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(12) Patent Application Publication (10) Pub. No.: US 2011/0244057 A1 Ehrenberg (43) Pub US 2011024.4057A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0244057 A1 Ehrenberg (43) Pub. Date: Oct. 6, 2011 (54) COMBINATION THERAPIES WITH Related U.S. Application Data TOPIRAMATE FOR SEIZURES, RESTLESS LEGS SYNDROME, AND OTHER (60) Provisional application No. 61/100,232, filed on Sep. NEUROLOGICAL CONDITIONS 25, 2008. Publication Classification (51) Int. Cl. (76) Inventor: Bruce L. Ehrenberg, New York, A633/26 (2006.01) NY (US) A63L/35 (2006.01) A633/06 (2006.01) A6IP 25/00 (2006.01) (21) Appl. No.: 13/120,933 A6IP 25/28 (2006.01) A6IP 25/08 (2006.01) (22) PCT Filed: Sep. 25, 2009 (52) U.S. Cl. .......... 424/648: 514/454; 424/682; 424/646 (57) ABSTRACT (86). PCT No.: PCT/US2009/058495 The invention provides compositions and methods of treating various conditions, including neurological conditions, with S371 (c)(1), pharmaceutical compositions including a sulfamate (e.g., (2), (4) Date: Jun. 9, 2011 topiramate) and magnesium. US 2011/024.4057 A1 Oct. 6, 2011 COMBINATION THERAPES WITH TOPIRAMATE FOR SEIZURES, RESTLESS LEGS SYNDROME, AND OTHER II NEUROLOGICAL CONDITIONS CROSS-REFERENCE TO RELATED APPLICATIONS 0001. This application claims the benefit of the priority date of U.S. Application No. 61/100,232, filed Sep. 25, 2008. For the purpose of any U.S. patent that may issue from the 0005 wherein RandR, are the same or different and are U.S. national phase correlate of the present application, the hydrogen, lower alkyl or are alkyl and are joined to form a content of the priority document is hereby incorporated by cyclopentyl or cyclohexyl ring, and (b) magnesium. While reference in its entirety. the invention is not limited to compositions that act by any particular mechanism, the amount of the magnesium can be TECHNICAL FIELD sufficient to potentiate the effect of the compound of Formula I or the pharmaceutically acceptable derivative thereof. In 0002 The present invention includes treatments for sev Some embodiments, the pharmaceutical compositions can eral neurological conditions, including epileptic seizures trig include a therapeutically effective amount of a compound of gered by migraine with or without aura, eclamptic seizures Formula I. and posteriorencephalopathy of late pregnancy, seizures and 0006. In some embodiments R. R. R. and Rs are inde status epilepticus associated with reversible posterior leu pendently hydrogen or lower alkyl. In other, separate embodi coencephalopathy in patients on immunosuppressants, Rest ments, R and R and/or R and Rs together are a group of Formula II. In other words, in Formula I, R. R. R. and Rs less Leg Syndrome (RLS), and Periodic Limb Movement can be, independently, hydrogen or lower alkyl or, in Formula Disorder (PLMD), with various combinations of the agents I, R and R and/or R and Rs together can be a group of topiramate (or another Sulfamate), magnesium, and iron. Formula II. 0007. Where X is CH R and Rs can be alkene groups SUMMARY joined to form a benzene ring. 0008. Where X is oxygen, R and R and/or R and Rs 0003. The present invention is based, in part, on the rec together can be a methylenedioxy group of Formula II: ognition that patients under physiologic stress from direct physical or mental trauma, often compounded by severe sleep deprivation (thus preventing repletion of the body's main II energy source—ATP) may accumulate Subtle tissue damage, especially in the posterior regions of the brain where the highest rate of routine waking metabolic activity is found. Those suffering from the movement disorders Restless Leg Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD), patients suffering from a sleep disorder such as narcolepsy, and pregnant patients who are at risk of an eclamptic seizure can be treated with a Sulfamate conforming to Formula I (e.g., topiramate) or with a combination of 0009. With respect to Formula II, R and R, can be the agents that include a compound of Formula I, magnesium same or different and can be hydrogen, lower alkyl or alkyl (magnesium Sulfate is currently the treatment of choice for and can be joined to form a cyclopentyl or cyclohexyl ring. eclampsia) and, optionally, iron. Accordingly, the invention 0010. In particular embodiments, the pharmaceutical features pharmaceutical compositions that include (a) a com composition of Formula I can be: pound of Formula I or a pharmaceutically acceptable deriva 0011 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- tive thereof: fructopyranose Sulfamate; 0012 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-3-L- fructopyranose Sulfamate; 0013 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- fructopyranose methylsulfamate; X 0014 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- CHOSONHR fructopyranose butylsulfamate; R4 | R2 00.15 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- fructopyranose ethylsulfamate; 0016 