Method for treating nicotine withdrawal

The invention provides a method for treating a condition resulting from the cessation and withdrawal of nicotine comprising administering an effective amount of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!-benzodiazepine.

FIELD OF THE INVENTION 
This invention provides a method for using 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!-benzodiazepine, 
for the treatment nicotine withdrawal and alleviation of the craving for a 
tobacco product. 
BACKGROUND OF THE INVENTION 
Over 25 years ago, the Surgeon General issued a report linking cigarette 
smoking to cancer, heart disease, respiratory disease and other 
conditions. Despite such information being available to the public, 
cigarette smoking remains a significant preventable cause of death in the 
United States and other developed countries. 
Benowitz, N. Eng. J. Med. 319:20, 1318-1330 (Nov. 17, 1988) notes that many 
people who smoke cigarettes would like to quit but cannot because they are 
addicted to the psychoactive drug that is the dependence-producing 
constituent of tobacco, nicotine. 
Benowitz notes that nicotine may also contribute to the diseases for which 
smoking is a risk factor, particularly heart disease. Nicotine is also 
present in other tobacco products that are smoked or chewed, which are 
also addictive and associated with heart, lung, and other serious disease 
states. 
Pharmacologic therapies are known to help those addicted to nicotine. 
Receptor antagonists such as mecamylamine have been used to reduce the 
satisfaction obtained from tobacco use. Unfortunately, this therapy has 
the short term effect of increasing tobacco consumption to overcome the 
receptor antagonism as well as other undesirable side effects. 
Non-receptor antagonists have also been used, such as clonidine to reduce 
the craving for tobacco and other tobacco related withdrawal symptoms. 
According to Benowitz, one recent study using clonidine treatment for six 
weeks was found to be more effective than placebo, but only for women. 
Benowitz reports that the most effective treatment thus far has been 
nicotine substitution therapy, using nicotine gum, or other nicotine forms 
to slowly wean individuals from the addiction to nicotine and the tobacco 
products containing nicotine. Unfortunately, the nicotine substitution 
therapy involves the administration of the psychoactive constituent of 
tobacco which has been identified as a contributor to the diseases 
associated with smoking. Nicotine substitution must be tapered, frequently 
leading to nicotine withdrawal and subsequent relapse to smoking. There is 
a need for a therapy having a desirable side effect profile, to relieve 
nicotine withdrawal symptoms, including the long term cravings for 
nicotine. 
It is known that the compound 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
can provide antipsychotic activity and is less likely to induce 
extrapyramidal symptoms. Surprisingly, Applicant has discovered that 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
can be useful for treating a condition which is a response produced by 
cessation and withdrawal from the use of nicotine. The compound 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!-benzodiazepine 
is known and described in U.S. Pat. No. 5,229,382, herein incorporated by 
reference in its entirety. 
SUMMARY OF THE INVENTION 
The presently claimed invention provides a method for treating a condition 
which is a response produced by cessation and withdrawal from the use of 
nicotine, comprising administering an effective amount of 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
or a pharmaceutically acceptable salt thereof to a patient in need of such 
treatment. 
DETAILED DESCRIPTION OF THE INVENTION 
The 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine c 
ompound is of the formula 
##STR1## 
or an acid addition salt thereof. The free base of formula (I) is 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
The substantially pure crystalline anhydrous Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-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 interplanar spacing: 
______________________________________ 
d I/I.sub.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-thieno2,3-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 interplanar spacing: 
______________________________________ 
d I/I.sub.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.sub.1 ". The detector was a Kevex silicon lithium solid 
state detector. 
As used herein "substantially pure" shall refer to anhydrous Form I 
associated with&lt;5% Form II; and most preferably it shall refer to&lt;2% Form 
II. It is further preferred that "substantially pure" shall refer to&lt;0.5% 
non-Form I polymorph. 
When the Form I polymorph is formulated as a pharmaceutical composition, 
"substantially pure" shall preferably refer to about&lt;15% Form II 
polymorph; more preferably, the term shall refer to about&lt;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&lt;5% Form II 
polymorph when the substantially pure substance is formulated. 
As used herein, the term 
"2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine" 
refers to a technical grade of 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
when no specific solvate or polymorph is named. Typically, the technical 
grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-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-thieno2,3-b!1,5!benzodiazepine 
may contain less than about 1% undesired related substances. 
The term "crude" refers to a form of 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-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-thieno2,3-b!1,5!benzodiazepine 
may contain 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 "nicotine withdrawal" or "cessation and withdrawal 
from the use of nicotine" shall refer to a condition resulting from 
discontinued consumption of tobacco products and consequently, a result of 
discontinued consumption of nicotine. Such nicotine withdrawal conditions 
are characterized in the DSM-IV-R. Diagnostic and Statistical Manual of 
Mental Disorders, Revised, 3rd Ed. (1994). The DSM-IV-R was prepared by 
the Task Force on Nomenclature and Statistics of the American Psychiatric 
Association, and provides clear descriptions of diagnostic catagories. The 
skilled artisan will recognize that there are alternative nomenclatures, 
nosologies, and classification systems for pathologic psychological 
conditions and that these systems evolve with medical scientific progress. 
