Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-15
2002-07-16
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S454000, C514S455000, C514S456000, C514S459000, C514S601000
Reexamination Certificate
active
06420369
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).
Dementia is a mental disorder characterized by general impairment of intellectual functioning including memory, orientation, perception, language, alteration in mood and affect and impairment of judgment and abstraction. There may be marked change in personality and behavior.
Dementia is diagnosed according to its etiology, the two most common (among multiple etiologies) being: Alzheimer's dementia and Vascular dementia. Alzheimer's dementia, which accounts for 50-60% of dementias, is a progressive dementia in which all known reversible causes have been ruled out. Vascular dementia is dementia of cerebrovascular origin which progresses in a stepwise fashion. Dementia is generally progressive and irreversible unless the etiology is treatable (10%).
The clinical course of dementia may show “primary” or cognitive symptoms as well as “secondary or behavioral symptoms.” That is, patients with dementia (DSM IV) often exhibit troublesome and disruptive behaviors and symptoms of psychosis in addition to the cognitive impairments, presenting difficult management problems for both caregivers and healthcare providers. These include aggressive, non aggressive and verbally agitated behaviors (Cohen-Mansfield J. Marx M S. Rosenthal A S. Dementia and agitation in nursing home residents: how are they related? Psychology and aging. 5(1): 3-8,1990 March). Partial pharmacologic management of these behaviors include antipsychotics, benzodiazepines, beta-blockers, SSRI antidepressants and anticonvulsants (Yudofsky S C. Silver J M. Hales R E. Pharmacologic management of aggression in the elderly. Journal of Clinical Psychiatry. 51 Suppl: 22-8; discussion 29-32, 1990 October).
Both carbamazepine (Tariot P N, Erb R, Podgorski C A. Cox C. Patel S. Jakimovich L. Irvine C. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. American Journal of Psychiatry. 155(1): 54-61, 1998 January) and divalproex sodium (Kasckow, John W.; Mcelroy, Susan L.; Cameron, Renee L.; Mahler Leslie L.; Fudala Stanley J.; Curr. Ther. Res. (1997), 58(12), 981-989) have been shown to be efficacious in controlling behavioral agitation in some patients with dementia. Thus based on it's wider mode of action and in particular upon its GABA enhancing activity and the kainate/AMPA receptor inhibition of topiramate, we propose topiramate will be effective in the treatment of agitation and aggression in dementia. Indeed, this was the case in patients with dementia treated with the drug.
It is therefore an object of the invention to identify a method of treating dementia in a patient in need thereof. Still another object of the invention is to identify a method of treating behavioral and psychotic disturbances in dementia in a patient in need thereof.
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 dementia and/or behavioral and psychotic disturbances in dementia.
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 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 RCH
2
OSO
2
Cl.
The chlorosulfate of the formula RCH
2
OSO
2
Cl may then be reacted with an amine of the formula R
1
NH
2
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 reacti
Appollina Mary
Fonda Kathleen K.
Maier Leigh C.
Ortho-McNeil Pharmaceutical , Inc.
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