Use of glucocortid receptor modilators in the treatment of catecholamine-secreting tumors

Abstract

To provide a novel method for treating tumors, including neuroendocrine tumors (NETs) such as catecholamine-secreting tumors (CSTs). [Solution] This method involves treating Cushing's syndrome in patients with Cushing's syndrome who have NETs such as CST. The tumor may be treated with a glucocorticoid receptor (GR) modulator (GRM) such as a GR antagonist (GRA). The novel treatment can treat Cushing's syndrome, reduce tumor-induced catecholamine production, reduce catecholamine excess, alleviate symptoms of catecholamine excess, and improve the effectiveness of α- or β-adrenergic blockade, somatostatin or somatostatin analog treatment or imaging, or peptide receptor radionuclide therapy in patients with CST.

Description

[Background technology]

[0001] background Cushing's syndrome is characterized by excessive cortisol levels. Cushing's syndrome is associated with hypercortisolemia, a condition involving prolonged excessive circulation of cortisol. Cushing's syndrome can be classified into exogenous Cushing's syndrome, which results from the overuse of glucocorticoid drugs such as prednisone, dexamethasone, and hydrocortisone, and endogenous Cushing's syndrome, which results from abnormalities due to disregard of the HPA axis. Patients with Cushing's syndrome are usually prone to bruising; have abdominal obesity with thin arms and legs; have facial polycythemia; acne; proximal muscle weakness; and / or reddish-purple striae throughout the body.

[0002] In endogenous Cushing's syndrome, excess cortisol is typically caused by either a cortisol-producing tumor or a tumor that indirectly increases cortisol levels (e.g., by increasing adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH)). Endogenous Cushing's syndrome consists of ACTH-independent Cushing's syndrome, characterized by excessive cortisol production without increased ACTH secretion; and ACTH-dependent Cushing's syndrome, characterized by excessive ACTH secretion. ACTH-dependent Cushing's syndrome accounts for approximately 80% of patients with endogenous Cushing's syndrome and consists of two main forms: Cushing's disease and ectopic ACTH syndrome. The former arises from a pituitary tumor, and the latter from an extrapituitary tumor. Cases of these Cushing's syndromes resulting from excessive ACTH secretion by the pituitary gland are also referred to as Cushing's disease.

[0003] Pheochromocytoma (PHEO) and paraganglioma (PGL) are tumors arising from chromaffin cells derived from the embryonic neural crest. Most PHEO / PGL cases are known as scattered tumors, and mutations in genes including VHL (von Hippel-Lindau), RET (multiple endocrine neoplasm type 2), NF1 (neurofibroma type 1), SDH (succinate dehydrogenase subunits A, B, C, and D) and cofactors SDHAF2, MAX (MYC-related factor X), HIF2A (hypoxia-inducible factor 2A), FH (fumarate hydratase), and TMEM127 (transmembrane protein 127) account for approximately 40% of tumors. PGL has a higher tendency to metastasize, with an incidence of approximately 10% of all PHEO / PGL cases. Both types of tumors produce and normally secrete larger amounts of catecholamines (CATs) than the adrenal medulla, due to the upregulation of tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH), the major enzymes involved in CAT synthesis. In chromaffin and chromaffin cells, norepinephrine (NE) and epinephrine (E) are stored in vesicles, where they undergo passive leakage into the cytoplasm before being reabsorbed into the vesicle pool. Phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts NE to E, is primarily confined to this tissue and is absent in the sympathetic nervous system (which produces only NE), making the adrenal medulla by far the most important E-producing site in the body.

[0004] Glucocorticoids play a major role in regulating catecholamine synthesis. Wurtman et al. showed that pituitary gland resection in rats was associated with a significant decrease in adrenal gland weight and a marked decrease in PNMT activity.

[0005] Grouzmann et al. (PLoSONE Vol. 10 (No. 5): e0125426 (2015)) measured the effects of glucocorticoids on the transcription and protein expression of TH, DBH, and PNMT genes in catecholamine-secreting tumors. To experimentally evaluate the effects of glucocorticoids on PNMT, TH, and DBH gene expression in primary cell cultures, cells obtained from four PGLs and nine PHEOs (six mixed-type tumors and three NorAd-type tumors) were seeded in culture dishes and incubated for 24 hours with or without dexamethasone. No significant effect on PNMT mRNA was detected in PGL cells. DBH and TH mRNA were below the limit of quantification due to lower qPCR efficiency for these two genes, as the amount of material available after surgical resection was smaller compared to PNMT. In PHEO cells, dexamethasone induced a 2.8-fold upregulation of TH at 24 hours compared to dexamethasone-free incubated cells. No effect was recorded between mixed-type and noradrenergic PHEO cells regarding gene transcription of TH, DBH, and PNMT after 24 hours of incubation with dexamethasone, nor regarding DBH and PNMT. To demonstrate the correlation between gene and protein expression, TH, DBH, and PNMT protein concentrations were determined from dexamethasone-incubated cells and control cells after 24 hours of incubation. Compared to control cells, no activation of DBH and PNMT was observed in steroid-incubated cells, and simultaneously, the upregulation of TH detected in mRNA was not confirmed at the protein level.

[0006] Goodman et al. (J. Cell Biol. Vol. 78 (No. 1): pp. R1-R7 (1978)) showed that glucocorticoids increased the synthesis of tyrosine hydroxylase, the rate-limiting enzyme in the adrenergic pathway, in serially passaged cell lines derived from rat pheochromocytoma tumors.

[0007] Glucocorticoids are important regulators of phenylethanolamine N-methyltransferase (PNMT), the final enzyme in epinephrine biosynthesis, and affect both transcriptional and post-transcriptional effects. In vivo studies in rats have shown that depletion of corticosteroids by pituitary gland resection leads to decreased expression of PNMT mRNA and enzyme. These changes can be reversed by administering adrenocorticotropin, which stimulates endogenous glucocorticoid production, or by directly replacing corticosteroids with the synthetic glucocorticoid dexamethasone. Changes in the PNMT enzyme result from changes in both gene transcription and proteolysis. Glucocorticoids increase not only catecholamine secretion but also CAT storage in Chromaffin cells.

[0008] When untreated rats are administered either dexamethasone or the glucocorticoid agonist RU28362, PNMT mRNA levels are significantly elevated. While it remains unclear whether glucocorticoids are essential for PNMT transcriptional activity, glucocorticoid receptor-deficient mice do not express adrenal medulla PNMT despite chromaffin cells appearing superficially normal (Schmid et al., JSteroid Biochem Mol Biol. Vol. 53: pp. 33-35 (1995); Finotto et al., Development Vol. 126: pp. 2935-2944 (1999)). Glucocorticoid-induced transcriptional changes are mediated through the glucocorticoid response element (GRE) in the proximal 5-flanking sequence of the PNMT gene promoter. At least one putative GRE has been identified for each species-specific PNMT gene, including humans (Baetge et al., ProcNatlAcadSci USA. Vol. 85 (No. 10): pp. 3648-3652 (1988); Kaneda et al., J Biol Chem. Vol. 263 (No. 16): pp. 7672-7677 (1988)); Cattle (Baetge et al., ProcNatlAcadSci USA. Vol. 83 (No. 15): pp. 5454-5458 (1986); Batter et al., J Neurosci Res. Vol. 19 (No. 3): pp. 367-3652 Page 76 (1988); rats (Ross et al., JNeurosci. Vol. 10 (No. 2): pp. 520-530 (1990)); and mice (Morita et al., BrainResMol Brain Res. Vol. 13 (No. 4): pp. 313-319 (1992)). In the case of the rat PNMT gene, GRE was identified at -533 bp when the gene was first cloned (Ross et al., 1990). This GRE appears to be functional, but its responsiveness to glucocorticoid activation appears to be variable or weak.

[0009] Tai et al. (MolPharmacol. Vol. 61 (No. 6): pp. 1385-1392 (2002)) identified two overlapping (1 bp) glucocorticoid response elements (GREs) at -759 and -773 bp in the promoter of the rat phenylethanolamine N-methyltransferase (PNMT) gene, rather than the initially identified -533-bp GRE, as the primary cause of its glucocorticoid sensitivity. A dose-dependent increase in PNMT promoter activity was observed in RS1 cells transfected with a wild-type PNMT promoter-luciferase reporter gene construct and treated with dexamethasone (maximally activated at 0.1 μM). The type II glucocorticoid receptor antagonist RU486 (10 μM) completely inhibits the activation of the PNMT promoter by dexamethasone (1 μM), consistent with classical glucocorticoid receptor-mediated corticosteroid-stimulated transcriptional activity. Glucocorticoid receptors that bind to -759- and -773-bp GRE synergistically interact with Egr-1 and / or AP-2, stimulating PNMT promoter activity in dexamethasone-treated RS1 cells. In contrast, glucocorticoid receptors that bind only to -533-bp GRE appear to be involved in synergistic activation of the PNMT promoter through interaction with activator protein 2.

[0010] Further evidence regarding the role of cortisol in catecholamine-secreting tumors was found by Isobe et al. (Provided by J.Urol. Vol. 163: pp. 357-362 (2000)). Local cortisol production capacity in pheochromocytoma tissue is further supported by the expression of 17α-hydroxylase, an enzyme involved in glucocorticoid biosynthesis in tumors. PNMT expression was found to be associated with 17α-hydroxylase expression in tumors. Glucocorticoid receptor expression was also associated with PNMT expression in tumors.

