Compositions and methods for treating cns disorders
AssigneeSage Therapeutics, Inc.
InventorsGabriel Martinez Botella, Francesco G. Salituro, Albert Jean Robichaud, Boyd L. Harrison
Life of this patent
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Abstract
Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein (II), A, R1, R2, R3a, R4a, R4b, R5, R7a, and R7b are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.
Claims73
A compound of the Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R1 is hydrogen, C1-5 haloalkyl (e.g., C1-3 haloalkyl), C1-5 alkyl (e.g., C1-3 alkyl), C2-6 alkenyl, or C3-6 carbocylyl;
- each of R2a and R2b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocylyl, or —ORA2, wherein RA2 is hydrogen or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl;
- R3a is hydrogen or —ORA3, wherein RA3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R3b is hydrogen;
- or R3a and R3b are joined to form an oxo (═O) group;
- R4a is hydrogen, C1-6 alkyl, or —ORA4, wherein RA4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R4b is hydrogen or C1-6 alkyl;
- or R4a and R4b are joined to form an oxo (═O) group;
- or R4a and R4b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring);
- R5 is absent or hydrogen;
- each of R7a and R7b is independently hydrogen or halogen;
- represents a single or double bond, wherein when one of is a double bond, the other is a single bond;
- and when one of the is a double bond, R5 is absent.
The compound of any one of the preceding claims, wherein A is a carbon bound (e.g., A linked through a carbon atom) 5 or 6-membered heteroaryl, or 6-membered aryl.
The compound of any one of the preceding claims, wherein the compound is of the Formula (II-b):
- wherein:
- Ring E is heterocyclyl or heteroaryl.
The compound of any one of the preceding claims, wherein A is:
The compound of any one of the preceding claims, wherein A is an aryl ring.
The compound of any one of the preceding claims, wherein A is phenyl and n is 1 or 2.
The compound of any one of the preceding claims, wherein R1 is hydrogen, substituted C1-3 alkyl, or unsubstituted C1-3 alkyl.
The compound of any one of the preceding claims, wherein R1 is hydrogen, methyl, or methoxymethyl.
The compound of any one of the preceding claims, wherein R2 is hydrogen, —ORA2, wherein RA2 is hydrogen, or substituted or unsubstituted C1-6 alkyl (e.g., methyl, ethyl).
The compound of any one of the preceding claims, wherein R3a is —ORA3, wherein RA3 is hydrogen, or substituted or unsubstituted C1-6 alkyl (e.g., methyl).
The compound of any one of the preceding claims, wherein R4a is hydrogen, substituted C1-6 alkyl, or unsubstituted C1-6 alkyl (e.g., methyl).
The compound of any one of the preceding claims, wherein R4b is hydrogen, or substituted C1-6 alkyl, or unsubstituted C1-6 alkyl (e.g., methyl).
The compound of any one of the preceding claims, wherein each of R4a and R4a is independently unsubstituted C1-6 alkyl (e.g., methyl).
The compound of any one of the preceding claims, wherein each of R4a and R4a is independently hydrogen.
The compound of any one of the preceding claims, wherein R5 is hydrogen.
The compound of any one of the preceding claims, wherein n is 0.
The compound of any one of the preceding claims, wherein n is 1 and R6 is substituted or unsubstituted C1-6 alkyl, C1-6 haloalkyl, halogen (e.g., —F, —Br, —Cl), cyano, —ORA6, —C(═O)ORA6, —SRB6, —S(═O)RB6, or S(═O)2RB6, wherein RA6 is hydrogen or substituted or unsubstituted C1-6 alkyl (e.g., methyl, ethyl), C1-6haloalkyl (e.g., —CF3), and RB6 is substituted or unsubstituted C1-6 alkyl.
The compound of any one of the preceding claims, wherein n is 1 and R6 is halogen (e.g., —F, —Br, —Cl) or cyano.
The compound of any one of the preceding claims, wherein n is 1 and R6 is substituted or unsubstituted C1-6 alkyl (e.g., methyl).
The compound of any one of the preceding claims, wherein n is 1 and R6 is C1-6 haloalkyl, —ORA6, or —C(═O)ORA6, wherein RA6 is hydrogen or substituted or unsubstituted C1-6 alkyl (e.g., methyl, ethyl), C1-6haloalkyl (e.g., —CF3).
The compound of any one of the preceding claims, wherein n is 1 and R6 is SRB6, —S(═O)RB6, or S(═O)2RB6, wherein RB6 is substituted or unsubstituted C1-6 alkyl (e.g., methyl).
The compound of any one of the preceding claims, wherein n is 2 and R6 is independently selected from substituted or unsubstituted C1-6 alkyl, C1-6 haloalkyl, halogen (e.g., —F, —Br, —Cl), cyano, —ORA6, —C(═O)ORA6, —SRB6, —S(═O)RB6, or S(═O)2RB6, wherein RA6 is hydrogen or substituted or unsubstituted C1-6 alkyl (e.g., methyl, ethyl), C1-6 haloalkyl (e.g., —CF3), and RB6 is substituted or unsubstituted C1-6 alkyl.
