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US 12,686,700 B2Granted
Neuroactive steroids substituted in position 10 with a cyclic group for use in the treatment of CNS disorders
AssigneeSage Therapeutics, Inc.
InventorsMaria Jesus Blanco-Pillado, Francesco G. Salituro, Marshall Lee Morningstar
Life of this patent
Estimating the term…
Abstract
Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein n, R19, R5, R3a, R6a, R6b, R1, R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b, R17b, R15a, R15b, R16a and R16b are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.
Claims55
A method of therapeutically treating a CNS-related disorder related to GABA function in a subject suffering from the CNS-related disorder related to GABA function, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- represents a single or double bond, provided if a double bond is present, then one of R6a or R6b is absent;
- R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORA1, —N(RA1)2, —SRA1, —C(═O)RA1, —C(—O)ORA1, —C(═O)SRA1, —C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, —OC(═O)N(RA1)2, —OC(═O)SRA1, —OS(═O)2RA1, —OS(═O)2ORA1, —OS(═O)2N(RA1)2, —N(RA1)C(═O)RA1, —N(RA1)C(═NRA1) RA1, —N(RA1)C(═O)ORA1, —N(RA1)C(═O)N(RA1)2, —N(RA1)C(═NRA1) N(RA1)2, —N(RA1)S(═O)2RA1, —N(RA1)S(═O)2ORA1, —N(RA1)S(═O)2N(RA1)2, —SC(═O)RA1, —SC(═O)ORA1, —SC(═O)SRA1, —SC(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2ORA1, or —S(═O)2N(RA1)2, wherein each RA1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two RAI groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring;
- each of R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b, and R17b is independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORA1, —N(RA1)2, —SRA1, —C(═O)RA1, —C(═O)ORA1, —C(═O)SRA1, —C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, —OC(═O)N(RA1)2, —OC(═O)SRA1, —OS(═O)2RA1, —OS(═O)2ORA1, —OS(═O)2N(RA1)2, —N(RA1)C(═O)RA1, —N(RA1)C(═NRA1) RA1, —N(RA1)C(═O)ORA1, —N(RA1)C(═O)N(RA1)2, —N(RA1)C(═NRA1) N(RA1)2, —N(RA1)S(═O)2RA1, —N(RA1)S(═O)2ORA1, —N(RA1)S(═O)2N(RA1)2, —SC(═O)RA1, —SC(═O)ORA1, —SC(═O)SRA1, —SC(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2ORA1, or —S(═O)2N(RA1)2, wherein each RA1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two RAI groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring;
- R3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R5 is hydrogen or methyl;
- when is a double bond, R5 is absent;
- each of R6a and R6b is hydrogen, halogen, —CN, —NO2, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
- or R6a and R6b are joined to form an oxo (═O) group;
- each of R15a, R15b, R16a and R16b is independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORC3, —N(RC3)2, —SRC3, —C(═O)RC3, —C(═O)ORC3, —C(═O)SRC3, —C(═O)N(RC3)2, —OC(═O)RC3, —OC(═O)ORC3, —OC(═O)N(RC3)2, —OC(═O)SRC3, —OS(═O)2RC3, —OS(═O)2ORC3, —OS(═O)2N(RC3)2, —N(RC3) C(═O)RC3, —N(RC3) C(═NRC3) RC3, —N(RC3) C(═O)ORC3, —N(RC3) C(═O)N(RC3)2, —N(RC3) C(═NRC3) N(RC3)2, —N(RC3) S(═O)2RC3, —N(RC3) S(═O)2ORC3, —N(RC3) S(═O)2N(RC3)2, —SC(═O)RC3, —SC(═O)ORC3, —SC(═O)SRC3, —SC(═O)N(RC3)2, —S(═O)2RC3, —S(═O)2ORC3, or —S(═O)2N(RC3)2, wherein each RC3 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two RC3 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring;
- R19 is substituted or unsubstituted C3-C6 carbocyclyl or substituted or unsubstituted aryl;
- and
- n is 0, 1 or 2;
- wherein the CNS-related disorder related to GABA function is depression, seizure, tremor, epilepsy, or anxiety.
12 more elements
A method of inducing sedation and/or anesthesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- represents a single or double bond, provided if a double bond is present, then one of R6a or R6b is absent;
- R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORA1, —N(RA1)2, —SRA1, —C(═O)RA1, —C(═O)ORA1, —C(═O)SRA1, —C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, —OC(═O)N(RA1)2, —OC(═O)SRA1, —OS(═O)2RA1, —OS(═O)2ORA1, —OS(═O)2N(RA1)2, —N(RA1)C(═O)RA1, —N(RA1)C(═NRA1) RA1, —N(RA1)C(═O)ORA1, —N(RA1)C(═O)N(RA1)2, —N(RA1)C(═NRA1) N(RA1)2, —N(RA1)S(═O)2RA1, —N(RA1)S(═O)2ORA1, —N(RA1)S(═O)2N(RA1)2, —SC(═O)RA1, —SC(═O)ORA1, —SC(═O)SRA1, —SC(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2ORA1, or —S(═O)2N(RA1)2, wherein each RA1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two RAI groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring;
- each of R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b, and R17b is independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORA1, —N(RA1)2, —SRA1, —C(═O)RA1, —C(═O)ORA1, —C(═O)SRA1, —C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, —OC(═O)N(RA1)2, —OC(═O)SRA1, —OS(═O)2RA1, —OS(═O)2ORA1, —OS(═O)2N(RA1)2, —N(RA1)C(═O)RA1, —N(RA1)C(═NRA1) RA1, —N(RA1)C(═O)ORA1, —N(RA1)C(═O)N(RA1)2, —N(RA1)C(═NRA1) N(RA1)2, —N(RA1)S(═O)2RA1, —N(RA1)S(═O)2ORA1, —N(RA1)S(═O)2N(RA1)2, —SC(═O)RA1, —SC(═O)ORA1, —SC(═O)SRA1, —SC(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2ORA1, or —S(═O)2N(RA1)2, wherein each RA1 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two RAI groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring;
- R3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R5 is hydrogen or methyl;
- when is a double bond, R5 is absent;
- each of R6a and R6b is hydrogen, halogen, —CN, —NO2, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
- or R6a and R6b are joined to form an oxo (═O) group;
- each of R15a, R15b, R16a and R16b is independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORC3, —N(RC3)2, —SRC3, —C(═O)RC3, —C(═O)ORC3, —C(═O)SRC3, —C(═O)N(RC3)2, —OC(═O)RC3, —OC(═O)ORC3, —OC(═O)N(RC3)2, —OC(═O)SRC3, —OS(═O)2RC3, —OS(═O)2ORC3, —OS(═O)2N(RC3)2, —N(RC3) C(═O)RC3, —N(RC3) C(═NRC3) RC3, —N(RC3) C(═O)ORC3, —N(RC3) C(═O)N(RC3)2, —N(RC3) C(═NRC3) N(RC3)2, —N(RC3) S(═O)2RC3, —N(RC3) S(═O)2ORC3, —N(RC3) S(═O)2N(RC3)2, —SC(═O)RC3, —SC(═O)ORC3, —SC(═O)SRC3, —SC(═O)N(RC3)2, —S(═O)2RC3, —S(═O)2ORC3, or —S(═O)2N(RC3)2, wherein each RC3 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two RC3 groups are taken with the intervening atoms to form a substituted or unsubstituted heterocyclic ring;
- R19 is substituted or unsubstituted C3-C6 carbocyclyl or substituted or unsubstituted aryl;
- and
- n is 0, 1 or 2.
11 more elements
Dependencies are inferred from the claim text.