Steroid compounds as RORyt modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9505798-B2
Application number	US-201113989973-A
Country	US
Kind code	B2
Filing date	Nov 28, 2011
Priority date	Nov 29, 2010
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

Steroid compounds are disclosed that have a formula represented by the following:

and wherein m, n, t, u1, u2, v1, v2, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 3c , R 3d , and Y are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the treatment or prevention of a variety of conditions in mammals including humans, including by way of non-limiting example, inflammatory conditions, autoimmune disorders, cancer, and graft-versus-host disease.

First claim

What is claimed is:

1. A method for treating or ameliorating in a mammal a disease or condition that is causally related to RORγt activity in vivo, wherein the disease or condition is arthritis, diabetes, multiple sclerosis, uveitis, psoriasis, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, atherosclerosis, H. pylori infections, ulcers, inflammatory bowel disease, Crohn's disease, ulcerative colitis, sprue, food allergies or, experimental autoimmune encephalomyelitis (EAE), which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula III:

wherein
Y is CO 2 R 8 , CH 2 OH,

* denotes the attachment point; the subscript w is 0, 1, or 2;
the subscript x is 1, 2, or 3;
each R 5 and R 7 is independently H, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 8 is H or substituted or unsubstituted alkyl;

each R 1a and R 1b is independently OH, or O-acyl; or R 1a and R 1b together form

* denote the attachment points;
each R 6a and R 6b is independently H, substituted or unsubstituted alkyl, cycloalkyl, aryl or heteroaryl;

each subscript n is independently 0, 1, 2, 3, 4, or 5; and
each dotted bond is independently a single or a double bond;
or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.

2. The method according to claim 1 , wherein Y is CH 2 OH, CO 2 H, CO 2 Me, CO 2 Et,

* denotes the attachment point; the subscript w is 0, 1, or 2;
the subscript x is 1, 2, or 3; and R 5 and R 7 are as in claim 1 .

3. The method according to claim 1 , wherein Y is

* denotes the attachment point; and the subscript w is 0, 1, or 2.

4. The method according to claim 1 , wherein Y is

and R 5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl, and * denotes the attachment point.

5. The method according to claim 1 , wherein Y is

and R 5 is
alkyl, unsubstituted, or substituted with halo, phenyl, hydroxyl or methoxy;
alkenyl, unsubstituted, or substituted with alkyl, or phenyl;
cycloalkyl, unsubstituted, or substituted with hydroxyl or methoxy; or
aryl, unsubstituted, or substituted with substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol, and * denotes the attachment point.

6. The method according to claim 1 , wherein Y is

* denotes the attachment point;
the subscript x is 1, 2, or 3; and R 5 and R 7 are as in claim 1 .

7. The method according to claim 6 , wherein R 5 is alkyl, unsubstituted, or substituted with halo, phenyl, hydroxyl or methoxy,
alkenyl, unsubstituted, or substituted with alkyl, or phenyl;
cycloalkyl, unsubstituted, or substituted with hydroxyl or methoxy; or
aryl, unsubstituted, or substituted with substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol.

8. The method according to claim 6 , wherein R 7 is H.

9. The method according to claim 1 , wherein the compound is according to formula IVa, IVb, Va, Vb, VIa, VIb, VIc, or VId:

wherein
R 1a and R 1b are as in claim 1 ; z is 0, 1, 2, 3, 4, or 5; and each R 4 is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy; substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkyl sulfonyl, substituted or unsubstituted aryl sulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, hydroxyl, and thiol;

or a pharmaceutically acceptable salt, solvate or prodrug thereof;
and stereoisomers, isotopic variants and tautomers thereof.

10. The method according claim 9 , wherein z is 1 or 2; and each R 4 is independently selected from F, Br, Cl, I, OH, Me, Et, CF 3 , OCF 3 , CF 3 , NMe 2 , OMe, OEt, NO 2 , OPh, and SMe.

11. The method according to claim 1 , wherein each R 1a and R 1b is independently OH or OAc.

12. The method according to claim 1 , wherein R 1a and R 1b together form

* denote the attachment points;
each R 6a and R 6b is independently H, substituted or unsubstituted alkyl, cycloalkyl, aryl or heteroaryl.

13. The method according to

Assignees

• Littman Dan R
• Huh Jun R
• Manel Nicolas Gabriel Albert
• Ryan Daniel A
• Gin David Y
• Gin Mary S
• Krout Michael R
• Univ New York
• Memorial Sloan Kettering Cancer Center

Inventors

• Littman Dan R
• Huh Jun R
• Manel Nicolas Gabriel Albert
• Ryan Daniel A
• Gin David Y
• Krout Michael R

Classifications

• C07J17/005 Primary

  Glycosides · CPC title

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• C07J19/005

  Glycosides · CPC title