Therefore, the term "cessation and withdrawal from the use of nicotine" 
shall include, but is not limited to, the following conditions 
characterized in the DSM-IV-R: Nicotine Withdrawal; Nicotine-Related 
Disorder Not otherwise Specified; Nicotine Dependence, with physiological 
dependence; Nicotine Dependence, without physiological dependence; 
Nicotine Dependence, Early Full Remission; Nicotine Dependence, Early 
Partial Remission; Nicotine Dependence, Sustained Full Remission; and 
Nicotine Dependence, Sustained Partial Remission; Nicotine Dependence, On 
Agonist Therapy. 
The discontinued use of tobacco products, all of which contain nicotine, 
results in the onset of nicotine withdrawal syndrome. Individuals 
typically suffer the symptoms of nicotine withdrawal resulting from the 
discontinued use of tobacco in any form, including, but not limited to 
smoking of cigarette, cigar, or pipe tobacco, or the oral or intranasal 
ingestion of tobacco or chewing tobacco. Such oral or intranasal tobacco 
includes, but is not limited to snuff and chewing tobacco. The cessation 
of nicotine use or reduction in the amount of nicotine use, is often 
followed within 24 hours by dysphoric, depressed mood; insomnia; 
irritability, frustration or anger; anxiety; difficulty concentrating; 
restlessness; decreased heart rate; increased appetite or weight gain. 
These symptoms often cause clinically significant distress or impairment 
in social, occupational, or other important areas of functioning. The 
present invention is most preferably used to alleviate symptoms attributed 
to nicotine withdrawal when such symptoms are not due to a general medical 
condition and are not better accounted for by another medical disorder. 
The method of the present invention is preferably administered in 
connection with and/or subsequent to an educational and/or behavioral 
modification program to ensure continued abstinence from tobacco products. 
The method of the present invention is also highly beneficial to such 
programs by alleviating the suffering experienced from the nicotine 
withdrawal over the course of such programs. Therefore, the programs can 
be more effective by focusing on educational and behavioral modification 
goals, further reducing the incidence of program non-completion. 
Although the method of this invention is effective for any individual in 
need of treatment for the cessation and withdrawal of smoking, it may be 
particularly beneficial to use the method of this invention for an 
individual suffering from schizophrenia. 
The results of pharmacological studies show that 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-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 .sup.3 H-SCH233390 (Billard, et al. Life Sciences 35:1885 
(1984)) and the .sup.3 H spiperone (Seeman et al Nature 216:717 (1976)) 
binding assays respectively. Further, the anhydrous Form I compound is 
active at the 5-HT2 receptor and 5-HT1C receptor. The complex 
pharmacological profile of the compound provides a medicament which can be 
useful for the treatment of a condition resulting from cessation and 
withdrawal from the use of nicotine. 
In vivo animal and clinical observations support that 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-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, clinical subjects experienced pupilary constriction 
rather than the expected pupilary dilation. 
The usefulness of the compound for treating a condition resulting from 
cessation and withdrawal from the use of nicotine can be supported by the 
following study. 
I. Auditory Startle Response. 
Male Long Evans rats (Harlan Sprague Dawley) are individually housed in a 
controlled environment on a 12 hour light-dark cycle. The rats are given 
free access to food and water. All treatment groups contain from 8 to 10 
rats. 
The rats are anesthetized with halothane and Alzet osmotic minipumps (Alza 
Corporation, Palo Alto, Calif.) are implanted subcutaneously. Nicotine 
ditartrate is dissolved in physiological saline. Pumps are filled with 
nicotine ditartrate (6 mg/kg base/day) or the appropriate vehicle. Twelve 
days following implantation of pumps, rats are anesthetized with halothane 
and the pumps are removed. 
The auditory Startle Response is observed. 
The sensory motor reactions auditory startle response (peak amplitude, 
V.sub.max)! of individual rats are recorded using San Diego Instruments 
startle chambers (San Diego, Calif.). Startle sessions consist of a 5 
minute adaptation period at background noise level of 70.+-.2dBA 
immediately followed by 25 presentations of auditory stimuli (120.+-.3 dBA 
noise, 50 ms duration) presented at 8 second intervals. Peak startle 
amplitudes are averaged for all 25 presentations of stimuli for each 
session. Auditory startle responding is evaluated daily at 24 hour 
intervals on days 1-4 following nicotine withdrawal. 
The 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine c 
ompound is administed at six doses about 60 minutes before startle testing 
each day. 
