5-HT7 receptor antagonists

Details 5-HT7 receptor antagonists 5-HT7 receptor antagonists

2001-03-07

2002-11-26

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S415000, C546S139000, C548S469000

Reexamination Certificate

active

06486173

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds having pharmacological activity toward the 5-HT
7
receptor. Pharmaceutical compositions and methods for their use in the treatment of CNS disorders are described.
BACKGROUND OF THE INVENTION
The 5-HT
7
receptor is the most recent addition to the burgeoning family of 5-HT receptors. 5-HT
7
receptors have been cloned from rat, mouse, guinea pig, and human cDNA and exhibit a high degree of interspecies homology, (approximately 95%) but a low sequence homology with other 5-HT receptors (<40%). The pharmacological profile of this receptor is unique yet consistent across species. Thus, high 5-HT
7
receptor affinity is observed from 5-CT, 5-HT, 5-MeOT, and methiothepin, moderate affinity for 8-OHDPAT, clozapine, and ritanserin, and low affinity for pindolol, sumatriptan, and buspirone. Recent data have demonstrated the existence of four 5-HT
7
splice variants in humans and three in rat (Heidmann, et al.,
J. Neurochem.,
1997, 68, 1372-1381). Preliminary pharmacological comparison of the long (5-HT
7a
) and short (5-HT
7b
) forms of the receptor have revealed no substantial differences in receptor binding affinity (Jasper et al.,
J. Pharmocol.,
1997, 120, 298). 5-HT
7
receptors are positively coupled to adenylate cyclase when expressed in cell lines, native guinea pig hippocampus, and cultured vascular smooth muscle cells.
The greatest abundance of 5-HT
7
mRNA is found in the brain where it is discretely located within thalamus, hypothalamus, and various limbic and cortical regions. Autoradiographic techniques confirm that the distribution of 5-HT
7
receptor binding sites in rat and guinea pig brain matches, to a large extent, the mRNA distribution (To, et al.,
J. Pharmocol.,
1995, 115, 107-116).
Preliminary data support that the 5-HT
7
receptor may be involved in the pathophysiology of sleep disorders, depression, (Schwartz, et al.,
Adv. Int. Med.
1993, 38, 81-106) and schizophrenia (Roth, et al.,
J. Pharmacol. Exp. Ther.,
1994, 268, 1403-1410). The 5-HT
7
receptor stimulation has caused relaxation of the blood vessels in monkey (Leung, et al.
Br. J. Pharmocol.,
1996, 117, 926-930), dog (Cushing, et al.
J. Pharmocol. Exp. Ther.,
1996, 277, 1560-1566) and rabbit (Martin, et al.,
Br. J. Pharmocol.,
1995, 114, 383). Therefore, the therapeutic utility of 5-HT
7
receptor ligands requires the discovery of selective therapeutic agents. The present invention discloses novel 5-HT
7
receptor antagonists.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel inhibitors of the 5-HT
7
receptor or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating central nervous system disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):
or pharmaceutically acceptable salt forms thereof, wherein R
1
, X, Y, n and A are defined below, are effective 5-HT
7
inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula (I):
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
R
1
is selected from a C
6-10
carbocyclic aromatic residue substituted with 1-3 R
1a
, and a 5-10 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O, and S substituted with 0-2 R
1a
;
R
1a
is independently selected at each occurrence from halo, —NO
2
, —CN, —CF
3
and —CF
2
CF
3
;
X is selected from —S(O)
p
—, —C(O)—, —O—, —CH(OH)—, —CH(OC(O)CH
3
)—, —NR
4a
—, —S(O)
2
NR
4
— and a five membered saturated, partially saturated or unsaturated ring containing 0-2 heteroatoms selected from the group consisting of O and N;
