Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-03
2003-04-15
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
06548495
ABSTRACT:
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.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are chronic and acute pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
SUMMARY
The present invention is a compound of formula I
wherein
R is selected from the group consisting of cyano,
fluoro-lower alkyl,
lower alkoxy,
fluoro-lower alkoxy,
unsubstituted pyrrol-1-yl, and pyrrol-1-yl substitued by one to three substituents selected from the group consisting of
fluoro, chloro, cyano, unsubstituted phenyl or phenyl substituted by halogen,
—(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″;
R
2
is selected from the group consisting of
halogen,
hydroxy,
lower alkyl,
fluoro-lower alkyl,
lower alkoxy,
hydroxymethyl,
hydroxyethoxy,
lower alkoxy-(ethoxy)
m
, wherein m=1 to 4,
lower alkoxymethyl,
cyanomethoxy,
morpholine-4-yl,
thiomorpholine-4-yl,
1-oxothiomorpholine-4-yl,
1,1-dioxothiomorpholine-4-yl,
4-oxo-piperidine-1-yl
4-alkoxy-piperidine-1-yl,
4-hydroxy-piperidine-1-yl,
4-hydroxyethoxy-piperidine-1-yl,
4-lower alkyl-piperazine-1-yl,
alkoxycarbonyl,
2-dialkylamino-ethylsulfanyl,
N,N-bis lower alkylamino lower alkyl,
carbamoylmethyl,
alkylsulfonyl
lower alkoxycarbonyl-lower alkyl,
alkylcarboxy-lower alkyl,
carboxy-lower alkyl,
alkoxycarbonylmethylsulfanyl,
carboxymethylsulfanyl,
1,4-dioxa-8-aza-spiro[4.5]dec-8-yl,
carboxy-lower alkoxy,
cyano-lower alkyl,
2,3-dihydroxy-lower alkoxy,
carbamoylmethoxy,
2-oxo-[1,3]-dioxolan-4-yl-lower alkoxy,
N-(2-hydroxy-lower alkyl)-N-lower alkyl amino,
hydroxycarbamoyl-lower alkoxy,
2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5c]-pyrrol-5-yl,
lower alkoxy-carbamoyl-lower alkoxy,
3R-hydroxy-pyrrolidin-1-yl,
3,4-dihydroxy-pyrrolidin-1-yl,
2-oxo-oxazolidin-3-yl,
lower alkyl-carbamoylmethoxy,
aminocarbamoyl-lower alkoxy, and, when R
1
is unsubstituted pyrrol-1-yl or pyrrol-1-yl substituted as described above, hydrogen;
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″,
an unsubstituted five-membered aromatic heterocycle and a five-membered aromatic hetero cycle 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;
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,
—(CH
2
)
2-4
-piperidinyl or
3-hydroxy-lower alkyl;
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.
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.
As compounds of the present invention are metabotropic glutamate receptor agonists, they can be used to treat or prevent acute and/or chronic neurological disorders responsive to a metabotropic glutamate receptor agonist in a method of treatment comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
All tautomeric forms of the compounds of the invention are within the scope of the invention.
DETAILED DESCRIPTION
A preferred compound of the invention of formula I is the compound, wherein R
1
is trifluoromethyl. An exemplary preferred compound, wherein R
2
is morpholine, is selected from the group consisting of
4-(8-morpholin-4-yl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile,
4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-7-morpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-7-morpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(3-hydroxymethyl-isoxazol-5-yl)-phenyl]-7-morpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
4-[3-(5-hydroxymethyl-isoxazol-3-yl)-phenyl]-7-morpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.
Also preferred is a compound of formula I, wherein R
1
is trifluoromethyl and R
2
is thiomorpholine selected from the group consisting of
4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-7-thiomorpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
4-(4-oxo-8-thiomorpholin-4-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile.
A further preferred compound of formula I wherein R
1
is trifluoromethyl and R
2
is lower alkoxy is selected from the group consisting of
7-methoxy-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-methoxy-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,
4-(8-ethoxy-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile,
4-[3-(5-cycl
Adam Geo
Goetschi Erwin
Mutel Vincent
Wichmann Juergen
Woltering Thomas Johannes
Hoffmann-La Roche Inc.
Johnston George W.
Kifle Bruck
Rocha-Tramaloni Patricia S.
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