The compound 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
can be used for the methods of this invention, both in its free base and 
acid addition salt forms. The acid addition salts are preferably the 
pharmaceutically acceptable, non-toxic addition salts with suitable acids, 
such as those of inorganic acids, for example hydrochloric, hydrobromic, 
nitric, sulfuric or phosphoric acids, or of organic acids, such as organic 
carboxylic acids, for example glycollic, maleic, hydroxymaleic, fumaric, 
malic, tartaric, citric or lactic acid, or organic sulfonic acids for 
example methane sulfonic, ethane sulfonic, 2-hydroxyethane sulfonic, 
toluene-p-sulfonic or naphthalene-2-sulfonic acid. 
The compound 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
can be prepared using a process which comprises 
(a) reacting N-methylpiperazine with a compound of the formula 
##STR2## 
in which Q is a radical capable of being split off, or 
(b) ring-closing a compound of the formula 
##STR3## 
Appropriate reaction conditions and suitable values of Q can readily be 
chosen for these processes. 
In reaction (a) the radical Q can, for example, be an amino group or a 
mono- or dialkyl-substituted amino group (each alkyl substituent suitably 
containing 1 to 4 carbon atoms), hydroxyl, thiol, or an alkoxy, alkylthio 
or alkylsulfonyl group suitably containing 1 to 4 carbon atoms, for 
example a methoxy or methylthio group, or a halogen atom, especially a 
chlorine atom. Preferably, Q is amino (--NH.sub.2), hydroxyl or thiol, and 
amino is most preferred. The reaction is preferably carried out at a 
temperature of from 50.degree. C. to 200.degree. C. 
When Q is amino, the intermediate of formula (II) may also exist in the 
imino form: 
##STR4## 
and when Q is hydroxyl or thiol, the intermediates of formula (II) may 
exist in their amide and thioamide forms: 
##STR5## 
The amidine of formula (II) (Q is --NH.sub.2), can be in salt form, for 
example a salt of a mineral acid such as the hydrochloride, and can be 
reacted with N-methylpiperazine in an organic solvent such as anisole, 
toluene, dimethylformamide or dimethylsulfoxide, preferably at a 
temperature range of 100 to 150.degree. C. 
The amidine is prepared by condensing a thiophene compound of formula 
##STR6## 
with an ortho-halonitrobenzene, in the presence of a base, for example 
sodium hydride, in a solvent such as tetrahydrofuran or n-butyl lithium in 
tetrahydrofuran, or potassium carbonate or lithium hydroxide in 
dimethylsulfoxide or aqueous sodium hydroxide in dimethylsulfoxide, or 
with a tetraalkyl-ammonium salt in a two-phase system, to form a 
nitronitrile of formula: 
##STR7## 
which can be simultaneously reduced and ring-closed to the amidine of 
formula (II) employing, for example, stannous chloride and hydrogen 
chloride in aqueous ethanol or, alternatively by reduction with hydrogen 
and palladium/carbon or ammonium polysulfide followed by acid-catalyzed 
ring closure. The intermediate of formula (IIa) may be isolated using 
ammonium chloride (NH.sub.4 Cl) or ammonium acetate (NH.sub.4 OAc). 
When Q is hydroxyl, reaction (a) is preferably carried out in the presence 
of titanium tetrachloride which has the ability to react with the 
N-methylpiperazine to form a metal amine complex. Other metal chlorides 
such as those of zirconium, hafnium or vanadium may also be employed. The 
reaction can be carried out in the presence of an acid binding agent such 
as a tertiary amine, for example, triethylamine. 
Alternatively, the reaction can be carried out using excess of 
N-methylpiperazine to act as an acid-binding agent. A suitable organic 
solvent such as toluene or chlorobenzene can be used as a reaction medium, 
although the use of anisole is particularly desirable, at least as a 
co-solvent, in view of its ability to form a soluble complex with 
TiCl.sub.4. 
If desired, elevated temperatures, for example up to 200.degree. C., can be 
used to hasten the reaction and a preferred temperature range for carrying 
out the reaction is from 80.degree. C. to 120.degree. C. 
The intermediate amide of formula (II) (Q is --OH) can be prepared from the 
corresponding amidine (Q is --NH.sub.2) by alkaline hydrolysis, or can be 
derived from compounds of formula 
##STR8## 
in which R is an ester group, preferably C.sub.1-4 alkyl, by ring closure 
employing, for example, sodium methylsulfinyl methanide in a suitable 
solvent such as dimethylsulfoxide. Alternatively, the amide can be 
prepared by ring closure of an amino-acid, employing for example 
dicyclohexylcarbodiimide (DCC) in a suitable solvent such as 
tetrahydrofuran. The amino-acid can be obtained for example from the above 
esters by basic hydrolysis using for example sodium hydroxide in ethanol. 
