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

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

Ortho-McNeil Pharmaceutical, Inc. C:115078 127714/2 BACKGROUND OF ΊΉΕ INVENTION 5 10

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Gardoski, XF„, Shank, RJ1. and Dodgsom, S.P. J. M@d. Ck@m, Uh BBO- 15 8S7, 19B7; Maryanoff, B.E., Costanzo, MJ., Shank, R.P., Sehmpsky, JJ., Onsgon, MJE.,. and Vaught J.L. Bioorganic &amp;amp; Medicinal Chemistry Letters 3, 2653-2655, 1993, McComsey, D.F. and Maryanoff, BJE.» J. Or®. Chem. 1995). These compounds ate covered by three US Patents: Nos.4,513,006, 5,314,327 and 5,490,629. One of these compounds 2,3:4,5-bis-O-( 1 -methylethylidene)-®-B-ffractopyran©se 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, FAUGP1T, B J. WILDER, ILE. RAMSEY, RA. REIFS, L D. KRAMER, G.W. PLEDGER, RK KARIM et al., Epilepsia 36 &lt;S4) 33,1995; S.K. SACHDEO, R.C. SACHDEO, RA. REW, P. LHM and G. PLEDGER, Epilepsia 36 (S4) 33, 1995), and is currently marketed for the treatment of simple and complex partial seizure 25 1 127714/2 epilepsy with or without secondary generalized seizures ia Great Britain, Finland, fe© United Slates and Sweden and applications for regulatory approval are presently pending in numerous countries

Compounds of Formula I were initially found to possess anticonvulsant activity in. the traditional maximal electroshock seizure (MES) test in mis© (SHANK, R.P., GARDOCKI, J.F„, VAUGHT, XL., DAWS, C.B., SCHUPSKY, JX, RAPFA, DODGSGN, S J., NORTEY, S.O., 1© and MARYANOFF, B.E., Epilepsia 35 450-460, 1994). Subsequent- - -studies revealed feat Compounds of Formula Ϊ were also highly effective in fe© 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. ISHH, K. ISHfflARA, T. - 15 SERIKAWA, J. YAMADA,. and M. SASA, Ear. J. Pharmacol. 2_5_4 B3-S9, 1994), and in an animal model of kindled epilepsy (A. WAUQUEER and S. ZHOU, Epilepsy Res. 24. 73-77. 1996 in_pre§s). -

Process for the preparation of compounds of formula I is described in US 4,513,006.

Recent preclinical studies on topiramate have revealed previously 2© unrecognized pharmacological properties which suggest that topiramate should be effective in treating manic-depressive bipolar disorder (MDSD).

DISCLOSURE OF THE INVENTION 2Λ» © ·

Accordingly, it has been found that compounds of fee following formula I;

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127714/3

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wherein X is 0 or CH2. and Rj, R? R3, R4 and R5 are as defined hereinafter are useful in treating manic-depressive bipolar disorder (MDED).

DETAILED DESCRIPTION OF THE PREFERRED EMODIMENTS

The present invention provides a pharmaceutical composition for the treatment of manic-depressive bipolar disorder comprising as an active ingredient a compound of the formula I:

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.wherein ,...’-..··'·'·. X is CH 2 or oxygen;

Rt is hydrogen or alkyl; and R2, R3, R4 and R5 are independently hydrogen or lower alky, in addition, when X is oxygen, R2 an d R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II): 7-- 4 - 127714/2 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; in addition, if X is CH2, R4 and R5 may be joined together to form a benzene ring together with a pharmaceutically acceptable carrier. A particular group, off .compounds off ’formula (I), are those ' wherein X is .oxygen, and/both. Ri and R3/ arid. R4.and.R5. together are .methylenedioxy groups off the formula (Π), wherein Rg' and R7 .are both hydrogen,, both’ alkyl, or combine' to .-.form a, spiro .cyclopentyl or . cyclohexyl ring, in particular Where Rg and R7 are. both alkyl such. as methyl.. A second group of compounds are. those. wherein X is. CH2 . and- R4 and R5 are joined to form a benzene ring. . A third .group off compounds of formula (I) are. those wherein both R2 and Rg- are .. hydrogen. / . . The compounds off formula . (I) may be'. synthesized by the following methods: . WO s®/M23 3PCT/W7/MM9 (a) Reaction of aa alcohol of the formula RCH2OH with a chlorosulffamate of the formula CISQ2NH2 or QSO2NHR1 ia the presence of a base such as potassium a-butoxlde or sodium hydride at a temperature of about =20° to 25® C and in a solvent such as 5 toluene, THF or dimethylformamide wherein R is a moiety of the following formula (Hl):

