US 6,147,085 AGranted

Aminoalkyl substituted 9H-pyridino[2,3-b] indole and 9H-pyrimidino[4,5-b] indole derivatives

AssigneeNeurogen Corporation

InventorsRaymond F. Horvath, James W. Darrow, George D. Maynard

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Abstract

Disclosed are compounds of the formula: ##STR1## wherein Ar, R.sup.1, W and X are substituents as defined herein, which compounds are (1) antagonists at CRF.sub.1 receptors and are, therefore, useful in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety; and (2) are neuropeptide Y.sub.1 receptor antagonists, and are therefore useful in the treatment of a variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y.

Claims32

Dependent claims

A compound of the formula:

##STR57## or the pharmaceutically acceptable salts thereof wherein wherein
Ar is phenyl, mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, N-lower alkyl carboxamido, N,N-lower dialkyl carboxamido, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.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.sup.1 is hydrogen, halogen, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, or (C.sub.1 -C.sub.6 alkyl)-G.sup.1 --R.sup.2 where G.sup.1 is oxygen or sulfur and R.sup.2 is hydrogen or C.sub.1 -C.sub.6 alkyl;
W is C--R.sup.3 where R.sup.3 is hydrogen or C.sub.1 -C.sub.6 alkyl;
and
X is ##STR58## wherein V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or CH(C.sub.1 -C.sub.6 alkyl), with the proviso that both V.sup.1 and V.sup.2 cannot both be CO, CS or SO.sub.2 ;
Y.sup.1 and Y.sup.2 independently represent a bond or C.sub.1 -C.sub.6 alkylene;
A.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are independently Hydrogen or a lower alkyl group, or
A.sup.1 is C.sub.1 -C.sub.6 arylalkyl or C.sub.1 -C.sub.6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring, or
lower alkanoyl, lower alkylsulfonyl, with the proviso that R.sup.4 and R.sup.5 cannot both be alkanoyl or alkylsulfonyl;
or
A.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 is hydrogen or a C.sub.1 -C.sub.6 alkyl group and R.sup.5 forms a heterocycloalkyl group with Y.sup.1 when Y.sup.1 is alkylene;
or
A.sup.1 is NR.sup.4 R.sup.5 wherein NR.sup.4 R.sup.5 is a C.sub.3 -C.sub.6 heterocycloalkyl, or
A.sup.1 is NR.sup.4 R.sup.5 wherein NR.sup.4 R.sup.5 is a 5- or 6-membered nitrogen heterocycle optionally containing an oxygen or second nitrogen atom, or
A.sup.1 is a group of the formula:
##STR59## wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3;
and
G.sup.2 is
NR.sup.6 wherein R.sup.6 is hydrogen or C.sub.1 -C.sub.6 alkyl, or
CH(C.sub.0 -C.sub.6 alkylene)-G.sup.3 --R.sup.7 wherein G.sup.3 is CONH, CONH(C.sub.1 -C.sub.6 alkyl), NH, NH(C.sub.1 -C.sub.6 alkyl) and R.sup.7 is hydrogen or C.sub.1 -C.sub.6 alkyl;
or
CONH.sub.2, CO[N(C.sub.1 -C.sub.6 alkyl)R.sup.8 ] wherein R.sup.8 is hydrogen or C.sub.1 -C.sub.6 alkyl;
C.sub.1 -C.sub.6 arylalkyl or C.sub.1 -C.sub.6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
A.sup.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.6 alkylene)-G.sup.4 --R.sup.9 wherein G.sup.4 is oxygen or sulfur and R.sup.9 is hydrogen, trifluoromethyl or C.sub.1 -C.sub.6 alkyl;
##STR60## wherein heteroaryl is 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z.sup.1 is C.sub.1 -C.sub.6 alkyl;
and
V.sup.2, Y.sup.2 and A.sup.2 are as defined above;
##STR61## where Z.sup.2 is carbon or nitrogen;
where
when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R is carboxamido, or (C.sub.0 -C.sub.6 alkylene)-G -R wherein G5 is NH, NH(C.sub.1 -C.sub.6 alkyl) and R is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 arylalkyl or C.sub.1 -C.sub.6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
when Z is carbon, n is 1 or 2 and p is 1 or 2, R.sup.10 is amino;
or
when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2, R.sup.10 is hydrogen;
or
(iv) a nitrogen heterocycle of the formula:
##STR62## wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C.sub.1 -C.sub.6 alkylene)-G.sup.6 --R.sup.12 wherein G.sup.6 is NH, NH(C.sub.1 -C.sub.6 alkyl) and R.sup.12 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 arylalkyl or C.sub.1 -C.sub.6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring.

