Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-07-20
2002-12-17
Riley, Jezia (Department: 1656)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S001000, C514S111000, C514S118000, C514S439000, C514S455000, C514S459000, C514S463000
Reexamination Certificate
active
06495523
ABSTRACT:
BACKGROUND OF THE INVENTION
Compounds of formula I:
are structurally novel anticonvulsants (Maryanoff, B. E., Costanzo, M. J., Nortey, S. O., Greco, M. N., Shank, R. P., Schupsky, J. J., Ortegon, M. E., and Vaught, J. L.
J. Med. Chem.
1998, 41, 1315-1343), found to possess anticonvulsant activity in the traditional maximal electroshock seizure (MES) test in mice and rats (Shank, R. P. et al.,
Epilepsia
1994, 35, 450-460). These compounds, covered by U.S. Pat. Nos. 5,242,942 and 5,498,629, are structurally related to 2,3:4,5-bis-O-(1-methylethylidene)-&bgr;-D-fructopyranose sulfamate, topiramate, which 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, and is currently marketed in the United States of America, as well as other countries worldwide.
Recent preclinical studies on compounds of formula I have revealed previously unrecognized pharmacological properties, suggesting that such compounds will be effective in treating certain other neurological disorders. One of these, in particular, is acute ischemia-induced neurodegeneration, such as that which occurs during and after stroke, head trauma, spinal injury, non-fatal cardiac arrest, or major surgical procedures.
SUMMARY OF THE INVENTION
Accordingly, it has been found that anticonvulsant compounds of the following formula I:
wherein X is oxygen or methylene, and R
1
, R
2
, R
3
, R
4
, R
5
, and R
6
are as defined hereinafter, are useful in treating acute ischemia-induced neurodegeneration, such as occurs during and after head trauma, stroke, spinal injury, non-fatal cardiac arrest, or major surgical procedures.
DETAILED DESCRIPTION OF THE INVENTION
The sulfamates of the invention are of the following formula (I):
wherein
X is methylene or oxygen;
R
1
and R
2
are the same or different and chosen from hydrogen, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, benzyl, allyl, or C
1
-C
6
perfluoroalkylmethyl, or taken together as N
2
to define an azide group;
R
3
and R
4
are the same or different and chosen from hydrogen or C
1
-C
6
alkyl;
R
5
and R
6
may be the same or different and are selected from oxygen, a lone pair of electrons or NR
7
; wherein R
7
is selected from hydrogen, C
1
-C
6
alkyl, C
1
-C
6
perfluoroalkyl, arenesulfonyl, C
1
-C
6
alkoxycarbonyl or arenemethyloxycarbonyl.
As used herein alkyl, alkoxy and perfluoroalkyl include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl and n-octyl. Perfluoroalkyl radicals are defined as the previously described straight or branched chain alkyl radicals in which all of the hydrogen atoms have been replaced with fluorine atoms, e.g. trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Arenesulfonyl radicals include, for example, phenylsulfonyl, o-toluenesulfonyl, m-toluenesulfonyl, p-toluenesulfonyl (abbreviated as “Ts”), 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, and 5-dimethylamino-1-naphthalenesulfonyl.
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 R
3
, R
4
, R
5
and R
6
on the 6-membered ring. Preferably, the oxygens of the methylenedioxy group of formula I are attached on the same side of the 6-membered ring.
Cyclic sulfites are designated when either R
5
is oxygen and R
6
is a lone pair of electrons and vice versa. Cyclic sulfates are designated when R
5
and R
6
are both oxygen. Cyclic imidosulfites are designated R
5
is NR
7
and R
6
is a lone pair of electrons and vice versa. Cyclic imidosulfates are designated when R
5
is NR
7
and R
6
is oxygen and vice versa. Cyclic diimidosulfates are designated when R
5
and R
6
both equal NR
7
.
The system of stereodescription developed by Cahn, Ingold and Prelog and described in
Angew. Chem. Int. Ed. Engl.
