Dihydro-benzo [b][1,4]diazepin-2-one...

Details Dihydro-benzo [b][1,4]diazepin-2-one... Dihydro-benzo [b][1,4]diazepin-2-one...

2002-04-03

2003-04-08

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S517000

Reexamination Certificate

active

06544985

ABSTRACT:

FIELD OF INVENTION
This invention is a dihydro-benzo[b][1,4]diazepin-2-one derivative of the formula
The compounds of formula I are metabotropic glutamate receptor antagonists.
BACKGROUND
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) form the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the group II can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits.
SUMMARY
The present invention is a compound of formula I
wherein
X is a single bond or an ethynediyl group; wherein
when X is a single bond,
R
1
is selected from the group consisting of cyano,
halogen,
lower alkyl,
C
3
-C
6
-cycloalkyl,
lower alkoxy,
fluoro-lower alkoxy,
fluoro-lower alkyl,
unsubstituted pyrrol-1-yl, and pyrrol-1-yl substituted by between one and three substituents selected from the group consisting of
fluoro, chloro, cyano, —(CH
2
)
1-4
-hydroxy, fluoro-lower alkyl, lower alkyl, —(CH
2
)
n
-lower alkoxy, —(CH
2
)
n
—C(O)O—R″, —(CH
2
)
1-4
—NR′R″, hydroxy-lower alkoxy, and —(CH
2
)
n
—CONR′R″, unsubstituted phenyl, and phenyl substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, fluoro-lower alkyl, lower alkoxy, fluoro-lower alkoxy and cyano;
when X is an ethynediyl group,
R
1
is unsubstituted phenyl, or phenyl substituted by between one and three substituents
selected from the group consisting of halogen, lower alkyl, fluoro-lower alkyl,
C
3
-C
6
-cycloalkyl, lower alkoxy and fluoro-lower alkoxy;
R
2
is -selected from the group consisting of NR′R″, fluoro-lower alkoxy,
unsubstituted 3-oxo-piperazin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, and 3-oxo-piperazin-1-yl, pyrrolidin-1-yl or piperidin-1-yl substituted by R″;
R′ is selected from the group consisting of hydrogen,
lower alkyl,
C
3
-C
6
-cycloalkyl,
fluoro-lower alkyl and
2-lower alkoxy lower alkyl;
R″ is selected from the group consisting of hydrogen,
lower alkyl,
C
3
-C
6
-cycloalkyl,
fluoro-lower alkyl,
2-lower alkoxy lower alkyl,
—(CH
2
)
2-4
-di-lower alkylamino,
—(CH
2
)
2-4
-morpholinyl,
(CH
2
)
2-4
-pyrrolidinyl,
—(CH2)
2-4
-piperidinyl and
3-hydroxy-lower alkyl;
Y is —CH═or ═N—;
R
3
is selected from the group consisting of halogen,
lower alkyl,
fluoro-lower alkyl,
lower alkoxy,
cyano,
—(CH
2
)
n
—C(O)—OR″,
—(CH
2
)
n
—C(O)—NR′R″,
unsubstituted five-membered aromatic heterocycle, and a five-membered aromatic heterocycle, substituted by halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano, —(CH
2
)
n
—NR′R″, —(CH
2
)
n
—C(O)—OR″, —(CH
2
)
n
—C(O)—NR′R″, —(CH
2
)
n
—SO
2
—NR′R″ lower alkyl, or lower alkyl substituted by a substituent selected from the group consisting of fluoro, hydroxy, lower alkoxy, cyano and carbamoyloxy; and
n is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable addition salt thereof.
It has surprisingly been found that the compounds of formula I are metabotropic glutamate receptor antagonists. Compounds of formula I are distinguished by valuable therapeutic properties.
Objects of the present invention are: compounds of formula I or a pharmaceutically acceptable salt thereof; pharmaceutically active substances and their manufacture the use of a compound of the invention in the control or prevention of illnesses as described above; and the production of pharmaceutical compositions containing a therapeutically effective amount of the compound of formula I in a pharmaceutically acceptable carrier.
The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in absorption, pharmacokinetics in distribution and transport to the brain.
All tautomeric forms of the compounds of the invention are also embraced herewith.
DETAILED DESCRIPTION
Preferred are compounds of formula I wherein X is a single bond. Exemplarly preferred are compounds, wherein R
1
is trifluoromethyl, and especially those wherein R
3
is cyano, for example the following compounds:
4-(4-oxo-8-pyrrolidin-1-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile,
4-[8-(cyclopropylmethyl-methyl-amino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile,
4-[8-(cyclopropylmethyl-amino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile,
4-[4-oxo-8-(2,2,2-trifluoro-ethoxy)-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile, and
4-[8-(isopropyl-methyl-amino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo [b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile.
Further preferred are compounds, wherein X is a single bond, R
1
is trifluoromethyl and R
3
is an unsubstituted five-member aromatic heterocycle or a substituted five-membered aromatic heterocycle, substituted by halogen, fluoro-lower alkyl, fluoro-lower alkoxy, cyano, —(CH
2
)
n
—NR′R″, —(CH
2
)
n
—C(O)—OR″, —(CH
2
)
n
—C(O)—NR′R″, —(CH
2
)
n
—SO
2
—NR′R″, —(CH
2
)
n
—C(NH
2
)═NR″, hydroxy, lower alkoxy, lower alkylthio, unsubstituted lower alkyl or lower alkyl substituted by fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy. Examples of such compounds are the following:
7-dimethylamino-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-dimethylamino-4-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
7-dimethylamino-4-(3-imidazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-7-(methyl-propyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
7-(isobutyl-methyl-amino)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isopropyl-methyl-amino)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isobutyl-methyl-amino)-4-(3-{5-[(isopropyl-methyl-amino)-methyl]-[1,2,3]triazol-1-yl}-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isopropyl-methyl-amino)-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo [b][1,4]diazepin-2-one,
7-(methyl-propyl-amino)-4-(3-[1,2,3]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-(isobutyl-methyl-amino)

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