subject to induce weight loss. [0411) In another embodiment, a pharmaceutically acceptable formulation of a KAI? channel opener selected from a salt of a compound of Formulae I - VIII is co administered with an appetite suppressant to an overweight or obese subject to induce weight loss. [04121 In; another embodiment, a pharmaceutically acceptable formulation of a KArp channel open r selected from a salt of a compound of Formulae I - VIH is co administered 'with an anti-depressant to an overweight or obese subject to induce weight loss. [0413] In, another embodiment, a pharmaceutically acceptable formulation of a KATp channel opener selected from a salt of a compound of Formulae I - VIIF is co administered with anti-epileptic to an overweight or obese subject to induce weight loss. {0414] In another embodiment, a pharmaceutically acceptable formulation of a KATP channel opener is-selected from a salt of a compound of Formulae I - VIII is co administered with a non-thiazide diuretic to an overweight or obese subject to induce weight loss. (0415] In another embodiment, a pharmaceutically acceptable formulation of a KArP channel opener selected from a salt of a compound of Formulae I - VHI is co administered with a drug that induces weight loss by a mechanism that is distinct from diazoxide to an overweight or obese subject to induce weight loss. 89 [0416] lIi another embodiment, a pharmaceuticals acceptable formulation of a KAW channel opener selected from a salt of a compound of Formulae I - VIII is co administered with a drug that lowers blood pressure to an overweight, obesity prone or obese subject to induce weight loss and treat obesity associated co-morbidities. [04171 In another embodiment, a pharmaceutically acceptable formulation of a KAW channel opener selected from a salt of a compound of Formulae I - VIII is co administered with a drug that lowers cholesterol to an overweight, obesity prone or obese subject to induce weight loss and treat obesity associated co-morbidities. 104181 I another embodiment, a pharmaceutically acceptable formulation of a KAW channel opener selected from a salt of a compound of Formulae I - VIII is co administeredwith a drug that raises HDL associated cholesterol to an overweight, obesity prone or obese subject to induce weight loss and treat obesity associated co-morbidities. 10419] liq another embodiment, a pharmaceutically acceptable formulation of a KAW channel open selected from a salt of a compound of Formulae I - VIII is co administered with a drug that improves insulin sensitivity to an overweight, obesity prone or obese subject to induce weight loss and treat obesity associated co-morbidities. 104201 In! another embodiment, a pharmaceutically acceptable formulation of a Kxrp channel opener selected from a salt of a compound of Formulae I - VIII is co administered with a an anti-inflammatory to an overweight, obesity prone or obese subject to induce weight loss and treat obesity associated co-morbidities. [0421) In another embodiment, a pharmaceutically acceptable formulation of a KATP channel opener selected from a salt of a compound of Formulae I - VIII is co administered 'vith a drug that lowers circulating triglycerides to an overweight, obesity prone or obese subject to induce weight loss and treat obesity associated co-morbidities. f0422] In 'another embodiment, KATp channel openers selected from salts of compounds o Formulae I - VIII are co-formulated with sibutramine in a pharmaceuticplly acceptable formulation that is administered to an overweight, obesity prone or obesp subject to induce weight loss and treat obesity-associated co-morbidities. 90 [04231 In another embodiment, KATP channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with orlistat or other active that suppresses the action of gastric lipases in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity-associated co-morbidities. [04241 In another embodiment, KATp channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with a non-thiazide diuretic in a pharmaceutidally acceptable formulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity-associated co-morbidities. [0425] In' another embodiment, KATp channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with an appetite suppressant in a pharmaceuticpily acceptable formulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity-associated co-morbidities. [0426] In-another embodiment, KAT channel openers selected from salts of compounds of Formulae I - VDI are co-formulated with a cannabinoid receptor antagonist in ' pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity associated co-morbidities. [0427] In another embodiment, KATP channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with an anti-cholesteremic active in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obeso subject to induce weight loss and treat obesity-associated co-morbidities. [0428] In another embodiment, KAp channel openers selected from salts of compounds of ormulae I - VMI are co-formulated with an antihypertensive active in a pharmaceutically acceptable fbrmulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity-associated co-morbidities. 10429] In another embodiment, KA-w channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with an insulin sensitizing active in a 91 pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity-associated co-morbidities. [04301 Ir another embodiment, KATp channel openers selected from salts of compounds of Forrnulae I - VIII are co-fbrmulated with an anti-inflammatory active in a pharmaceutidally acceptable formulation that is administered to an overweight, obesity prone or obe4e subject to induce weight loss and treat obesity-associated co-morbidities. [04311 In another embodiment, KAl, channel openers selected from salts of compounds of Formulae I - VI1 are co-formulated with an anti-depressant active in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obe4e subject to induce weight loss and treat obesity-associated co-morbidities. 104321 In another embodiment, KArp channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with an anti-epileptic active in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity-associated co-morbidities. 10433] In another embodiment, KAT? channel openers selected from salts of compounds of Formulae I - Viii are co-formulated with an active that reduces the incidence of atherosclerotic plaque in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity-associated co-morbidities. [04341 In'another embodiment, KAW channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with an active that lowers circulating concentrations of triglycerides in a pharmaceutically acceptable formulation that is administered to an overweight, obesity prone or obese subject to induce weight loss and treat obesity-a'ssociated co-morbidities. 104351 The reduction of circulating triglycerides in an overweight, obese or obesity prone subject is achieved by the administration of an effective amount of an oral dosage form of a KA-re channel opener, selected from a salt of a compound of Formulae I - VIII. 92 [0436] Ain oral dosage form of KArP channel opener selected from a salt of a compound of Formulae I - VIII can be used to administer a therapeutically effective dose of KArP channel opener to an overweight or obesity prone subject in need thereof to maintain weight, as it is preferable to maintain weight in an obese subject once some weight loss h'as occurred when the alternative is to regain weight. [0437] In another embodiment of the invention, KAT channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with a drug to treat obesity. Such co-fornmulations can be formulated for oral administration once per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period of 2 to 24 hours. Such obesity treatment drugs include, but are not limited td: sibutramine hydrochloride (5-30 mg), orlistat (50-360 mg), phentermine hydrochloride or resin complex (15 to 40 mg), zonisanide (100 to 600 mg), topiramate (64 to 400 mg), naltrexone hydrochloride (50 to 600 mg), or rimonabant (5 to 20 mg). [0438] Afiurther embodiment of the co-formulation contains KAT channel openers selected from salts of compounds of Formulae I - VIII and a drug to treat obesity. Such co-formulations can be formulated for oral administration twice per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period,of 2 to 12 hours. Such obesity treatment drugs include, but are not limited to: sibutramine hydrochloride (2.5 to 15 mg), orlistat (25 to 180 mg), phentermine hydrochloride or resin complex (7.5 to 20 mg), zonisamide (50 to 300 mg), topirarnate (32 to 200 mg), naltrexone hydrochloride (25 to 300 mg), or rimonabant (2.5 to 10 mg). [0439] .In another embodiment of the invention KATP channel openers selected from salts of compounds of Formulas I -. VIII are co-formulated with a drug to treat obesity, diabetes, metabolic syndrome or an obesity related comorbidity. Such drugs to treat these conditions include drugs that: agonizes the oil-noradrenergic receptor; agonizes the #2 noradrenergic. receptor, stimulates noradrenalin release; blocks noradrenalin uptake; stimulates 5-hT release; blocks 5-HT uptake; is a serotonin (5-hydroxytryptamine) 2C receptor agonist; antagonizes acetyl-CoA carboxylase 2; agonizes the D1-receptor; antagonizes the H3-receptor; is a leptin analogue; agonizes the leptin receptor, sensitizes CNS tissue to the action of leptin; agonizes the MC4 receptor; agonizes NPY-YI; agonizes NPi-Y2; agonizes NPY-Y4; agonizes NPY-Y5; antagonizes the MCH receptor; 93 blocks CRHBP; agonizes the CRH receptor; agonizes the urocortin receptor antagonizes the galanin r ceptor; antagonizes the orexin receptor; agonizes the CART receptor, agonizes the 'mylin receptor, agonizes the Apo(A") receptor; antagonizes the CB-1 receptor, is an MSH analogue; inhibits PTP-IB; antagonizes PPAR-yreceptor; is a short acting bromocriptine; agonizes somatostatin; increases adiponectin; increases CCK activity, increases PYY activity; increases GLP-1 activity; decreases ghrelin activity; is a selective 133 btimulator or agonist; agonizes thyroid receptor; inhibits gastrointestinal lipases or other digestive enzymes; blocks absorption of dietary fat; or block de-novo fatty acid synthesis. Additionally, such drugs to treat obesity may include, but are not limited to those that antagonize or agonize the function or expression of I1I8 hydroxysteroid dehydrogenase Lype 1; acetyl-CoA carboxylase 1; ADAM 12, member 12 of a disintegrin and metalloprotease family or its shorter secreted form; agouti related protein; angiatensinogen; adipocyte lipid binding protein; adipocyte fatty acid binding protein; adrenergic receptors; acylation-stimulating protein; bombesin receptor subtype-3; C/EBP, CCAAT/enhancer binding protein; cocaine- and amphetamine-regulated transcript; chblecystokinin; cholecystokinin A receptor; CD36, fatty acid translocase; corticotropin releasing hormone; diacylglycerol acyltransferases; E2F transcription factor; eukarjotic translation initiation factor 4e binding protein 1; estrogen receptor; fatty acid synthase; fibroblast growth factor, forkhead box C2; glucose-dependent insulinotropid peptide; GIP receptor; inhibitory G protein alpha-subunit; glucagon- like peptide-1; GIP-1 receptor; glycerol-3-phosphate acyltransferase; glycerol 3-phosphate dehydrogenase; stimulatory G protein alpha-subunit; high-mobility group phosphoprotein isoform I-C; 'iormone sensitive lipase; inducible nitric oxide synthase; Janus kinases; lipoprotein lipase; melanocortin-3 receptor; melanocortin-4 receptor; mitochondrial GPAT; metallothionein-I and -11; nescient helix-loop-helix 2; neuropeptide Y; neuropeptide Y-1 receptor, neuropeptide Y-2 receptor; neuropeptide Y-4 receptor, neuropeptide Y-5 receptor; plasminogen activator inhibitor-1; PPARgamma co-activator 1; pro-opiomelanocortin; peroxisome proliferator-activated receptor; protein tyrosine phosphatase 1-B; regulatory subunit Ibeta of protein kinase A; retinold X receptor, steroidogenic'factor 1; single-minded 1; sterol regulatory element binding protein; tyrosine hydroxylase; thyroid hormone receptor a2; uncoupling protein; nerve growth ,factor induced protein; leucine zipper transcription factor; a-melanocyte-stimulating hormone. 94 104401 In another embodiment of the invention, KATp channel openers selected from salts of comilounds of Formulae I - VIII are co-formulated with a drug to treat diabetes. Such co-forniulations can be formulated for oral administration once per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period of 2 to 24 hours. Such diabetes treatment drugs include, but are not limited to: acarbose (50 to 300 mg), miglitol (25 to 300 mg), metformin hydrochloride (300 to 2000 mg), repaglinide (1-16 mg), nateglinide (200 to 400 mg), or rosiglitizone (5 to 50 mg). 10441] In' a further embodiment, the co-formulation can be formulated for oral administration twice per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period of 2 to 12 hours. Such drugs to treat-diabetes include, but are not limited to: acerbose (25 to 150 mg), miglitol (12.5 to 150 ig), metformin hydrochloride (150 to 1000 rg), repaglinide (0.5 to 8 mg), nateglinide (1,00 to 200 mg), or rosiglitizone (2.5 to 25 mg). (04421 In another embodiment of the invention, KA,? channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with a drug to treat elevated cholesterol. Such co-formulations can be formulated for oral administration once per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the.active over a period of 2 to 24 hours. Such drugs to treat elevated cholesterol include, but are not limited to: pravastatin, simvastatin, atorvastatin, fluvastatin, rodsuvastatin or lovastatin (10 to 80 mg). 104431 In'a further embodiment, the co-formulation can be formulated for oral administration twice per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period of 2 to 12 hours. Such drugs to treat 'levated cholesterol include, but are not limited to: pravastatin, simvastatin, atorvastatin, fluvastatin, rosuvastatin or lovastatin (5 to 40 mg). 104441 In another embodiment of the invention, KATp channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with a drug to treat depression. Sich co-formulations can be formulated for oral administration once per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained 95 release of the active over a period of 2 to 24 hours. Such drugs to treat depression include, but re not limited to: citalopram hydrobromide (10 to 80 mg), escitalopram hydrobromide (5 to 40 mg), fluvoxwnine maleate (25 to 300 mg), paroxetine hydrochlorid (12.5 to 75 mg), fluoxetine hydrochloride (30 to 100 mg), setraline hydrochloride (25 to 200 mg), amitriptyline hydrochloride (10 to 200 mg), desipramine hydrochloride (10 to 300 mg), nortriptyline hydrochloride (10 to 150 mg), duloxetine hydrochloride (20 to 210 mg), venlafaxine hydrochloride (37.5 to 150 mg), pheneIzine sulfate (10 to 30 mg), bupropion hydrochloride (200 to 400 mg), or mirtazapine (7.5 to 90 mg). [04451 IR a further embodiment, the co-formulation can be formulated for oral administration twice per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active for 2 to 12 hours. Such drugs to treat depression include, but are not limited to: citalopram hydrobromide (5 to 40 mg), escitalopram iydrobromide (2.5 to 20 mg), fluvoxamine maleate (12.5 to 150 mg), paroxetine hydrochloride (6.25 to 37.5 mg), fluoxetine hydrochloride (15 to 50 mg), setraline hydrochloride (12.5 to 100 mg), amitriptyline hydrochloride (5 to 100 mg), desipramine hydrochloride (5 to 150 mg), nortriptyline hydrochloride (5 to 75 mg), duloxetine hydrochloride (10 to 100 mg), venlafaxine hydrochloride (18 to 75 mg), phenelzine sWlfate (5 to 15 mg), buproplon hydrochloride (100 to 200 mg), or mirtazapine (4 to 45 mg). [0446] In' another embodiment of the invention, KATp channel openers selected from salts of compounds of Formulae I- VIII are co-formulated with a drug to treat hypertension.i Such co-formulations can be formulated for oral administration once per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period of 2 to 24 hours. Such drugs to treat hypertension include, but are not limited to: enalapril maleate (2.5 to 40 mg), captopril (2.5 to 150 mg), lisinopril (10 to 40 mg), benzaepril hydrochloride (10 to 80 mug), quinapril hydrochloride (10 to 80 mg), peridopril erbumine (4 to 8 mg), ramipril (1.25 to 20 mg), trandolapril (1 to 8 mg), fosinopril sodium (10 to 80 mg), moexipril hydrochloride (5 to 20 mg), losartan potassium (25 to 200 mg), irbesartan (75 to 600 mg), valsartan (40 to 600 mg), candesartan cilexetil (4 to 64 mg), olmesartan medoxamil (5 to 96 80 mg), telmisartan (20 to 160 mg), eprosartan mesylate (75 to 600 mg), atenolol (25 to 200 mg), pro ranolol hydrochloride (10 to 180 mg), metoprolol tartrate, succinate or fumarate (251to 400 mg), nadolol (20 to 160 mg), betaxolol hydrochloride (10 to 40 mg), acebutolol hydrochloride (200 to 800 mg), pindolol (5 to 20 mg), bisoprolol funarate (5 to 20 mg), nifedipine (15 to 100 mg), felodipine (2.5 to 20 mg), amlodipine besylate (2.5 to 20 mg), ni ardipine (10 to 40 mg), nisoldipine (10 to 80 mg), terazosin hydrochloride (1 to 20 mg), doxasoxin mesylate (4 to 16 mg), prazosin hydrochloride (2.5 to 10 mg), or alfuzosin hydrochloride (10 to 20 mg). 104471 In a further embodiment, the co-fornulation can be formulated for oral administration twice per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of active over a period of 2 to 12 hours. Such drugs to treat hypertension include, but are not limited to: enalapril maleate (1.25 to 20 mg), captopril (2 to 75 mg), lisinopril (5 to 20 mg), benzaepril hydrochloride (5 to 40 mg), quinapril hydrochloride (5 to 40 mg), peridopril erbumine (2 to 4 mg), ramipril (1 to 10 mg), trandolapril (1 to 4 mg), fosinopril sodium (5 to 40 mg), moexipril hydrochloride (2.5 to 10 mg, losartan potassium (12.5 to 100 mg), irbesartan (37.5 to 300 mg), valsartan (20 to 300 mg), candesartan cilexetil (2 to 32 mg), olmesartan medoxamil (2.5 to 40 mg), tel'misartan (10 to 80 mg), eprosartan mesylate (37.5 to 300 mg), atenolol (12.5 to 100 mg), piopranolol hydrochloride (5 to 90 mg), metoprolol tartrate, succinate or furmarate (I2.S to 200 mg), nadolol (10 to 80 mg), betaxolol hydrochloride (5 to 20 mg), acebutolol hydrochloride (100 to 400 mg), pindolol (2.5 to 10 mg), bisoprolol fumarate (2.5 to 10 mg), nifedipinc (7.5 to 50 mg), felodipine (I.to 10 ing), amlodipine besylate (1 to 10 mg), nidardipine (5 to 20 mg), nisoldipine (5 to 40 mg), terazosin hydrochloride (1 to 10 mg), dokasoxin mesylate (2 to 8 mg), prazosin hydrochloride (I to 5 mg), or alfuzosin hydrochloride (5 to 10 mg). 104481 In'another embodiment of the invention, KATP channel openers selected from salts of compounds of Formulac 1- VIII are co-formulated with a diuretic. Such co formulations can be fbrmulated for oral administration once per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period of 2 to 24 hours. Such diuretics can include, but are not limited to: amiloride hydrochloride (I to 10 mg), spironolactone (10 to 100 mg), triamterene (25 to 97 200 mg), burpetanide (0.5 to 4 mg), furosenide (10 to 160 mg), ethacrynic acid or ethacrynate sodium (10 to 50 mg), tosemide (5 to 100 mg), chlorthalidone (10 to 200 mg), indapamide (1 to 5 mg), hydrochlorothiazide (10 to 100 mg), chlorothiazide (50 to 500 img), bendrolumethiazide (5 to 25 mg), hydroflumethiazide (10 to 50 mg), mythyclothiazide (1 to 5 mg), and polythiazide (I to 10 mg). 104491 In a further embodiment, the co-formulation can be formulated for oral adnnistration twice per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period of 2 to 12 hours. Such diuretics include, but are not limited to: amiloride hydrochloride (0.5 to 5 mg), spironolactorie (5 to 50 mg), triamterene (12 to 100 mg), bumetanide (0.2 to 2 mg), furosemide (5 to 80 mg), ethacrynic acid or ethacrynate sodium (5 to 25 mg), tosemide (2 to 50 mg), chlorthalidone (5 to 100 mg), indapamide (0.5 to 2.5 mg), hydrochlorothiazide (5 to 50 mg),'chlorothiazide (25 to 250 mg), bendroflumethiazide (2 to 12.5 mg), hydroflumetliiazide (5 to 25 mg), mythyclothiazide (0.5 to 2.5 mg), and polythiazide (0.5 to 5 mg). 104501 In- another embodiment of the invention, KATP channel openers selected from salts of compounds of Formulae I - VIII are co-formulated with a drug to treat inflammation or pain. Such co-formulations can be formulated for oral administration once per 24 hours, for delayed release of the active until gastric transit is compete, and for sustained release of the active over a period of 2 to 24 hours. Such drugs to treat inflammation' or pain include, but are not limited to: aspirin (100 to 1 000mg), tramadol hydrochloride (25 to 150 mg), gabapentin (100 to 800 mg), acetominophen (100 to 1000 mg), carbamazepine (100 to 400 mg), ibuprofen (100 to 1600 mg), ketoprofen (12 to 200 mg), fenprofen sodium (100 to 600 mg), flurbiprofen sodium or flurbiprofen (50 to 200 mg), or combinations of these with a steroid or aspirin. f04511 In a further embodiment, the co-formulation can be formulated for oral administration twice per 24 hours, for delayed release of the active until gastric transit is complete, and for sustained release of the active over a period of 2 to 12 hours. Such drugs to treat inflammation or pain include, but are not limited to: aspirin (100 to 650 mg), tramadol hydrochloride (12 to 75 mg), gabapentin (50 to 400 mg), acetominophen (50 to 500 mg), carbamazepine (50 to 200 mg), ibuprofen (50 to 800 mg), ketoprofen (6 98 to 100 mg), #enprofen sodium (50 to 300 mg), flurbiprofen sodium or flurbiprofen (25 to 100 mg), or combinations of these with a steroid or aspirin. [04521 A method of inducing loss of greater than 25% of initial body fat in an overweight or obese subject can be achieved by the prolonged administration of an oral dosage form of a KATp channel opener- selected from a salt of a compound of Fomulae I - Vl. [0453] A method of inducing loss of greater than 50% of initial body fat in an overweight or obese subject can be achieved by the prolonged administration of an oral dosage form of a KATp channel opener selected from a salt of a compound of Formulae I VITI. (04541 A',method of inducing loss of greater than 75% of initial body fat in an overweight oj obese subject can be achieved by the prolonged administration of an oral dosage fdrm of a KATp channel opener- selected from a salt of a compound of Formulae I -- VfI. [04551 A method of inducing preferential loss of visceral fat in an overweight or obese subject can be achieved by the prolonged administration of an oral dosage form of a KArP channel opener selected from a salt of a compound of Formulae I -Vill. 10456] A'method of inducing loss of body fat and reductions in circulating triglycerides in an overweight or obese subject can be achieved by the prolonged administration of an oral dosage form of a KArp channel opener-. selected from a salt of a compound of Formulae I - VIII. 104571 In some embodiments, the invention provides a polymorph of a salt, which salt includes diazoxide and a cation selected from the group consisting of an alkali metal and a compound comprising a tertiary amine or quaternary ammonium group. In some embodiments, the cation is choline. [0458] In some embodiments, the polymorph of diazoxide choline salt is of Form A having characteristic peaks in the XRPD patten at values of two-theta (Cu Kai, 40 kV, 40 99 mA) at approximately 9.8, 10.5, 14.9, 17.8, 17.9, 18.5, 19.5, 22.1, 22.6,26.2,29.6, and 31.2 degrees. [0459] I some embodiments, the polymorph of diazoxide choline salt is of Form B having characteristic peaks in the XRPD pattern at values of two-theta (Cu Kc, 40 kV, 40 mA) at approximately 8.9, 10.3, 12.0, 18.3, 20.6, 24.1, 24.5, 26.3, 27.1, and 28.9 degrees. 