Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-29
2003-02-18
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S284000, C544S285000
Reexamination Certificate
active
06521630
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1yl)-propyl-1,2,3,4-tetrahydroquinazoline-2,4-dione compounds, and pharmaceutically acceptable salts thereof, as well as to the use of these compounds to selectively block serotonin reuptake and 5-HT
2A
receptor binding in mammalian central nervous systems (CNS). The present invention is also directed to the use of these compounds in a methods of treatment of various diseases, disorders and conditions, as well as pharmaceutical compositions useful therefor. Further, the present invention is directed to methods for the preparation of 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)propyl-1,2,3,4-tetrahydroquinazoline-2,4-dione compounds and intermediates useful therefore.
Serotonin (5-hydroxytryptamine, “5-HT”) is a monoamine neurotransmitter active in the central nervous systems (“CNS”) of mammals, including humans. The cell bodies of serotoninergic cells are located in the brain stem, and the axons project therefrom into a variety of other areas, e.g., the amygdala, hippocampus, hypothalamus, nucleus accumbens and the striatum. Serotonin-producing cells store the neurotransmitter in intracellular vesicles, where it is either converted with monoamine oxidase (“MAO,” EC 1.4.3.4) into 5-hydroxyindoleacetic acid (“5-HIAA”) or released into synapses. In the synapses, serotonin is either resorbed into the presynaptic neurons and stored within intracellular vesicles of the presynaptic neurons or remains available for interaction with serotonin receptors, e.g., the 5-HT
2A
receptor, in post-synaptic membranes.
Altered functioning of this serotonin-based neurotransmission system has been implicated (see, e.g.,
Lancet
, 2:717-719 (1989)) in a variety of CNS-related disorders, both psychiatric and non-psychiatric. These disorders include, without limitation, schizophrenia, psychosis, depression, aggression, sleep disorders, anxiety disorders, migraines, compulsive disorders, bipolar disorders, vision disorders, emesis, feeding disorders, learning disorders, sexual behavior disorders, phobias and substance abuse disorders. Compounds that either block serotonin reuptake into presynaptic neurons or that antagonize its interaction with post-synaptic membrane receptors have a wide variety of potential applications in the treatment of mammals, including humans, afflicted with CNS-related disorders. The compounds act to restore some semblance of normal neurotransmitter functioning. Moreover, compounds which accomplish these objectives selectively can be used with a lower risk of attendant and unwanted side effects, e.g., sexual dysfunction et al.
Shimazaki et al (U.S. Pat. No. 5,296,487) describe quinazoline derivatives having activity as serotonergic, as well as alpha-adrenergic and dopaminergic, agents. However, the compounds disclosed in that reference are not known to avoid common side effects such as sexual dysfunction. In addition, while Shimazaki et al. describe the serotonergic activity of such compounds as being due to serotonin receptor antagonism, Shimazaki et al. do not describe the serotonergic activity of these compounds as that of a serotonin reuptake inhibitor and effective for the treatment of schizophrenia, psychosis, depression, aggression, sleep disorders, anxiety disorders, migraines, compulsive disorders, bipolar disorders, vision disorders, emesis, feeding disorders, learning disorders, sexual behavior disorders, phobias and substance abuse. Moreover, the examples described by Shimazaki et al. are limited to compounds that have a butyl linker between the quinazolinedione and the tetrahydropyridyl moiety. In contrast, this invention discloses compounds with a propyl link between the quinazolinedione and the tetrahydropyridine moiety which is a critical element in these compounds for substantially increasing receptor selectivity and for decreasing cardiovascular and peripheral side effects necessary for treating central nervous system disorders as disclosed in this invention.