[0011] Both the medulla and ganglia are part of the autonomic nervous system. The distribution of glucocorticoid receptor-like immunoreactivity (GR-LI) in the CNS has already been described in detail (Fuxe et al., Endocrinology Vol. 117 (No. 5): pp. 1803-1812 (1985), Gustafsson et al., EndocrRev. Vol. 8 (No. 2): pp. 185-234 (1987)), and in all brain regions, immunoreactivity was localized to the nucleus of the cell body. Ceccatelli et al. (ActaPhysiol.Scand. Vol. 37: pp. 559-550 (1989)) showed that the presence of GR-LI only in the cytoplasm of chromaffin cells in the adrenal gland was unexpected. Double staining experiments (GR and PNMT) showed that GR-LI is largely limited to PNMT-immune-reactive cell bodies, i.e., adrenaline cells. This localization is consistent with the early research by Wurtman and Axelrod (J. Biol. Chem. Vol. 241 (No. 10): pp. 2301-23015 (1966)) and demonstrates the importance of steroids in PNMT synthesis.

[0012] Several unrelated cases of pheochromocytoma crisis (PC) have been reported after administration of exogenous glucocorticoids; however, there is largely no evidence that these drugs cause adverse events in patients with pheochromocytoma. Rosas et al. (EurJ Endocrinol. 158(3): pp. 423-429 (2008)) reported four cases of pheochromocytoma crisis induced by exogenous glucocorticoids. When investigating incidental adrenal masses, glucocorticoids should ideally be administered only after pheochromocytoma has been ruled out. However, there have been no reported cases of dexamethasone 1 mg being administered as a DST to patients with pheochromocytoma; however, higher, lower doses of dexamethasone, such as 2 mg, may induce PC. Patients with pheochromocytoma presenting as an adrenal incidentaloma may also be at risk if exposed to glucocorticoids given as pretreatment in patients with contrast agent allergies.

[0013] Somatostatin receptors 1 (sst1) and 2 (sst2) are expressed in both paragangliomas and pheochromocytomas. De Bruin et al. (J ClinEndocrinol Metab. Vol. 97 (No. 2): pp. 455-462 (2012)) showed that hypercortisolemia downregulates the expression of somatostatin receptor 2 (sst2). Somatostatin analogs that bind to somatostatin receptors are currently in clinical trials in patients with catecholamine-secreting tumors. Patients with catecholamine-secreting tumors usually have normal cortisol levels (normocortisolemic), but when cortisol activity increases at the tumor level, s It may affect the expression of st2, which could consequently affect the efficacy of somatostatin analogs.

[0014] Current treatments for metastatic catecholamine-secreting tumors include chemotherapy with cyclophosphamide, vincristine, and dacarbazine. Other available chemotherapy currently in clinical trials include tyrosine kinase inhibitors. Ultimately, patients with metastatic disease without large lesions may be eligible for MIBG therapy.

[0015] Patients with Cushing's syndrome may have catecholamine-secreting tumors. Therefore, there is a need for therapies and compositions for treating patients with neuroendocrine tumors, including for treating patients with catecholamine-secreting tumors. In particular, there is a need for therapies and compositions for treating patients with Cushing's syndrome who have neuroendocrine tumors, including for treating patients with Cushing's syndrome who have catecholamine-secreting tumors. [Prior art documents] [Non-patent literature]

[0016] [Non-Patent Document 1] Grouzmann et al. (PLoS ONE Vol. 10 (No. 5): e01254, p. 26 (2015)) [Non-licensed Document 2] Goodman (J. Cell Biol. 78, Vol. 1): R1-R7 (1978) [Non-licensed Document 3] Schmid, J Steroid Biochem Mol Biol. Volume 53: Pages 33~35 (1995) [Non-licensed Document 4] Finotto, Development 126 volumes: pages 2935~2944 (1999) [Non-licensed Document 5] Baetge, Proc Natl Acad Sci USA. Volume 85 (No. 10): Pages 3648~3652 (1988) [Non-licensed Document 6] Kaneda, J Biol Chem. Volume 263 (No. 16): Pages 7672~7677 (1988)) [Non-licensed Document 7] Baetge, Proc Natl Acad Sci USA Volume 83 (No. 15): Pages 5454~5458 (1986) [Non-licensed Document 8] Batter, J Neurosci Res. Volume 19 (No. 3): Pages 367~376 (1988)) [Non-licensed Document 9] Ross, J Neurosci. Volume 10 (No. 2): 520~30 pages (1990) [Non-licensed Document 10] Morita, Brain Res. Volume 13 (No. 4): pp. 313-319 (1992) [Non-licensed Document 11] Tai (Mol Pharmacol. 61 (No. 6): 1385-1392 (2002)) [Non-licensed Document 12] Isobeら(J.Urol.163 volume:357~362 pages (2000) [Non-licensed Document 13] Fuxe, Endocrinology Volume 117 (No. 5): Pages 1803~1812 (1985) [Non-licensed Document 14] Gustafsson et al., Endocr Rev. 8 (No. 2): pp. 185-234 (1987) [Non-Patent Document 15] Ceccatelli et al. (Acta Physiol.Scand.37:559-560 (1989) [Non-Patent Document 16] Wurtman and Axelrod (J. Biol. Chem. Vol. 241 (No. 10): pp. 2301-23015 (1966)) [Non-Patent Document 17] Rosas et al. (Eur J Endocrinol. Vol. 158 (No. 3): pp. 423-429 (2008)) [Non-Patent Document 18] De Bruin et al. (J Clin Endocrinol Metab. Vol. 97 (No. 2): pp. 455-452 (2012)) [Overview of the project] [Means for solving the problem]

[0017] Abstract This application discloses a novel method for treating tumors, including neuroendocrine tumors such as catecholamine-secreting tumors. This application discloses a novel method for treating Cushing's syndrome in patients having tumors, including neuroendocrine tumors such as catecholamine-secreting tumors. In embodiments, a catecholamine-secreting tumor is brought into contact with a glucocorticoid receptor modulator; in embodiments, a catecholamine-secreting tumor in a patient with Cushing's syndrome is brought into contact with a glucocorticoid receptor modulator, thereby treating Cushing's syndrome in the patient. For example, the method disclosed herein includes administering an effective amount of a glucocorticoid receptor modulator (GRM), such as a glucocorticoid receptor antagonist (GRA), to a patient in need, thereby reducing catecholamine production by the tumor. For example, the method disclosed herein includes administering an effective amount of a GRM such as GRA (e.g., mifepristone) to a patient with Cushing's syndrome, thereby treating Cushing's syndrome and reducing catecholamine production by the tumor. In embodiments, the tumor may be a metastatic or unresectable catecholamine-secreting tumor. In embodiments, the tumor may be a neuroendocrine tumor. The catecholamine-secreting tumor may be a pheochromocytoma, a paraganglioma, or other tumor. In some cases, the catecholamine-secreting tumor may be a metastatic tumor; an unresectable non-malignant tumor; or an unresectable multifocal non-malignant tumor.

[0018] The applicant hereby discloses a method for treating a catecholamine-secreting tumor, comprising administering a compound capable of modulating the glucocorticoid receptor (GR) to provide a beneficial therapeutic effect. In embodiments, the patient is a patient with Cushing's syndrome, and the method treats Cushing's syndrome in the patient. Embodiments of the method comprise administering an effective amount of a glucocorticoid receptor modulator to the patient, without the patient being concurrently administered an exogenous glucocorticoid receptor agonist. Embodiments of the method comprise administering an effective amount of a glucocorticoid receptor modulator (GRM) to the patient, without the patient i) requiring further treatment with a glucocorticoid receptor antagonist, and ii) being concurrently administered an exogenous glucocorticoid receptor agonist. In embodiments, the glucocorticoid receptor modulator is a glucocorticoid receptor antagonist (GRA). In embodiments, the GRA is mifepristone.

[0019] In the embodiment, beneficial therapeutic effects include: reduction of catecholamine excess in patients with catecholamine-secreting tumors; recovery of symptoms of catecholamine excess in patients with catecholamine-secreting tumors; improvement of the effectiveness of alpha and beta-adrenergic receptor blockade in patients with catecholamine-secreting tumors; and There are improvements in the therapeutic efficacy of somatostatin analogs in patients with the condition; improvements in the efficacy of somatostatin analogs when used in imaging diagnostics; improvements in the efficacy of peptide receptor radionuclide therapy (PRRT) in patients with catecholamine-secreting tumors; and other therapeutic benefits.

[0020] In embodiments, beneficial therapeutic effects include: treatment of Cushing's syndrome and reduction of catecholamine excess in patients with Cushing's syndrome who have catecholamine-secreting tumors; treatment of Cushing's syndrome and recovery from symptoms of catecholamine excess in patients with Cushing's syndrome who have catecholamine-secreting tumors; treatment of Cushing's syndrome and improvement of the effectiveness of alpha and beta-adrenergic receptor blockade in patients with Cushing's syndrome who have catecholamine-secreting tumors; treatment of Cushing's syndrome and improvement of the therapeutic effectiveness of somatostatin analogs in patients with Cushing's syndrome who have catecholamine-secreting tumors; treatment of Cushing's syndrome and improvement of the effectiveness of somatostatin analogs when used in imaging diagnostics in patients with Cushing's syndrome; treatment of Cushing's syndrome and improvement of the effectiveness of peptide receptor radionuclide therapy (PRRT) in patients with Cushing's syndrome who have catecholamine-secreting tumors; and other therapeutic advantages.

[0021] In the embodiment, the glucocorticoid receptor antagonist (GRA) may be a steroidal GRA, a GRA having a cyclohexyl-pyrimidine skeleton, a GRA having a condensed azadecalin skeleton, a GRA having a heteroarylketone condensed azadecalin skeleton, or a GRA having an octahydro condensed azadecalin skeleton. In the embodiment, the GRA is mifepristone.