Thioamides of formula (II) (Q is --SH), iminothioethers, iminoethers or 
iminohalides, or other derivatives containing active Q radicals as 
specified above, tend to be more reactive towards N-methylpiperazine and 
can usually be reacted without the necessity for the presence of 
TiCl.sub.4, but otherwise employing the same conditions of temperature and 
solvent. 
The thioamide of formula (II) (Q is --SH) can be prepared by treating a 
solution of the corresponding amide in an anhydrous basic solvent, such as 
pyridine, with phosphorous pentasulfide. Similarly, the amide can be 
converted to the iminothioether, iminoether or iminohalide, or other 
derivatives containing active Q radicals, by treatment with conventional 
reagents such as for example in the case of the iminochloride, phosphorous 
pentachloride. 
The intermediate compounds of formula (II) in which Q is a radical capable 
of being split off, particularly those in which Q is --NH.sub.2, --OH or 
--SH and when Q is --NH.sub.2 salts thereof, are novel compounds, and form 
a further aspect of the present invention. 
With regard to reaction (b) above, the compound of formula (III) may be 
ring-closed by employing, for example, titanium tetrachloride as catalyst 
and anisole as solvent, and the reaction is preferably carried out at a 
temperature of 100.degree. C. to 250.degree. C., for example from 
150.degree. C. to 200.degree. C. 
The intermediate compound of formula (III) is preferably prepared in situ 
without isolation by reacting a compound of formula 
##STR9## 
in which R is an ester group, preferably C.sub.1-4 alkyl, with 
N-methylpiperazine, by heating to a temperature of between 30.degree. C. 
and 120.degree. C., for example about 100.degree. C., in a suitable 
solvent such as for example anisole, and employing TiCl.sub.4 as catalyst. 
The compound of formula (IV) can be prepared from the corresponding nitro 
compound of formula 
##STR10## 
Such compounds of formula (V) in which R is an ester group, such as for 
example C.sub.1-4 alkyl, are novel and form a further aspect of the 
invention. 
If convenient this nitro compound can be converted to the amine of formula 
(IV) without isolation, before reaction with N-methylpiperazine. 
Intermediate compounds of formula (V) can be made by condensation of a 
thiophene of formula 
##STR11## 
with an ortho-halonitrobenzene, preferably ortho fluoro- or chloro- 
nitrobenzene, in the presence of a base, for example, (a) sodium hydride 
in a solvent such as for example tetrahydrofuran and at a temperature of 
from -20.degree. C. to 30.degree. C., or (b) anhydrous potassium carbonate 
or lithium hydroxide in a solvent such as dimethylsulfoxide at a 
temperature of from 90.degree. C. to 120.degree. C. The compound of 
formula (V) is converted to that of formula (IV) by reduction, for example 
catalytically, employing hydrogen and palladium/carbon, or chemically, 
employing stannous chloride and hydrogen chloride in aqueous ethanol, or 
ammonium polysulfide, or zinc in aqueous ammonium chloride. 
It will be appreciated that the compound of formula (I) may be isolated per 
se or may be converted to an acid addition salt using conventional 
methods. 
The compound has an IC.sub.50 of less than 1 mM in the .sup.3 H-QNB binding 
assay described by Yamamura, HI and Snyder, SH in Proc.Nat.Acad.Sci. USA 
71 1725 (1974) indicating that it has muscarinic-cholinergic activity. 
The 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-2,3-b!1,5!benzodiazepine 
compound is effective over a wide dosage range, the actual dose 
administered being dependent on the condition being treated. For example, 
in the treatment of adult humans, dosages of from about 0.25 to 50 mg, 
preferably from 1 to 30 mg, and most preferably 1 to 20 mg per day may be 
used. A once a day dosage is normally sufficient although divided doses 
may be administered. For treatment of a condition resulting from cessation 
and withdrawal from the use of nicotine, a dose range of from 1 to 30 mg, 
preferably 1 to 20 mg per day is suitable. Radiolabelled 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-2,3-b!1,5!benzodiazepine, 
can be detected in the saliva and thus the compound can potentially be 
monitored in patients to assess compliance. 
A preferred formulation of the invention is a solid oral formulation 
comprising from about 1 to about 20 mg or 1 to 10 mg of active anhydrous 
Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
as an effective amount of the active ingredient. 
Most preferably, the solid oral formulation is contained in packaging 
materials which protect the formulation from moisture and light. For 
example, suitable packaging materials include amber colored high density 
polyethylene bottles, amber colored glass bottles, and other containers 
made of a material which inhibits the passage of light. Most preferably, 
the packaging will include a desiccant pack. The container may be sealed 
with an aluminum foil blister to provide the desired protection and 
maintain product stability. 
The 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-2,3-b!1,5!benzodiazepine 
compound will normally be administered orally or by injection and, for 
this purpose, it is usually employed in the form of a pharmaceutical 
composition. 
