Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-21
2002-05-14
Ramsuer, Robert W. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S121000, C544S129000, C544S130000, C544S360000, C546S187000, C546S196000
Reexamination Certificate
active
06387899
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new piperidinyl- or piperazinyl-substituted 3,4-dihydro-2H-1-benzopyran derivatives as (R)-enantiomers, (S)-enantiomers or racemates in the form of free base or pharmaceutically acceptable salts or solvates 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-hydroxytryptamine receptors, designated h5-HT
1B
-receptor (previously called the 5-HT
1D&bgr;
-receptor) in mammals including man.
It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.
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 believed to be involved in many different types of psychiatric disorders. For instance it is believed 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 disorders and sexual disturbances.
The 5-HT Receptors
The various effects of 5-HT may be related to the fact that serotonergic 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 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 reducing the 5-HT released 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 which 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. The effect on the other receptors chosen from, for example, the 5-HT
1A
, 5-HT
2A
, D
1
, D
2
A, 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, CONR
2
or NR
2
SO
2
wherein R
2
is H or C
1
-C
6
alkyl;
R
1
is H, C
1
-C
6
alkyl or C
3
-C
6
cycloalkyl;
R
3
is C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl or (CH
2
)
n
-aryl, wherein 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
;
wherein 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
alkylphenyl, an optionally substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O, S, SO and SO
2
wherein the 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
;
wherein 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; and
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 selected from N, O, S, SO and SO
2
;
wherein R
5
is H, OH, CF
3
, OCF
3
, halogen, C
1
-C
6
alkyl or C
1
-C
6
alkoxy;
n is 0-4;
R
9
is C
1
-C
6
alkyl, C
3
-C
6
cycloalkyl OCF
3
, OCHF
2
, OCH
2
F, halogen, CONR
6
R
7
, CN, CF
3
, OH, C
1
-C
6
alkoxy, NR
6
R
7
, SO
3
CH
3
, SO
3
CF
3
, SO
2
NR
6
R
7
, an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C
1
-C
6
alkyl; or COR
8
; wherein R
6
, R
7
and R
8
are as defined above,
as (R)-enantiomers, (S)-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof which possess a high selective effect at the h5-HT
1B
receptor and also show 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 or S preferably is a 5- or 6-membered heteroaromatic ring and may be furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl. The heteroaromatic ring can be either substituted or unsubstituted.
In the present context the heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO or SO
2
may optionally contain a carbonyl function and is preferably a 5-, 6- or 7-membered heterocyclic ring and may be imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thio
Berg Stefan
Linderberg Mats
Ross Svante
Thorberg Seth-Olov
Ulff Bengt
AstraZeneca AB
Ramsuer Robert W.
White & Case LLP
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