10460] In some embodiments, the polymorph of diazoxide choline salt is of Form A having chara teristic infrared absoibances at 2926, 2654, 1592, 1449, and 1248 cm" 104611 Ir some embodiments, the polymorph of diazoxide choline salt is of Form B having characteristic Infrared absorbances at 3256, 2174, 2890, 1605, 1463, and 1235 cm-. [0462] In some embodiments, the polymorph of diazoxide includes potassium as the cation. 10463] In some embodiments, the polymorph of diazoxide potassium salt is of Form A having characteristic peaks in the XRPD pattern at values of two-theta (Cu K, 40 kV, 40 mA) at approximately 6.0, 8.1, 16.3, 17.7, 18.6, 19.1, 22.9, 23.3, 23.7, 24.7, 25.4, 26.1, 28.2, 29.6, and 30.2 degrees. [0464] Inisome embodiments, the polymorpb of diazoxide potassium salt is of Form B having characteristic peaks in the XRPD pattern at values of two-theta (Cu Ka., 40 kV, 40 mA) at approximately 8.5, 10.8, 16.9, 18.2, 21.6, 25.5, 26.1, and 28.9 degrees. 104651 Insome embodiments, the polymorph of diazoxide potassium salt is of Form C having characteristic peaks in the XRPD pattern at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 5.7, 6.1, 17.9, 23.9, 25.1, and 37.3 degmes. [04661 Insome embodiments, the polymorph of diazoxide potassium salt is of Form D having characteristic peaks in the XRPD pattern at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 5.7, 6.2, 8.1, 8.5, 8.8, 16.9, 18.6, 23.2, 24.5, 25.8, and 26.1 degrees. 100 [0467] Ir some embodiments, the polymorph of diazoxide potassium salt is of Form B having characteristic peaks in the XRPD patten at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 6.7, 7.1, 14.1, and 21.2 degrees. [0468] In some embodiments, the polymorph of diazoxide potassium salt is of Form P having charabteristic peaks in the XRPD pattern at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 8.5, 9.0, 18.7, 20.6, 23.5, 27.5, and 36.3 degrees. [04691 In some embodiments, the polymorph of diazoxide potassium salt is of Form G having characteristic peaks in the XR.PD pattern at values of two-theta (Cu Ket, 40 kV, 40 mA) at approximately 5.2, 5.5, 13.1, 16.5, 19.3, 22.8,24.8, 26.4,28.7, and 34.1 degrees. [04701 In some embodiments, the polymorph of diazoxide potassium salt is of Form A having characteristic infrared absorbances at 1503, 1374, 1339, 1207, 1131, 1056, and 771 cm-. [0471] Inisome embodiments, the polymorph of diazoxide potassium salt is of Form B having characteristic infrared absorbances at 1509, 1464, 1378, and 1347 cm-1. [04721 In some embodiments, the polymorph of diazoxide potassium salt is of Form C having characteristic infrared absorbances at 1706, 1208, 1146, and 746 cm- 1 . [0473] Insome embodiments, the polymorph of diazoxide potassium salt is of Form D having characteristic infrared absorbances at 1595, 1258, 1219, and 890 cm- . 104741 In some embodiments, the polymorph of diazoxide potassium salt is of Form Ehaving characteristic infrared absorbances at 1550, 1508, 1268, 1101, and 1006 cm- 1 . 10475] In some embodiments, the polymorph of diazoxide potassium salt is of Form F having characteristic infrared absorbances at 1643, 1595, 1234, 1145, and 810 ci'. 10476] In some embodiments, the polymorph of diazoxide potassium salt is of Form G having characteristic infrared absorbances at 1675, 1591, 1504, 1458, 1432, 1266, 999, 958, 905, and'872 cm''. 101 [0477] In some embodiments, the polymorpb of diazoxide choline salt is of Form A having characteristic peaks in the XRPD pattern substantially as shown in FIG. 16(a), and an NMR spectrum substantially as shown in FIG. 17(a). [0478] In some embodiments, the polymorph of diazoxide choline salt is of Form B having characteristic peaks in the XRPD pattern substantially as shown in FIG. 16(c) and an NMR spectrum substantially as shown in FIG. 17(b). 10479] In some embodiments, the polymorph of diazoxide potassium salt includes one or more of Forms A-G, wherein each of the Forms A-G has characteristic peaks in the XRPD pattern substantially as shown in FIG. 18-19. [0480] In some embodiments of the invention there are provided methods fbr producing a diazoxide choline salt, which methods include suspending diazoxide in a solvent (e.g., alcohols such as methanol, i-BuOH, i-AmOH, t-BuOH, and the like, ketones, tetrahydrofuran, dimethylformamide, n-methyl pyrrolidinone, and the like) and mixing with a choline salt (e.g., choline hydroxide), adding a co-solvent (e.g., MTBE, EtOA, IPA, c-Hexane, heptane, toluene, CH 2

CL

2 , dioxane, and the like) to the suspension under conditions sufficient to cause formation and precipitation of said diazoxide choline salt, and harvesting the precipitate to provide the diazoxide choline salt. 10481] In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is 2-rnethyltetrahydrofbran (2-MeTHF). 104821 In some embodiments, the diazoxide and the solvent are present at a ratio of about I g diazoxide per I mL solvent to about I g diazoxide per 5 mL solvent. In some embodiments', the diazoxide and the solvent are present at a ratio of about I g diazoxide per 3 mL solNent. 104831 In some embodiments, the choline salt is a solution in MeOH. In some embodimentsi the choline salt is choline hydroxide in about a 45% solution (e.g., 40%, 41%, 42%, 43%, 44%, 45%, 46%,47%, 48%, 49%, 50%) in MeOH. (0484] In some embodiments, the choline salt is added as I equivalent of diazoxide. [0485] In'some embodiments, the co-solvent is MTBE. 102 [0486) In some embodiments, the amount of co-solvent added is in a ratio to the amount of the solvent of about 3:14 (solvent:co-solvent) (e.g., 3:12, 3:13, 3:14, 3:15, 3:16). 104871 Iq some embodiments, the process of making polymorphs of diazoxide choline salt includes the step of seeding with crystals of diazoxide choline salt polymorph Form B prior to the harvesting step. 104881 In some embodiments for the method fbr producing a diazoxide choline salt the salt incluIes polynorph Form B substantially free of polymorph Form A, the polymorph Form B having characteristic peaks in the XRPD pattern at values of two theta (Cu Kco, 40 kV, 40 mA) at approximately 8.5, 10.8, 16.9, 18.2, 21.6, 25.5, 26.1, and 28.9 degrees. [04891 In. some embodiments for the method of treating obesity or obesity-related morbidity in an obese subject, the compound is a compound of Formula V. [0490) In some embodiments for the method of treating obesity or obesity-related morbidity in an obese subject, the compound is a compound of Formula VI. [04911 In. some embodiments for the method of treating obesity or obesity-related morbidity in an obese subject, the compound is a compound of Formula VII. [04921 In. some embodiments for the method of treating obesity or obesity-related morbidity in $n obese subject, the compound is a compound of Formula VIII. 10493] ln some embodiments for the method of treating obesity or obesity-related morbidity in an obese subject, the method further comprises administering a drug selected from the group consisting of Sibutramine, Orlistat, Rimonabant, an appetite suppressant, a non-thiazid diuretic, a drug that lowers cholesterol, a drug that raises HDL cholesterol, a drug that lovers LDL cholesterol, a drug that lowers blood pressure, a drug that is an anti-depressant, a drug that is an anti-epileptic, a drug that is an anti-inflammatory, a drug that is an appetite suppressant, a drug that lowers circulating triglycerides, and a drug that is used to induce weight loss in an overweight or obese individual. 103 104941 1 some embodiments for the method of treating obesity or obesity-related morbidity in an obese subject, the method further comprises administering a pharmaceuti4ally active agent other than the KATp channel opener. in some embodiments, the other pharmaceutically active agent is an agent useful for the treatment of a condition selected front the group consisting of obesity, prediabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention, obesity associated co-morbidities, ischenic and reperfusion injury, epilepsy, cognitive impairment, schizophrenia, mania, and other psychotic condition. 10495] I, some embodiments for the method for treating a subject suffering from or at risk for Alzheimer's disease (AD), the method includes administration to a subject a therapeutically effective amount of a salt of diazoxide including salts provided herein. In some emboditnents for the method for treating a subject suffering from or at risk for AD, the method includes administration to a subject a therapeutically effective amount of a compound according to any of Formulae I-VIIl. In some embodiments, the compound is diazoxide or a salt thereof. 104961 AD is a neurodegenerative disorder neuropathologically characterized by abnormal accumulations of intracellular neurofibrilary tangles and extracellular amyloid plaques throughout cortical and limbic brain regions and the loss of synapses and neurons. AD-is further characterized by significant cognitive and memory impairment. P amyloid plaques form from the # amyloid peptide (i.e., "Ap", H-Asp-Ala-Glu-Phe-Arg His-Asp-Ser-ily-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val Gly-Ser-Asn-Lys-Gly-Ala-lie-Ile-G3ly-Leu-Met-Val-Gly-Gly -Val-Val-lle-Ala-OH, SEQ ID NO.__), either 1-40 or 1-42 peptide, which is released from amyloid precursor protein following cleavage by gamma secretase. In addition to forming plaques, the P amyloid peptides are cytotoxic either as the monomer or as a short-lived oligomeric intermediate. # amyloid peptides (monomers, diners or oligomers) can be identified both in CSF (cerebrospinal fluid) and in serum. Amyloid angiopathy is characterized by AO deposition and may contribute to the cerebrovascular abnormalities that precede the onset of AD. 10497] Th'e invention will now be described with reference to the following non limiting examples. 104 EXAMPLES A. Potassium AT? Channel Activator Containing Formulations 1. Compressed Tablet Formulations ofDazoxide salt or derivative 104981 Diazoxide salt or a derivative thereof at about 15-30% by weight is mixed with hydroxy'propyl methylcellulose at about 55-80% by weight,, ethylcellulose at about 3-10 wt/vol % and magnesium stearate (as lubricant) and talc (as glidant) each at less than 3% by weight. The mixture is used to produce a compressed tablet as described in Reddy et al., AAPSPharm Sci Tech 4(4):1-9 (2003). The tablet may be coated with a thin film as discussed below for microparticles. 104991 A tablet containing 100 mg of diazoxide salt or a derivative thereof will also contain approximately 400 mg of hydroxypropyl cellulose and 10 mg of ethylcellulose. A tablet containing 50 mg of diazoxide salt or a derivative thereof will also contain approximately 200 mg of hydroxypropyl cellulose and 5 mg of ethylcellulose. A tablet containing 25 mg of diazoxide salt or a derivative thereof will also contain approximately 100 mg of hydroxypropyl cellulose and 2.5 mg of ethylcellulose. 2. Engapsulated Coated Microparticle Formulation ofDiazoxide Salt or derivative 105001 Diazoxide salt or a derivative thereof is encapsulated into microparticles in accordance with well known methods (see, e.g. U.S. Patent No. 6,022,562). Microparticley of between 100 and 500 microns in diameter containing diazoxide salt or a derivative thereof, alone or in combination with one or more suitable excipient, is formed with the assistance of a granulator and then sieved to separate microparticles having the appropriate size. Microparticles are coated with a thin film by spray drying using commercial iTstrumentation (e.g. Uniglatt Spray Coating Machine). The thin film comprises ethl cellulose, cellulose acetate, polyvinylpyrrolidone and/or polyacrylamide. The coating solution for the thin film may include a plasticizer which may be castor oil, diethyl phthalAtc, triethyl citrate and salicylic acid. The coating solution may also include a lubricating agent which may be magnesium stearate, sodium oleate, or polyoxyethylenated sorbitan laurate. The coating solution may fIrther include an 105 excipient such as talc, colloidal silica or of a mixture of the two added at 1.5 to 3% by weight to prevent caking of the film coated particles. 3. Fdrmulationsfor controlled release of diazoxide or derivative 3.1. Formulation of a tableted form of diazoxide or a derivativefor controlled release [05011 Prior to mixing, both the active ingredient and hydroxypropyl methylcellulose (Dow Methotel K4M P) are passed through an ASTM 80 mesh sieve. A mixture is formed from 'I part diazoxide salt or a derivative thereof to 4 parts hydroxypropyl methylcelluldse. After thorough mixing, a sufficient volume of an ethanolic solution of etbylcellulos4 as a granulating agent is added slowly. The quantity of ethylcellulose per tablet in the 1nal formulation is about 1/10th part. The mass resulting from mixing the granulating agent is sieved through 22/44 mesh. Resulting granules are dried at 40'C for 12 hours and Ithereafter kept in a desiccator for 12 hours at room temperature. Once dry the granules retained on 44 mesh are mixed with 15% fines (granules that passed through 44 mesh). Tdlo and magnesium stearate are added as glidant and lubricant at 2% of weight each. A colorant is also added. The tablets are compressed using a single punch tablet compression machine. 3... Formulation of a compression tabletedform of diazoxide or a derivative thereof that provides for controlled release. 10502] Diazoxide salt or a derivative thereof at 20-40% weight is mixed with 30/a weight hydrokypropyl methylcellulose (Dow Methocel KIOOLV P) and 20-40% weight impalpable lactose. The mixture is granulated with the addition of water. The granulated mixture is wet milled and then dried 12 hours at 11 0*C. The dried mixture is dry milled. Following milling, 25% weight ethylcellulose resin is added (Dow Ethocel 10FP or Ethocel 1 0OFP) followed by 0.5% weight magnesium stearate. A colorant may also be added. The tablets are compressed using a single punch tablet compression machine (Dasbach et al., Poster at AAPS Annual Meeting Nov. 10-14 (2002)). 3.3. Formulation of a compression coated tabletedform of diazoxide or a derivative thereof that provides for controlled release. [05031 The core tablet is formulated by mixing either 100 mg of diazoxide salt or a derivative thei-eof with 10 mg of ethylcellulose (Dow Ethocel I0FP), or by mixing 75 mg 106 of diazoxide or a derivative thereof with 25 mg lactose and 10 mg of ethylcellulose (Dow Ethocel IOFP), or by mixing 50 mg of diazoxide or a derivative thereof with SO mg of lactose and 10 mg of ethylcellulose (Dow Ethocel lOFP). The core tablets are formed on an automated press with concave tooling. The compression coating consisting of 400 mg of polyethylene oxide (Union Carbide POLYOX WSR Coagulant) is applied and compressed tp 3000 psi (Dasbach et al., Poster at AAPS Annual Meeting Oct. 26-30 (2003)). 3.4. Formulation of a controlled release tableted form of diazoxide choline salt . 3.4.1 Controlled Release Formulations 10504] Controlled release tableted formulations of diazoxide choline salt were developed and investigated with respect to a variety of properties known by those of skill in the pharmaceutical art relating to the manufacture of tableted formulations including, for example, pase and consistency of manufacture, appearance (e.g., sheen, compressibilily, microscopic appearance), and dissolution properties (e.g., rate, order and extent of dissolution). Tablets were produced individually on a press, where the final blend of diazoxide choline salt and excipient was weighed out to the desired total tablet weight prior to compression. As shown in Table 2, Formulations A-H, J, and L contained 50.0 mg diaz9xide as the choline salt (i.e., 72.5 mg total diazoxide choline salt present), and Formulations I and K contained 200.0 mg diazoxide as the choline salt (i.e., 290.0 mg total diazoxide choline salt present). The manufacture of formulation L is exemplary of the manufacturing methods available to the skilled artisan. For formulation L, diazoxide choline salt, talc, and approximately half of the colloidal silicon dioxide (Cab-o-sil) were mixed in a KU-5 mixer bowl with an impeller speed of about 300 rpm and a chopper speed of about 3000 rpm for about 4 min. The mixture was passed through a co-mil equipped with a 024R screen, square-edged paddle, and 0.175" spacer. To this milled mixture in a 9-qt V-shell blender was added Emcompress through a #20 mesh hand screen with blending for about 10 mini. To this mixture was added PEO N750 and PEO 303, which had been passed through a #20 mesh hand screen, with blending for about 10 min. To this mixture was added Pruv and the remainder of the Cab-o-sil, having been passed through a *20 mesh hand screen, with blending for about 5 min. The mixture was 107 subjected to dressing (Manesty Beta Press) using 0.2220" x 0.5720" caplet shaped tooling (Set #21.) Table 2. Exemplary Formulations for Diazoxide Choline salt. Formulation INGREDIENT Amount per tablet (mg) A. Diazoxide Choline 72.50 Kollidon SR 100.0 PEO N303 25.00 Emcompress 50.50 Pruv 2.00 TOTAL WEIGHT 250.0 B. Diazoxide Choline 72.50 Methocel K100M 237.3 Emcompress 35.00 Magnesium Stearate 3.50 Cab-o-sil 1.75 TOTAL WEIGHT 350.0 C. Diazoxide Choline 72.50 Kollidon SR 105.0 PEO N303. 35.0 Emcompress 134.1 Pruv 3.50 TOTAL WEIGHT 350.1 D. Diazoxide Choline 72.50 Methocel K100M 175.1 Emcompress 97.30 Magnesium Stearate 3.50 Cab-o-sil 1.75 TOTAL WEIGHT 350.2 E. Diazoxide Choline 72.50 PEO N750 NF 105.0 PEO N303 NF 52.50 Emcompress 116.6 -Prm '. 3150 .108 TOTAL WEIGHT 350.1 F. Diazoxide Choline 72.50 Kollidon SR 105.0 PEO N303 7.00 Emcompress 162.1 Pruv 3.50 TOTAL WEIGHT 350.1 G. Diazoxide Choline 72.50 Methocel K100M 175.1 Emcompress 105.1 Magnesium Stearate 3.50 Cab-o-sil 1.75 TOTAL WEIGHT 358.0 H. Diazoxide Choline 72.50 PEO N750 NF 105.0 PEO N303 NF 35.01 Emcompress 134.1 Pruv 3.50 TOTAL WEIGHT 350.1 I. Diazoxide Choline 290.0 Methocel K100M 240.0 Emcompress 258.0 Magnesium Stearate 8.00 Cab-o-sil 4.00 TOTAL WEIGHT 800.0 J. Diazoxide Choline 72.50 PEO N750 NF 105.0 PEO N303 NF 52.50 Emcompress 116.6 Pruv 3.50 Talc 3.50 Cab-o-sil 1.75 109 TOTAL WEIGHT 355.4 K. Diazoxide Choline 290.0 PEO N750 NF 249.0 PEO N303 NF 124.5 Emcompress 145.3 Pruv 8.30 Talc 8.30 Cab-o-sil 4.15 TOTAL WEIGH T 829.6 L. Diazoxide Choline 72.51 PEO N750 NF 105.1 PEO N303 NF 52.54 Emcompress 111.4 Pruv 3.50 Talc 3.50 Cab-o-sil 1.75 TOTAL WEIGHT 350.3 105051 Microscopic observation of the tablets having Formulation A revealed a grainy texture of the hiazoxide choline salt, and at the 29% loading of diazoxide choline salt in Formulation A the blend had poor flow characteristics. Accordingly, the loading of diazoxide choline was reduced in Formulation B. A caplet shaped tooling, approximately 6 mm x 15 mmn was found to result in acceptable tablet appearance, sheen, and ease of compressibility. However, Formulation B also exhibited poor blend flow. 105061 Subsequent formulations (e.g., Formulations C-L) incorporated a milling step of the diazoxide choline salt piior to incorporation into the tablet blend. A milling study was conducted, using a test mill equipped with different screen sizes to evaluate and determine a suitable milling process. Particle size was determined by visual comparison with 40 jpm reference beads. As shown in Table 3, use of the 024R screen resulted in the best recovery of API (i.e., "active pharmaceutical ingredient" = diazoxide as the diazoxide choline salt) providing the broadest range of particle sizes. Accordingly, material milled through a 024R screen was selected for subsequent formulation. 110 Table 3. M4Ing study for diazoxide choline salt prior to formulation Screen/PaddIp/Spacer/Speed API loaded/API recovered Particle size (g) (AM) 01 8R/square/0.200'/80% 50.0/36.5 -100-200 024R/square0.200"/80% 50.0/42.0 -100-250 039R/square/0.200"/80% 50.0/42.0 -150-250 3.4.2. Dissolution Studies [05071 Dissolution of tablets with formulation as set forth in Table 4 was investigated. One or more tablets (e.g., I or 2) of the indicated tableted formulation were placed into a volume of buffer (e.g., 900 mL) with known buffer salt concentration (e.g., 0.05 M potassium phosphate, pH 8.6; 0.05 M potassium phosphate, pH 7.5), with or without surfactant (e.g., 0.05% CTAB), at a known temperature (e.g., 37 OC). Stirring conditions en ployed paddles at, for example, 50 RPM. Aliquots (e.g, 10 mL) removed as a function of time were filtered (e.g., 0.45 gm GMF Filter) prior to analysis. Table 4. Diskolution study for formulations of diazoxide choline salt (entries are % dissolved diazoxide) Time (hr) Entry Protocol 0 1 2 3 6 9 12 38 24 C 0.0 2.9f4.5 5-7 9.4 13.0 16.6 D _ _ 0.0 4.5 7.8 11.0 19.1 25.6 31.3 F b 29 36 44 54 G b 30 39 50 67 H b 50 75 91 101 I b 25 37 48 57 J b 34 53 76 104 K b 25 43 64 94 _ _ 2 141~f 62 92 Column 1: Entry from Table 2. Column 2: Protocol a) 0.05 M potassium phosphate, pH 8.6, 37 *C; Protocol b) 0.05 M potassium phosphate, pH 7.5, 0.05% CTAB, 37 *C. 105081 The dissolution profile (i.e., % dissolved with time) of Proglycem@ capsules (100 mg) and controlled-release tablet formulations of diazoxide as provided herein is shown in Table 5. The 50 mg tablet entry of Table 5 refers to Formulation J (Table 2) 11.1 wherein talc d cab-o-sil was present at 2% and 1%, respectively. The 200 mg tablet entry of Table 5 refers to Formulation K (Table 2) wherein talc and cab-o-sil are present at 2% and 1%, respectively Table 5. Dissolutlon profile of 100 mg Proglycem@& (capsule) and diazoxide choline salt (tablet) 10 m200 mg tablet 50 mg tablet Tinie (hr) diazoxide choline diazoxide choline I ~Proglycem@g salt salt 0 0 0 0 3 79 22 25 6 85 36 39 12 92 54 70 24 98 88 99 105091 As evidenced by Table 5, the I 00-mg Proglycem@ capsule provides for faster dissolution o diazoxide relative to tablets described herein. Approximately 79% diazoxide cothponent of Proglycem@ is recovered in dissolution buffer after 3-hr. In contrast, the 50 and 200-mg tablets described in Table 5 dissolved at levels of 25% and 22%, respectively, at 3-hr. At 12-hr, 100-mg Proglycem@ capsule dissolved at 92%, whereas the 51) and 200-mg tablets dissolved at 70% and 54%, respectively. Approximately total dissolution is observed with 100-nmg Proglycem capsule and 50 mg tablet at 2;4 hrs. . 