Method for differentially diagnosing ACTH-dependent Cushing's syndrome

Patent metadata

Field	Value
Publication number	US-9829495-B2
Application number	US-201615236015-A
Country	US
Kind code	B2
Filing date	Aug 12, 2016
Priority date	Aug 13, 2015
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

This invention provides for an improved method for differentially diagnosing ACTH-dependent Cushing's syndrome. Current practice for differentially diagnosing ectopic ACTH syndrome and Cushing's Disease measures relative ACTH concentrations from the inferior petrosal venous sinus compared to fluid obtained from a periphery venous sample. This is performed before and after administration of exogenous corticotropin releasing factor, or after administration of metyrapone. This invention uses glucocorticoid receptor antagonists to induce release of endogenous CRH which stimulates ACTH to increase in patients with ectopic ACTH syndrome but not in those with Cushing's Disease.

First claim

What is claimed is:

1. A method of concurrently treating Cushing's syndrome and differentially diagnosing adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in a patient where the differential diagnosis is between ectopic ACTH syndrome and Cushing's disease, the method comprising the steps of:
(i) selecting a patient with Cushing's syndrome and also elevated ACTH levels;
(ii) administering a dose of glucocorticoid receptor antagonist (GRA) sufficient to increase ACTH from the pituitary gland by at least two fold in persons with normal Hypothalamus Pituitary Adrenal (HPA) function;
(iii) waiting for at least two hours; and,
(iv) obtaining from the patient an ACTH concentration ratio wherein the ratio is derived from the ACTH concentrations in fluid obtained from either the left or right inferior petrosal venous sinus and from fluid obtained from a periphery venous sample;

wherein an ACTH concentration ratio of greater than 3 for the ACTH concentration from the inferior venous sinus sample over the periphery venous sinus sample is diagnostic of Cushing's disease.

2. The method of claim 1 wherein the periphery venous sample is a jugular venous sample.

3. The method of claim 1 wherein the glucocorticoid receptor antagonist is a selective inhibitor of the glucocorticoid receptor.

4. The method of claim 1 wherein a first and second sampling of the ACTH concentrations in the are taken 5-10 minutes apart from both the inferior petrosal venous sinus and a periphery venous sample.

5. The method of claim 1 , wherein the glucocorticoid receptor antagonist comprises a steroidal backbone with at least one phenyl-containing moiety in the 11-β position of the steroidal backbone.

6. The method of claim 5 wherein the phenyl-containing moiety in the 11-β position of the steroidal backbone is a dimethylaminophenyl moiety.

7. The method of claim 5 , wherein the glucoocoricoid receptor antagonist is mifepristone.

8. The method of claim 1 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of 11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9 estradien-3-one and (17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one.

9. The method of claim 1 , wherein the glucocorticoid receptor antagonist is (11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

10. The method of claim 1 , wherein the glucocorticoid receptor antagonist has a non-steroidal backbone.

11. The method of claim 10 , wherein the glucocorticoid receptor antagonist backbone is a cyclohexyl pyrimidine.

12. The method of claim 11 , wherein the cyclohexyl pyrimidine has the following formula:

wherein
the dashed line is absent or a bond;
X is selected from the group consisting of O and S;
R 1 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted with from 1 to 3 R 1a groups;
each R 1a is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkyl OR 1b , halogen, C 1-6 haloalkyl, C 1-6 haloaloxy, OR 1b , NR 1b R 1c , C(O)R 1b , C(O)OR 1b , OC(O)R 1b , C(O)NR 1b R 1c , NR 1b C(O)R 1c , SO 2 R 1b , SO 2 NR 1b R 1c , cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
R 1b and R 1c are each independently selected from the group consisting of H and C 1-6 alkyl;
R 2 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkyl-OR 1b , C 1-6 alkyl NR 1b R 1c and C 1-6 alkylene heterocycloalkyl;
R 3 is selected from the group consisting of H and C 1-6 alkyl;
Ar is aryl, optionally substituted with 1-4 R 4 groups;
each R 4 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 haloalkyl and C 1-6 haloalkoxy;
L 1 is a bond or C 1-6 alkylene; and
subscript n is an integer from 0 to 3,
or salts thereof.

13. The method of claim 10 , wherein the glucocorticoid receptor antagonist backbone is a fused azadecalin.

14. The method of claim 13 , wherein the fused azadecalin is a compound having the following 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,
or salts thereof.

15. The method of claim 10 , wherein the glucocorticoid receptor antagonist backbone is a heteroaryl ketone fused azadecalin or an octahydro fused azadecalin.

16. The method of claim 15 , wherein the heteroaryl ketone fused azadecalin has 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);
alternativ

Assignees

• Corcept Therapeutics Inc

Inventors

• Moraitis Andreas G

Classifications

• G01N2800/048

  Pituitary or hypothalamic - pituitary relationships, e.g. vasopressin or ADH related · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• G01N2333/695

  Corticotropin [ACTH] · CPC title

• G01N33/74 Primary

  involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors} · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title