Oxysterols and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2018201643-A1
Application number	US-201615742422-A
Country	US
Kind code	A1
Filing date	Jul 6, 2016
Priority date	Jul 6, 2015
Publication date	Jul 19, 2018
Grant date	—

Abstract

Compounds are provided according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

First claim

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or C 1-6 alkyl;
each of R 2 and R 3 is independently hydrogen, C 1-6 alkyl, carbocyclyl, or heterocyclyl, or
R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-8 membered ring;
each of R 4 and R 5 is independently hydrogen;
R 8 is absent or hydrogen;
represents a single or double bond, wherein when one is a double bond, the other is a single bond and R 8 is absent; and
at least one hydrogen is replaced by a moiety cleavable under biological conditions.

2 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or C 1-6 alkyl;
each of R 2 and R 3 is independently hydrogen, C 1-6 alkyl, carbocyclyl, heterocyclyl, or
R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-8 membered ring;
each of R 4 and R 5 is independently hydrogen or a moiety cleavable under biological conditions;
R 8 is absent or hydrogen; and
represents a single or double bond, wherein when one is a double bond, the other is a single bond and R8 is absent.

3 . The compound of claim 1 , wherein R 4 and R 5 are not both hydrogen.

4 . (canceled)

5 . (canceled)

6 . The compound of claim 1 , wherein each of R 4 and R 5 is independently hydrogen, —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)OR c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , —(CH 2 ) p OC(O)R c , or —(CH 2 ) p C(O)OR c ;
each of R a and R b is independently selected from —OR d or alkyl;
each R c is independently alkyl (e.g., —CH 2 NH 2 , —CH 2 CH 2 CO 2 H, —CH(CH(CH 3 ) 2 )NH 2 , —CH 2 CH 2 C(O)OH, or —CH(CH 3 )NH 2 );
each R d is independently hydrogen or alkyl;
each x is independently 1 or 2; and
each of n, m, p is independently 1, 2, 3, or 4.

7 . (canceled)

8 . The compound of claim 1 , wherein R 1 is C 1-6 alkyl (e.g., substituted or unsubstituted C 1-6 alkyl).

9 . (canceled)

10 . The compound of claim 8 , wherein R 1 is hydrogen, methyl (e.g., —CH 3 , —CF 3 or —CH 2 OCH 3 ), ethyl, or isopropyl.

11 . (canceled)

12 . The compound of claim 1 , wherein each of R 2 and R 3 is independently hydrogen, methyl (e.g., —CH 3 , —CF 3 ), ethyl, isopropyl, cyclopropyl, or butyl.

13 . The compound of claim 1 , wherein R 4 is a moiety cleavable under biological conditions and R 5 is hydrogen.

14 . The compound of claim 1 , wherein R 4 is hydrogen and R 5 is a moiety cleavable under biological conditions.

15 . The compound of claim 1 , wherein each of R 4 and R 5 is a moiety cleavable under biological conditions.

16 . (canceled)

17 . The compound of claim 16 , wherein when R 4 is hydrogen and R 5 is —S(O) x R b and x is 2, R b is not —OH.

18 . The compound of claim 16 , wherein not both of R 4 or R 5 are hydrogen.

19 . The compound of claim 1 , wherein R 4 is —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)OR c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , —(CH 2 ) p OC(O)R c , or —(CH 2 ) p C(O)OR c ;
R 5 is hydrogen;
each of R a and R b is independently selected from —OR d or alkyl;
each R c is independently alkyl (e.g., —CH 2 NH 2 , —CH 2 CH 2 CO 2 H, —CH(CH(CH 3 ) 2 )NH 2 , —CH 2 CH 2 C(O)OH, or —CH(CH 3 )NH 2 );
each R d is independently hydrogen or alkyl;
each x is independently 1 or 2; and
each of n, m, p is independently 1, 2, 3, or 4.

20 . The compound of claim 1 , wherein R 4 is hydrogen;
R 5 is —P(O)(R a ) 2 , —S(O) x R b , —C(O)R c , —C(O)OR c , —C(O)N(R d ) 2 , —(CH 2 ) x C(O)N(R d ) 2 , —(CH 2 ) n OP(O)(R a ) 2 , —(CH 2 ) m OS(O) x R b , —(CH 2 ) p OC(O)R c , or —(CH 2 ) p C(O)OR c ; each of R a and R b is independently selected from —OR d or alkyl; each R c is independently alkyl (e.g., —CH 2 NH 2 , —CH 2 CH 2 CO 2 H, —CH(CH(CH 3 ) 2 )NH 2 , —CH 2 CH 2 C(O)OH, or —CH(CH 3 )NH 2 ); each R d is independently hydrogen or alkyl; each x is independently 1 or 2; each of n, m, p is independently 1, 2, 3, or 4; wherein when R 5 is —S(O) x R b and x is 2, R b is not —OH.

21 - 63 . (canceled)

64 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

65 . The compound of claim 1 , wherein the compound is selected from the group consisting of:

66 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof of and a pharmaceutically acceptable carrier.

67 . A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.

68 . (canceled)

69 . A method for treating or preventing a disorder comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, wherein the disorder is a gastrointestinal (GI) disorder e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistula), colon polyps, cancer, colitis.

70 . The method according to claim 69 , wherein the disorder is inflammatory bowel disease.

71 . The method according to claim 69 , wherein the disorder is cancer, diabetes, or a sterol synthesis disorder.

72 . A method for treating or preventing a CNS-related condition comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof.

73 . The method according to claim 72 , wherein the CNS-related condition is an adjustment disorder, anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), cognitive disorder (including Alzheimer's disease and other forms of dementia), dissociative disorder, eating disorder, mood disorder (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorder (including schizoaffective disorder), sleep disorder (including insomnia), substance-r

Assignees

• Sage Therapeutics Inc

Inventors

• Salituro Francesco G
• Robichaud Albert Jean
• Martinez Botella Gabriel

Classifications

• C07J9/005 Primary

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title

• C07J9/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07J41/0055

  the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives · CPC title