Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-03-19
2002-08-06
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S363000, C544S364000, C544S375000, C544S376000, C544S333000, C546S281100, C546S146000, C546S175000, C546S194000, C546S202000, C546S256000, C549S043000, C549S048000
Reexamination Certificate
active
06429312
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to dibenzothiophenecarboxamide derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to N-aminoalkyldibenzothiophenecarboxamides and to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in the treatment or prevention of various 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
3
receptor subtype has recently been identified (Sokoloff et al., Nature, 347: 146 (1990). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D
3
receptor may play a major role in the etiology of schizophrenia. Selective D
3
antagonists may be effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics. Compounds of the present invention demonstrate high affinity and selectivity in binding to the D
3
receptor subtype. They may be of potential use in treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias may also be treated directly or indirectly by modulation of D
3
receptors.
U.S. Pat. No. 5,395,835 discloses N-aminoalkyl-2-napthalamides which have affinity at dopamine D
3
receptors. The compounds the present invention differ significantly from this prior art in that they possess a dibenzothiophenecarboxamide substructure.
Murray et al., in Bioorg. Med. Chem. Let., 5: 219 (1995), describes 4-carboxamido-biphenyls said to have affinity for dopamine D
3
receptors.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with dopamine receptor subtypes. Thus, the invention provides compounds of general Formula I useful in the treatment and/or prevention of various neuropsychological disorders. The invention also provides pharmaceutical compositions comprising compounds of Formula 1.
The invention further relates to the use of such compounds and compositions in the treatment of affective disorders such as schizophrenia, depression, Alzheimer's disease and certain movement disorders such as Parkinsonism and dystonia. Compounds of this invention are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. Further, the compounds of the present invention are useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorder.
Since dopamine D
3
receptors are concentrated in the limbic system (Taubes,
Science
265 (1994) 1034) which controls cognition and emotion, compounds which interact with these receptors also have utility 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 involving memory impairment or attention deficit disorders can also be treated with the compounds of this invention that interact specifically with the dopamine D
3
receptor subtype.
Furthermore, compounds of this invention may be useful in treatment of depression, memory-impairment or Alzheimer's disease by modulation of D
3
receptors which selectively exist in limbic area known to control emotion and cognitive functions. The compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse (Caine and Koob, Science, 260: 1814 (1993)) and obsessive compulsive disorder (Goodman et al., Clin. Psychopharmacol., 7: 35 (1992)). The interaction of the compounds of the invention with dopamine receptor subtypes is demonstrated below. This interaction results in the pharmacological activities of these compounds.
Accordingly, a broad embodiment of the invention is directed to a compound of Formula I:
or the pharmaceutically acceptable acid addition salts thereof, wherein:
R
1
, R
2
, R
3
, R
4
are the same or different and represent hydrogen, C
1
-C
6
alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C
1
-C
6
alkoxy, —O
2
CR′, —NHCOR′, —COR′, —SO
m
R′, where R′ is C
1
-C
6
alkyl and wherein m is 0, 1 or 2; or
R
1
, R
2
, R
3
, R
4
independently represent —CONR′R″, or —NR′R″ where R′ and R″ independently represent hydrogen or C
1
-C
6
alkyl;
R
5
is hydrogen or C
1
-C
6
alkyl; and
R represents an aminoalkyl group.
Thus, the invention relates to the use of compounds of formula I in the treatment and/or prevention of neuropsychochological disorders including, but not limited to, 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.
DETAILED DESCRIPTION OF THE INVENTION
In addition to compounds of general formula I described above, the invention encompasses compounds of general formula IA:
wherein:
R
1
, R
2
, R
3
, R
4
, R
5
are as defined above; and
R represents an aminoalkyl group of the formula
where
A represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms;
Z is N or C;
R
6
and R
7
are the same or different and represent hydrogen or C
1
-C
6
alkyl; or
R
6
and R
7
together with the the 6-membered ring to which they are attached form a 5 to 8-membered ring; and
W is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl; each of which is optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.
Preferred compounds of formula IA include those where R
1
-R
4
are hydrogen and A is alkylene of 3-5 carbon atoms.
In addition to compounds of general formula I described above, the invention encompasses compounds of general formula IB:
wherein:
R
1
, R
2
, R
3
, R
4
, and R
5
are as defined above;
R
6
and R
7
are the same or different and represent hydrogen or C
1
-C
6
alkyl; or
R
6
and R
7
together with the the 6-membered ring to which they are attached form a 5 to 8-membered ring; and
A, Z and W are as defined above.
The present invention further encompasses compounds of Formula II:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, and R
7
, A, and W are as defined above.
Preferred compounds of formula II are those where R
1
-R
5
are hydrogen; A is C
3
-C
5
alkylene; and W is quinolinyl, naphthyl or a phenyl group optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
4
alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy. More preferred compounds of formula II are those where R
1
-R
5
are hydrogen; A is C
3
-C
5
alkylene; and W is 8-quinolinyl, naphthyl or a phenyl group optionally substituted with up to two groups in the 2 and/or 3 positions (relative to the point of attachment of the phenyl group to the piperazine ring), the groups being independently selected from halogen, C
1
-C
4
alkyl, and C
1
-C
4
alkoxy. Particularly preferred compounds of formula II are those where R
1
-R
5
are hydrogen; A is C
4
alkylene; and W is 8-quinolinyl, naphthyl or a phenyl
Chen Xi
Yuan Jun
Bernhardt Emily
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
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