Wade et al. (U.S. Pat. No. 4,007,191) describe tetrahydropyridyl-alkyl 2,3-dihydro-3-hydroxy-1H-benz(de)isoquinolin-1-ones having antidepressant activity. Hong et al. (U.S. Pat. No. 3,726,979) describe serotonin-antagonist quinazoline derivatives. Vidrio et al. (U.S. Pat. No. 3,919,425) indicate that certain 3 substituted 2,4-dioxoquinazolines have vasodilating activity. Shin et al. (U.S. Pat. No. 3,274,194) describe quinazoline dione derivatives that have anti-inflammatory and sedating activity. Moreover, Villalobos-Molina et al. (
Eur. J. Pharmacol
., 277(2/3):181-5 (1995) and
Drug Dev. Res
. 23(3): 281-7 (1991)) describe 2,4-(1H,3H)-quiazolinedione-3-[3-(4-phenyl-1-piperazinyl)propyl] (pelanserine) as having blood pressure lowering, 5-HT
2A
serotonin receptor binding activity. However, none of these documents describe or suggest either the 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-propyl-1,2,3,4-tetrahydroquinazoline-2,4-dione compounds of the present invention, provided herein, or the therapeutic uses of the present invention.
SUMMARY OF THE INVENTION
The present invention provides 4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-propyl-1,2,3,4-tetrahydroquinazoline-2,4-dione compounds of formula (I):
and pharmaceutically acceptable salts thereof, wherein
A is (CH
2
)
n
where n is equal to 0, 1 or 2;
U is CH
2
, NH, or NR
3
,
where R
3
is selected from the group consisting of H, (C
1
-C
6
)
m
alkyl, C(═O)—(C
1
-C
6
)alkyl, where m=1 or 2;
R
1
and R
2
are selected independently from H, (C
1
-C
6
)alkyl, Cl, F, CN, nitro, CF
3
, —NHC(O)R
6
and —OR
7
, or R
1
and R
2
, together with the atoms to which they are attached, form a carbocyclic or heterocyclic five- or six-membered ring,
where R
6
and R
7
are selected independently from H, (C
1
-C
6
)alkyl or a 5- to 7 membered aryl or heteroaryl ring;
R
4
and R
5
are selected from H, (C
1
-C
6
)alkyl, Cl, F, —CF
3
, —CN, —NHC(═O)R
6
, —OR
7
, a 5-to 7-membered aryl or heteroaryl ring, where m, R
6
and R
7
are as defined above;
V is CH, CR
3
, or N, where R
3
is as defined above;
W is CH
2
, C(O), or S(O)
2
;
X is C or N;
Y is CH, CR
1
, CR
2
, or N, where R
1
and R
2
are as defined above.
The present invention also relates to methods for preparing compounds of formula (I). In addition, the present invention provides a method for inhibiting serotonin reuptake or serotonin receptor binding in the central nervous system of a mammal, said method comprising administering to the mammal a serotonin receptor binding-inhibiting effective amount or a serotonin reuptake-inhibiting effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. This invention further provides a method of treating a mammal afflicted with various diseases, disorders and conditions, said method comprising administering to the mammal a therapeutically effective amount of a compound of formula I.
Preferred compounds of formula (I) are those wherein A is (CH
2
)
n
where n is equal to 1 or 2, and U, V, W, X, Y, R
1
, R
2
, R
3
, R
4
, R
5
,R
6
and R
7
are as defined above.
Other preferred compounds of formula (I) are those wherein n is equal to zero (i.e. without a bridging A group); W is C(═O); X is C; Y is C; V is CH or N; and U, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined above.
More preferred compounds of formula (I) are those wherein n is equal to zero (i.e. without a bridging A group); W is C(═O); X is C; Y is C; V is CH or N; U is NH, and R
1
, R
2
, R
4
, R
5
are independently chosen from the group consisting of hydrogen, halo, —CF
3
, nitro, (C
1
-C
6
)alkyl, hydroxy or methoxy.
In the most preferred embodiments of this invention, n is equal to zero (i.e. without a bridging A group); W is C(═O); X is C; Y is C; V is CH; U is NH, and R
1
, R
2
, R
4
, R
5
are independently chosen from the group consisting of hydrogen, halo, —CF
3
, nitro, methyl, hydroxy or methoxy.
Specifically, the more preferred embodiments of this invention are:
5-Chloro-3-{3-[4-(4-chlor
Butler Todd William
Fliri Anton Franz Joseph
Gallaschun Randall James
Jones Brian Patrick
Ragan John Anthony
Ginsburg P. H.
Joran A. D.
Pfizer Inc.
Richardson P. C.
Shah Mukund J.
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