Accordingly, pharmaceutical compositions comprising 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine, 
as active ingredient associated with a pharmaceutically acceptable carrier 
may be prepared. In making the compositions of the invention conventional 
techniques for the preparation of pharmaceutical compositions may be used. 
For example, the active ingredient will usually be mixed with a carrier, 
or diluted by a carrier, or enclosed within a carrier which may be in the 
form of a capsule, sachet, paper or other container. When the carrier 
serves as a diluent, it may be solid, semi-solid or liquid material which 
acts as a vehicle, excipient or medium for the active ingredient. The 
active ingredient can be adsorbed on a granular solid container for 
example in a sachet. Some examples of suitable carriers are lactose, 
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium 
phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, 
methyl- and propyl-hydroxy-benzoate, talc, magnesium stearate or mineral 
oil. The compositions of the invention may, if desired, be formulated so 
as to provide quick, sustained or delayed release of the active ingredient 
after administration to the patient. For example, one such preferred quick 
release formulation is described in U.S. Pat. Nos. 5,079,018, 5,039,540, 
4,305,502, 4,758,598, and 4,371,516, hereby incorporated by reference. 
Such formulation most preferably comprises 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine, 
water, hydrolyzed gelatin, and mannitol. 
Depending on the method of administration, the compositions for the 
treatment of central nervous system conditions may be formulated as 
tablets, capsules, injection solutions for parenteral use, gel or 
suspension for transdermal delivery, suspensions or elixirs for oral use 
or suppositories. Preferably the compositions are formulated in a unit 
dosage form, each dosage containing from 0.25 to 100 mg, more usually 1 to 
30 mg, of the active ingredient. When a sustained release formulation is 
desired, the unit dosage form may contain from 0.25 to 200 mg of the 
active ingredient. A preferred formulation of the invention is a capsule 
or tablet comprising 0.25 to 75 mg or 1 to 30 mg of active ingredient 
together with a pharmaceutically acceptable carrier therefor. A further 
preferred formulation is an injection which in unit dosage form comprises 
0.25 to 30 mg or 1 to 30 mg of active ingredient together with a 
pharmaceutically acceptable diluent therefor. 
The materials for the present invention can be purchased or prepared by a 
variety of procedures well known to those of ordinary skill in the art. 
The 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepi 
ne compound can be prepared as described by Chakrabarti in U.S. Pat. No. 
5,229,382 ('382), herein incorporated by reference in its entirety. It is 
most desirable to prepare a rapidly dissolving formulation comprising 
substantially pure crystalline Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
Such substantially pure crystalline Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
may be prepared using the techniques described herein by the Preparation 
section herein infra. 
As used herein mixing steps may be accomplished using common agitation 
methods such as stirring, shaking, and the like. As used herein the phrase 
"producing crystalline product from the mixture" shall refer to 
crystallization from the stated mixture of compound and solvent. Further, 
the artisan recognizes that crystallization processes may include seeding, 
chilling, scratching the glass of the reaction vessel, and other such 
common techniques. 
Compound characterization methods include, for example, x-ray powder 
pattern analysis, thermogravimetric analysis (TGA), differential scanning 
calorimetery (DSC), titrametric analysis for water, and H.sup.1 -NMR 
analysis for solvent content.

The following examples are provided for purposes of illustration and are 
not to be construed as limiting the scope of the claimed invention. 
PREATION 1 
Crystalline Form II 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
A 10 gram sample of crude 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was suspended in methylene chloride (100)gm and stirred at ambient 
temperature (20.degree.-25.degree. C.) for a period of 1 hour. The slurry 
was vacuum filtered and the filtrate was recovered. The stirred filtrate 
was chilled to 0.degree.-5.degree. C. in an ice bath and the solvent was 
slowly evaporated under a stream of nitrogen to a thick paste. 
Approximately 3/4 of the solvent was removed by evaporation. A quantity of 
prechilled methylene chloride (30 gm, 0.degree.-5.degree. C.) was mixed 
into the thick paste. The resulting slurry was vacuum filtered and allowed 
to air dry on the filter. The isolated solid was further dried in a vacuum 
oven at 50.degree. C. for a period of 30 minutes. Isolated: 4.8 gm. X-ray 
powder characterization: Form II+CH.sub.2 Cl.sub.2 Solvate. 
The isolated solid was redried in a vacuum oven at 50.degree. C. under a 
stream of nitrogen for a period of 30 hours Isolated: 4.5 gm X-ray powder 
characterization: Form II. (described supra.) 
PREATION 2 
Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
A sample of ethyl acetate which was saturated with technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was contacted with Form II 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
(0.3 g), a seed of anhydrous Form I 
2methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
and stirred at about 25.degree. C. for about 5 hours. The reaction product 
was isolated by vacuum filtration and dried under ambient conditions. 
