US 6,664,261 B2Granted

Pyrazolopyrimidines as CRF receptor antagonists

AssigneeNeurocrine Biosciences, Inc.

InventorsChen Chen, Thomas R. Webb, James R. McCarthy, Terence J. Moran, Keith M. Wilcoxen, Charles Huang

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Abstract

This invention concerns compounds of formula including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein R1 is NR4R5 or OR5; R2 is C1-6alkyl, C1-6alkyloxy or C1-6alkylthio; R3 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfoxy or C1-6alkylthio; R4 is hydrogen, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl or C1-6alkyloxyC1-6alkyl; R5 is C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, Ar1CH2, C1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyl, C3-6alkenyl, thienylmethyl, furanylmethyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)amino, C1-6alkylcarbonylC1-6alkyl, C1-6alkyl substituted with imidazolyl; or a radical of formula —Alk—O—CO—Ar1; or R4 and R5 taken together with the nitrogen atom to which they are attached may form an optionally substituted pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group; having CRF receptor antagonistic properties; pharmaceutical compositions containing such compounds as active ingredients; methods of treating disorders related to hypersecretion of CRF such as depression, anxiety, substance abuse, by administering an effective amount of a compound of formula (I).

Claims14

Dependent claims

A compound of formula

including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein
R1 is NR4R5 or OR5;
R2 is C1-6alkyl, C1-6alkyloxy or C1-6alkylthio;
R3 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfoxy or C1-6alkylthio;
R4 is hydrogen, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl or C1-6alkyloxyC1-6alkyl;
R5 is C1-8alkyl, mono- or di(C3-6cycloalkyl)methyl, Ar1CH2, C3-6alkenyl, C1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyl, thienylmethyl, furanylmethyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)amino, C1-6alkylcarbonylC1-6alkyl, C1-6alkyl substituted with imidazolyl;
or a radical of formula —Alk—O—CO—Ar1;
or R4 and R5 taken together with the nitrogen atom to which they are attached may form a piperidinyl, homopiperidinyl or morpholinyl group, optionally substituted with C1-6alkyl or C1-6alkyloxyC1-6alkyl;
and
Ar is phenyl substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, trifluoromethyl, hydroxy, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino and mono- or di(C1-6alkyl)amino;
pyridinyl;
pyridinyl substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, trifluoromethyl, hydroxy, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino, mono- or di(C1-6alkyl)amino and piperidinyl;
and wherein said substituted phenyl may optionally be further substituted with one or more halogens;
Ar1 is phenyl;
phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, di(C1-6alkyl)aminoC1-6alkyl, trifluoromethyl and C1-6alkyl substituted with morpholinyl;
or pyridinyl;
and
Alk is C1-6alkanediyl.

15 more elements

A method for treating a physiological condition or disorder in a warm-blooded animal arising from the hypersecretion of corticotropin-releasing factor comprising administering to said animal an effective amount of a compound of the formula

including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein
R1 is NR4R5 or OR5;
R2 is C1-6alkyl, C1-6alkyloxy or C1-6alkylthio;
R3 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfoxy or C3-6cycloalkyl;
R4 is hydrogen, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkyenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl or C1-6alkyloxyC1-6alkyl;
R5 is C1-8alkyl, mono-or di(C3-6cycloalkyl)methyl, Ar1CH2, C3-6alkenyl, C1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyl, thienylmethyl, furanylmethyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)amino, C1-6alkylcarbonylC1-6alkyl, C1-6alkyl substituted with imidazolyl;
or a radical of formula —Alk—O—CO—Ar1;
or R4 and R5 taken together with the nitrogen atom to which they are attached may form a pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group, optionally substituted with C1-6alkyl or C1-6alkyloxyC1-6alkyl;
Ar is phenyl;
phenyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-6alkyl, trifluoromethyl, hydroxy, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino and mono- or di(C1-6alkyl)amino;
pyridinyl;
pyridinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, C1-6alkyl, trifluoromethyl, hydroxy, cyano, C1-6alkyloxy, benzyloxy, C1-6alkylthio, nitro, amino, mono- or di(C1-6alkyl)amino and piperidinyl;
and wherein said substituted phenyl may optionally be further substituted with one or more halogens;
Ar1 is phenyl;
phenyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, C1-6alkyl, C1-6alkyloxy, di(C1-6alkyl)aminoC1-6alkyl, trifluoromethyl and C1-6alkyl substituted with morpholinyl;
or pyridinyl;
and
Alk is C1-6alkanediyl.

15 more elements

Dependencies are inferred from the claim text.