Use of topiramate or derivatives thereof for the manufacture of a medicament for the treatment of manic-depressive bipolar disorders

Use of topiramate or a derivative thereof for the manufacture of a medicament for the treatment of bipolar disorder

background of the invention

Compounds of formula (I) are structurally novel antiepileptic compounds that are highly effective anticonvulsants in animal testing (Maryanoff, BE, Nortey, SO, Gardocki, JF, Shank, RP and Dodgson, SPJ Med. Chem. 30, 880-887, 1987; Maryanoff, BE, Constanzo, MJ, Shank, RP, Schupsky, JJ, Ortegon, ME, and Vaught JL Bioorganic & Medicinal Chemistry Letters 3, 2653-2656, 1993, McComsey, DF and Maryanoff, BE, J. Org. Chem. 1995].

<chemistry id="i"><img file="KR20000022233A_D0001.tif" /></chemistry>

This compound is covered by US Pat. Nos. 4,513,006, 5,384,327 and 5,498,629. One of these compounds, 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate, also known as topiramate, has been tested in clinical trials of human epilepsy. It has been shown to be effective as an adjuvant or monotherapy in the treatment of simple and complex epileptic seizures and secondary epileptic seizures [E. FAUGHT, BJ WILDER, RE RAMSEY, RA REIFE, LD KRAMER, GW PLEDGER, RM KARIM. et al, Epilepsia 36(S4)33, 1995; SK SACHDEO, RC SACHDEO, RA REIFE, P. LIM and G. PLEDGER, Epilepsia 36(S4)33, 1995], is currently being marketed in the UK, Finland, USA and Sweden for the treatment of simple and complex epileptic seizures with or without secondary epilepsy, and patent applications are pending in several countries around the world. .

Compounds of formula (I) were first shown to have anticonvulsant activity during typical maximal electroshock epileptic seizures (MES) in mice (SHANK, RP, GARDOCKI, JF, VAUGHT, JL, DAVIS, CB, SCHUPSKY, JJ , RAFFA, RB, DODGSON, SJ, NORTEY, SO, and MARYANOFF, BE, Epilepsia 35 450-460, 1994]. Subsequent studies have shown that the compound of formula (I) is also very effective in the MES test in rats. More recently, topiramate has been used in several epilepsy rodent models [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 animal models of severe epilepsy [A. WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77, 1996] were found to be effective in blocking epileptic seizures.

Recent latency studies of topiramate have revealed previously unrecognized pharmacological properties suggesting that topiramate is effective in the treatment of manic-depressive bipolar disorder (MDBD).

Accordingly, it has been found that compounds of formula (I) are effective for the treatment of bipolar disorder (MDBD).

Formula I

<img file="KR20000022233A_D0002.tif" />

In the above formula (I),

X is O or CH₂ego,

R₁, R₂, R₃, R₄ and R₅is as defined hereinafter.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The sulfamates of the present invention are compounds of formula (I):

Formula I

<img file="KR20000022233A_D0003.tif" />

In the above formula (I),

X is CH₂ or oxygen,

R₁is hydrogen or alkyl,

R₂, R₃, R₄ and R₅is independently hydrogen or lower alkyl, and when X is oxygen, R₂and R₃and/or R₄and R₅together form a methylenedioxy group of formula (II).

<chemistry id="ii"><img file="KR20000022233A_D0004.tif" /></chemistry>

In the above formula (II),

R₆ and R₇are the same or different and are hydrogen, lower alkyl or alkyl, and combine with each other to form a cyclopentyl or cyclohexyl ring.

R₁is in particular hydrogen or alkyl having from about 1 to 4 carbon atoms, such as methyl, ethyl and iso-propyl. Throughout this specification, alkyl includes straight-chain and branched-chain alkyl. R₂, R₃, R₄, R₅, R₆ and R₇Alkyl for is alkyl having about 1 to 3 carbon atoms and includes methyl, ethyl, iso-propyl and n-propyl.

A particular group of compounds of formula (I) is that X is oxygen and R₂and R₃, and R₄and R₅together with a methylenedioxy group of formula II (wherein R₆ and R₇are both hydrogen, both alkyl, or together form a spiro cyclopentyl or cyclohexyl ring, in particular R₆ and R₇are both alkyls such as methyl). A second group of compounds of formula I wherein X is CH₂and R₄and R₅is a compound that bonds together to form a benzene ring. A third group of compounds of formula I are R₂and R₃Both of these compounds are hydrogen.

Compounds of formula (I) can be synthesized by the following methods:

(a) formula RCH₂an alcohol of OH, where R is the formula <img file="KR20000022233A_D0005.tif" />is a residue of the formula ClSO₂NH₂ or ClSO₂NHR₁is reacted in a solvent such as toluene, THF or dimethylformamide at about -20 to 25°C in the presence of a base such as potassium a-butoxide or sodium hydride.