3.4.3. Excipient Compatibility Studies 105101 Studies to determine the compatibility of diazoxide choline salt for various excipients are summarized in Table 6. Each mixture of excipient (100 mg) and diazoxide choline salt (100 mg) was made in acetonitrile to 10 mL Samples were assayed immediately (i.e., "Initial" column of Table 6) and at one-month storage under conditions a) 40 *C/75%:RH (relative humidity), and b) 50 *C. 112 Table 6. Ex ipient compatibility study for diazoxide choline salt. 1 Month I Month ExciientInitial Excipient 40 *C/75% RH 50 *C %(w/w) %0(w/w) Hydroxyrpropylmethyl cellulose (HMPC) 98.8 101.4 96.6 Hydroxypropllcellulose (HPC) 103.1 97.4 100.8 Ethylcellulose (EC) 90.6 102.0 99.7 99.5* Methylcelluloge (MC) 102.3 100.3 99.1 Carboxymethyl cellulose Na (CMC Na) 96.8 101.6 99.5 Starch 1500 103.3 90.6 95.2 81.2 99.8 100.9 Kollidon SR IDO.2* Polyethyleneocide N3 03 (PEO) 81.0 99.2 990 99.1 * Dibasic Calcium Phosphate 98A 102.9 102.2 Sodium Stearyl Fumarate 98.9 101.1 103.7 Magnesium Stearate 100.1 101.4 99.3 Colloidal Silicon Dioxide (Cab-o-sil) 99.0 99.4 104.S Microcrystallie Cellulose 96.8 98.6 107.0 Lactose Monoiydrate 94.5 99.2 103.0 Mannitol 111.7 98.1 81.3 Diazoxide Control N/A 99.0 99.4 * Re-assayed [05111 Initial low results for ethylcellulose, Kollidon SR, and polyethyleneoxide were investigated by re-preparing samples of diazoxide choline salt and excipient. As shown in Table 6, initial sample recovery (i.e., column "Recovery") of the re-prepared samples indicates method accuracy. 10512) Nd reportable impurities were detected in any sample, and no degradation was observed in tle samples stored for one-month with the exception of mannitol wherein 81.3% of diazoxide was recovered after 1-month at 50 *C. 113 3.4.3. Stability Studies for Diazoxide Choline Controlled Release Tablets [05131 Studies to determine the stability of formulations of diazoxide choline salt as the controlled release tablet were conducted on sample formulations as described in Table 2, results of 4hich are shown in Table 7. In these studies, storage conditions were the following: a) 25 *C/60% RH, and b) 40 *C/75% RH. In Table 7, the term "Appearance" refers to the physical appearance of the tablets of the study. The term "Assay (o)" refers to the percentage of diazoxide choline salt assayed with respect to nominal (i.e., 50 mg or 200 mg) content of the sampleThe term "Dissolution (%)" refers to the amount, expressed as a percentage, of diazoxide choline salt assayed by method described herein. Table 7. Stability Study for Formulations of Diazoxide Choline Salt. Test Time point Initial I month 2 months 50 mg tablet, Formulation J, 25 *C/60% AL Appearance White tablets White tablets White tablets Assay (%) 95.8 102.9 99.3 Dissolution (ao): 3 hr 24 19 15 . 6 hr 41 30 27 12 hr 62 48 52 24 hr 92 90 94 50 mg tablet. Formulation J, 40 *C/75% RJH Appearance White tablets White tablets White tablets Assay (%) 95.8 103.2 99.4 Dissolution (Vo): 3 hr 24 10 10 6 hr 41 22 21 12hr 62 50 46 24 hr 92 90 84 200 mg tablet. Formulation K, 25 *C/ 6 0% R! Appearance White tablets White tablets White tablets Assay (%) 95.9 100.9 100.3 114 Dissolution (%): 3 hr 34 15 13 6lhr 53 .31 30 12 hr 76 69 68 24 hr 104 101 96 200 mg tablet, Formulation K 40 *C/75% RH Appearance White tablets White tablets White tablets Assay (%) 95.9 99.6 . 100.0 Dissolution (6o ): 3 hr 34 10 10 6 hr 53 26 28 12 hr 76 60 61 24 hr ' 104 90 90 3.5. A controlled release dosage form of diazoxide or a derivative thereof using an osmotically controlled release system. 105141 Diazoxide salt or a derivative thereof is formulated as an osmotically regulated release systeni. In general, two components, and an expandable hydrogel that drives release of the active drug is assembled with diazoxide salt or a derivative thereof into a semipermeable bilaminate shell. Upon assembly a hole is drilled in the shell to facilitate release of active upon hydration of the hydrogel. 10515] A dosage form adapted, designed and shaped as an osmotic delivery system is manufactured as follows: first, a diazoxide salt or a derivative thereof composition is provided by blending together into a homogeneous blend of polyethylene oxide, diazoxide salt or a derivative thereof and hydroxypropyl methylcellulose. Then, a volume of denatured anhydrous ethanol weighing 70% of the dry mass is added slowly with continuous mixing over 5 minutes. The freshly prepared wet granulation is screened through a 20 mesh screen through a 20 mesh screen, dried at room temperature for 16 hours, and again screened through a 20 mesh screen. Finally, the screened granulation is mixed with 0.5%.weight of magnesium stearate for 5 minutes. [0516] A hydrogel composition is prepared as follows: first, 69% weight of polyethylene oxide weight, 25% weight of sodium chloride and 1% weight ferric oxide 115 are separately screened through a 40 mesh screen. Then, all the screened ingredients are mixed with 5% weight of hydroxypropyl methylcellulose to produce a homogeneous blend. Next, a volume of denatured anhydrous alcohol equal to 50% of the dry mass is added slowly to the blend with continuous mixing for 5 minutes. The freshly prepared wet granulatin is passed through a 20 mesh screen, allowed to dry at room temperature for 16 hours, and again passed through a 20 mesh screen. The screened granulation is mixed with 0..5% weight of magnesium stearate for 5 minutes (see U.S. Patent No. 6,361,795 by Kuczynski, et al.). 10517] The diazoxide salt composition, or a derivative thereof, and the hydrogel composition, ore compressed into bilaminate tablets. First the diazoxide salt or a derivative thereof composition is added and tamped. The hydrogel composition is then added and the laminae are pressed under a pressure head of 2 tons into a contacting laminated arrangement. 105181 The bilaminate arrangements are coated with a semipermeable wall (i.e. thin film). The wall forming composition comprises 93/a cellulose acetate having a 39.8% acetyl content and 7% polyethylene glycol. The wall forming composition is sprayed onto and around the bilaminate. 105191 Firially, an exit passageway can be drilled through the semipermeable wall to connect the diazoxide salt or a derivative thereof drug lamina with the exterior of the dosage system. Residual solvent is removed by drying at 50* C and 50% humidity. The osmotic systerps are dried at 50* C to remove excess moisture (see U.S. Patent No. 6,361,795 by Ikuczynski, et al.). 4. Preparation of Diazoxide Salts 4.1; Preparation of the Sodium Salt 105201 Th* sodium salt of diazoxide was prepared by dissolving 300 mg of diazoxide in approximately 45 nL methyl ethyl ketone (MEK). The diazoxide/MEK solution was heated at 75*0 on an orbital shaker to ensure dissolution. To the solution was added 1.3 mL of IM NaOI (1 molar equivalent). The combined solutions were heated at 75*C for approximately'30 minutes and allowed to cool to room temperature. The mixture was concentrated under reduced pressure, and dried In vacuo at 55 0 C and 30 in. Hg. 116 Elemental analysis: Calculated, 38.03% C, 2.39% H, 11.09% N and 9.1% Na; Found, 38.40% C, 2.25% H, 10.83% N and 7.4% Na. 105211 A Aodium salt of diazoxide was also prepared by dissolving 300 mg of diazoxide in approximately 45 mL acetonitrile. The diazoxide/acetonitrile solution was heated at 75"U( on an orbital shaker to ensure dissolution. To the solution was added 1.3 mL of I M NdOH (approximately I molar equivalent). The combined solutions were heated at 75"y for approximately 30 minutes and allowed to cool to room temperature. The mixture yas concentrated under reduced pressure, and dried in vacuo at 550C and 30 in. Hg. 4. . Preparation ofthe Potassium Salt [0522) Tle potassium salt of diazoxide was prepared by dissolving 300 mg of diazoxide in approximately 45 mL methyl ethyl ketone (MEK). The diazoxide/MEK solution was heated at 75"C on an orbital shaker to ensure dissolution. To the solution was added approximately 1.3 mL of I M KOH (1 molar equivalent) and the solution was returned to th orbital shaker, heated at 75"C for approximately 30 minutes and allowed to cool to room temperature. The solvent was removed under reduced pressure and the solid was dried In vacuo at 55*C and 30 in. Hg. Elemental analysis: Calculated, 33.59% C, 2.81% H, 9.77% N and 13.63% K; Found, 34.71% C, 2.62% H, 9.60% N and 10.60% K. [05231 The potassium salt of diazoxide was also prepared by dissolving 300 mg of diazoxide in approximately 45 mL tetrahydrofuran (THF). The diazoxide/THF solution was heated at 75*C on an orbital shaker to ensure dissolution. To the solution was added approximately 1.3 mL of 1 M KOH (I molar equivalent) and the resulting solution was returned to the orbital shaker, heated at 75"C for approximately 30 minutes and allowed to cool to root temperature. THF was removed under reduced pressure and the solid was dried in vacuo at 55*C and 30 in. Hg. 4.3. Preparation of Choline Sail 4.3.1. Preparation of the Choline Salt: proof of concept [0524] Th; choline salt of diazoxide was prepared by dissolving 300 mg of diazoxide in approximately 45 mL methyl ethyl ketone (MEK). The diazoxide/MEK solution was 117 heated at 75*C on an orbital shaker to ensure dissolution. To the solution was added approximately 315 mg of 50 wt. % of choline hydroxide (I molar equivalent) and the solution was }eturned to the orbital shaker and stirred at 75 0 C fbr approximately 30 minutes. Th4 solvent was removed under reduced pressure, and the solid was dried in vacuo at 550o and 30 in. Hg. Elemental analysis: Calculated, 46.77% C, 5.86% H, and 12.00% N; Found, 46.25% C, 6.04% H, and 12.59% N. 4.3.2. Process ofpreparation of the Choline Salt [05251 An investigation of the minimum solvent volumes required to optimize the formation of the diazoxide choline salt was perfonned in MeCN, THF, MEK, and 2 MeTHF on small scale in the presence and absence of MTBE. Analyses by 1 H NMR and XRPD of all reactions were consistent with the assigned structure and Form B of diazoxide chdline salt. 4.3.2.1. Solvent Efficiency Study with Single Solvent System. 10526] investigation of single solvent system synthesis of diazoxide choline salt using solvents THF, MEK, and 2-MeTRF were conducted, results of which are shown in Table 8. These results suggest that precipitation can be achieved with a single solvent system in THF or 2-MeTHF. The best results, (i.e., Table 8 entries 14-17) obtained with 2-MeTHF. However, it vas observed that in 2-MeTHF at 3-volumes and above, complete dissolution was not achieed after addition of choline hydroxide. Table 8. Solvent Efficiency of a Single Solvent System Entry Solvent Solvent volume Yield (%) Polymorphio Form I THF 1.0 7 B 2 THF 2.0 n/a /a 3 THF 3.0 20 B 4 THF 4.0 28 B 5 THF 5.0 32 B 6 THF 6.0 42 B 7 THF 7.0 53 B 8 THF 8.0 50 B 9 MEK 4.0 n/a n/a 10 2-MeTHF 1.0 n/a n/a 118 Entry . Solvent Solvent volume Yield (%) Polymorphic Form 11 2-MeTHF 2.0 48 B 12 Z-MeTHF 3.0 41 B 13 2-MeTHF 4.0 48 B 14 2-MeTHF 5.0 71 B 15 2-McTHF 6.0 71 B 16 2rMeTHF 7.0 72 13 17 2--MeTHF 8.0 67 B n/a: Samples Were either seen to form a gum, or no precipitate was observed. 4.3.2.2. Solvent Efficiency Study with Binary Solvent Systems. [05271 The addition of a second solvent at 1-20 volumes (i.e., 1-8, 9,10, 11, 12, 13, 14, 15, 16, 171, 18, 19, 20) to the solvent volumes of Table 8 was envisaged to optimize diazoxide salt production yields. Results of investigation of methods to enhance precipitation and Increase yield employing binary solvent system synthesis of diazoxide choline salt using solvents THF, MeCN, MEK, and 2-MeTHF and co-solvent MTBE are shown in Table 9. Optimum conditions fbr the preparation of the diazoxide choline salt obtained within 1-3 volumes of THF (see Table 8, entries 1-3), with 3 volumes being the ratio of choice to eliminate excessive drag during stirring of slurry in large scale production. Table 9. Solient Efficlency of a Binary Solvent System Entry Solvent Solvent Co-Solvent Yield (%) Polymorphic Volume (12 Vol) Form 1 THF 1.0 MTBE 96 B 2 THF 2.0 MTBE 96 1B 3 THF 3.0 MTBE 91 B 4 'THF 4.0 MTBE 90 13 5 THF 5.0 MTBE 84 B 6 THF 6.0 MTBE 90 B 7 THF 7.0 MTBE 94 B 8 'THF 8.0 MTBE 94 B 9 XMeCN 1.0 MTBE 92 B 119 Entry Solvent Solvent Co-Solvent Yield (%) Polymorphic Volume (12 Vol) Form o10 eCN 2.0 MTBE 90 B 11 yeCN 3.0 MTBE 87 B 12 MeCN 4.0 MTBE 79 B 13 MeCN 5.0 MTBE 79 B 14 MeCN 6.0 MTBB 75 B 15 MeCN 7.0 MTBB 70 B 16 MeCN 8.0 MTBE 74 B 17 MEK 4.0 MTBE 83 B 18 2-MeTH4F 1.0 MTBE 97 B 19 2-MeTHF 2.0 MTBB 94 B 20 2-MeTHF 3.0 MTBE 94 B 21 2-l'yiTHF 4.0 MTBB 95 B 22 2-MeTHF 5.0 MTBB 97 B 23 2-MeTHF 6.0 MTBE 94 B 24 2-4/eTHF 7.0 MTBE 97 B 25 2-MeTHF 8.0 MTBE >99 B 4.3.2.3. Co-Solvent Efficiency and Optimization with MTBE. 105281 Regults of optimization of co-solvent (MTBE) volume in the presence of 3 volumes of soli'vent are shown in Table 10. Table 10. CorSolvent Efficiency and Optimization with MTBE Entry Solvent MTBE Volume Yield (%) Form I MeCN 8.0 76 B 2 MeCN 14.0 85 B 3 THF 6.0 93 B 4 THF 8.0 93 B 5 THF 14.0 98 B (05291 Optimized conditions for the production of the choline salt of diazoxide in a binary solvent system obtained with 3:14 (i.e., 1 4.7) THF/MTBE (v/v). 120 4.3.2.4. Optimization of Cooling Profile. 10530] Optimization for the controlled precipitation of diazoxide choline salt was conducted by.varying the cooling temperatures and hold times. Reactions were carried out in MeCN, THF, and 2-MeTHF (3 vol) with MTBB (14 vol). The results are presented in Table 11. These results suggest that optimum crystal growth was achieved with cooling to 0-S *C for eight hours in THF and 2-MeTHF (Entries 5-6) when compared to those in MeCN (Entries 1, 2, and 4). These results however did not indicate enhanced precipitation when compared to previous studies carried out in THF and 2-MeTHF when the slurries were allowed to stir for two hours. In addition no notable improvements were observed for the additional cooling to -15 "C or with the filtration at ambient temperature. Table 11. Cooling Profile Optimization for Controlled Precipitation Entry Solvent Cooling Temp. Hold Time Yield (%) Form (*C (hr) _ _ I MeCN 0-5 2 89 B 2 MeCN -10-+--15 2 85 B 3 THF RT 2 80 B 4 MeCN RT 2 85 B 5 THF 0-5 8 94 B 6 2-4eTHF 0-5 8 95 B 4.3.2.5. Optimization of Rate of Co-solvent addition. [05311 Th'e effect of rate and hold time of co-solvent addition on the precipitation of diazoxide choline salt was examined. The reactions were carried out on 500 mg scale in three volumes of primary solvent and 14 volumes of MTBE (TRF and 2-MeTHF) or 1:3 volume ratio (MeCN). Addition of the co-solvent was made dropwise in one portion for Entry 1, and for Entries 2 and 3 the co-solvent was added at a rate of I m1J20 minutes for a total hold tirie of 140 minutes for the addition of 7 mL. The results, presented in Table 12, indicate that optimum precipitation of diazoxide choline salt was achieved by the addition of MTBE with 20 minute hold times in between additions in THF or 2-MeTHF (entries 2-3). Table 12. Optimization of Rate of Co-solvent addition solvent Hold Time Addition Rate Yield (%) Form 121 I MeCN 60 n/a 87 B 2 THF 140 1.0/20 96 B 3 2-tleTHF 140 1.0/20 96 B 4.3.2.6. Thermal Stability Study. 105321 The stability of the isolated diazoxide choline salt was investigated to determine opimal drying conditions to minimize residual solvents without degradation. Samples of the diazoxide choline salt prepared in THF and MTBE (Entries 1-4) were dried under vacuum at 40 *C for various durations on small scale (100 mg). The study was then cared out on 5 g scale (Entry 5) at 30 "C for eight hours under vacuum to show reproducibility on large scale. The results are presented in Table 13. Analyses of the samples of T4ble 13 by 1H NMR, XRPD, and HPLC indicated that elevated temperatures and prolonged drying times did not degrade the compound or affect the fonn of the compound. Table 13. Thermal Stability Study Entry Drying Temp Time (h) OVI Polymorphic (C) (THF/MTBE) Form (PPM) 1 RT 12 376/248 B 2 40 20 317/160 B 3 40 28 276/127 B 4 40 42 268/128 B 5 30 8 241/509 B 4.3.2.6. Demonstration of 50-g Scale synthesis ofDiazoxide Choline Salt in THF. [05331 The preparation of the diazoxide choline salt was carried out in a binary solvent system of THF and MTBE with a ratio of 1:4.7 (solvent/co-solvent) volumes and cooling to 0-3 "C for two hours with stirring. A demonstration run for the large scale production utilizing the modified procedure was carried out on 50 g-scale. Diazoxide (50 g) as a hot (62 *C) suspension in THF (140 mL) was treated with choline hydroxide (45% solution in MeOH, 1.0 equiv) added (2 mL/min)-over 30 minutes. The resulting solution was stirred for 30 minutes, followed by cooling to 52 "C for the addition of MTBE (14 vol) over 45 minutes. On addition of two volumes of co-solvent precipitation was 122 observed. The resultant slurry was then allowed to cool naturally to ambient temperature followed by further cooling to 0-5 *C with an ice/water bath and an additional 2 hr stirring. The precipitate was isolated by vacuum filtration, and the filter cake rinsed with ice cold MTE (-50 mL) and dried under vacuum at room temperature for 12 hours. OVI analysis indicated that THF levels were above the recommended ICH guidelines (799 ppm) and the material was returned to the oven at 30 *C for eight hours to give diazoxide choline salt [70.87 g, 97% yield, 97% purity AUC] as a white crystalline solid. Analyses by 1H NMR, XRPD, and HPLC were consistent with the assigned structure of Form B while maintaining a high purity with good yield. 4.3.2.7. Demonstration of 50-g Scale synthesis ofDiazoxide Choline Salt in 2-MeTHF. 105341 A 60-g level synthesis was duplicated in 2-MeTHF/MTBE as an alternative to THF/MTBE (or the large scale production of the diazoxide choline salt described above. No issues or concerns arose during the reaction other than complete dissolution was not achieved afte addition of the choline hydroxide. A white precipitate fbrned after addition of the co-solvent, which was isolated via vacuum filtration and dried under vacuum at 30.*C for eight hours to give diazoxide choline salt (71.51 g, 97% yield] as a white crystalline solid. Analyses by ,H, XRPD, and HPLC were consistent with the assigned structure and Form B. OVI analysis showed 2-MeTHF and MTBE levels of 125 and 191 ppm, respectively, which were below the ICH guidelines. 4.3.2.8. 2 50-g Scale synthesis ofDiazoxide Choline Salt In THF. {0535] Larger scale preparation of the diazoxide choline salt was carried out in a binary-solven system of THF and MTBE with a ratio of 1:4.7 (vv) volumes. Diazoxide as a hot (62 OC) suspension in THF (745 mL) was treated with choline hydroxide as a 45% solutionin MeOH (1.0 equiv) added over 30 minutes. The resulting solution was stirred for 30 4ninutes, followed by cooling to 52 00 for the addition of MTBE (14 vol) over 45 minutes. On addition of two volumes of co-solvent, precipitation was observed. The resultant slurry was then allowed to cool naturally to ambient temperature followed by cooling to 0-5 *C with an ice/water bath. The precipitate was isolated by vacuum filtration, and the filter cake rinsed with ice cold MTBE (approximately 250 mL) and dried under vacuum at 30 *C for 38 hours to give diazoxide choline salt (350.28 g, 97.7% 123 yield) as a wHite crystalline solid. Analyses by ' NMR, XRPD, and HPLC were consistent with the assigned structure of Form B while maintaining a high purity with good yield. 4.3.2.9. 2-kg Scale Synthesis ofDiazoxide Choline Salt in THF. [05361 A 12-L reaction flash was charged with 2.0 kg diazoxide and 5.0-L TIF with stirring and heating to 55 *C. Choline hydroxide (45% solution in methanol, 2.32 L) was added dropwise to this reaction mixture over about 2.5 hr with stirring. The temperature was naintaind at 60 ± 5 *C. After addition of choline hydroxide, stirring was continued for about 30 min. The reaction mixture was clarified by in-line 10 micron filtration upon transfer to a 22-L reaction flask pre-charged with 2-L pre-filtered THF, into which was added 1 O-L pre-filtered MTBE dropwise. This reaction mixture was transferred to another flask'which was then charged with an additional 30-L pre-filtered MTBE dropwise, with adjustment of temperature to < 5 *C and stirring for about 2 hr. Diazoxide choline salt was recovered by vacuum filtration to afford 2.724 kg (94%) diazoxide choline salt (99.8%, HPLC purity), confirmed by 'H NMR, IR, and UV/Visible analysis. 4.4. Preparation of the Hexamethyl Hexamethylene Diammonium Hydroxide Salt 10537] Tlge hexamethyl hexamethylene ammonium salt of diazoxide was prepared by dissolving 50'mg of diazoxide in approximately 7.5 mL methyl ethyl ketone (MEK). The diazoxide/MMK solution was heated at 75 0 C on an orbital shaker to ensure dissolution. To the solution was added approximately 2.17mL of 0.1M hexamethyl hexamethylene ammonium hydroxide solution (I molar equivalent) and the solution was stirred at 75*C for an additional 10 minutes and then cooled to room temperature at the rate of 30*C/h. The solvent vwas removed under reduced pressure, and the solid was dried in vacuo at 55*C and 30 in. Hg. 4.5. Failure to Obtain Salts ofDiazoxide and derivatives 4.5.1. Failure to Obtain Salts from Alkali Metal Hydroxides 105381 U.S. Patent Number 2,986,573 ("the '573 patent") describes the synthesis of diazoxide metal salts in aqueous or non-aqueous solutions in the presence of an alkali metal alkoxide. According to the '573 Patent, diazoxide can be dissolved in an alkali metal solution, and the salt obtained upon evaporation. Also described is a method for 124 forming salts from non-aqueous media wherein diazoxide and sodium methoxide are dissolved in anhydrous methanol and the solvent is evaporated to obtain the sodium salt of diazoxide as a white solid. [0539] Attempts were made to prepare a diazoxide salt from alkali metal hydroxides by the method described in the '573 patent. Salt preparation was carried out in aqueous media by dissolving diazoxide in a basic solution I M NaOH, followed by evaporation of the solvent. A solid was obtained and analyzed by XRPD (X-Ray Powder Diffraction) and NMR. However, this analysis confirmed that the solid obtained was the diazoxide starting material and not a salt. [05401 Salt preparation was carried out in non-aqueous media by dissolving diazoxide in anhydrous methanol in the presence of either sodium methoxide or potassium methoxide and stirring the mixture at 60*C for 15 minutes. The mixture was then cooled to room temperature while stirred. After approximately two hours, a solid was recovered, isolated by filtration, and dried in vacuo. Analysis by XRPD confirmed that the solid obtained was the diazoxide starting material and not a salt. 4.5.2. Preparation of Salts in Methanol or Ethanol According to the '573 Patent [05411 The preparation of diazoxide salts in methanol and ethanol was attempted using 22 different counter-ions according to the methods described by the '573 Patent. For example, 20 mg of diazoxide was dissolved in 5 mL of ethanol and stirred and heated to ensure dissolution of the diazoxide. To the stirred solution was added approximately 1 molar equivalents of sodium methoxide. The solution was stirred for approximately 10 15 minutes at 60 0 C, and cooled to room temperature for approximately 2 hours. The resulting solid precipitate was concentrated under a nitrogen stream, and collected by filtration. The product was dried in vacuo and analyzed by XRPD. As shown in Figure 15, XRPD of the solids collected from the sodium methoxide experiment, (as well as the solids collected from the potassium methoxide experiment, which was run under similar conditions), revealed that the solid was the diazoxide starting material and that no sodium or potassium salt was prepared. In Figure 15, (d) is the XRPD pattern of free form diazoxide, (b) is the XRPD pattern of the product of potassium methoxide in methanol, and (c) is the XRPD pattern of the product of sodium methoxide in methanol. LMR_324092.1 125 [0542] Although not wishing to be bound by any theory, it is believed that a possible explanation f6r the failure to prepare diazoxide salts by the methods of the '573 Patent (i.e., in the presence of alcohols, e.g., methanol or ethanol), is that the alcohol may have an effect on thie stability of the alkali salts of diazoxide. This was sapportedby UV spectroscopy aalysis of alkali salts of diazoxide (sodium and potassium). Both the sodium and potassium salts of diazoxide were synthesized by reacting diazoxide with NaOH or KQ1i in MEK. Elemental analysis, NMR and XRPD confirmed that the salts were made. [0543) Upon dissolution of the sodium or the potassium salt in acetonitrile, the UV spectrum shows a shift into the red region of the spectrum for the Xa from approximatel 268 nm for the free form of diazoxide to approximately 298 run for both the potassium and sodium salt (see Figure 1). Similarly, these salts can be stabilized in aqueous solutions by elevating the pH to above 9.0. A similar shift in the absorption maximum at pH 9.0 is measured using UV spectroscopy. Subsequent adjustment of the pH from great r than 9.0 to less than 6.2 results in the hydrolysis of the salt as measured by the recovery of the UV absorption pattern of the diazoxide free base (see Figure 2). In contrast, whenithe sodium or the potassium salt is dissolved in methanol, the UV-Vis spectrum of the salt was identical to that of the diazoxide starting material, (see Figure 3). [05441 These results demonstrate that using methanol as the solvent is incompatible with the synthesis of alkali salts of diazoxide. In addition, the results show that isolation of an alkali metal salt of diazoxide (or any other salt) in the presence of an alcohol, such as methanol, nay not be possible. 