[0022] Methods disclosed herein include methods for reducing catecholamine production and tumor burden in patients with metastatic or unresectable catecholamine-secreting tumors. Methods disclosed herein include methods for treating Cushing's syndrome and methods for reducing catecholamine production and tumor burden in patients with metastatic or unresectable catecholamine-secreting tumors. In embodiments, the method includes administering an effective amount of GRA to a patient with metastatic or unresectable catecholamine-secreting tumors at a daily dose of between 1 and 1000 mg / kg / day, or between 1 and 500 mg / kg / day, or between 0.1 and 200 mg / kg / day, or between 0.1 and 100 mg / kg / day, or between 0.1 and 50 mg / kg / day, or between 0.1 and 20 mg / kg / day, or between 0.1 and 15 mg / kg / day, or between 0.1 and 10 mg / kg / day, or between 0.1 and 5 mg / kg / day, or between 0.1 and 3 mg / kg / day, for at least 5 weeks.

[0023] In embodiments, GRA is mifepristone, and the method comprises administering an effective amount of mifepristone to a patient with metastatic or unresectable catecholamine-secreting tumors at a daily dose of between 0.1 and 100 mg / kg / day, or between 0.1 and 50 mg / kg / day, or between 0.1 and 20 mg / kg / day, or between 0.1 and 15 mg / kg / day, or between 0.1 and 12 mg / kg / day, or between 0.1 and 10 mg / kg / day, or between 0.1 and 5 mg / kg / day, or between 0.1 and 3 mg / kg / day, or between 0.1 and 1 mg / kg / day, for at least 5 weeks. In embodiments, the patient is a patient with Cushing's syndrome who has metastatic or unresectable catecholamine-secreting tumors.

[0024] The methods disclosed herein include the use of GRA as monotherapy and in combination with other therapeutic agents in patients with catecholamine-secreting tumors for the purpose of controlling catecholamine excess, restoring symptoms of catecholamine excess, or both. The methods disclosed herein include the use of GRA as monotherapy and in combination with other therapeutic agents in patients with catecholamine-secreting tumors for the purpose of a) treating Cushing's syndrome, controlling catecholamine excess, b) treating Cushing's syndrome, restoring symptoms of catecholamine excess, or both. In embodiments, other therapeutic agents used in combination with GRA include chemotherapeutic agents, adrenergic antagonists (e.g., alpha-adrenergic receptor antagonists, beta-adrenergic receptor antagonists, and antagonists having mixed alpha- and beta-adrenergic antagonistic activity), radiotherapeutic agents (e.g., compounds containing radioactive moieties such as peptides for use in peptide receptor radionuclide therapy (PRRT)), somatostatin, and somatostatin receptor agonists (e.g., somatostatin analogs) for controlling catecholamine excess, restoring symptoms of catecholamine excess, or both, in patients such as those with Cushing's syndrome who have catecholamine-secreting tumors. In embodiments, somatostatin or somatostatin analogs are used in imaging (e.g., tumor imaging). In embodiments, other agents may be administered in combination with GRA, simultaneously, or at different times.

[0025] In embodiments, the applicant provides a method for reducing the catecholamine excess discussed herein, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist. In embodiments, the applicant provides a method for reducing the catecholamine excess discussed herein, wherein the patient is not concurrently administered an exogenous estrogen receptor ligand; ii) the patient is not concurrently administered an exogenous selective androgen receptor modulator; iii) the patient is not concurrently administered an exogenous selective androgen receptor modulator; iv) the patient is not concurrently administered an exogenous D-homoandrosta-17-YL-carbamate derivative; and v) the patient is not concurrently administered an exogenous glucocorticoid receptor agonist.

[0026] In the embodiment, a pharmaceutical composition essentially comprising GRA is administered to patients such as those with Cushing's syndrome who have a catecholamine-secreting tumor in an amount effective in reducing catecholamine secretion by the tumor, or in an amount effective in restoring symptoms of catecholamine excess in the patient. In the embodiment, a pharmaceutical composition essentially comprising mifepristone is administered to patients such as those with Cushing's syndrome who have a catecholamine-secreting tumor in an amount effective in reducing catecholamine secretion by the tumor, or in an amount effective in restoring symptoms of catecholamine excess in the patient.

[0027] In embodiments, a pharmaceutical composition comprising GRA and other active agents is administered to patients, such as patients with Cushing's syndrome who have catecholamine-secreting tumors, in amounts effective for controlling catecholamine excess in the patient, reversing symptoms of catecholamine excess, or both. In embodiments, the other active agents present in the pharmaceutical composition may include one or more of alpha-adrenergic receptor antagonists, beta-adrenergic receptor antagonists, somatostatins, and somatostatin analogs (e.g., somatostatin receptor agonists). In embodiments, the pharmaceutical composition comprises mifepristone and one or more of the following: adrenergic antagonists (e.g., alpha-adrenergic receptor antagonists, beta-adrenergic receptor antagonists, and antagonists having mixed alpha- and beta-adrenergic antagonist activity), somatostatin, and somatostatin analogs (e.g., somatostatin receptor agonists).

[0028] The methods and compositions disclosed herein provide improved methods and treatments for patients such as those with Cushing's syndrome who have catecholamine-secreting tumors. [Modes for carrying out the invention]

[0029] Detailed explanation The applicant provides definitions of several terms used in this disclosure.

[0030] definition

[0031] The abbreviations used herein have their conventional meanings within the scope of chemical and biological technology.

[0032] All ranges listed herein are inclusive, and each range listed herein includes the minimum and maximum doses within that range. For example, the range "between 1 and 1000 mg / kg / day" includes doses of 1 mg / kg / day and 1000 mg / kg / day.

[0033] As used herein, the term “bonding” refers to a sustained (albeit brief or intermittent) contact or adhesion between two compounds.

[0034] As used herein, the terms “affinity,” “binding affinity,” and related terms refer to the strength and specificity of binding, such as the binding between a ligand and its receptor. “High affinity” is used in relation to the relative binding of two ligands to a receptor, where a high-affinity ligand binds at a lower concentration than a “low-affinity” ligand. For example, in competitive binding experiments, a high-affinity ligand will bind to the receptor in competition with a reference ligand at a lower concentration than a low-affinity ligand would bind to the receptor in competition.

[0035] The term "specific binding" refers to a bond that is more selective and typically stronger than mere nonspecific adhesion between compounds. Specific binding may also be exemplified by the binding that occurs between a ligand and its receptor.

[0036] The term "binding constant" may be used to refer to a measure of binding specificity. A useful constant for providing information about binding strength and specificity is the equilibrium dissociation constant K. d and its reciprocal equilibrium association constant (or affinity constant) K a There is.

[0037] As used herein, the term "inhibition constant" refers to K i This refers to the equilibrium dissociation constant K for a simple reversible inhibitor. dIt is of the same class. Inhibition of the binding between a ligand and its receptor, or inhibition of the action resulting from the binding between a ligand and its receptor, may take many forms, including competitive inhibition, uncompetitive inhibition, and non - competitive inhibition. The inhibition constant is expressed in units of concentration and is K in the range of nanomolar concentration (nm). i An inhibitor having i is a more effective inhibitor than an inhibitor having K in the range of micromolar concentration (μm). When comparing the inhibitory effects of two inhibitors, for example, an inhibitor having K i in the range of nm will be called a "more potent inhibitor", and an inhibitor having K i in the range of μm will be called a "weaker inhibitor". Similarly, an inhibitor having K i in the range of nm will be called a "potent inhibitor", and an inhibitor having K i in the range of μm will be called a "weak inhibitor".

[0038] "Patient" or "subject in need thereof" refers to a human having or suspected of having a catecholamine - secreting tumor, a neuroendocrine tumor, or a catecholamine - secreting neuroendocrine tumor. Catecholamine - secreting tumors can be identified and / or monitored by detecting the tumor, by detecting elevated levels of catecholamines, by detecting symptoms caused by the catecholamine - secreting tumor, and by combinations of these. Neuroendocrine tumors can be detected and / or monitored by detecting the tumor or by detecting symptoms caused by the tumor.

[0039] As used herein, the term "catecholamine(s)" is used as understood by those skilled in the medical arts and refers to small molecules including dopamine, norepinephrine, and epinephrine (adrenaline).

[0040] "To treat," "to treat," and "treatment" refer to any signs of success in treating or recovering from a disease or condition, which include any objective or subjective parameters such as reduction of symptoms; remission; reduction, or making the disease or condition tolerable to the patient; delaying the rate of degeneration or decline; preventing the final stage of degeneration from decreasing; or improvement of the patient's physical or mental health. Treatment or recovery of symptoms may be based on objective or subjective parameters; which include the results of a physical examination; histopathological examination (e.g., analysis of biopsy tissue); laboratory analysis of urine, saliva, tissue samples, serum, plasma, or blood (e.g., to detect cortisol or catecholamine levels); or imaging (e.g., imaging of catecholamine-secreting tumors or detectably labeled somatostatin analogs). Effective treatment refers to a reduction in catecholamine production, a decrease in catecholamine secretion, a decrease in the patient's blood catecholamine or cortisol levels, a decrease in catecholamine-secreting tumor volume (e.g., size, mass, volume, survival rate, or growth of the catecholamine-secreting tumor), or an increase in tumor cell death in the catecholamine-secreting tumor.

[0041] As used herein, "administered with or immediately after a meal" means that the therapeutic composition is administered with a meal or within approximately 30 minutes of the patient beginning to eat.

[0042] As used herein, the terms “administer simultaneously or sequentially” refer to administering a GRM compound such as GRA and a somatostatin receptor ligand compound (e.g., somatostatin or a somatostatin analog (SSA)) in such a manner that the two compounds are simultaneously present in the body in amounts effective for treating catecholamine-secreting tumors.