(b) formula RCH₂OH alcohol to formula SO₂Cl₂reacted with sulfuryl chloride of about -40 to 25 ° C in the presence of a base such as triethylamine or pyridine in a solvent such as diethyl ether or methylene chloride to form RCH₂OSO₂Chlorosulfamate of Cl is prepared.

Then, the formula RCH₂OSO₂Chlorosulfate of Cl with formula R₁NH₂Compounds of formula (I) can be prepared by reaction with an amine of The reaction conditions of (b) are described in T. Tsuchiya et al., Tet. Letters, No. 36, P. 3365-3368 (1978)].

(c) formula RCH₂The chlorosulfate of OSOCl is reacted with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile, as described in M. Hedayatullah, Tet. Lett. p. 2455-2458 (1975), formula RCH₂OSO₂N₃to obtain azidosulfate of Then, azidosulfate, for example, a noble metal and H₂by catalytic hydrogenation using R or by heating with copper metal in a solvent such as methanol.₁This hydrogen is reduced to a compound of formula (I).

Formula RCH₂Starting materials for OH are commercially available or can be obtained as known in the art. For example, R₂and R₃,and R₄and R₅RCH is the same and is a group of formula II₂Starting materials for OH are described in RF Brady, Carbohydrate Research, Vol. 14, p. 35-40 (1970)] or the formula R₆COR₇Trimethylsilyl enol ether of a ketone or aldehyde of can be obtained. The trimethylsilyl enol ether reaction is described in J. Org. Chem. Vol. 38, No. 22, p. 3935 (1973).

Also, the carboxylic acid of formula RCOOH and the aldehyde of formula RCHO can be reduced by standard reduction techniques, for example, from about 0 to 100 in an inert solvent such as diglyme, THF or toluene with lithium aluminum hydride, sodium borohydride or borane-THF complex. C, for example, by reacting as described in HO House, "Modern Synthetic Reactions", 2nd Ed., p.45-144 (1972), with formula RCH₂It can be reduced to a compound of OH.

Compounds of formula (I) may also be prepared by the methods described in US Pat. No. 4,513,006, which is incorporated herein by reference.

Compounds of formula (I) include various individual isomers and racemates thereof, for example R in the 6-membered ring₂, R₃, R₄and R₅alpha and beta conjugates of, i.e., those above and below the ring plane are included. Preferably, the oxygen of the methylenedioxy group of formula (II) is bonded to the same side of the 6-membered ring.

Although bipolar disorder is a progressive mental disorder of unknown etiology [cf. F. GOODWIN and KR JAMISON, Manic-Depressive Illness, Oxford University Press, New York, 1990], it is hypothesized that the recurrence of bipolar disorder is caused by electrophysiological exacerbations. (F. GOODWIN and KR JAMISON, Manic-Depressive Illness, Oxford University Press, New York, p.405-407, 1990). Topiramate has been shown to be effective in blocking severe epileptic seizures in rats (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77, 1996].

For the treatment of bipolar disorder, the compound of formula (I) may be used at a dose of about 50 to 200 mg per day for an average adult, usually divided into two doses. A unit dose contains about 25 to 100 mg of active ingredient.

In order to prepare the pharmaceutical composition of the present invention, one or more sulfamate compounds of formula (I) are combined with a pharmaceutical carrier which may take a wide variety of forms depending on the desired dosage form, for example oral, suppository or parenteral. and mix well according to conventional pharmaceutical mixing techniques. Conventional pharmaceutical media can be used to prepare compositions for oral dosage form. Accordingly, suitable carriers and additives for liquid oral preparations such as suspensions, elixirs and solutions include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like, and include powders, capsules and tablets. Suitable carriers and additives for solid oral preparations include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. In terms of ease of administration, tablets and capsules are the most advantageous oral dosage unit forms, and in this case, solid pharmaceutical carriers are certainly used. Optionally, tablets may be coated with sugar or enteric coated by standard techniques. Suppositories can be prepared using cocoa butter as the carrier. In the case of parenteral preparations, the carrier usually comprises sterile water, although other ingredients may be included, for example, to increase solubility or to aid in a preservative effect. Suspensions for injection can also be prepared using suitable liquid carriers, suspending agents, and the like. Topiramate is preferably administered orally as a round tablet containing 25 mg, 100 mg or 200 mg of the active agent. 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 oxides and polysorbates 80.

The pharmaceutical compositions herein contain, for example, about 25 to 100 mg of active ingredient per dosage unit such as tablets, capsules, powder injections, teaspoonfuls, suppositories.