Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-31
2002-06-25
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S392000, C544S395000, C514S255030, C514S319000, C546S206000
Reexamination Certificate
active
06410530
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the new compounds, piperidinyl- or piperazinyl-substituted-1,2,3,4-tetrahydronaphthalene derivatives as (R)-enantiomers, (S)-enantiomers or racemates in the form of a free base or pharmaceutically acceptable salts thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds 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-hydroxy-tryptamine receptors, designated the 5-HT
1D
-receptor in mammals including man.
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 piperidinyl or piperazinyl radical in the aromatic ring. Said class of 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 piperidinyl 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 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. The invention concerns compounds which have an effect on 5-HT neurotransmission.
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 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, &bgr;-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 raphé nuclei which upon stimulation by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby reduce the 5-HT release at the nerve terminals. Another subtype of inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the 5-HT
1D
receptors (in rodents the 5-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 5-HT
1D
autoreceptor will accordingly increase the synaptic 5-HT concentration and enhance the transmission in the 5-HT system. The antagonist would thus produce an antidepressant effect making it useful as a medication for depression.
Other localizations of 5-HT
1D
receptor subtype also exist. A large part of these receptors appear to be located on nerve terminals of other neuronal systems (so called heteroreceptors). Since the 5-HT
1D
receptor mediates inhibitory responses, an antagonist of this receptor subtype might also increase the release of other neurotransmitters than 5-HT.
Compounds having 5-HT
1D
activity may according to well known and recognized pharmacological tests be divided into full agonists, partial agonists and antagonists.
DISCLOSURE OF THE INVENTION
The primary object of the present invention is to provide compounds having a selective effect at the 5-HT
1D
receptor, preferably antagonistic properties, as well as having a good bioavailability. The effect on the other receptors chosen from, for example, the 5-HT
1A
, 5-HT
2A
, D
1
, D
2A
, D
3
, &agr;
1
and &agr;
2
receptor has been investigated.
Accordingly, the present invention provides compounds of the formula I
wherein
X is N or CH;
Y is NR
2
CH
2
, CH
2
—NR
2
, NR
2
—CO, CO—NR
2
or NR
2
SO
2
;
R
1
is H, C
1
-C
6
alkyl or C
3
-C
6
cycloalkyl;
R
2
is H or C
1
-C
6
alkyl;
R
3
is C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl or (CH
2
)
n
-aryl,
where aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R
4
and/or R
5
;
R
4
is H, C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, halogen, CN, CF
3
, OH, C
1
-C
6
alkoxy, NR
6
R
7
, OCF
3
, SO
3
CH
3
, SO
3
CF
3
, SO
2
NR
6
R
7
, phenyl, phenyl-C
1
-C
6
alkyl, phenoxy, C
1
-C
6
alkyl, phenyl, C
1
-C
6
alkyl-heterocyclic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO
2
, an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO
2
, wherein the optional substituent(s) is(are) selected from C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl and phenyl-C
1
-C
6
alkyl; or COR
8
;
R
5
is H, OH, CF
3
, OCF
3
, halogen, C
1
-C
6
alkyl or C
1
-C
6
alkoxy,
R
6
is H, C
1
-C
6
alkyl or C
3
-C
6
cycloalkyl;
R
7
is H, C
1
-C
6
alkyl or C
3
-C
6
cycloalkyl;
R
8
is C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl, CF
3
, NR
6
R
7
, phenyl, or a heterocyclic ring containing one or two heteroatoms or substituted heteroatoms selected from N, O, S, SO and SO
2
;
n is 0-4;
as (R)-enantiomer, (S)-enantiomer or a racemate in the form of the free base or a pharmaceutically acceptable salt or hydrate thereof which possesses a high selective effect at the 5-HT
1D
receptor and also shows sufficient bioavailability after oral administration.
In the present context C
1
-C
6
alkyl may be straight or branched. C
1
-C
6
alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl.
In the present context C
1
-C
6
alkoxy may be straight or branched. C
1
-C
6
alkoxy may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy, n-hexyloxy or i-hexyloxy.
In the present context C
3
-C
6
cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclohexyl.
In the present context halogen may be fluoro, chloro, bromo or iodo.
In the present context the heteroaromatic ring containing one or two heteroatoms selected from N, O and S preferably is a 5- or 6-membered heteroaromatic ring and may be furyl, imidazoly
Berg Stefan
Florvall Lennart
Ross Svante
Thorberg Seth-Olov
AstraZeneca AB
Liu Hong
Raymond Richard L.
White & Case LLP
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