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1© (fe) Reaction of an alcohol of the formula RCHjOH with sulfurylchloride of the formula SO2CI2 i® &amp;amp;e 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 ehlorosulfate of the formula RCH2OSO2CI. 15

The ehlorosulfate of the formula RCH2OSO2CI may then be reacted with an amine of the formula R1NH2 at a temperature of abut 40° to· 25° C an a solvent such as methylene chloride or acetonitrile to produce a compound of formula (I). The reaction 2© conditions for (fe) are also described by T. Tsuchiya. et al. in Tet. Letters, No. 36, p. 3365 to 3368 (1978). (c) Reaction of the ehlorosulfate RCH2OSOQ with a metal azide such as sodium azide in a solvent such as methylene chloride or 25 acetonitrile yields an azidosulfate of the formula RCH2OSO2N3 as 5

WO 5§/®0W jPCT/U§97/l©M® described by M. Hedayatullah in Tet. Lett. p. 2455-245S (1975). Th® azidosulfate is then reduced to a compound of formula (1) wherein

Rl is hydrogen by catalytic hydrogenation, e.g. with a noble metal and Hl or by heating with copper metal in a solvent such as \ · 5 methanol.

The starting materials of the formula RCHlOH may be obtained commercially or as known in the art. For example, starting materials ... ... of. the formula RCHlOH wherein both Rl and R3,.and R4 and R5 are 10 identical and are of the formula (Π) 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 RgCORy ketone or aldehyde with fructose af a temperature of about 25° C, in a solvent such a halocarbon, e.g. methylene chloride in th® presence of a protic 15 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. Vol. 38, No. 22, p. 3935 (1973).

Further, carboxylic acids and aldehydes of the formulae RCOOH 20 and RCHO may be reduced to compounds of the formula RCHjOH 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 toy KO. House in "Modem, Synthetic 25 Reactions", 2nd. Ed., pages 45 to 144 (1972). 8 W©»’»223

Th© compounds of formula I: may also be made by th© process disclosed US Patent: N©.4,513,006, which is incorporated by reference

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The compounds of formula I include the various individual isomers as well as the racemates thereof, e.g., th© various alpha and beta attachments, i.e., .below and above the plane of the drawing, of R2s R3? R4 and R5 on the 6-membered ring. Preferably, the oxygens of the methylenedioxy group (II) are attached on the same side of "the-6-membefed""~ring.

Manic-depressive bipolar disorder is a progressive psychiatric disorder of unknown etiology (F. GOODWIN and K.R. JAMISON, Manic-Depressive illness, Oxford University Press, New. York, 1990).; however, recurrences of manic-depressive illness have been hypothesized to be caused by electrophysiologic kindling (F. GOODWIN and K.R. JAMISON, Manic-Depressive Illness, Oxford University Press, New York, pp 405-407, 1990). Topiramate has been shown to be effective in blocking kindled seizures in rats; A. WAUQUIER and S. ZHOU, Epilepsy Res. 2A 73-77, 1996 in press).

For treating manic-depressive bipolar disorder, a compound of formula (I) may be employed at a daily dosage in the range of about 5© to 20© mg, usually in two divided -doses, for an average adult human. A unit dose would contain about 25 to 100 mg of the active 7

I WO 9S/W123

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 5 wide variety of forms depending on the form of preparation desired for administration, e.g., oral, by suppository, or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example,, suspensions, elixirs and solutions, -10— suitable- carriers—and-additives-include water, glycols, .oils, alcohols, flavoring . agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the 15 like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which' case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. Suppositories may be prepared, in which case cocoa '20 butter could be used as the carrier For .parenterals, the carrier will usually comprise sterile water, though other, ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the 25 like may be employed. Topiramate is currently available for oral administration. in - round tablets containing 25 mg, WO mg or 200 mg of active agent. The tablets contain the following inactive ingredients; lactose hydrous, pregelatinized starch, microcrystalline cellulose, 8 W© 98ΛΦ123 1?ΟΤ/Ο§®)7Α©®)4© sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and polysorhafe 80. 5 . The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder injection, teaspoonful, suppository, and the like from about 25 to about 100 mg. of the active ingredient.