AU759756B2 - Anticonvulsant derivatives useful in treating alcohol dependency, addiction and abuse - Google Patents

Description

WO 00/23059 PCT/US99/23769 ANTICONVULSANT DERIVATIVES USEFUL IN TREATING ALCOHOL DEPENDENCY, ADDICTION AND ABUSE BACKGROUND OF THE INVENTION Compounds of Formula I: X CH 2

OSO

2

NHR

R,

R2 R4

R

3 are structurally novel antiepileptic compounds that are highly effective anticonvulsants in animal tests (Maryanoff, B.E, Nortey, Gardocki, Shank, R.P. and Dodgson, S.P. J. Med. Chem. 30, 880-887, 1987; Maryanoff, Costanzo, Shank, Schupsky, Ortegon, and Vaught J.L. Bioorganic Medicinal Chemistry Letters 3, 2653-2656, 1993). These compounds are covered by US Patent No.4,513,006. One of these compounds 2,3:4,5-bis-O-(1methylethylidene)-B-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 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, VAUGHT, DAVIS, SCHUPSKY, RAFFA, R.B., DODGSON, NORTEY, and MARYANOFF, 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 NAKAMURA, S. TAMURA, WO 00/23059 PCT/US99/23769 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).

Preclinical studies on topiramate have revealed previously unrecognized pharmacological properties which suggest that topiramate will be effective in treating alcohol addiction and abuse.

DISCLOSURE OF THE INVENTION Accordingly, it has been found that compounds of the following formula I: X CH20SO 2

NHR

R2 R4 R3 wherein X is O or CH2, and Rl, R2, R3, R4 and R5 are as defined hereinafter are useful in treating alcohol addiction and abuse.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIEMENTS The sulfamates of the invention are of the following formula X ,CH20SO 2

NHR

wherein X is CH2 or oxygen; RI is hydrogen or alkyl; and WO 00/23059 PCT/US99/23769 R2, R3, R4 and R5 are independently hydrogen or lower 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): R6\ 7°- R6 0-

C

R7 O0 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, R4 and R5 are defined by the alkatrienyl group =C-CH=CH-CH=.

A particular group of compounds of formula 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 is that wherein both R2 and R3 are hydrogen.

The compounds of formula may be synthesized by the following methods: Reaction of an alcohol of the formula RCH20H with a chlorosulfamate of the formula CISO2NH2 or CISO2NHR1 in the presence of a base such as potassium abutoxide or sodium hydride at a temperature of about -200 to 250 C and in a solvent such as toluene, THF or dimethylformamide wherein R is a moiety of the following formula (III): WO 00/23059 PCT/US99/23769 A CH20SO 2

NHR

R,

R4

R

3 Reaction of an alcohol of the formula RCH20H with sulfurylchloride of the formula SO2C12 in the presence of a base such as triethylamine or pyridine at a temperature of about -40° to 250 C in a solvent such as diethyl ether or methylene chloride to produce a chlorosulfate of the formula RCH20SO2C1.

The chlorosulfate of the formula RCH20SO2C1 may then be reacted with an amine of the formula RINH2 at a temperature of abut 400 to 250 C in a solvent such as methylene chloride or acetonitrile to produce a compound of formula The reaction conditions for are also described by T. Tsuchiya et al. in Tet. Letters, No.

36, p. 3365 to 3368 (1978).

Reaction of the chlorosulfate RCH20SO2C1 with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile yields an azidosulfate of the formula RCH20SO2N3 as described by M. Hedayatullah in Tet.

Lett. p. 2455-2458 (1975). The azidosulfate is then reduced to a compound of formula wherein RI 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 RCH20H may be obtained commercially or as known in the art. For example, starting materials of the formula RCH20H wherein both R2 and R3 and R4 and R5 are identical and are of the formula (II) may be obtained by the method ofR. F. Brady in Carbohydrate Research, Vol. 14, p. 35 to (1970) or by reaction of the trimethylsilyl enol ether of a R6COR7 ketone or aldehyde with fructose at a temperature of about 250 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 RCH20H 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 0

C,

e. g. as described by H. O. House in "Modem Synthetic Reactions", 2nd Ed., pages 45 to 144 (1972).

The compounds of formula I: may also be made by the process disclosed in 5,387,700, which is incorporated by reference herein.

The compounds of formula I include the various individual isomers as well as the racemates thereof, e. the various alpha and beta attachments, i. 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 6membered ring.

