U.S. patent application number 10/101948 was filed with the patent office on 2002-10-10 for crystalline dibenzothiazepine derivative and its use as an antipsychotic agent.
This patent application is currently assigned to Zeneca Limited. Invention is credited to Snape, Evan William.
Application Number | 20020147186 10/101948 |
Document ID | / |
Family ID | 10816746 |
Filed Date | 2002-10-10 |
United States Patent
Application |
20020147186 |
Kind Code |
A1 |
Snape, Evan William |
October 10, 2002 |
Crystalline dibenzothiazepine derivative and its use as an
antipsychotic agent
Abstract
Crystalline 11-(4-[2-(2-hydroxyethoxy)
ethyl]-1-piperazinyl)-dibenzo[b,f] [1,4]thiazepine (I) may be
prepared by crystallising 11-(4-[2-(2-hydroxyethoxy)
ethyl]-1-piperazinyl)-dibenzo[b,f] [1,4]thiazepine from a
non-aromatic solvent such as ethyl acetate, isobutyl acetate,
methyl iso-butylketone or methyl tert-butyl ether, preferably in
the absence of water. The crystalline material produced may be
converted into a pharmaceutically acceptable salt such as a
fumarate. The crystalline 11-(4-[2-(2-hydroxyethoxy)
ethyl]-1-piperazinyl)-dibenzo [b,f] [1,4]thiazepine may be used to
treat psychoses.
Inventors: |
Snape, Evan William;
(Bristol, GB) |
Correspondence
Address: |
PILLSBURY WINTHROP, LLP
P.O. BOX 10500
MCLEAN
VA
22102
US
|
Assignee: |
Zeneca Limited
|
Family ID: |
10816746 |
Appl. No.: |
10/101948 |
Filed: |
March 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10101948 |
Mar 21, 2002 |
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09463452 |
Jan 27, 2000 |
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6372734 |
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09463452 |
Jan 27, 2000 |
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PCT/GB98/02260 |
Jul 28, 1998 |
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Current U.S.
Class: |
514/211.13 ;
540/551 |
Current CPC
Class: |
A61P 25/00 20180101;
C07D 281/16 20130101; A61P 25/18 20180101 |
Class at
Publication: |
514/211.13 ;
540/551 |
International
Class: |
A61K 031/554; C07D
417/04 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 1, 1997 |
GB |
9716161.6 |
Claims
1. A compound which is crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1
-piperazinyl)-dibenzo[b,f][1,4]thiazepine.
2. A compound as claimed in claim 1 in which the crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne is greater than 90% pure.
3. A compound as claimed in claim 2 wherein the crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne is greater than 99% pure.
4. A process for preparing crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl)-1--
piperazinyl)-dibenzo[b,f][1,4]thiazepine, or a pharmaceutically
acceptable salt thereof which comprises crystallising
11-(4-[2-(2-hydroxyethoxy)ethy- l]-1-piperazinyl
)-dibenzo[b,f][1,4]thiazepine from a non-aromatic solvent; and
whereafter. when a pharmaceutically acceptable salt is required,
reacting 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenz-
o[b,f][1,4]thiazepine with an acid which affords a pharmaceutically
acceptable anion.
5. A process for preparing
1-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)--
dibenzo[b,f][1,4]thiazepine, or a pharmaceutically-acceptable salt
thereof, which comprises crystallising
11-(4-[2-(2-hydroxyethoxy)ethyl]-
1-piperazinyl)-dibenzo[b,f][1,4]thiazepine from a solution of
1-(4-[2-(2-hydroxyethoxy)ethyl-1-piperazinyl)-debenzo[b,f][1,4]thiazepine
in a non-aromatic solvent and in which the solution is
substantially free from water.
6. A process as claimed in any one of claims 4 or 5 wherein the
non-aromatic solvent is selected from an ester of formula
R.sup.1CO.sub.2R.sup.2 wherein R.sup.1 and R.sup.2 are alkyl
groups; an ether of formula R.sup.3OR.sup.4 wherein R.sup.3 and
R.sup.4 are alkyl groups. and a ketone of formula R.sup.5COR.sup.6
wherein R.sup.5 and R.sup.6 are alkyl groups.
