Cyclobutaindolecarboxamide compounds

Details Cyclobutaindolecarboxamide compounds Cyclobutaindolecarboxamide compounds

2001-04-12

2002-09-17

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06452015

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new cyclobutaindolecarboxamide compounds, and pharmaceutical compositions containing them.
The compounds of the present invention are useful in the treatment of disorders of the central nervous system, such as anxiety, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders, drug abuse, cognitive disorders, psychoses, depression and mood disorders.
PRIOR ART DESCRIPTION
Numerous polycyclic and heterocyclic compounds containing a urea function have been described in the literature as antagonists of various serotonergic receptors, thus enabling them to be used in the treatment of disorders of the central nervous system. This applies more especially to the Patent Applications WO 95/29177, WO 96/23783 and WO 98/47868, while patent specification U.S. Pat. No. 5,514,690 describes aminocarbonylquinoline and indoline compounds and claims them for their property of activating potassium pumps. In addition to being new, the compounds of the present invention have proved very active in the treatment of disorders of the central nervous system, and more especially have demonstrated strong activity in the Vogel conflict test in the rat, and in the marble-burying test in the mouse. The results obtained in the first test allows the use of the compounds of the invention in the treatment of clinical phenomena associated with anxiety to be proposed, and the results obtained in the second test demonstrates the strong therapeutic potential of the compounds of the invention in the treatment of illnesses associated with mood disorders.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates more especially to the compounds of formula (I):
wherein:
n represents an integer of from 0 to 6,
R
1
represents a group selected from hydrogen, hydroxy, cyano, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)alkoxycarbonyl, carboxy, aminocarbonyl (the amino moiety optionally being substituted by one or two identical or different groups selected from linear or branched (C
1
-C
6
)alkyl, aryl and aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched) and NR
4
R
5
wherein R
4
and R
5
, which may be identical or different, represent a group selected from linear or branched (C
1
-C
6
)alkyl, aryl, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, heteroaryl, heteroaryl. (C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, cycloalkyl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, linear or branched (C
2
-C
6
)alkenyl and linear or branched (C
2
-C
6
)alkynyl,
R
2
represents a group selected from hydrogen, linear or branched (C
1
-C
6
)alkyl, hydroxymethyl, a group of formula
wherein:
T represents a monocyclic or polycyclic (C
3
-C
12
)cycloalkyl group, it being possible for one of the carbon atoms of the cycloalkyl optionally to be replaced by a group selected from oxygen, selenium, a group of formula S(O)
p
wherein p represents an integer of from 0 to 2 inclusive, and a group of formula SiR
6
R
7
wherein R
6
and R
7
, which may be identical or different, represent a linear or branched (C
1
-C
6
)alkyl group,
U represents a bond or a methylene group,
V represents a bond, an oxygen atom or a group S(O)
q
wherein q is an integer of from 0 to 2 inclusive, and
W represents a group selected from aryl, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, and cycloalkyl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched,
and
R
3
represents a group selected from hydrogen, linear or branched (C
1
-C
6
)alkyl, aryl and heteroaryl,
to their isomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base.
An aryl group is to be understood as a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl, each of which groups is optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)-alkoxy, nitro, cyano, linear or branched (C
1
-C
6
)trihaloalkyl, amino, monoalkylamino, di-(C
1
-C
6
)alkylamino in which the alkyl moieties may be linear or branched, (C
1
-C
6
)-trihaloalkoxy in which the alkoxy moiety may be linear or branched, amino(C
1
-C
6
)alkylaminocarbonyl (the nitrogen atoms of each of the amino moieties optionally being substituted by identical or different linear or branched (C
1
-C
6
)alkyl groups), pyridyl, pyridyloxy and pyridyloxymethyl, the latter three groups optionally being substituted by a linear or branched (C
1
-C
6
)alkyl group.
A heteroaryl group is to be understood as an aromatic monocyclic system, or a bicyclic system in which one of the rings is aromatic and the other ring is aromatic or partially hydrogenated, having from 5 to 12 ring members and containing one, two or three identical or different hetero atoms selected from oxygen, nitrogen and sulphur, each of the groups optionally being substituted by one or more identical or different groups selected from the substituents described for the aryl group defined above.
A cycloalkyl group is to be understood as a mono- or poly-cyclic system having from 3 to 12 ring members and optionally containing one or more unsaturations, wherein the unsaturations do not confer an aromatic character to the said ring system.
Isomers is to be understood as optical isomers (enantiomers (enantiomers and diastereoisomers).
Amongst the pharmaceuticaly acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic, camphoric acid, etc.
Amongst the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
According to an advantageous embodiment of the invention, preferred compounds of the invention are compounds of formula (I) wherein R
2
represents a hydrogen atom.
According to another advantageous embodiment of the invention, preferred compounds of the invention are compounds of formula (I) wherein R
2
represents a group of formula
wherein T is as defined for formula(I), n is 1, and R
1
represents a cyano group or an amino group optionally substituted by one or two identical or different groups selected from linear or branched (C
1
-C
6
)alkyl and aryl-(C
1
-C
6
)alkyl in which the alkyl moiety may be linear or branched.
In another advantageous embodiment, preferred compounds of the invention are compounds of formula (I) wherein n is 0, R
1
represents a hydrogen atom or a cyano group and R
2
represents a group of formula -U-V-W wherein U represents a single bond, V represents a group of formula S(O)
p
wherein p is as defined for formula (I) and W represents an aryl group.
Especially advantageously, preferred compounds of the invention are compounds of formula (I) wherein n is 0, R
1
represents a hydrogen atom or a cyano group and R
2
represents a hydrogen atom.
The substituent R
3
preferred in accordance with the invention is the heteroaryl group and, more especially, the pyridyl group.
The following are preferred compounds of the invention:
N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
5-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
6-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
6-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
5-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
7-cyano-N-(3-pyridyl)-1,2,6,7-tetrahydro-3H-cyclobuta[e]indole-3-carboxamide,
7-(hydroxymethyl)-N-(3-pyridyl)-2,3,6,7-tetrahydro-1H-cyclobuta[g]indole-1-carboxamide,
6-[(dimethylamino)methyl]-6-

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