Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-15
2001-04-10
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06214867
ABSTRACT:
BACKGROUND OF THE INVENTION
Compounds of Formula 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 Vaught J. L.
Bioorganic & Medicinal Chemistry Letters
3, 2653-2656, 1993). These compounds are covered by U.S. Pat. No. 4,513,006. One of these compounds 2,3:4,5-bis-O-(1-methylethylidene)-&bgr;-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, 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, J. F., VAUGHT, J. L., DAVIS, C. B., SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J., NORTEY, 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).
The conditions known as familial, essential and senile tremor cannot be distinguished on the basis of physiologic and pharmacologic properties. These are in the class of action tremors that oscillate with a frequency of about 4-8 hz, with variable amplitude. The familial form tends to be inherited as an autosomal trait and can begin in childhood, but typically onset is in adulthood and persists for life. If an inheritance pattern is not evident, the tremor is referred to as an essential tremor. Essential tremor also known as benign or idiopathic tremor begins early in adult life and persists. If tremor becomes evident in late life, it is known as a senile tremor. For purposes of the present application, the term “essential tremor” as used hereinafter, shall refer to and include familial, essential and senile tremor.
These are relatively common tremors with an estimated prevalence of 415 per 100,000 for people over age 40. Early on, the tremor may be limited to the upper extremities, particularly noticeable in the hands, but also may present as a nodding or side to side ‘no’ movement of the head. Typically, the tremor involves both head and upper extremities as the patient ages, but the lower extremities are spared. Frequently, the jaw, lips, tongue and larynx can be involved. The voice may quiver similar to that observed for Kathryn Hepburn.
Essential tremor is made worse by stimulants such as caffeine and by anxiety or stressful situations. The term ‘benign’ tremor can be misleading as even slight tremors may be disabling to a surgeon or fine craftsman or a tremor noticeable in public may be socially disturbing.
Treatments for essential tremor are currently available, but are limited due to their side effects and other problems. Alcohol is one of the oldest self-initiated therapies and it has been suggested that this may be a precipitant to alcoholism. Other sedatives are useful, particularly benzodiazepines and barbiturates, but these also have significant abuse potential and can be excessively sedating. Beta-blockers such as propranolol are the most accepted form of therapy but the response is quite variable. Propranolol appears to assist 50% of patients treated but it does not cure the tremor. However, adverse events such as impotence and depression can occur in many patients. The potential for cardiovascular side effects exist, including bradycardia, hypotension, arrhythmia and even cardiac arrest upon withdrawal. As such, beta-blockers must be used with great caution in the elderly. Notably, older patients seem to respond less requiring higher dosages in this population. Stereotactic neurosurgery to destroy a portion of the thalamus has been employed as treatment of last resort. Potential complications of this technique are numerous including difficulty with gait, speech and limb movements. (R. Adams, R. Victor,
Principles of Neurology,
McGraw Hill, 1989). Thus, a need remains for an effective treatment for essential tremor.
It is therefore an object of the invention to identify a method of treating essential tremor in a patient in need thereof. Still another object of the invention is to identify a method of treating essential tremor with fewer of the debilitating side effects present with current therapies.
DISCLOSURE OF THE INVENTION
Accordingly, it has been found that compounds of the following formula I:
wherein X is O or CH
2
, and R1, R2, R3, R4 and R5 are as defined hereinafter are useful in treating essential tremor.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The sulfamates of the invention are of the following formula (I):
wherein
X is CH
2
or oxygen; R
1
is hydrogen or C
1
-C
4
alkyl; and R
2
, R
3
, R
4
and R
5
are independently hydrogen or C
1
-C
3
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):
wherein R
6
and R
7
are the same or different and are hydrogen, C
1
-C
3
alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring.
R
1
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 R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are of about 1 to 3 carbons and include methyl, ethyl, iso-propyl and n-propyl. When X is CH
2
, R
4
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 ═C—CH═CH—CH═.
A particular group of compounds of formula (I) is that wherein 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
6
and R
7
are both alkyl such as methyl. A second group of compounds is that wherein X is CH
2
and R
4
and R
5
are joined to form a benzene ring. A third group of compounds of formula (I) is that wherein both R
2
and R
3
are hydrogen.
A particularly preferred compound for use in the methods of the present invention is 2,3:4,5-bis-O-(1-methylethylidene)-&bgr;-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 RCH
2
OH with a chlorosulfamate of the formula CISO
2
NH
2
or CISO
2
NHR
1
in the presence of a base such as potassium t-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 RCH
2
OH with sulfurylchloride of the formula SO
2
Cl
2
in the presence of a bas
Henley III Raymond
Ortho-McNeil Pharmaceutical , Inc.
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