Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-01-13
2001-11-20
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S459000, C514S517000
Reexamination Certificate
active
06319903
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., Epilcpsia 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).
Cluster headache is an excruciating painful disorder associated with considerable suffering which is characterized by severe, short duration, unilateral orbital-temporal pain, Ipsilateral autonomic dysfunction and chronobiological disturbances. (A. Kudrow, The pathogenesis of a cluster headache, Curr. Opin. Neurol. 7:278-282, 1994; Headache Classification Committee of the International Headache Society, Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain, Cephalgia S7:1-96, 1988). Although treatment is often successful, some patients have intractable pain. Thus, a need remains for effective treatments for cluster headaches.
Studies on five patients treated with topiramate have revealed previously unrecognized pharmacological properties which suggest that topiramate is effective in treating cluster headaches.
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 cluster headaches.
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 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 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 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 RCH
2
OSO
2
Cl with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile yields an azidosulfate of the formula RCH
2
OSO2N
3
as described by M. Hedayatullah in Tet. Lett. p. 2455-2458 (1975). The azidosulfate is then reduced to a compound of formula (I) wherein R
1
is hydrogen by catalytic hydrogenation, e.g. with a noble metal and H
2
or by heating with copper metal in a solvent such as methanol.
The starting materials of the formula RCH
2
OH may be obtained commercially or as known in the art. For example, starting materials of the formula RCH
2
OH wherein both R
2
and R
3
and R
4
and R
5
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 R
6
COR
7
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 “Modem 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. Pat. Nos. 4,513,006, 5,387,700 and 5,387,700, all of which are incorporated herein by reference. More particularly, topiramat
Carrazana Enrique J.
Wheeler Steve D.
Appollina Mary
Ortho-McNeil Pharmaceutical , Inc.
Peselev Elli
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