Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-21
2001-09-18
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S121000
Reexamination Certificate
active
06291458
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new pharmaceutically acceptable salts of N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide as the (R)-enantiomer, the (S)-enantiomer or the racemate or as solvates of said salts, a process for their preparation, pharmaceutical formulations containing said salts or solvates and to the use of said active salts or solvates in therapy.
An object of the invention is to provide compounds for therapeutic use, especially compounds having a selective effect at a subgroup of 5-hydroxytryptamine receptors, designated the h5-HT
1B
-receptor (previously called the 5-HT
1D&bgr;
-receptor) in mammals including man, which compounds are easily formulated into pharmaceutical formulations.
It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.
PRIOR ART
Different classes of piperazinyl substituted benzanilide derivatives as 5-HT
1D
antagonists are disclosed in inter alia EP 533266, EP 533267, EP 533268, GB 2273930 and WO 95/11243.
WO 94/13659 discloses an extremely broad class of fused benzo compounds having a para substituted piperidyl or piperazinyl radical in the aromatic ring, said class or compounds is stated to bind to the 5-HT
1A
receptor.
WO 94/21619 discloses a fully aromatic naphthalene ring system which may be substituted with a piperidyl or piperazinyl group, said compounds are also stated to be potent serotonin (5HT
1
) agonists and antagonists.
EP 402923 discloses 2-aminoalkyl or alkylenaromatic substituted 1,2,3,4-tetrahydronaphthalene derivatives having a further nitrogen substitution in the 5 position in the tetraline ring, said compounds act as dopamine agonists.
BACKGROUND OF THE INVENTION
Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and/or 5-hydroxytryptamine(5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occurring in depressed patients.
Serotonin, or 5-HT, activity is thought to be involved in many different types of psychiatric disorders. For instance it is thought that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior.
The compound of formula I below in base form has an extremely low solubility in water and a slow release rate which rate is pH dependent, i.e. the rate is different in the stomach and the intestines. From a pharmaceutical formulation point of view it is very difficult to dissolve the base rapidly enough and maintain the same dissolved in the gastric juice until a sufficient amount of substance has been absorbed.
The 5-HT Receptors
The various effects of 5-HT may be related to the fact that serotoninergic neurons stimulate the secretion of several hormones, e.g. cortisol, prolactin, B-endorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. With the aid of molecular biology techniques, to date these receptors have been classified as 5-HT
1
, 5-HT
2
, 5-HT
3
, 5-HT
4
, 5-HT
5
, 5-HT
6
and 5-HT
7
with the
5
-HT
1
receptor further divided into the 5-HT
1A
, 5-HT
1B
, 5-HT
1D
, 5-HT
1E
and 5-HT
1F
subtypes. Each receptor subtype is involved in a different serotonin function and has different properties.
Regulation of the 5-HT transmission
The release of 5-HT at the nerve terminals is feedback-regulated by two different subtypes of 5-HT receptors. Inhibitory 5-HT
1A
autoreceptors are located on the cell bodies in the raphe nuclei which upon stimulation by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby reducing the 5-HT release at the nerve terminals. Another subtype of inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the h5-HT
1B
receptors (in rodents the r5-HT
1B
receptors) which regulate the synaptic concentration of 5-HT by controlling the amount of 5-HT that is released. An antagonist of these terminal autoreceptors thus increases the amount of 5-HT released by nerve impulses as has been shown in both in vitro and in vivo experiments.
The use of an antagonist of the terminal h5-HT
1B
autoreceptor will accordingly increase the synaptic 5-HT concentration and enhance the transmission in the 5-HT system. It would thus produce an antidepressant effect making it useful as a medication for depression.
Other localizations of h5-HT
1B
receptor subtype also exist. A large part of these postsynaptic receptors appear to be located on nerve terminals of other neuronal systems (so called heteroreceptors). Since the h5-HT
1B
receptor mediates inhibitory responses an antagonist of this receptor subtype might also increase the release of other neurotransmitters than 5-HT.
Compounds having h5-HT
1B
activity may according to well known and recognised pharmacological tests be divided into full agonists, partial agonists and antagonists.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide compounds having a selective effect at the h5-HT
1B
receptor, preferably antagonistic properties, as well as having a good bioavailability and which may easily be formulated into pharmaceutical formulations. The compounds according to the invention have surprisingly solved the above problem since they are dissolved rapidly enough and are maintained dissolved in the gastric juice until a sufficient amount of substance has been absorbed
Accordingly, the present invention provides pharmaceutically acceptable salts of the compound of formula I or solvates of said salt in which the compound of formula I is as the (R)-enantiomer, the (S)-enantiomer or the racemate,
with the proviso that
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide hydrogen (2S,3S)-tartrate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide hydrogen (2R,3R)-tartrate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide benzenesulfonate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzarnide hydrogen 1,2-ethanedisulfonate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide hydrogen maleate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzarnide hydrogen sulfate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide D-gluconate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide hydrogen succinate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide methanesulfonate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide hydrogen (S)-maleate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide dihydrogen citrate and
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide hydrochloride are excluded,
which salts possess a high selective effect at the h5-HT
1B
receptor, are easily formulated into pharmaceutical formulations and also show sufficient bioavailability after oral administration.
The preferred enantiomers are the (R)-enantiomers.
Berg Stefan
Sohn Daniel
Astrazeneca AB
Ramsuer Robert W.
White & Case LLP
LandOfFree
Morpholinobenzamide salts does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Morpholinobenzamide salts, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Morpholinobenzamide salts will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2473053