Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-01
2003-04-22
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253040, C514S266300, C540S582000, C540S583000, C540S584000, C544S286000, C544S362000
Reexamination Certificate
active
06552015
ABSTRACT:
The present invention is directed to 2-[(azabicycloalkyl)alkylenyl]isoquinolin-3-one derivatives and pharmaceutically acceptable salts thereof, to pharmaceutical compositions thereof, and to the use thereof to block selectively serotonin reuptake and 5-HT
2A
receptor binding in the central nervous system of a mammal. The present invention is also directed to the use of the 2-[(azabicycloalkyl)alkylenyl]isoquinolin-3-one derivatives of the invention in a method for the treatment of various diseases, disorders and conditions of the central nervous system. Further, the present invention is directed to processes for the preparation of said 2-[(azabicycloalkyl)alkylenyl]isoquinolin-3-one derivatives and intermediates useful therein.
Serotonin (5-hydroxytryptamine, “5-HT”) is a monoamine neurotransmitter active in the central nervous systems 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 central nervous system 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 central nervous system 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, etc.
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. 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 quinazolinedione 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)-quinazolinedione-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 2-[(azabicycloalkyl)alkylenyl]isoquinolin-3-one compounds of the present invention, provided herein, or the therapeutic uses of the present invention.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula (I):
and pharmaceutically acceptable salts thereof, wherein the group
wherein
A is (CH
2
)
n
, where n is 1 or 2;
E is selected from the group consisting of N, CH, C—OH, C—CN, C—O—(C
1
-C
6
)alkyl, and C—(C
1
-C
6
)alkyl;
U is CH
2
, NH, —(CHR
3
)
m
— or NR
3
, where R
3
is selected from the group consisting of H, (C
1
-C
6
)alkyl and C(═O)—(C
1
-C
6
)alkyl;
m is 0 or 1;
k is 1 or 2;
R
1
and R
2
are selected independently from H, (C
1
-C
6
)alkyl, halo, CN, nitro, CF
3
, —NHC(O)R
6
and —OR
7
, where R
6
and R
7
are selected independently from H, (C
1
-C
6
)alkyl, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring; or R
1
and R
2
, if on adjacent carbon atoms, together with the atoms to which they are attached, if adjacent, form a carbocyclic or heterocyclic five- or six-membered ring;
R
4
and R
5
are selected from H, (C
1
-C
6
)alkyl, halo, —CF
3
, nitro, —CN, —NHC(═O)R
6
, —OR
7
, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring; where R
6
and R
7
are as defined above;
V is CH, CR
8
, or N, where R
8
is H, (C
1
-C
6
)alkyl, halo, —CF
3
, nitro, —CN, —NHC(═O)R
6
, —OR
7
, a 5- to 7-membered aryl ring, or a 5- to 7-membered heteroaryl ring; wherein R
6
and R
7
are as defined above;
W is CH
2
, C(O), or S(O)
2
; and
Y is CH, CR
1
, CR
2
, or N, where R
1
and R
2
are as defined above.
Preferred compounds of formula (I) are those wherein
A is (CH
2
)
n
where n is equal to 1 or 2;
W is C(═O);
Y is CH;
V is CH or N;
E is CH or N
U is NH; and
k, m, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are all as defined above.
Other preferred compounds are those wherein
A is (CH
2
)
n
where n is equal to 1 or 2;
W is C(═O);
Y is CH;
V is CH or N;
E is CH or N
U is NH; and
k, m, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
are all as defined above.
Further preferred compounds are those wherein
A is (CH
2
)
n
where n is equal to 1 or 2;
W is C(═O);
Y is CH;
V is CH or N;
E is CH or N
U is NH; and
k, m, R
1
, R
2
, R
3
, R
4
, R
6
, R
7
and R
8
are all as defined above.
More preferred compounds of formula (I) are those wherein
A is (CH
2
)
n
where n is equal to 2;
W is C(═O);
Y is CH;
V is CH or N;
E is N
U is NH;
k is 1 or 2; and
R
1
, R
2
, R
4
, and R
5
are independently chosen from the group consisting of hydrogen, halo, —CF
3
, nitro, (C
1
-C
6
)alkyl, hydroxy and methoxy.
The most preferred embodiments of this invention, are compounds of formula (I) where
A is (CH
2
)
n
where n is 2;
k is 1;
E is N;
W is C(═O);
Y is CH;
V is CH;
U is NH; and
R
1
, R
2
, R
4
, and R
5
are independently chosen from the group consisting of hydrogen, hydroxy, methoxy, F, Cl, —CF
3
, CN, nitro, (C
1
-C
6
)alkyl, a 5- to 7-membered aryl ring, and a 5- to 7-membered heteroaryl ring.
Specific embodiments of the invention are:
8-chloro-3-{3-[3-(4-chlorophenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-propyl}-1H-quinazoline-2,4-dione;
8-chloro-3-[3-(8-p-tolyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-propyl]-1H-quinazoline-2,4-dione;
8-chloro-3-{3-[8-(4-chloro-phenyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-propyl}-1H-quinazoline-2,4-dione;
3-{3-[3-(4-chloro-phenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-propyl}-6-methyl-1H-quinazoline-2,4-dione;
3-{3-[3-(4-chloro-phenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-propyl}-1H-quinazoline-2,4-dione;
3-[3-(3-p-tolyl-3,8-diazabicyclo[3.2.1]oct-8-yl)-propyl]-1H-quinazoline-2,4-dione;
3-{3-[3-(4-chloro-phenyl)-8-azabicyclo[3.2.1]oct-8-yl]-propyl}-1H-quinazoline-2,4-dione;
3-[3-(3-phenyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-1H-quinazoline-2,4-dione;
3-[3-(3-p-tolyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-1H-quinazoline-2,4-dione;
8-chloro-3-[3-(3-p-tolyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-propyl]-1H-quinazoline-2,4-dione;
8-chloro-3-{3-[3-(2,4-dimethyl-phenyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]-propyl}-1H-quinazoline-2,4-dione;
8-chloro
Butler Todd William
Fliri Anton Franz Joseph
Gallaschun Randall James
Ginsburg P. H.
Joran A. D.
Kifle Bruck
Pfizer Inc.
Richardson P. C.
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