Yield: 0.25 g. X-ray powder analysis indicated that the product was 
anhydrous Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
PREATION 3 
Technical Grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
##STR12## 
Intermediate 1 
In a suitable three neck flask the following was added: 
Dimethylsulfoxide (analytical): 6 volumes 
Intermediate 1: 75 g 
N-Methylpiperazine (reagent): 6 equivalents 
Intermediate 1 can be prepared using methods known to the skilled artisan. 
For example, the preparation of the Intermediate 1 is taught in the '382 
patent. 
A sub-surface nitrogen sparge line was added to remove the ammonia formed 
during the reaction. The reaction was heated to 120.degree. C. and 
maintained throughout the duration of the reaction. The reactions were 
followed by HPLC until.ltoreq.5% of the intermediate 1 was left unreacted. 
After the reaction was complete, the mixture was allowed to cool slowly to 
20.degree. C. (about 2 hours). Each reaction mixture was then transferred 
to an appropriate three neck round bottom flask and water bath. To this 
solution with agitation was added 10 volumes reagent grade methanol and 
the reaction was stirred at 20.degree. C. for 30 minutes. Three volumes of 
water was added slowly over about 30 minutes. The reaction slurry was 
cooled to zero to 5.degree. C. and stirred for 30 minutes. The product was 
filtered and the wet cake was washed with chilled methanol. The wet cake 
was dried in vacuo at 45.degree. C. overnight. The product was identified 
as technical 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
Yield: 76.7%; Potency: 98.1% 
The procedure of Preparation 3 was repeated substantially as described 
above and provided a yield of 81% with a potency of 101.1%. 
PREATION 4 
Technical Grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
Intermediate 1 (supra) was suspended in DMSO (3.2 vol.) and toluene (4.5 
vol.). A portion (.apprxeq.0.65 vol.) of the solvent was removed by 
distillation at 120.degree.-125.degree. C. The mixture was cooled to 
110.degree. C., N-methylpiperazine(NMP, 4.2 equiv.) was added and the 
mixture heated back to reflux (120.degree.-125.degree. C.). Another 
portion (.apprxeq.1 vol.) of the solvent was removed by distillation to 
dry the reaction mixture. A vigorous reflux was desired to drive the 
reaction to completion (about 7 hrs.) by removing ammonia from the 
reaction. The product was isolated by the slow addition of water (12.75 
vol.) to the cooled (10.degree. C.) reaction solution. The product was 
collected by filtration and washed with chilled water (2 vol.). The crude 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was dried in vacuo at 60.degree. C. The product was recrystallized from 
hot toluene (5 vol.) to give a technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
After drying in vacuo at 50.degree. C., the technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was recrystallized again from ethyl acetate (10 vol.)/toluene (0.62 
vol.)/methanol (3.1 vol.)to give 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
as a methanol solvate. The methanol solvate upon drying at&gt;50.degree. C. 
was converted to an anhydrous technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
PREATION 5 
Form I from acetone 
A 3.0 g sample of technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was suspended in acetone (30 g). The mixture was stirred and heated to 
about 60.degree. C. The mixture was maintained at about 60.degree. C. for 
about 30 minutes. The mixture was allowed to cool to about 25.degree. C. 
The resulting product was isolated using vacuum filtration. The product 
was identified as Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
using x-ray powder analysis. Yield: 0.8 g. 
PREATION 6 
Form I Using tetrahydrofuran 
An 8.0 g sample of technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was suspended in tetrahydrofuran (25 g). The mixture was stirred and 
heated to about 60.degree. C. The mixture was maintained at about 
60.degree. C. for about 30 minutes. The mixture was allowed to cool to 
about 25.degree. C. The resulting product was isolated using vacuum 
filtration. The product was identified as Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
using x-ray powder analysis. Yield: 1.3 g. 
PREATION 7 
Form I Using ethyl acetate 
A 270 g sample of technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was suspended in ethyl acetate (2.7 L). The mixture was heated to about 
76.degree. C. and maintained at about 76.degree. C. for about 30 minutes. 
The mixture was allowed to cool to about 25.degree. C. The resulting 
product was isolated using vacuum filtration. The product was identified 
as Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
using x-ray powder analysis. Yield: 197 g. 
PREATION 8 
Form I from t-butanol 
A 1.0 g sample of technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
was suspended in tert-butanol (30 g). The stirred mixture was heated to 
about 60.degree. C. and maintained at about 60.degree. C. for about 30 
minutes. The mixture was allowed to cool to about 25.degree. C. The 
resulting product was isolated using vacuum filtration. The product was 
identified as Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
using x-ray powder analysis. Yield: 0.3 g. 
PREATION 9 
Form I from Slurry Conversion of Form II in Toluene 
A 0.5 g sample of technical grade 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
and a 0.5 g sample of Form II 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
were suspended in toluene (5 ml), presaturated with 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine. 
The mixture was stirred in a sealed vial at about ambient temperature for 
about 22 hours. The resulting product was isolated using vacuum filtration 
and dried under vacuum at about 45.degree. C. The product was identified 
as Form I 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
using x-ray powder analysis. 
