Description of Related Art A working definition of migraine is a benign recurring headache and/or neurologic dysfunction, more common in women than men. Classic migraine (migraine with aura) refers to the syndrome of a severe, throbbing headache which often is preceeded by sensory, motor or visual symptoms, referred to as an "aura." Common migraine (migraine without aura) denotes a headache without the aura. Common migraine is the most frequent headache type reported by patients.

Many drugs are now available for prophylactic treatment of migraine. They must be taken daily. The major drugs for prophylaxis are propanolol, amitriptyline, valproate, verapamil, phenelzine, and methysergide. Use of methysergide carries with it the danger of retroperitoneal fibrosis. Aspirin-like drugs , including aspirin, naproxen, ibuprofen, mefenamic acid, flufenamic acid, and tolfenamic acid are in use as prophylactic agents. The high dosage of these compounds required for effectiveness is a drawback. It has been estimated that the probability of success with any one of the available prophylactic antimigraine drugs is about 60 to 75% (Harrison' s Principles of Internal Medicine, eds. Isselbacher et al . , McGraw-Hill, Inc., New York, 1994, p. 69) . Accordingly, development or identification of drugs for prophylactic treatment of migraine is an area of continuing medical need.

SUMMARY OF THE INVENTION The invention features administering sulfamates of the following formula (I) :

wherein X iε O or CH ₂ and R _lf R ₂ , R ₃ , R ₄ , and R ₅ are as hereinafter defined, to prophylactically control migraines in non-epileptic subjects. The most preferred compound is topira ate, described below. Topiramate has been used to treat epileptics, including epileptics who suffer from migraine, to prevent seizures.

The above discussed and other featues and attendant advantages of the present invention will become better understood by reference to the following detailed description of the invention, and from the claims. DETAILED DESCRIPTION

By treating migraine patients with the sulfa ate compound of formula (I) or a pharmaceutically acceptable salt or derivative thereof, a substantial decrease in frequency of migrainous episodes can be achieved. The administered compound is a sulfamate of the following formula:

wherein

X is CH ₂ or oxygen;

R _χ is hydrogen or lower (C-^C _g ) alkyl; and R ₂ , R ₃ , R 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 R3 and/or R ₄ and R ₅ together may be a methylenedioxy group of the following formula (II) :

R ₆ O-

\ / C II

/ \ R ₇ O-

wherein

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,

R i- ⁿ 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 R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are preferably of about 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl. When X is CH ₂ , R and R ₅ may combine to form a benzene ring fused to the 6- membered X-containing ring, i.e., R ₄ and R ₅ are defined by the alkatrienyl group =CH-CH=CH-CH=.

In a particular group of compounds of formula (I) , X is oxygen and both R ₂ and R ₃ and R ₄ and R ₅ together are methylenedioxy groups of the formula (II) wherein R ₆ and R ₇ are both hydrogen, both alkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, in particular where

R _g and R ₇ are both alkyl such as methyl. A second group of compounds is that wherein X is CH ₂ and R and R ₅ are joined to form a benzene ring. A third group of compounds of formula (I) iε that wherein both R ₂ and R ₃ are hydrogen.

Compounds of formula I which are preferred for uεe in the method of the invention are tetrahydro-2H-pyran- 2-yl)methane εulfamate, 2,3:4,5-bis-0-(l- methylethyldiene)-0-D-fructopyranoεe εulfamate, and 2,3:4,5-bis-0-(1-methylethyldiene)-/3-D-fructopyranoεe methylεulfamate. A most preferred compound is 2,3:4,5- biε-θ-(l-methylethyldiene)-3-D-fructopyranoεe εulfamate, alεo known as topiramate, having the chemical εtructure shown in formula III:

By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable ester or εalt of εuch eεter of the compoundε of formula (I) or any other compoundε which upon adminiεtration to the recipient iε capable of providing (directly or indirectly) a compound of formula (I) or an anti-migraine active metabolite or reεidue thereof.

It will be appreciated by thoεe εkilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivativeε thereof at any of the functional groupε in the compoundε. Of

particular interest are derivatives in which the sulfamate portion is masked by an imidate group that can be removed in a physiological milieu to generate the parent drug, as discloεed in U.S. Patent No. 5,258,402, and incorporated herein by reference. Such derivativeε are commonly known aε prodrugε. Other derivativeε of intereεt include εorbopyranoεe sulfamateε (U.S. Patent No. 5,384,327), fructopyranose cyclic sulfiteε and εulfateε (U.S. Patent No. 5,242,942), and phenylethyl sulfamates (U.S. Patent No. 4,792,569), as well as acetazolamide (U.S. Patent Nos. 2,554,816 and 2,980,679).

It will be appreciated by those skilled in the art that the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position.

