Compounds of Formula I: 
are structurally novel antiepileptic compounds that are highly effective anticonvulsants in animal tests (Maryanoff, B. E., Nortey, S. O., Gardocki, J. F., Shank, R. P. and Dodgson, S. P. J Med. Chem . 30, 880-887, 1987; Maryanoff, B. E., Costanzo, M. J., Shank, R. P., Schupsky, J. J., Ortegon, M. E., and Vaught J. L. Bioorganic and Medicinal Chemistry Letters 3, 2653-2656, 1993). These compounds are covered by three U.S. Pat. Nos.: 4,513,006, 5,242,942, and 5,384,327. One of these compounds 2,3:4,5-bis-O-(1-methylethylidene)-xcex2-D-fructopyranose sulfamate known as topiramate has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in treating simple and complex partial seizures and secondarily generalized seizures (E. FAUGHT, B. J. WILDER, R. E. RAMSEY, R. A. REIFE, L D. KRAMER, G. W. PLEDGER, R. M. KARIM et. al., Epilepsia 36 (S4) 33, 1995; S. K. SACHDEO, R. C. SACHDEO, R. A. REIFE, P. LIM and G. PLEDGER, Epilepsia 36 (S4) 33, 1995), and is currently marketed for the treatment of simple and complex partial seizure epilepsy with or without secondary generalized seizures in approximately twenty countries including the United States, and applications for regulatory approval are presently pending in several additional countries throughout the world.
Compounds of Formula I were initially found to possess anticonvulsant activity in the traditional maximal electroshock seizure (MES) test in mice (SHANK, R. P., GARDOCKI, J. F., VAUGHT, J. L., DAVIS, C. B., SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J., NORTEY, S. O., and MARYANOFF, B. E., Epilepsia 35 450-460, 1994). Subsequent studies revealed that Compounds of Formula I were also highly effective in the MES test in rats. More recently topiramate was found to effectively block seizures in several rodent models of epilepsy (J. NAKAMURA, S. TAMURA, T. KANDA, A. ISHII, K. ISHIHARA, T. SERIKAWA, J. YAMADA, and M. SASA, Eur. J. Pharmacol. 254 83-89, 1994), and in an animal model of kindled epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24 73-77, 1996).
Recent preclinical studies on topiramate have revealed previously unrecognized pharmacological properties which suggest that topiramate should be effective in treating some other neurological disorders. One of these is chronic neurodegenerative disorders such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, multiple sclerosis, diabetic neuropathies, retinopathy, peripheral nerve injury and brain and spinal neurodegeneration arising as a result of head trauma or spinal injury.
Accordingly, it has been found that compounds of th e following formula I: 
wherein X is O or CH2, and R1, R2, R3, R4 and R5 are as defined hereinafter are useful in treating chronic neurodegenerative conditions, such as occurs in Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, multiple sclerosis, diabetic neuropathies, retinopathy, peripheral nerve injury and brain and spinal neurodegeneration arising as a result of head trauma or spinal injury.
The sulfamates of the invention are of the following formula (I): 
wherein
X is CH2 or oxygen;
R1 is hydrogen or alkyl; and
R2, R3, R4 and R5 are independently hydrogen or alkyl and, when X is CH2, R4 and R5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R2 and R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II): 
wherein
R6 and R7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.
R1 in particular is hydrogen or alkyl of about 1 to 4 carbons, such as methyl, ethyl and iso-propyl. Alkyl throughout this specification includes straight and branched chain alkyl. Alkyl groups for R2, R3, R4, R5, R6 and R7 are of about 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl. When X is CH2, R4 and R5 may combine to form a benzene ring fused to the 6-membered X-containing ring, i.e., R4 and R5 are defined by the alkatrienyl group xe2x95x90Cxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90.
A particular group of compounds of formula (I) is that wherein X is oxygen and both R2 and R3 and R4 and R5 together are methylenedioxy groups of the formula (II), wherein R6 and R7 are both hydrogen both alkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, in particular where R6 and R7 are both alkyl such as methyl. A second group of compounds is that wherein X is CH2 and R4 and R5 are joined to form a benzene ring. A third group of compounds of formula (I) is that wherein both R2 and R3 are hydrogen.