[0043] As used herein, the terms “effective dose,” “effective amount,” or “therapeutic effective dose” refer to the amount of one or more pharmacological agents effective in treating, eliminating, or alleviating at least one symptom of the disease being treated. In some cases, “effective dose,” “effective amount,” or “therapeutic effective dose” may refer to the amount of a functional agent or pharmaceutical composition useful in exhibiting a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. In some cases, an effective dose or similar refers to an amount effective in lowering catecholamine levels. In some cases, an effective dose or similar refers to an amount effective in lowering cortisol levels (e.g., serum cortisol, salivary cortisol, or urinary free cortisol). In some cases, an effective dose or similar refers to an amount effective in lowering catecholamine levels or cortisol levels, or a combination thereof, by at least 10%, 20%, 30%, 40%, 50%, 60%, 75%, 90%, 99%, or more.

[0044] As used herein, the terms “effective in reducing catecholamine production” and “effective in reducing catecholamine secretion” and similar terms refer to a method, treatment, composition, or amount that can reduce the production and / or secretion of catecholamines (single or multiple) by a neuroendocrine tumor or other tumor compared to the production and / or secretion of such tumor by such tumor in the absence of such method, treatment, composition, or amount.

[0045] As used herein, the term “catecholamine-secreting tumor” refers to an adenoma, adenocarcinoma, neuroendocrine tumor, pituitary tumor, or other tumor that produces catecholamines. Generally, catecholamine-secreting tumors also secrete catecholamines. In some cases, catecholamine-secreting tumors can increase blood, plasma, or serum levels of catecholamines or blood, plasma, serum, or urinary (e.g., free urinary) catecholamine levels in subjects with catecholamine-secreting tumors compared to subjects without such tumors. Catecholamine-secreting (e.g., catecholamine-secreting) tumors may typically be neuroendocrine tumors (NETs) that produce and / or secrete catecholamines.

[0046] "Pharmacopoeia-acceptable excipients" and "pharmacopoeia-acceptable carriers" refer to substances that assist in the administration and absorption of the active agent to the target, may be included in the composition of the present invention, and do not cause severely harmful toxic effects to the patient. Non-limiting examples of pharmacopoeia-acceptable excipients include water, sodium chloride (NaCl), physiological saline solution, Ringer's lactate solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorants. Those skilled in the art will recognize that other pharmacopoeia may be useful in the present invention.

[0047] As used herein, the term “steroid,” and the phrase “steroid skeleton” in the context of glucocorticoid receptor antagonists including the phrase “steroid,” refer to glucocorticoid receptor antagonists that include modifications to the basic structure of cortisol, an endogenous steroidal glucocorticoid receptor ligand. The basic structure of the steroid skeleton is provided as formula I: [ka] The two most common known classes of structural modifications of the cortisol steroid skeleton that produce glucocorticoid antagonists are modifications of the 11-β hydroxyl group and modifications of the 17-β side chain (see, for example, Lefebvre (1989) J. Steroid Biochem. Vol. 33: pp. 557-563).

[0048] As used herein, the terms “progesterone receptor” and “PR” refer to naturally occurring receptors that bind to progesterone.

[0049] The term "aldosterone" refers to the structure: [ka] This refers to naturally occurring mineralocorticoid hormones that possess [certain properties].

[0050] The mineralocorticoid receptor (MR), also known as the type I glucocorticoid receptor (GRI), is activated by aldosterone in humans.

[0051] The term "cortisol" has a structure: [ka] This refers to naturally occurring glucocorticoid hormones (also known as hydrocortisone) that possess the properties of [unclear].

[0052] As used herein, the term glucocorticoid receptor (GR) refers to a receptor that binds to glucocorticoids such as cortisol, dexamethasone, or other molecules. Glucocorticoid receptors, also known in humans as corticosteroid receptors or type II glucocorticoid receptors (GRII), are activated in humans by cortisol (or by corticosterone ("cortisone") in some other animals, such as rats and mice). The human cortisol receptor (GRII receptor, Genbank: P04150) specifically binds to cortisol and / or cortisol analogs (e.g., dexamethasone). The term includes isoforms of GRII, recombinant GRII, and mutant GRII.

[0053] As used herein, the term glucocorticoid receptor modulator (GRM) refers to an agent that affects the action of the glucocorticoid receptor (GR). Such modulation may include activation (agonist action), partial activation (partial agonist action), inhibition (reduction of receptor activation under conditions that would otherwise be activated, such as in the presence of cortisol), and blockade (achievement of suppression or near-complete achievement of receptor activation under conditions that would otherwise be activated, such as in the presence of cortisol). GRMs may affect GR activity by increasing or decreasing GR activity. Examples of GRMs include steroids, and in embodiments, pyrimidinedione compounds; azadecalin compounds; fused ring azadecalin compounds; heteroaryl-ketone fused ring azadecalin compounds; and other compounds.

[0054] As used herein, the terms “glucocorticoid agonist,” “glucocorticoid receptor agonist,” “glucocorticoid receptor type II agonist,” and “GRII agonist” refer to compounds or drugs that can bind to and activate the cortisol receptor. Such drugs include, for example, cortisol, dexamethasone, prednisone, and other compounds and drugs that bind to and activate GRII.

[0055] As used herein, the terms “glucocorticoid antagonist,” “glucocorticoid receptor antagonist,” “glucocorticoid antagonist,” “glucocorticoid receptor type II antagonist,” “GRII antagonist,” and “GRA” refer to agents that inhibit the action of the cortisol receptor; such inhibition may include interference with the binding of glucocorticoid agonists, such as cortisol, dexamethasone, or other compounds or agents that can bind to and activate the cortisol receptor. GRA is a glucocorticoid receptor modulator. The inhibition constant (K) for GRA against the human cortisol receptor is given below. i The mM may be between about 0.0001 nM and about 1,000 nM; preferably between about 0.0005 nM and about 10 nM, most preferably between about 0.001 nM and about 1 nM. Therefore, the terms “glucocorticoid receptor antagonist” and “GRA” refer to any composition or compound that partially or completely inhibits (antagonizes) the binding of a glucocorticoid receptor (GR) agonist, such as cortisol or a synthetic or natural cortisol analog, to GR. “Specific glucocorticoid receptor antagonist” refers to any composition or compound that inhibits any biological reaction associated with the binding of GR to an agonist. “Specific” means that the drug is intended to preferentially bind to GR rather than to other nuclear receptors such as mineralocorticoid receptors (MR) or progesterone receptors (PR).

[0056] "Specific" means that the drug preferentially binds to the glucocorticoid receptor (GR) rather than other nuclear receptors such as the mineralocorticoid receptor (MR), androgen receptor (AR), or progesterone receptor (PR). Specific glucocorticoid receptor antagonists have an affinity (1 / 10th K) that is 10 times greater than their affinity for MR, AR, or PR. d It is preferable that the specific glucocorticoid receptor antagonist binds to GR at a value of 1 / 100. In a more preferred embodiment, the specific glucocorticoid receptor antagonist has an affinity 100 times greater than its affinity for MR, AR, or PR (1 / 100 of K). d Combine with GR using the value.

[0057] As used herein, "mifepristone" refers to GRA that binds to GRII (and also to the progesterone receptor). Mifepristone (11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4,9-dien-3-one) has the following structure: [ka] It has the following characteristics. Mifepristone is also known, for example, RU486, RU38, 486, and 17-beta-hydroxy-11-beta-(4-dimethylaminophenyl)-17-alpha-(1-propynyl)-estra-4,9-dien-3-one.

[0058] As used herein, "RU28362" refers to the glucocorticoid receptor agonist [11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-trien-3-one].

[0059] As used herein, the phrase “non-steroidal skeleton” in the context of glucocorticoid receptor antagonists, including that phrase, refers to glucocorticoid receptor antagonists that do not share structural homology with or are not modifications of cortisol. Such compounds include synthetic mimetic and analogues of proteins, including partial peptides, pseudopeptides, and non-peptide molecular entities.

[0060] Nonsteroidal GRA compounds also include GRAs having a cyclohexyl-pyrimidine skeleton, a condensed azadecalin skeleton, a heteroarylketone-condensed azadecalin skeleton, or an octahydro-condensed azadecalin skeleton. An exemplary GRA having a cyclohexyl-pyrimidine skeleton is described in U.S. Patent No. 8,685,973. An exemplary GRA having a condensed azadecalin skeleton is described in U.S. Patent Nos. 7,928,237 and 8,461,172. An exemplary GRA having a heteroarylketone-condensed azadecalin skeleton is described in U.S. Patent No. 8,859,774. An exemplary GRA having an octahydro-condensed azadecalin skeleton is described in U.S. Patent Application Publication No. 2015-0148341.

[0061] The description of compounds useful in the methods disclosed herein and suitable for the pharmaceutical compositions disclosed herein is described in accordance with the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted with one or more of a number of substituents, such substitutions are selected such that, in accordance with the principles of chemical bonding, the resulting compounds are not inherently unstable and / or are likely to be unstable under ambient conditions such as in water, neutral, or physiological conditions, as would be known to those skilled in the art.

[0062] When substituents are identified by conventional chemical formulas and written from left to right, they similarly encompass chemically identical substituents that would be obtained by writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0063] "Alkyl" refers to a linear or branched saturated aliphatic radical having the indicated number of carbon atoms. 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 and C 5~6 It can contain any number of carbon atoms, such as C 1~6 Alkyl compounds, though not limited to these, include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl.