with the proviso that when X is a five membered saturated, partially saturated or unsaturated ring containing 0-2 heteroatoms selected from O and N, R
1
may be an unsubstituted C
6-10
carbocyclic aromatic residue;
R
4
is selected from hydrogen and C
1-6
alkyl;
R
4a
is taken together with R
1
to form a 5 or 6-membered fused heterocyclic ring containing 1-2 heteroatoms selected from O or N, and substituted with 1 or 2 carbonyl groups;
Y is C
1-3
alkylene;
A is selected from a 5 or 6 membered saturated, partially saturated or unsaturated ring which contains from 0-1 heteroatoms selected from N, O and S substituted with 0-3 R
5
, napthyl substituted with 0-3 R
5
, and napthyl fused with ring B substituted with 0-3 R
5
;
R
5
is selected from C
1-5
alkyl, halo and —OCH
3
;
n is selected from 1, 2, and 3; and
p is selected from 0, 1, and 2.
[2] In a preferred embodiment, the present invention provides novel compounds, wherein:
R
1
is phenyl substituted with 1-3 R
1a
;
R
1a
is selected independently at each occurrence from halo, —CN, —CF
3
and —CF
2
CF
3
;
X is selected from —S(O)
2
—, —S—, —NR
4a
—, —C(O)—, isoxazolyl and isoxazolinyl;
R
4a
is taken together when R
1
is phenyl to form a 5 membered fused cyclic urea;
Y is propylene;
A is selected from phenyl substituted with 0-3 R
5
, napthyl substituted with 0-3 R
5
and napthyl fused with ring B substituted with 0-3 R
5
;
R
5
is selected independently at each occurrence from C
1-5
alkyl, halo and —OCH
3
; and
n is selected from 1 and 2.
[3] In a more preferred embodiment, the present invention provides novel compounds, wherein:
R
1
is phenyl substituted with 1-3 R
1a
;
R
1a
is selected independently at each occurrence from para-halo and meta-fluoro;
X is selected from —S(O)
2
—, —S— and —C(O)—;
Y is propylene;
A is phenyl substituted with 0-2 R
5
;
R
5
is selected independently at each occurrence from C
1-5
alkyl, halo and —OCH
3
; and
n is selected from 1 and 2.
[4] In a further more preferred embodiment, the present invention provides novel compounds, wherein:
R
1
is phenyl substituted with 1-3 R
1a
;
R
1a
is meta-fluoro;
X is selected from —S(O)
2
—, —S— and —C(O)—;
Y is propylene;
A is phenyl substituted with 0-2 R
5
;
R
5
is selected independently at each occurrence from C
1-5
alkyl, halo and —OCH
3
; and
n is selected from 1 and 2.
[5] In an even further more preferred embodiment, the present invention provides a compound selected from the group:
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))isoindole,
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-hydroxybutyl)) isoindole,
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-acetoxybutyl)) isoindole,
2-((4-(4-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl)) benz[f]isoindole,
2-((4-(4-Pyridyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
2-((4-(3-Fluorophenyl)-4-oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((4-(4-fluorophenyl)-4-oxobutyl))-1H-benz[de] isoquinoline,
2-((4-Oxo-4-(2-thienyl)butyl))-1,2,3,4-tetrahydroisoquinoline,
6,7-Dimethoxy-2-((4-(4-fluorophenyl)oxobutyl))-1,2,3,4-tetrahydroisoquinoline,
2-((3-(1,3-Dihydro-2H-benzimidazol-2-one)-1-ylpropyl))-1,2,3,4-tetrahydroisoquinoline,
2-(3-Phenylisoxazol-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline,
(+/−)-2-((3-(4-Fluorophenyl)-2-isoxazolin-5-yl)methyl-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((3-(4-fluorophenoxy)propyl))isoindole,
2-((3-(4-Fluorophenylthio)propyl))-1,2,3,4-tetrahydroisoquinoline,
1,3-Dihydro-2-((3-(4-fluorophenylthio)propyl))isoindole,
1,3-Dihydro-2-((3-(4-fluorophenylsulfonyl)propyl)) isoindole,
2-((3-(4-F

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