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- fructopyranose octylsulfamate; 0004 where X is CH or oxygen, R is hydrogen or lower 0017 2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- alkyl, and R. R. R. and Rs are independently hydrogen or fructopyranose 2-propenylsulfamate; lower alkyl, or R and R and/or R and Rs together may be a 0018 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- group of the following Formula II: fructopyranose phenylmethylsulfamate; US 2011/024.4057 A1 Oct. 6, 2011 0019 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- leading to constipation. To the contrary, orally ingested mag fructopyranose cyclopropylsulfamate; nesium has a known laxative effect and thus, in the combined 0020 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- form, there is often a need to adjust the dosing of the two fructopyranose cyclobutylsulfamate; elements to reach a balance with respect to gastrointestinal 0021 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- motility. In some embodiments, the present compositions can fructopyranose (2.2.2-trifluoroethyl)sulfamate: include only magnesium and iron to produce satisfactory 0022 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- improvement with minimal or no side effects. fructopyranose dimethylsulfamate; 0036 Hypomagnesemia, hypercalciuria, and nephrocalci 0023 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- nosis (HHN) are the most common causes of progressive fructopyranose diethylsulfamate; nephropathy that presents with low Mg" and for which early 0024 2.3-O-(1-methylethylidene)-4,5-O-sulfonyl-B-D- replacement of the mineral ion can delay or prevent kidney fructopyranose azido Sulfamate; damage. Thus, adding Mg" to the Formula I composition 0025 (S)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-3- could circumvent the self-contained carbonic anhydrase D-fructopyranose Sulfamate; inhibitory activity and avoid the markedly elevated renal 0026 (R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-B- stone production rate that destroys the kidney. Since treat D-fructopyranose Sulfamate; ment of the Susceptible population may prevent the bad out 0027 2.3-O-(1-ethylpropylidene)-4,5-O-sulfonyl-f-D- come, it could be justified to consider recommending to the fructopyranose Sulfamate; public the increased use of the over-the-counter mineral as a 0028 2.3-O-(1-methylethylidene)-4,5-O-N-(4-meth Supplement if the data showing widespread magnesium defi ylbenzenesulfonyl)imidosulfonyl-B-D-fructopyranose ciency can be verified. Magnesium is a mineral like fluoride Sulfamate; and chloride, two ions that have already been routinely added 0029 2.3-O-(1-methylethylidene)-4,5-O-N-(4-meth to the general water Supply. ylbenzenesulfonyl)imidosulfonyl-B-D-fructopyranose 0037. The present pharmaceutical compositions can be Sulfamate; formulated for oral or parenteral administration, and particu 0030 2.3-O-(cyclohexylidene)-4,5-O-sulfonyl-f-D-fruc lar formulations are described further below. topyranose Sulfamate; or 0038. The compositions, including those that contain a 0031 (S)-4,5-O-N-(1,1-dimethylethoxycarbonyl)imi compound of Formula I (with or without a potentiating dosulfinyl-2,3-O-(1-methylethylidene)-beta-D-fructopy amount of magnesium) are also useful in treating a patient ranose Sulfamate. who is suffering from RLS or PLMD, especially if that patient 0032. In any of the present embodiments, the compound of is already taking pramipexole, known to cause a severe Formula I can be 2.3:4,5-bis-O-(1-methylethylidene)-beta insomnia of its own, associated with profound daytime D-fructopyranose Sulfamate (topiramate). sleepiness. Such severe sleep disruption can increase the risk 0033 While pharmaceutically acceptable derivatives are ofa true epileptic seizure, or exacerbate a pre-existing seizure discussed further below, we note here that such derivatives disorder, especially in genetically pre-disposed individuals encompass pharmaceutically acceptable salts (e.g., an alkali who have inherited one of the known epilepsy mutations (e.g., metal salt, an ammonium salt, or a crystalline choline salt). a chloride or potassium channelopathy). In addition, familial Pharmaceutically acceptable derivatives can also be com hemiplegic migraine is a relatively rare syndrome which pre pounds of Formula I that include a masking chemical group sents with atypical seizures involving unilateral slow rhyth (e.g., an imidate group) that is dissociated from the compound mic 1 HZ twitching, poorly responsive to routine anticonvul in vivo. sants, and associated with PLEDs in the EEG. These patients 0034. The precise amounts of the agents administered can have a known channelopathy involving the calcium pores, vary and can be readily determined by one of ordinary skill in with the majority of families showing linkage to the CACN2 the art using the techniques and procedures known to one of gene, where a variety of mutations have been found.
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