4.5.3. Failure to Obtain Saltsfrom Acidic Counter Ions [05451 Salt formation with diazoxide was also attempted using acidic counter-ions,. such as, for example, hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, Acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumario acid, benzoic acid, undecylenic acid, salicylic acid and quinic acid. Hcdwever, no salt formation was observed for any acid in any solvent, 126 [0546] Fdr example, 100 mg of diazoxide Was dissolved in 50 mL of acetone and heated to 35*0. To a stirred solution was added approximately 4.65 molar equivalents of HCI. The reaction mixture was allowed to cool to room temperature for approximately 3 hours, with no precipitation observed. Solvent was removed in vacuo. The resulting solid was analyzed by XRPD, and the observed XRPD pattern was consistent with the free form diazoxide starting material. In all cases, the attempted synthesis of diazoxide salts from acifls was unsuccessful in all solvents attempted. 4.0 Preparation of/Salts of Compounds of Formulae V- VIII [05471 The chloride salt of 3-amino-4-methyl-1,2,4-benzothiadiazine-1,I -dioxide is prepared dissolving approximately 300 mg (1.4 mmol) in 45 mL acetonitrile, The mixture is heated to approximately 75*C and stirred for 30 min. To the stirred solution, approximately; 1 molar equivalent of HCl is added dropwise, and stirred for approximately 30 min at 750C. The mixture is cooled to room temperature and the solvent is removed under reduced pressure, affording the chloride salt as a solid. [05481 The sodium salt of 3 -amino- 4 -methyl-1,2,4-benzothiadiazine-1,I-dioxide is prepared dissolving approximately 300 mg (1.4 mmol) in 45 mL acetonitrile. The mixture is heated to approximately 75*C and stirred for 30 min. To the stirred solution, approximately I molar equivalent of NaOH is added dropwise, and stirred for approximately 30 min at 75*C. The mixture is cooled to room temperature and the solvent is removed under reduced pressure, affording the sodium salt as a solid. 5. Characterization ofPrepared Diazoxide Salts [05491 Synthesis of the desired salts was confirmed by X-Ray Powder Diffraction (XRPD), UV-Vis spectroscopy, and NMR. All spectra were compared with the spectra of the free form diazoxide (i.e., not a salt). Differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), FTIR (Fourier transform infrared spectroscopy), NMR, UV vis spectroscopy and moisture sorption analysis were also performed. 5.1. Experimental Procedures [05501 DSC analysis were conducted with a Mettler 822 DSC, by measuring the amount of energy released by a sample, as the sample was heated from 300C to between 300-500C at a rate of I 0C/min. Typical applications of DSC analysis include 127 determination of melting point temperature and the heat of melting; measurement of the glass transition temperature; curing and crystallization studies; and identification of phase transformations. 10551] TGA measurements were conducted with a Mettler 851 SDTA/fGA, by measuring wdlght loss as a function of increasing temperature, as the samples were heated from 30"C to 230*C at a rate of 1 0*C/min. The TGA can be used to analyze deabsorption and decomposition behavior, characterize oxidation behavior, set burnout or conditioning parameters (temperature/ramp rate/time), and determine chemical composition. 10552] XRPD samples were analyzed with a Shimadzu XRD-6000 system, using a Cu KA, 40 kV, 40 mA X-ray tube. The divergence and scatter slits were 1.00 deg, and the receiving slit'was 0.30 mm. Samples were continuously scanned at a range of 3.0-45.0 deg, with a step size of 0.04 deg., at a scan rate of 2 deg/min. 10553) Fo urier Transform Infrared Spectroscopy was measured with a Thermo Nicolet Avatar 370 with a Smart Endurance Attenuated Total Reflection (ATR) attachment. Compressed samples were analyzed, with corrections for background noise being made. Using the IR spectrum, chemical bonds and the molecular structure of organic compounds can be identified. Attenuated total reflectance (ATR) allows for the analysis of thin films, organic and inorganic, in areas as small as 10-15 microns. [05541 Nuclear Magnetic Resonance (NMR) was performed with a 400 MHz Bruker Avance with A 4mm CP/MAS H-X probe. Acquisition of 'H NMR spectra were performed by,taking between 5-10 mg of the sample, dissolved in approximately 0.78 mL of DMSO-d 6 .; Spectra were acquired with either 16 or 32 scans, using a pulse delay of i.0 sec, with a 10 psec (30*) pulse width. [0555J U" spectroscopy was performed with a Perkin-Elmer Lambda 25 spectrometer.'Samples were dissolved in acetonitrile, water and a buffer system having a pH between 5.6 and 10. Spectra were acquired between 340 and 190 nm, using a 1 cm path length with background correction. [05561 Moisture Sorption Analysis was performed with a Hiden IGAsorp Moisture Sorption Instrument. Samples were first dried at 0% relative humidity at 25*C until an 128 equilibrium vieight was reached, or for a maximum of 4 hours. Samples were then subjected to a'n isothermal (25 0 C) scan from 10 - 90% relative humidity in steps of 10%. The samples were allowed to equilibrate to an asymptotic weight at each point for a maximum of 4 hours. Following absorption, a desorption scan from 85% relative humidity (at 25"C) was run in steps of -10%, again allowing a maximum of 4 hours for the samples t9 equilibrate. The resulting samples after desorption were dried at 80 0 C for two hours and analyzed by XRPD. S.. . Free Form Diazoxide Characterization [05571 The free form of diazoxide was characterized by XRPD, differential scanning calorimetry (5SC), thermal gravimetric analysis (TGA), moisture sorption, 'H NMR, FTIR and UV'vis spectroscopy to provide a baseline for comparison with the salts. Free form diazoxide is highly crystalline, as shown by the XRPD pattern. (See Figure 4(a)). The DSC shows a large endothermic event at 330"C, and TGA shows that the free form of diazoxide is anhydrous, where diazoxide shows no weight loss below 200*C, and a weight loss of only 0.2% below 230*C. Moisture absorption of the free form diazoxide shows the material to be non-hygroscopic. Absorption of water by diazoxide was tested at between 0 - 90% relative humidity (RH) at 25"C, showing absorption of approximately 0.04 wt% at 60% RH and 0.20 wto at 90% RH. The molecule does not form a stable hydrate, as shown by the lack of hysteresis during desorption. Additionally, the XRPD pattern for the diazoxide before and after absorption of water indicate the same crystalline form. 105581 UV-vis spectroscopy measurements taken of the free form diazoxide in neutral aqueous solution show a mnax at approximately 268 rn. In acetonitrile, the hnax was 264 am, demonstrating a small solvatochromic shift. As shown in Figure 2, as pH increased the 6nax also increased, from approximately 265 nm to approximately 280 nm, due to a change in the electronics of the molecule. 10559] StUdies were also conducted to evaluate the likelihood for conversion and degradation uider thermal stress. Samples were heated in a closed environment, protected front light, at 60*C for approximately 14 days. The diazoxide showed no conversion or degradation at 7 days or 14 days. Diazoxide samples were found to be consistent witA the starting material with respect to XRPD and DSC. 129 [0560] Slbrry studies to determine propensity of inter-conversion of the solid form were conducted on the free form diazoxide at room temperature, in the absence of light, using water, isopropyl alcohol, dichloromethane and toluene. Approximately 20 mg of the free form diazoxide was stirred for 14 days. Analysis by XRPD, DSC and HPLC were consistent with the starting material, indicating that the free form of diazoxide did not convert tcj alternate crystal fbrms. 5.. Characterization of Sodium Diazoxide Salt [0561] The XRPD pattern of the sodium salt of diazoxide was analyzed, showing the material to be crystalline. (See Figure 4(d)). The DSC analysis revealed a major exothermic event at 448 0 C. Small transitions below 400"C are likely due to sample imperfectionsI. TGA analysis showed weight loss of 0.2% and 0.03% below 120*C, which may be the result of bound solvent. Moisture absorption performed from 0 - 90% relative humidity at 25*C showed the material to be hygroscopic as the sample deliquesced af 90% relative humidity. The sample absorbed 1.2 wt% of water at 60% RH, and 6.6 4t% water at 80% RH. Hysteresis was observed upon desorption at 65 and 55% RH, indicating possible hydrate formation. (Possible hydrate formation was noted, although the amount of water absorbed was less than 0.5 mole). 'H NMR showed a chemical shift in the aromatic and methyl resonances of the sodium salt, as expected due to changes to the aromatic system. See Figure 5 showing NMR spectrum for the free form of diazoxide (a)and the sodium salt of diazoxide (c). FTIR showed expected changes for the sodium salt. 105621 Elemental analysis of the salt indicated that the salt was formed in a ratio of approximately 1:1, with the percentage of sodium being slightly low (approximately 3.4%). This deficiency may be due to matrix effects, as NMR indicated the sample had a relatively high purity. [05631 UV-vis measurements in neutral aqueous solution show a knax of approximately 271 rim. (See Figure 1). This value is slightly higher than free form diazoxide (265 nm). In acetonitrile, the ?max of the sodium salt exhibits a solvatochromic shift to approximately 296 nrn. (See Figure 3). An increase in the pH of the solution is; expected to producea bathochromic shift from approximately 265 nm to approximately 280 nmn. 130 [0564) Sdlubility measurements performed at pH 2, 7, and 12 in 10 mM phosphate buffer at rooni temperature showed solubility of the sodium salt of diazoxide to be 13.0 mg/mL, 18.1 ing/mL and 48.6 mg/mL, respectively. [05651 Form conversion and degradation under thermal stress were conducted as described for the free form diazoxide salt and showed the salt had little propensity to change form or degrade over a period of 14 days. Similarly, slurry studies were conducted as klescribed for the free form diazoxide in n-heptane, dichloromethane and toluene showed no propensity of inter-conversion, See Figure 6, wherein (a) is the XRPD pattern for the sodium salt of diazoxide, (b) is the XRPD pattern for the sodium salt after the slurry study, and (c) the XRPD of the free form of diazoxide. 5.4. Characterization of Potassium Diazoxide Salt [05661 The XRPD pattern for the potassium salt of diazoxide was analyzed, showing the material to be crystalline. (See Figure 4(b)). The DSC analysis revealed two major exothermic events at 128 and 354"C. (See Figure 7). Small endotherms are likely due to sample impurities or the presence of solvent. TGA analysis showed weight loss of 7.7% below 220"C,'which may be the result of moisture sorption. (See Figure 8). Theoretical weight loss for a monohydrate of the diazoxide salt is 6.6%. Moisture absorption performed from 0 - 90% relative humidity at 25"C showed the material to be hygroscopic as the sample deliquesced at 90% relative humidity, showing 38.3 wt% water. The sample absorbed 5.4 wt% of water at 60% RH. Hysteresis was observed upon desorption, however the niaterial was determined to be a hemihydrate from 0 -- 30% RH and a monohydrate from 35 -- 75% RH. XRPD following the desorption analysis indicated that the sample had changed to an alternate crystalline form. 'H NMR showed a chemical shift in the ardmatic and methyl resonances of the sodium salt, as expected due to changes to the aromatic system. (See Figure 5 showing spectrum of the free form diazoxide (a) and the Potassium salt of diazoxide (b)). FTIR showed expected changes for the potassium salt. [0567) Eldmental analysis of the potassium salt indicated that the salt was formed in a ratio of approximately 1:1, with the percentage of potassium being slightly low (approximately 1.6%). This deficiency may be due to matrix effects, as NMR indicated the sample had a relatively high purity. 131 105681 UV-vis measurements of the potassium diazoxide salt in neutral aqueous solution sho', a N of approximately 265 mu, which is equivalent to the diazoxide free form G. (See Figure 1. In acetonitrile, the N.. of the potassium salt exhibits a solvatochromic shift to approximately 296 nm. (See Figure 3). The potassium salt was used in a pH dependency study and showed that increasing the pH of the solution resulted in a bathochronic shift of the A from approximately 265 nm to approximately 280 nm. [05691 Solubility measurements performed at pH 2,7, and 12 in 10 mM phosphate buffer at room temperature showed solubility of the sodium salt of diazoxide to be 9.9 mg/mL, 14.4 rhg/mL and 43.0 mg/mL, respectively. The potassium salt displayed greater solubility than'the free form diazoxide, and demonstrated similar solubility to the sodium diazoxide salt., The XRPD pattern of solids obtained after the solubility analysis indicated that the potassium salt had changed back to the free form diazoxide material. 105701 Propensity for form conversion and degradation under thermal stress were conducted as described for the free form diazoxide salt The XRPD pattern of the sample after 7 and 14 days showed unique peaks, as compared with the potassium salt starting material. Analysis by DSC after 14 days also showed unique peaks as well. Using a gradient area percent assay, HPLC did not show any significant degradation of the potassium salt. (05711 Slurry studies were conducted as described for the free form diazoxide in n heptane, dichloromethane and toluene showed no propensity of inter-conversion. XRPD analysis of saniples after 7 and 14 days showed unique peaks similar to those observed with the thermal stress study. See Figure 9, wherein (a) is the XRPD pattern of the potassium salt of diazoxide, (b) is the XRPD pattern of the potassium salt of diazoxide after the slurry study in toluene, and (c) the XRPD pattern of the potassium salt after 14 days of the slurry study in toluene. Analysis by DSC after 14 days also showed unique peaks as compared with the starting material. HPLC using a gradient area percent assay did not show any significant degradation after the study. 5.5. Characterization of Choline Diazoxide Salt 105721 - The.XRPD pattern of the choline salt of diazoxide was analyzed, showing the material to be crystalline. (See Figure 10 (b)). The DSC analysis revealed a major 132 exothermic events at 167 0 C. (See Figure 11). A smaller endothermic event was seen at 11 9*C and is likely due to sample impurities or the presence of residual solvent. TGA analysis showed weight loss of 0.8% between 100 and 140 0 C, which may be the result of residual solvents. (See Figure 12). Moisture absorption performed from 0 -90% relative humidity at 2$*C showed the material to be hygroscopic as the sample absorbed over 28% at 80% relative humidity, and deliquesced at 90% RH. Hysteresis was not observed upon desorption, indicating the choline salt does not form a stable hydrate. The XRPD pattern following the desorption analysis indicated that the sample had changed to an alternate crystalline form during the hydration and subsequent desorption. (See Figure 13 (c)) 'H NMR.was consistent with a 1:1 molar ratio of diazoxide to counter-ion, and had the expected differences in the chemical shift of the aromatic and methyl resonances, as expected due to the change in the local environment of the aromatic system due to the presence of thb choline counter-ion. (See Figure 14 (b)). FTIR showed expected changes for the choline salt, similar to those seen with the sodium and potassium salts. 105731 Elemental analysis of the choline salt indicated that the salt was formed in a ratio of approximately 1:1. This is consistent with the 'H NMR. [05741 UV-vis measurements of the choline diazoxide salt in neutral aqueous solution show a )G of approximately 268 nm, which is close to the X." for the diazoxide free form of 265 nm. In acetonitrile, the ?. of the choline salt exhibits a solvatochromic shift to approximately 296 nrn. which is consistent with the sodium and potassium diazoxide salts. The potassium salt was used in a pH dependency study and showed that increasing the pH of the solution resulted in a bathochromic shift of the Nn from approximately 265 nm to approximately 280 nm. [05751 Solubility measurements performed at pH 2, 7, and 12 in 10 mM phosphate buffer at room temperature showed solubility of the sodium salt of diazoxide to be 28.2 mg/mL, 41.5 rmg/mL and greater than 293 mg/mL, respectively. The choline salt displayed greater solubility than the free form diazoxide after being allowed to equilibrate for 12 hours. The XRPD pattern of the solids obtained after the solubility analysis (at pH 2 and 7 only) indicated that the choline salt had changed back to the free form diazoxide material. 133 105761 Propensity of the choline salt for form conversion and degradation under thermal stress were conducted as described for the free form diazoxide salt. XRPD analysis of the sample after 7 and 14 days showed an XRPD pattern consistent with the starting rnaterial, as well as the presence of additional unique peaks. (More unique peaks were present after 14 days than after 7 days). Analysis by DSC after 14 days did not show any significant difference, with a small endotherm at 117*C and a large endothenn at 168*C. (Initial DSC showed endotherms at 119*C and a large endotherm at 167*C). Using a gradient area percent assay, HPLC did not show any significant degradation of the choline salt. (05771 Slurry studies were conducted as described for the free form diazoxide in n-heptane, dicloromethane and toluene showed no propensity of inter-conversion. XRPD analysis of samples after 7 and 14 days showed signal associated with the starting material, with'additional unique peaks present (See Figure 13 (c)). The XRPD pattern of slurry study samples from n-heptane showed signals associated with the starting material, as well as other additional unique signals. The XRPD pattern of slurry samples from dichloromethane and toluene were consistent with spectra obtained after the thermal studies and the moisture sorption analysis. Analysis by DSC after 14 days revealed a small endothern at 109*C, and a major endotherm at 167*C. HPLC using a gradient area percent assay did not show any significant degradation after the study. 5.6. Characterization ofDiazoxide Salt of Hexamethyl Hexamethylene Diammonium Hydroxide (H HDADI) [0578] The XRPD pattern of the HHDADH salt of diazoxide was analyzed, showing the material to be a crystalline solid. (See Figure 10(c)). Integration of the 'H NMR spectra was consistent with a 2:1 molar ratio of diazoxide to counter-ion (wherein the HHDADH counter-ion is divalent), and had the expected differences in the chemical shift of the aromatic and methyl resonances due to the change in the local environment of the aromatic system due to the presence of the choline counter-ion. (See Figure 14(c)). The h, of the HHDADH diazoxide salt in acetonitrile measured by UV-vis is 296 num, which is consistent with the sodium, potassium and choline diazoxide salts. 134 105791 A summary of the characterization of the free form diazoxide and the potassium, sodium, choline and hexamethyl hexamethylene diammonium hydroxide salts of diazoxide are presented in Table 14. Table 14: Summary of Characterization and Solubility for Diazoxide and Salts Test Vree form Potassium Sodium Choline HHDADH diazoxide salt diazoxide salt diazoxide salt XRPD Orystalline crystalline crystalline crystalline crystalline FTIR consistent consistent consistent consistent N/A DSC single multiple Single two N/A dndotherm at endotherms below exotherm endotherms 330"C 300*C above 400*C below 200 0 C UV in aqueous 268 nm 265 nrn 271 nm 268 nm N/A acetonitrile 264 nm 296 nm 296 nm 296 nm 296 nm TGA <1% 7.7 (monohydrate <1% <]% N/A Moisture rion- deliquescent - deliquescent - deliquescent N/A Sorption liygroscopic - hemi/monohydrate potential -no no hysteresis hemihydrate hysteresis Solubility N/A pH 2.0 d.4 mg/mL 9.9 mg/mL 13.0 mg/mL 28.2 mg/mL pH 7.0 0.04 mg/mL 14.4 mg/mL 18.1 mg/mL 41.5 mg/mL pH 12.0 4.8 mg/mL 43.0 mg/mL 48.6 mg/mL I>293 mg/mL I [0580] Additional solubility studies were conducted fbr diazoxide free base form and diazoxide choline salt, as reported in Table 15. Each determination was carried out in duplicate, slurrying each sample in a 100 mM phosphate buffer solution, pH 7.00. Duplicate samples were then titrated to pH 7.0 and pH 8.8 using a 0.1 N phosphoric acid solution, followed by stirring for 18h at ambient temperature. After this time all samples were centrifuged, and the supernatant was diluted with mobile phase (MeCN/ Water.). Solubility was'then obtained using a calibration curve for diazoxide by HPLC analysis. In Table 15, th'e term "Diazoxide, free from" refers to the free base of diazoxide; the term "Diazoxide, choline salt" is the choline salt of diazoxide as described herein; the term "Diazoxide, choline salt, milled" refers to the choline salt of diazoxide which has been milled by methods described herein. Table 15 shows that in 100mM phosphate buffer, pH 7, and with titration with 0. IN phosphoric acid to a pH of about 6.8 to 8.8, solubility is notably suppressed compared to solubility at pH 10-11. Furthermore, the diazoxide 135 choline salts w ere found to have increased solubility when compared to the parent free base. Table 15: Sibumary of Solubility for Diazoxide and Diazoxide Choline Salt. Sample Phosphate PNHr Sample amount buffer IN twtration after Solubility amount (mL) w,1N 18b [mg/mL) (Mg) (nL) (mL) OAN slurry Diazoxid$ free fonn 49.23 1 0.01 6.87 6.90 0.07 Diazoide 47.64 1 --- 7.30 7.31 0.07 free fbr Diazoxide cholinedsa 1 t 44.34 1 0.15 7.22 7.45 0.12 Diazoidel 48.26 1 0.11 8.81 8.64 0.18 eboline salt Diazoxidd, choline salt, 45.35 1 0.14 7.32 7.36 0.12 milled Diazoxide, choline salt, 53.15 1 0.16 8.50 8.52 0.20 milled Diazoxide; choline salt 50.0 1 10.57 42.11 Diazoxidel choline salt, 50.0 3 -- --- 10.52 32.88 milled, --- " Indicates no titration was conducted. 