2-(2, 3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles:...

Details 2-(2, 3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles:... 2-(2, 3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles:...

1999-09-29

2001-09-11

Kifle, Bruck (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S242000, C546S196000, C546S210000, C548S300100, C548S311100, C548S312400, C549S229000, C549S356000, C549S398000

Reexamination Certificate

active

06288230

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to 2-(2,3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles and to pharmaceutical compositions containing such compounds. It also relates to the use of such compounds in the treatment or prevention of psychotic disorders such as schizophrenia and other central nervous system diseases.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D
2
receptors in the striatal region of the brain. The dopamine D
4
receptor subtype has recently been identified (Nature, 350: 610 (Van Tol et al., 1991); Nature, 347: 146 (Sokoloff et al., 1990)). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics indicates that the D
4
receptor plays a major role in the etiology of schizophrenia. Selective D
4
antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.
U.S. Pat. No. 5,428,164 describes phenylimidazole derivatives.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with dopamine subtypes. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I:
or pharmaceutically acceptable acid addition salts thereof wherein:
n is 1, 2, or 3;
R
1
represents hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R
2
represents halogen or C
1
-C
6
alkyl;
R
N
is
where
A is alkylene of 1 to 4 carbon atoms;
X is either a carbon atom, CH, or nitrogen; and
R
3
represents either an (un)substituted aryl or a heteroaryl group; and
R
4
is hydrogen or C
1
-C
6
alkyl.
Dopamine D
4
receptors are concentrated in the limbic system (Science, 265: 1034 (Taubes, 1994)) which controls cognition and emotion. Therefore, compounds that interact with these receptors are useful in the treatment of cognitive disorders. Such disorders include cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders include those involving memory impairment or attention deficit disorders.
Compounds of the present invention demonstrate high affinity and selectivity in binding to the D
4
receptor subtype. These compounds are therefore useful in treatment of a variety of neuropsychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D
4
receptors.
Compounds of this invention are also useful in the treatment of depression, memory-impairment or Alzheimer's disease by modulation of D
4
receptors since they exist selectively in areas known to control emotion and cognitive functions.
Thus, in another aspect, the invention provides methods for treatment and/or prevention of neuropsychochological or affective disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents. In addition, the compounds of the invention are useful in treatment of depression, memory-impairment or Alzheimer's disease. Further, the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.
In yet another aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I.
In another aspect, the invention provides intermediates useful in the preparation of compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the invention encompasses aminomethylimidazole derivatives of Formula I. Preferred compounds of Formula I are those where n is 1 and are represented by Formula IA.
where R
1
, R
2
, R
4
, and R
N
are as defined above for Formula I.
Suitable R
3
groups include aryl and heteroaryl groups optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, phenyl, amino, mono- or di(C
1
-C
6
)alkylamino, and perfluoroalkyl, such as trifluoromethyl. Other substituents include lower, i.e. C
1
-C
6
, alkylthio, C
1
-C
6
acyloxy, aryl, and heteroaryl. These latter aryl and heteroaryl substituents may also be substituted in a fashion similar to the parent aryl or heteroaryl group.
Representative aryl groups are aromatic carbocyclic groups having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
Representative heteroaryl groups (aromatic heterocycles) include groups having one or more aromatic ring systems of 5, 6, or 7 members, preferably 5 or 6 members, containing at least one and up to four hetero atoms, preferably one or two hetero atoms, selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.
The hetero aryl R
3
groups are bound to the parent piperazine, piperidine or tetrahydropyridine group via a carbon atom in the hetero aryl group, preferably a carbon atom immediately adjacent a hetero atom such as nitrogen in the hetero aryl group.
Preferred compounds of Formula IA are those where X is nitrogen and R
3
is pyrimidinyl, phenyl, pyridyl, naphthyl, benzyl, 4,5-benzopyrimidin-2-yl, or isoquinolinyl, preferably 1-isoquinolinyl, each of which R
3
groups is optionally unsubstituted or substituted with up to three groups selected from halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, hydroxy, phenyl, amino, mono- or di(C
1
-C
6
)alkylamino, or trifluoromethyl.
Other preferred compounds of Formula IA are those where X is carbon or CH and R
3
is pyrimidinyl, phenyl, pyridyl, naphthyl, benzyl, benzopyrimidin-yl, or isoquinolinyl, preferably 1-isoquinolinyl, each of which R
3
group is optionally unsubstituted or substituted with up to three groups selected from halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, hydroxy, phenyl, amino, mono- or di(C
1
-C
6
)alkylamino, or trifluoromethyl.
More preferred compounds of Formula IA are those where A is methylene, R
3
is phenyl, 2-pyridyl, pyrimidin-2-yl, 1-or 2-naphthyl, quinolinyl, preferably 2-quinolinyl, isoquinolinyl, preferably 1-isoquinolinyl, 4,5-benzopyrimidin-2-yl or benzoisothiazol-3-yl, each of which is optionally substituted with up to three groups selected from halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
6
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, phenyl, nitro, trifluoromethyl or trifluoromethoxy.
Thus, the invention encompasses compounds of Formula II:
where R
1
, R
2
, and R
3
are as defined above for Formula I.
Preferred compounds of Formula II include those where R
3
is phenyl, pyridyl, more preferably 2-pyridyl, pyrimidin-2-yl, 1 or 2 naphthyl, quinolinyl, isoquinolinyl, preferably 1-isoquinolinyl, benzopyrimidinyl or benzoisothiazol-3-yl, each of which is optionally substituted with up to three groups selected from halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
6
alkylthio, hydroxy, amino, mono- or di(C
1
-C
6
)alkylamino, cyano, nitro, phenyl, trifluoromethyl or trifluoromethoxy.
More preferred compounds of Formula II i

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