[0064] "Alkoxy" refers to an alkyl group that has an oxygen atom to bond to the alkyl group: alkyl-O-. Regarding alkyl groups, the alkoxy group is C 1~6 It can have any suitable number of carbon atoms, such as the following. Examples of alkoxy groups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.

[0065] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0066] "Haloalkyl" refers to the alkyl group defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. Regarding alkyl groups, haloalkyl groups are C 1~6It can have any suitable number of carbon atoms. For example, haloalkyls include trifluoromethyl and fluoromethyl. In some cases, the term "perfluoro" can be used to define a compound or radical in which all hydrogens are replaced by fluorine. For example, a perfluoromethane is 1,1,1-trifluoromethyl.

[0067] A "haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. Regarding alkyl groups, a haloalkoxy group is C 1~6 It can have any suitable number of carbon atoms. The alkoxy group can be substituted with 1, 2, 3, or more halogens. When all hydrogens are replaced with halogens, for example fluorine, the compound is persubstituted, for example, perfluorinated. Examples of haloalkoxys, but not limited to these, include trifluoromethoxy, 2,2,2,-trifluoroethoxy, and perfluoroethoxy.

[0068] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic, or bridging polycyclic ring assembly containing 3 to 12, or the number of ring atoms indicated. Cycloalkyl is C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 , and C 3~12It can contain any number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Examples of saturated monocyclic cycloalkyl rings include norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups, but not limited to these, include cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. 3~8 When referring to cycloalkyl groups, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3~6 In the case of cycloalkyl groups, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0069] A "heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Further heteroatoms may also be useful, including, but are not limited to, B, Al, Si, and P. Heteroatoms can also be oxidized, such as -S(O)- and -S(O)2-, but are not limited to these. Heterocycloalkyl groups can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any preferred number of heteroatoms, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4, may be included in the heterocycloalkyl group. Examples of heterocycloalkyl groups include aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thiethane, thiolane (tetrahydrothiophene), thian (tetrahydrothiopyran), oxazolidine, isooxalidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can also condense to aromatic compounds or non-aromatic ring systems, forming members that may include indoline, but are not limited to these.

[0070] When heterocycloalkyls contain 3 to 8 ring members and 1 to 3 heteroatoms, typical members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyls can also form rings with 5 to 6 ring members and 1 to 2 heteroatoms, and typical members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0071] "Aryl" refers to an aromatic ring system having any preferred number of ring atoms and any preferred number of rings. An aryl group can contain 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms and any preferred number of ring members, such as 6 to 10, 6 to 12, or 6 to 14. An aryl group can be monocyclic, condensed to form a bicyclic or tricyclic group, or linked by bonds to form a biaryl group. Typical aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linkage. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. An aryl group may be substituted or unsubstituted.

[0072] A "heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. Further heteroatoms may also be useful, including, but are not limited to, B, Al, Si, and P. Heteroatoms can also be oxidized, but are not limited to, N-oxides, -S(O)-, and -S(O)2-. A heteroaryl group can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any preferred number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5, may be contained in a heteroaryl group. A heteroaryl group can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Possible heteroaryl groups include pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can condense with aromatic ring systems such as phenyl rings to form members including, but are not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazines (quinoxaline), benzopyrimidines (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophenes, and benzofurans. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups may be substituted or unsubstituted.

[0073] Heteroaryl groups can be linked at any position on the ring. For example, pyrroles include 1-, 2-, and 3-pyrroles; pyridines include 2-, 3-, and 4-pyridines; imidazoles include 1-, 2-, 4-, and 5-imidazoles; pyrazoles include 1-, 3-, 4-, and 5-pyrazoles; triazoles include 1-, 4-, and 5-triazoles; tetrazoles include 1-, and 5-tetrazoles; pyrimidines include 2-, 4-, 5-, and 6-pyrimidines; pyridazines include 3-, and 4-pyridazines; 1,2,3-triazines include 4-, and 5-triazines; 1,2,4-triazines include 3-, 5-, and 6-triazines; 1,3,5-triazines include 2-triazines; thiophenes include 2-, and 3-thiophenes; and furans include 2 There are - and 3-furans, as thiazoles there are 2-, 4- and 5-thiazoles, as isothiazoles there are 3-, 4- and 5-isothiazoles, as oxazoles there are 2-, 4- and 5-oxazoles, as isoxazoles there are 3-, 4- and 5-isoxazoles, as indoles there are 1-, 2- and 3-indoles, as isoindoles there are 1- and 2-isoindoles, as quinolines there are 2-, 3- and 4-quinolines, as isoquinolines there are 1-, 3- and 4-isoquinolines, as quinazolines there are 2- and 4-quinazolines, as sinnolines there are 3- and 4-sinnolines, as benzothiophenes there are 2- and 3-benzothiophenes, and as benzofurans there are 2- and 3-benzofurans.

[0074] Some heteroaryl groups have 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those with 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those with 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Other heteroaryl groups include pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole, which have 5 to 6 ring members and 1 to 2 ring heteroatoms containing N, O, or S.

[0075] Some heteroaryl groups consist of 5 to 10 ring members and only a nitrogen heteroatom, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups consist of 5 to 10 ring members and only an oxygen heteroatom, such as furan and benzofuran. Some other heteroaryl groups consist of 5 to 10 ring members and only a sulfur heteroatom, such as thiophene and benzothiophene. Furthermore, other heteroaryl groups include 5 to 10 ring members and at least 2 heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and sinnoline.

[0076] A "heteroatom" refers to an O, S, or N atom.

[0077] "Salt" refers to an acid acid or base salt of the compound used in the method of the present invention. Exemplary examples of pharmaceutically acceptable salts include inorganic acid salts (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid salts (e.g., acetic acid, propionic acid, glutamic acid, citrate), and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide). It should be understood that pharmaceutically acceptable salts are non-toxic. Further information regarding preferred pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0078] "Isomers" refer to compounds that have the same chemical formula but are structurally distinguishable.

[0079] A "tautomer" refers to one of two or more structural isomers that exist in equilibrium and can be easily converted from one form to the other.

[0080] As used herein, the term “chemotherapy” typically refers to medical treatments used to treat cancer. Chemotherapy treatments include the use of agents that are toxic to cancer tissue and cells, or that act to slow or reduce the growth or spread of cancer tissue and cells. Chemotherapy agents include antitumor agents, which may be derived from natural compounds (e.g., taxol); may be the action of naturally occurring hormones, growth factors, or immunoactive molecules, may mimic, reduce, or block them; may be synthetic small molecules; may be antibodies or antibody conjugates; or may be other agents. Examples of chemotherapeutic agents, but not limited to those mentioned above, include taxanes, taxols, docetaxel, paclitaxel, actinomycin, anthracyclines, doxorubicin, daunorubicin, barurubicin, bleomycin, cisplatin, trastuzumab (Herceptin®), trastuzumab emtansine (Kadcyla®), imatinib (Gleevec®), and eribulin (Halaven®).

[0081] As used herein, the terms “pharmaceutical composition” and “formulation” refer to a composition suitable for administration to a patient to treat a pathological condition or to restore the symptoms of a pathological condition. A pharmaceutical composition comprises an active ingredient (e.g., GRA; or a combination of GRA and other active agents such as, for example, an adrenergic antagonist or somatostatin or somatostatin analog), and pharmaceutically acceptable excipients. In embodiments, a pharmaceutical composition comprises one or more active ingredients and one or more pharmaceutically acceptable excipients.

[0082] As used herein, the term “pharmaceutically acceptable excipient” refers to a substance that may be present in a pharmaceutical composition to assist the administration and absorption of the active agent to the target, and does not cause severely harmful toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solution, Ringer's lactate solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorants. Those skilled in the art will recognize that other pharmaceutically acceptable excipients may be useful in the present invention.

[0083] As used herein, the terms “sustained-release,” “delayed-release,” “long-acting,” “extended-release,” and similar terms refer to a pharmaceutical composition or formulation comprising at least one active ingredient (e.g., GRA, an adrenergic antagonist, somatostatin, a somatostatin analog, or a combination thereof) formulated to maintain therapeutic concentrations of one or more active ingredients in a patient over a longer period compared to formulations not intended for such sustained-release. In some cases, a sustained-release formulation maintains therapeutic concentrations of one or more active ingredients for one, two, three, four, five, or six weeks, or at least these periods. In some cases, a sustained-release formulation is administered to a patient every one, two, three, four, five, or six weeks. Examples of commercially available sustained-release formulations, but not limited to these, include the sustained-release formulations of somatostatin analogs octreotide LAR, extended-release lanreotide, and lanreotide autogel.

[0084] As used herein, the term “adrenergic receptor” refers to naturally occurring receptors that bind to adrenergic compounds such as catecholamines (e.g., dopamine, norepinephrine, and epinephrine). Adrenergic receptors may be one of several subtypes, including one of two common subtypes called “alpha-adrenergic receptors” and “beta-adrenergic receptors.” The binding and action of adrenergic agonists, as well as the binding and effects of adrenergic antagonists, may differ between alpha-adrenergic and beta-adrenergic receptors. Examples of alpha-adrenergic receptor agonists (e.g., sympathomimetic agents) include, for example, phenylephrine, guanethidine, and other compounds. Examples of beta-adrenergic receptor agonists (e.g., beta-agonists) include, for example, isoproterenol and isoprenaline.

[0085] As used herein, the term “adrenergic antagonist” refers to compounds that reduce the activation of adrenergic receptors, such as alpha-adrenergic receptor antagonists, beta-adrenergic receptor antagonists, and antagonists having mixed alpha- and beta-adrenergic antagonist activity. Examples of alpha-adrenergic receptor antagonists (e.g., alpha-blockers) include phentolamine, prazosin, and yohimbine. Examples of beta-adrenergic receptor antagonists (e.g., beta-blockers) include propranolol, timolol, and esmolol.