6. Po morphic Forms ofDiazoxide Salts [0581] Polymorphic forms of the salts of diazoxide, characterization, and preparation thereof are described. 136 6.1. Polymorphic Forms of the Choline Salt of Diazoxide 6.1.1. Demonstration of Preparation of Polymorphic Form B ofthe Choline Salt of Diazoxide [0582] A l-L round bottom flask was charged with diazoxide (5 g), MEK (750 mL) and choline hydroxide (5.25 g of 50 wt % solution in water), and heated to 77*C. The mixture was allowed to cool to approximately -30 *C, and filtered to remove insoluble brown residues. The filtrate was then concentrated under reduced pressure to afford yellow oil, which was dried in vacuo at 55"C and 30 in. Hg to afford approximately 7.8 g as a waxy solid. The solids were dried in vacuo at 55 0 C and 30 in. Hg to afford 7.13 g of the choline salt of diazoxide as a crystalline solid. Elemental analysis. Theoretical: C 46.77%, H 6.04% and N 12.59%. Measured: C 45.44%, H 5.98% and N 11.46%. 6.1.2. Characterization of the Polymorphic Form B of the Choline Salt of Diazoxide [05831 The polymorphic Form B of the choline salt of diazoxide was analyzed by XRPD, DSC, and 'H NMR. As shown in Figure 16, the two identified polymorphic forms of the choline salt of diazoxide show different XRPD patterns. See Figure 16, wherein (a) shows the polymorphic Form A of the choline salt of diazoxide. 105841 As shown in Figure 17, 'H NMR of the polymorphic Form B of the choline salt of diazoxide shows no change from the polymorphic Form A. [05851 Moisture absorption of the polymorphic Form B crystal structure of the choline salt of diazoxide performed from 0 - 80% relative humidity (RH) at 25 0 C showed the material to be hygroscopic as the sample absorbed over 14.5% at 70% relative humidity, and deliquesced at 80% RH. The XRPD pattern following the desorption analysis indicated that the sample remained in the Form B crystal structure during the hydration and subsequent desorption. [05861 Solubility measurements performed at pH 2, 7, and 12 in 10 mM phosphate buffer at room temperature showed solubility of the Form B crystal structure of the choline salt of diazoxide to be 32.8 mg/mL, 80.1 mg/mL and 216 mg/mL, respectively. .MR_324092.1 137 The XRPD pqttem of the solids obtained after the solubility analysis (at pH 2 and 7) indicated that'Form B of the choline salt of diazoxide was still present 105871 Slurry experiments were perfumed on each form to determine the propensity for conversion and to search for possible new and/or uniqe forms. Upon slurrying Form B in CH2CI2, 1 n-heptane, and toluene, form conversion was not observed. 16.1.3. Demonstration of Preparation of the Polymorphic Form A of the 1 Choline Salt ofDiazoxide from the Polymorphic Form B of the Choline :Salt ofDiazoxide [05881 Approximately 20 mg of the Form B polymorph of the choline salt of diazoxide was added to approximately 1 mL of acetone and heated to approximately 55*C. The mixture was filtered while hot and placed in a refrigerator (4*C) for 16 hours. No precipitatewas observed. The solvent was evaporated down to dryness using a gentle stream of nitrogen. The resultant solids were also dried in vacuo at room temperature and 30 in. Hg. XRiPD analysis showed the salt had converted from the Form B polymorph to the Form A polymorph. :6.1.4. Characterization ofthe Polymorphic Form A ofthe Choline Salt of Diazoxide 105891 Form A is an anhydrous crystalline form of diazoxide choline, with an endothermic event at approximately 165 *C in the DSC (see Figure 20). The XRPD pattern for Forin A is unique compared to that of Form B as shown in Figure 21. FTIR (ATR) spectroscopy additionally indicates differences between the two forms. 1 H NMR analysis affords a spectrum consistent with diazoxide and a 1:1 ratio of compound/counterion. NMR data also indicate that the magnetic environment of the diazoxide structure changes between free and polymorph forms, as evidenced by a movement in c emical shift of the aromatic and methyl proton resonances. In addition, the resonance Aue to the amine proton is not observed which suggests deprotonation in solution. Weight loss by TGA is less than 1% and may be due to residual solvent. The temperature of weight loss is above 100 *C which suggests that solvent may have been bound (i.e., solyate material). Moisture-sorption analysis conducted at 25 *C from 0 to 80% RH (adsorption) and 75 to 0% RH (desorption) shows Form A to be a hygroscopic solid, showing 2.4 wt % water at 60% RH. The sample was found to have deliquesced 138 above 75% Rd. In comparison, Form B is also hygroscopic and showed 7.4 wt % water at 60% RH arid deliquesced at 80% RH. XRPD analysis following the moisture-sorption experiment affords a pattern consistent with Form A. Solubility studies conducted on both forms at pH 2, 7, and 12 in phosphate buffer showed differences, with Form A showing 28, 41, and >293 mg/mL respectively. Solubility concentrations were determined using area-percent calculations with HPLC calibration curves. Slurry experiments vere performed on each form to determine propensity for conversion and to see if a unique form could be generated. Upon slurrying Form A in CH2CI2, n-heptane, and toluene, conversion to Form B was observed after seven days. These results suggest that Form A is less thermodynamically stable under these conditions than Form B according to Ostwald's Rule of Stages. 6..5. Screening for Polymorphic Forms ofDiazoxide Choline Salt 10590] A polymorph screening study of diazoxide choline salt was conducted with a series of crystallization and slurry conditions. As described herein, interconversion of diazoxide choline salt forms A and B was observed during this investigation. Each polymorphic form of diazoxide choline salt resulting from this study was characterized using the techniques and procedures described herein. A summary of characterization tests is listed in Table 16. Table 16. Characterization of Forms A and B of Diazoxide Choline Salt In Screening Study Experiment Form A Form B XRPD* Crystalline Crystalline DSC Endotherm -=165 *C Endotherm =160 *C TGA <1% FTIR (ATR)*'* Consistent w/ structure Consistent w/ structure 'H NMR Consistent w/ 1:1 ratio Consistent w/ 1:1 ratio Moisture Sorption Hygroscopic - deliquesced Hygroscopic - deliquesced at 90% RH at 80% RH pH 2: 28 mg/mL pH 2: 33 mg/mL Solubility pH 7:41 mg/mL pH 7: 80 mg/mL pH 12: >293 mg/mL pH 12: 216 mg/mL 139 Started to convert to F6rm Stable after 14 days at 60 Thermal 0 B after 14 days at 60 *C *C Converted to Form B after 7 Stable after 14 days in Slurries days in n-heptane, toluene, CH2Ch, THF, and t-AmOH and CH2Ch ' *Major peaks ;(2-0): Form A (9.8, 10.5, 14.9, 17.8, 17.9, 18.5, 19.5, 22.1, 22.6, 26.2, 29.6, 31.2); Form B (89, 10.3, 12.0, 18.3, 20.6, 24.1, 24.5, 26.3, 27.1, 28.9). ** Unique FT1R (ATR) absorbances (cm'): Form A (2926, 2654, 1592, 1449, 1248); Form B (3.56, 2174, 2890, 1605, 1463, 1235). 6.1.5.1. Solubility Screen in organic solvents. [05911 Di~zoxide choline, prepared in MEK using choline hydroxide as 50 wt % solution in water (see above) displayed some solubility in the following solvents: acetonitrile, acetone, ethanol, IPA, MEK, DMF, and methanol. These solvents were chosen due to 'differences in functionality, polarity, and boiling points and their ability to dissolve diazokide. Other solvents which showed poor ability to dissolve salts were used as antisolvents and in slurry experiments where some solubility was observed: dioxane, MTBE, EtOAc, IPAc, THF, water, cyclohexane, heptane, CH2C2, and toluene. [0592] Solvents for crystallizations during screening were chosen based on the solubility screen summarized in Table 17. Crystallizations of diazoxide choline from all conditions afforded a total of two forms, A and B. Forms A and B were found to be anhydrous polymorphs of diazoxide choline. Form B was observed to be generated from most solvents used. It was difficult-to isolate pure Form A on large scales (>50 mg) as conditions observed to produce Form A on a smaller scale (approximately 50 mg or less) were found to result in Form B or mixtures of both forms on larger scales. Based on room-temperaiure slurry experiments, anhydrous Form B was found to be the most thermodynamically stable form in this study. Form A readily converted to Form B in all slurry solvents utilized. 140 Table 17. Solubility Screen for Diazoxide Choline Salt Solvent Cmpd Solvent Conc. Temp. Soluble (mg) (ML) (mg/mL) ("C) McCN 1.7 0.25 >6.80 rt Yes Dioxane 1.4 5.00- 0.28 55 No Acetone 1.9 0.25 7.60 55 Yes MTBE 2.4 5.00 0.48 55 No EtOH 1.5 0.25 >6.00 rt Yes EtOAc 1.2 5.00 0.24 55 No IPAc 1.4 5.00 0.28 55 No IPA 1.8 0.25 7.20 55 Yes THF 1.1 5.00 0.22 55 No MEK 1.8 1.00 1.80 55 Yes DMF 1.2 0.25 >4.80 rt Yes Water 2.0 5.00 0.40 55 No MeOH 1.9 0.25 7.60 55 Yes c-Hexane 2.0 5.00 0.40 55 No Heptane 1.9 5.00 0.38 55 No CH2C2 1.3 5,00 0.26 55 Partially Toluene , 1.4 5.00 0.28 55 No 6.1.5.2. Single-Solvent Crystallizations [05931 Fast coolingprocedure: Diazoxide (approximately 20 mg) was weighed out into vials and enough solvent (starting with 0.25 mL) was added until the material completely dissolved at elevated temperature. After hot filtration the vials were placed in a refrigerator (4 *C) for 16 hours. After the cooling-process the samples were observed for precipitates which were isolated by filtration. Vials not demonstrating precipitates were evaporated down to dryness using a gentle stream of nitrogen. All solids were dried in vacuo at anibient temperature and 30 in. Hg. [0594] Slow cooling procedure: Diazoxide (approximately 30 mg of choline salt) was weighed out into vials and enough solvent was added until the material went into solution at elevated temperature. After hot filtration the vials were then slowly cooled to 141 room temperature at the rate of 20 *C/h and stired'at room temperature fbr 1-2 hours. All solids were dried in vacuo at ambient temperature and 30 in. Hg. [0595] Baged on the initial solubility study, seven solvents were selected for the fast cooling crystaIllization: acetonitrile, acetone, ethanol, IPA, MEK, DMF, and methanol. Table 18 shows a list of the'solvents that were used and the amount of solvent needed to dissolve the material. After the cooling-process precipitates were noticed in samples # 2, 3, 5, and 6, the solids were isolated by'filtration. The other samples (# 1, 4, and 7) were evaporated down to dryness using a gentle stream of nitrogen. The diazoxide choline salts were found to be consistent with Fom A by XRPD analysis for all solids with the exception of sample #2 (consistent with the freeform) and sample #5 (consistent with Form B with referred orientation observed). Table 18. Sil gle-Solvent Crystallization of Diazoxide Choline Salt Using Fast Cooling Proc edure Entry Solvedt BP Cmpd Solvent Cone Temp. Precipitate Form (*C) (mg) Ant (mg/mL) (*C) (mL) I Acetone 56 21.0 1.00 21.00 55 NofEvap A 2 MeOli 64 20.3 0.25 81.20 55 Yes FF* 3 EtOH 78 21.3 0.25 85.20 62 Yes A 4 MEK 80 19.6 1.25 15.68 75 No/Evap A 5 MeCN 81 20.6 0.25 82.40 55 Yes Unique 6 IPA 1 82 22.8 0.25 91.20 62 Yes A 7 DMF 153 26.0 0.25 104.00 55 No/Evap A 10596! In accordance with the data obtained from fast-cooling experiments, four solvents whic6 showed precipitation of solids were chosen for the slow-cooling experiments: MeOH, EtOH, MeCN, and IPA (Table 19). All obtained analyzable solids of the choline'salt were found to be consistent with Form B by XRPD with the exception of Entry #1 which was consistent with diazoxide freeform and Entry #2 which was not analyzable. Mother liquor of Entry #2 was concentrated to dryness and the residual solids were analyzed by XRPD and found to be Form B material. As a result of obtaining freeform material from the single-solvent crystallizations in methanol, three more alcohols were tested for the single-solvent crystallizations using fast- and slow-cooling 142 procedures. Tables 20 and 21 provide a list of the solvents that were used and the amount of solvent needed to dissolve the material. XRPD patterns of the fast-cooling procedure showed freeform of diazoxide from isobutanol, Form B from isoanyl alcohol, and Form A from tert-arnyl alcohol compared to the slow-cooling procedure, which afforded Form B material from all three solvents. Table 19. Single-Solvent Crystallization of Diazoxide Choline Salt Using Slow Cooling Procidure Solvent Bolling Material Solvent Conc. Temp. Precipitate Form Point Amount Amount (mg/mL) ("C) (C) (mg) (mL) MeOH 64 32.1 0.3 107.00 62 Yes FF* EtOH 78 33.3 0.3 111.00 75 Yes NA** MeCN 81 3D.9 0.3 103.00 62 Yes B IPA 82 33.7 0.3 112.33 80 Yes B Table 20. Sin gle-Solvent Crystallization of Diazoxide Choline Salt Using Fast Cooling Procedure Solvent Boiling Material Solvent Conc. Temp. Precipitate Form Point Amount Amount (mg/mL) (*C) ("C) (rag) (mL) i-BuOH- 108 29.7 0.3 99.00 78 Yes (sm)* i-AmOH1 130' 29.6 0.3 98.67 82 Yes B t-AmOH 102 29.5. 0.3 98.33 95 No/Evap A Table 21. Single-Solvent Crystallization of Diazoxide Choline Salt Using Slow Cooling Procedure Solvent Bolling Material Solvent Conc. Temp. Precipitate Form Point Amount Amount (mg/mL) (!C) ("C) (rg) (mL) i-BuOH 108 33.0 0.3 110.00 92 Yes B I-AmOH 130, 28.2 O.3' 94.00~ 92 Yes B 1-AmOH 102 29.0 0.4 72.50 92 Yes B 143 105971 The results of the choline salt single-solvent fast- and slow-cooling crystallizatior~s (see Tables 19 to 21) indicated that Form A was more likely to be isolated with fast-cooling profiles and Form B with slow-cooling profiles. 6.1.5.3. Binary Solvent Crystallizations [0598] Bihary-solvent crystallizations of the choline salt were performed using four primary solvents (MeOH, EtOH, IPA, and MeCN) and nine cosolvents (MTBE, EtOAc, IPAc, THF, c-hexane, heptane, toluene, CH2Cl2, and dioxane) with a fast-cooling profile (supra). XRPD patterns showed that Form B was obtained from mixtures of MeOH with MTBE, EtOAy, IPAc, toluene, and dioxane. As shown in Table 22, Form A was obtained from mixtures' of MeOH with THF and with CH2Cl2 after evaporating the solvent to dryness. The inixtures of MeOH with cyclohexane and beptane provided the freeform of diazoxide. All solids obtained from fast-cooling procedures with EtOH, IPA, and MeCN as primary solvents provided Form B material. Table 22. Binary-Solvent Crystallizations of Choline Salt of Diazoxide Using Fast Cooling Procedure and MeOH as a Primary Solvent DIazoride M iOHq* Antisolvent Amount Precipitate Form Amt (mL) (mL) (mg) 27.8 0.3 MTBE 1.4 Yes B 30.7 0.3 EtOAc 6.0 Yes B 32.0 0.3 IPAc 6,0 Yes B 31.9 O.J THF 6.0 No/Evap to Dry A 29.5 0.3 c-Hexane 2.0 Ycs (small) FP* 30.2 0.3 Heptane 2.0 Yes FF** 29.3 0.3 Toluene 6.0 Yes B 32.0 - 0. CH2C12 6.0 No/Evap to Dry A 28.8 0.3 Dioxane 6.0 Yes * Solids were dissolved at 62 *C. ** Freeform of diazoxide. [05991 Binary-solvent recrystallizations of the choline salt with the slow-cooling procedure were performed using two primary solvents (IPA and MeCN) and nine cosolvents (MTBE, EtOAc, IPAc, THF, c-hexane, heptane, toluene, CH2Ch, and 144 dioxane). All solids obtained from a slow-cooling procedure with IPA and MeCN as primary solvents provided Form B material based on XRPD analysis. The results of binary-solvent crystallizations indicated that Form B was the most thermodynamically stable form of diazoxide choline. 6.1.5.4. Binary Solvent Crystallizations Using Water as a Cosolven [06001 In pn attempt to investigate the formation of hydrates of the choline salt, experiments ywas performed using fast- and slow-cooling procedures and water as a cosolvent. [06011 The fast cooling procedure (supra) was used with the exception of using different primary solvents which were miscible with water: acetone, acetonitrile, DMF, IPA, i-BuOH, i-AmOH, and t-AmOH. Water was utilized in these crystallizations as a cosolvent. All 'solids obtained from the fast-cooling procedure with water as the cosolvent provided diazoxide freeform material by XRPD analysis. [0602] To compare the results obtained from the fast-cooling procedure a set of experiments was performed using a slow-cooling procedure and water as a cosolvent. All obtained solids were analyzed by XRPD and afforded patterns consistent with diazoxide freeforrn. Without wishing to be bound by theory, these results suggest that the conditions used for crystallization caused dissociation of the choline salt. A small amount of a second crop was obtained in each sample, but only two samples were analyzable by XRPD and indicated that the samples were freeform material. All mother liquors were evaporated to dryness and the residual solids were also analyzed by XRPD to afford patterns consistent with Form B of the choline salt, 6.1.5.5. Metastable Zone Width Estimation [0603] Form B: To produce a robust process, an understanding of the solubility profiles of the Various solid forms under consideration is required. From a practical standpoint, this involves the measurement of the metastable zone width (MSZW) of pure forms, whereby the saturation and supersaturation curves of the different forms are generated over a well defined concentration and temperature range. This knowledge can then be used to design a crystallization protocol that should ideally favor a selective crystal growth of the desired form. 145 10604] Form B of diazoxide choline salt showed moderate solubility in a solvent mixture made-of MeCN/MeOH/MtBE (10:1:12, volume ratios). The wide width of the metastable zone as shown in Table 23 gives many seeding options. During the MSZW measurement,: aliquots from the crystallizing material were withdrawn and analyzed by XRPD to ensure that no form conversion occurred during the experiment. Indeed, the material remained unchanged during the test. Table 23. Meta-Stable Zone Width For Form B Diazoxide Choline Salt in McCN/MeOH/MtBE (10;1:12) (v/v). Conc. Temp. In Temp. Out Temp. Range (mg/mL) . (*C) (*C) ("C) 30.8 53.2 35.0 18.2 28.5 49.0 33.6 15.4 26.5 47.0 32.0 15.0 24.7 43.8 29.1 14.7 23.2 40.5 28.5 12.0 21.9 38.0 26.0 12.0 10605] Form A: The metastable zone width for Form could not be estimated because this polymorphic form converted during the experiment to Form B. 6.1.5.6. Crystallization of Form A ofDiazoxide Choline Salt [0606] The choline salt of diazoxide (160.3 mg) was dissolved in 1 mL of IPA at 55 *C which was then passed through a Millipore 0.45 pM filter into a clean vial. This vial was placed in freezer a -20 *C overnight. Solids were not noticed and the flask was scratched with a micro-spatula. The vial was placed bick in the freezer and nucleation was noticed after ten minutes. The solids were collected by vacuum filtration and washed with I mL of MtBI3. The solids were dried in vacuo at 40 0C and 30 in, Hg to afford 70 mg (43.6% recovery) of Form A as determined by XRPD. 146 6.1.5.7. 500-mg Scale Crystallization ofForm ) ofDiazoxide Choline Salt 106071 Thb choline salt of diazoxide (524.3 mg) was dissolved in 3 mL of IPA at 78 'C and this solution was then cooled to 55 "C for the addition of MtBE. The MtBE (4 mL) was added until nucleation was observed. After nucleation the batch was allowed to cool to room temperature at a rate of 20 *C /h. The solids were collected by vacuum filtration and washed with 1 mL of MtBE. The solids were dried in vacuo at 40 *C and 30 in. of Hg to afford 426.7 mg (81.3% recovery) of Form B as determined by XRPD. 6.1.5.8. 2-g Scale Crystallization of Form B of Diazoxide Choline Salt [06081 The choline salt of diazoxide (2.0015 g) was dissolved in 5.5 mL of IPA at 78 *C to afford a clear solution. This solution was passed through a Millipore Millex FH 0.45 AM filter. This solution was then cooled to 55 *C. MtBE was added in 1 mL portions, with; a two minute interval between portions. Nucleation was'noted after the second addition of MtBE. This suspension was allowed to cool to room temperature at a rate of 20 "C /h and stirred at this temperature for 16 hours. The solids were collected by vacuum filtration and washed with I mL of MtBE. The solids were dried in vacuo at 40 *C and 30 in. 6f Hg to afford 1.6091 g (80.4% recovery) of Form B as determined by XRPD. 6.1.5.9. Detection ofForm Impurities 106091 Mixtures of diazoxide choline Forms A and B were prepared by adding a minor amount of Form A to Form B. Samples were lightly ground by hands with a mortar and pe tle for approximately one minute. Samples were then analyzed by XRPD analysis. XRPD analysis was found to be suitable for detecting 5% of Form A in Form B. 6.. Polymorphic Forms of the Potassium Salt of Diazoxide 106101 A summary of characterization tests for three common crystalline fbnns of diazoxide potassium salt are listed in Table 24. Solvents for crystallizations were chosen based on the 'olubility screen summarized below. Crystallizations of diazoxide potassium salt from all conditions provided herein afforded a total of seven unique crystalline forms, A through 0. Forms C, D, and F were found to be the most common during the crystallization screen, and were therefore scaled up for further characterization. 147 Table 24. Results Summary of Characterization Tests'for Salt of Diazoxide Potassium Experiment Form C Form D Form F XRPD* Crystalline Crystalline Crystalline DSC 187; 360 *C 130, 191, 352 *C 191, 363 *C TGA 8.4%** 4.5%** 13.1%** FTIR (ATR)t Consistent w/ Consistent w/ Consistent w/ -structure structure structure 'H NMR Consistent w/ Consistent w/ Consistent w/ structure** structure structure** Moisture Sorption Hygroscopic - Hygroscopic - deliquesced at 90% deliquesced at 90% RH Hygroscopic- RH , deliquesced at 90% RH Solubility N/A pH 2: 29 mg/mL N/A pH 7: 33 mg/mL pH 12: 59 mg/mL Thermal Stable (7 days) Stable (7 days) Stable (7 days) Slurries Converted to Form Converted to Form Converted to Form D D D *XRPD Major peaks (2-0): Form A (6.0, 8.1, 16.3, 17.7, 18.6, 19.1, 22.9, 23.3, 23.7, 24.7, 25.4, 26.1, 28.2, 29;6, 30.2); Form (8.5, 10.8, 16.9, 18.2, 21.6, 25.5, 26.1, 28.9); Form C (5.7, 6.1, 17.9, 23.9, 25.1, 37.3); Form b (5.7, 6.2, 8.1, 8.5, 8.8, 16.9, 18.6, 23.2, 24.5, 25.8, 26.1); Form E (6.7, 7.1, 14.1, 21.2); Form F (8.5, 9.0, 18.7, 20.6, 23.5, 27.5, 36.3); Form 6 (5.2, 5.5, 13.1, 16.5, 19.3, 22.8, 24.8, 26.4,28.7, 3 4.1); *Unique PTlR (ATR) absorbances (cm-1'): Form A (1503, 1374, 1339,1207, 1131, 1056, 771); Form B (1509, 1464, 1378, 1347); Form C (1706, 1208, 1146, 746); Form b (1595, 1258, 1219, 890); Form F (1550, L508, 1268, 1101,1006). 