The compounds of formula (I) may be synthesized by the following methods:
(a) Reaction of an alcohol of the formula RCH2OH with a chlorosulfamate of the formula ClSO2NH2 or ClSO2NHR1 in the presence of a base such as potassium xcex1-butoxide or sodium hydride at a temperature of about xe2x88x9220xc2x0 to 25xc2x0 C. and in a solvent such as toluene, THF or dimethylformamide wherein R is a moiety of the following formula (III): 
(b) Reaction of an alcohol of the formula RCH2OH with sulfurylchloride of the formula SO2Cl2 in the presence of a base such as triethylamine or pyridine at a temperature of about xe2x88x9240xc2x0 to 25xc2x0 C. in a solvent such as diethyl ether or methylene chloride to produce a chlorosulfate of the formula RCH2OSO2Cl.
The chlorosulfate of the formula RCH2OSO2Cl may then be reacted with an amine of the formula R1NH2 at a temperature of about 40xc2x0 to 25xc2x0 C. in a solvent such as methylene chloride or acetonitrile to produce a compound of formula (I). The reaction conditions for (b) are also described by T. Tsuchiya et al. in Tet. Letters, No. 36, p. 3365 to 3368 (1978).
(c) Reaction of the chlorosulfate RCH2OSO2Cl with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile yields an azidosulfate of the formula RCH2OSO2N3 as described by M. Hedayatullah in Tet. Lett. p. 2455-2458 (1975). The azidosulfate is then reduced to a compound of formula (I) wherein R1 is hydrogen by catalytic hydrogenation, e.g. with a noble metal and H2 or by heating with copper metal in a solvent such as methanol.
The starting materials of the formula RCH2OH may be obtained commercially or as known in the art. For example, starting materials of the formula RCH2OH wherein both R2 and R3 and R4 and R5 are identical and are of the formula (II) may be obtained by the method of R. F. Brady in Carbohydrate Research, Vol. 14, p. 35 to 40 (1970) or by reaction of the trimethylsilyl enol ether of a R6COR7 ketone or aldehyde with fructose at a temperature of about 25xc2x0 C., in a solvent such a halocarbon, e.g. methylene chloride in the presence of a protic acid such as hydrochloric acid or a Lewis Acid such as zinc chloride. The trimethylsilyl enol ether reaction is described by G. L. Larson et al in J. Org. Chem. Volaa 38, No. 22, p. 3935 (1973).
Further, carboxylic acids and aldehydes of the formulae RCOOH and RCHO may be reduced to compounds of the formula RCH2OH by standard reduction techniques, e.g. reaction with lithium aluminum hydride, sodium borohydride or borane-THF complex in an inert solvent such a diglyme, THF or toluene at a temperature of about 0xc2x0 to 100xc2x0 C., e.g. as described by H. O. House in xe2x80x9cModern Synthetic Reactionsxe2x80x9d, 2nd Ed., pages 45 to 144 (1972).
The compounds of formula I: may also be made by the process disclosed in U.S. Pat. Nos. 4,513,006, 5,242,942, and 5,384,327, which are incorporated by reference herein.
The compounds of formula I include the various individual isomers as well as the racemates thereof, e.g., the various alpha and beta attachments, i.e., below and above the plane of the drawing, of R2, R3, R4 and R5 on the 6-membered ring. Preferably, the oxygene of the methylenedioxy group (II) are attached on the same side of the 6-membered ring.
The ability of the compounds of formula I to treat chronic neurodegenerative disorders is based from the results of studies in which topiramate was found to promote neurite outgrowth in neuronal cells in culture and to enhance nerve regeneration and recovery of function after injury in vivo
In studies in vitro, cultures of rat hippocampal and cerebral cortical cells were established from embryonic day 18 pups. The cells were grown in culture wells (plates) for seven days in the presence of various concentrations of topiramate (0.1 nM-100 nM), or the neurotrophic factors BDNF (brain-derived neurotrophic, 10 ng) and xcex1-MSH (alpha-melanocyte stimulating hormone, 50 nM), or vehicle (isotonic saline). Each compound was added to the culture medium in a specified set of wells at the time the cells were plated and then again four days later when the culture media was removed and replaced with fresh media. On the seventh day in culture, the cells were treated with formalin, a tissue fixative. Subsequently, the cells were treated with a fluorescein-labeled antibody specific for microtubule associated protein-2 (MAP-2), a selective marker for dendritic processes. The amount of fluorescein-labeled antibody bound to MAP-2 (FITC signal) in each well was analytically determined. This information was then used to calculate the relative degree of neurite outgrowth for the cells in each well. When compared to cells grown in medium containing only vehicle, the topiramate-treated cells exhibited a significantly higher level of FITC signal, thereby indicating that topiramate induced an increase in neurite outgrowth. For hippocampal cells, the increase was significantly higher (P less than 0.05) at concentrations ranging from 100 nM to 100 xcexcM (FIG. 1).
USPTO Backgrounds
USPTO Backgrounds