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Dependencies are inferred from the claim text.

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Abstract

A compound of the formula:

##STR57## or the pharmaceutically acceptable salts thereof wherein wherein
Ar is phenyl, mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, carboxamido, N-lower alkyl carboxamido, N,N-lower dialkyl carboxamido, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.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.sup.1 is hydrogen, halogen, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, or (C.sub.1 -C.sub.6 alkyl)-G.sup.1 --R.sup.2 where G.sup.1 is oxygen or sulfur and R.sup.2 is hydrogen or C.sub.1 -C.sub.6 alkyl;
W is C--R.sup.3 where R.sup.3 is hydrogen or C.sub.1 -C.sub.6 alkyl;
and
X is ##STR58## wherein V.sup.1 and V.sup.2 are CH.sub.2, CO, CS, SO.sub.2 or CH(C.sub.1 -C.sub.6 alkyl), with the proviso that both V.sup.1 and V.sup.2 cannot both be CO, CS or SO.sub.2 ;
Y.sup.1 and Y.sup.2 independently represent a bond or C.sub.1 -C.sub.6 alkylene;
A.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 and R.sup.5 are independently Hydrogen or a lower alkyl group, or
A.sup.1 is C.sub.1 -C.sub.6 arylalkyl or C.sub.1 -C.sub.6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring, or
lower alkanoyl, lower alkylsulfonyl, with the proviso that R.sup.4 and R.sup.5 cannot both be alkanoyl or alkylsulfonyl;
or
A.sup.1 is NR.sup.4 R.sup.5 wherein R.sup.4 is hydrogen or a C.sub.1 -C.sub.6 alkyl group and R.sup.5 forms a heterocycloalkyl group with Y.sup.1 when Y.sup.1 is alkylene;
or
A.sup.1 is NR.sup.4 R.sup.5 wherein NR.sup.4 R.sup.5 is a C.sub.3 -C.sub.6 heterocycloalkyl, or
A.sup.1 is NR.sup.4 R.sup.5 wherein NR.sup.4 R.sup.5 is a 5- or 6-membered nitrogen heterocycle optionally containing an oxygen or second nitrogen atom, or
A.sup.1 is a group of the formula:
##STR59## wherein e and f are independently 1, 2 or 3 and the sum of e and f is at least 3;
and
G.sup.2 is
NR.sup.6 wherein R.sup.6 is hydrogen or C.sub.1 -C.sub.6 alkyl, or
CH(C.sub.0 -C.sub.6 alkylene)-G.sup.3 --R.sup.7 wherein G.sup.3 is CONH, CONH(C.sub.1 -C.sub.6 alkyl), NH, NH(C.sub.1 -C.sub.6 alkyl) and R.sup.7 is hydrogen or C.sub.1 -C.sub.6 alkyl;
or
CONH.sub.2, CO[N(C.sub.1 -C.sub.6 alkyl)R.sup.8 ] wherein R.sup.8 is hydrogen or C.sub.1 -C.sub.6 alkyl;
C.sub.1 -C.sub.6 arylalkyl or C.sub.1 -C.sub.6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
A.sup.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.6 alkylene)-G.sup.4 --R.sup.9 wherein G.sup.4 is oxygen or sulfur and R.sup.9 is hydrogen, trifluoromethyl or C.sub.1 -C.sub.6 alkyl;
##STR60## wherein heteroaryl is 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z.sup.1 is C.sub.1 -C.sub.6 alkyl;
and
V.sup.2, Y.sup.2 and A.sup.2 are as defined above;
##STR61## where Z.sup.2 is carbon or nitrogen;
where
when Z.sup.2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R is carboxamido, or (C.sub.0 -C.sub.6 alkylene)-G -R wherein G5 is NH, NH(C.sub.1 -C.sub.6 alkyl) and R is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 arylalkyl or C.sub.1 -C.sub.6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
when Z is carbon, n is 1 or 2 and p is 1 or 2, R.sup.10 is amino;
or
when Z.sup.2 is nitrogen, n is 1 or 2 and p is 1 or 2, R.sup.10 is hydrogen;
or
(iv) a nitrogen heterocycle of the formula:
##STR62## wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C.sub.1 -C.sub.6 alkylene)-G.sup.6 --R.sup.12 wherein G.sup.6 is NH, NH(C.sub.1 -C.sub.6 alkyl) and R.sup.12 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 arylalkyl or C.sub.1 -C.sub.6 heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino, lower alkylcarboxamido, lower alkyl, lower alkoxy, with the proviso that 2 adjacent substituents can together form a 5-7 fused cycloalkyl or heterocycloalkyl ring.

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