WO2000042995A2

WO2000042995A2 - Use of anticonvulsant derivatives for treating transformed migraine

Info

Publication number: WO2000042995A2
Application number: PCT/US2000/001382
Authority: WO
Inventors: Doreen L. Potter
Original assignee: Ortho-Mcneil Pharmaceutical, Inc.
Priority date: 1999-01-21
Filing date: 2000-01-20
Publication date: 2000-07-27
Also published as: AU3582600A; WO2000042995A3; AR022321A1

Abstract

The use of anticonvulsant derivatives of formula (I) for treating transformed migraine is disclosed. Wherein X is CH2 or oxygen; R1 is hydrogen or C1-C4 alkyl; and R2, R3, R4 and R5 are independently hydrogen or C1-C3 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): wherein R6 and R7 are the same or different and are hydrogen, C1-C3 alkyl or R6 and R7 together with the carbon to which they are attached are joined to form a cyclopentyl or cyclohexyl ring.

Description

ANTICONVULSANT DERIVATIVES USEFUL IN TREATING TRANSFORMED MIGRAINE

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from United States provisional application Serial No. 60/116,544, filed January 21, 1999, the contents of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Compounds of Formula I:

I

are structurally novel antiepileptic compounds that are highly 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, 880-887, 1987; Maryanoff, B.E., Costanzo, M.J., Shank, R.P., Schupsky, J.J., Ortegon, M.E., and Naught J.L. Bioorganic & Medicinal Chemistry Letters 3, 2653-2656, 1993). These compounds are covered by US Patent Νo.4,513,006. One of these compounds 2,3:4,5-bis-O-(l-methylethylidene)-β-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 (E. FAUGHT,

BJ. 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_JS4) 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, J.F., NAUGHT, J.L., DAVIS, C.B., SCHUPSKY, J.J., RAFFA, R.B., DODGSOΝ, S.J., ΝORTEY, S.O., and MARYANOFF, B.E., 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 (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 kindled epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77, 1996).

Transformed migraine is a condition in which migraine sufferers, because of increased analgesic or ergotamine usage, progress to a syndrome of daily headache compounded by habituation and increasing dependence on analgesic medication. It has a separate classification under the guidelines of the International Headache Society ("IHS"). This separate classification has been supported by the Second International Workshop on Headache (Headache Classification Committee of the International Headache Society, Cranial Neuralgias and Facial Pain, Cephalgia 8 (Supp. 7):l-96, 1988). Transformed migraine is distinctly different from chronic tension type headache ("CTTH") in its classification by the IHS. (Headache Classification Committee of the International Headache Society, (Oleson) 1988). Pathophysiologically it is believed that the underlying disorder is up-regulated 5HT receptors. (Srikiatkhachorn et al., Up Regulation of 5HT2 Serotonin Receptor; A Possible Mechanism of Transformed Migraine, Headache 34:8-11, 1994). To emphasize its distinctness from CTTH, the headaches can be readily precipitated using acetazolamide whereas CTTH cannot. (Shirai et al., Acetazolimide Testing of Cerebral Vasodilator Capacity Provokes "Vascular" but not Tension Headaches, Headache 36(10):589-94, 1996).

The classic transformed migraine patient is female (F:M ratio is 3:1) and approximately 35-40 years old with a history of migraine from the teens. The onset of transformation is gradual in 80%, sudden in 20%. The episodes are aggravated by menstruation and ovulation, and analgesic abuse is present in at least 40% of subjects. Classically, the headache wakes the patient from sleep and, as a consequence, 71% have difficulty in initiation and maintenance of sleep. Most take analgesics in anticipation of the onset of the transformed migraine. Currently, treatment is withdrawal of all medication (Mathew et al, Transformed or Evolutive Migraine Headache, Headache 27:102-106, 1987; Mathew, Rebound Headache, American Association for the Study of Headache, Scottsdale Nov. 1998). There may be an increase in the intensity and duration of the headache initially, but this will typically improve over 2 weeks. It may take as long as 8-12 weeks for complete washout to occur. Concomitant prophylactic medications are valuable if the subject discontinues the drug abuse; otherwise, the outlook remains poor for relief. Although the prevalence of transformed migraine is only 1.4 % (CTTH is 2.8 %) (Sher et al., Epidemiology of Frequent Headache, Headache June 1997), it is responsible for 2/3 to 3/4 of the visits to pain clinics (Manzoni et al., Clinical Features of Daily Chronic Headache and its Different Subtypes, Cephalgia l l(Supp 11): 292- 293, 1991). Thus, a need remains to find an effective treatment for transformed migraine.

DISCLOSURE OF THE INVENTION

Accordingly, it has been found that compounds of the following formula I:

wherein X is O or CH2, and Rj, R₂, R₃, R₄ and R₅ are as defined hereinafter are useful in treating transformed migraine.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The sulfamates of the invention are of the following formula (I):

wherein

X is CH2 or oxygen; Rl is hydrogen or - alkyl; and

R2, R3, R4 and R5 are independently hydrogen or CrC₃ 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):

wherein R6 and R7 are the same or different and are hydrogen, Cj-C₃ alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.

Rl in particular is hydrogen or alkyl of about 1 to 4 carbons, such as methyl, ethyl, iso- propyl, n-propyl, n-butyl, isobutyl, sec-butyl and t-butyl. Alkyl throughout this specification includes straight and branched chain alkyl. Alkyl groups for R2, R3, R4, R5, R 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, i.e., R4 and R5 are defined by the alkatrienyl 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 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 (I) is that wherein both R2 and R3 are hydrogen.

