MXPA01004015A - Anticonvulsant derivatives useful in treating alcohol dependency, addiction and abuse. - Google Patents

Abstract

Anticonvulsant derivatives useful in treating alcohol dependency, addiction and abuse are disclosed.

Description

USEFUL ANTICONVULSIVE DERIVATIVES FOR THE TREATMENT OF DEPENDENCY, ADDICTION AND ALCOHOL ABUSE BACKGROUND OF THE INVENTION The compounds of the formula I: They are structurally novel antiepileptic compounds that are very 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, 800-887, 1987; Maryanoff, B.E., Costanzo, M.J., Shank, R.P., Schupsky, J.J., Ortegon, M.E., and Vaught J.L. Bioorganic & Medicinal Chemistry Letters 3, 2653-2656, 1993). These compounds are included in the patent of E.U.A. No. 4,513,006. One of these compounds, 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose stearate, known as topiramate, has been shown in clinical trials of human epilepsy to be effective as adjuvant therapy or as monotherapy to treat seizures simple and complex partial and secondarily generalized seizures (E: FAUGHT, B: J: WILDER, RE, RAMSEY, RA, REIFE, LD KRAMER, G: W: PLEDGER, R: M: KARIM et al., Epilepsy 36 (S4 ) 33, 1995, SKSACHDEO, RC SACHDEO, RA REIFE, P. LIM and G. PLEDGER, Epilepsy 36 (S4) 33, 1995), and is currently distributed for the treatment of simple and complex partial epileptic seizures with or without secondary generalized seizures in approximately 20 countries including the United States and applications for regulatory approval are currently pending in several other countries throughout the world. Initially it was observed that the compounds of formula I possess anticonvulsant activity in the traditional maximum electroshock convulsion test (MES) in mice (SHANK, RP, GARDOCKI, JF, VAUGHT, JL, DAVIS, CB, SCHUPSKY, JJ, RAFFA, RB, DODGSON, SJ, NORTEY, SO, AND MARYANOFF, BE, Epilepsy 35 450-460 Subsequent studies revealed that the compounds of formula I were also very effective in the MES tests in rats.Most recently it was observed that topiramate effectively blocks seizures in various types of epilepsy in rodents (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 induced epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77, 1996) Preclinical studies in topiramate have revealed previously unrecognized pharmacological properties. suggesting that topiramate will be effective in the treatment of addiction n and alcohol abuse.