EXAMPLE 1 
A portion of the hydroxypropyl cellulose was dissolved in purified water to 
form a solution for granulation. The remaining hydroxypropyl cellulose 
(total of 4.0% w/w final tablet weight), which was an extra fine grade, 
was combined with the 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
(1.18% w/w), lactose (79.32% w/w) and a portion of the crospovidone (5% 
w/w) in a high shear granulator. All ingredients were security sieved 
prior to addition and dry blended in the granulator. This mixture was then 
granulated with the hydroxypropyl cellulose solution in the high shear 
granulator. The granulation was wet sized using standard methods. The wet 
granulation was then dried in a fluidized bed dryer and sized. The 
material was then added to a tumble bin mixer. 
The running powders consisting of microcrystalline cellulose (granular) 
(10% w/w), magnesium stearate (0.5% w/w), and the remainder of the 
crospovidone were added to the sized granulation. The mixture was blended 
and compressed with the appropriate tooling on tablet compression 
equipment. 
Subcoating 
Hydroxypropyl methylcellulose (10% w/w) was mixed with purified water to 
form a solution. Core tablets were divided into approximately equal 
sections and spray coated with the hydroxypropyl methylcellulose solution. 
The operation was performed in a perforated coating pan. 
Coating of Core Tablets 
Color Mixture White (hydroxypropyl methylcellulose, polyethylene glycol, 
polysorbate 80, and titanium dioxide) was mixed with purified water to 
form the coating suspension. Subcoated tablets were divided into 
approximately equal sections and spray coated with the coating suspension 
described above. The operation was performed in a perforated coating pan. 
The coated tablets were lightly dusted with carnauba wax and imprinted with 
appropriate identification. 
EXAMPLE 2 
The process substantially as described above in Example 1 was repeated 
using the following ingredients to provide pharmaceutically elegant tablet 
formulations containing 1, 2.5, 5, 7.5, and 10 mg 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine, 
respectively, per tablet: 
1 mg 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
per tablet 
______________________________________ 
Names of Quantity 
Ingredients (mg/tablet) 
______________________________________ 
Active Ingredient 
2-methyl-4-(4-methyl- 
1.0 
1-piperazinyl)-10H- 
thieno2,3-b!1,5! 
benzodiazepine 
Other Ingredients 
Lactose 67.43 
Hydroxypropyl 3.40 
Cellulose 
Crospovidone 4.25 
Microcrystalline 8.50 
Cellulose 
Magnesium Stearate 
0.42 
Subcoating 
Hydroxypropyl 1.70 
Methylcellulose 
Coating 
Color Mixture White 
3.47 
Polishing 
Carnauba Wax trace 
Imprinting 
Edible Blue Ink trace 
______________________________________ 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
2.5 mg Tablets 
______________________________________ 
Names of Quantity 
Ingredients (mg/tablet) 
______________________________________ 
Active Ingredient 
2-methyl-4-(4-methyl- 
2.5 
1-piperazinyl)-10H- 
thieno2,3-b!1,5! 
benzodiazepine 
Other Ingredients 
Lactose 102.15 
Hydroxypropyl 5.20 
Cellulose 
Crospovidone 6.50 
Microcrystalline 13.00 
Cellulose 
Magnesium Stearate 
0.65 
Subcoating 
Hydroxypropyl 2.60 
Methylcellulose 
Coating 
Color Mixture White 
5.30 
Polishing 
Carnauba Wax trace 
Imprinting 
Edible Blue Ink trace 
______________________________________ 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
5.0 mg Tablets 
______________________________________ 
Names of Quantity 
Ingredients (mg/tablet) 
______________________________________ 
Active Ingredient 
2-methyl-4-(4-methyl- 
5.00 
1-piperazinyl)-10H- 
thieno2,3-b!1,5! 
benzodiazepine 
Other Ingredients 
Lactose 156.00 
Hydroxypropyl 8.00 
Cellulose 
Crospovidone 10.00 
Microcrystalline 20.00 
Cellulose 
Magnesium Stearate 
1.00 
Subcoating 
Hydroxypropyl 4.00 
Methylcellulose 
Coating 
Color Mixture White 
8.16 
Polishing 
Carnauba Wax trace 
Imprinting 
Edible Blue Ink trace 
______________________________________ 
2-methyl-4 -(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
7.5 mg Tablets 
______________________________________ 
Names of Quantity 
Ingredients (mg/tablet) 
______________________________________ 
Active Ingredient 
2-methyl-4-(4-methyl- 
7.50 
1-piperazinyl)-10H- 
thieno2,3-b!1,5! 