7. A process as claimed in claim 6 wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are selected from (1-4C)alkyl.
8. A process as claimed in claim 6 wherein the non-aromatic solvent
is selected from ethyl acetate, isobutyl acetate, methyl
iso-butylketone and methyl tert-butyl ether.
9. A process as claimed in any one of claims 4 to 8 wherein the
solvent is selected from methyl tert-butyl ether.
10. A process of purifying
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
-dibenzo[b,f][1,4]thiazepine comprising crystallising
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne from methyl tert-butylether in the absence of water.
11. A process as claimed in claim any one of claims 4 to 10 wherein
the
11-(4-[2-(2-hyddroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazep-
ine and the non-aromatic solvent are heated to give a solution and
the temperature of the solution containing the
11-(4-[2-(2-hydroxyethoxy)ethy-
l]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine is decreased to
ambient temperature and then further decreased to about O C over a
period greater than 1 hour.
12. A process as claimed in claim 11 wherein the temperature is
decreased from ambient temperature to 0.degree. C. over a period of
about 2 to 4 hours.
13. A process as claimed in claim 11 or 12 wherein the temperature
is decreased from ambient temperature to 0.degree. C. over a period
of about 3 hours.
14. A process as claimed in claim any one of claims 4 to 13 wherein
the quantity of the non-aromatic solvent is that which, when
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne is dissolved in it, gives a concentration (before
crystallisation) of about 120 to 160 mg/ml.
15. A process as claimed in claim 14 wherein the quantity of
non-aromatic solvent gives a 135 to 145 mg/ml.
16. A process as claimed in any one of claims 4 to 15 in which
comprises reacting crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibe-
nzo[b,f][1,4]thiazepine with fumaric acid to give the fumarate salt
of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne.
17. A process for preparing crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-
-piperazinyl)-dibenzo[b,f][1,4]thiazepine. or a pharmaceutically
acceptable salt thereof, from a solution of
11-(4-[2-(2-hydroxyethoxy)eth-
yl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine in an aromatic
solvent which process comprises: a) adding water and an acid to the
solution of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne in the aromatic solvent; b) separating the aqueous and organic
phases: c) adding a non-aromatic solvent and a base to the aqueous
phase; d) separating the aqueous and the non-aromatic solvent
phases; e) drying the non-aromatic solvent phase: f) crystallising
11-(4-[2-(2-hydroxyethoxy)et-
hyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine from the
non-aromatic solvent; and whereafter, if a pharmaceutically
acceptable salt is desired. reacting the
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dib-
enzo[b,f][1,4]thiazepine with an acid which affords a
pharmaceutically acceptable anion.
18. A process as claimed in claim 17 wherein the aromatic solvent
is toluene.
19. A process as claimed in claim 17 or 18 wherein step (f) is
carried out as claimed in any one of claims 4 to 17.
20. A pharmaceutical composition comprising crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne and a pharmaceutically acceptable diluent or carrier.
21. The use of crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
-dibenzo[b,f][1,4]thiazepine in the manufacture of a medicament for
treating neuropsychiatric disorders.
22. The use of crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
-dibenzo[b,f][1,4]thiazepine in the manufacture of a medicament for
treating psychoses.
Description
[0001] The present invention relates to a process for the
preparation of thiazepine derivatives and, in particular. to the
preparation of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne and salts thereof.
[0002] The compound,
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-diben-
zo[b,f][1,4]thiazepine (Formula I) 1
[0003] exhibits useful antidopaminergic activity and may be used.
for example as an antipsychotic agent with a substantial reduction
in the potential to cause side effects such as acute dystonia,
acute dyskinesia. pseudo-Parkinsonism and tardive dyskinesia.
