Anticonvulsant derivatives useful in treating chronic neurodegenerative disorders

Anticonvulsant derivatives useful in treating chronic neurodegenerative conditions are disclosed.

BACKGROUND OF THE INVENTION

Compounds of Formula I:

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.

DISCLOSURE OF THE INVENTION

Accordingly, it has been found that compounds of th e following formula I:

wherein X is O or CH 2 , 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.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The sulfamates of the invention are of the following formula (I):

wherein

X is CH 2 or oxygen;

R 1 is hydrogen or alkyl; and

R 2 , R 3 , R 4 and R 5 are independently hydrogen or alkyl and, when X is CH 2 , R 4 and R 5 may be alkene groups joined to form a benzene ring and, when X is oxygen, R 2 and R 3 and/or R 4 and R 5 together may be a methylenedioxy group of the following formula (II):

wherein

R 6 and R 7 are the same or different and are hydrogen, lower alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.

R 1 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 R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are of about 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl. When X is CH 2 , R 4 and R 5 may combine to form a benzene ring fused to the 6-membered X-containing ring, i.e., R 4 and R 5 are defined by the alkatrienyl group C CH CH CH .

A particular group of compounds of formula (I) is that wherein X is oxygen and both R 2 and R 3 and R 4 and R 5 together are methylenedioxy groups of the formula (II), wherein R 6 and R 7 are both hydrogen both alkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, in particular where R 6 and R 7 are both alkyl such as methyl. A second group of compounds is that wherein X is CH 2 and R 4 and R 5 are joined to form a benzene ring. A third group of compounds of formula (I) is that wherein both R 2 and R 3 are hydrogen.

The compounds of formula (I) may be synthesized by the following methods:

(a) Reaction of an alcohol of the formula RCH 2 OH with a chlorosulfamate of the formula ClSO 2 NH 2 or ClSO 2 NHR 1 in the presence of a base such as potassium -butoxide or sodium hydride at a temperature of about 20 to 25 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 RCH 2 OH with sulfurylchloride of the formula SO 2 Cl 2 in the presence of a base such as triethylamine or pyridine at a temperature of about 40 to 25 C. in a solvent such as diethyl ether or methylene chloride to produce a chlorosulfate of the formula RCH 2 OSO 2 Cl.

The chlorosulfate of the formula RCH 2 OSO 2 Cl may then be reacted with an amine of the formula R 1 NH 2 at a temperature of about 40 to 25 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 RCH 2 OSO 2 Cl with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile yields an azidosulfate of the formula RCH 2 OSO 2 N 3 as described by M. Hedayatullah in Tet. Lett. p. 2455-2458 (1975). The azidosulfate is then reduced to a compound of formula (I) wherein R 1 is hydrogen by catalytic hydrogenation, e.g. with a noble metal and H 2 or by heating with copper metal in a solvent such as methanol.

The starting materials of the formula RCH 2 OH may be obtained commercially or as known in the art. For example, starting materials of the formula RCH 2 OH wherein both R 2 and R 3 and R 4 and R 5 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 R 6 COR 7 ketone or aldehyde with fructose at a temperature of about 25 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 0 to 100 C., e.g. as described by H. O. House in Modern Synthetic Reactions , 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 R 2 , R 3 , R 4 and R 5 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 -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<0.05) at concentrations ranging from 100 nM to 100 M (FIG. 1 ).

To prepare the pharmaceutical compositions of this invention, one or more sulfamate compounds of formula (I) are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., i.v. Sterile injectable formulations will be prepared using appropriate solubilizing agents. A unit dose would contain about 10 to 100 mg of the active ingredient. Topiramate is currently available for oral administration in round tablets containing 25 mg, 100 mg or 200 mg of active agent. The tablets contain the following inactive ingredients: lactose hydrous, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorbate 80.