148 Form (1643, 1595, 1234, 1145, 810). Form G (1675, 1591, 1504, 1458, 1432, 1266, 999, 958, 905, 872). ** Data indicates a half-molar equivalent of acetone, water, or dioxane for Forms C, D, andF respectively. (0611] Diazoxide potassium Forms C, D, and F were observed to be an acetone solvate, a hemihydrate, and a dioxane solvate of diazoxide potassium, respectively. Form C is an acetone solvate that was generated predominantly when acetone was used in the crystallization. Form D, a hemihydrate, was observed to be generated from most solvents used. Form Fis a dioxane solvate generated when dioxane was used as an antisolvent. Forms A, B, i, and G were not commonly observed during the crystallization. Elemental analysis data indicated that the unique forms observed may be mixtures and/or have residual solve t(s) present. [0612] Based on room-temperature slurry experiments presented, Form D was found to be the most thermodynamically stable form of those discovered in this study. Forms C and F readily bonverted to Form D in all slurry solvents utilized. Without wishing to be bound by thcry, since nonaqueous solvents were used, the material may have converted to the hemihydrate, Form D, upon removal from the solvent. 6.2.1. Demonstration of Preparation of Polymorphic Form A of the Potassium Salt ofDiazoxide [0613] T e polymorphic Form A of the potassium salt of diazoxide was prepared as described above. 6.2.2. Demonstration of Preparation of the Polymorphic Form B of the Potassium Salt ofDiazoxide [0614) Diazoxide (2.95 g) was combined with 450 mL of methyl ethyl ketone and heated to approximately 77"C to dissolve the diazoxide. To the solution was added approximately 13 mL of IM potassium hydroxide at a rate of approximately 20 mL/min, stirred and allowed to cool to room temperature. The solution was stirred at room temperature flr -16 h. The solvent was removed under reduced pressure, and the residual solids were dried in vacuo at 57 "C and 30 in. Hg to afford 3.7 g of the potassium salt. 149 6.2.3. Characterization of Ike Polymorphic Form B ofthe Potassium Salt of Diazoxide [0615] The Form B polymorph of the potassium salt of diazoxide was analyzed by XRPD, and 11NMR. Figure 18 shows the XRPD. pattern of (a) the Form A polymorph of the potassium salt of diazoxide and (b) the Form B polymorph of the potassium salt of diazoxide. 10616] The 'H NMR of the Form B polymorph of the potassium salt of diazoxide shows no char ge from the Form A polymorph. 6.2.4. Demonstration of Preparation ofthe Polymorphic Form A of the *Potassium Salt of Diazoxide from Form B 10617) Approximately 20 mg of the Form B polymorph of the diazoxide potassium salt was added to 2 mL of acetone and heated until the material completely dissolved at 55"C. The solution was hot filtered and placed in a refrigerator (4"C) for 16 hours. No precipitate was formed. The solvent was evaporated down to dryness using a gentle stream of nitrogen and the resultant solids were dried In vacuo at room temperature and 30 in. Hg. Th& solid was analyzed by XRPD to determine the physical form. See Figure 18(a). 1 6.2.5. Preparation of the Polymorphic Form C of the Potassium Salt of Diazoxide from Form B f0618] Approximately 20 mg of the Form B polymorph of the diazoxide potassium salt was added, to 6 mL of ethyl acetate and heated until the material completely dissolved at 75"C. The solution was hot filtered and placed in a refigerator (4*C) for 16 hours. No precipitate wag formed. The solvent was evaporated down to dryness using a gentle stream of nitrogen and the resultant solids were dried in vacuo at room temperature and 30 in. Hg. The solid was analyzed by XRPD to determine the physical form. See Figure 18(c). 6.2.6. Preparation of the Polymorphic Form D of the Potassium Salt of 'Diazoxide from Form B 10619] Approximately 20 mg of the Form B polymorph of the diazoxide potassium salt was added'to 0.3 mL of isopropyl alcohol and heated until the material completely dissolved at 62*C. The solution was hot filtered and placed in a refrigerator (4*C) for 16 150 hours. No precipitate was formed. The solvent was ev*aporated down to dryness using a gentle stream pf nitrogen and the resultant solids were dried in vacuo at room temperature and 30 in. Hg. The solid was analyzed by XRPD to determine the physical form. See Figure 39(a). 62.7. Preparation of the Polymorphic Form E of the Potassium Salt of Diazoxide from Form B [0620]' Approximately 20 mg of the Form B polymorph of the diazoxide potassium salt was added to 2.5 mL of tert-amyl alcohol and heated until the material completely dissolved at 94*C. The solution was hot filtered and placed in a refrigerator (4 0 C) for 16 hours. No pre ipitate was formed. The solvent was evaporated down to dryness using a gentle stream 6f nitrogen and the resultant solids were dried in vacuo at room temperature and 30 in. Hg.' The solid was analyzed by XRPD to determine the physical form. See Figure 19(b). ,6.2.& Preparation of the Polymorphic Form F of the Potassium Salt of' Diazoxidefrom Form B 10621] Approximately 20 mg of the Form B polymorph of the diazoxide potassium salt was added to 0.6 mL of acetonitrile and heated until the material completely dissolved at 80*C. The solution was hot filtered, 6 mL of dioxane was added, and the solution was placed in a refrigerator (4"C) for 16 hours. No precipitate was formed. The solvent was evaporated down to dryness using a gentle stream of nitrogen and the resultant solid were dried in vacuo at room temperature and 30 in. Hg. The solid was analyzed by X.PD to determine the physical form. See Figure 19(c). 6.2.9. Preparation of the Polymorphic Form G of the Potassium Salt of .Diazoxide from Form B 106221 Approximately 22.3 mg of the Form B polymorph of the diazoxide potassium salt was added to 0.5 mL of isoamyl alcohol and heated until the material completely dissolved at 73 0 C. The solution was hot filtered, 6 mL of isopropyl acetate was added, and the solution was placed in a refrigerator (4*C) for 16 hours. No precipitate was formed. The solvent was evaporated down to dryness using a gentle stream of nitrogen and the resultant solids were dried In vacuo at room temperature and 30 in. Hg. The solid was analyzed by XRPD to determine the physical form. See Figure 19(d). 151 J06231 As shown in Tables 25 and 26, both the solvent used for recrystallization and the rate of cooling (i.e., fast cooling vs. slow cooling during the recrystallization) effect the crystal structure obtained once the product is isolated. Table 25. Fat cooling of Potassium Salt of Diazoxide in Various Solvents Solvent Cinpd Solvent Recovery Form (mg) (ML) (mg) THF 20.8 6.5 14.2 B EtOAc 21.1 6.0 10.6 C MeCN 21.2 0.5 n/a C+D IPA 22.7 0.3 n/a D Water 20.6 1.5 n/a Free form diazoxide tAA 21.9 2.5 16.7 E IAA 19.7 0.3 n/a D DMF 21.6 0.3 15.9 G Table 26. Slow cooling of Potassium Salt of Diazoxide in Various Solvents Solvent Cmpd Solvent Recovery Form (mg) (mL) (mg) EtOAo 20.4 6.0 7.1 D MeCN 22.8 0.5 13.8 C IPA 21.5 0.3 13.2 C Water 20.9 1.5 1.2 Free form diazoxide tAA 21.5 2.5 15.4 E 1AA 20.6 0.3 6.6 D 6.2.10. Polymorphs Obtained by Recrystallization of the Potassium Salt of Diazoxide in Binary Solvents 106241 As shown in Tables 27 and 28, recrystallization of the potassium salt of diazoxide from a variety of binary solvent systems also demonstrated conversion of the potassium salt to an alternate form. Use of acetonitrile as the primary solvent is shown in 152 Table 27 and ise of acetone as the primary solvent-is shown in Table 28. As shown in Table 27, recr~tallization of the Form B polymorph of the potassium salt of diazoxide from acetonitrile using methyl tert-butyl ether, ethyl acetate, isopropyl acetate, tetrahydrofuran, c-hexane, heptane, toluene and dichloromethane as the secondary solvent all yielded the'D Form polymorph of the potassium salt. Recrystallization from acetonitrile using dioxane as the secondary solvent yielded the F Form polymorph of the diazoxide salt of potassium. Table 27. Recrystallization in Acetonitrile Acetonitrile ISecondary Cmpd Recovery Form (mL) solvent (mg) (mg) 0.6 ;MTBE 20.7 13.7 D 0.6 tEtOAc 23.4 9.5 D 0.6 IPAc 20.0 13.3 D 0.6 THF 20.3 6.4 D 0.6 c-Hexane 20.4 9.6 D 0.6 Heptane 20.3 10.8 D 0.6 Toluene 23.6 16.1 D 0.6 :Dichloromethane 21.3 12.7 D 0.6 Dioxane 20.7 12.6 F 106251 As shown in Table 28, recrystallization of the Form B polymorph of the potassium sal( of diazoxide from acetone using methyl tert-butyl ether, tetrahydrofuran, and c-hexane is the secondary solvent all yielded the Form A polynorph of the potassium salt of diazoxide. Recrystallization from acetone using ethyl acetate, heptane, toluene and dichloromethene as the secondary solvent all yielded the C Form polymorph of the potassium sal;. Recrystallization from acetone using isopropyl acetate as the secondary solvent yieldeil the D Form polymorph of the diazoxide salt of potassium. Recrystallization from acetone using dioxane as the secondary solvent yielded the F Form polymorph of the diazoxide salt of potassium. 153 Table 28. Reerystallization in Acetone Acetone Other Solvent Amt Recovery Form (ML) (mg) (mg) 2.0 MTBE 20.2 13.9 A 2.0 Et6Ac 21.6 4.8 C 2.0 1PAc 20.6 11.6 D 2.0 T.20.9 12.0 A 2.0 c-Ilexane 21.3 12.3 A 2.0 Heptane 20.6 12.7 C 2.0 -Toluene 20.4 13.3 C 2.0 Dichloromethane 21.1 13.0 C 2.0 Di6xane 20.4 12.5 F :6.2.11. Screening for Polymorphic Forms ofDiazoxide Potassium Salt. [0626] A jolymorphic screening study of diazoxide potassium salt was conducted with a series of crystallization conditions described below. 6.2.11.1. Solubility Screening for Polymorphic Forms of.Diazoxide Potassium Salt. [0627] Diazoxide potassium, prepared in MEK using I M potassium hydroxide solution in water, displayed some solubility in the following ten solvents: acetone, THF, EtOAc, MEK, MeCN, IPA, water, t-AmOH, I-AmOH, and DMF. These solvents were chosen due to differences in functionality, polarity, and boiling points and their ability to dissolve diazoxide. Solvents affording poor to fair solubility were used as antisolvents in binary/ternary prystallizations as well as slurry studies. Table 29 sumnmarizes the results of the solubility screen. Table 29. Soldbility of Diazoxide Potassium Salt in Various Solvent Solvent Cihpd Solvent Cone. Temp. Soluble A t (ML) (mg/mL) (OC) (ig) MeCN 1.' 2.00 0.85 55 Yes Dioxane 1.4 5.00 0.28 55 No Acetone 1.6 4.00 0.40 55 Yes 154 Solvent Cmpd Solvent Conc. Temp. Soluble Amt (ML) (mg/mL) ("C) (u~g) MTBE t. 5.00 0.36 55 No EtOH 2.? 0.75 2.93 55 Yes EtOAo 1. 5.00 0.36 55 No IPAc 1.7 5.00 0.34 55 No IPA 2.1 1.00 2.10 55 Yes THF 1.8 5.00 0.36 55 Partially MEK 1.5 5.00 0.30 55 Partially DMF 1.0 0.25 >6.40 rt Yes Water 1.5 5.00 0.30 55 No MeOH 1.5 0.25 6.00 55 Yes c-Hexane 1.5 5.00 0.30 55 No Heptane 1.2 5.00 0.24 55 No CH2Ch I .3 5.00 0.26 55 No Toluene 1.4 5.00 0.28 55 No 6.2.11.2. Single-Solvent Screening for Polymorphic Forms of Diazoxide Potassium Salt. [0628] Single-solvent crystallizations of potassium salt were performed using ten solvents: acetone, THF, EtOAc, MEK, MeCN, IPA, water, t-AmrOH, i-AmOH, and DMF for the fast-cooling procedure and six solvents (EtOAc, MeCN, IPA, water, r-AmOH, and I-AmOH) for the slow-cooling procedures. The "fast" and "slow" cooling procedures were as described above. Four of the solvents were excluded from the slow-cooling experiments because they did not provide solids during fast-cooling experiments and needed to be evaporated to dryness. Tables 30 and 31 provide a list of the solvents that were used and the amount of solvent needed to dissolve the material. All solids were analyzed by XRPD to determine the physical form and six unique patterns (Forms A-B, G) were observed. .155 Table 30. Single-Solvent Crystallizations of Potassium Salt of Diazoxide Using Fast Cooling Solvent BP Cmpd Solvent Colc Temp Precipitate Form (0C) Amt Amt (mg/mL) ("C) (Ing) (mL) Acetone 56 20.7 2.0 10.35 55 No/Evap A THF* 65 20.8 6.5 3.20 63 No/Evap B EtOAc 76 21.1 6.0 3.52 75 Yes C MEK 80 20.2 4.0 5.05 75 No/Evap A MeCN 81 21.2 0.5 42.40 80 Yes C+D IPA 82 22.7 0.3 75.67 62 Yes D Water 100' 20.6 1.5 13.73 95 Yes FF t-AmOH 103 21.9 2.5 8.76 95 Yes B I-AmOH 130 19.7 0.3 65.67 73 Yes D DMP 153' 21.6 0.3 72.00 RT No/Evap G *Solids were not completely dissolved. Table 31. SinIe-Solvent Crystalizations of Potassium Salt of Diazoxide Using Slow Solvent BP Cmpd Solvent Cone Temp Precipitate Form ("C Amt Amt (mg/1L) (*C) (mg) (mL) EtOAc 76 20.4 6.0 3.40 75 Yes D MeCN 81 22.8 0.5 45.60 80 Yes C IPA 82 21.5 0.3 71.67 80 No/Evap C Water 100 20.9 1.5 13.93 95 Yes FF t-AmiOHR 103 21.5 2.5 8.60 95 Yes E i-AmOH 130 20.6 0.3 68.67 80 Yes D 6.2.11.3. Binary-Solvent Screening for Polymorphic Forms of Diazoxide Potassium Salt. [06291 Binrary-solvent crystallizations of the potassium salt utilizing fast-cooling procedure were performed using MeCN, acetone, and isoamyl alcohol as primary solvents and the following nine cosolvents: MTBE, EtOAc, IPAc, THF, c-hexane, heptane, toluerie, CH2Ch, and dioxane. Table 32 is representative, employing acetonitrile as primary solvent XRPD patterns from crystallizations using acetonitrile as a primary 156 solvent were consistent with Form D with only one exception being the solids obtained from the mixture of MeCN/dioxane afforded a unique pattern (Fonn F) material. Table 32. Binary-Solvent Crystallzations of Potassium Salt of Diazoxide Using Fast cooling Proce~lure and McCN as a Primary Solvent Ctnpd McCN* Anti- Amt Precipitate Fon Ant (nL) solvent (ML) (mg) 20.7 0.6. MTBE 1.0 Yes D 23.4 0.6 EIOAc 6.0 Yes D 20.0 0.6 IPAc 3.0 Yes D 20.3 0.6 THF 6.0 No/Evap. D To ppt 20.4 0.6 c-Hexane 2.9 Yes D 20.3 0.6 Heptmne 2.0 Yes D 23.6 0.6 Toluene 1.0 Yes D 21.3 0.6, CHC2 1.0 Yes D 20.7 0.6 Dioxane 6.0 Yes F * Solids were dissolved at 80 *C. [0630) XRPD patterns from binary crystallizations with acetone as primary solvent employing a fast cooling procedure afforded four forms A, C, D, and F. Mixtures of acetone with MITBE, THF, and cyclohexane provided Form A material; Form C was obtained from the mixtures of acetone with EtOAc, heptane, toluene, and CH2Cl2. The mixture of acet'ne with IPAc afforded Form D, and the mixture of acetone with dioxane afforded Form F solids. [0631] XRPD patterns from binary crystallizations with isoamyl alcohol as the primary solvent employing a fast cooling procedure afforded five forms: C, D, E, F, and 0. Form C was obtained from crystallizations using MTBE and EtOAc as cosolvents; Form D was obtained from mixtures of isoamyl alcohol with heptane, toluene, and CH2Clz; Form t was crystallized out of i-AmOH/THF and i-AmOH/cyclohexane; Form G was obtained from i-AmOH/IPAc and Form F was obtained from i-AmOH/dioxane, Form D was the most common form observed from the crystallizations, and Form F was observed only rhen dioxane was used as an antisolvent 157 [0632] Birfary solvent recrystallizations of the potassium salt with the slow-cooling procedure were performed using three primary solvents (MeCN, acetone, and i-AmOH) and eight cosolvents (MTBE, EtOAc, IPAc, c-hexane, heptane, toluene, CH2Cb, and dioxane). All solids were analyzed by XRPD to determine the physical form. Two patterns were observed to be Forms C and D respectively with additional peaks present. Other crystalli7ations provided Forms D, C, or F. Form D was obtained from the following solvent mixtures: MeCN/MTBE, MeCN/IPAc, MeCN/toluene, MeCN/CHzCh and also from the mixtures of i-AmOH with MTBE, IPAc, cyclohexane, heptane, and toluene. Form C was obtained from MeCN/heptane, i-AmOH/EtOAc, and mixtures of acetone with M4TBE, EtOAc, IPAc, cyclohexane, heptane, toluene, and CH2Ch. Form F was crystallizeal from the mixtures of MeCN/dioxane and i-AmOH/dioxane. The solvent mixture of MeCN/EtOH provided amorphous material. Elemental analysis results indicate that the forms observed may not be pure and/or have bound or residual solvents present. Forms ;C, D, and F were found to be the most common forms of the potassium salt isolated anaI based on the results, these forms were chosen for scale-up and further characterizatioA. Differences were found in the XRPD pattems and FTIR spectra of the scale-up lots which were attributed to differences in impurity profiles, crystallinity, and form purity. 6.2.11.4. Characterzation of Polymorphic Form C ofDiazoxide Polassium Salt. 10633] For C of diazoxide potassium salt is an acetone solvate with a 2:1 ratio of diazoxide/solvent. It is a crystalline form of diazoxide potassium, with endothermic events at 187 and 360 *C in the DSC. The XRPD patten for Form C is unique compared to all other forms observed. FTIR (ATR) spectroscopy showed differences between forms. 'H NMR spectra were found to be consistent with the structure of diazoxide with a half-molar equivalent of acetone present. NNR data also indicated that the magnetic environment of the diazoxide structure had changed evidenced by a movement in chemical shift o'the aromatic and methyl proton resonances. In addition, the resonance due to the amine proton was not observed which suggested deprotonation in solution. Weight loss by TGA was 8.9%, consistent with a half-molar equivalent of acetone, and occurred near 180 "C consistent with the endotherm observed in the DSC experiment. Moisture-sorptien analysis conducted at 25 *C from 0 to 90% RH (adsorption) and 85 to 158 0% RH (desorption) showed Form C to be a hygroscopic solid, showing approximately 47 wt % water at 90% RH which indicated the sample deliquesced. In comparison, Forms D and F (henihydrate and dioxane solvate) showed approximately 26 and 22 wt % water at 90% "H respectively. XRPD analysis following the moisture-sorption experiment afforded a pattern consistent with Form D. Slurry experiments were performed on 50/50 mixtures of Forms C, D, and F to determine propensity for conversion and to see if a unique form could be generated. Upon shrrying Form C mixtures in ethyl acetate, acetonitrile, and isopropanol conversion to Form D was observed in all solvents. Without wishing to be bound by theory, these results as well as conversion of Form F to Form D in these conditions suggest that Form D is more thermodynami ally stable than Form C and F according to Ostwald's Rule of Stages. A thermal-stability experiment on Form C at 60 *C found the form to be stable. Conversion to another forrb was not observed. 6.2.11.5. Characterization ofPolymorphic Form D ofDiazoxide Potassium Salt. 106341 Fo~n D of diazoxide potassium salt is a hemihydrate. It is a crystalline form of diazoxide potassium, with endothermic events at 130, 191, and 352 *C in the DSC. FTIR (ATR) spectroscopy showed differences between forms. 1 H NMR spectra were found to be consistent with the structure of diazoxide. NMR data also indicated that the magnetic environment of the diazoxide structure had changed evidenced by a movement in chemical shift pf the aromatic and methyl proton resonances. In addition, the resonance due to the amine proton was not observed which suggested deprotonation in solution. Weight loss by TGA was 4.5%, consistent with a half-molar equivalent of water, and occurred near 110 *C consistent with the endotherm observed in the DSC experiment. Moisture-sorption analysis conducted at 25 *C from 0 to 90% RH (adsorption) and 85 to 0% RH (desorption) showed Form D to be a hygroscopic, showing approximately 26 wt % water at 904 RH. In comparison, Forms C and F (acetone and dioxane solvates) showed approximately 47 and 22 wt % water at 90% RH, respectively. XRPD analysis following the rpoisture-sorption experiment afforded a pattern consistent with Form D. Solubility studies were conducted at pH 2, 7, and 12 for Form D and showed 29, 33, and 59 mg/mL respectively. Solubility concentrations were determined using area-percent calculations with an HPLC calibration curve. Slurry experiments were performed on 159 50/50 mixtures of Forms C, D, and F to determine their propensity for conversion and to see if a unique form could be generated. Upon slurrying mixtures of Form D with Form C or Form F in ethyl acetate, acetonitrile, and isopropanol conversion to Form D was observed in all solvents. 6.211.6. Characterization of Polymorphic Form FofDiazoxide . Potassium Salt. 10635] Form F of diazoxide potassium salt is a dioxane solvate with a 2:1 ratio of diazoxide/solvent. It is a crystalline form of diazoxide potassium, with endothermic events at 191 and 363 "C in the DSC. The XRPD pattern for Form F is unique compared to all other forms observed. FTIR (ATR) spectroscopy showed differences between forms. 'H N1VR spectra were found to be consistent with the structure of diazoxide with a half-molar equivalent of dioxane present, NMR data also indicated that the magnetic environment of the diazoxide structure had changed as evidenced by a movement in chemical shift of the aromatic and methyl proton resonances. In addition, the resonance due to the amine proton was not observed which suggested deprotonation in solution. Weight loss by TGA was 13.1%, consistent with a half-molar equivalent of dioxane, and occurs near 180 *C consistent with the endotherm observed in the DSC experiment. Moisture-sorption analysis conducted at 25 "C from 0 to 90% RH (adsorption) and 85 to 0% RH (desorption) showed Form F to be a hygroscopic solid, showing approximately 22 wt % water at 90% RH. In comparison, Forms C and D (acetone solvate and hemihydrate) showed approximately 47 and 26 wt % water at 90% RH, respectively. XRPD analysis following the moisture-sorption experiment afforded a pattern consistent with Form D. Slurry experiments were performed on 50/50 mixtures of Forms C, D, and F to determine their propensity fbr conversion and to see if a unique fbrm could be generated. Upon slurrying mixtures of Form F with Form C and Form D in ethyl acetate, acetonitrile, and isopropanol conversion to Form D was observed in all solvents. B. In vivo Obedity Testing 1. Obesity animal model [06361 Formulations of salts of any of the compounds of Formulae I - IV prepared as described hereih can be tested for efficacy in an animal model of obesity as described by Surwit et al. (Endocrinology 141:3630-3 637 (2000)). Briefly, 4-week-old B6 male mice 160 are housed 5/cage in a temperature-controlled (22*C)'room with a 12-h light, 12-h dark cycle. The high fat (HF) and low fat (LF) experimental diets contain 58% and 11% of calories from fat, respectively. A group of mice are fed the HF diet for the first 4 weeks of the study; tlie remaining 15 mice are fed the LF diet. The mice assigned to the LF diet are maintained on this diet throughout the study as a reference group of lean control mice. At week 4, all IF-fed mice a reassigned to 2 groups of mice. The first group remains on the HP diet throughout the study as the obese control group. The remaining 3 groups of mice are fed the Hf diet and administered the controlled release formulation of salts of any of the cornpounds of Formulae I - IV at about 150 mg of active per kg per day as a single dose adijainistered by oral savage. Animals are weighed weekly, and food consumption is measured per cage twice weekly until the diets are changed at week 4, whereupon body weight and food intake are determined daily. The feed efficiency (grams of body weight gained per Cal consumed) is calculated on a per cage basis. Samples for analysis of insulin, glucose, and leptin are collected on day 24 (4 days before the diets are changed), on day 32 (4 days after the change), and biweekly thereafter. In all cases food is removed 8 h before samples are collected. Glucose is analyzed by the glucose oxidas method. Insulin and leptin concentrations are determined by double antibody RIA. The insulin assay is based on a rat standard, and the leptin assay uses a mouse standard. At the termination of the study, a postprandial plasma sample is collected and analyzed for triglyceride and nonesterified fatty acid concentrations. After 4 weeks of drug treatment, a subset of 10 animals from each group is killed. The epididymal white adipose tissue (EWAT), retroperitoneal (RP) fat, interscapular brown adipose tissue (IBAT) fat pads, and gastrocnemius muscle are removed, trimmed, and weighed. The percent body fat is estimated from the weight of the epididymal fat pad. A subset of five animals from each group is injected i.p. with 0.5 g/kg glucose. At 30 min post injection, a plasma sample is collected and analyzed for glucose content by the glucose oxidase method. 