Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-12-03
2003-10-28
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06638928
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of treatment for irritable bowel syndrome and for nonulcer dyspepsia.
BACKGROUND OF THE INVENTION
2,3-Benzodiazepines
Certain 2,3-benzodiazepines have been explored extensively for their potent CNS modulating activity. Compounds such as tofisopam (Grandaxin®)(structure shown below, with the atom numbering system indicated), girisopam, and norisopam have demonstrated substantial anxiolytic and antipsychotic activity.
Tofisopam has been shown in humans to have an activity profile that is significantly different from that of widely used 1,4-benzodiazepine (BZ) anxiolytics such as diazepam (Valium®) and chlordiazepepoxide (Librium®). The 1,4-benzodiazepines, in addition to having sedative-hypnotic activity, also possess muscle relaxant and anticonvulsant properties which, though therapeutically useful in some disease states, are nonetheless potentially untoward side effects. Thus the 1,4-benzodiazepines, though safe when administered alone, may be dangerous in combination with other CNS drugs, including alcohol.
Tofisopam, in contrast, is a non-sedative anxiolytic that has no appreciable sedative, muscle relaxant or anticonvulsant properties See Horvath el al.,
Progress in Neurobiology,
60 (2000), 309-342, the entire disclosure of which is incorporated herein by reference. In clinical studies, tofisopam improved rather than impaired psychomotor performance and showed no interaction with ethanol (Id.). These observations comport with data that show that tofisopam does not interact with central BZ receptors and binds only weakly to peripheral BZ receptors.
Other 2,3-benzodiazepines that are structurally similar to tofisopam have been investigated and shown to have varying activity profiles. For example, GYKI-52466 and GYKI-53655 (structures shown below) act as noncompetitive glutamate antagonists at the AMPA (&agr;-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) site, and have demonstrated neuroprotective, muscle relaxant and anticonvulsant activity (Id.). Another group of 2,3-benzodiazepines that have been investigated are represented by the compound GYKI-52895, and show activity as selective dopamine uptake inhibitors with potential use in antidepressant and anti-Parkinsonism therapy.
Tofisopam is a racemic mixture of (R)- and (S)-enantiomers. This is due to the asymmetric carbon, i.e., a carbon with four different groups attached, at the 5-position of the benzodiazepine ring.
The structure and conformational properties of tofisopam have been determined by NMR, CD and x-ray crystallography See Visy el al.,
Chirality
1:271-275 (1989), the entire disclosure of which is incorporated herein by reference. The 2,3-diazepine ring exists as two different conformers. The major conformers, (+)R and (−)S have the 5-ethyl group in a quasi-equatorial position. In the minor conformers, (−)R and (+)S, the 5-ethyl group is positioned quasi-axially. Thus, racemic tofisopam may exist as four molecular species, i.e., two enantiomers, each of which exists in two conformations. The sign of the optical rotation is reversed upon inversion of the diazepine ring from one conformer to the other. In crystal form, tofisopam exists only as the major conformations, with dextrorotatory tofisopam being of the (R) absolute configuration. See Toth et al.,
J Heterocyclic Chem.,
20:709-713 (1983); Fogassy et al.,
Bioorganic Heterocycles
, Van der Plas, H. C., Ötvös, L, Simongi, M., eds. Budapest Amsterdam: Akademia; Kiado-Elsevier, 229:233 (1984), the entire disclosures of which are incorporated herein by reference.
Differential binding of these two conformations of tofisopam is reported in binding studies with human albumin See Simongi et al.
Biochem. Pharm.,
32(12), 1917-1920, 1983, the entire disclosure of which is incorporated herein by reference. The two conformers have also been reported as existing in equilibrium See Zsila et al.,
Journal of Liquid Chromatography
&
Related Technologies,
22(5), 713-719, 1999; and references therein, the entire disclosures of which are incorporated herein by reference.
The optically pure (R)-enantiomer of tofisopam (R)-1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine) has been isolated and shown to possess the nonsedative anxiolytic activity of the racemic mixture. See U.S. Pat. No. 6,080,736; the entire disclosure of which is incorporated herein by reference.
Metabolism of Tofisopam
Tofisopam is metabolized in human, rat, dog, monkey and rabbit to one or more of six major metabolites, depending on the host species:
Metabolism of tofisopam
Tofisopam is metabolized in human, rat,
dog, monkey and rabbit to one or more of six
major metabolites, depending on the host species:
Compound #
Compound Name
1
1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-
methoxy-5H-2,3-benzodiazepine
2
1-(3,4-dimethoxyphenyl)4-methyl-5-ethyl-7-methoxy-8
hydroxy-5H-2,3-benzodiazepine
3
1-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7,8-
dimethoxy-5H-2,3-benzodiazepine
4
1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-
dimethoxy-5H-2,3-benzodiazepine
5
1-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-
7-hydroxy-8-methoxy-5H-2,3-benzodiazepine
6
1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-
7-hydroxy-8-methoxy-5H-2,3-benzodiazepine
See Tomori et al.,
Journal of Chromatography,
241 (1982), p. 89-99.
Of the compounds named above, Compounds 1, 3 and 5 have been identified as metabolites in humans. These compounds have been synthesized and tested in certain pharmacological assays. See C. Ito, “Behavioral Pharmacological Study on the Structure Activity Relationship of Benzodiazepine Derivatives: With Particular Reference to the Activity of 2,3-Benzodiazepine,”
J. Tokyo Med. College,
39:369-384 (1981).
In an assay of inhibition of aggression in mice, Compound 1 and 3 showed 0% inhibition of aggression and Compound 5 showed a 28.6% inhibition of aggression. In an assay of muricide (mouse killing behavior) in rats, Compound 3 exhibited 0% inhibition of muricide while Compounds 1 and 5 each exhibited a 20% inhibition of muricide. In assays testing for anti-noradrenergic effects, Compound 1 exhibited no effect, while Compounds 3 and 5 demonstrated measurable activity. See Ito, Id.
Compounds 1, 3, 5 and 6 are also disclosed in U.S. Pat. No. 4,322,346, the entire disclosure of which is incorporated herein by reference. Compound 3 is reported therein to demonstrate narcosis-potentiating activity in mice.
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a common disorder that has a pronounced effect on the quality of life and that accounts for a large proportion of healthcare costs. IBS is defined on the basis of the recently modified Rome criteria as (A) the presence for at least 12 weeks (not necessarily consecutive) in the preceding 12 months of abdominal discomfort or pain that cannot be explained by structural or biochemical abnormalities, and (B) at least two of the following three (1) pain relieved with defecation; (2) pain, when the onset thereof is associated with a change in the frequency of bowel movements (diarrhea or constipation); and pain, when the onset thereof is associated with a change in the form of the stool (lose, watery, or pellet-like). IBS may be divided into four subcategories according to whether the predominant symptom is abdominal pain, diarrhea, constipation, or constipation alternating with diarrhea.
Approximately 15 percent of U.S. adults report symptoms that are consistent with the diagnosis of the IBS; the disease affects three times as many women as men. Whether this difference reflects a true predominance of the disorder among women or merely the fact women are more likely to seek medical care has not been determined. IBS is the most common diagnosis made by gastroenterologists in the United States and accounts for 12 percent of visits to primary care providers. It is estimated that only 25 percent of persons with this condition seek medical care for it, and studies suggest that those who seek care are more likely to have beha
Harris Herbert W.
Kucharik Robert F.
Drinker Biddle & Reath lLLP
Spivack Phyllis G.
Vela Pharmaceuticals, Inc.
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