1966, 5, 385 is used herein to describe the absolute stereochemistry of stereogenic sulfur atoms. For example, the structure of (R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-&bgr;-D-fructopyranose sulfamate is shown below:
Compounds of formula (I) can exist in the &bgr;-D-fructopyranose and the &bgr;-L-fructopyranose absolute configurations. As used herein, the &bgr;-D-fructopyranose absolute configuration is defined as:
and the &bgr;-L-fructopyranose absolute configuration is defined as:
Compounds of formula (I) can also exist in the pseudo-&bgr;-D-fructopyranose and the &bgr;-L-fructopyranose absolute configurations. As used herein, the pseudo-&bgr;-D-fructopyranose absolute configuration is defined as:
and the pseudo-&bgr;-L-fructopyranose absolute configuration is defined as:
A particular group of compounds of formula I is that wherein X is oxygen or methylene; R
1
and R
2
are the same or different and selected from hydrogen, methyl, or ethyl, or different with one equal to hydrogen and the other selected from cyclopropyl or cyclobutyl; R
3
and R
4
are the same or different and selected from hydrogen, methyl, or ethyl; R
5
and R
6
are both oxygen, or one is oxygen and the other a lone pair of electrons.
Preferred compounds of formula (I) are those wherein the compounds are in the &bgr;-D-fructopyranose absolute configuration wherein X is oxygen or methylene; R
1
and R
2
are as defined above; R
3
and R
4
are methyl; R
5
and R
6
are oxygen. Particularly preferred compounds of formula (I) are those in the &bgr;-D-fructopyranose absolute configuration wherein; X is oxygen; R
1
and R
2
are the same or different and selected from hydrogen, methyl, or ethyl, or different with one equal to hydrogen and the other selected from cyclopropyl or cyclobutyl; R
3
and R
4
are the same or different and selected from hydrogen, methyl, or ethyl; R
5
and R
6
are both oxygen, or one is oxygen and the other a lone pair of electrons.
In addition, the compounds of this invention also include any pharmaceutically acceptable salts, for example: alkali metal salts, such as sodium and potassium; ammonium salts; monoalkylammonium salts; dialkylammonium salts; trialkylammonium salts; tetraalkylammonium salts; and tromethamine salts. Hydrates and other solvates of the compound of the formula (I) are included within the scope of this invention.
Examples of specific compounds of formula (I) are:
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-&bgr;-D-fructopyranose sulfamate, i.e. where the compound is in the &bgr;-D-fructopyranose absolute configuration, X is oxygen, R
1
and R
2
are hydrogen, R
3
and R
4
are methyl, R
5
and R
6
are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-&bgr;-L-fructopyranose sulfamate, i.e. where the compound is in the &bgr;-L-fructopyranose absolute configuration, X is oxygen, R
1
and R
2
are hydrogen, R
3
and R
4
are methyl, R
5
and R
6
are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-&bgr;-D-fructopyranose methylsulfamate, i.e. where the compound is in the &bgr;-D-fructopyranose absolute configuration, X is oxygen, R
1
is hydrogen, R
2
is methyl, R
3
and R
4
are methyl, R
5
and R
6
are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-&bgr;-D-fructopyranose butylsulfamate, i.e. where the compound is in the &bgr;-D-fructopyranose absolute configuration, X is oxygen, R
1
is hydrogen, R
2
is n-butyl, R
3
and R
4
are methyl, R
5
and R
6
are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-&bgr;-D-fructopyranose ethylsulfamate, i.e. where the compound is in the &bgr;-D-fructopyranose absolute configuration, X is oxygen, R
1
is hydrogen, R
2
is ethyl, R
3
and R
4
are methyl, R
5
and R
6
are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-&bgr;-D-fructopyranose octylsulfamate, i.e. where the compound is in the &bgr;-D-fructopyranose absolute c
Costanzo Michael J.
Maryanoff Bruce E.
Shank Richard P.
Ortho McNeil-Pharmaceutical, Inc.
Palo Ralph R.
Riley Jezia
LandOfFree
Tricyclic monosaccharide derivatives useful in treating... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tricyclic monosaccharide derivatives useful in treating..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tricyclic monosaccharide derivatives useful in treating... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2918917