2. Treatment of obesky in humans f0637] Forriulations of salts of any of the compounds of Formulae I - IV prepared as described hereiA can be tested for efficacy in obese humans, as described by Alemzadeh (Alemzadeh et al., J Clin EndocrMetab 83:1911-1915 (1998)). Subjects consist of moderate-to-morbidly obese adults with a body mass index (BMI) greater than or equal to 161 30 kg/m 2 . Each subject undergoes a complete physical examination at the initial evaluation, boay weight being measured on a standard electronic scale and body composition being measured by DEXA. 106381 Bekore initiation of the study, all subjects are placed on a hypocaloric diet for a lead-in period of 1 week. This is designed to exclude subjects who are unlikely to be compliant. and to ensure stable body weight before treatment. Up to 50 subjects are tested at each dosage-of drug. Daily dosage is set at 100,200, and 300 mg/day. The daily dose is divided into ,2 doses for administration. The dose is administered as either one, two or three 50 mg capsules or tablets at each time of administration. Subjects are dosed daily for up to 12 months. Subjects are reviewed weekly, weighed, and asked about any side effects or concprrent illnesses. 106391 Twinty-four-hour dietary recall is obtained from each subject. The dietary recalls are analyzed using a standard computer software program. All subjects are placed on a hypocaloric diet and encouraged to participate in regular exercise. 10640) Befbre commencing, and after completion of the study, the following laboratory tests are obtained: blood pressure, fasting plasma glucose, insulin, cholesterol, triglycerides, f ee fatty acids (FFA), and glycohemoglobin, and measures of rate of appearance and oxidation of plasma derived fatty acids. Additionally, routine chemistry profiles and fasting plasma glucose are obtained weekly to identify those subjects with evidence of gli'cose intolerance and/or electrolyte abnormalities. Glucose is analyzed in plasma, by the glucose oxidase method. 10641) Insulin concentration is determined by RIA using a double-antibody kit. Cholesterol and triglycerides concentrations are measured by an enzymatic method. Plasma FFA is determined by an en2ymatic colorimetric method. SI was assessed by an iv glucose tolerance test (IVGTT) using the modified minimal model. After an ovemight fast, a glucose bolus (300 mg/kg) was administered iv, followed (20 min later) by a bolus of insulin. Blood for determination of glucose and insulin is obtained from a contra lateral vein at -40, -15, 0, 2, 3, 4, 5, 6, 8, 10, 19, 22, 25, 30, 40, 50, 70,100, 140, and 180 min. SI and glucose effectiveness (SG) are calculated using Bergman's modified minimal-model 'computer program before and afler the completion of the study. Acute 162 Insulin response to glucose is determined over the-first 19 min of the IVGTT, and the glucose disappearance rate (Kg) is determined from &-19 min of the IVGTT. Body composition ismeasured by bioelectrical impedance before and at the completion of the study. Resting energy expenditure (REE) is measured by indirect calorimetry after an overnight 12-h' fast, with subjects lying supine for a period of 30 min. Urine is collected over the corresponding 24 h, for measurement of total nitrogen and determination of substrate use, before and after the study. 3. Treatment of obesity in humans by coadministering diazoxide and phentermine 106421 Evaluation of a prolonged co-administration of solid oral dosage fbrm of salts of any of the compounds of Formulae I- IV thereof in combination with phentermine can be conducted in humans with moderate-to-morbid obesity and a body mass index (BMl) greater than or equal to 30 kg/m 2 . Each subject undergoes a complete physical examination at' the initial evaluation, body weight being measured on a standard electronic scale and body composition by DEXA. [06431 Before initiation of the study, all subjects are placed on a hypocaloric diet for a lead-in period of I week. This is designed to exclude subjects who are unlikely to be compliant and o ensure stable body weight before treatment. Up to 100 subjects are tested. Daily dosage of salts of any of the compounds of Formulae I - IV is set at 200 mg. The daily-dose is divided into 2 doses for administration. The dose is administered as either a 100 mg capsule or a 100 mg tablet at each time of administration. Subjects are dosed daily for up to 12 months. Phentermine is administered as a single daily dose of 15 mg. Subjects are reviewed every two weeks, weighed, and asked about any side effects or concurrent illnesses. 10644] Allsubjects are continued on a hypocaloric diet and encouraged to participate in regular exercise. Before commencing, and after completion of the study, laboratory tests as described in the example above are obtained. 4. Prevention of diabetes in prediabetic humans [06451 The example describes use of salts of any of the compounds of Formulae I IV in a prediabetic subject to prevent the occurrence of diabetes. Subjects included in the study all have elevated risk of developing diabetes as measured by one of two methods. 163 In a fasting ghtcose assay theS have plasma glucose values between 100 and 125 mg/dl indicating impaired fasting glucose, or in an oral glucose tolerance test they have plasma glucose values between 140 and 199 mg/dl at 2 hours post-glucose load indicating they have impaired'glucose tolerance. Treatment is initiated in any subject meeting either criteria. Treated subjects receive either 200 mg diazoxide per day as a 100 mg capsule or tablet twice per day or as two 100 mg capsules or tablets once per day. Placebo treated subjects receive either one placebo capsule or tablet twice per day or two placebo capsules or tablets once per day. [06461 Treatment is continued for once year with OGTT or fasting glucose measured monthly. 5. A stained release coformulation of diazoxide HCI and metformin HC1 use to treat diabetic patients [0647] A sustained release co-formulation of diazoxide HCl and metfonnin HCl is produced by forming a compressed tablet matrix that includes 750 mg of metformin MCI and 100 mg ofldiazoxide HCl. These active ingredients are blended with sodium carboxymethyl cellulose (about 5% (w/w)), hypromellose (about 25% (w/w), and magnesium stearate (<2% (w/w)). The compressed tablet is further coated with a combination of'ethylcellulose (80% (w/w)) and methyl cellulose (20% (w/w)) as a thin film to controlrate of hydration and drug release. [0648] Type I diabetic patients are treated with the oral dosage form by administrationof two tablets once per day or one tablet every 12 hours. Treatment of the patient with the drug is continued until one of two therapeutic endpoints is reached, or for so long as the patient derives therapeutic benefit from administration. The two therapeutic endpoints that would serve as the basis fbr the decision to cease treatment include the patient reaching a Body Mass Index (BMI (kg/M 2 )) between 18 and 25 or the re-establishment of normal glucose tolerance in the absence of treatment. The patient is monitored periodically for (a) glucose tolerance using an oral glucose tolerance test, (b) glycemic control using a standard blood glucose assay, (c) weight gain or loss, (d) progression ofdiabetic complications, and (e) adverse effects associated with the use of these active ingredients. 164 6. Prevention or treatment of weight gain in a patient treated with olanzapine 10649] Phqrmacotherapy for schizophrenia is initiated for a patient meeting DSM II R criteria for schizophrenia. The patient is administered 10 mg of olanzapine (Zyproxa, Lilly) once per day. Adjunctive therapy to the patient for schizophrenia includes 250 mg equivalent of alproic acid as divalproex sodium (Depakote, Abbott Labs). Weight gain, dyslipidemia ahd impaired glucose tolerance, and metabolic syndrome are high frequency adverse eventsin patients treated with this combination of anti-psychotics. Weight gain, dyslipidemia, impaired glucose tolerance or metabolic syndrome are treated by the co administration-of a therapeutically effective dose of a KArp channel opener. The patient is treated with administration of 200 mg/day of salts of any of the compounds of Formulae I - IV as a once daily tablet formulation. Administration of salts of any of the compounds of Formulae I 2 IV continues until the weight gain, dyslipidemia, impaired glucose tolerance or metabolic syndrome is corrected or until treatment of the patient with olanzapine is discontinued. Dyslipidemia is detected by measuring circulating concentrations of total, HDL, and LDL cholesterol, triglycerides and non-esterified fatty acids. Impaired glucose tolerance is detected through the use of oral or IV glucose tolerance tests, Metabolic syndrome is detected by measuring its key risk factors including central obesity, dyslipidemia, impaired glucose tolerance, and circulating concentrations' of key proinflammatory cytokines. 7. Comparison of Single Doses ofDazoxide Administered as Proglycem@ Oral Suspension or as Diazoxide Choline Controlled-Release Tablets In Obese Subjects. 7.1 'Experimental Design 7UL Objective of Study. 10650) Clinical studies employing a randomized, open-label, parallel protocol comparing the safety, tolerability and bioavailability (i.e., pharmacokinetics) in obese subjects of Proglycem@ (oral suspension) and diazoxide choline salt (controlled-release tablet) were conducted. The study evaluated the safety and tolerability of a single 200 mg does (approximately 2 mg/kg) of diazoxide. The study further compared the single dose pharmacokinetics of an oral suspension of the free base of diazoxide (Proglycem@) with a controlled-release tableted formulation of diazoxide choline salt under fasting conditions in obese subjects. 165 17.1.2. Rationale for Study. [06511 Diazoxide choline was selected as an alternative molecule for the oral administrationlof diazoxide because of significantly greater aqueous solubility over diazoxide free base, rapid conversion to diazoxide base on exposure to an aqueous environment, and incompatibility with incorporation into sustained release formulations. The fate of dia oxide choline in an aqueous medium in vitro has been extensively characterized. Without wishing to be bound by theory, once solubilized from the controlled-relesse tablet formulation, prior to absorption, the salt hydrolyzes to the free base of diazoxide and choline hydroxide. This was extensively characterized using UVNis absorbance, and occurred at all physiological relevant pH values from pH 2.0 to pH 8.5. This tjydrolysis occurred in deionized water and buffered aqueous solutions, and in polar solvents that contained trace amounts of water. Thus, diazoxide, as the free base, is the molecuhar form absorbed following oral administration of the choline salt of diazoxide to animals or humans. Serum and plasma assays used in TK and PK analysis measure diazoxide.ftee base concentrations. Dissolution assays measure diazoxide free base. Differences in plasma concentration-time profiles of diazoxide will be dependent on the time course of release of diazoxide choline fiom the tablet matrix in the intestinal tract. Historically, both oral suspension and immediate release capsule formulations of diazoxide have been commercially available, marketed as Proglycem@. The oral suspension had been shown to be highly bioavailable and rapidly absorbed upon administration. Because of the difficulty in characterizing dissolution from the oral suspension, the in-vitro dissolution of Proglycem@ capsules was compared under standardized conditions to that of diazoxide choline controlled-release tablets (50 mg and 200 mg). 7.1.3. Inclusion Criteria. [0652] Inclusion criteria for the present study included age 18 to 65 years old inclusive and 6MI between 30 and 45 kg/m 2 , inclusive, and signed informed consent. Female participants were required to be either postmenopausal for at least 1 year, surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy], or practicing a medically acceptable method of birth control. Inclusion criteria further included freedom from serious medical disorders involving the kidneys, digestive system, heart and blood vessels, lungs, liver, eyes, nerves, brain, skin, endocrine system, bones or 166 blood. Subjects, other than their obese condition, were generally healthy as documented by medical history, physical examination, vital sign, 12-lead ECG, and clinical laboratory assessments. Characteristics of the subjects randomized in the study are provided in Table 33. Table 33. Characteristics of subjects randomized In the study Parameter Proglycem Oral Suspension (n=15) Diazodide Choline Controlled-Release Tablet (n--15) MeantSD (range) Mean*SD (range) Age (yr) 32.5*12.1 (18-56) 27.9+12.6 (19-54) BMI (kg/m 2 ) 32.9*4.3 (30.2-44.8) 33.8-3.2 (31.4-42.1) Gender 9/6 7/8 (male/female) 7.1.4. Exclusion Criteria. 10653) Excqusion criteria included treatment with an investigational drug within 28 days prior to dosing, presence or history of a clinically significant disorder, clinical laboratory test Values outside of the accepted reference range, reactive screen for HBV, HCV, or HIV, bse of any medication affecting body weight, lipid or glucose metabolism within 2 months, use of any systemic prescription medication from 14 days prior to screening to dosing except hormonal contraceptives, use of any drug known to induce or inhibit hepatic drug metabolism from 28 days prior to screening until dosing, positive test for drug of abuse, current tobacco use, positive pregnancy screen, or pregnant or breastfeeding. 7.1.5. Randomization. 106541 A total of 30 subjects were randomized in the present study. Fifteen subjects were randomized to each arm. For convenience, the 30 subjects were broken up into two cohorts. Cohort I checked into the clinic on October 12, 2006, was dosed on October 14, 2006, remained in the clinic for 72 hours following dose administration, returning at 96 and 120 hours after dose administration. Cohort I included 10 subjects randomized to receive Proglycem Oral Suspension and 5 subjects randomized to receive a Diazoxide Choline Controlled-Release Tablet. Cohort 2 checked into the clinic on October 14, 167 2006, were dosed on October i6,2006, remained'in the'clinic for 72 hours following dose administration, returning at 96 and 120 hours after dose administration. Cohort 2 included 5 subjects randomized to receive Proglycem@ Oral Suspension and 10 subjects randomized to receive a diazoxide choline controlled-release tablet. All subjects completed the study. 7.1.6. Dosing. 106551 Subjects randomized to the Proglycem@ Oral Suspension arm received a single 200 mg dose (4 mL) taken with 240 mL of room temperature water. Subjects randomized to the diazoxide choline controlled-release tablet, arm received a single tablet containing 290 mg of diazoxide choline, which is equivalent to 200 mg of diazoxide. Doses were administered after an overnight fast, and fasting continued until approximately 4.25 hours after dose administration at which time a standardized meal was served. 7.1.7. SaCety Monitoring. 10656] Clilical laboratory tests including hematology, clinical serum chemistry and urinalysis were, conducted at screening and at end of study. Hematology included measurements of hemoglobin, hematocrit, white blood cell count with differential, red blood cell count and platelet count. Clinical serum chemistry included evaluation of sodium, potassium, BUN, creatinine, total bilirubin, total protein, albumin, alkaline phosphatase, AST, ALT, glucose, total cholesterol, HDL-cholesterol, and triglycerides. Urinalysis included pH. specific gravity, protein, glucose, ketones, bilirubin, blood, nitrites, urobilinogen, leukocytes, and microscopic urine analysis if sample was dipstick. positive. All adverse events were recorded. Vital signs were collected at screening, at one hour prior t'o dosing, and after dose administration at 1, 3, 6, 9, 12, 24, 48, 72 and 120 hours. Continuous two-lead cardiac monitoring (telemetry) was performed on subjects from 24 hours prior to dose administration (to establish baseline data) until 24 hours after dose administration. .1,8, Exploratory Endp oints. 106571 Three exploratory endpoints were evaluated in the study. Blood glucose, Insulin and non-esterified fatty acids (NEFA) were measured prior to dosing and at 1, 3, 6, 9, 12, 24, and 48 hours post dosing. Blood glucose and insulin levels were also 168 assessed at end of study. Data collected at times 1, 3, 24, and 48 hours after dose administration were obtained under fasting conditions. The remaining data points were post-prandial measures. Samples for pharmacokinetic analysis to evaluate bioavailability were collected -prior to dosing and after dose administration at 1, 2, 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, 72, 96, and 120 hours. 7.2. Results 7.2.1. Adverse Events. [0658] The adverse events observed with each of the two formulations are summarized inTables 34 and 35. With the single exception, a moderate headache requiring treatment with acetaminophen in a subject treated with Proglycem@ Oral Suspension, al6 adverse events were mild. Both formulations appeared to be well tolerated in theistudy. One subject administered with diazoxide choline controlled-release tablet experienced mild loss of appetite. Because most obese and obese diabetic animal model studies of diazoxide show some reduction in feed consumption, loss of appetite was, therefore, considered part of the pharmacodynamic response to the drug in obese patients, ratherthan an adverse event. Table 34. Adverse events (AE) in subjects administered Proglycem@D Oral Suspension (n=-15) Hours Post Corrective Adverse Event Outcome Dosing Treatment Gastrointestinal Nause" 2.75 Mild None Resolved Neurological Therapy required Headache 20.0 Moderate acetaminophen Resolved Headacheb 6.25 Mild None Resolved Assisted to supine Dizziness' 1.0 Mild position Resolved Assisted to supine Dizziness' 3.25 Mild position Resolved Assisted to supine Dizzlnessd 1.0 Mild position Resolved 169 Assisted to supine Dizzinessd 4.25 Mild position Resolved Miscellaneous ChillO 6.25 Mild None Resolved Dermatitis fmm ECG patches" 4.75 Mild None Resolved Number of subjects with at least one AB - 5, AEs followed by the same superscript letter are the same subject Table 35. Adverse events (AE) in subjects administered Diazoxide Choline Controlled-Release Tablet (n=15) Hours Post Corrective Adverse Event Dosing Treatment Outcome Gastrointestinal Nausea" 1.5 Mild None Resolved Dry Heaves" 1.6 Mild None Resolved Neurological Assisted to supine Lightheaded 12.0 Mild position Resolved Dizziness 8 20.0 Mild None Resolved Miscellaneous Chillsr 2.0 Mild None Resolved Back Pain 2.0 Mild None Resolved Warm 8 20.0 Mild None Resolved Number of subj bcts with at least one AE 4, A.Es followed by the same superscript letter are the same subject .2.2. Clinical Chemistry. (06591 A summary of fasting glucose, fasting insulin, NEFA, and serum sodium (Na), potassium (K) and creatinine level is provided in Table 36. Neither treatment resulted in 170 significant cha ges in serum Na, K or creatinine from baseline to end of study. Treatment with diazoxide primarily impacts glucose-stimulated insulin secretion rather than basal insulin secretion. Fasting glucose levels increased slightly in the first 3 hours following dose' administration. This increase was more pronounced in the Proglycem@8 Oral Suspension arm as compared to the diazoxide chbline controlled-release tablet arm. These results a-e consistent with the differences in measured rates of dissolution from these formulations (see Table 5 herein) and the PK levels (see Figures 24 and 25 herein). In this study, there is no evidence for a reduction in fasting insulin after the administration of the single dose of diazoxide. There is also no evidence for a significant increase in fasting glucose as measured at 24 or 48 hours after dose administration. The most sensitive pharmacodynamic response measure is NEFA. Diazoxide treatment normally results in a sholt-term increase in NEFA, which returns to levels at or below baseline in about 6 hours. Both formulations showed this transient increase in NEFA. Treatment with ProglycerA@ Oral Suspension resulted in a statistically significant increase (p<O.001) in NEPA at 3 hours, which by 6 hours after dose administration had returned to levels well beldw baseline. Similarly the increase in NEFA at 3 hours after administration of diazoxide choline controlled-release tablets was statistically significant (p<0.0012). '4EFA levels in the diazoxide choline control ed-rel ease tablet treated subjects also returned to levels well below baseline by 6 hours after dose administration. Table 36. Fasting glucose, fasting insulin, non-esterifled fatty acid (NEFA), serum sodium (Na), potassium (K) and creatinine of subjects Parameter Proglycein Oral Diazoxide Choline Suspension (n=1S) Controlled-Release Tablet (u=15) Fasting Glucose (mg/dL) MeanASD (range) Mean+SD (range) Baseline 93-+6 (83-104) 93A6 (83-108) 1 h post-dose 99.4+7 (89-117) 97.9k7 (92-117) 3 h post.dose 102.816 (93-113) 98.0W7 (90-112) 24 h post-dose 97+5 (87-106) 98;8 (88-118) 48 h post-dose 92t:5 (84-103) 9315 (83-104) Fasting Insulin (JIU/nl) Baseline 8.65.2 (2.9-24.1) 9.913.3 (4.4-16.3) 171 24 h post-dose 12.0±8.9 (6.1-41.9) 11.1*3.3 (5.5-17.0) 48 h post-dose 9.5±5.7 (4.0-28.9) 11.1*2.9 (5.3-17.8) NEFA (smol/L) 1 h post-dose 0.36*0.11 (0.21-0.65) 0.34*0.14 (0.09-0.67) 3 h post-dose 0.53+0.13 (0.31-0.78) 0.55*0.19 (0.28-0.88) 6 h post-dose 0.13±0.07 (0.07-0.32) 0.11*0.04 (0.07-0.21) 24 h post-dose 0.36*0.10 (0.23-0.62) 0.40A0.18 (0.25-0.97) 48 h post-dose 0.38+0.13 (0.2-0.66) 0.39A0.15 (0.17-0.65) Na (mEq/L) Baseline 138.0*2.0 (135-142) 138.1+2.6 (134-143) End of Study 138.7+1.1 (137-141) 139.3A2.3 (135-144) K (mmol/L) Baseline 4.4*0.4 (3.9-5.5) 4.2+0.3 (3.8-5.1) End of Study 4.4±0.3(3.9-5.2) 4.2+0.3(3.8-5.2) Creatinine (mg/dL) Baseline 0.9*0.1 (0.7-1.1) 0.9d0.2 (0.7-1.4) End of Study 1.0±0.1 (0.8-1.3) 0.9±0.2 (0.6-1.3) 106601 All other clinical laboratory tests, including hematology, clinical serum chemistry, and urinalysis were within normal ranges for obese subjects. 