3-aryl substituted pyrazolo[4,3-d]pyrimidine...

Details 3-aryl substituted pyrazolo[4,3-d]pyrimidine... 3-aryl substituted pyrazolo[4,3-d]pyrimidine...

1999-10-22

2001-04-03

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...

C544S283000, C544S061000, C544S262000, C540S467000, C540S470000, C540S481000

Reexamination Certificate

active

06211187

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain pyrazolo[4,3-d]pyrimidine derivatives which selectively bind to corticotropin-releasing factor (CRF) receptors. More specifically, the invention relates to 3-aryl substituted pyrazolo[4,3-d]pyrimidine derivatives. The invention further relates to pharmaceutical compositions comprising such compounds. It also 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
International Application PCT/US93/11333 describes pyrazolo[3,4-d]pyrimidines said to be CRF antagonists. Bull. Chem. Soc. Japan. 52(1), 208-11, (1979) describes the synthesis of 3-phenyl-pyrazolo[4,3-d]pyrimidines.
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, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;
R
1
is lower alkyl;
R
2
is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy having 1-6 carbon atoms;
R
3
and R
4
are the same or different and represent hydrogen, lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, or alkenyl;
phenyl, 2-, 3-, or 4- pyridinyl, 2- or 3-thienyl or 2-, 4- or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;
phenyl-, 2-, 3-, or 4-pyridinyl-, 2- or
3
-thienyl-, or 2-, 4- or
5
-pyrimidinyl-lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl;
cycloalkyl or cycloalkyl lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl; or
2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally monosubstituted with lower alkyl;
provided that not both R
3
and R
4
are hydrogen; or
R
3
and R
4
taken together represent —(CH
2
)
n
—A—(CH
2
)
m
— where n is 2,or3;
A is methylene, 1,2-phenylene, oxygen sulfur or NR
6
, wherein R
6
is lower alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2-or 3-thienyl or 2-, 4- or 5-pyrimidinyl, or phenyl-, 2-, 3-or 4-pyridinyl-, 2-or 3-thienyl-, or 2-, 4- or 5-pyrimidinylalkyl; and
m is 1,2 or 3.
These compounds are highly selective partial agonists or antagonists at CRF receptors and are useful in 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 encompasses of Formula II:
wherein
R
a
represents halogen, hydroxy, lower alkyl, or lower alkoxy;
R
b
, and R
c
independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
R
1
is lower alkyl;
R
2
is hydrogen or lower alkyl; and
R
3
and R
4
are the same or different and represent hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl;
provided that not both R
3
and R
4
are hydrogen.
Preferred compounds of Formula II are those where R
3
and R
4
independently represent C
1
-C
6
alkyl (i.e., lower alkyl) optionally substituted with halogen, hydroxy, or C
1
-C
6
alkoxy, Ar is phenyl that 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 the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. More preferred compounds of Formula II are those where Ar is phenyl that is trisubstituted with C
1
-C
6
alkyl, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the pyrazole ring is substituted. Most preferred compounds of Formula II are those where Ar is phenyl that is trisubstituted in the 2, 4, and 6 positions (para and both ortho positions relative to the point of attachment to the pyrazole ring) with C
1
-C
3
alkyl, most preferably methyl. Particularly preferred compounds of Formula II are those where R
3
and R
4
are independently hydrogen or C
1
-C
4
alkyl, e.g., methyl, ethyl, propyl, butyl, or cyclopropylmethyl, provided not both R
3
and R
4
are hydrogen.
The invention further encompasses compounds of Formula III:
wherein
R
a
represents halogen, hydroxy, lower alkyl, or lower alkoxy;
R
b
, and R
c
independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
R
1
is lower alkyl;
R
2
is hydrogen or lower alkyl; and
R
3
and R
4
are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, or alkenyl;
phenyl, 2-, 3-, or 4- pyridinyl, or 2-, 4- or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy; or
phenyl-, 2-, 3-, or 4pyridinyl-, or 2-, 4- or 5-pyrimidinyl-lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl,
provided that not both R
3
and R
4
are hydrogen.
Further, the invention encompasses compounds of Formula IV:
wherein
R
a
represents halogen, hydroxy, lower alkyl, or lower alkoxy;
R
b
, and R
c
independently represent hydrogen halogen, hydroxy, lower alkyl, or lower alkoxy;
R
1
is lower alkyl;
R
2
is hydrogen or lower alkyl; and
R
3
and R
4
taken together represent with the nitrogen atom to which they are attached represent —(CH
2
)
n
—A—(CH
2
)
m
— where
n is 2, or 3;
A is methylene, 1,2-phenylene, oxygen, sulfur or NR
6
, wherein R
6
is lower alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2-or 3-thienyl or 2-, 4- or 5-pyrimidinyl, or phenyl-, 2-, 3-or 4-pyridinyl-, 2-or 3-thienyl-, or 2-, 4- or 5-pyrimidinylalkyl; and
m is 1,2 or 3.
Preferred compounds of the invention have Formula V:
wherein
R
a
, and R
b
and R
c
independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, with the proviso that not both R
a
and R
c
are hydrogen;
R
1
is lower alkyl;
R
2
is hydrogen or lower alkyl; and
R
3
and R
4
are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, alkenyl, 2-hydroxyethyl or 3-hydroxypropyl, provided that not both R
3
and R
4
are hydrogen.
Other preferred compounds of Formula V are those where R
3
and R
4
independently represent C
1
-C
6
alkyl (i.e., lower alkyl) optionally substituted with halogen, hydroxy, or C
1
-C
6
alkoxy.
More preferred compounds of Formula V are those where R
a
, R
b
, and R
c
are methyl. Particularly preferred compounds of Formula V are those where R
a
, R
b
, and R
c
are methyl, R
1
and R
2
independently represent lower alkyl, and R
3
and R
4
are independently hydrogen or C
1
-C
4
alkyl, e.g., methyl, ethyl, propyl, butyl, or cyclopropylmethyl, provided not both R
3
and R
4
are hydrogen.
Other preferred compounds of the invention have Formula VI:
wherein
R
a
, R
b
, and R
c
independently represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, with the proviso that not both R
a
and R
c
are hydrogen;
R
1
is lower alkyl;
R
2
is hydrogen or lower alkyl; and
R
3
and R
4
are the same or different and represent hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, alkenyl, 2-hydroxyethyl or 3-hydroxypropyl, provided that not both R
3
and R
4
are hydrogen.
Other preferred compounds of Formula VI are those where R
3
and R
4
independently represent C
1
-C
6
alkyl (i.e., lower alkyl) optionally substituted with halogen, hydroxy, or C
1
-C
6
alkoxy.
More preferred compounds of Formula VI are

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