Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-03-09
2001-12-18
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S376000, C544S392000, C544S394000
Reexamination Certificate
active
06331629
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines and 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
, 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 may play 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.
Various 4-benzylpiperazines have been described. See, for example,
Arch. Med. Res
., 25: 435-440 (Terron et al., 1994) and
Toxicol. Appl. Pharmacol
., 7: 257-267 (Schmidt and Martin, 1965).
SUMMARY OF THE INVENTION
This invention provides novel compounds which interact with dopamine subtypes. Accordingly, in a broad aspect, the invention provides compounds of Formula I:
or pharmaceutically acceptable addition salts thereof, wherein:
X, Y and Z are the same or different and represent CR
c
or nitrogen;
R
c
represents hydrogen, halogen or C
1
-C
6
alkyl;
R
1
and R
2
independently represent hydrogen, halogen, hydroxy,
C
1
-C
6
alkyl, trifluoromethyl, trifluoromethoxy or SO
2
NH
2
, provided that, when Y and Z represent CH, and R
3
and R
4
are both hydrogen, R
1
and R
2
are not hydrogen simultaneously; or
R
1
and R
2
together represent a C
1
-C
2
alkylene dioxy group or a C
1
-C
3
alkylene oxy group;
R
3
and R
4
are the same or different and represent hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, alkylthio, hydroxy, amino, mono or dialkyl amino where each alkyl is C
1
-C
6
alkyl, cyano or trifluoromethyl;
A represents C
1
-C
4
alkylene; and
R
5
, R
6
, and R
7
independently represent 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 neurospychological 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.
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 by modulation of D
4
receptors which selectively exist in limbic area known to control emotion and cognitive functions. 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.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the invention encompasses substituted 1-(2-naphthyl) and 1-(2-azanaphthyl)-4-(1-phenylmethyl)piperazines of Formula I. Preferred compounds of Formula I are those where at least one of R
1
and R
2
is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or where R
1
and R
2
together represent 3,4-methylenedioxy. Still other preferred compounds of Formula I are those where
represents 4-alkylquinolinyl, 4,6-dialkylquinolinyl, 4,7-dialkylquinolinyl, 4,8-dialkylquinolinyl, 4-haloquinolinyl, or 4-alkyl-6-alkoxyquinolinyl. Preferably, only Z is R
c
. More preferred compounds of Formula I are those where at least one of R
1
and R
2
is chloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl, trifluoromethyl, trifluoromethoxy, or where R
1
and R
2
together represent 3,4-methylenedioxy. Particularly preferred compounds of Formula I are those where R
2
is hydrogen and R
1
is methyl or chloro. In addition, preferred compounds of Formula I are those where A is methylene or ethylene, and R
5
is hydrogen.
Particularly preferred compounds of Formula I are those where
represents quinolin-2-yl, 5,6,7,8-tetrahydroquinolin-2-yl, quinoxalin-2-yl, or naphth-2-yl.
The invention also encompasses compounds of formula II:
wherein:
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
c
, and R
7
carry the same definitions as set forth above for Formula I.
Preferred compounds of Formula II are those where at least one of R
1
and R
2
is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or where R, and R
2
together represent 3,4-methylenedioxy. Still other preferred compounds of Formula II are those where the both R
3
and R
4
are hydrogen, or the R
c
, R
3
and R
4
substitution on the quinoline ring provides a 4-alkylquinolinyl, 4,6-dialkylquinolinyl, 4,7-dialkylquinolinyl, 4,8-dialkylquinolinyl, 4-haloquinolinyl, or 4-alkyl-6-alkoxyquinolinyl compound. More preferred compounds of Formula II are those where A is methylene and at least one of R
1
and R
2
is chloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl, trifluoromethyl, trifluoromethoxy, or where R
1
and R
2
together represent 3,4-methylenedioxy. Particularly preferred compounds of Formula II are those where R
3
and R
4
are hydrogen, A is methylene, R
2
is hydrogen and R
1
is methyl or chloro.
Particularly preferred compounds of Formula II are quinolin-2-yl derivatives where R
3
and R
4
are hydrogen. Other particularly preferred compounds of Formula II are 5,6,7,8-tetrahydroquinolin-2-yl derivatives where R
3
and R
4
are hydrogen.
Also encompassed within the invention are compounds of Formula III:
wherein:
R
1
, R
2
, R
31
R
4
, R
5
, R
6
, and R
7
carry the same definitions as set forth above for Formula I.
Preferred compounds of Formula III are those where at least one of R
1
and R
2
is halogen, alkyl, trifluoromethyl, trifluoromethoxy, or where R
1
and R
2
together represent 3,4-methylenedioxy. More preferred compounds of Formula III are those where A is methylene and at least one of R
1
and R
2
is chloro, fluoro, methyl, ethyl, butyl, isopropyl, n-propyl, trifluoromethyl, trifluoromethoxy, or where R
1
and R
2
together represent 3,4-methylenedioxy. Particularly preferred compounds of Formula III are those where R
3
and R
4
are hydrogen, A is methylene, R
2
is hydrogen and R
1
is methyl or chloro.
Particularly preferred compounds of Formula III are quinoxalin-2-yl derivatives where R
3
and R
4
are hydrogen.
The invention further provides compounds of formula IV:
wherein:
R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, and R
7
ca
Gangly Ashit
Greenlee William
Wasley Jan W. F.
Bernhardt Emily
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
Sarussi Steven J.
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