2-aminoalkylaminoquinolines as dopamine D4 ligands

Details 2-aminoalkylaminoquinolines as dopamine D4 ligands 2-aminoalkylaminoquinolines as dopamine D4 ligands

2000-03-08

2001-11-06

Huang, Evelyn Mei (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S256000, C514S258100, C544S331000, C544S333000, C544S363000, C546S163000

Reexamination Certificate

active

06313141

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to aminoquinoline derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to 2-quinolyl(azacycloalkylalkyl)amines and pharmaceutical compositions and preparations containing such compounds. It also relates to the use of such compounds in the treatment or prevention of neuropsychochological 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. See Nature 350: 610 (Van Tol et al., 1991) and Nature, 347: 146 (Sokoloff et al., 1990). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D
4
receptor plays a role in the etiology of schizophrenia. Consequently, selective D
4
antagonists are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics.
U.S. Pat. No. 5,093,333 describes N-substituted-2-aminoquinolines said to be M
1
receptor agonists.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes. A broad aspect of the invention is directed to compounds of Formula I:
wherein:
R
1
, R
2
, and R
3
independently represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono(C
1
-C
6
) alkylamino, di(C
1
-C
6
) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R
6
is hydrogen or C
1
-C
6
alkyl; and
Q represents a substituted azacycloalkylalkyl group of the formula:
 where
W is nitrogen, CH or COH;
A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms; and
T is an aryl or heteroaryl moiety optionally substituted with up to two groups selected from hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono(C
1
-C
6
) alkylamino, di(C
1
-C
6
) alkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
In yet another aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I.
Since dopamine D
4
receptors are concentrated in the limbic system (Taubes,
Science
265: 1034, 1994) which controls cognition and emotion, compounds which 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. In addition, disorders involving memory impairment or attention deficit disorders can be treated with the compounds of this invention. These compounds interact specifically with the dopamine D
4
receptor subtype.
The compounds of the invention demonstrate high affinity and selectivity in binding to the D
4
receptor subtype. The use of the compounds of this invention in methods of treating neuropsychological disorders is predicated on the ability of the compounds to bind selectively to a dopamine receptor subtype, the D
4
receptor. The compounds of the invention can therefore be used in the treatment of 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.
Thus, in another aspect, the invention provides methods for treating and/or preventing neuropsychological disorders including, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents. It also provides methods of treating affective disorders such as Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia.
The invention further provides methods for treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. The compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorder.
DETAILED DESCRIPTION OF THE INVENTION
In addition to the compounds of Formula I above, the invention encompasses compounds of Formula IA:
wherein:
R
1
, R
2
, R
3
, R
4
and R
5
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono(C
1
-C
6
) alkylamino, di(C
1
-C
6
) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R
6
is hydrogen or C
1
-C
6
alkyl;
W is nitrogen, COH, or CH;
Y and Z independently represent nitrogen or CH; and
A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms.
In Formula IA, the dashed segment represents either a single bond resulting in a 3,4 dihydroquinoline; or a double bond resulting in a quinoline.
In the compounds of the invention, “W” preferably represents nitrogen or COH. Preferred “T” groups in Formula I are 6-membered carbocyclic aromatic ring systems having zero, one or two nitrogen atoms. Particularly preferred “T” groups are phenyl, 2-pyridinyl, and 2-pyrimidinyl. The particularly preferred “T” groups are optionally mono- or disubstituted with halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono(C
1
-C
6
) alkylamino, di(C
1
-C
6
) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
Preferred compounds of Formula IA are those where R
6
is hydrogen, methyl or ethyl.
Preferred “T” groups in Formula I are
The invention also provides compounds of Formula II:
wherein:
R
1
, R
2
, R
3
, R
4
and R
5
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono(C
1
-C
6
) alkylamino, di(C
1
-C
6
) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R
6
is hydrogen or C
1
-C
6
alkyl;
W is nitrogen, COH, or CH;
Y and Z independently represent nitrogen or CH; and
A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms.
Preferred compounds of Formula II are those where R
6
is hydrogen, methyl or ethyl. Particularly preferred compounds of Formula II are those where
In addition, the invention encompasses compounds of Formula III:
wherein:
R
1
, R
2
, R
3
, R
4
and R
5
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, hydroxy, amino, mono(C
1
-C
6
) alkylamino, di(C
1
-C
6
) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;
R
6
is hydrogen or C
1
-C
6
alkyl;
W is nitrogen, COH, or CH;
Y and Z independently represent nitrogen or CH; and
A represents an alkylene group of from 2-5 carbon atoms optionally substituted with one or more alkyl groups having from one to four carbon atoms.
In preferred compounds of Formula III, R
6
is hydrogen, methyl or ethyl.
In certain situations, compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For example, where R
6
in Formula I is a methyl group, the resulting compound can be present as (R) and (S) stereoisomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. R

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