Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-12
2001-10-09
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S140000, C546S148000, C548S374100, C548S375100
Reexamination Certificate
active
06300360
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain pyrazole derivatives which selectively bind to corticotropin-releasing factor (CRF) receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.
2. Description of the Related Art
A variety of pyrazoles have been described in the prior art. International Patent Application Publication No. WO96/01254 (Jan. 18, 1996) discloses certain pyrazole derivatives as herbicides. International Patent Application Publication No. W094/13643 (Jun. 23, 1994) discloses certain pyrazoles and pyrazolopyrimidines as CRF antagonists. International Patent Application Publication No. W094/13644 (Jun. 23, 1994) and International Patent Application Publication No. W094/13661 (Jun. 23, 1994) also disclose certain substituted pyrazoles which have CRF antagonistic activities. German Patent DD210265 (Jun. 06, 1984) discloses certain pyrazoles as xanthine oxidase inhibitors.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with CRF receptors.
The invention provides pharmaceutical compositions comprising compounds of Formula I. It further relates to the use of such compounds in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I:
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, mono, disubstituted, or trisubstituted with halogen, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted,
A is CH
2
or C═O;
R
1
is hydrogen, C
1
-C
6
alkyl;
R
2
is hydrogen, C
1
-C
6
alkyl, or C
1
-C
6
alkenyl;
Z is a group of the formula
where
R
4
is hydrogen, C
1
-C
6
alkyl, or (C
1
-C
6
)alkyl—W—R
8
, where W is O, S NH, or N(C
1
-C
6
)alkyl, and R
8
is hydrogen or C
1
-C
6
alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;and
E represents CHR
5
where R
5
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, or trifluoromethyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or a saturated 5- or 6- membered ring or a partially unsaturated ring having one or two double bonds;
or
E is a group of the formula
where
R
3
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, or trifluoromethyl; and
the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or a saturated 5- or 6-membered ring or a partially unsatuate ring having one or two double bonds; or
Z is —NR
6
R
7
where R
6
and R
7
are the same or different and represent
hydrogen, C
1
-C
6
alkyl, (C
1
-C
6
)alkyl-Y—R
9
, wherein Y is O, S NH, N(C
1
-C
6
alkyl), and R
9
is hydrogen or C
1
-C
6
alkyl; or
aryl(C
1
-C
1
)alky, wherein aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is mono- or disubstituted with halogen, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C-
6
)alkoxy; or
R
6
and R
7
taken together represent —(CH
2
)
n
—Y—(CH
2
)
m
— wherein n is 2, or 3, Y is CH
2
, O, S or NR
6
, wherein R
6
is C
1
-C
6
alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, or 2-, 4-, or 5-pyrimidinyl and m is 1, 2 or 3.
These compounds are highly selective partial agonists or antagonists at CRF receptors and are usefull irp the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression and anxiety.
DETAILED DESCRIPTION OF THE INVENTION
In addition to the compounds of Formula I above, the invention provides compounds encompassed by Formula IIA:
wherein
Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyidinyl, 2- or 3- thienyl, 4- or 5-pyrimidinyl, mono, disubstituted, or trisubstituted with halogen, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted,
R
1
is hydrogen, C
1
-C
6
alkyl;
R
2
is hydrogen, C
1
-C
6
alkyl, or C
1
-C
6
alkenyl;
Z is a group of the formula
where
R
4
is hydrogen, C
1
-C
6
alkyl, or (C
1
-C
6
)alkyl-W—R
8
, where W is O, S NH, or N(C
1
-C
6
) alkyl, and R
4
is hydrogen or C
1
-C
6
alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;and
E represents CHR
5
where R
5
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, or trifluoromethyl, phenl, naphthyl, pyridinyl, pyrimidinyl, thienyl imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or a saturated 5- or 6-membered ring or a partially unsaturated ring having one or two double bonds;
or
E is a group of the formula
where
R
3
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, or trifluoromethyl; and
the B ring is phenyl, naphthyl pyridinyl, pyrinudinyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyrazinyl, or a saturated 5- or 6-membered ring or a partially unsaturated ring having one or two double bonds; or
Z is —NR
6
R
7
where R
6
and R
7
are the same or different and represent
hydrogen, C
1
-C
6
alkyl, (C
1
-C
6
)alkyl-Y—R
9
, wherein Y is O, S NH, N(C
1
-C
6
alkyl), and R
9
is hydrogen or C
1
-C
6
alkyl; or
aryl(C
1
-C
6
)alkyl, wherein aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5- pyrimidinyl, each of which is mono- or disubstituted with halogen, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C
6
) alkoxy; or
R
6
and R
7
taken together represent —(CH
2
)
n
—Y—(CH
2
)
m
— wherein n is 2, or 3, Y is CH
2
, O, S or NR
6
, wherein R
6
is C
1
-C
6
alkyl, phenyl 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, and m is 1, 2 or 3.
Preferred compounds of formula IIA are those where Z is 1,2,3,4-tetrahydroisoquinoline, 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline or 3-methoxymethyl-1,2,3,4-tetrahydroisoquinoline.
The invention also provides compounds of formula IIB:
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C
1
-C
6
alkyl, or C
1
-C
6
alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;
R
1
is hydrogen, C
1
-C
6
alkyl;
R
2
is hydrogen, C
1
-C
6
alky, or C
1
-C
6
alkenyl;
Z is a group of the formula
where
R
4
is hydrogen, C
1
-C
6
alkyl, or (C
1
-C
6
)alkyl-W—R
8
, where W is O, NH, or N(C
1
-C
6
) alkyl, and R
8
is hydrogen or C
1
-C
6
alkyl;
m is 0, 1 or 2;
n is 0, 1 or 2;and
E represents CHR
5
where R
5
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, trifluoromethyl, phenyl, naphthyl, pyridinyl, pyrimidinyl thienyl, imidazolyl, pyrrolyl, pyrazolyl pynyl, or a saturated 5- or 6-membered ring or a partially unsaturated ring having one or two double bonds;
or
E is a group of the formula
where
R
3
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy, halogen, or trifluoromethyl; and
the B ring is phenyl, naphthyl, pyridinyl, pyrimidinyl or a saturated 5- or 6-membered ring or a partially unsaturated ring having one or two double bonds; or
Z is —NR
6
R
7
where R
6
and R
7
are the same or different and represent
hydrogen, C
1
-C
6
alkyl (C
1
-C
6
)alkyl-Y—R
9
, wherein Y is O, S NH, N(C
1
-C
6
alkyl), and R
9
is hydrogen or C
1
-C
6
alkyl; or
aryl(C
1
-C
6
)alkyl, wherein aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is mono- or disubstituted with halogen, hydroxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy; or
R
6
and R
7
taken together represent —(CH
2
)
n
—Y—(CH
2
)
m
— wherein n is 2, or 3, Y is CH
2
, O, S or NR
6
, wherein R
6
is C
1
-C
6
alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, or 2-, 4-
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
Ramsuer Robert W.
Sarussi Steven J.
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