Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-18
2001-04-03
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06211173
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of compounds of the general formula I for the treatment of patients suffering from sleep disorders and/or sleep disturbances. The present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Sleep disorders and sleep disturbances are those known to be included in the definition by those skilled in the art, which includes e.g. insomnia, agitation, restlessness.
Benzodiazepines are widely used in the pharmacological treatment of sleep disorders and/or sleep disturbances . These compounds are endowed with numerous side effects such as amnesia, induction of tolerance and high abuse potential. Thus there exists a need for a compound in the treatment sleep disorders and/or sleep disturbances which causes less side effects than known compounds.
Preclinical experiments have shown that dopamine D1 receptor antagonists, including NNC 0756 ((+-8-chloro-7-hydroxy-3-methyl-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine) markedly enhance the time spent in sleep through an increase in both REM and non-REM sleep (“Differential effects of dopamine D1 and D2 receptor antagonist antipsychotics on sleep-wake patterns in the rat”, Ongini et al. (1993), Journ. Pharm. Exp. Ther., 266 (2), 726-731) whereas the dopamine D1 receptor agonist SKF 38393 reduced the amount of REM sleep and increased the duration of wakefulness (“The dopamine D1 receptor is involved in the regulation of REM sleep in the rat”, Trampus et al. (1991), Eur. Journ. Pharm., 194, 189-194).
Ideally, a hypnotic should have a short half life, so that the compound, when administered at bed time, is cleared from the body in the morning. Therefore, compounds like NNC 0756, having a relatively long half life, is not well suited with respect to this indication.
In EP 5,298 and EP 5,299, 7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives are described. It is stated that these compounds have antipsychotic and antidepressive effects.
In European Patent No. 0200455, 8-chloro-2,3,4,5-tetrahydro-1H-3-benzazepines including NNC 0756 (+)-8-chloro-7-hydroxy-3-methyl-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine are described These compounds are described as dopamine antagonists having antipsychotic and antidepressive effects.
European Patent No. 0347672 describes 8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepines. These compounds are described as dopamine antagonists useful as neuroleptics in the treatment of various mental disorders, e.g manic-depressive disorders. There is no disclosure in the application of using the compounds to treat sleep disorders.
One object of the present invention is to provide compounds which can effectively be used in the treatment or prevention of sleep disorders and/or sleep disturbances, e.g. insomnia, and which have a short half life, so that the compounds, when administered at bed time, are cleared from the body in the morning.
DESCRIPTION OF THE INVENTION
It has, surprisingly, been found that compounds of the general formula I
wherein
R
3
is hydrogen, C
1-4
-alkyl or C
3-7
-cycloalkyl; R
4
is hydrogen or R
4
together with R
10
represents a bridge which connects the positions to which R
4
and R
10
are linked, said bridge being —CH
2
—CH
2
—, —CH═CH—, —O—CH
2
— or —S—CH
2
—, provided that when the bridge contains a heteroatom, the bridge member linked to the benzazepine nucleus is always a carbon atom;
R
7
is hydroxy or C
1-4
-alkoxy;
R
10
, R
11
, R
12
independently represent hydrogen, trifluoromethyl, halogen or a straight or branched C
1-4
-alkyl; or R
10
together with R
4
represents a bridge as described in connection with the definition of R
4
; or R
10
together with R
11
represents a bridge, or R
11
together with R
12
represents a bridge, the bridge in both cases being chosen among —O—CH
2
—CH
2
—, —O—CH
2
—CH
2
—CH
2
—, —O—CH═CH—, —CH
2
—CH
2
—CH
2
—, —CH
2
—CH═CH— or —CH
2
—CH
2
—CH
2
—CH
2
—;
R
13
is hydrogen, halogen or C
1-4
-alkyl;
or a pharmaceutically acceptable salt thereof, can be used for the manufacture of a pharmaceutical composition for the treatment or prevention of sleep disorders and/or sleep disturbances.
Thus the compounds of the above general formula I can be used in methods for treating or preventing sleep disorders and/or sleep disturbances.
It has been demonstrated that that the compounds of formula I are useful in the treatment or prevention of sleep disorders and/or sleep disturbances, such as insomnia, i.e. delay of sleep onset, difficulty staying asleep, awakening too early.
Within the present invention, compounds of formula I are used for treatment or prevention of sleep disorders and/or sleep disturbances in a patient.
Within its scope the invention includes all optical isomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixture thereof.
The scope of the invention also includes all tautomeric forms of the compounds of formula I.
As used herein, the terms “C
1-4
-alkyl” includes straight or branched chain alkyl radicals containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like.
The term “C
3-7
-cycloalkyl” as used herein refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term “C
1-4
-alkoxy” includes straight or branched chain alkoxy radicals containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
“Halogen” includes chloro, fluoro, bromo and iodo.
Preferred compounds include those in which R
3
is C
1-4
-alkyl, especially methyl; R
4
is hydrogen or R
4
together with R
10
represents a bridge being —CH
2
—CH
2
— or —CH═CH—; R
7
is hydroxy; R
10
R
11
, R
12
independently represent hydrogen, halogen, trifluormethyl or methyl; or R
10
together with R
11
represents a bridge being —O—CH
2
—CH
2
—, —O—CH═CH—, —CH
2
—CH
2
—CH
2
— or —CH
2
—CH═CH—, or R
11
together with R
12
represents a bridge being —O—CH
2
—CH
2
—, —O—CH═CH—, —CH
2
—CH
2
—CH
2
— or —CH
2
—CH═CH—; R
13
is hydrogen.
To be included by this invention are all pharmaceutically acceptable salts of the mentioned compounds of formula I.
As used herein the term “patient” includes any mammal which could benefit from treatment of sleep disorders. The term particularly refers to a human patient, but is not intended to be so limited.
The compounds of formula I are prepared according to known methods, such as those described in European Patent No. 0347672, the contents of which are incorporated herein by reference.
Within the present invention, the compounds of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, lactic acid, oxalic acid, succinic acid, malonic acid, phthalic acid, fumaric acid, mandelic acid, methane-sulfonic acid, ethane-sulfonic acid, .malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and the like. The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The compounds of formula I and their salts are useful within human and veterinary medicine, for example, in the treatment of patients suffering from a sleep disorder and/or sleep disturbance. For use within the present invention, the compounds of formula I and their pharmaceutic
Fink-Jensen Anders
Foged Christian
Cenes Limited
Fay Zohreh
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
LandOfFree
Use of 2,3,4,5-tetrahydro-1H-3-benzazepines for the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of 2,3,4,5-tetrahydro-1H-3-benzazepines for the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of 2,3,4,5-tetrahydro-1H-3-benzazepines for the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2495838