Chemistry: fischer-tropsch processes; or purification or recover – Group viii metal containing catalyst utilized for the... – Iron containing catalyst
Reexamination Certificate
1999-02-16
2001-08-14
Krass, Frederick (Department: 1614)
Chemistry: fischer-tropsch processes; or purification or recover
Group viii metal containing catalyst utilized for the...
Iron containing catalyst
C514S974000
Reexamination Certificate
active
06274636
ABSTRACT:
This invention provides a method for using 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, for the treatment of a tic disorder featuring one or more vocal tics.
A tic is a sudden, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalization. A tic is experienced as irresistible but can be suppressed for varying lengths of time. Common simple motor tics include eye blinking, neck jerking, shoulder shrugging, facial grimacing, and coughing. Common simple vocal tics include throat clearing, grunting, sniffing, snorting, and barking. Common complex motor tics include facial gestures, grooming behaviors, jumping, touching, stamping, and smelling an object. Common complex vocal tics include repeating words or phrases out of context, coprolalia (use of socially unacceptable words, frequently obscene), palilalia (repeating one's own sounds or words), and echolalia (repeating the last heard sound, word, or phrase).
Tic disorders are distinguished from compulsions because compulsions are complex and performed in response to an obsession or according to rules that must be applied rigidly. In contrast to a compulsion, tics are typically less complex and are not aimed at neutralizing the anxiety resulting from an obsession.
Often tic disorders can be caused or exacerbated by the use of certain medications which may include antipsychotic agents. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (American Psychiatric Association, 1994) p 101. (Hereinafter, DSM-IV) Surprisingly, Applicant has discovered that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine can be useful for treating tic disorders featuring multiple motor tics and one or more vocal tics; one motor tic and one vocal tic; one motor tic and multiple vocal tics; and for vocal tics. Applicant unexpectedly discovered that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b)][1,5]benzodiazepine can be useful for treating not only movement tics but vocal tics as well.
It is known that the compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine can provide antipsychotic activity and is less likely to induce extrapyramidal symptoms. However, Applicant has discovered that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine can be useful for treating a vocal tic disorder which may feature one or more motor tics as well. The method of use claimed herein may provide the longed for new treatment option for a tic disorder, wherein, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine has demonstrated a favorable safety profile in human clinical trials. 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 tic disorder comprising administering an effective amount of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine or a pharmaceutically accept-able salt thereof to a patient in need of such treatment.
The present invention further provides the use of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine for the manufacture of a medicament for the treatment of a tic disorder.
Additionally, the invention provides a formulation adapted for the treatment of a tic disorder containing 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.
It is preferred that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine is anhydrous Form II.
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 the above compound is 2-methyl-4-(4-methyl-1—piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.
The substantially pure crystalline anhydrous 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
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 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 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 interplaner 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 II associated with <5% Form I; and most preferably it shall refer to <2% Form I. It is further preferred that “substantially pure” shall refer to <0.5% non-Form II polymorph.
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 “tic disorder” or “tic disorders” shall include tic disorders featuring multiple motor tics and one or more vocal tics; one motor tic and one vocal tic; one motor tic and multiple vocal tics; and for vocal tic(s). Examples include, but are not limited to, Transient Tic Disorder, Tourette's Disorder, Chronic Vocal Tic Disorder, and Tic Disorder not otherwise specified as described by DSM-IV, page 101. It is particularly preferred that the term refers to Tourette's Disorder.
The results of pharmacological studies show that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine has muscarinic cholinergic receptor activity. The compound is active at the dopamine D-1 and D-2 receptors as indicated by an IC50 of less than 1 uM in the 3H-SCH233390 (Billard, et al. Life Sciences 35:1885 (1984)) and the 3H spiperone (Seeman, et al. Nature 216:717 (1976)) binding assays respectively. Further, the anhydrous Form II compound is active at the 5-HT-2 receptor and 5-HT1C receptor. The complex pharmacological profile of the compound provides a medicament which can be useful for the treatment of a tic disorder.
In vivo animal and clinical observations support that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine has a complex muscarinic receptor subtype profile. For example, rats exposed to an overdose of the compound surprisingly exhibited significant salivation. Further
Eli Lilly and Company
Krass Frederick
Palmberg Arleen
Vorndran-Jones MaCharri
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