[0086] As used herein, “somatostatin” and “SST” refer to any form of the naturally occurring peptide hormone known as “growth hormone inhibitory hormone (or “factor”),” “growth hormone release inhibitory hormone (or “factor”),” “somatotropin release inhibitory hormone (or “factor”),” or any other name as understood by those skilled in the art. Human somatostatin is described in Uniprot P61278. Somatostatin occurs as at least two forms, a long form (e.g., 28 amino acids in humans) and a short form (e.g., 14 amino acids in humans), and acts (e.g., by reducing or blocking the release of growth hormone (somatotropin)). Thus, somatostatin is an inhibitory polypeptide having two main biologically active forms, SST14 and SST28. In some cases, the ligand is a pre- or pre-pro form of somatostatin, or an analogue thereof.

[0087] As used herein, the term somatostatin receptor refers to certain G protein-coupled seven-transmembrane receptors that bind to somatostatin. Five somatostatin receptor subtypes are known, designated SSTR1 to SSTR5, respectively.

[0088] As used herein, the terms “somatostatin receptor ligand,” “somatostatin ligand analog,” or “somatostatin analog” refer to any ligand of any one of the somatostatin receptor subtypes (SSTR1 to SSTR5). A “somatostatin analog” mimics the action of somatostatin to at least some extent. Examples of somatostatin analogs include, but are not limited to, pasireotide, octreotate, lanreotide, and derivatives thereof, including, for example, labeled (e.g., radiolabeled and detectably labeled).

[0089] In some cases, the somatostatin receptor ligand is somatostatin. In some cases, the somatostatin ligand is a somatostatin analog. In preferred embodiments, the somatostatin analog is an agonist of the somatostatin receptor. In some cases, the somatostatin ligand preferentially binds to or activates the somatostatin type 2 receptor (SSTR2). In some cases, the somatostatin receptor ligand preferentially binds to or activates the somatostatin type 5 receptor (SSTR5). In some cases, the somatostatin receptor ligand preferentially binds to or activates SSTR2 and SSTR5. In some cases, the somatostatin receptor ligand preferentially binds to or activates SSTR2, SSTR3, and SSTR5. The somatostatin receptor ligand may be provided or administered as a long-acting, extended, or delayed-release formulation.

[0090] Exemplary somatostatin receptor ligands include, but are not limited to, peptide somatostatin receptor ligands, such as those described in U.S. Patent No. 8,946,154. Exemplary somatostatin receptor ligands include, but are not limited to, somatostatin polypeptides derived from Oncorhynchus mykiss, such as those described in U.S. Patent No. 6,818,739, and their analogues or derivatives. Exemplary somatostatin receptor ligands include, but are not limited to, antibodies that bind to or activate one or more somatostatin receptor subtypes (e.g., any one of SSTR1-5, or a combination thereof). Exemplary somatostatin receptor ligands include, but are not limited to, non-peptide somatostatin receptor ligands, such as those described in U.S. Patent No. 7,189,856. Exemplary somatostatin receptor ligands include, but are not limited to, somatostatin receptor ligands, such as those described in U.S. Patent No. 6,358,941.

[0091] Exemplary somatostatin receptor ligands include, but are not limited to, selective somatostatin receptor ligands. For example, a somatostatin receptor ligand can be selective for one of SSTR1-5 (e.g., selectively bind or selectively activate). In some cases, a somatostatin receptor ligand is selective for SSTR1 (e.g., selectively binds or selectively activates). In some cases, a somatostatin receptor ligand is selective for SSTR2. In some exemplary cases, a somatostatin receptor ligand is selective for SSTR3 (e.g., selectively binds or selectively activates). In some cases, a somatostatin receptor ligand is selective for SSTR4 (e.g., selectively binds or selectively activates). In some cases, a somatostatin receptor ligand is selective for SSTR5 (e.g., selectively binds or selectively activates).

[0092] In some cases, somatostatin receptor ligands are selective to two somatostatin receptors selected from the group consisting of SSTR1-5 (e.g., selectively bind or selectively activate). For example, a somatostatin receptor ligand can be selective to SSTR1 and 4. Another example is that a somatostatin receptor ligand can be selective to SSTR2 and 5. In some cases, somatostatin receptor ligands are selective to three somatostatin receptors selected from the group consisting of SSTR1-5 (e.g., selectively bind or selectively activate). In some cases, somatostatin receptor ligands are selective to four somatostatin receptors selected from the group consisting of SSTR1-5 (e.g., selectively bind or selectively activate). Exemplary selective somatostatin receptor ligands include, but are not limited to, those described by Rohrer et al., 1998, Science 282:737. Examples of selective somatostatin receptor ligands include, but are not limited to, those described in U.S. Patent Application Publication 2006 / 0089299.

[0093] In some cases, the somatostatin receptor ligand is octreotide, 111 The ligand is selected from the group consisting of in-octreotide, octreotate, pasireotide, lanreotide, and their analogs or derivatives. In some cases, the somatostatin receptor ligand binds to a detectable label or a cytotoxic agent. Exemplary detectable labels include spin labels, fluorescent labels, and radionuclides. Exemplary cytotoxic agents include radionuclides and cytotoxic chemotherapeutic agents.

[0094] As used herein, the term “somatostatin imaging” refers to an imaging method in which somatostatin or a somatostatin analog is labeled (e.g., conjugated with a radioactive, fluorescent, or other detectable element or compound), administered to a subject, and the label is detected. Detection of the label is useful, for example, for determining the location of somatostatin receptors in a subject, and may be particularly useful for determining ectopic or otherwise inappropriately located somatostatin receptors in a subject.

[0095] In some embodiments, the method includes administering a somatostatin analog (SSA). In some cases, the somatostatin analog is selected from the group consisting of octreotide, octreotate, pasireotide, lanreotide, and derivatives thereof. In some cases, the somatostatin analog is radiolabeled. In some cases, the radiolabeled somatostatin analog is, for example, 111 In or 123 It is radiolabeled with labels suitable for imaging, such as I. In some cases, somatostatin analogs are used, for example, 111 In, 131 I, 90 Y, 177 Lu, or 213 They are radiolabeled with labels suitable for radionuclide therapy, such as Bi. In some cases, the therapeutic radionuclides are 111 In, 90 Y, 177 Lu, and 213 Selected from the group consisting of Bi. In some cases, therapeutic radionuclides are 90 Y, 177 Lu, and 213 Selected from the group consisting of Bi. In some cases, somatostatin analogs are 32 P, 45 Ti, 48 V, 49 V, 59 Fe, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 65 Zn, 67Cu, 67 Ga, 68 Ga, 71 As, 72 As, 76 As, 76 Br, 77 As, 89 Sr, 90 Y, 99m Tc, 111 In, 117m Sn, 123 I, 125 I, 131 I, 149 Pm, 153 Gd, 153 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 201 Tl, 203 Pb, 209 Pb, 209 Bi, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, and 225 is labeled with a radionuclide selected from the group consisting of Ac. In some cases, the somatostatin analog is 123 I-Tyr 3 -octreotide, 111 In-DTPA-D-Phe 1 -octreotide, 111 In-DTPA 0 octreotide, 90 Y-DOTA, Tyr 3 octreotide, or 177 Lu-DOTA, Tyr 3 octreotate. In some cases, the subject who needs it has an inoperable or metastatic catecholamine-secreting tumor, or an inoperable metastatic catecholamine-secreting tumor. In some cases, the inoperable and / or metastatic catecholamine-secreting tumor is a neuroendocrine tumor.

[0096] In some cases, somatostatin analogs are administered as sustained-release formulations. In other cases, somatostatin analogs are administered as octreotide LAR, lanreotide PR, or lanreotide autogel.

[0097] As used herein, the phrase “peptide receptor radionuclide therapy” or its acronym “PRRT” refers to a therapeutic intervention in which a ligand becomes radioactive by binding to a radioactive element or compound, is administered to a subject, and the radioactive ligand binds to its receptor, delivering a therapeutic dose of radiation. PRRT may be effective when a tumor inappropriately expresses or overexpresses a receptor to which a radioactive ligand can be administered. In embodiments, if a tumor inappropriately expresses or overexpresses a somatostatin receptor, radiolabeled somatostatin or a radiolabeled somatostatin analog may be administered to the patient.

[0098] Treatment method

[0099] Methods disclosed herein include methods for treating tumors such as catecholamine-secreting tumors, which involve administering compounds capable of modulating glucocorticoid receptors (GRs) to provide beneficial therapeutic effects. In embodiments, the patient with a catecholamine-secreting tumor is a patient with Cushing's syndrome, and the method treats Cushing's syndrome in the patient. For example, a method disclosed herein includes administering an effective amount of a glucocorticoid receptor modulator (GRM), such as a glucocorticoid receptor antagonist (GRA), to a patient in need, thereby reducing catecholamine production by the tumor. In embodiments, the disclosed method includes administering an effective amount of a glucocorticoid receptor modulator (GRM), such as a glucocorticoid receptor antagonist (GRA), to a patient with Cushing's syndrome who has a tumor, thereby reducing catecholamine production by the tumor and consequently treating Cushing's syndrome. In embodiments, the tumor may be a neuroendocrine tumor.

[0100] Embodiments of the method include administering an effective amount of glucocorticoid receptor modulator to a patient, wherein the patient is not simultaneously administered an exogenous glucocorticoid receptor agonist. Embodiments of the method include administering an effective amount of glucocorticoid receptor modulator to a patient, wherein the patient i) does not require any further treatment with the glucocorticoid receptor modulator, and ii) is not simultaneously administered an exogenous glucocorticoid receptor agonist. In embodiments, the GR modulator is a glucocorticoid receptor antagonist (GRA). Therefore, in embodiments, the method includes administering an effective amount of GRA to a patient, wherein the patient i) does not require any further treatment with the GRA, and ii) is not simultaneously administered an exogenous glucocorticoid receptor agonist.

