MXPA00007627A - Topiramate and related derivatives for treating schizophrenia - Google Patents

Abstract

Topiramate and related derivatives for treating schizophrenia are disclosed in the present application.

Description

TOPLRAMATO AND RELATED DERIVATIVES FOR THE TREATMENT OF SCHIZOPHRENIA BACKGROUND OF THE INVENTION The compounds of formula I: are structurally novel antiepileptic compounds that are highly effective anticonvulsants in animal tests (Maryanoff, BE, Nortey, SO, Gardocki, JF, Shank, RP and Dodgson, SPJ Med. Chem 30, 880-887, 1987; Maryanoff, BE, Costanzo, MJ, Shank, RP, Schupsky, JJ, Ortegon, ME, and Vaught JL Bioorganic &Medicinal Chemistry Letters 3, 2653-2656, 1993). These compounds are covered by the US patent. No. 4,513,006. One such compound, 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulphamate known as topiramate has been shown in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in the treatment of simple and complex partial lesions and generalized secondary lesions (E. FAUGHT, BJ WILDER, RE RAMSEY, RA REIFE, L D. KRAMER, GW PLEDGER, RM KARIM et al., Epilepsy 36 (S4) 33, 1995, SK SACHDEO, RC SACHDEO, RA REIFE, P. LIM and G. PLEDGER, Epilepsy 36 (S4) 33, 1995), and is currently marketed for the treatment of epilepsy of simple and complex partial injury with or without secondary generalized lesions in approximately twenty countries including the United States, and requests for regulatory approval are currently pending in several additional countries throughout the world. The compounds of formula I were initially discovered to possess anticonvulsant activity in the traditional maximal electro shock (MES) test 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, 1994). Subsequent studies revealed that the compounds of formula I were also highly effective in the MES test in rats. More recently, topiramate was found to effectively block lesions in several rodent models of epilepsy (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 inflammatory epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77, 1996). Preclinical studies on topiramate have revealed previously unrecognized pharmacological properties suggesting that topiramate will be effective in the treatment of schizophrenia.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, it has been discovered that the compounds of the following formula I: wherein X is O or CH2, and R1, R2, R3, R4 and R5 are as defined herein below, are useful in the treatment of schizophrenia.

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, R and R5 can be alkene groups bound to form a benzene ring and, when X is oxygen, R2 and R3 and / or R4 and R5 together they can be a methylenedioxy group of the following formula (II): in which R6 and R are the same or different and are hydrogen, lower alkyl or are alkyl and are linked 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. Alkyl by this specification includes straight and branched chain alkyl. The alkyl groups for R2, R3, R4, R5, Re and R7 are from about 1 to 3 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 6-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 formula (I) 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 R are both hydrogen both alkyl or they combine to form a spiro cyclopentyl or cyclohexyl ring, in particular wherein R6 and R7 are both alkyl as methyl. A second group of compounds is in which X is CH2 and * and R5 are linked to form a benzene ring. A third group of compounds of formula (I) is that in which R2 and R3 are hydrogen.

The compounds of formula (I) can be synthesized by 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 potassium a-butoxide or sodium hydride at a temperature of about -20 ° C 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) The reaction of an alcohol of the formula RCH2OH with sulfuryl chloride of the formula SO2CI2 in the presence of a base such as triethylamine or pyridine at a temperature of -40 ° to 25 ° C in a solvent such as diethyl ether or methylene chloride to produce a chlorosulfate of the formula RCH2OSO CI. The chlorosulfate of the formula RCH2OSO2CI can then be reacted with an amine of the formula R1NH2 at a temperature of 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 RCH2OSO2CI with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile affords 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 R-i 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 R2 and R3 and R4 and R5 are identical and are of the formula (II) can be obtained by the method of R. F. Brady in Carbohydrate Research, Vol. 14, p. 35 to 40 (1970) or by reaction of the enol trimethylsilyl ether of a ketone R6COR or aldehyde with fructose at a temperature of 25 ° C, in a solvent such as a halocarbon, for example methylene chloride in the presence of a protic acid such as hydrochloric acid or a Lewis acid such as zinc chloride. The reaction of the enol trimethylsilyl ether is described by G. L. Larson et al in J. Org. Chem. Volaa 38, No. 22, p. 3935 (1973). Additionally, the carboxylic acids and aldehydes of the formulas RCOOH and RCHO can be reduced to compounds of the formula RCH2OH 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 0 ° to 100 ° C, for example as described by HO House in "Modern Synthetic Reactions", 2nd Ed, pages 45 to 144 (1972). The compounds of formula I: can also be manufactured by the process described in 5,378,700, which is incorporated herein by reference. The compounds of formula I include the various individual isomers as well as the racemates thereof, for example, the various alpha and beta adhesions, ie below and above the plane of the drawing, R2, R3, R4 and Rs on the ring of 6 members Preferably, the oxygen of the methylenedioxy group (II) is adhered on the same side of the 6-membered ring. Schizophrenia is a lifelong chronic mental weakness that exhibits several characteristics including positive and negative symptoms, cognitive deficits, which begin at the onset of maturity and the deterioration of the previous level of functioning. Glutaminergic abnormalities have been implicated in the pathophysiology of the disease including the psychotomimetic effects of PCP, a noncompetitive NMDA receptor antagonist (Tamminga CA. Schizophrenia and glutaminergic transmission.Critical reviews in Neurobiology.12 (1-2): 21- 36, 1998). Recent evidence suggests altered densities of glutaminergic AMPA receptor sites in the caudate nucleus in schizophrenia (Noga JT Hyde TM Herman MM Spurney CF Bigelow LB.

