# US 10,117,852 B2 · Glucocorticoid receptor modulators to treat pancreatic cancer

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- Number: US 10,117,852 B2
- Document ID: US10117852B2
- Status: Granted
- Kind: B2
- Application number: 15/915,477
- Filed: 2018-03-08
- Published: 2018-07-12
- Granted: 2018-11-06
- Earliest claimed: 2016-09-09
- Assignees: Corcept Therapeutics, Inc.
- Applicants: Corcept Therapeutics, Inc.
- Inventors: Hazel Hunt; Thaddeus S. Block
- Web page: https://patentgrep.com/patent/US10117852B2

## CPC

- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/03: aromatic
- A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63)
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 33/243: Platinum; Compounds thereof
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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 GRM may be a nonsteroidal GRM, and may be a nonsteroidal SGRM. The non-ACTH-secreting pancreatic tumor may be an exocrine pancreatic tumor. 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 SGRM, such as a nonsteroidal SGRM. The nonsteroidal SGRM may comprise: a fused azadecalin structure; a heteroaryl ketone fused azadecalin structure; or an octahydro fused azadecalin structure.

## Claims

### Claim 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 a chemotherapeutic agent and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce the tumor load of the pancreatic tumor in the subject, wherein said administering comprises administering a combination therapy comprising administering said chemotherapeutic agent according to an intermittent dosing regimen, and wherein said SGRM is a compound comprising a heteroaryl ketone fused azadecalin structure, said compound having the formula:
wherein
R1 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 R1a;
each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, N-oxide, C3-8 cycloalkyl, and C3-8 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 R2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1 6 haloalkyl, C1 6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-C1-6 alkoxy, CN, OH, NR2aR2b, C(O)R2a, C(O)OR2a, C(O)NR2aR2b, SR2a, S(O)R2a, S(O)2R2a, C3-8 cycloalkyl, and C3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R2c groups;
alternatively, two R2 groups linked to the same carbon are combined to form an oxo group (═O);
alternatively, two R2 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 R2d groups;
R2a and R2b are each independently selected from the group consisting of hydrogen and C1-6 alkyl;
each R2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, CN, and NR2aR2b;
each R2d is independently selected from the group consisting of hydrogen and C1-6 alkyl, or two R2d groups attached to the same ring atom are combined to form (═O);
R3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R3a groups;
each R3a is independently selected from the group consisting of hydrogen, halogen, and C1-6 haloalkyl; and
subscript n is an integer from 0 to 3;
or salts and isomers thereof.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The method of claim 1, wherein the chemotherapeutic agent is selected from the group consisting of antimicrotubule agents, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, antimetabolites, mitotic inhibitors and combinations thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein the chemotherapeutic agent is an antimicrotubule agent selected from a taxane and a vinca alkaloid.

### Claim 5 (depends on 3)

The method of claim 3, wherein the chemotherapeutic agent is selected from the group consisting of nanoparticle albumin-bound paclitaxel (nab-paclitaxel), 5-fluorouracil (5-FU), gemcitabine, cisplatin and capecitabine.

### Claim 6 (depends on 1)

The method of claim 1, wherein the nonsteroidal selective glucocorticoid receptor modulator compound comprising a heteroaryl ketone fused azadecalin structure has the formula:

### Claim 7 (depends on 1)

The method of claim 1, wherein said intermittent administration is selected from administration every two days, every three days, and every four days.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound comprising a heteroaryl ketone fused azadecalin structure is administered intermittently.

### Claim 9 (depends on 8)

The method of claim 8, wherein said intermittent administration of said compound comprising a heteroaryl ketone fused azadecalin structure comprises intermittent administration selected from administration every two days, every three days, and every four days.

