Substituted imidazole derivatives: GABAA receptor ligands
AssigneeNeurogen Corporation
InventorsGeorge Maynard, Linda M. Gustavson, Bingsong Han
Life of this patent
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Abstract
Substituted imidazole derivatives that bind to GABAA receptors are provided. Such compounds may be used to modulate ligand binding to GABAA receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABAA receptors (e.g., receptor localization studies).
Claims41
A compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 represents 5- to 10-membered aryl or heteroaryl, which is unsubstituted or substituted with from 1 to 4 groups independently selected from R5;
- R2 represents C1–C8alkyl, C2–C8alkenyl, C2–C8alkynyl, C3–C10cycloalkyl or (C3–C10cycloalkyl)C1–C8alkyl, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from R5;
- R3 and R4 are each independently selected from:
- (a) hydrogen, halogen, nitro and cyano;
- and
- (b) groups of the formula:
- wherein:
- (i) G is a bond, C1–C8alkylene, —NH—, —N(RB)—, —(RB)N— —O—, —C(═O)—, —C(═O)NH—, —C(═O)NRB—, —S(O)m—, —CH2C(═O)—, —S(O)mNH—, —S(O)mNRB—, —NHC(═O)—, —C(═NRB)—, HC═N—, —NRBC(═O)—, —NHS(O)m— or —NRBS(O)—;
- and
- (ii) RA and RB are independently selected from C1–C8alkyl, C2–C8alkenyl, and C2–C8alkynyl;
- and
- (iii) m is 0, 1 or 2;
- and
- R5 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, C1–C8alkyl, C1–C8alkoxy, mono- and di(C1–C8alkyl)amino, C3–C10cycloalkyl, (C3–C10cycloalkyl)alkyl, (C3–C10cycloalkyl)alkoxy, C2–C9heterocycloalkyl, C1–C8alkenyl, C1–C8alkynyl, halo(C1–C8)alkyl, halo(C1–C8)alkoxy, oxo, amino(C1–C8)alkyl and mono- and di(C1–C8alkyl)amino(C1–C8)alkyl.
A compound which is 2-{1-[1-Ethyl-5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-ylmethyl]-1H-imidazol-2-yl}-6-fluoro-pyridine.
A compound which is 2-{1-[1-Ethyl-4-methyl-5-(3-trifluoromethyl-phenyl)-1H-imidazol-2-ylmethyl]-1H-imidazol-2-yl}-6-fluoro-pyridine.
A compound which is 2-{1-[1-Ethyl-4-methyl-5-(2-pyridyl)-1H-imidazol-2-ylmethyl]-1H-imidazol-2-yl}-6-fluoro-pyridine.
A compound which is 2-{1-[1-Ethyl-5-methyl-4-(2-pyridyl)-1H-imidazol-2-ylmethyl]-1H-imidazol-2-yl}-6-fluoro-pyridine.
A compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 represents 5- to 10-membered heteroaryl, which is unsubstituted or substituted with from 1 to 4 groups independently selected from R5;
- R2 represents C1–C8alkyl, C2–C8alkenyl, C2–C8alkynyl, C3–C10cycloalkyl or (C3–C10cycloalkyl)C1–C8alkyl, each of which is unsubstituted or substituted with from 1 to 3 substituents independently selected from R5;
- R3 and R4 are each independently selected from:
- (a) hydrogen, halogen, nitro and cyano;
- and
- (b) groups of the formula:
- wherein:
- (i) G is a bond, C1–C8alkylene, —NH—, —N(RB)—, —(RB)N— —O—, —C(═O)—, —C(═O)NH—, —C(═O)NRB—, —S(O)m—, —CH2C(═O)—, —S(O)mNH—, —S(O)mNRB—, —NHC(═O)—, —C(═NRB)—, HC═N—, —NRBC(═O)—, —NHS(O)m— or —NRBS(O)—;
- and
- (ii) RA and RB are independently selected from C1–C8alkyl, C2–C8alkenyl, C2–C8alkynyl and 3- to 12-membered carbocycles and heterocycles having 1 ring or 2 fused, pendant or spiro rings, each of which is unsubstituted or substituted with from 1 to 4 substituents independently selected from R5;
- and
- (iii) m is 0, 1 or 2;
- and
- R5 is independently selected at each occurrence from halogen, hydroxy, nitro, cyano, amino, C1–C8alkyl, C1–C8alkoxy, mono- and di(C1–C8alkyl)amino, C3–C10cycloalkyl, (C3–C10cycloalkyl)alkyl, (C3–C10cycloalkyl)alkoxy, C2–C9heterocycloalkyl, C1–C8alkenyl, C1–C8alkynyl, halo(C1–C8)alkyl, halo(C1–C8)alkoxy, oxo, amino(C1–C8)alkyl and mono- and di(C1–C8alkyl)amino (C1–C8)alkyl.
Dependencies are inferred from the claim text.