DESCRIPTION OF THE INVENTION Accordingly, it has been observed that the compounds of the following formula I: wherein X is O or CH2, and R1, R2, R3, R4 and R5 are as defined hereinafter, are useful in the treatment of alcohol addiction and abuse.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The sulfamates of the invention are of the following formula (I): wherein X is CH2 or oxygen; Ri is hydrogen or alkyl; and R2, R3, R4 and R5 are independently hydrogen or lower alkyl and, when X is CH2, R4 and R5 can be alkene groups attached to forming 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 Re 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 isopropyl. The alkyl in this specification includes straight and branched chain alkyl. The alkyl groups for R2, R3, R4, R5, Re and R7 are from about one to three carbons and include methyl, ethyl, isopropyl and n-propyl. When X is CH2, R4 and R5 can be combined to form a benzene ring fused to the six-membered ring containing X, that is, R4 and R5 are defined by the alktrienyl group = C-CH = CH-CH =. A particular group of compounds of the formula (I) is that in which X is oxygen and both R2 and R3 and R4 and R5 together are methylenedioxy groups of the formula (II), wherein Re and R7 are both hydrogen, both alkyl or combine to form a cyclopentyl or cyclohexyl spiro ring in particular when Re and R7 are both alkyl and methyl. A second group of compounds is one in which X is CH2 and R4 and R5 are joined to form a benzene ring. A third group of compounds of the formula (I) is that in which both R 2 and R 3 are hydrogen. The compounds of the formula (I) can be synthesized with the following methods: a) Reaction of an alcohol of the formula RCH2OH with a chlorosulfamate of the formula CISO2NH2 or CISO2NHR1 in the presence of a base such as sodium a-butoxide or sodium hydride a temperature of about -20 ° to 25 ° C and in a solvent such as toluene, THF or dimethylformamide in which R is a portion of the following formula (III): (b) Reaction of an alcohol of the formula RCH 2 H in the presence of a base such as triethylamine or pyridyra 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 RCH2HOSO2CI. The chlorosulfate of the formula RCH HOSO2CI can then be reacted with an amine of the formula R? NH2 at a temperature of about 40 ° to 25 ° C in a solvent such as methylene chloride or acetonitrile to produce a compound of the 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) The reaction of the chlorosulfate RCH2HOSO2CI 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) in which R1 is hydrogen by catalytic hydrogenation, for example 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 can be obtained commercially or as is known in the art. For example, the starting materials of the formula RCH2OH in which both R2 and R3 and R4 and R5 are identical and are of the formula (II) can be obtained by the method of R.F. Brandy in Carbohydrate Research, Vol. 14, p 35 to 40 (1970) or by reaction of the trimethylsilylene ether of a ketone R6COR7 or aldehyde with fructose at a temperature of about 25 ° C, in a solvent such as halocarbon, for example, methylene in the presence of a protic acid such as hydrochloric acid or a Lewis acid such as zinc chloride. The reaction of trimethylsilylene ether is described by G.L. Larson et al in J. Org. Chem. Volaa 38, No. 22, p. 3935 (1973). In addition, the carboxylic acids and aldehydes of the formula RCOOH and RCHO can be reduced to compounds of the formula RCH20H by standard reduction techniques, for example, reaction with lithium aluminum hydride, sodium borohydride or borane-THF complex in an inert solvent as diglyme, THF or toluene at a temperature of about 0 ° to 100 ° C, for example as described by H. O. House in "Modern Synthetic Reactions", 2nd Ed., Pages 45 to 144 (1972). The compounds of the formula I: can also be made by the process described in 5,387,700, which is included by way of reference herein. The compounds of the formula I include several individual isomers as well as their racemates, for example, the various alpha and beta linkages, that is, below and on the drawing plane of R2, R3, R4 and R5 in the 6-membered ring. Preferably, the oxygen of the methylenedioxy group (II) are attached to the same side of the 6-membered ring. The activity of the compounds of the formula I to treat alcohol dependence, addiction and abuse became evident in experimental research studies using a rat intermittent ethanol ingestion (CIÉ) model to induce signs of alcohol withdrawal . Abstinence from substances of abuse such as ethanol is experimentally typified in rodents by anxiety, aggressive behavior, and hyperlocomotion, vocalization, aversion to being touched and susceptibility to seizures (E. Majchrowicz E, Psychopharmacologia 43, 245-254, 1975). Chronic ethanol with repeated abstinence in rats leads to a type condition caused with a persistently increased severity of withdrawal (N. 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 described as the chronic intermittent ethanol (CIÉ) model of drug dependence. In CIÉ animals the hippocampus is in a state of hypoinhibition due to the decrease in the functional properties of the GABAA receptors (M. 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 for attacks induced by pentylenetetrazole (PTZ), and the inhibitory neurotransmitter GABA. In humans, alcohol dependence is due, in part, to changes induced by alcohol in the state of the brain that result in the signs and symptoms of withdrawal similar to those observed in the CIÉ (REF) rats. Therefore in CIE rats there seems to be an adequate model of alcohol dependence in humans. Consequently, compounds that reduce or prevent signs of abstinence in CIÉ rats would be expected to exert similar effects on the signs of abstinence from humans with alcohol dependence. In the study of topiramate using CIÉ rats, the degree of abstinence induced by ethane! it was measured quantitatively by the degree to which the threshold for PTZ-induced attacks was reduced. When topiramate was administered to the ICD rats (40 mg / kg, ip) 1 hour before the PTZ injection into the tail vein, the seizure threshold was considerably higher than for the ICD rats treated with the vehicle. (P <0.05) and was basically the same for control rats treated chronically with saline instead of ethanol (The RW Johnson Pharmaceutical Research Institute Document ID EDMS-USRA- 2321301: 3.0). Therefore, based on the threshold for seizures induced by PTZ as a proxy for signs of ethanol withdrawal, topiramate basically prevented this specific abstinence sign in CIE rats. To treat alcohol dependence, addiction and abuse, a compound of formula (I) may be used at a daily dose on the scale of about 32 to 512 milligrams, generally in two divided doses, for an average adult human. A unit dose would contain approximately 16 to 128 milligrams of the active ingredient. To prepare the pharmaceutical compositions of this invention, one or more sulfamate compounds of the formula (I) are intimately mixed with a pharmaceutical carrier according to the techniques • Conventional drug composition, whose carrier can take a wide variety of forms depending on the form of preparation desired for administration, eg, oral, suppository, or parenteral When preparing the compositions in oral dosage form, they can be used any of the usual pharmaceutical media. 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 powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, agents disintegrants and the like. Due to their easy administration, tablets and capsules represent the most favorable oral dosage form, in which case solid pharmaceutical carriers are obviously used. If desired, the tablets may be coated with sugar or enterics by standard techniques. Suppositories can be prepared, in which case cocoa butter can be used as a carrier. For parenterals, the carrier will generally comprise sterile water, although other ingredients may be included, for example for purposes such as aiding solubility or for its preservation. Injectable solutions can also be prepared in which case suitable stabilizing agents can be used. 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: hydrated lactose, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide and polysorbate 80. The pharmaceutical compositions herein will contain, per dosage unit, for example, tablet, capsule, powder injection, spoonful, suppository and the like of about 25 to about 200 mg of the active ingredient.

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound of the formula I wherein X is CH2 or oxygen; Ri is hydrogen or alkyl; and R, R3, R4 and R5 are independently hydrogen or lower alkyl and, when X is CH2, R4 and R5 can be alkene groups bonded to form a benzene ring and, when X is oxygen, R2 and R3 and / or R4 and R5 together can be a methylenedioxy group of the following formula (II): in which Re and R7 are the same or different and are hydrogen, lower alkyl or are alkyl and join to form a cyclopentyl or cyclohexyl ring, for the manufacture of a medicament for treating dependence, addiction and abuse of alcohol in a mammal.

2. The use according to claim 1, wherein the compound of the formula I is topiramate.

3. The use according to claim 1, wherein the medicament provides from about 32 to 512 mg of the compound of the formula I to the mammal.

4. The use according to claim 1, wherein the medicament provides approtely 16 to 128 mg of the compound of the formula I to the mammal.