Pyrimido [4,5,b]indolizine derivatives and aza...

Details Pyrimido [4,5,b]indolizine derivatives and aza... Pyrimido [4,5,b]indolizine derivatives and aza...

2001-02-23

2002-12-17

Rao, Deepak R. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C540S467000, C540S470000, C540S481000, C540S544000, C540S553000, C540S575000, C540S600000, C544S003000, C544S055000, C544S060000, C544S063000, C544S096000, C544S115000

Reexamination Certificate

active

06495686

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to pyrido[2,3-b]indolizine derivatives and aza analogues thereof that selectively bind to corticotropin-releasing factor (CRF) receptors. It 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
Posselt, K., Arzneim.-Forsch. 1978, 28, 1056-65, describe the synthesis of 10-(4-methoxyphenyl)pyrido[2,3-b]indolizine. Volovenko et al., Khim. Geterotsikl. Soedin. 1991, 6, 852, describe the synthesis of 2-chloro and 2-methylthio-10-tosylmethylpyrimido[4,5-b]indolizine.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with CRF receptors.
In one aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I. In another aspect, it provides compositions useful in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety. These compositions include a compound of Formula I. Further, in a third aspect, the invention provides methods of treating such stress related disorders.
Accordingly, a broad aspect of the invention is directed to compounds of Formula I:
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidyl, each of which is optionally mono-, di-, or trisubstituted with halogen, trifluoromethyl, hydroxy, amino, mono- or di(C
1
-C
6
) alkyl amino, carboxamido, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R
1
and R
2
independently represent
C
1
-C
6
alkyl;
C
3
-C
7
cycloalkyl;
C
3
-C
7
cycloalkyl(C
1
-C
6
)alkyl;
C
1
-C
6
alkoxy(C
1
-C
6
)alkyl; or
aryl(C
1
-C
6
)alkyl where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl or 2-, 4 or 5-pyrimidyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
6
alkoxy, or (C
1
-C
6
alkylene)—A—R
4
, wherein A is O, S, NH, or N(C
1
-C
6
alkyl) and R
4
is hydrogen, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkyl; or
R
1
and R
2
taken together represent —(CH
2
)
n
—A—(CH
2
)
m
— wherein n is 2, 3 or 4, A is methylene, oxygen, sulfur, or NR
5
, wherein R
5
is hydrogen, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkyl, and m is 0, 1, or 2;
R
3
is C
1
-C
6
alkyl, or (C
1
-C
6
alkylene)—G—R
6
, wherein G is O, S, NH, or N(C
1
-C
6
alkyl) and R
6
is hydrogen, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkyl; and
W, X, Y, and Z are independently N or C—R
7
, wherein R
7
is hydrogen, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkyl.
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.
Another aspect of the invention is directed to intermediates useful in the preparation of the compounds of Formula I.
In a further aspect, the invention provides methods for making the compounds of Formula I and the intermediates for preparing such compounds.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of Formula I are those where Ar is phenyl substituted in the 2, 4, and 6 positions, preferably with methyl, ethyl or propyl; naphthyl substituted in the 2 and 6 positions, preferably with methyl, ethyl or propyl; or 3-pyridyl substituted in the 2, 4, and 6 positions, preferably with methyl, ethyl or propyl; 5-pyrimidiyl substituted in the 2, 4, and 6 positions, preferably with methyl, ethyl, or propyl. Particularly, preferred components of Formula I include those where the Ar group is substituted in the 2 and 6 or the 2, 4, and 6 positions with methyl.
Preferred compounds of the invention have Formula II:
wherein Ar, R
1
, R
2
, and R
3
are as defined above for Formula I; and
X, Y, and Z are independently N or C—R
7
, wherein R
7
is hydrogen, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkyl.
Preferred compounds of Formula II are those where X and Z are both CH and Y is CH or nitrogen. More preferred compounds of Formula II are those where R
3
is C
1
-C
4
alkyl or C
3
-C
6
cycloalkyl(C
1
-C
3
)alkyl. Other more preferred compounds of Formula II are those where R
1
and R
2
independently represent C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl(C
1
-C
6
)alkyl, —(CH
2
)
2
O(CH
2
)
2
—; and Ar is phenyl trisubstituted with C
1
-C
3
alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula II are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
Other particularly preferred compounds of Formula II are those where X, Y and Z are all CH.
Other preferred compounds of the invention have Formula III
wherein Ar, R
1
, R
2
, and R
3
are as defined above for Formula I; and
X and Z are independently N or C—R
7
, wherein R
7
is hydrogen, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkyl
More preferred compounds of Formula III are those where R
3
is C
1
-C
4
alkyl or C
3
-C
6
cycloalkyl(C
1
-C
3
)alkyl. Other more preferred compounds of Formula III are those where R
1
and R
2
independently represent C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl(C
1
-C
6
)alkyl, —(CH
2
)
2
O(CH
2
)
2
—; and Ar is phenyl trisubstituted with C
1
-C
3
alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula III are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
Still other preferred compounds of the invention have formula:
wherein
wherein Ar, R
1
, R
2
, and R
3
are as defined above for Formula I; and
W, X, and Z are independently N or C—R
7
, wherein R
7
is hydrogen, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkyl.
Preferred compounds of Formula IV are those where X and Z are both CH.
More preferred compounds of Formula IV are those where R
3
is C
1
-C
4
alkyl or C
3
-C
6
cycloalkyl(C
1
-C
3
)alkyl. Other more preferred compounds of Formula IV are those where R
1
and R
2
independently represent C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl(C
1
-C
6
)alkyl, —(CH
2
)
2
O(CH
2
)
2
—; and Ar is phenyl trisubstituted with C
1
-C
3
alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula IV are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
Other particularly preferred compounds of IV are those where W is CH and X and Z are both CH.
Yet other preferred compounds of the invention have formula:
wherein Ar, R
1
, R
2
, and R
3
are as defined above for Formula I; and
X and Z are independently N or C—R
7
, wherein R
7
is hydrogen, C
3
-C
7
cycloalkyl, or C
1
-C
6
alkyl.
Preferred compounds of Formula V are those where R
3
is C
1
-C
4
alkyl or C
3
-C
6
cycloalkyl(C
1
-C
3
)alkyl. Other more preferred compounds of Formula V are those where R
1
and R
2
independently represent C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl(C
1
-C
6
)alkyl, —(CH
2
)
2
O(CH
2
)
2
—; and Ar is phenyl trisubstituted with C
1
-C
3
alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula V are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
The invention also provides intermediates useful in preparing compounds of Formula I. These intermediates ha

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