Phenylethynyl and styryl derivatives of imidazole and fused...

Details Phenylethynyl and styryl derivatives of imidazole and fused... Phenylethynyl and styryl derivatives of imidazole and fused...

2001-11-28

2004-03-16

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S230500, C544S034000, C544S102000

Reexamination Certificate

active

06706707

ABSTRACT:

BACKGROUND OF THE INVENTION
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.
Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to 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. According to their sequence homology, signal transduction mechanisms and agonist selectivity, 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 first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
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 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.
Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression and pain. Selective mGluR5 antagonists are especially useful for the treatment of anxiety and pain.
SUMMARY OF THE INVENTION
The present invention is a method of treatment of mGluR5 receptor mediated disorders by administering a therapeutically effective amount phenylethenyl and phenylethynyl derivatives of the compound formula
wherein
R
1
, R
2
, R
3
, R
4
and R
5
, are independently selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
-halogen, lower alkoxy, —(CH
2
)
n
—NRR′, —(CH
2
)
n
—N(R)—C(O)-lower alkyl, aryl or heteroaryl which is unsubstituted or substituted by one or more lower alkyl residues;
R, R′ and R″ are independently selected from the group consisting of hydrogen and lower alkyl;
A is selected from the group consisting of —CH═CH— or —C≡C—; and
B is selected from the group consisting of
wherein
R
6
is selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
—C(O)OR and halogen;
R
7
is selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
—C(O)OR′, halogen, nitro, unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl;
R
8
is selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
—OH, —(CH
2
)
n
—C(O)OR″ and aryl;
R
9
is lower alkyl;
R
10
is selected from the group consisting of hydrogen, lower alkyl and halogen;
R
11
is selected from the group consisting of hydrogen and alkyl;
R
12
is —(CH
2
)
n
—N(R)—C(O)-lower alkyl;
R
13
selected from the group consisting of hydrogen and lower alkyl;
R
14
, R
15
, R
16
and R
17
are independently selected from the group consisting of, hydrogen, lower alkyl, —(CH
2
)
n
-halogen and lower alkoxy;
R
18
, R
19
and R
20
are independently selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
-halogen and lower alkoxy;
R
21
is hydrogen or lower alkyl;
R
22
is selected from the group consisting of hydrogen, lower alkyl and lower alkyl with at least one substituent selected from the group consisting of hydroxy or halogen;
R
23
is selected from the group consisting of hydrogen, lower alkyl, lower alkanoyl and nitro;
R
24
, R
25
and R
26
, are independently selected from the group consisting of hydrogen and lower alkyl;
n is 0, 1, 2, 3, 4, 5 or 6;
X is —CH
2
—, —O— or —S—; and
Y is —CH═ or —N═;
or a pharmaceutically acceptable salt thereof.
Some compounds of the present formula I are known compounds and are described in the literature. For example the synthesis of 1-methyl-2-phenylethynyl-1H-imidazole, 1-methyl-5-phenylethynyl-1H-imidazole and 1-methyl-4-phenylethynyl-1H-imidazole as well as the synthesis of the corresponding phenylethenyl derivatives is described in Chem. Pharm. Bull. 1987, 35(2), 823-828. The compounds have been prepared by palladium catalyzed reaction of corresponding halogen-1,3-azoles with phenylacetylene or styrene. 1-Methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole can be synthesized as nonlinear optical chromophore according to Chem Mater. 1994, 6(7), 1023-1032. The preparation of 2-alkyl-5-phenylethynyl-1H-imidazole-4-carboxaldehydes as intermediates for the manufacture of substituted imidazoles for use as angiotensin II blockers has been described in WO 91/00277. 1-Methyl-5-(2-phenyl-ethenyl)-1H-imidazole has also been prepared as intermediate for the synthesis of heterocyclic food mutagens according to Environ. Health Perspect. 1986, 67, 41-45.
It has now surprisingly been found that compounds of formula I are metabotropic glutamate receptor antagonists having valuable therapeutic properties.
The present invention also relates to novel compounds of the formula
wherein
R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from the group consisting of, hydrogen, lower alkyl, —(CH
2
)
n
-halogen, lower alkoxy, —(CH
2
)
n
—NRR′, —(CH
2
)
n
—N(R)—C(O)-lower alkyl, aryl, unsubstituted heteroaryl and heteroaryl substituted by one or more lower alkyl residues;
R, R′ and R″ are selected from the group consisting hydrogen and lower alkyl;
B is selected from the group consisting of
wherein
R
6
is selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
—C(O)OR and halogen;
R
7
is selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
—C(O)OR′, halogen, nitro, unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl;
R
8
is selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
—OH, —(CH
2
)
n
—C(O)OR″ and aryl;
R
9
is lower alkyl;
R
10
is selected from the group consisting of hydrogen, lower alkyl and halogen;
R
11
is hydrogen or alkyl;
R
12
is —(CH
2
)
n
—N(R)—C(O)-lower alkyl;
R
13
is hydrogen or lower alkyl;
R
14
, R
15
, R
16
and R
17
are independently selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
-halogen and lower alkoxy;
R
18
, R
19
and R
20
are independently selected from the group consisting of hydrogen, lower alkyl, —(CH
2
)
n
-halogen or lower alkoxy;
R
21
signifies hydrogen or lower alkyl;
R
22
signifies hydrogen, lower alkyl or lower alkyl carrying at least one substituents selected from hydroxy and halogen;
R
23
is selected from the group consisting of hydrogen, lower alkyl, lower alkanoyl and nitro;
R
24
, R
25
and R
26
are independently selected from the group consisting of hydrogen and lower alkyl;
n is 0, 1, 2, 3, 4, 5 or 6;
X is —CH
2
—, —O— or —S—; and
Y is —CH═ or —N═;
and pharmaceutically acceptable salt thereof; with the exception of
1-methyl-2-phenylethynyl-1H-imidazole,
1-methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole,
1-methyl-5-phenylethynyl-1H-imidazole, and
1-methyl-4-phenylethynyl-1H-

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