Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-11-25
2003-01-14
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S878000, C514S879000
Reexamination Certificate
active
06506746
ABSTRACT:
This invention provides a method of using 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, for the treatment of cognitive dysfunction.
Alzheimer's Disease is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, and judgment. Eventually, a global defect develops that involves all aspects of higher cortical function. Initiative diminishes, and the patient may become distractible. In addition to the decreased cognitive function, specific disturbances of speech, motor activity, and recognition of perceptions may be discernible. Normal personality traits may become exaggerated or caricatured. The initial affective change may be dominated by irritability, with periods of anger and violence. The patient commonly exhibits impoverished thought process and delusions. As the disease progresses uncontrollable agitation commonly develops. To date, Alzheimer's Disease has proven to be incurable.
Palliative treatments to alleviate the symptoms of cognitive dysfunctions of disease processes such as Alzheimer's Disease could improve the quality of life for both the patient and the patient's caregiver. Such treatments could minimize or delay the emergence of symptoms requiring hospitalization or institutional care. Therefore, such treatments are desirable for both health economic purposes and for the enhancement of the quality of life when a cognitive dysfunction is present.
Further, although the cholinergic neurons degenerate, it is characteristic of Alzheimer's Disease that the postsynaptic muscarinic receptors in the forebrain and hippocampus still exist. Muscarinic cholinergic agonists are therefore useful in the treatment of Alzheimer's Disease and in improving the cognitive functions of those afflicted with Alzheimer's Disease.
Surprisingly, and in accordance with this invention, Applicants have discovered that the compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine can be useful for the treatment of a cognitive dysfunction, particularly Alzheimer's Disease. The compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine is known and described in U.S. Pat. No. 5,229,382, herein incorporated by reference in its entirety.
The presently claimed invention provides a method for treating a cognitive dysfunction comprising administering an effective amount of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine to a patient in need of such treatment.
Further, the invention provides a method for the palliative treatment of a cognitive dysfunction comprising administering an effective amount of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine to a patient in need of such treatment. The 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine compound is particularly useful for the palliative treatment of Alzheimer's Disease.
The 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine compound is of the formula
or an acid addition salt thereof. The free base of formula (I) is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.
The substantially pure crystalline anhydrous Form I 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (Form I) has a typical X-ray powder diffraction pattern substantially as follows, using a Sieman's D5000 diffractometer equipped with a copper radiation source, wherein represents the interplaner spacing:
d
I/I
1
10.2689
100.00
8.577
7.96
7.4721
1.41
7.125
6.50
6.1459
3.12
6.071
5.12
5.4849
0.52
5.2181
6.86
5.1251
2.47
4.9874
7.41
4.7665
4.03
4.7158
6.80
4.4787
14.72
4.3307
1.48
4.2294
23.19
4.141
11.28
3.9873
9.01
3.7206
14.04
3.5645
2.27
3.5366
4.85
3.3828
3.47
3.2516
1.25
3.134
0.81
3.0848
0.45
3.0638
1.34
3.0111
3.51
2.8739
0.79
2.8102
1.47
2.7217
0.20
2.6432
1.26
2.6007
0.77
Form II 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (Form II) has a typical X-ray powder diffraction pattern substantially as follows, using a Sieman's D5000 diffractometer equipped with a copper radiation source, wherein d represents the interplaner spacing:
d
I/I
1
9.9463
100.00
8.5579
15.18
8.2445
1.96
6.8862
14.73
6.3787
4.25
6.2439
5.21
5.5895
1.10
5.3055
0.95
4.9815
6.14
4.8333
68.37
4.7255
21.88
4.6286
3.82
4.533
17.83
4.4624
5.02
4.2915
9.19
4.2346
18.88
4.0855
17.29
3.8254
6.49
3.7489
10.64
3.6983
14.65
3.5817
3.04
3.5064
9.23
3.3392
4.67
3.2806
1.96
3.2138
2.52
3.1118
4.81
3.0507
1.96
2.948
2.40
2.8172
2.89
2.7589
2.27
2.6597
1.86
2.6336
1.10
2.5956
1.73
The x-ray powder diffraction patterns set forth herein were obtained with a copper K of wavelength=1.541A. The interplanar spacings in the column marked “d” are in Angstroms. The typical relative intensities are in the column marked “I/I
1
”. The detector was a Kevex silicon lithium solid state detector.
As used herein “substantially pure” shall refer to anhydrous Form I associated with <5% Form II; and most preferably it shall refer to <2% Form II. It is further preferred that “substantially pure” shall refer to <0.5% non-Form I polymorph.
As used herein “substantially pure” shall refer to anhydrous Form I associated with about <5% Form II; and most preferably it shall refer to about <2% Form II. It is further preferred that “substantially pure” shall refer to <0.5% related substances. When the Form I polymorph is formulated as a pharmaceutical composition, “substantially pure” shall preferably refer to about <15% Form II polymorph; more preferably, the term shall refer to about <10% Form II polymorph when the Form I polymorph is formulated as a pharmaceutical, and it is especially preferred that the term shall refer to about <5% Form II polymorph when the substantially pure substance is formulated.
As used herein, the term “2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine” refers to a technical grade of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine when no specific solvate or polymorph is named. Typically, the technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine contains less than about 5% undesired related substances and may be a mixed polymorph. Such technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine usually contains less than about 1% undesired related substances.
The term “crude” refers to a form of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine typically associated with undesired polymorph and/or greater than about 5% undesired related substances. Such crude grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine may contains less than about 1% undesired related substances.
As used herein, the term “mammal” shall refer to the Mammalia class of higher vertebrates. The term “mammal” includes, but is not limited to, a human. The term “treating” as used herein includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established.
As used herein, the term “palliative treatment” shall refer to a treatment designed for the relief of symptoms of cognitive dysfunction, rather than curing the disease. Such symptoms of cognitive dysfunction may include, but are not limited to progressive loss of memory, cognition, reasoning, judgment, aspects of higher cortical function, diminished initiative, excessive distraction, speech, motor activity, recognition of perceptions, exaggerated or caricatured personality traits, irritability, excessive anger, violence, uncontrollable agitation, and delusions. The method of this invention is particularly usefu
Eli Lilly and Company
Krass Frederick
Lentz Nelsen L.
Palmberg Arleen
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