[0004] The compound of formula I is described in granted European
Patent EP 240,228. This patent describes the properties of the
compound of formula I and its synthesis from
dibenzo[b,f][1,4]thiazepine-11(10-H)-one- . In this synthetic route
it is necessary to prepare and purify the compound
2-(2-hydroxyethoxy)ethyl-1-piperazine (HEEP).
[0005] Granted European Patent EP 282,236 describes an improved
process for the preparation of the compound of formula I which
obviates the need to prepare and purify the compound
2-(2-hydroxyethoxy)ethyl)-1-piperazine since this improved process
does not use 2-(2-hydroxyethoxy)ethyl-1-piper- azine. It also
obviates the need to use carboxyethyl piperazine which is used to
prepare 2-(2-hydroxyethoxy)ethyl-1-piperazine.
[0006] Many Pharmaceuticals are developed as salts of
pharmacologically acceptable acids or bases. This is usually done
if the biologically active substance itself has a physical form
which makes it unsuitable to handle in manufacturing processes.
Most manufacturing processes involve materials handling in mixing
and formulation which is facilitated by the active materials being
either a liquid or free-flowing high melting solids. Although salts
can be made with suitable acids or bases these often add nothing to
the therapeutic benefit of the pharmaceutical and are therefore
redundant biologically. It would be better if the pharmaceutical
could be manufactured as the pure active substance.
[0007] The reported synthesis of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-pipera-
zinyl)-dibenzo[b,f][1,4]thiazepine provides
11-(4-[2-(2-hydroxyethoxy)ethy-
l]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine as a fumarate salt
since it has been necessary to prepare the salt to efficiently
obtain a sufficiently pure product. Moreover. to prepare the
fumarate salt it has been necessary to first prepare the hydrogen
fumarate salt and subsequently convert it to the fumarate.
[0008] The present invention is based. at least in part. on an
improved method of purifying the compound of formula I. and in
particular on a method of purifying the compound of formula I such
that the compound of formula I is obtained in a crystalline
form.
[0009] According to the present invention there is provided
crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne.
[0010] The crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dib-
enzo[b,f][1,4]thiazepine may be converted into one of its
pharmaceutically acceptable salts and so the present invention also
provides crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][4,1]thiazepi-
ne or a pharmaceutically acceptable salt prepared therefrom.
[0011] The crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dib-
enzo[b,f][1,4]thiazepine is generally provided in a substantially
pure form. It is generally preferred that the crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne is greater than 90% pure. more preferably 99% or greater than
99% pure.
[0012] According to the present invention there is also provided a
process for preparing crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
-dibenzo[b,f][1,4]thiazepine or a pharmaceutically acceptable salt
thereof which comprises crystallising
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazi-
nyl)-dibenzo[b,f][1,4]thiazepine from a non-aromatic solvent; and
whereafter, when a pharmaceutically acceptable salt is required,
reacting
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne with an acid which affords a pharmaceutically acceptable
anion.
[0013] According to the present invention there is also provided a
process for preparing crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-
-dibenzo[b,f][1,4]thiazepine or a pharmaceutically acceptable salt
thereof which comprises crystallising
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazi-
nyl)-dibenzo[b,f][1,4]thiazepine from a non-aromatic solvent
substantially in the absence of water;
[0014] and whereafter, when a pharmaceutically acceptable salt is
required, reacting
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenz-
o[b,f][1,4]thiazepine with an acid which affords a pharmaceutically
acceptable anion.
[0015] The crystallisation may be initiated with the aid of a seed
crystal.
[0016] The salts of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenz-
o[b,f][1,4]thiazepine will generally comprise acid-addition salts.
Convenient salts may be selected from those pharmaceutically
acceptable salts known in the art. These may be obtained by any
conventional salt preparation method known in the art. For example.
salts may be obtained by reacting
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][-
1,4]thiazepine with a convenient acid. such as. hydrochloric acid.
maleic acid. fumaric acid, citric acid, phosphonic acid.
methanesulphonic acid and sulphuric acid.
[0017] Preferred salts include fumarate salts and in particular the
hemi-fumarate salt. It is generally preferred that the fumerate
salt of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne is
bis-[11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,-
4]thiazepine]fumarate.
[0018] It is generally preferred, for example, that the solvent is
dry. It is further preferred that the
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazi-
nyl)-dibenzo[b,f][1,4]thiazepine is also dry so that the solution
formed on dissolving
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f-
][1,4]thiazepine in the solvent is substantially free from water.
More especially. the solution formed in the crystallisation process
should be free from water.
[0019] Thus, in a preferred embodiment there is provided a process
for preparing
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,-
4]thiazepine, or a pharmaceutically-acceptable salt thereof, which
comprises crystallising
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-d-
ibenzo[b,f][1,4]thiazepine from a solution of
11-(4-[2-(2-hydroxyethoxy)et- hyl]-1-piperazinyl)-dibenzo[b,f
][1,4]thiazepine in a non-aromatic solvent which is free from
water. The crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl-
]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine may, if desired, be
converted to a pharmaceutically-acceptable salt, as mentioned
above.
[0020] Examples of suitable solvents include, for example esters
such as those of formula R.sup.1CO.sub.2R.sup.2 wherein R.sup.1 and
R.sup.2 are alkyl groups; ethers of formula R.sup.3OR.sup.4
wherenin R.sup.3 and R.sup.4 are alkyl groups; and ketones of
formula R.sup.5COR.sup.6 wherein R.sup.5 and R.sup.6 are alkyl
groups.
[0021] Particular values of R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 include, for example, (1-6C)alkyl such as
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, pentyl and hexyl. Conveniently, R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are selected from (1-4C)alkyl.
[0022] Specific examples of suitable solvents include, for example,
ethyl acetate. isobutyl acetate, methyl iso-butylketone and methyl
tert-butyl ether.
[0023] Solvents of particular interest include. for example.
ethers. Thus. a solvent of particular interest is methyl tert-butyl
ether.
[0024] The temperature ofthe solution containing
11-(4-[2-(2-hydroxyethoxy-
)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine may be decreased
during the crystallisation. In general, the temperature will be
decreased to about O C. Conveniently, the temperature is decreased
gradually over a period of time. Thus, in a specific example. the
temperature is decreased to ambient temperature (about 25.degree.
C.) and then further decreased to about O C over a period greater
than 1 hour and generally greater than 2 hours. In particular. the
temperature is decreased from ambient temperature to 0.degree. C.
over a period of about 2 to 4 hours, preferably about 3 hours.
Where a seed crystal is used it will generally be added to the
crystallisation mixture when that mixture is at ambient
temperature. In the case where the temperature is decreased, the
seed crystal will, in general, be added just before the temperature
is decreased (from ambient temperature).
[0025] The quantity of solvent employed to crystallise
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne will vary according to the precise solvent selected. In
particular the quantity of solvent is that which. when
11-(4-[2-(2-hydroxyethoxy)ethyl]--
1-piperazinyl)-dibenzo[b,f][1,4]thiazepine is dissolved in it.
gives a concentration (before crystallisation) of about 120 to 160
mg/ml, more particularly 130 to 150 mg/ml. It is generally
preferred that the quantity of solvent is that which gives a
concentration (before crystallisation) of about 135 to 145
mg/ml.
[0026] In a particular embodiment of the present invention there is
provided a method of purifying
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperaz-
inyl)-dibenzo[b,f][1,4]thiazepine comprising crystallising
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne from methyl tert-butylether in the absence of water.
[0027] Preferred, particular and specific conditions include those
mentioned above.
[0028] As mentioned above, the crystalline product may, if desired,
be converted to a pharmaceutically acceptable salt.
[0029] In a further embodiment of the present invention there is
provided a method of preparing the fumarate salt of
11-(4-[2-(2-hydroxyethoxy)ethy-
l]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine, which method
comprises reacting crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibe-
nzo[b,f][1,4]thiazepine with fumaric acid.
[0030] The crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dib-
enzo[b,f][1,4]thiazepine will generally be prepared as herein
before defined.
[0031] Crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo-
[b,f][1,4]thiazepine will generally be reacted with the fumaric
acid in a solvent such as an alcohol. Examples of suitable alcohols
will include methanol and ethanol. A particularly suitable solvent
is ethanol which may convenienetly be in the form of industrial
methylated spirits (IMS).
[0032] The present invention also provides a method of preparing
crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][-
1,4]thiazepine. or a pharmaceutically acceptable salt thereof. from
a solution of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][-
1,4]thiazepine in an aromatic solvent which process comprises:
[0033] a) adding water and an acid to the solution of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne in the aromatic solvent;
[0034] b) separating the aqueous and organic phases;
[0035] c) adding a non-aromatic solvent and a base to the aqueous
phase;
[0036] d) separating the aqueous and the non-aromatic solvent
phases;
[0037] e) drying the non-aromatic solvent phase;
[0038] f) crystallising
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-di-
benzo[b,f][1,4]thiazepine from the non-aromatic solvent; and
whereafter, if a pharmaceutically acceptable salt is desired.
reacting the
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne with an acid which affords a pharmaceutically acceptable
anion.
[0039] Particular, preferred and specific values include the values
mentioned above.
[0040] The aromatic solvent is preferably toluene.
[0041] It will be appreciated that the amount/strength of acid
added in step (a) will be such that the aqueous phase is made
acidic and the amount/strength of base added in step ((c) will be
such that the aqueous phase is made basic.
[0042] The compound of this invention is a central nervous system
depressant and may be used as a tranquilizer for the relief of
hyperactivity states. for example, in mice, cats, rats, dogs and
other mammalian species, and additionally for the management of
psychotic states in man, in the same manner as chlorpromazine. For
this purpose the
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne. or physiologically acceptable acid addition salt thereof, may
be administered orally or parenterally in a conventional dosage
form such as tablets, pill, capsule. injectable or the like. The
dosage in mg/kg of body weight of a compound of the present
invention in mammals will vary according to the size of the animal
and particularly with respect to the brain/body weight ratio. In
general. a higher mg/kg dosage for a small animal such as a dog
will have the same effect as a lower mg/kg dosage in an adult
human. A minimum effcctive dosage for the compound of formula I
will be at least about 1.0 mg/kg of body weight per day for mammals
with a maximum dosage for a small mammal such as a dog. of about
200 mg/kg per day. For humans, a dosage of about 1.0 to 40 mg/kg
per day will be effective. for example. about 50 to 2000 mg/day for
an average person weighing 50 kg. The dosage can be given once
daily or in divided doses, for example, 2 to 4 doses daily. The
dose may be conventionally formulated in an oral or parenteral
dosage form by compounding about 25 to 500 mg per unit of dosage of
conventional vehicle, excipient, binder, preservative. stabilizer.
flavor or the like as called for by accepted pharmaceutical
practice, for example, as described in U.S. Pat. No. 3,755,340. The
compound of formula I (or salt) may be used in pharmaceutical
compositions as previously described or be contained in or
co-administered with one or more known drugs.
[0043] Thus. according to the present invention there is also
provided a pharmaceutical composition comprising crystalline
11-(4-[2-(2-hydroxyetho-
xy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine, or a
pharmaceutically acceptable salt prepared therefrom, together with
a pharmaceutically acceptable diluent or carrier.
[0044] In particular, there is provided a pharmaceutical
composition comprising crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-di-
benzo[b,f][1,4]thiazepine and a pharmaceutically acceptable diluent
or carrier.
[0045] The present invention also provides a method of treating
neuropsychiatic disorders (in particular, a method of treating
psychoses, more particularly schizophrenia) using crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne, or a pharmaceutically acceptable salt prepared therefrom.
[0046] In particular, the present invention provides a method of
treating neuropsychiatic disorders, comprising administering an
effective amount of crystallinel
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b-
,f][1,4]thiazepine to a warm-blooded mammal such as man. In
particular, the present invention provides a method of treating
psychoses, more particularly schizophrenia.
[0047] The present invention also provides the use of crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne in the manufacture of a medicament for treating neuropsychiatric
disorders and in particular psychoses such as schizophrenia.
[0048] As mentioned above, the present invention offers advantages
over known methods of preparing
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl-
)-dibenzo[b,f][1,4]thiazepine and its salts.
[0049] Firstly, the present invention provides crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne. In particular the invention provides proceses for the
preparation crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][-
1,4]thiazepine which is of high purity. In general, the crystalline
material had a high melting point consistent with a crystalline
solid of high purity and good quality.
[0050] Previously, pure
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-di-
benzo[b,f][1,4]thiazepine has been obtained by provision of a
purified salt, the fumarate. This has necessitated preparation of
the hydrogen fumarate salt followed by subsequent conversion to the
fumarate salt. This conversion is a relatively low output process
which requires the use of relatively dilute reaction mixtures to
ensure the formation of the desired fumarate salt rather than a
mixture of hydrogen fumarate and fumarate salt forms.
[0051] By utilising purified crystalline
11-(4-[2-(2-hydroxyethoxy)ethyl]-- 1-piperazinyl)-dibenzo[b,f
][1,4]thiazepine, the fumarate salt may be prepared in a relatively
high output process since the difficulties associated with
obtaining the correct salt form are minimised.
[0052] The present invention also provides processes for the
preparation of
11-(4-[2-(2-hydroxyehtoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiaz-
epine and its salts in a more productive manner than previously
reported which uses plant and/or materials such as solvents more
efficiently.
[0053] The invention will now be illustrated by the following
non-limiting examples in which, unless stated otherwise:
[0054] (i) temperature are given in degrees Celsius (C): operations
were carried out at room or ambient temperature, that is. at a
temperature in the range of 18-25C.
[0055] (ii) evaporation of solvent was carried out using a rotary
evaporator under reduced pressure (600-4000 pascals; 4.5-30 mmHg)
with a bath temperature of up to 60 C;
[0056] (iii) in general. the course of reactions was followed by
TLC and/or HPLC and reaction times are given for illustration
only;
[0057] (iv) melting points are uncorrected and (dec) indicates
decomposition; the melting points given are those obtained for the
materials prepared as described: polymorphism may result in
isolation of materials with different melting points in some
preparations;
[0058] (v) all final products were essentially pure by TLC and/or
HPLC and had satisfactory nuclear magnetic resonance (NMR) spectra
and microanalytical data.
[0059] (vi) yields are given for illustration only;
[0060] (vii) reduced pressures are given as absolute pressures in
pascals (Pa); other pressures are given as gauge pressures in
bars;
[0061] (viii) chemical symbols have their usual meanings; the
following abbreviations have also been used: v(volume), w(weight),
mp (melting point), L (liters), ml (milliliters), g (grams), mmol
(millimoles), mg (milligrams), min (minutes). h (hours),
IMS(industrial methylated spirits); and
[0062] The
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,-
4]thiazepine was prepared as described in granted European Patent
No. EP 282,236. This compound may also be prepared as described in
granted European Patent No.240,228.
EXAMPLE 1
[0063] (a) Water (106 ml) was added to a stirred mixture of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne (59 g) in toluene at 40.degree. C. Concentrated hydrochloric
acid (21.4 ml) was added to the mixture and the mixture was stirred
vigorously for 15 minutes at 40.degree. C. The phases were
separated.
[0064] Methyl tert-butyl ether (256 ml) was added to the aqueous
phase. Aqueous sodium hydroxide solution (15.4 ml density 1.5
g/cm.sup.3) was added and the mixture was warmed to 45.degree. C.
and stirred vigorously for 15 minutes. The mixture was allowed to
settle and the phases were separated. The organic phase was washed
with water (2.times.25 ml) at 45.degree. C. and then dried by
distillation at 55 .degree. C. using a Dean and Stark separator.
The dried mixture was allowed to cool to 25.degree. C. seeded and
stirred overnight to give a solid. The mixture was cooled to 0
.degree. C. and maintained at 0 .degree. C. for 4 hours. The solid
was collected by filtration. washed with methyl tert-butyl ether
and dried in a vacuum oven at 50 .degree. C. overnight.
[0065] There was thus obtained
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazi-
nyl)-dibenzo[b,f][1,4]thiazepine (46.7g) as a white crystalline
solid. m.p. 82-84.degree. C.
[0066] (b) IMS (35 ml) was added to free base (30.0 g) and the
stirred mixture was heated at 60.degree. C. in a 100 ml flask to
give a solution. This solution was transferred to a 500 ml reactor
vessel via a sinter. The 100 ml flask was washed with warm (60 C.)
IMS (10 ml) and the washings added to the reactor vessel. The
mixture in the reactor vessel was warmed to 60.degree. C. with
stirring.
[0067] Fumaric acid (4.65 g) and IMS (60 ml) were added to the 100
ml flask. The mixture was heated to 60.degree. C. with stirring to
give a solution which contained a small number of solid lumps of
material. The mixture was added to the reaction vessel via the
sinter so as to filter the mixture and remove the lumps. The
resulting mixture in the reaction vessel was stirred to give
crystalline material.
[0068] IMS (10 ml) was added to the 100 ml flask, warmed to
60.degree. C. and transferred to the reaction vessel. The thick
crystalline mass in the reaction vessel was heated to reflux and
then allowed to cool to ambient temperature, to give a solid. The
stirred mixture was cooled to 0.degree. C. and the temperature of
the mixture maintained at this temperature for 1 hour. The solid
was collected by filtration and washed with cool (0 to 5.degree.
C.) IMS (30 ml). This IMS had been used to wash the reaction vessel
out. The solid was dried in a vacuum oven at 55.degree. C.
overnight to give
bis-[11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-di-
benzo[b,f][1,4]thiazepine] fumarate as a white crystalline solid
(32.7 g); 94.4% yield).
EXAMPLE 2
[0069] Using a similar method to that described in Example 1.
11-(4-[2-(2-hydroxyethoxy)ethyl)-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne was crystallised from the solvents listed below in place of
methyl tert-butylether.
1 Solvent Strength (%) Yield (%) M.P. (.degree. C.) Ethyl
acetate.sup.[1] 100 39.7 --.sup.[2] Iso-butyl acetate 97.5 70.1
83-86 Methyl iso-butylketone 99.4 69.7 83-86 Methyl
iso-butylketone.sup.[3] 99.3 67.8 83-86 Methyl tert-butylether 100
86 83-86 Methyl tert-butylether 99 81 83-86 .sup.[1]crystallised
from previously isolated
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepi-
ne .sup.[2]good solid .sup.[3]80% charge
[0070] Strength is a measure of purity. The % strength is the % of
desired ingredient,
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][-
1,4]thiazepine, in the weight of material isolated.
EXAMPLE 3
[0071] The following illustrate representative pharmaceutical
dosage forms containing a compound of
11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)--
dibenzo[b,f][1,4]thiazepine and salts thereof., for example as
illustrated in any of the previous Examples, (hereafter referred to
as "compound X"), for therapeutic or prophylactic use in
humans:
2 mg/tablet (a) Tablet Compound X 50.0 Mannitol, USP 223.75
Croscarmellose sodium 6.0 Maize starch 15.0
Hydroxypropylmethylcellulose (HPMC), 2.25 Magnesium stearate 3.0
(b) Capsule Compound X 10.0 Mannitol, USP 488.5 Croscarmellose
sodium 15.0 Magnesium stearate 1.5
[0072] The above formulations may be obtained by conventional
procedures well known in the pharmaceutical art. The tablets may be
enteric coated by conventional means, for example to provide a
coating of cellulose acetate phthalate.
* * * * *