7.2.3. Vital Signs. 106611 A giaph depicting sitting blood pressure at baseline and at various times following dose ,administration is provided in Figure 22. Neither treatment was associated with a sustained reduction or increase in blood pressure, nor was there any clear trend from baseline over 6, 9, 12, or 24 hours after dose administration. Pulse rates dropped incrementally from baseline levels in the period from dose administration to 3 hours post dosing (Figure 23). Pulse rates rose to levels equivalent to baseline or slightly above baseline in the period from 6 to 12 hours after dose administration, and remained at baseline levels from 24 hours after dose administration to the end of the study (Figure 23). Review of the baseline cardiac telemetry data for all subjects was conducted the morning of dosing. Based on the absence of clinical significant abnormalities, all subjects were aflowed to proceed with dosing. The cardiac telemetry data from study 172 time 0 to 24 hours after dose administration was evaluated. No clinically significant abnormalities (e.g. arrhythmias) were observed. 7.2.4. Preliminary Evaluation ofDiazoxide Plasma Pharmacokinetics. 106621 Cormpared to the Proglycem@ Oral Suspension, the diazoxide choline controlled-release tablet had a 30% lower peak exposure (Cmax) and a 15% lower total exposure (AUd) when the formulations were administered orally as 200 mg equivalents of diazoxide (Table 37). The timing of the peak plasma concentration (Tmax) occurred at a median tirrie of 4 hr after administration of the oral suspension and 20 hr after administration bf the diazoxide choline controlled-release tablet. The terminal half-life for diazoxide was similar with both formulations (29 hr for the oral suspension and 32 hr for the tablet). The two formulations had similar between-patient variability for Cmax and AUC. The most notable difference between the two formulations following a single dose was the lower, broader peak of the concentration-time profile of the tablet formulation (Figures 24 and 25). The peak concentration for the tablet averaged about 30% less and occurred about 16 hours later than the suspension. Figures 24 and 25 illustrate that the mean peak concentration was virtually unchanged between 12-hr and 24-hr post-dose following administration of the diazoxide choline controlled-release tablet formulation. Because of a more sustained release pattern, the tablet formulation was predicted to have a greater accumulation factor with chronic dosing than was the oral suspensions (3.,96 vs. 2.84). Simulations of repeated once-daily dosing with the two formulations (assuming linear pharmacokinetics) predicted that the two formulations would have similar trough concentrations at steady-state (22-23 pg/mL) (see Figure 26). Table 37. Summary Statistics for Plasma Diazoxide Pharmacokinetic Parameters after a Single Dose of Two Formulations Diazoxide Choline Controlled-Release Tablets AUC(o Cmax Tmax 24) AUC(O-120) AUC(0-o) Az TI/2 Accum pg/mL hr g.hr/mL pg-br/mL jig-hr/mL 1/hr hr Factor N 15 15 15 15 15 15 15 15 173 Mean 9.25 22.1 166 553 618 0.0242 31.9 3.96 Geomean 9.07 19.6 157 531 588 0.0229 30.2 3.74 St Dev '1.89 11.5 54 160 198 0.0085 10.6 1.48 SEM 0.49 3.0 14 41 51 0.0022 2.7 0.38 CV% 20.5% 52.0% 32.5% 28.9% 32.0% 35.2% 33.3% 37.5% Median 9.08 20.0 164 518 586 0.0237 29.3 3.80 Min 5.53 8.00 74.6 261 274 0.0144 15.9 2.26 Max 13.2 48.0 266 842 1024 0.0437 48.3 7.84 Diazoxide Oral Suspension (Proglycem) AUC(0 Gmax Tmax 24) AUC(0-120) AUC(0-o) Nz T1/2 Accum pg/mL hr pg-hr/mL pgehr/mL pgehr/mL I/hr hr Factor N 15 15 15 15 15 15 15 15 Mean 13.5 6.67 245 643 696 0.0256 28.6 2.84 Geomean 13.3 5.36 243 629 677 0.0249 27.9 -2.79 St Dev .3 5.49 35 142 173 0.0068 6.3 0.57 SEM 0.6 1.42 9 37 45 0.0018 1.6 0.15 CV% 17.1% 82.3% 14.4%. 22.1% 24.9% 26.7% 22.0% 20.0% Median 1'3.3 4.00 245 620 671 0.0234 29.6 2.86 Min 10.1 2.00 183 464 488 0.0180 16.1 1.84 Max 18.0 24,0 314 926 1054 0.0430 38.5 4.25 174 7.3 Conclusions of Comparison of Single Doses ofDiazoxide Administered as Proglycem@ Oral Suspension or as Diazoxide Choline Controlled-Release Tablets in Obese Subjects. [0663] The~present clinical study on the comparison of a single dose of diazoxide choline controlled-release tablet with an equivalent dose of diazoxide administered as Proglycem@ Oral Suspension in obese patients indicates that both formulations were well tolerated. With a single exception, moderate headache requiring treatment with acetaminophen'in one subject treated with Proglycem@, all adverse events were mild. Diazoxide choline controlled-release tablets appear to have a better CNS safety profile than Proglycenj Oral Suspension as evidenced by the absence of headaches and reduced rate of dizziness. Exploratory endpoints showed no detrimental impact. Preliminary pharmacokinetic analysis showed that compared to Proglycem(V Oral Suspension, the diazoxide cholihe controlled-release tablet had a 30% lower peak exposure (Cmax) and a 15%16 lower total exposure (AUC) for the same 200 mg diazoxide equivalent dose. The timing of the peak plasma concentration (Tmax) occurred at a median time of 4 hr after administration of the oral suspension and 20 hr after administration of the diazoxide choline tablet. The terminal half-life for diazoxide is similar with both formulations (29 hr for the oral suspension and 32 hr for the tablet). The two formulations had similar between-patient variability for Cmax and AUC. [0664] All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually. 10665] One Ikilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variances, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims. 175 10666] Definitions provided herein are not intended to be limiting from the meaning commonly understood by one of skill in the art unless indicated otherwise. 106671 The inventions illustratively described herein may suitably be practiced in the absence of anyelement or elements, limitation or limitation's, not specifically disclosed herein. Thus, for example, the terms "comprising", "including," containing", etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown,and described or portions thereof, but it is recognized that various modifications ae possible within the scope of the invention claimed. Thus, it should be understood tha although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention. 10668] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terins of Markush groups, those skilled in the art will recognize that the invention is alsq thereby described in terms of any individual member or subgroup of members of the.Markush group. 176

Claims

2. The salt of claim 1, wherein said KATP channel opener comprises diazoxide.
3. A polymorph of a salt, said salt comprising: diazoxide, and 10 a cation selected from the group consisting of choline and potassium cation.
4. The polymorph of a salt according to claim 3, wherein said cation is choline.
5. A polymorph Form A or polymorph Form B of said salt according to claim 4, said polymorph Form A having characteristic peaks in the XRPD pattern at values of two theta (Cu Ka, 40 kV, 40 mA) at approximately 9.8, 10.5, 14.9, 17.8, 17.9, 18.5, 19.5, 15 22.1, 22.6, 26.2, 29.6, and 31.2 degrees, and said polymorph Form B having characteristic peaks in the XRPD pattern at values of two-theta (Cu Kac, 40 kV, 40 mA) at approximately 8.9, 10.3, 12.0, 18.3, 20.6, 24.1, 24.5, 26.3, 27.1, and 28.9 degrees.
6. The polymorph of a salt according to claim 3, wherein said cation is potassium cation. 20 7. A polymorph Form A, polymorph Form B, polymorph Form C, polymorph Form D, polymorph Form E, polymorph Form F or polymorph Form G of said salt according to claim 6, said polymorph Form A having characteristic peaks in the XRPD pattern at values of two-theta (Cu Kt, 40 kV, 40 mA) at approximately 6.0, 8.1, 16.3, 17.7, 18.6,
19.1, 22.9, 23.3, 23.7, 24.7, 25.4, 26.1, 28.2, 29.6, and 30.2 degrees, said polymorph 25 Form B having characteristic peaks in the XRPD pattern at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 8.5, 10.8, 16.9, 18.2, 21.6, 25.5, 26.1, and 28.9 degrees, said polymorph Form C having characteristic peaks in the XRPD pattern at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 5.7, 6.1, 17.9, 23.9, 25.1, and 37.3 degrees, said polymorph Form D having characteristic peaks in the XRPD pattern at 180 values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 5.7, 6.2, 8.1, 8.5, 8.8, 16.9, 18.6, 23.2, 24.5, 25.8, and 26.1 degrees, said polymorph Form E having characteristic peaks in the XRPD pattern at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 6.7, 7.1, 14.1, and 21.2 degrees, said polymorph Form F having 5 characteristic peaks in the XRPD pattern at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 8.5, 9.0, 18.7, 20.6, 23.5, 27.5, and 36.3 degrees, and said polymorph Form G having characteristic peaks in the XRPD pattern at values of two-theta (Cu Ka, 40 kV, 40 mA) at approximately 5.2, 5.5, 13.1, 16.5, 19.3, 22.8, 24.8, 26.4, 28.7, and
34.1 degrees. 10 8. A pharmaceutical formulation comprising the salt according to any one of claims 1 to 7. 9. The formulation according to 8 that is suitable for oral administration. 10. The formulation according to 8 or claim 9 further comprising at least one component that substantially inhibits release of the KATp channel opener from the 15 formulation until after gastric transit. 11. Use of a formulation according to any one of claims 8 to 10 for the manufacture of a pharmaceutical for treating a subject suffering from Prader Willi Syndrome. 12. Use of a formulation according to any one of claims 8 to 10 for the manufacture of a pharmaceutical for 20 (i) inhibiting fasting insulin secretion, inhibiting glucose stimulated insulin secretion, elevating energy expenditure, elevating beta oxidation of fat, or inhibiting hyperphagia, in an obese, overweight or obesity prone subject, comprising administering to said subject a therapeutically effective amount of said formulation; (ii) maintaining weight loss in an obese, overweight, or obesity prone subject, 25 comprising administering to said subject a therapeutically effective amount of said formulation; (iii) preventing the transition to diabetes of a prediabetic subject comprising administering to said subject a therapeutically effective amount of said formulation; (iv) preventing or treating weight gain, dyslipidemia, diabetes or impaired glucose 30 tolerance in a subject treated with an anti-psychotic drug, comprising administering to 181 said subject a therapeutically effective amount of said formulation; (v) treatment of a subject suffering from or at risk for Alzheimer's disease, comprising administering to said subject a therapeutically effective amount of said formulation; 5 (vi) treatment of a subject suffering from hypoglycemia, comprising administration to said subject a therapeutically effective amount of said formulation; or (vii) treating hyperlipoproteinemia characterized by elevated triglyceride comprising administering said formulation. 13. Use of a pharmaceutical formulation comprising a salt comprising: 10 an anion of a KATP channel opener selected from the group consisting of Formula I to IV and a cation selected from the group consisting of an alkali metal cation and a compound comprising an ammonium comprising a tertiary amine group, R 2 b N FN RI R~Ra 1500 0 Formula I Formula It ') O R N R1 RR YR 20 Formula III Formula IV wherein in Formula I: R' is selected from the group consisting of hydrogen, CI-C 6 alkyl, substituted C1-C 6 alkyl, cycloalkyl, and substituted cycloalkyl provided however 25 that when R' is a substituted Cl-C 6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; R2 is hydrogen; X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, Ci-C 6 alkyl, substituted C 1 -C 6 alkyl, Ci-C 6 30 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted Ci-C 6 alkoxy, provided however that when an atom of the chain is substituted with substituted C 1 -C 6 alkyl, 182 substituted C 1 -C 6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; 5 wherein in Formula II: R' is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R' is a substituted C 1 -C 6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; 10 R 2 b is hydrogen; X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted C 1 -C 6 alkoxy, provided however that when an atom of the chain is substituted with substituted C 1 -C 6 alkyl, 15 'substituted C I-C 6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; wherein in Formula III: 20 R' is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1 -C 6 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, C 1 -C 6 alkyl, 25 substituted C 1 -C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R3 is a substituted CI-C 6 alkyl, then the substituent does not include an amino group; and R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however 30 that when R 4 is a substituted C 1 -C 6 alkyl, then the substituent does not include an amino group; wherein in Formula IV: R' is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, 183 substituted CI-C 6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1 -C 6 alkyl, then the substituent does not include an amino group; R2b is hydrogen; R 3 is selected from the group consisting of hydrogen, halogen, CI-C 6 alkyl, 5 substituted C 1 -C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 3 is a substituted C I-C 6 alkyl, then the substituent does not include an amino group; and R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however 10 that when R 4 is a substituted Ci-C 6 alkyl, then the substituent does not include an amino group. for the manufacture of a pharmaceutical for: (i) restoring normal glucose tolerance in a diabetic subject, comprising administering to said subject a therapeutically effective amount of said formulation; 15 (ii) delaying or preventing the progression of diabetes in a diabetic subject, comprising administering to said subject a therapeutically effective amount of said formulation; (iii) inducing beta-cell rest or improving insulin sensitivity or both in a subject with type I diabetes, comprising administering to said subject a therapeutically effective 20 amount of said formulation; and (iv) preserving pancreatic function in a subject with type I diabetes, comprising administering to said subject a therapeutically effective amount of said formulation. 14. Use of a formulation comprising a salt comprising 25 anion of a KATP channel opener selected from the group consisting of Formula I to IV and a cation selected from the group consisting of an alkali metal cation and a compound comprising an ammonium comprising a tertiary amine group, R 2 b 2Y X N R' ,S" NR 2 a / a 1AY 0 0 Formula I Formula 11 184 R N R' 5 wherein in Forn Formula III Formula IV R' is selected from the group consistmg ot hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R' is a substituted C 1 -C 6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; 10 R 2 a is hydrogen; X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted CI-C 6 alkoxy, provided however that when an atom of the chain is substituted with substituted C I-C 6 alkyl, 15 substituted C 1 -C 6 alkoxy or substituted cycloalkyl, then the substituent does not include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; wherein in Formula II: 20 R' is selected from the group consisting of hydrogen, CI-C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl, and substituted cycloalkyl provided however that when R' is a substituted CI-C 6 alkyl or a substituted cycloalkyl, then the substituent does not include an amino group; R 2 is hydrogen; 25 X is a 1, 2 or 3 carbon atom chain, wherein each atom is optionally substituted with halogen, hydroxyl, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cycloalkyl, substituted cycloalkyl, or substituted CI-C 6 alkoxy, provided however that when an atom of the chain is substituted with substituted CI-C 6 alkyl, substituted C1-C 6 alkoxy or substituted cycloalkyl, then the substituent does not 30 include an amino group; and wherein ring B is saturated, monounsaturated, polyunsaturated or aromatic; wherein in Formula III: 185 R1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1 -C 6 alkyl, then the substituent does not include an amino group; R2' is hydrogen; 5 R3 is selected from the group consisting of hydrogen, halogen, C-C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 3 is a substituted C 1 -C 6 alkyl, then the substituent does not include an amino group; and R4 is selected from the group consisting of hydrogen, halogen, C-C 6 alkyl, 10 substituted C 1 -C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when RW is a substituted C-C 6 alkyl, then the substituent does not include an amino group; wherein in Formula IV: R' is selected from the group consisting of hydrogen, C-C 6 alkyl, 15 substituted C 1 -C 6 alkyl, and cycloalkyl provided however that when R' is a substituted C 1 -C 6 alkyl, then the substituent does not include an amino group; R 2 is hydrogen; R 3 is selected from the group consisting of hydrogen, halogen, C-C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however 20 that when R3 is a substituted C 1 -C 6 alkyl, then the substituent does not include an amino group; and R 4 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, cycloalkyl and substituted cycloalkyl provided however that when R 4 is a substituted C 1 -C 6 alkyl, then the substituent does not include an 25 amino group. for the manufacture of a pharmaceutical for treating a subject suffering from Prader Willi Syndrome comprising administering to said subject a therapeutically effective amount of said formulation. 15. The use of claim 13 or claim 14, wherein said cation comprising an ammonium 30 is choline or hexamethyl hexamethylene diammonium, or wherein said alkali metal cation is selected from a sodium cation or a potassium cation. 186 16. The use of any one of claims 13 to 15, wherein said pharmaceutical formulation is suitable for oral administration. 17. The use of claim 16, wherein said pharmaceutical formulation comprises at least one component that substantially inhibits release of the KATP channel opener from the 5 formulation until after gastric transit. 18. The use of any one of claims 13 to 17, wherein said pharmaceutical formulation comprises one or more additional pharmaceutically active agents. 19. The use of claim 18, wherein said one or more additional pharmaceutically active agents are useful for the treatment of a condition selected from the group consisting of 10 obesity, prediabetes, diabetes, hypertension, depression, elevated cholesterol, fluid retention, or other obesity associated co-morbidities, ischemic and reperfusion injury, epilepsy, cognitive impairment, schizophrenia, mania, and other psychotic condition. 20. The use of claim 18, wherein said one or more additional pharmaceutically active agents comprise a pharmaceutically active agent that improves insulin sensitivity or 15 glucose utilization or glycemic control where the mode of action is not enhanced insulin secretion. 21. The use of any one of claims 18 to 20, wherein said one or more additional pharmaceutically active agents are selected from the group consisting of acarbose, miglitol, metformin, repaglinide, nateglinide, rosiglitizone, proglitizone, ramipril, and 20 metaglidasen. 22. A method for the preparation of a salt of diazoxide comprising: reacting one equivalent of a cation source selected from the group consisting of sodium hydroxide, potassium hydroxide, choline hydroxide, and hexamethyl hexamethylene diammonium dihydroxide with diazoxide, wherein said diazoxide is 25 dissolved in a solvent selected from the group consisting of acetonitrile, methyl ethyl ketone (MEK), tetrahydrofurane (THF), and 2-methyltetrahydrofurane (2MeTHF), and removing the solvent. 23. A method of treatment for: 187 (i) restoring normal glucose tolerance in a diabetic subject, comprising administering to said subject a therapeutically effective amount of said formulation; (ii) delaying or preventing the progression of diabetes in a diabetic subject, comprising administering to said subject a therapeutically effective amount of said 5 formulation; (iii) inducing beta-cell rest or improving insulin sensitivity or both in a subject with type I diabetes, comprising administering to said subject a therapeutically effective amount of said formulation; and (iv) preserving pancreatic function in a subject with type I diabetes, 10 comprising administering to said subject a therapeutically effective amount of said formulation comprising the step of administering to a subject in need of said treatment a pharmaceutical formulation as used in any one of claims 13 to 21. 24. A method for the treatment for Prader Willi Syndrome comprising administering 15 to a subject in need thereof a pharmaceutical formulation as used in any one of claims 13 to 21. 25. A method of treatment for: (i) inhibiting fasting insulin secretion, inhibiting glucose stimulated insulin secretion, elevating energy expenditure, elevating beta oxidation of fat, or inhibiting 20 hyperphagia, in an obese, overweight or obesity prone subject, comprising administering to said subject a therapeutically effective amount of said formulation; (ii) maintaining weight loss in an obese, overweight, or obesity prone subject, comprising administering to said subject a therapeutically effective amount of said formulation; 25 (iii) preventing the transition to diabetes of a prediabetic subject comprising administering to said subject a therapeutically effective amount of said formulation; (iv) preventing or treating weight gain, dyslipidemia, diabetes or impaired glucose tolerance in a subject treated with an anti-psychotic drug, comprising administering to said subject a therapeutically effective amount of said formulation; 30 (v) treatment of a subject suffering from or at risk for Alzheimer's disease, comprising administering to said subject a therapeutically effective amount of said formulation; 188 (vi) treatment of a subject suffering from hypoglycemia, comprising administration to said subject a therapeutically effective amount of said formulation; or (vii) treating hyperlipoproteinemia characterized by elevated triglyceride comprising administering said formulation 5 comprising the step of administering to a subject in need of said treatment a pharmaceutical formulation according to any one of claims 8 to 12. 26. A method for the treatment of Prader Willi Syndrome comprising administering to a subject in need thereof a pharmaceutical formulation according to any one of claims 8 to 12. 10 27. A salt of a diazoxide prepared by the method according to claim 22. 28. A salt comprising an anion of a KATP channel opener selected from the group consisting of Formula I to IV; a polymorph of a salt; a pharmaceutical formula comprising the salt; use of a formulation; use of a pharmaceutical formulation; a method for the preparation of a salt of diazoxide; a method of treatment substantially as herein 15 described with reference to any one of the drawings and/or examples but excluding comparative examples.