Isoquinolinamine and phthalazinamine derivatives:...

Details Isoquinolinamine and phthalazinamine derivatives:... Isoquinolinamine and phthalazinamine derivatives:...

2000-08-25

2002-03-05

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C546S143000, C514S247000, C514S310000

Reexamination Certificate

active

06353103

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to isoquinolinamine and phthalazinamine 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
Isoquiolinamines and phthalazinamines have been described in the prior art. For example, Sindler-Kulyk et al,
J. Org. Chem.,
48(8), 1275-81, (1983) describe a 1-phenyl-4-isoquinolinamine. British Patent GB 1303061 disclose aminophthalazines said to have antiinflammatory activity. Holava et al.,
J. Med. Chem.,
12, 555-6, (1969), describe a 4-phenyl-1-phthalazinamine.
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 will 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 4pyridinyl, 2- or 3thienyl, 4- or 5pyrimidinyl, 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 phthalazinamine or isoquinolinamine ring is substituted;
R
1
and R
2
are the same or different and represent
hydrogen, C
1
-C
6
alkyl, halogen, hydroxy, C
1
-C
6
alkoxy,
NH
2
, NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)
2
, NO
2
, cyano, trifluoromethyl;
R
3
and R
4
are the same or different and represent
hydrogen, C
1
-C
6
alkyl optionally substituted with halogen, hydroxy, or C
1
-C
6
alkoxy; or
aryl(C
1
-C
6
)alkyl, where 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 optionally mono- or disubstituted with halogen, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy; or C
1
-C
6
alkyl-Y—R
5
, wherein Y is O, S NH, N(C
1
-C
6
alkyl), and R
5
is hydrogen or C
1
-C
6
alkyl; and
W is N or C—R
6
, where in R
6
is hydrogen or C
1
-C
6
alkyl.
These compounds are highly selective partial agonists or antagonists of 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.
The invention further encompasses methods for treating mammals, such as, for example, humans and companion animals (i.e., cats and dogs) suffering from PTSD, depression, and/or anxiety. Such methods comprise administering to a patient mammal an amount effective of a compound of Formula I to relieve the depression, anxiety or PTSD.
DETAILED DESCRIPTION OF THE INVENTION
In addition to the compounds of Formula I above, the invention provides compounds encompassed by Formula II:
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, 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 phthalazinamine ring is substituted;
R
1
and R
2
are the same or different and represent hydrogen, C
1
-C
6
alkyl, halogen, hydroxy, C
1
-C
6
alkoxy, NH
2
, NH(C
1
-C
6
alkyl), N(C
1
-C
6
alkyl)
2
, NO
2
, cyano, trifluoromethyl; and
R
3
and R
4
are the same or different and represent
hydrogen, C
1
-C
6
alkyl optionally substituted with halogen, hydroxy, or C
1
-C
6
alkoxy; or
aryl(C
1
-C
6
)alkyl, where 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 optionally mono- or disubstituted with halogen, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy; or C
1
-C
6
alkyl-Y—R
5
, wherein Y is O, S NH, N(C
1
-C
6
alkyl), and R
5
is hydrogen or C
1
-C
6
alkyl.
In preferred compounds of Formula II, R
3
and R
4
are not both hydrogen simultaneously. Preferred compounds of formula II are those where R
3
and R
4
independently represent C
1
-C
6
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 phthalazinamine ring is substituted. More preferred compounds of Formula II are those where R
1
and R
2
are independently hydrogen or lower alkyl, most preferably hydrogen or C
1
-C
3
alkyl; and 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 phthalazinamine ring is substituted. Most preferred compounds of Formula II are those where R
1
and R
2
are hydrogen; and R
3
and R
4
independently represent C
1
-C
6
alkyl optionally substituted with halogen, hydroxy, or C
1
-C
6
alkoxy, 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 phthalazinamine 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 that not both R
3
and R
4
are hydrogen simultaneously.
The invention also provides compounds of formula III:
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, 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 phthalazinamine ring is substituted; and
R
3
and R
4
are the same or different and represent
hydrogen, C
1
-C
6
alkyl optionally substituted with halogen, hydroxy, or C
1
-C
6
alkoxy; or
aryl(C
1
-C
6
)alkyl, where 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 optionally mono- or disubstituted with halogen, hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy; or C
1
-C
6
alkyl-Y—R
5
, wherein Y is O, S NH, N(C
1
-C
6
alkyl), and R
5
is hydrogen or C
1
-C
6
alkyl.
In preferred compounds of Formula III, R
3
and R
4
are not both hydrogen simultaneously. Preferred compounds of formula III are those where R
3
and R
4
independently represent C
1
-C
6
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 phthalazinamine ring is substituted. Most preferred compounds of Formula III are those where R
3
and R
4
independently represent C
1
-C
6
alkyl optionally substituted with halogen, hydroxy, or C
1
-C
6
alkoxy, 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 phthalazinamine ring) with C
1
-C
3
alkyl, most preferably methyl. Particularly preferred compounds of Formula III 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 that not both R
3
and R
4
are hydrogen simultaneously.
The invention provides compounds of formula IV
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, C
1
-C
6
alkyl, C
1
-C
6
alkoxy with the proviso that at least one

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