Glucocorticoid receptor modulators to treat pancreatic cancer

Patent metadata

Field	Value
Publication number	US-12370175-B2
Application number	US-202318124959-A
Country	US
Kind code	B2
Filing date	Mar 22, 2023
Priority date	Sep 9, 2016
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

Abstract

Methods and compositions for treating a subject hosting a non-ACTH-secreting pancreatic tumor are disclosed. The methods include administering to the subject a chemotherapeutic agent and a glucocorticoid receptor modulator (GRM), preferably a selective glucocorticoid receptor modulator (SGRM), to reduce the tumor load in the subject. The non-ACTH-secreting pancreatic tumor may be an exocrine pancreatic tumor. The GRM may be a nonsteroidal GRM or a nonsteroidal SGRM. The nonsteroidal SGRM may be a nonsteroidal compound comprising: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure. Pharmaceutical compositions comprising a chemotherapeutic agent and a GRM are disclosed. The GRM in such pharmaceutical compositions may be a nonsteroidal GRM, and may be a nonsteroidal SGRM. The nonsteroidal SGRM may comprise: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.

First claim

What is claimed is:

1. A method of treating a subject hosting a non-ACTH-secreting pancreatic tumor, the method comprising administering to the subject an effective amount of an antimicrotubule agent selected from a vinca alkaloid and a taxane, and administering between about 20 milligrams per day (mg/day) and about 1000 mg/day of a nonsteroidal selective glucocorticoid receptor modulator (SGRM), wherein the SGRM comprises a fused azadecalin structure having the formula:

wherein
L 1 and L 2 are members independently selected from a bond and unsubstituted alkylene;
R 1 is a member selected from unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, —OR 1A , NR 1C R 1D , —C(O) NR 1C R 1D , and —C(O) OR 1A , wherein
R 1A is a member selected from hydrogen, unsubstituted alkyl and unsubstituted heteroalkyl,
R 1C and R 1D are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl,
wherein R 1C and R 1D are optionally joined to form an unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen;
R 2 has the formula:

wherein
R 2G is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF 3 ;
J is phenyl;
t is an integer from 0 to 5;
X is —S(O 2 )—; and
R 5 is phenyl optionally substituted with 1-5 R 5A groups, wherein
R 5A is a member selected from hydrogen, halogen, —OR 5A1 , S(O 2 )NR 5A2 R 5A3 , —CN, and unsubstituted alkyl, wherein
R 5A1 is a member selected from hydrogen and unsubstituted alkyl, and
R 5A2 and R 5A3 are members independently selected from hydrogen and unsubstituted alkyl,
and salts thereof; or

a heteroaryl-ketone fused azadecalin structure having the formula:

wherein
R 1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R 1a ;
each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, N-oxide, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;
ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , SR 2a , S(O)R 2a , S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R 2c groups;
alternatively, two R 2 groups linked to the same carbon are combined to form an oxo group (═O);
alternatively, two R 2 groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R 2d groups;
R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
each R 2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, and NR 2a R 2b ;
each R 2d is independently selected from the group consisting of hydrogen and C 1-6 alkyl, or two R 2d groups attached to the same ring atom are combined to form (═O);
R 3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R 3a groups;
each R 3a is independently selected from the group consisting of hydrogen, halogen, and C 1-6 haloalkyl; and
subscript n is an integer from 0 to 3;
and salts thereof; or

an octahydro fused azadecalin structure having the formula:

wherein
R 1 is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R 1a ;
each R 1a is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, N-oxide, and C 3-8 cycloalkyl;
ring J is selected from the group consisting of an aryl ring and a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S;
each R 2 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl-C 1-6 alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , SR 2a , S(O)R 2a , S(O) 2 R 2a , C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl having from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S;
alternatively, two R 2 groups on adjacent ring atoms are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 to 3 R 2c groups;
R 2a , R 2b and R 2c are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;
each R 3a is independently halogen; and
subscript n is an integer from 0 to 3,

and salts thereof,
to reduce the tumor load of the pancreatic tumor.

2. The method of claim 1 , wherein the non-ACTH-secreting pancreatic tumor is an exocrine pancreatic tumor.

3. The method of claim 1 , wherein the antimicrotubule agent is a vinca alkaloid selected from the group consisting of vinorelbine, vincristine, vindesine, vinblastine, vincaleukoblastine, and combinations thereof.

4. The method of claim 1 , wherein the antimicrotubule agent is a taxane selected from the group consisting of docetaxel, paclitaxel, nanoparticle albumin-bound paclitaxel (nab-paclitaxel), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel), polyglutamate bound-paclitaxel (PG-paclitaxel), ANG105 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), glucose-conjugated paclitaxel, and combinations thereof.

5. The method of claim 1 , wherein the antimicrotubule agent is selected from the group consisting of nab-paclitaxel, paclitaxel, docetaxel, vinorelbine, vincristine, and vinblastine.

6. The method of claim 1 , wherein the antimicrotubule agent is a taxane selected from docetaxel, paclitaxel, and nab-paclitaxel.

7. The method of claim 1 , wherein the nonsteroidal selective glucocorticoid receptor modulator is a compound comprising a fused azadec

Assignees

• Corcept Therapeutics Inc

Inventors

• Hunt Hazel
• Block Thaddeus S

Classifications

• A61K31/473

  ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• A61K31/03

  aromatic · CPC title