### Claim 10

A method of treating a subject hosting a non-ACTH-secreting pancreatic tumor, the method comprising administering to the subject an effective amount of a chemotherapeutic agent and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce the tumor load of the pancreatic tumor in the subject, wherein said administering comprises administering a combination therapy comprising administering said chemotherapeutic agent according to an intermittent dosing regimen, and wherein said SGRM is a compound comprising a fused azadecalin structure, said compound having the formula:
wherein
L1 and L2 are members independently selected from a bond and unsubstituted alkylene;
R1 is a member selected from unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, —OR1A, —NR1CR1D, —C(O)NR1CR1D, and —C(O)OR1A, wherein
R1A is a member selected from hydrogen, unsubstituted alkyl and unsubstituted heteroalkyl,
R1C and R1D are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl,
wherein R1C and R1D 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;
R2 has the formula:
wherein
R2G is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF3;
J is phenyl;
t is an integer from 0 to 5;
X is —S(O2)—; and
R5 is phenyl optionally substituted with 1-5 R5A groups, wherein
R5A is a member selected from hydrogen, halogen, —OR5A1, S(O2)NR5A2R5A3, —CN, and unsubstituted alkyl, wherein
R5A1 is a member selected from hydrogen and unsubstituted alkyl, and
R5A2 and R5A3 are members independently selected from hydrogen and unsubstituted alkyl,
or salts and isomers thereof.

### Claim 11 (depends on 10)

The method of claim 10, wherein the nonsteroidal selective glucocorticoid receptor modulator compound comprising a fused azadecalin structure has the formula:

### Claim 12 (depends on 10)

The method of claim 10, wherein said intermittent administration is selected from administration every two days, every three days, and every four days.

### Claim 13 (depends on 10)

The method of claim 10, wherein the compound comprising a fused azadecalin structure is administered intermittently.

### Claim 14 (depends on 13)

The method of claim 13, wherein said intermittent administration of said compound comprising a fused azadecalin structure comprises intermittent administration selected from administration every two days, every three days, and every four days.

### Claim 15 (depends on 10)

The method of claim 10, wherein the chemotherapeutic agent is selected from the group consisting of antimicrotubule agents, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, antimetabolites, mitotic inhibitors and combinations thereof.

### Claim 16

A method of treating a subject hosting a non-ACTH-secreting pancreatic tumor, the method comprising administering to the subject an effective amount of a chemotherapeutic agent and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM) to reduce the tumor load of the pancreatic tumor in the subject, wherein said administering comprises administering a combination therapy comprising administering said chemotherapeutic agent according to an intermittent dosing regimen, and wherein said SGRM is a compound comprising an octahydro fused azadecalin structure, said compound having the formula:
wherein
R1 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 R1a;
each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, N-oxide, and C3-8 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 R2 is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl-C1-6 alkoxy, CN, OH, NR2aR2b, C(O)R2a, C(O)OR2a, C(O)NR2aR2b, SR2a, S(O)R2a, S(O)2R2a, C3-8 cycloalkyl, and C3-8 heterocycloalkyl having from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S;
alternatively, two R2 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 R2 groups;
R2a, R2b and R2c are each independently selected from the group consisting of hydrogen and C1-6 alkyl;
each R1a is independently halogen; and
subscript n is an integer from 0 to 3,
or salts and isomers thereof.

### Claim 17 (depends on 16)

The method of claim 16, wherein the nonsteroidal selective glucocorticoid receptor modulator compound comprising an octahydro fused azadecalin structure has the formula:

### Claim 18 (depends on 16)

The method of claim 16, wherein said intermittent administration comprises intermittent administration selected from administration every two days, every three days, and every four days.

### Claim 19 (depends on 16)

The method of claim 16, wherein the compound comprising an octahydro fused azadecalin structure is administered intermittently.

### Claim 20 (depends on 19)

The method of claim 19, wherein said intermittent administration of said compound comprising an octahydro fused fused azadecalin structure comprises intermittent administration selected from administration every two days, every three days, and every four days.

### Claim 21 (depends on 16)

The method of claim 16, wherein the chemotherapeutic agent is selected from the group consisting of antimicrotubule agents, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, antimetabolites, mitotic inhibitors and combinations thereof.