Beta-carboline compounds

Details Beta-carboline compounds Beta-carboline compounds

2000-07-21

2002-02-26

Morris, Patricia L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S085000, C546S086000, C546S087000

Reexamination Certificate

active

06350757

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new &bgr;-carboline compounds, and to pharmaceutical compositions containing them. The new compounds have a serotonergic activity on receptors of the 5-HT
2
family.
Serotonin is a neurotransmitter that acts on 5-HT (5-hydroxytryptamine) receptors both centrally and peripherally. To date, fourteen sub-types of serotonin receptor have been identified and classified within seven families, 5-HT
1
to 5-HT
7
. Of the 5-HT
2
family, the sub-types 5-HT
2A
, 5-HT
2B
and 5-HT
2C
are known. Those sub-types play a similar role in their specificity for a large number of ligands (Trends. Pharmacol. Sci., 1995, 16, 105-110, Neuropharmacology, 1994, 33, 275-317).
Since the compounds are capable of modulating the activity of 5-HT
2
receptors and especially of 5-HT
2C
and 5HT
2B
receptors they are likely to be of use in the treatment of complaints such as sleep disorders, (Psychopharmacology, 1989, 97, 436-442; Neuropharmacol., 1994, 33, 467-471), appetite disorders (Psychopharmacology, 1997, 133, 309-312), panic attacks, phobias, anxiety (Br. J. Pharmacol., 1996, 117, 427-434; Neuropharmacology, 1997, 36, 793-802), depression (Biol. Psychiatry, 1996, 39, 1000-1008; Neuroscience, 1999, 91(2), 587-597), impulsive and aggressive disorders (Pharm. Biochem. Behavior, 1991, 39, 729-736), sexual disorders (Clinical Neuropharmacology, 1997 20(3), 210-214), migraine (Progress in Drug Research, 1998, 51, 219-244, ed. Springer Verlay), schizophrenia and psychosis (Eur. J. Pharm., 1993, 245, 179-182; Biol. Psychiatry, 1998, 44, 1099-1117).
PRIOR ART DESCRIPTION
A large number of &bgr;-carboline compounds have already been described in the literature. That applies more especially to Patent Application EP 0 620 223, which claims tetrahydro-pyrido-indole compounds, those compounds having a strong affinity for 5-HT
2C
receptors. The Patent Applications EP 0 320 079 and EP 0 300 541 claim &bgr;-carboline compounds, dihydro-&bgr;-carboline and tetrahydro-&bgr;-carboline, which have a strong fibrinolytic activity. Finally, Patent Application WO 95/24200 describes compounds having in particular a tetrahydro-&bgr;-carboline structural pattern. Those compounds are specific antagonists of 5-HT
2B
receptors.
In addition to the fact that the compounds of the present invention are new, they have proved to be potent selective ligands of 5-HT
2
receptors and, in particular, of 5-HT
2C
and 5HT
2B
antagonists, thus rendering them potentially useful in the treatment of depression, psychosis, schizophrenia, phobia, anxiety, panic attacks, sleep disorders, appetite disorders, impulsive and aggressive disorders, sexual disorders and migraine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more specifically to compounds of formula (I):
wherein:
represents a single or double bond capable optionally of conferring an aromatic character to the ring carrying them,
R
1
represents a group selected from:
hydrogen,
linear or branched (C
1
-C
6
)alkyl,
—R
6
-aryl, —R
6
-cycloalkyl, —R
6
-heterocycle, in which groups R
6
represents a linear or branched (C
1
-C
6
)alkylene group,
—CO
2
R
7
wherein R
7
represents a linear or branched (C
1
-C
6
)alkyl group, an aryl group, a cycloalkyl group, a heterocycle, an —R
6
-aryl group, an —R
6
-cycloalkyl group or an —R
6
-heterocycle wherein R
6
is as defined hereinbefore,
—COR
8
wherein R
8
represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group, a cycloalkyl group, a heterocycle, an —R
6
-aryl group, an —R
6
-cycloalkyl group or an —R
6
-heterocycle wherein R
6
is as defined hereinbefore, and
—CONH—R
8
wherein R
8
is as defined hereinbefore,
or R
1
does not exist when the nitrogen atom carrying it is already carrying an intracyclic double bond,
R
2
represents a group selected from
cyano,
—CO
2
R
8
wherein R
8
is as defined hereinbefore,
—CONHR
8
wherein R
8
is as defined hereinbefore,
mono(C
1
-C
6
)alkylamino(C
1
-C
6
)alkylaminocarbonyl, di(C
1
-C
6
)alkylamino-(C
1
-C
6
)-alkylaminocarbonyl, the alkyl moieties of each of which groups may be linear or branched,
—NR
8
R
9
wherein R
8
is as defined hereinbefore and R
9
represents a group as defined for R
8
,
—NH—CO
2
R
7
wherein R
7
is as defined hereinbefore, and
—COR
8
wherein R
8
is as defined hereinbefore,
R
3
and R
4
together form a (C
3
-C
10
)cycloalkyl group,
R
5
represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group or an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety may be linear or branched,
Ra, Rb, Rc and Rd, which may be identical or different, each represents, independently of the others, a group selected from hydrogen, halogen, linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched trihalo-(C
1
-C
6
)alkyl, linear or branched trihalo-(C
1
-C
6
)alkoxy, nitro, cyano, amino, linear or branched (C
1
-C
6
)alkylamino, di(C
1
-C
6
)alkylamino in which each alkyl moiety may be linear or branched, aryl, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, carboxy, linear or branched (C
1
-C
6
)alkylcarbonyloxy, linear or branched (C
1
-C
6
)acyl, aryloxy and aryl-(C
1
-C
6
)alkoxy in which the alkoxy moiety may be linear or branched,
to their isomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that:
“cycloalkyl” is to be understood as a mono- or bi-cyclic group that is saturated (or optionally contains one or more unsaturations that do not confer an aromatic character to the ring system), contains from 3 to 10 carbon atoms, and is optionally substituted by one or more identical or different groups selected from halogen, hydroxy, linear or branched (C
1
-C
6
)alkyl and linear or branched (C
1
-C
6
)alkoxy,
“aryl” is to be understood as a phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indenyl or indanyl group, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, amino, linear or branched (C
1
-C
6
)alkylamino, di(C
1
-C
6
)alkylamino in which each of the alkyl moieties may be linear or branched, aryloxy, aryl-(C
1
-C
6
)alkoxy which the alkoxy moiety may be linear or branched, linear or branched trihalo(C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)acyl, linear or branched (C
1
-C
6
)alkoxycarbonyl, linear or branched (C
1
-C
6
)alkylaminocarbonyl and oxo,
“heterocycle” is to be understood as a saturated or unsaturated, mono- or bi-cyclic group of aromatic or non-aromatic character having from 5 to 12 ring members and containing one, two or three hetero atom, identical or different, hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heterocycle may be optionally substituted by one or more identical or different groups selected from halogen, hydroxy, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, nitro, oxo, and amino (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups).
Among the heterocycles there may be mentioned, by way of indication and without implying any limitation, the groups pyridinyl, thienyl, furyl, imidazolyl, 4H-pyranyl-4-one, pyrazinyl, pyrimidinyl, isoxazolyl, tetrazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, quinazolinyl, pyrrolidinyl, piperidyl, piperazinyl, 1,2,3-thiadiazolyl, . . . .
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
Acc

Affiliated with

Also associated with

Rating

Beta-carboline compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Beta-carboline compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Beta-carboline compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2960372