Deazapurine derivatives; a new class of CRF1 specific ligands

Details Deazapurine derivatives; a new class of CRF1 specific ligands Deazapurine derivatives; a new class of CRF1 specific ligands

1999-08-05

2001-08-28

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S256000, C514S267000, C514S292000, C514S293000, C514S300000, C514S211100, C514S217050, C514S217060

Reexamination Certificate

active

06281220

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel substituted deazapurine derivatives which selectively bind to CRF receptors. More specifically, it relates to pyrrolo[3,2-d]pyrirnidin-4-amines, pyrrolo[3,2-b]pyridin-4-amines, and pyrrolo[3,2-b]pyridin-4-amines, and their use as antagonists of Corticotropin-Releasing Factor in the treatment of various disease states.
2. Description of the Related Art
Corticotropin-releasing factor (CRF) antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazoline derivatives, respectively. The importance of CRF antagonists is described in the literature, for example, as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference in its entirety. CRF antagonists are considered effective in the treatment of a wide range of diseases including stress-related illnesses, such as stress-induced depression, anxiety, and headache. Other diseases considered treatable with CRF antagonists are discussed in U.S. Pat. No. 5,063,245 and Pharm. Rev., 43: 425-473 (1991).
International application WO 9413676 Al discloses pyrrolo[2,3-d]pyrimidines as having Corticotropin-Releasing Factor antagonist acitivity. J. Het. Chem. 9, 1077 (1972) describes the synthesis of 9-Phenyl-pyrrolo[3,2-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 treating stress related disorders such as post trumatic 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, where the phenyl group is mono-, di-, or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, with the proviso that at least one of the ortho positions of the phenyl group is substituted; or
Ar is 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidyl, each of which is optionally mono-, di-, or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, with the proviso that at least one of the ortho positions of the Ar substituent is substituted;
X is CH or nitrogen;
R
1
is lower alkyl;
R
2
is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy; or
R
1
and R
2
taken together represent —(CH
2
)
n
—A—(CH
2
)
m
—,
where n is 2, 3 or 4, A is methylene, oxygen, sulfur or NR
6
, where R
6
is lower alkyl, and
m is 0, 1 or 2;
R
3
and R
4
are the same or different and represent
hydrogen or lower alkyl;
phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-thienyl, or 2-, 4-, or 5-pyrinidyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;
phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2- or 3-thienyl lower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl;
cycloalkyl having 3-8 carbon atoms or cycloalkyl lower alkyl where the cycloalkyl portion has 3-8 carbon atoms;
2-hydroxyethyl or 3-hydroxypropyl optionally mono or disubstituted with lower alkyl with the proviso 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, or 3,
A is methylene, 1,2 phenylene, oxygen, sulfur or NR
6
, wherein R
6
is lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2-or 3-thienyl or 2-, 4-, or 5-pyrimidyl, phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2-or 3-thienyl lower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl; and
m is 1, 2 or 3; and
R
5
is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.
These compounds, i.e., substituted deazapurine derivatives, 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 trumatic stress disorder (PTSD) as well as depression and anxiety.
Thus, the invention provides compounds, including pharmaceutically acceptable salts of the compounds of formula I, and pharmaceutical compositions for use in treating disease states associated with Corticotropin-releasing factor. The invention further provides methods including animal models relevant to the evaluation of the interaction of the compounds of the invention with CRF receptors. This interaction results in the pharmacological activities of these compounds.
DETAILED DESCRIPTION OF THE INVENTION
In this document, all temperatures will be stated in degrees Celsius. All amounts, ratios, concentrations, proportions and the like will be stated in weight units, unless otherwise stated, except for ratios of solvents, which are in volume units.
In addition to compounds of general formula I described above, the invention encompasses compounds of general formula IA:
wherein
Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, with the proviso that at least one of the ortho positions of the Ar substituent is substituted;
X is CH or nitrogen;
R
1
is lower alkyl;
R
2
is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy; or
R
1
and R
2
taken together represent —(CH
2
)
n
—A—(CH
2
)
m
—,
where n is 2, 3 or 4, A is methylene, oxygen, sulfur or NR
6
, where R
6
is lower alkyl, and
m is 0, 1 or 2;
R
3
and R
4
are the same or different and represent
hydrogen or lower alkyl;
phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-thienyl, or 2-, 4-, or 5-pyrimidyl, each of which is mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;
phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2- or 3-thienyl lower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl;
cycloalkyl having 3-8 carbon atoms or cycloalkyl lower alkyl where the cycloalkyl portion has 3-8 carbon atoms;
2-hydroxyethyl or 3-hydroxypropyl optionally mono or disubstituted with lower alkyl with the proviso that not both R3 and R4 are hydrogen; or
R
3
and R4 taken together 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-pyridyl, 2-or 3-thienyl or 2-, 4-, or 5-pyrimidyl, phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2- or 3-thienyl lower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl, and
m is 1, 2 or 3; and
R
5
is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.
In the compounds of the invention, preferred NR
3
R
4
groups include the following:
Preferred compounds of formula I are those where R
1
is methyl, ethyl or propyl or isopropyl; R
2
is lower alkyl, halogen, or thio lower alkyl; R
5
is lower alkyl or halogen; and R
7
, R
8
, and R
9
represent methyl, ethyl, propyl or isopropyl.
The invention provides compounds of formula II
wherein
R
4
represents hydrogen or lower alkyl;
R
1
, R
7
, R
8
, and R
9
represent lower alkyl; and
R
3
represents lower alkyl, or cycloalkyl lower alkyl.
Preferred compounds of formula II are those where R
1
is methyl, ethyl or propyl or isopropyl; and R
7
, R
8
, and R
9
represent methyl, ethyl, propyl or isopropyl. Particularly preferred compounds of formula II are those where R
1
is methyl, and R
7
, R
8
, and R
9
represent methyl.
The invention provides compounds of formula III
wherein
R
4
represents hydrogen or lower alkyl;
R
1
, R
7
, R
8
, and R
9
represent lower alkyl; and
R
3
represents lower alkyl, or cycloalkyl lower alkyl; and
R
5
is lower alkyl, halogen, or thio lower alkyl.
Preferred compounds of formula III are those where R
1
is methyl, ethyl or propyl or isopropyl; R
5
is halogen or thio lower alkyl; and R
7
, R
8
, and R
9
represent methyl, ethyl, propyl or isopropyl. Particularly preferred compounds of formula III are those where R
1
is methyl; R
5
is halogen, thiomethyl; and R
7
, R
8
, and R
9
represent methyl, ethyl, propyl or isopropyl.
The invention provides compounds of formula IV
wherein
R
4
represents hydrogen or lower alkyl;
R
1
,

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