Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-29
2001-11-13
Aulakh, C. S. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S201000, C546S202000, C546S205000, C546S234000, C514S320000, C514S324000, C514S331000
Reexamination Certificate
active
06316470
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to substituted 2-(4-benzylpiperazin-1-yl) and 2-(1-benzylpiperidin-4-yl)ethanones 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 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
The invention provides novel compounds which interact with dopamine receptor subtypes. Accordingly, in a broad aspect, the invention provides compounds of Formula I:
wherein:
Y represents oxygen or sulfur;
Z is nitrogen or CH;
R
1
, R
2
and R
3
independently represent hydrogen, halogen, hydroxy, lower alkoxy, C
l
-C
6
alkyl, trifluoromethyl or trifluoromethoxy;
R
4
and R
4
′ independently represent hydrogen or C
1
-C
6
alkyl; or
R
4
and R
4
′ together with the atom to which they are attached form a ring having from 3-7 members;
R
5
represents hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or C
1
-C
6
alkylthio;
R
6
is hydrogen or C
1
-C
6
alkyl; or
R
5
and R
6
together represent C
1
-C
5
alkylene, C
1
-C
4
alkyleneoxy, C
1
-C
4
alkylenethio where the oxygen or sulfur atoms are immediately adjacent the phenyl ring, and together with the atoms to which they are attached form a ring having from 5-9 members; and
R
7
, R
8
, R
9
, R
10
, and R
11
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 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 a yet further aspect, the invention provides intermediates useful for preparing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the invention encompasses substituted 2-(4-benzyl)-piperazinyl- and piperidinyl-1-ethanones of Formula I. Preferred compounds of Formula I are those where R
2
and R
3
are not both hydrogen simultaneously. Other preferred compounds of Formula I are those where R
7
, R
8
, R
9
, and R
10
are hydrogen. In the compounds of the invention, R
11
is preferably hydrogen, methyl or ethyl, most preferably hydrogen.
As noted, the invention encompasses compounds where R
5
and R
6
together represent C
1
-C
5
alkylene, C
1
-C
4
alkyleneoxy, and C
1
-C
4
alkylenethio. In these compounds, the oxygen or sulfur atoms are immediately adjacent the phenyl ring carrying the R
5
group. In such cases, R
5
and R
6
together with the atoms to which they are attached form a ring having from 5-9 members. Examples of such rings include the following:
Preferred among these bicyclic ring systems are compounds where n is 0 or an integer of 1 or 2.
In these compounds, R
4
and R
4
′ independently represent hydrogen or C
1
-C
6
alkyl, or R
4
and R
4
′ together with the atom to which they are attached form a ring having from 3-7 members. Representative resulting Spiro ring systems include the following:
Compounds in which R
5
and R
6
together with the atoms to which they are attached form a ring having from 5-9 members as discussed above are represented by Formula II:
wherein
X represents oxygen, or sulfur, or CH;
Y is oxygen or sulfur;
Z is nitrogen or CH;
n is zero or an integer of from 1-4;
R
1
, R
2
and R
3
independently represent hydrogen, halogen, hydroxy, lower alkoxy, C
1
-C
6
alkyl, trifluoromethyl or trifluoromethoxy;
R
4
and R
4
′ independently represent hydrogen or C
1
-C
6
alkyl; or C
1
-C
6
R
4
and R
4
′ together with the atom to which they are attached form a ring having from 3-7 members;
R
7
, R
8
, R
9
, R
10
, and R
11
independently represent hydrogen or C
1
-C
6
alkyl.
Preferred compounds of Formula II are those where R
2
and R
3
are not simultaneously hydrogen. In preferred compounds of Formula II, R
4
and R
4
′ are independently hydrogen or C
1
-C
4
alkyl. In other preferred compounds of Formula II, n is 0 or 1, and more preferably 0.
A preferred group of compounds of Formula II are those where Y is oxygen, X is CH
2
and Z is CH. Such compounds are depicted by Formula IIa:
wherein n, R
1
, R
2
, R
3
, R
4
, R
4
′ R
7
, R
8
, R
9
, R
10
, and R
11
are as defined above for Formula II.
In the compounds of Formula IIa, R
11
is preferably hydrogen, methyl or ethyl. In preferred compounds of Formula IIa, R
1
is hydrogen or halogen, and R
2
and R
3
are independently selected from hydrogen, C
1
-C
6
alkyl, and halogen. More preferred such compounds of Formula IIa are those where R
11
is hydrogen or methyl, R
1
is hydrogen or halogen, and not both of R
2
and R
3
are hydrogen simultaneously. Particularly preferred compounds of Formula IIa are those where R
11
is hydrogen or methyl, R
2
is hydrogen, R
3
is methyl, methoxy, chloro, or fluoro, R
4
and R
4
′ are independently hydrogen or lower alkyl, most preferably C
1
-C
2
alkyl, and R
1
is hydrogen or halogen.
Another preferred group of compounds of Formula II are those where Z is nitrogen and X is CH
2
. Such compounds are generally represented by Formula II
Kover Renata Xavier
Terdjanian Silva
Thurkauf Andrew
Tran Jennifer
Aulakh C. S.
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
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