3-aryl substituted pyrazolo[4,3-d]pyrimidine deriviatives; corticotropin-releasing factor receptor (CRF1) specific ligands
AssigneeNeurogen Corporation
InventorJun Yuan
Life of this patent
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Abstract
This invention encompasses compounds of the formula wherein Ar represents a mono- , di- or trisubstituted aryl group where at least one position on Ar ortho to the point of attachment to the pyrazole ring is substituted; and R1 represents lower alkyl; R2 is hydrogen or lower alkyl; and R3 and R4 independently represent organic and inorganic substituents, which compounds are highly selective partial agonists or antagonists or human CRF1 receptors and are useful in the diagnosis and treatment of treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.
Claims14
A pharmaceutical composition comprising a compound of the formula:
- or the pharmaceutically acceptable salts thereof together with at least one pharmaceutically acceptable carrier 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, lower alkyl, or lower alkoxy, provided that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;
- R1 is lower alkyl;
- R2 is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy having 1-6 carbon atoms;
- R3 and R4 are the same or different and represent hydrogen, lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, or alkenyl;
- phenyl, 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, lower alkyl, or lower alkoxy;
- phenyl-, 2-, 3-, or 4-pyridinyl-, 2- or 3-thienyl-, or 2-, 4- or 5-pyrimidinyl-lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl;
- cycloalkyl or cycloalkyl lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl;
- or
- 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally monosubstituted with lower alkyl;
- provided that not both R3 and R4 are hydrogen;
- or
- R3 and R4 taken together represent —(CH2)n—A—(CH2)m — where n is 2, or 3;
- A is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein R6 is lower alkyl, phenyl, 2-, 3-, or 4- pyridinyl, 2-or 3-thienyl or 2-, 4- or 5-pyrimidinyl, or phenyl, 2-, 3-or 4-pyridinyl-, 2-or 3-thienyl-, or 2-, 4- or 5-pyrimidinylalkyl;
- and
- m is 1, 2 or 3.
A method of treating stress disorders comprising administering to a patient in need of such treatment a compound of the formula:
- or the pharmaceutically acceptable salts thereof together with 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, lower alkyl, or lower alkoxy, provided that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;
- R1 is lower alkyl;
- R2 is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy having 1-6 carbon atoms;
- R3 and R4 are the same or different and represent hydrogen, lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, or alkenyl;
- phenyl, 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, lower alkyl, or lower alkoxy;
- phenyl-, 2-, 3-, or 4-pyridinyl-, 2- or 3-thienyl-, or 2-, 4- or 5-pyrimidinyl-lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl;
- cycloalkyl or cycloalkyl lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl;
- or
- 2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally monosubstituted with lower alkyl;
- provided that not both R3 and R4 are hydrogen;
- or
- R3 and R4 taken together represent —(CH2)n—A—(CH2)m— where is 2, or 3;
- A is methylene, 1,2-phenylene, oxygen, sulfur or NR6, wherein R6 is lower alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2-or 3-thienyl or 2-, 4- or 5-pyrimidinyl, or phenyl, 2-, 3-or 4-pyridinyl-, 2-or 3-thienyl-, or 2-, 4- or 5-pyrimidinylalkyl;
- and
- m is 1, 2 or 3
- to a patient in need thereof.
Dependencies are inferred from the claim text.