Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-06
2002-03-12
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...
C514S183000, C514S212050, C514S293000, C544S328000, C544S331000, C544S333000, C540S479000, C540S583000, C546S082000, C546S087000, C546S113000
Reexamination Certificate
active
06355651
ABSTRACT:
BACKGROUND (IF THE INVENTION
1. Field of the Invention
This invention relates to novel substituted pyrrolopyridine derivatives which selectively bind to Corticotropin-Releasing Factor (CRF) receptors. More specifically, it relates to tetrahydro-5H-pyrido[2,3-b]indol-4-amines, 9H-pyrido[2,3-b]indol-4-amines, and 1H-pyrrolo[2,3-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., 4: 425-473 (1991).
International application WO 9413676 A1 discloses pyrrolo[2,3-d]pyrimidines as having Corticotropin-Releasing Factor antagonist activity. 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. Further, the invention provides pharmaceutical compositions comprising compounds of Formula I. It further relates to the use of such compounds and compositions in treating 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 optionally substituted aryl or heteroaryl;
R
1
is hydrogen or alkyl;
R
7
is hydrogen or alkyl
R
2
is hydrogen, halogen, alkyl or alkoxy; or
R
1
and R
2
taken together with the ring to which they are attached form a 5-9 membered saturated or aromatic ring optionally having a hetero atom selected from oxygen, sulfur or nitrogen;
R
3
and R
4
are independently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl groups; or
R
3
and R
4
together with the nitrogen atom to which they are attached form a 5-8 membered ring; and
R
5
is hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy or thioalkoxy having 1-6 carbon atoms.
The compounds of the invention 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 (PRSD) 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 addition to the novel compounds of the instant invention described by general formula I above, the invention encompasses compounds of formula IA:
wherein
Ar is phenyl, 2-, 3, - or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally di- or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions of Ar is substituted;
R
1
is hydrogen or lower alkyl;
R
7
is hydrogen or 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
, wherein R
6
is hydrogen or lower alkyl, and m is 0, 1 or 2; or
R
1
and R
2
taken together represent —CH═E—CH═CH—, where E is CH or N;
R
3
and R
4
are not both hydrogen and independently represent
hydrogen, lower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 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;
phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;
cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or
R
3
and R
4
taken together represent —(CH
2
)
n
—G—(CH
2
)
m
—
where n is 2, or 3;
m is 1,2or3; and
G 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-pyrimidinyl, or
R
6
is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl; and
R
5
is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.
Preferred compounds of formula I are those where Ar is a disubstituted aryl or heteroaryl group having substituents in one ortho position and the para position. More preferred compounds of formula I are those where Ar is a trisubstituted aryl or heteroaryl group having substituents in both ortho positions and the para position, i.e., a 2, 4, 6-trisubstituted aryl group. The most preferred aryl group is phenyl. The preferred aryl substituents are lower alkyl groups or halogen, particularly fluorine. More preferred aryl substituents are methyl groups.
Other preferred compounds of formula I are those where the NR
3
R
4
group is a disubstituted amino group, e.g., dialkyl amino. A particularly preferred NR
3
R
4
group is dipropylamino.
In compounds of formula I, R
5
is preferably lower alkyl and, more preferably, methyl; and R
7
is preferably hydrogen.
In still other preferred compounds of formula I, 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 NMe, and m is 0, 1 or 2.
The invention further provides compounds of formula II
wherein
Ar is phenyl, 2-, 3, - or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is monosubstituted or optionally di- or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the ortho positions of Ar is substituted;
R
7
is hydrogen or alkyl;
R
3
and R
4
are not both hydrogen and independently represent
hydrogen, lower alkyl, phenyl, 2-, 3-, or 4pyridyl, 2- or 3-diienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;
phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl;
cycloalkyl having 3-8 carbon atoms, cycloalkyl lower alkyl, 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally mono or disubstituted with lower alkyl; or
R
3
and R
4
taken together represent —(CH
2
)
n
—G—(CH
2
)
m
—
where n is 2, or 3;
m is 1, 2 or 3; and
G 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-pyrimidinyl, or
R
6
is phenylalkyl, 2-, 3-, or 4-pyridylalkyl, 2- or 3-thienylalkyl, or 2-, 4- or 5-pyrimidinyl alkyl, where each alkyl is lower alkyl; and
R
5
is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.
Preferred compounds of formula II are those where Ar is a disubstituted aryl or heteroaryl group having substituents in one ortho position and the para position. More preferred compounds of formula II are those where Ar is a trisubstituted aryl or heteroaryl group having substituents in both ortho positions and the para position, i.e., a 2, 4, 6-trisubstituted aryl group. The most prefer
Horvath Raymond F.
Hutchison Alan
Huang Evelyn Mei
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
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