[0101] GRA compounds may be administered together with, simultaneously with, or in close proximity to other treatments or pharmaceutical substances. Other treatments or pharmaceutical substances may include, for example, chemotherapeutic agents, alpha-adrenergic receptor antagonists, beta-adrenergic receptor antagonists, radiotherapy agents (e.g., compounds containing radioactive moieties such as peptides for use in peptide receptor radionuclide therapy (PRRT)), somatostatins, and somatostatin receptor agonists (e.g., somatostatin analogs). In embodiments, GRA compounds may be administered as a pharmaceutical composition also containing other active agents, one or more of adrenergic antagonists, somatostatins, and somatostatin analogs.

[0102] For example, administering a GRA effective in reducing cortisol activity in combination with an adrenergic antagonist may synergistically enhance the effectiveness of such adrenergic antagonist treatment administered to treat neuroendocrine tumors. In one embodiment, the neuroendocrine tumor is present in a patient with Cushing's syndrome, and the method treats Cushing's syndrome in the patient. In a further example, increased cortisol activity at the tumor level may affect the expression of somatostatin receptors such as sst2, which may consequently affect the effectiveness of somatostatin or somatostatin analogs. Therefore, administering a GRA effective in reducing cortisol activity at the tumor level may improve the effectiveness of somatostatin or somatostatin analogs administered to treat neuroendocrine tumors. Other concomitant and synergistic activities resulting from administering GRMs (such as GRA) together with or in close proximity to other drugs such as chemotherapeutic agents, alpha-adrenergic receptor antagonists, beta-adrenergic receptor antagonists, radiotherapy agents, somatostatins, and somatostatin receptor agonists (e.g., somatostatin analogs) can improve the effectiveness of methods for treating neuroendocrine tumors compared to methods in which such other drugs are used in the absence of GRMs (such as GRA).

[0103] In embodiments, beneficial therapeutic effects include: reduction of catecholamine excess in patients with catecholamine-secreting tumors; recovery of symptoms of catecholamine excess in patients with catecholamine-secreting tumors; improved effectiveness of alpha and beta-adrenergic receptor blockade in patients with catecholamine-secreting tumors; improved therapeutic effectiveness of somatostatin analogs in patients with catecholamine-secreting tumors; improved effectiveness of somatostatin analogs when used in imaging diagnostics; improved effectiveness of peptide receptor radionuclide therapy (PRRT) in patients with catecholamine-secreting tumors; and other therapeutic advantages. In embodiments, beneficial therapeutic effects include: treatment of Cushing's syndrome in patients with catecholamine-secreting tumors who have Cushing's syndrome.

[0104] In embodiments, the glucocorticoid receptor modulator is a glucocorticoid receptor antagonist (GRA). In embodiments, the GRA is a glucocorticoid type II (GRII) receptor antagonist. In embodiments, the GRA preferentially binds to the GRII receptor compared to its binding to the glucocorticoid type I (GRI) receptor. In embodiments, the GRA reduces the activation of the GRII receptor. In embodiments, the GRA reduces the activity of the GRII receptor. In embodiments, the GRA may bind to the progesterone receptor (PR), or it may bind to the glucocorticoid receptor with higher affinity than it binds to the PR. In embodiments, the GRA is mifepristone. In embodiments, the GRA is a selective inhibitor of the glucocorticoid receptor. In embodiments, the GRA may bind only slightly to the PR, or not measurably to the PR.

[0105] In some embodiments, GRA comprises a steroid skeleton having at least one phenyl-containing moiety at the 11-β position of the steroid skeleton. In some cases, the phenyl-containing moiety at the 11-β position of the steroid skeleton is a dimethylaminophenyl moiety. In some cases, GRA is mifepristone. In some embodiments, GRA 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)androst-4,9(11)-dien-3-one. In some embodiments, GRA is (11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

[0106] In the embodiment, GRAs include compounds having a cyclohexyl-pyrimidine skeleton; GRAs having a condensed azadecalin skeleton; GRAs having a heteroarylketone condensed azadecalin skeleton; and GRAs having an octahydro condensed azadecalin skeleton.

[0107] In some embodiments, the GRA has a non-steroidal skeleton. In some cases, the glucocorticoid receptor antagonist skeleton is a cyclohexylpyrimidine. In some cases, the cyclohexylpyrimidine has the following formula: [ka]

[0108] (In the formula, dashed lines are absent or combined; X is selected from the group consisting of O and S; R 1 This is 1 to 3 R 1a Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, which are substituted as needed with each R 1a H and C are independent of each other. 1~6 Alkyl, C 2~6 Alkenil, C 2~6Alkinyl, 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 SO2R 1b SO2NR 1b R 1c Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R 1b and R 1c These are H and C, respectively, independently. 1~6 Selected from the group consisting of alkyl; R 2 H, C 1~6 Alkyl, C 1~6 Alkyl-OR 1b , C 1~6 Alkyl NR 1b R 1c and C 1~6 Selected from the group consisting of alkylene heterocycloalkyl; R 3 H and C 1~6 Selected from the group consisting of alkyl groups; Ar has 1 to 4 R 4 The base is an aryl that has been substituted as needed; each R 4 H and C are independent of each other. 1~6 Alkyl, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl and C 1~6 Selected from the group consisting of haloalkoxys; L 1 is a combination or C 1~6 They are alkylenes (where the subscript n is an integer from 0 to 3), or they have salts and isomers thereof.

[0109] In some cases, GRAs with a nonsteroidal skeleton are condensed azadecalin. In some cases, condensed azadecalin is given by the following formula: [ka] (In the formula, L 1 and L 2 is a member selected independently of bonded and unsubstituted alkylenes; R 1 This includes unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, and -OR 1A , NR 1C R 1D -C(O)NR 1C R 1D , and -C(O)OR 1A The members are selected from, where R 1A R is a member selected from hydrogen, unsubstituted alkyl, and unsubstituted heteroalkyl, 1C and R 1D is a member independently selected from unsubstituted alkyl and unsubstituted heteroalkyl groups, where R 1C and R 1D These may join as needed, forming an unsubstituted ring with the nitrogen to which they are bonded, where the ring may contain further ring nitrogen as needed; R 2 The formula is: [ka] It has, Here, R 2G 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)-; R 5 This is 1 to 5 R 5A A phenyl compound substituted as needed with a group, where R 5A is hydrogen, halogen, -OR 5A1 , S(O2)NR 5A2 R 5A3The member is selected from , -CN, and unsubstituted alkyl groups, where R 5A1 R is a member selected from hydrogen and unsubstituted alkyl groups, 5A2 and R 5A3 The compound is a member independently selected from hydrogen and unsubstituted alkyl groups, or a compound having salts and isomers thereof.

[0110] In some cases, GRAs with a nonsteroidal skeleton are heteroarylketone condensed azadecalin or octahydro condensed azadecalin. In some cases, heteroarylketone condensed azadecalin is given by the formula: [ka]

[0111] (In the formula, R 1 It has 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, and R 1a A heteroaryl ring, optionally substituted with 1 to 4 groups independently selected from each of the following; each R 1a is 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 The group consisting of heterocycloalkyls is independently selected; ring J is selected from the group consisting of cycloalkyl rings, heterocycloalkyl rings, aryl rings and heteroaryl rings, where the heterocycloalkyl and heteroaryl rings have 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; each R 2 is hydrogen, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl-C 1~6Alkoxy, 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)2R 2a , C 3~8 Cycloalkyl, and C 3~8 A heterocycloalkyl group is independently selected from the group consisting of heterocycloalkyl groups, where the heterocycloalkyl group has 1 to 4 R 2c Substituted as needed at the base; or two R linked to the same carbon 2 The groups link together to form an oxo group (=O); or two R groups 2 The groups are linked to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, where the heterocycloalkyl ring has 1 to 3 R 2d Substituted as needed in the base; R 2a and R 2b is hydrogen and C 1~6 Each R is independently selected from the group consisting of alkyl groups; 2c is hydrogen, halogen, hydroxyl, C 1~6 Alkoxy, C 1~6 Haloalkoxys, CN, and NR 2a R 2b Independently selected from the group consisting of; each R 2d is hydrogen and C 1~6 Two R atoms, independently selected from the group consisting of alkyl groups, or bonded to the same ring atom. 2d The groups are linked together to form (=O); R 3 This is 1 to 4 R 3a Selected from the group consisting of phenyl and pyridyl, each as necessary substitutions at the base; each R 3a These are hydrogen, halogens, and C 1~6 Independently selected from the group consisting of haloalkyls (where the subscript n is an integer from 0 to 3), or having salts and isomers thereof.

[0112] In some cases, octahydrocondensed azadecalin is given by formula: [ka]

[0113] (In the formula, R 1 It has 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, and R 1a A heteroaryl ring, optionally substituted with 1 to 4 groups independently selected from each of the following; each R 1a is hydrogen, C 1~6 Alkyl, halogen, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxys, N-oxides, and C 3~8 The group consisting of cycloalkyls is independently selected; ring J is selected from the group consisting of aryl rings and heteroaryl rings having 5 to 6 ring members and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; each R 2 is 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)2R 2a , C 3~8 Cycloalkyl and carbon atoms having 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. 3~8 Independently selected from the group consisting of heterocycloalkyls; or two R atoms on adjacent ring atoms 2The groups are linked to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, where the heterocycloalkyl ring has 1 to 3 R 2c Substituted as needed in the base; R 2a , R 2b and R 2c is hydrogen and C 1~6 Each R is independently selected from the group consisting of alkyl groups; 3a These are halogens (where n is an integer from 0 to 3), or have salts and isomers thereof.

