Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-28
2001-01-16
Bernhardt, Emily (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S167000, C546S175000, C546S276700
Reexamination Certificate
active
06175015
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to indolecarboxamide derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to fused indolecarboxamides such as carbozolecarboxamides, tetrahydrocarbazolecarboxamides, and fused cycloalkylindolecarboxamides, 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 said to have affinity at dopamine D
3
receptors. The compounds of the present invention differ significantly from this prior art in that they possess a dibenzofurancarboxamide substructure.
U.S. Pat. No. 3,932,456 discloses compounds of the formula:
wherein each of R
1
and R
2
is hydrogen, (lower)alkyl, cycloalkyl of 3 to 6 ring carbon atoms, alkenyl of 3 to 6 carbon atoms having the vinyl unsaturation in other than the 1-position of the alkenyl group, or R
1
and R
2
taken together with the nitrogen atom to which they are attached is pyrrolidino, piperidino, N-(lower) alkylpiperazino, or morpholino; each A is alkylene of 2 to about 8 carbon atoms and separates its adjacent Y and amino nitrogen by an alkylene chain of at least 2 carbon atoms; each Y is oxygen, or N—R wherein R is hydrogen, methyl or ethyl; and R
3
is hydrogen or (lower) primary or secondary alkyl; or a pharmaceutically acceptable acid addition salt thereof. These compounds are said to be useful as pharmaceuticals for preventing or inhibiting a viral infection
International application WO94/14773 discloses compounds said to have affinity for the 5-HT
1
-like receptor and utility in the treatment of migraine. The compounds disclosed in that application have the following formula:
wherein R
1
represents halogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, hydroxy, NO
2
, —NR
4
R
5
, R
4
R
5
NCO(CH2)
m
—, R
4
R
5
NSO
2
(CH2)
m
—, R
6
CONH(CH2)
m
—or R
7
SO
2
(CH2)
m
—; R
4
and R
5
each independently represent hydrogen or C
1
-C
4
alkyl or N
4
R
5
represents a 5- to 7-member heterocyclic ring; R
6
represents hydrogen or C
1
-C
4
alkyl; R
7
represents C
1
-C
4
alkyl; m is zero, 1, or 2; n is zero or 1 to 5; R
2
and R
3
each independently represent hydrogen, C
1
-C
6
alkyl or benzyl or —NR
2
R
3
represents a pyrrolidino, piperidino or hexahydroazepino ring; and A represents a bond, a C
1
-C
5
alkylene chain or a C
1
-C
5
alkenyl chain wherein the double bond is not adjacent the nitrogen atom. Murray et al., Bioorg. Med. Chem. Let., 5: 219 (1995), describe 4carboxarnido-biphenyls said to have affinity at dopamine D
3
receptors.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with doparnine 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 I.
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: 1034 (1994)) which controls cognition and emotion, compounds that interact with these receptors are also 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 involving memory impairment or attention deficit disorders can also be treated with the compounds of this invention which interact specifically with the dopamine D
3
receptor subtype.
Furthermore, the compounds of this invention are useful in treatment of depression, memory-impairment or Alzheimer's disease by modulation of D
3
receptors which selectively exist in limbic areas known to control emotion and cognitive functions. The compounds of the present invention are also useful for the treatment of other disorders that 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 compounds of the invention interact with dopamine receptor subtypes resulting in the pharmacological activity 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:
where R
a
and R
b
independently represent hydrogen, C
1
-C
6
alkyl, hydroxy, C
1
-C
6
alkoxy, or amino mono- or disubstituted with C
1
-C
6
alkyl; and
n is an integer from one to four;
R
1
and R
2
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′, or —SO
m
R′, where R′ is C
1
-C
6
alkyl and where m is 0, 1 or 2; or
R
1
and R
2
independently represent —CONR′R″ or —NR′R″ where R′ and R″ independently represent hydrogen or C
1
-C
6
alkyl;
R
3
is hydrogen, C
1
-C
6
alkyl, or —COR′″ where R′″ is C
1
-C
6
alkyl;
R
4
is hydrogen or C
1
-C
6
alkyl; and
R represents an azacycloalkylalkyl 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
the A ring, R
1
, R
2
, R
3
, and R
4
are as defined above for Formula I; and
R
p
represents an azacycloalkylalkyl group of the formula
where
Q 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
5
and R
6
are the same or different and represent hydrogen or C
1
Wasley Jan
Yuan Jun
Bernhardt Emily
McDonnell Boehnen Hulbert & Berhoff
Neurogen Corporation
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