According to the present invention, there is provided a method for in treating alcohol dependency, addiction and abuse comprising administering to a mammal afflicted with such condition a therapeutically effective amount for treating such condition of a compound of the formula I:

X

CH

2

OSO

2

NHR

4 R4 3 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 lower 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):

R,

R7 0wherein

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.

The activity of the compounds of formula I in treating alcohol dependency, addiction and abuse was evidenced in experimental research studies using a rat model of chronic intermittent ethanol (CIE) ingestion to induce alcohol withdrawal signs. Withdrawal from abused substances like ethanol is typified experimentally in rodents by anxiety, aggressive behavior, hyperlocomotion, vocalization, aversion to handling, and seizure susceptibility Majchrowicz E, Psychopharmacologia 43, 245-254,1975). Chronic ethanol with repeated withdrawal in rats leads to a kindling-like condition with persistently heightened withdrawal severity Kokka, D. W. Sapp, A. M. Taylor and R. W. Olsen, Alcohol: Clin Exp Res 17, 525-531,1993). This experimentally induced condition has been termed the chronic intermittent ethanol (CIE) model of drug dependence. In CIE animals, the hippocampus is in a state ofhypoinhibition due to a decrease in the functional properties of GABAA receptors Kang, I. Spigelman, D. W. Sapp and R. W. Olsen, Brain Res 709, 221-228,1996). These observations suggest a connection between the effects of chronic intermittent ethanol, a reduced threshold to seizures induced by pentylenetetrazol (PTZ), and the inhibitory neurotransmitter GABA. In humans, alcohol dependency is due, in part, 20 to alcohol induced changes in the state of the brain that result in withdrawal signs and symptoms similar to those observed in CIE rats (REF). Therefore CIE in rats appears to be an appropriate model of alcohol dependency in humans. Consequently, compounds that reduce or prevent withdrawal signs in CIE rats would be expected to exert similar effects on withdrawal signs in humans with alcohol dependency. In the study on topiramate using 25 CIE rats, the degree of ethanol-induced withdrawal was measured *~o WO 00/23059 PCT/US99/23769 quantitatively by the degree to which the threshold for PTZ-induced seizures was reduced. When topiramate was administered to CIE rats (40 mg/kg, 1 hr prior to tail vein injection of PTZ, the threshold for seizures was significantly higher than for CIE rats treated with vehicle (P<0.05) and was essentially the same as for control rats chronically treated with saline rather than ethanol (The R.W. Johnson Pharmaceutical Research Institute Document ID EDMS-USRA-2321301:3.0). Therefore, based on the threshold for PTZ-induced seizures as representative of ethanol withdrawal signs, topiramate essentially prevented this specific withdrawal sign in CIE rats.

For treating alcohol dependency, addiction and abuse, a compound of formula may be employed at a daily dosage in the range of about 32 to 512 mg, usually in two divided doses, for an average adult human. A unit dose would contain about 16 to 128 mg of the active ingredient.

To prepare the pharmaceutical compositions of this invention, one or more sulfamate compounds of formula 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, 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, 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 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 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 solutions may also be prepared in which case appropriate stabilizing agents may be employed. Topiramate is currently available for oral administration in round tablets containing 25 mg, 100 mg or 200 mg WO 00/23059 PCT/US99/23769 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 The pharmaceutical compositions herein will contain, per dosage unit, tablet, capsule, powder injection, teaspoonful, suppository and the like from about 25 to about 200 mg of the active ingredient.

Claims (4)

1. A method for treating alcohol dependency, addiction and abuse comprising administering to a mammal afflicted with such condition a therapeutically effective amount for treating such condition of a compound of the formula I: X 2 NHR R, R2 R4 R3 wherein X is CH 2 or oxygen; RI is hydrogen or alkyl; and R 2 R 3 R 4 and R 5 are independently hydrogen or lower 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 R4 and R 5 together may be a methylenedioxy group of the following formula (II): R6 R7 0- R7 wherein R6 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.

2. The method of claim 1 wherein the compound of formula I is topiramate.

3. The method of claim 1, wherein the therapeutically effective amount is of from about 32 to 512 mg. 20

4. The method of claim 1, wherein the amount is from about 16 to 128 mg. A method according to any of one of the preceding claims for treating alcohol %ooo: 3dependency, addiction and abuse substantially as hereinbefore described.