# US 2019/0169226 A1 · Neuroactive steroids, compositions, and uses thereof

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- Number: US 2019/0169226 A1
- Document ID: US20190169226A1
- Status: Published application
- Kind: A1
- Application number: 16/269,779
- Filed: 2019-02-07
- Published: 2019-06-06
- Earliest claimed: 2014-06-18
- Assignees: Sage Therapeutics, Inc.
- Applicants: Sage Therapeutics, Inc.
- Inventors: Boyd L. Harrison; Gabriel Martinez Botella; Albert Jean Robichaud; Francesco G. Salituro
- Web page: https://patentgrep.com/patent/US20190169226A1

## CPC

- C07J 41/005: {the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives}
- C07J 5/0015: {not substituted in position 16}
- C07J 7/002: {not substituted in position 16}
- C07J 7/009: {by only one oxygen atom doubly bound}
- C07J 17/00: Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton (cardanolide, bufanolide C07J19/00)
- C07J 1/0011: {substituted in position 17 by a keto group}
- C07J 7/007: {not substituted in position 17 alfa}
- C07J 7/0085: {by an halogen atom}
- C07J 13/007: {with double bond in position 17 (20)}
- C07J 21/00: Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J 21/006: {at position 3}
- C07J 21/008: {at position 17}
- C07J: STEROIDS (seco-steroids C07C)

## Abstract

Described herein are steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R1, R2a, R2b, R3, R4, R5a, R5b, R6, and Z are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.

## Claims

### Claim 1

A method for treating a CNS-related disorder in a human subject in need thereof comprising administering to the human subject a therapeutically effective amount of a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof or b) a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl;
each of R2a and R2b is independently hydrogen, C1-C6 alkyl, halo, cyano, —ORA, or —NRBRC, or
R2a and R2b together with the carbon atom to which they are attached form a ring;
R3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)RA, —C(O)ORA, or —C(O)NRBRC;
R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or —ORA;
represents a single or double bond, wherein when one is a double bond, the other is a single bond;
wherein when the between —CR6 and —CR5aR5b is a double bond, then one of R5a or R5b is absent; and
when one of the is a double bond, R6 is absent;
each of R5a and R5b is independently absent, hydrogen, C1-C6 alkyl, or halo;
R6 is absent or hydrogen;
Z is —CR7aR7b—, wherein each of R7a and R7b is independently hydrogen or C1-C6 alkyl, or R7a and R7b, together with the carbon atom to which they are attached, form a ring;
RA is hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of RB and RC is independently hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is methyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein both R2a and R2b are hydrogen.

### Claim 4 (depends on 1)

The method of claim 1, wherein R3 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, C(O)RA, —C(O)ORA, or —C(O)NRBRC.

### Claim 5 (depends on 4)

The method of claim 4, wherein R3 is —C(O)NRBRC.

### Claim 6 (depends on 1)

The method of claim 1, wherein R4 is hydrogen, C1-C6 alkyl, or —OH.

### Claim 7 (depends on 6)

The method of claim 6, wherein R4 is hydrogen.

### Claim 8 (depends on 1)

The method of claim 1, wherein both R2a and R2b are hydrogen, the between —CR6 and —CR5aR5b is a single bond, and both R5a and R5b are hydrogen.

### Claim 9 (depends on 1)

The method of claim 1, wherein Z is —CH2—.

### Claim 10 (depends on 1)

The method of claim 1, wherein R7a is hydrogen and R7b is C1-C6 alkyl.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl;
each of R2a and R2b is independently hydrogen, C1-C6 alkyl, halo, cyano, —ORA, or —NRBRC, or
R2a and R2b together with the carbon atom to which they are attached form a ring;
R3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)RA, —C(O)ORA, or —C(O)NRBRC;
R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or ORA;
each of R5a and R5b is independently absent, hydrogen, C1-C6 alkyl, or halo;
Z is —CR7aR7b—, wherein each of R7a and R7b is independently hydrogen or C1-C6 alkyl, or R7a and R7b, together with the carbon atom to which they are attached, form a ring;
RA is hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of RB and RC is independently hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring; or
RD is hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.

### Claim 12 (depends on 11)

The method of claim 11, wherein R1 is methyl.

### Claim 13 (depends on 11)

The method of claim 11, wherein R3 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, —C(O)RA, —C(O)ORA, or —C(O)NRBRC.

### Claim 14 (depends on 11)

The method of claim 11, wherein R3 is C1-C6 alkyl.

### Claim 15 (depends on 11)

The method of claim 11, wherein R4 is hydrogen.

### Claim 16 (depends on 11)

The method of claim 11, wherein both R2a and R2b are hydrogen and both R5a and R5bare hydrogen.

### Claim 17 (depends on 11)

The method of claim 11, wherein the compound of Formula (Ia) is selected from a group consisting of:

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is a compound of Formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or heterocyclyl;
each of R2a and R2b is independently hydrogen, C1-C6 alkyl, halo, cyano, —ORA, or —NRBRC, or
R2a and R2b together with the carbon atom to which they are attached form a ring;
R3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)RA, —C(O)ORA, or —C(O)NRBRC;
R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, or ORA;
each of R5a and R5b is independently absent, hydrogen, C1-C6 alkyl, or halo;
Z is —CR7aR7b—, wherein each of R7a and R7b is independently hydrogen or C1-C6 alkyl, or R7a and R7b, together with the carbon atom to which they are attached, form a ring;
RA is hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each of RB and RC is independently hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring; or
RD is hydrogen, C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.

### Claim 19 (depends on 18)

The method of claim 18, wherein R1 is methyl.

### Claim 20 (depends on 18)

The method of claim 18, wherein R3 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, —C(O)RA, —C(O)ORA, or —C(O)NRBRC.

### Claim 21 (depends on 18)

The method of claim 18, wherein R3 is C1-C6 alkyl.

### Claim 22 (depends on 20)

The method of claim 20, wherein R3 is —C(O)NRBRC.

### Claim 23 (depends on 18)

The method of claim 18, wherein R4 is —OH.

### Claim 24 (depends on 18)

The method of claim 18, wherein R4 is hydrogen.

### Claim 25 (depends on 18)

The method of claim 18, wherein both R2a and R2b are hydrogen and both R5a and R5bare hydrogen.

### Claim 26 (depends on 18)

The method of claim 18, wherein the compound of Formula (Ib) is selected from a group consisting of:

### Claim 27 (depends on 1)

The method of claim 1, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, a sleep disorder, autism spectrum disorder, pain, seizure, status epilepticus, depression, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.

### Claim 28 (depends on 27)

The method of claim 27, wherein the CNS-related disorder is depression.

### Claim 29 (depends on 28)

The method of claim 28, wherein the depression is postpartum depression.

### Claim 30 (depends on 27)

The method of claim 27, wherein the CNS-related disorder is a major depressive disorder.

### Claim 31 (depends on 27)

The method of claim 27, wherein the CNS-related disorder is tremor.

### Claim 32 (depends on 31)

The method of claim 31, wherein the tremor is essential tremor.

### Claim 33 (depends on 27)

The method of claim 27, wherein the compound is administered orally, subcutaneously, intravenously, or intramuscularly.

### Claim 34 (depends on 29)

The method of claim 29, wherein the compound is administered orally.