Imidazole derivatives

Details Imidazole derivatives Imidazole derivatives

2001-12-20

2003-08-26

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S341000, C514S383000, C514S385000, C546S272400, C546S272700, C546S274100, C548S255000, C548S262200, C548S269400, C548S300100

Reexamination Certificate

active

06610723

ABSTRACT:

SUMMARY OF THE INVENTION
The present invention relates to compounds of formula
having valuable CNS, learning and memory forming pharmacological properties.
BACKGROUND OF THE INVENTION
Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmaceutical properties. Therapeutic indications for NMDA NR-2B receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, depression and chronic and acute pain.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to novel imidazole derivatives of formula
wherein
A is phenyl, pyridin-2-yl, pyridin-3-yl, or piperidin-1-yl;
R
1
and R
2
are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, cycloalkyl, lower alkenyl, trifluoromethyl, —O-trifluoromethyl, —S-trifluoromethyl, S-lower alkyl, lower alkoxy, —CHF
2
, —C(lower alkyl)F
2
, —OCHF
2
, phenyl, nitro, benzyloxy, hydroxy and amino, or alternatively, R
1
and R
2
together with the carbon atoms to which they are attached in any adjacent positions, form a group selected from —CH═CH—CH═CH—, —CH═CH—CH═N—, —(CH
2
)
3
—, —O—CH
2
—O—, —O—CF
2
—O—, —CH
2
—O—CH
2
— and —CH
2
CH
2
—O—;
R
3
is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, phenyl, S-lower alkyl, amino, lower alkyl-amino, —NHC(O)-lower alkyl and hydroxy-lower alkyl;
R
4
and R
5
are each independently selected from hydrogen and lower alkyl, or alternatively, R
4
and R
5
together with the carbon atoms to which they are attached form the group —(CH
2
)
4
—;
R
6′
and R
6
are each independently selected from hydrogen and lower alkyl;
X is —N< or
Y is ═N—, —NH—, —N═CH— or —CH═;
Z is —CR
7
, —N═, —NR
7
—, —N═CR
7
—, ═CH—N═C(R
7
)— or ═N—CH═CH—;
R
7
is hydrogen, —CH
2
OH or lower alkyl;
n is 0, 1 or 2;
m is 0 or 1; and
the dotted line may be 1, 2 or 3 bonds;
and to pharmaceutically acceptable acid addition salts thereof.
The heterocyclic aromatic group
in formula I may have the following structure:
Thus, by way of example, the following type of compounds are encompassed by formula I:
wherein substituents are as described above.
The novel compounds of the invention and their salts have valuable therapeutic properties. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
Objects of the invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the preparation of the compounds of formula I and salts thereof, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of NMDA-mediated disorders.
The present invention embraces racemic mixtures and all their corresponding enantiomers.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. Preferred lower alkyl groups contain from 1 to 4 carbon atoms.
As used herein, the term “lower alkenyl” denotes a C
2
-C
7
carbon group, having at least one double bond in the chain.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
The term “lower alkoxy” denotes a group wherein the alkyl residue is as defined above and the alkyl group is connected to the remainder of the molecule via an oxygen atom.
The term “cycloalkyl” denotes a carbon ring with 3 to 6 carbon atoms, preperred is cyclopropyl.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Preferred compounds of formula I are those wherein A is phenyl, for example the following group of compounds:
wherein
R
1
and R
2
are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, trifluoromethyl, S-lower alkyl, lower alkoxy,
—OCHF
2
, phenyl, nitro, benzyloxy, hydroxy and amino, or alternatively, R
1
and R
2
together with the carbon atoms to which they are attached form a group selected from —(CH
2
)
3
—, —O—CH
2
—O—, —CH
2
—O—CH
2
— and —CH
2
CH
2
—O—;
R
3
is selected from the group consisting of hydrogen, lower alkyl, phenyl, S-lower alkyl, amino, lower alkyl-amino, —NHC(O)-lower alkyl and hydroxy-lower alkyl;
R
4
and R
5
are each independently selected from hydrogen and lower alkyl, or alternatively, R
4
and R
5
together with the carbon atoms to which they are attached form the group —(CH
2
)
4
—;
R
6
and R
6′
are each independently selected from hydrogen and lower alkyl;
X is —N< or
Y is ═N—, —NH—, —N═CH— or —CH═;
Z is —CR═, —N═, —NH—, —N═CR
7
—, ═CH—N═C(R
7
)— or ═N—CH═CH—;
R
7
is hydrogen or lower alkyl;
n is 0, 1 or 2;
m is 0 or 1; and
the dotted line may be 1, 2, or 3 bonds;
and pharmaceutically acceptable acid addition salts thereof.
Especially preferred compounds of formula
in the scope of the present formula I are those, wherein A is phenyl, R
1
and R
2
are each independently selected from lower alkyl, —CHF
2
, —C(lower alkyl)F
2
, CF
3
and halogen, or alternatively, R
1
and R
2
together with the corresponding carbon atoms to which they are attached form the group —(CH
2
)
3
—; R
3
is lower alkyl or amino; and R
4
, R
5
R
6
, and R
6′
are hydrogen. Examples of such compounds are:
1H-imidazole, 1-[[1-(4-chloro-3-methylphenyl)-1H-imidazol-4-yl]methyl]-2-ethyl-;
1H-imidazole, 1-[[1-(4-chloro-3-methylphenyl)-1H-imidazol-4-yl]methyl]-2-methyl-;
1H-imidazole, 1-[[1-(2,3-dihydro-1H-inden-5-yl)-1H-imidazol-4-yl]methyl]-2-methyl-;
1H-imidazole, 1-[[1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methyl]-2-methyl;
1-[1-(4-chloro-3-methyl-phenyl)-1H-imidazol-4-yl-methyl]-1H-imidazol-2-yl-amine;
1H-imidazole, 1-[[1-[3-(1,1-difluoroethyl)phenyl]-1H-imidazol-4-yl]methyl]-2-methyl-;
1H-imidazole, 1-[[1-(3-difluoromethyl-4-fluorophenyl)-1H-imidazol-4-yl]methyl]-2-methyl-; and
1H-imidazole, 1-[[1-[3-(1,1-difluoroethyl)-4-fluorophenyl]-1H-imidazol-4-yl]methyl]-2-methyl-.
Further preferred are compounds of formula
in the scope of the present formula I, wherein A is phenyl, R
1
and R
2
are each independently selected from halogen; R
3
is lower alkyl or hydrogen; and R
4
, R
5
, R
6
, and R
6
are hydrogen. An Example of such a compound is:
1-(3,4-dichloro-phenyl)-3-(2-methyl-imidazol-1-yl-methyl)-1H-pyrazole.
Further preferred are compounds of formula
in the scope of the

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