A particularly preferred compound for use in the methods of the present invention is 2,3:4,5-bis-O-(l-methylethylidene)-β-D-fructopyranose sulfamate, known as topiramate. Topiramate has the following structural formula

The compounds of formula (I) may 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° to 25° C and in a solvent such as toluene, THF or dimethylformamide wherein R is a moiety of the following formula (III):

(b) Reaction of an alcohol of the formula RCH2OH with sulfurylchloride of the formula SO2CI2 in the 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 chlorosulfate of the formula RCH2OSO2CI.

The chlorosulfate of the formula RCH2OSO2CI may then be reacted with an amine of the formula R1NH2 at a temperature of abut 40° to 25° C in a solvent such as methylene chloride or acetonitrile to produce a compound of 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) Reaction of the chlorosulfate RCH2OSO2CI 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) 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 RCH2OH may be obtained commercially or as known in the art. For example, starting materials of the formula RCH2OH wherein both R2 and R3 and R4 and R5 are identical and are of the formula (II) 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 R6COR7 ketone or aldehyde with fructose at a temperature of about 25° 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 RCH2OH 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 by H.O. House in "Modern Synthetic Reactions", 2nd Ed., pages 45 to 144 (1972).

The compounds of formula I: may also be made by the processes disclosed in U.S. Patent Nos. 4,513,006, 5,387,700 and 5,387,700, all of which are incorporated herein by reference. More particularly, topiramate may be prepared following the process described in Examples 1 to 3 of U.S. 5,387,700.

The compounds of formula I include the various individual isomers as well as the racemates thereof, e.g., the various alpha and beta attachments, i.e., below and above the plane of the drawing, of R2, R3, R4 and R5 on the 6-membered ring. Preferably, the oxygen of the methylenedioxy group (II) are attached on the same side of the 6- membered ring.

The term "transformed migraine," as used herein refers to and includes the conditions known as transformed headache, rebound headache, analgesic rebound headache, ergotamine rebound headache, chronic daily headache, and drug induced headache. The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

The activity of the compounds of formula I in treating tansformed migraine was evidenced in experimental research studies of four patients as indicated in the examples which follow.

For treating transformed migraine, a compound of formula (I) may be employed at a daily dosage in the range of about 15 mg to about 1000 mg, preferably, about 50 mg to about 400 mg, most preferably, about 100 mg to about 300 mg for an average adult human, administered one to four times per day, preferably, one to two times per day. A unit dose typically contains about 25 to about 200 mg of the active ingredient.

In a preferred embodiment of the present invention for treating transformed migraine, topiramate is administered as follows: one 25 mg tablet h.s. for one week then, two 25 mg tablets h.s. for one week then, three 25 mg tablets b.i.d. for one week then, four 25 mg tablets b.i.d.

Patient keeps a migraine calendar and is reevaluated in 4 weeks. If improved, patient is switched to 100 mg tablets bid. If only partial improvement is seen, dose is increased as follows:

One 100 mg tablet in a.m. and two 100 mg tablets h.s. for one week then, two 100 mg tablets b.i.d.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

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 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, 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 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 80.

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 200 mg of the active ingredient. The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

EXAMPLE 1

Four patients (3 females, 1 male) ages 33 to 49 with a history of (intractable headaches (2 rebound, 2 transformed migraine) were placed on therapy with topiramate. Patients were titrated weekly in 25- to 50-mg increments until pain relief or highest tolerated dose of topiramate was achieved. At four week intervals the number of daily headaches reported during the prior four weeks was compared to the number of headaches during the four weeks prior to initiation of topiramate. A Mann- Whitney U Test was used to compare means. Results are provided in Table 1. All four patients reported a decrease in the number of daily headaches, and improvement was significant following treatment with topiramate.

Table 1:

na - not available HA - headache tx - treatment

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

WHAT IS CLAIMED IS:

1. A method for treating transformed migraine in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the formula I:

wherein

X is CH2 or oxygen;

Rl is hydrogen or C C₄ alkyl; and

R2, R3, R4 and R5 are independently hydrogen or d-C₃ 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):

C /°-

R₇ / \ O —

wherein R6 and R7 are the same or different and are hydrogen, d-C₃ alkyl or

R6 and R7 together with the carbon to which they are attached 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 from about 15 mg to about 1000 mg.

4. The method of claim 1, wherein the therapeutically effective amount is from about 100 mg to about 300 mg.

5. The method of claim 1, wherein the compound is administered as a pharmaceutical composition.

6. A method for decreasing the number of daily headaches in a subject suffering from transformed migraine comprising administering to the subject a therapeutically effective amount of a compound of the formula I:

wherein

X is CH2 or oxygen; Ri is hydrogen or Cι-C alkyl; and

wherein R6 and R7 are the same or different and are hydrogen, C₁-C3 alkyl or R6 and R7 together with the carbon to which they are attached are joined to form a cyclopentyl or cyclohexyl ring.

7. The method of claim 6, wherein the compound of formula I is topiramate.

8. The method of claim 6, wherein the therapeutically effective amount is from about 15 mg to about 1000 mg.

9. The method of claim 6, wherein the therapeutically effective amount is from about 100 mg to about 300 mg.

10. The method of claim 6, wherein the compound is administered as a pharmaceutical composition.