Weinberger DR. Kleinman JE. Glutamate receptors in the postmortem striatum of schizophrenic, suicide and control brains, Synapse. 27 (3): 168-76, 1997 Nov.). Neurotransmission of GABA in the prefrontal cortex appears to be upset in schizophrenia (Woo YU.Whitehead RE.Melchitzky DS.LWD.A subclass of Prefrontal gamma-aminobutyric axon termináis are selectively altered in schizophrenia.Proceedings of the National Academy of Sciences of the United States of America 95 (9): 5341-6, 1998 Apr 28). It has also been suggested that GABA might be involved in hypothetical dopamine hyperactivity in schizophrenia (Daniel P. Van Kammen, Gamma-Aminobutyric Acid (Gaba) and the Dopamine Hypothesis of Schizophrenia, Am J Psychiatry 134: 2, 138-143, February 1997). Based on the known improvement of brain GABA activity and reduced glutamate receptor activity of Topiramate (Brown SD, Wolf HH, Swinyard EA, Twyman, RE, White HS, The novel anticonvulsant topiramate enhancers, GABA-medicated chloride flux, Epilepsy 1993: 34 ( Suppl.2): 122, White HS, Brown S, Woodhead JH, Skeen GA, Wolf HH Topiramate enhancers GABA-medicated chloride flux and GABA-evoked currents in mouse brain neurons and increases seizure threshold Epilepsy Res. 1997; 28: 167-179; Coulter DA, Sombati S, DeLorenzo RJ Topiramate effects on excitatory amino acid-medicated responses n Cultured hippocampal neurons: selective blockade of kainate currents Epilepsy 1995: 36 (Suppl 3): S40; Severt L, Gibbs III JW, Coulter DA, Somabati S, DeLorenzo RJ.

Topiramate selectively blocks kainate currents in cultured hippocampal neurons. Epilepsy 1995: 36 (Suppl 4): 38), topiramate is useful in the treatment of schizophrenia. For the treatment of schizophrenia, a compound of formula (I) can be used on a suitable daily dosage scale, but preferably a scale of about 32 to 512 mg, usually in two divided doses, for an average human adult. A unit dose would contain approximately 16 to 128 mg of the active ingredient. To prepare the pharmaceutical compositions of this invention, one or more sulfamate compounds of formula (I) are intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier can take a wide variety of forms depending on the Desired form of preparation for administration, for example, orally, by suppository, or parenterally. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be used. Thus, for oral liquid 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 of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which those solid pharmaceutical carriers are obviously used. If desired, the tablets may be sugar coated or enterically coated by standard techniques. Suppositories can be prepared, in which case the cocoa butter could be used as the vehicle. For parenterals, the carrier will normally comprise sterile water, although other ingredients, for example, for purposes such as assisting solubility or for preservation, may be included. 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, carnuba 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, injection powder, spoonful, suppository and the like of 25 to 200 mg of the active ingredient.

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. A method for the treatment of schizophrenia comprising administering to a mammal afflicted with said condition a therapeutically effective amount for the treatment of said condition of a compound of the formula I: wherein X is CH2 or oxygen; R-i is hydrogen or alkyl; and R2, R3, R4 and 5 are independently hydrogen or lower alkyl and, when X is CH2, -ty R5 can be alkene groups bound to form a benzene ring and, when X is oxygen, R2 and R3 and / or R and R5 together they can be a methylenedioxy group of the following formula (II): 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.

2. The method according to claim 1 further characterized in that the compound of formula I is topiramate.

3. The method according to claim 1, further characterized in that the therapeutically effective amount is 32 to 512 mg.

4. The method according to claim 1, further characterized in that the amount is from 16 to 128 mg.