benzodiazepine 
Other Ingredients 
Lactose 234.00 
Hydroxypropyl 12.00 
Cellulose 
Crospovidone 15.00 
Microcrystalline 30.00 
Cellulose 
Magnesium Stearate 
1.50 
Subcoating 
Hydroxypropyl 6.00 
Methylcellulose 
Coating 
Color Mixture White 
12.24 
Polishing 
Carnauba Wax trace 
Imprinting 
Edible Blue Ink trace 
______________________________________ 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
10.0 mg Tablets 
______________________________________ 
Names of Quantity 
Ingredients (mg/tablet) 
______________________________________ 
Active Ingredient 
2-methyl-4-(4-methyl- 
10.00 
1-piperazinyl)-10H- 
thieno2,3-b!1,5! 
benzodiazepine 
Other Ingredients 
Lactose 312.00 
Hydroxypropyl 16.00 
Cellulose 
Crospovidone 20.00 
Microcrystalline 40.00 
Cellulose 
Magnesium Stearate 
2.00 
Subcoating 
Hydroxypropyl 8.00 
Methylcellulose 
Coating 
Color Mixture White 
16.32 
Polishing 
Carnauba Wax trace 
Imprinting 
Edible Blue Ink trace 
______________________________________ 
EXAMPLE 4 
Pulvule Formulation 
A pulvule formulation is prepared by blending the active with silicone 
starch, and filling it into hard gelatin capsules. 
______________________________________ 
Per 300 mg capsule 
______________________________________ 
Compound of the invention 
30.0 mg 
Silicone 2.9 mg 
Starch flowable 267.1 mg 
______________________________________ 
EXAMPLE 5 
Tablet Formulation 
A tablet formulation is made by granulating the active with appropriate 
diluent, lubricant, disintegrant and binder and compressing 
______________________________________ 
Compound of the invention 
10.0 mg 
Magnesium stearate 0.9 mg 
Microcrystalline cellulose 
75.0 mg 
Povidone 15.0 mg 
Starch, directly 204.1 mg 
compressible 
______________________________________ 
EXAMPLE 6 
Aqueous Injection Formulation 
An aqueous injection of active is prepared as a freeze-dried plug, for 
reconstitution in a suitable, sterile diluent before use (to a total 
volume of 10 ml). 
Compound of the invention is contacted with Mannitol N Hydrochloric acid 
and/or N sodium hydroxide to adjust pH to 5-5.5. 
______________________________________ 
Compound of the invention 
20.0 mg 
Mannitol 20.0 mg 
N Hydrochloric acid and/or N 
sodium 
hydroxide to adjust pH to 5-5.5. 
______________________________________ 
EXAMPLE 7 
Controlled Release IM Formulation 
A controlled release injection for intramuscular injection is formed from a 
sterile suspension of micronised active in an oleaginous vehicle. 
______________________________________ 
Compound of the invention 
50.0 mg 
Aluminium stearate 0.04 mg 
Sesame oil 2 ml 
______________________________________ 
EXAMPLE 8 
Capsule Formulation 
A formulation is prepared by blending the active with silicone starch and 
starch, and filling it into hard gelatine capsules. 
______________________________________ 
Per 300 mg capsule 
______________________________________ 
Compound of the invention 
2.5 mg 
Starch flowable with 0.96% 
222.5 mg 
silicone 220 
Starch flowable 75.0 mg 
______________________________________ 
EXAMPLE 9 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
Granules 
The granules were produced by blending the mannitol and Hydroxymethyl 
propyl cellulose in a high shear mixer; granulating with the aqueous 
suspension of 
2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno2,3-b!1,5!benzodiazepine 
and polysorbate 20; wet sized and subsequently dried in a fluid bed dryer. 
These are dry sized and reblended prior to packaging. 
______________________________________ 
INGREDIENT MG/SACHET 
______________________________________ 
1a. 250 mg total weight Sachets 
Active 
2-methyl-4-(4- 2.50 
methyl-1-piperazinyl)- 
10H-thieno2,3-b!1,5! 
benzodiazepine 
Other Ingredients 
Mannitol 234.97 
Hydroxypropyl methyl 
12.50 
cellulose 3 cps 
Polysorbate 20 0.028 
1b. 750 mg total weight Sachets 
Active 
2-methyl-4-(4- 7.50 
methyl-1-piperazinyl)- 
10H-thieno2,3-b!1,5! 
benzodiazepine 
Other Ingredients 
Mannitol 704.93 
Hydroxypropyl methyl 
37.49 
cellulose 3 cps 
Polysorbate 20 0.08 
1c. 1000 mg total weight Sachets 
Active 
2-methyl-4-(4- 10.0 
methyl-1-piperazinyl)- 
10H-thieno2,3-b!1,5! 
benzodiazepine 
Other Ingredients 
Mannitol 939.90 
Hydroxypropyl methyl 
49.99 
cellulose 3 cps 
Polysorbate 20 0.11 
______________________________________ 
Such granules are most preferably contacted with an acidic medium if a 
suspension or solution is desired.