The compound of any one of the preceding claims, wherein n is 2 and R6 is independently selected from halogen (e.g., —F, —Br, —Cl).
The compound of any one of the preceding claims, wherein n is 2 and one of R6 is fluorine.
The compound of any one of the preceding claims, wherein R1 is unsubstituted C1-3 alkyl and at least one of R2, R3a, R4a or R4b is not hydrogen.
A pharmaceutical composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.
A method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C3-6 carbocylyl;
- R2 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocylyl, or —ORA2, wherein RA2 is hydrogen or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl;
- R3a is hydrogen or —ORA3, wherein RA3 is hydrogen, C1-6 alkyl C2-6alkenyl, C2-6alkynyl, or C3-6 carbocylyl, and R3b is hydrogen;
- or R3a and R3b are joined to form an oxo (═O) group;
- R4a is hydrogen, C1-6 alkyl, or —ORA4, wherein RA4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R4b is hydrogen or C1-6 alkyl;
- R4a and R4b are joined to form an oxo (═O) group;
- or R4a and R4b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring).
- R7a is hydrogen or halogen;
- R7b is hydrogen;
- R5 is absent or hydrogen;
- and
- represents a single or double bond, wherein
- when one of is a double bond, the other is a single bond;
- and
- when one of the is a double bond, R5 is absent.
A method for treating seizure in a subject, comprising administering to the subject an effective amount of a compound of the Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C3-6 carbocylyl;
- R2 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocylyl, or —ORA2, wherein RA2 is hydrogen or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl;
- R3a is hydrogen or —ORA3, wherein RA3 is hydrogen, C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R3b is hydrogen;
- or R3a and R3b are joined to form an oxo (═O) group;
- R4a is hydrogen, C1-6 alkyl, or —ORA4, wherein RA4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R4b is hydrogen or C1-6 alkyl;
- R4a and R4b are joined to form an oxo (═O) group;
- or R4a and R4b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring).
- R7a is hydrogen or halogen;
- R7b is hydrogen;
- R5 is absent or hydrogen;
- and
- represents a single or double bond, wherein
- when one of is a double bond, the other is a single bond;
- and
- when one of the is a double bond, R5 is absent.
A method for treating epilepsy or status or status epilepticus in a subject, the method comprising administering to the subject an effective amount of a compound of the Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C3-6 carbocylyl;
- R2 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocylyl, or —ORA2, wherein RA2 is hydrogen or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl;
- R3a is hydrogen or —ORA3, wherein RA3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R3b is hydrogen;
- or R3a and R3b are joined to form an oxo (═O) group;
- R4a is hydrogen, C1-6 alkyl, or —ORA4, wherein RA4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R4b is hydrogen or C1-6 alkyl;
- R4a and R4b are joined to form an oxo (═O) group;
- or R4a and R4b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring).
- R7a is hydrogen or halogen;
- R7b is hydrogen;
- R5 is absent or hydrogen;
- and
- represents a single or double bond, wherein
- when one of is a double bond, the other is a single bond;
- and
- when one of the is a double bond, R5 is absent.
A method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of one of a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C3-6 carbocylyl;
- R2 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocylyl, or —ORA2, wherein RA2 is hydrogen or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl;
- R3a is hydrogen or —ORA3, wherein RA3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, or C3-6 carbocylyl, and R3b is hydrogen;
- or R3a and R3b are joined to form an oxo (═O) group;
- R4a is hydrogen, C1-6 alkyl, or —ORA4, wherein RA4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R4b is hydrogen or C1-6 alkyl;
- R4a and R4b are joined to form an oxo (═O) group;
- or R4a and R4b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring).
- R7a is hydrogen or halogen;
- R7b is hydrogen;
- R5 is absent or hydrogen;
- and
- represents a single or double bond, wherein
- when one of is a double bond, the other is a single bond;
- and
- when one of the is a double bond, R5 is absent.
A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof.
A kit comprising a solid composition comprising a compound of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- Ring A is carbocyclyl, heterocyclyl, aryl, or heteroaryl;
- R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C3-6 carbocylyl;
- R2 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocylyl, or —ORA2, wherein RA2 is hydrogen or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl;
- R3a is hydrogen or —ORA3, wherein RA3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, or C3-6 carbocylyl, and R3b is hydrogen;
- or R3a and R3b are joined to form an oxo (═O) group;
- R4a is hydrogen, C1-6 alkyl, or —ORA4, wherein RA4 is hydrogen, C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocylyl, and R4b is hydrogen or C1-6 alkyl;
- R4a and R4b are joined to form an oxo (═O) group;
- or R4a and R4b together with the carbon atom to which they are attached form a ring (e.g., a 3-6-membered ring (e.g., carbocycyl or heterocyclyl ring).
- R7a is hydrogen or halogen;
- R7b is hydrogen;
- R5 is absent or hydrogen;
- and
- represents a single or double bond, wherein
- when one of is a double bond, the other is a single bond;
- and
- when one of the is a double bond, R5 is absent;
- and a sterile diluent.
Dependencies are inferred from the claim text.