Pharmaceutically acceptable εaltε of the compoundε of formula (I) include thoεe derived from pharmaceutically acceptable, inorganic and organic acids and baεeε. Exampleε of εuitable acidε include hydrochloric, hydrobromic, εulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, formic, benzoic, malonic, napthalene-2- εulphonic and benzeneεulphonic acidε. Other acidε εuch as oxalic acid, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining compounds useful in the method of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g. sodium) , alkaline earth metal (e.g. magnesium) ammonium and NR ₄ (where R is C-^ alkyl) salts.

Synthesiε. The anti-migraine εulfamate derivativeε employed in the method of the invention can

be syntheεized according to the methodε diεcloεed in U.S. Patent No. 4,513,006, which iε incorporated by reference. Other methodε well known in the art for preparing the diεclosed sulfamate compounds, precursors, prodrugs, or derivatives thereof are also available, for example, those disclosed in U.S. Patent Nos. No. 5,258,402, 5,384,327, 5,242,942, 4,792,569, 2,554,816 and 2,980,679, all of which are incorporated by reference. Pharmaceutical Compositions. Pharmaceutical compositions of the anti-migraine sulfamate derivatives of the invention can be prepared according to the methods disclosed in U.S. Patent No. 4,513,006, which is incorporated by reference. Treatment and Dosage. The amount of a compound of formula (I) useful for treatment of migraine in non- epileptic subjects will vary not only with the particular compound selected but also with the route of administration, and the age and condtion of the patient treated. In general, suitable doseε are in the range of from about 1/2 to 15 mg/kg body weight per day, preferably in the range of 1 to 10 mg/kg day, moεt preferaby in the range of 1 to 5 mg/kg day. The method of the invention can conveniently adminiεter daily dosageε of compoundε of formula (I) in unit dosageε, for example, containing 50 to 400 mg, conveniently 100 to 200 mg, of active ingredient per unit doεage form. Suitable treatment iε given l or 2 timeε daily, depending upon clearance rate. Accordingly, the desired dose may be preεented in a εingle doεe or aε divided doεeε administered at appropriate intervals, for example as two, three, four or more sub-doεeε per day.

Treatment iε preferably commenced before the onεet of a migraine episode and continued indefinitely.

While it is posεible that, for uεe in the method of the invention, compounds of formula (I) may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation or composition which may further include a pharmaceutically acceptable carrier. The carrier must be ' acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to patient. The following examples are intended to illustrate but not limit the invention. While they are typical, other procedures known to those εkilled in the art may alternatively be uεed to illuεtrate the embodimentε and methodε of the invention. EXAMPLES

EXAMPLE 1 ANTI-MIGRAINE ACTIVITY IN EPILEPTIC PATIENTS The following example fallε outside the scope of the appended claims. Patient 1, an epileptic, εuffered from complex partial seizures and frequent episodeε of migraine, εome of which were temporally related to hiε εeizureε. Seizureε and migraineε were incompletely responsive to large doses of calcium channel blockers added to his anti-epileptic drug regimen. Patient 2 suffered from complex partial seizureε and frequent, εevere migraine episodes, requiring regular use of sumatripan.

Patient 1 took topiramate daily for 18 monthε. Patient 2 took topiramate daily for 10 monthε. Patient 1 used 600 mg/d with subεtantial improvement in migrainouε episodes; his curent dosage is 800 mg/d. Patient 2 uεed 400 mg/d with substantial improvement of her migraine headaches.

Except for one migrainous aura, Patient 1's migraine episodes were nearly completely controlled and

all calcium channel blockerε were able to be withdrawn. Patient 1 did not experience any adverεe effectε from topiramate. Patient 2 had εeveral episodes of basilar migraine without headache in the fifth and sixth months of toprimate use during brief cessation of her propanolol therapy, but was migraine-free thereafter until the tenth month, when she experienced 2 nocturnal generalized tonic clonic seizures, and subsequently died.

After taking 800 mg/d of topiramate, Patient 1 had not experienced any migrainous episodeε. Verapamil, nimodipine, and cimetidine (given to increase verapamil levels) were succesεfully withdrawn. Patient 2 experienced substantially leεε frequent migraine headacheε after taking topiramate 200 mg/d, eliminating the average uεe of 2 adminiεtrationε of sumatriptan per week once she was taking 300 mg/d of topiramate.

EXAMPLE 2 ANTI-MIGRAINE ACTIVITY IN NON-EPILEPTIC PATIENTS

To prevent migraine in non-epileptic patients, an effective amount of a pharmaceutical composition containing a sulfamate of formula (I) , in particular 2,3:4,5-bis-O-(1-methylethyldiene) -β-O-fructopyranose sulfamate (topiramate) is orally administered daily to the patient. The daily dosage is in the range of about 50 mg to 1000 mg for an average adult human. What is claimed is: