SELS D'ADDITION D'ACIDE DE COMPOSES DE 2,3,4,5-TETRAHYDRO-1H-3-BENZAPEPINE

ACID ADDITION SALTS OF 2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINE COMPOUNDS

Abrégé français

L'invention concerne une série de sels cristallins de (S)(+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-méthyl-2,3,4,5-tétrahydro-1H-3-benzazépine-7-ol, leur préparation et leur utilisation en tant qu'agents thérapeutiques.

Abrégé anglais

The invention provides a series of crystalline salts of (S) (+)-8-chloro-5-
(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepine-7-ol, their preparation and use as therapeutic agents.

Revendications

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CLAIMS
1. Crystalline salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-
benzofuran-7-yl)-3-methyl-2,3,4, 5-tetrahydro-1H-3-benzazepine-7-ol,
derived from fumaric acid, L(+)-tartaric acid, maleic acid and L(+)-
mandelic acid.
2. A crystalline salt according to claim 1 which is (S) (+)-8-chloro-
5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-
1H-3-benzazepin-7-ol, hemifumarate; (S)(+)-8-chloro-5-(5,6-dichloro-
2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-ben-
zazepin-7-ol, L(+)-hemitartrate, (S) (+)-8-chloro-5-(5,6-dichloro-2,3-
dihydrobenzofuran-7-yl)-3-methyl-2,3,4, 5-tetrahydro-1H-3-benzazepin-7-
ol, maleate; (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-
3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol, L(+)-mandelate.
3, The use of a crystalline salt according to claims 1 or 2 as a
medicament.
4. The use of a salt according to claims 1 or 2 for the preparation of
a pharmaceutical compusition for treating an indication related to
dysfunctions of the dopamine D-1 receptor system.
5. A pharmaceutical composition comprising a crystalline salt
according to claim 1 or 2 together with a pharmaceutically acceptable
carrier or diluent.
6. A pharmaceutical composition for use in treating an indication
related to dysfunctions of the dopamine D-1 receptor system comprising
an effective amount of a crystalline salt according to claim 1 or 2,
together with a pharmaceutically acceptable carrier or diluent.

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7. The pharmaceutical composition according to claim 5 or 6 in the
form of an oral dosage unit containing from 0.1-400 mg of the active
ingredients.
8. A process for the preparation of crystalline acid addition salts of
(S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-
2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol according to claims 1 or 2,
which process comprises dissolving the acid of the corresponding
addition salt and (S)(+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-
7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-ol in a common
solvent, and crystallising the resulting salt from the solution.
9. A method of treating an indication related to dysfunctions of the
dopamine D-1 receptor system in a mammal comprising administering an
effective amount of a crystalline salt according to claim 1 or 2.
10. A method according to claim 9 wherein the indication is related
to psycosis.
11. A method of treating an indication related to dysfunctions of the
dopamine D-1 receptor system in a mammal comprising administering a
pharmaceutical composition according to claim 5.
12. A process for the manufacture of a pharmaceutical composition
to be used in the treatment of an indication related to dysfunctions of
the dopamine D-1 receptor system, which process comprises bringing a
crystalline salt according to claim 1 or 2 into a galenical dosage form.

Description

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Acid Addition Salts of 2,3,4,5-tetrahydro-1H-3-benzazepine Compounds
The present invention relates to crystalline salts of tS) ( + )-8-chloro-5-
(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-
1 H-3-benzazepine-7-ol, their preparation and use as therapeutic agents.
International patent appl. No. W0 93/17012 discloses a class of com-
pounds exhibiting strong antidopaminergic effects and thus making them
useful in treatment of disorders in the central nervous system related to
dysfunctions of the dopamine D-1 receptor system, e.g. psychosis, pain,
15 depression and Parkinson's disease.
In example 3 of International appl. No. W0 93/17012 the preparation of
(S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yi)-3-methyl-
2,3,4,5-tetrahydro-lH-3-benzazepine-7-ol of formula l:
C 1~ ~N--CH ( I )
c
is described.
Because of its poor solubility, it is preferred that the compound of
formula I is used as a therapeutic agent in the form of an acid addition
salt.

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Further, it has been found that some acid addition salts of the compound
of formula I do form alternate polymorphic forms. This is pharmaceuti-
cally undesirable because of the potential that the salt occurs in more
than one crystalline form making it very difficult to predict how the
5 various parts of the body will react to the different crystalline forms.
In general, for commercial use it is important to have a physiologically
acceptable salt with good bioavailability, good handling properties, and
reproducible crystalline form.
Surprisingly, it has now been found that a series of new pharmaceuti-
cally acceptable acid addition salts of the compound of formula I can be
obtained in a reproducible crystalline form.
15 Accordingly, the present invention provides a series of crystalline salts of
(S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-
2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol derived from organic acids
such as fumaric, tartaric, maleic and mandelic acids.
Preferred salts of the invention are (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-
dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-
ol, hemifumarate; (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofu-
ran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L( + )-hemi-
tartrate; (S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-
methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol, maleate; (S) (+)-8-
chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-
tetrahydro-1 H-3-benzazepin-7-ol, L( + )-mandelate.
The acid addition salts of the (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihy-
drobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol
are prepared by dissolving the acid of the corresponding addition salt and

