C7, c12, and c16 substituted neuroactive steroids and their methods of use
AssigneeSage Therapeutics, Inc.
InventorsAlbert Jean Robichaud, Gabriel Martinez Botella, Boyd L. Harrison, Francesco G. Salituro, Andrew Griffin, Maria Jesus Blanco-Pillado
Life of this patent
Estimating the term…
Abstract
Described herein are neuroactive steroids of Formula (I), Formula (V), or Formula (IX) or a pharmaceutically acceptable salt thereof; wherein each instance of R2, R3, R4, R5, R6, R7, R11a, R11b, R12, R16, R17, R19, and are as herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such as for inducing sedation and/or anesthesia.
Claims52
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond as valency permits;
- each of R2, R4, R6, R11a, and R11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RA1 groups are joined to form an heterocyclic or heteroaryl ring;
- and RA2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- or R11a and R11b together form oxo;
- R3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R5 is absent or hydrogen;
- and represents a single or double bond, wherein when one of at site is a double bond, the other is a single bond;
- when both of are single bonds, then R5 is hydrogen;
- and when one of the is a double bond, R5 is absent;
- R17 is alkoxy, cyano, nitro, aryl, heteroaryl, or —C(O)RB1, —C(O)CH2RB1, or —C(O)CH2CH2RB1, wherein RB1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl;
- R19 is hydrogen or alkyl;
- and
- R7 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1.
2-5. (canceled)
The compound of claim 2, wherein R3 is C1-C6 alkyl.
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The compound of claim 2, wherein the compound of Formula (I) is a compound of Formula (II-c) or (II-d):
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14-17. (canceled)
19-31. (canceled)
A compound of Formula (V):
- or a pharmaceutically acceptable salt thereof,
- wherein represents a single or double bond as valency permits;
- each of R2, R4, R6, R11a, and R11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RA1 groups are joined to form an heterocyclic or heteroaryl ring;
- and RA2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- or R11a and R11b together form oxo;
- R3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R5 is absent or hydrogen;
- and represents a single or double bond, wherein when one of at site is a double bond, the other is a single bond;
- when both of are single bonds, then R5 is hydrogen;
- and when one of the is a double bond, R5 is absent;
- R17 is alkoxy, cyano, nitro, aryl, heteroaryl, —C(O)RB1, —C(O)CH2RB1, or —C(O)CH2CH2RB1, wherein RB1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl;
- R19 is hydrogen or alkyl;
- and R12 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1.
33-35. (canceled)
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44-47. (canceled)
49-57. (canceled)
A compound of Formula (IX):
- or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond as valency permits;
- each of R2, R4, R6, R11a, and R11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RA1 groups are joined to form an heterocyclic or heteroaryl ring;
- and RA2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- or R11a and R11b together form oxo;
- R3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R5 is absent or hydrogen;
- and represents a single or double bond, wherein when one of at site is a double bond, the other is a single bond;
- when both of are single bonds, then R5 is hydrogen;
- and when one of the is a double bond, R5 is absent;
- R17 is alkoxy, cyano, nitro, aryl, heteroaryl, —C(O)RB1, —C(O)CH2RB1, or —C(O)CH2CH2RB1, wherein RB1 is hydrogen, —OH, —N(RA1)2, alkoxy, aryl, or heteroaryl;
- R19 is hydrogen or alkyl;
- and R16 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1.
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69-72. (canceled)
74-81. (canceled)
85-99. (canceled)
103-104. (canceled)
Dependencies are inferred from the claim text.