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the compound of formula I in a common solvent, and crystallizing the
resulting salt from the solution.
Examples of the common solvents include lower aliphalic alcohols such
as ethanol, methanol, 2-propanol, 2-butanol, 1-hexanol and solvents like
isobutylmethylketone and tetrahydrofuran.
The present invention also provides pharmaceutical compositions com-
prising crystalline salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-
benzofuran-7-yl)-3-methyl-2,3,4,~-tetrahydro-1 H-3-benzazepine-7-ol and
a pharmaceutically acceptable carrier.
The compositions of this invention are usually adapted for oral admini-
stration, but formulations for dissolution for parenteral administration are
also within the scope of this invention.
The composition is usually presented as a unit dose composition contain-
ing 0.01 mg - 1000 mg for oral dosing. Typical dosage for antiphsy-
chotic effect would vary between 0.1 - 400 mg, preferably between
1.0 - 200 mg per day divided in 2 or 3 doses when administered orally.
Preferred unit dosage forms include in solid form, tablets or capsules, in
liquid form, solutions, suspensions, emulsions, elixirs or capsules filled
with the same, or in form of sterile injectable solutions.
The composition of this invention may be formulated by conventional
methods of galenic pharmacy.
Conventional excipients are such pharmaceutically acceptable organic or
30 inorganic carrier substances suitable for parenteral or oral application
which do not deleteriously react with the active compound.

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Examples of such carriers are water, salt solutions, alcohols,
polyethylene glycols, polyhydroxyethoxylated castor oil, syrup, peanut
oil, olive oil, gelatin, lactose, terra alba, sucrose, agar, pectin, acacia,
amylose, magnesium stearate, talc, silicic acid, stearic acid, fatty acid
5 monoglycerides and diglycerides, pentaerythritol fatty acid esters,
hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and mixed, if desired,
with auxiliary agents, such as binders, lubricants, preservatives, dis-
10 integrants, stabilizers, wetting agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or colouring substances and the like,
which do not deleteriously react with the active compound.
For parenteral application, particularly suitable are injectable solutions or
15 suspensions, preferably aqueous solutions with the active compound
dissolved in polyhydroxylated castor oil.
For oral administration, particularly suitable are tablets, dragees, or cap-
sules having talc and/or a carbohydrate carrier or binder or the like, the
20 carrier preferably being lactose and/or corn starch and/or potato starch.
A syrup, elixir or like can be used when a sweetened vehicle can be
employed .
A typical tablet, which may be prepared by conventional tabletting tech-
25 niques, contains:
Active compound 10 mg !'
Lactosum 67.8 mg Ph.Eur.
Avicel~' 31.4 mg
AmberliteC' IRP 88 1.0 mg
Magnesii stearas 0.25 mg Ph.Eur.

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The invention also provides methods of treatment of certain disorders in
the central nerveous system related to dysfunctions of the dopamine D-1
receptor system, e.g. psychosis, depression, pain and Parkinson's
disease in mammals including humans which methods comprises admini-
5 stering an effective amount of a pharmaceutically acceptable crystallinesalt of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-
methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol.
The invention further provides pharmaceutically acceptable crystalline
salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-
methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7-ol for use in the treatment
of disorders in the central nerveous system related to dysfunctions of the
dopamine D-1 receptor system, e.g. psychosis, depression, pain and
Parkinson's disease.
The acid addition salts of (S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydro-
benzofuran-7-yl)-3-methyl-2,3,4,5-~etrahydro-1 H-3-benzazepine-7-ol of
the invention were synthesized and crystallized from common solvents
as described in the following examples.
EXAMPLE 1
(S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-
2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, hemifumarate
(S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-
2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol (7.97 9, 20 mmol) was dis-
solved 99% ethanol at 70~C. Fumaric acid (2.32 g, 20 mmol) was
30 added. The solution was cooled to 0~C, and the resulting suspension
was filtered. The filtercake was washed with 99% ethanol (3 x 20 ml)
and dried to constant weight.
-

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Yield: 8.80 9 (96%) of white crystalline product. M.p. by DSC: 298~C.
Elemental Analysis: (C21H20CI3N,04, 456.8 g/mol)
Calculated: C 55.22 H 4.41 N 3.07 %
Found: C 55.30 H 4.55 N 3.94 %
Alternate polymorphic forms: None
EXAMPLE 2
(S) (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-
2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L~ + )-hemitartrate
The preparation was carried out analogously to the preparation in
Example 1 using L( + )-tartaric acid and 20 mmol of the compound of for-
mula 1.
Yield: 7.75 g (82%) of white crystalline product. M.p. by DSC: 276~C.
Elemental Analysis: (C2lH2lCI3NlO5, 473.8 g/mol~:
Calculated: C 53.24 H 4.47 N 2.96 ~/O
Found: C 53.21 H 4.55 N 2.80 ~/0
Alternate polymorphic form: None
EXAMPLE 3
(S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-
2,3,4,5-tetrahydro- 1 H-3-benzazepin-7-ol, maleate
The preparation of the compound was carried out analogously to the
preparation in Example 1 using maleic acid, and 20 mmol of the com-
pound of formula 1.

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Yield: 7.61 9 ~74%) of white crystalline product. M.p. by DSC: 234OC,
Elemental Analysis: (C23H22CI3Nl08, 514.8 g/mol):
Calculated: C 53.66 H 4.31 N 2.72 %
Found: C 53.79 H 4.37 N 2.56 %
Alternate polymorphic form: None
EXAMPLE 4
(S) ( + )-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-3-methyl-
2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol, L( ~ )-mandelate
The preparation of the compound was carried out analogously to the
preparation in Example 1 using L( +)-mandelic acid, and 20 mmol of the
compound of formula 1.
Yield: 10.35 9 (94%) of white crystalline product. M.p. by DSC: 249~C.
Elemental analysis: (C27H2~CI3N105, 550.9 g/mol):
Calculated: C 58.87 H 4.76 N 2.54 %
Found: C 58.97 H 4.88 N 2.50 %
Alternate polymorphic form: None