[0114] In embodiments, the method disclosed herein provides a method for reducing catecholamine production and tumor volume in patients with metastatic or unresectable catecholamine-secreting tumors, the method comprising administering an effective amount of GRA at a daily dose between 1 and 1000 mg / kg / day for at least 5 weeks, provided that i) the patient does not require any further treatment with a glucocorticoid receptor antagonist, and ii) the patient is not concurrently administered an exogenous glucocorticoid receptor agonist. In embodiments of a method for reducing catecholamine production and tumor volume in patients with metastatic or unresectable catecholamine-secreting tumors, an effective dose of GRA is administered under the same conditions for at least 5 weeks at a daily dose between 1 and 1000 mg / kg / day, or between 1 and 500 mg / kg / day, or between 0.1 and 200 mg / kg / day, or between 0.1 and 100 mg / kg / day, or between 0.1 and 50 mg / kg / day, or between 0.1 and 20 mg / kg / day, or between 0.1 and 15 mg / kg / day, or between 0.1 and 10 mg / kg / day, or between 0.1 and 5 mg / kg / day, or between 0.1 and 3 mg / kg / day. In embodiments, the metastatic or unresectable catecholamine-secreting tumor is present in a patient with Cushing's syndrome, and the administration of GRA treats Cushing's syndrome in the patient. In embodiments, GRA is administered once daily. In this embodiment, GRA is administered once daily with or immediately after a meal.

[0115] In embodiments, GRA is mifepristone, and the method comprises administering an effective amount of mifepristone at a daily dose between 0.1 and 100 mg / kg / day, or between 0.1 and 50 mg / kg / day, or between 0.1 and 20 mg / kg / day, or between 0.1 and 15 mg / kg / day, or between 0.1 and 12 mg / kg / day, or between 0.1 and 10 mg / kg / day, or between 0.1 and 5 mg / kg / day, or between 0.1 and 3 mg / kg / day, or between 0.1 and 1 mg / kg / day, under the same conditions for at least 5 weeks.

[0116] In embodiments, GRA is used as monotherapy in patients with catecholamine-secreting tumors to control catecholamine excess, to restore symptoms of catecholamine excess, or for both. In embodiments, GRA is used as monotherapy in patients with catecholamine-secreting tumors to treat Cushing's syndrome, to control catecholamine excess, to restore symptoms of catecholamine excess, or for all three. In embodiments, GRA is used in combination with chemotherapy in patients with catecholamine-secreting tumors to control catecholamine excess, to restore symptoms of catecholamine excess, to treat Cushing's syndrome, or for all three. In embodiments, GRA is used in combination with somatostatin or a somatostatin receptor agonist (e.g., a somatostatin analog) in patients with catecholamine-secreting tumors to control catecholamine excess, to restore symptoms of catecholamine excess, to treat Cushing's syndrome, or for all three. In embodiments, GRA is used in combination with chemotherapy, somatostatin, or a somatostatin receptor agonist (e.g., a somatostatin analog) in patients with catecholamine-secreting tumors to control catecholamine excess, to alleviate symptoms of catecholamine excess, to treat Cushing's syndrome, or for all three purposes. In embodiments, somatostatin, or a somatostatin analog or receptor agonist, is used in imaging (e.g., tumor imaging). In embodiments, GRA is administered once daily. In embodiments, GRA is administered once daily with or immediately after a meal.

[0117] In embodiments, GRA is used in patients with catecholamine-secreting tumors in combination with alpha-adrenergic and / or beta-adrenergic receptor antagonists to control catecholamine excess, to restore symptoms of catecholamine excess, to treat Cushing's syndrome, or for all three purposes. In embodiments, GRA is used in combination with chemotherapy and alpha or beta-adrenergic receptor antagonists in patients with catecholamine-secreting tumors in combination with radiotherapy agents (e.g., compounds containing a radioactive portion such as a peptide for use in peptide receptor radionuclide therapy (PRRT)) in combination with radiotherapy agents (e.g., compounds containing a radioactive portion such as a peptide for use in peptide receptor radionuclide therapy (PRRT)). In embodiments, GRA is used in combination with chemotherapy and radiotherapy agents (e.g., compounds containing a radioactive portion, such as a peptide, for use in peptide receptor radionuclide therapy (PRRT)) in patients with catecholamine-secreting tumors to control catecholamine excess, to alleviate symptoms of catecholamine excess, to treat Cushing's syndrome, or for all three purposes. In embodiments, GRA is administered once daily. In embodiments, GRA is administered once daily with or immediately after a meal.

[0118] In some cases, the patient is administered a composition essentially consisting of a glucocorticoid receptor antagonist (GRA) in an effective amount to reduce catecholamine secretion in a patient with a catecholamine-secreting tumor. In embodiments, the patient is a patient with Cushing's syndrome, and the composition essentially consisting of GRA is administered in an effective amount to reduce catecholamine secretion to treat Cushing's syndrome in a patient with a catecholamine-secreting tumor. In some cases, the patient is administered a composition essentially consisting of GRA in an effective amount to restore symptoms of catecholamine excess in a patient with a catecholamine-secreting tumor. In embodiments, the patient is administered a composition containing GRA in an effective amount to reduce catecholamine production or secretion in a patient with a catecholamine-secreting tumor, along with other agents; the other agents may be administered in combination with GRA, simultaneously, or at different times. In embodiments, a patient is administered a composition containing GRA in an amount effective to restore symptoms of catecholamine excess in a patient with a catecholamine-secreting tumor, along with other agents; the other agents may be administered in combination with GRA, simultaneously, or at different times. In embodiments, a patient is administered a composition containing GRA in an amount effective to treat Cushing's syndrome. In embodiments, a patient is administered a composition containing GRA in an amount effective to treat Cushing's syndrome, in order to provide one or more of the other benefits disclosed herein.

[0119] In embodiments, other agents may include chemotherapeutic agents; or adrenergic blockers (e.g., alpha-adrenergic receptor blockers, or beta-adrenergic receptor blockers, or adrenergic antagonists active at both alpha- and beta-adrenergic receptors); or somatostatins or somatostatin analogs; or radiotherapy agents (e.g., compounds containing a radioactive moiety such as a peptide for use in peptide receptor radionuclide therapy (PRRT)); and combinations thereof. In embodiments, methods disclosed herein, which involve treating a patient with GRA and other agents, include, for example, a method for treating a patient receiving chemotherapy to treat a catecholamine-secreting neuroendocrine tumor; a method for treating a patient with Cushing's syndrome who has received chemotherapy to treat a catecholamine-secreting neuroendocrine tumor; a method for treating a patient who has received an alpha-adrenergic receptor blocker, or a beta-adrenergic receptor blocker, or both, to treat a catecholamine-secreting neuroendocrine tumor; a method for treating a patient who has received an alpha-adrenergic receptor blocker, or a beta-adrenergic receptor blocker, or both, to treat a catecholamine-secreting neuroendocrine tumor; a method for treating a patient who has received a somatostatin analogue to treat a catecholamine-secreting neuroendocrine tumor; a method for treating a patient who has received a somatostatin analogue for imaging related to the diagnosis or treatment of a catecholamine-secreting neuroendocrine tumor; and a method for treating a patient who has received peptide receptor radionuclide therapy (PRRT) to treat a catecholamine-secreting neuroendocrine tumor. In the embodiment, GRA is administered once daily. In the embodiment, GRA is administered once daily with or immediately after a meal.

[0120] In embodiments of a method for treating a patient with a catecholamine-secreting tumor, the patient is administered a composition comprising another active agent and GRA in an effective amount to reduce catecholamine secretion in the patient with the catecholamine-secreting tumor. In embodiments, the patient with the catecholamine-secreting tumor is a patient with Cushing's syndrome, and the patient is administered a composition comprising another active agent and GRA in an effective amount to reduce catecholamine secretion in order to treat Cushing's syndrome in the patient with the catecholamine-secreting tumor. In embodiments, the patient is administered a composition comprising another active agent and GRA in an effective amount to restore symptoms of catecholamine excess in the patient with the catecholamine-secreting tumor. In embodiments, the other agent may be an adrenergic blocker (e.g., an alpha-adrenergic receptor blocker or a beta-adrenergic receptor blocker, or an adrenergic antagonist active at both alpha- and beta-adrenergic receptors); may be a somatostatin; or a somatostatin analog. In embodiments, the composition may contain a combination of GRA and two or more other agents, the other agents being selected from adrenergic blockers (e.g., alpha-adrenergic receptor blockers and beta-adrenergic receptor blockers, somatostatin, and somatostatin analogs). In embodiments, GRA is administered once daily. In embodiments, GRA is administered once daily with or immediately after a meal.

[0121] In embodiments, the method disclosed herein includes a method for reducing catecholamine production and tumor load in patients with metastatic or unresectable catecholamine-secreting tumors, the method comprising administering an effective dose of mifepristone at a daily dose between 0.1 and 50 mg / kg / day for at least 5 weeks. In embodiments, the patient is a patient with Cushing's syndrome, and the treatment is effective for treating Cushing's syndrome in the patient. In embodiments, the method disclosed herein includes a method for reducing catecholamine production and tumor load in patients such as patients with Cushing's syndrome who have metastatic or unresectable catecholamine-secreting tumors, the method comprising administering an effective dose of mifepristone at a daily dose between 0.1 and 50 mg / kg / day for at least 5 weeks, provided that the patient is not concurrently administered an exogenous glucocorticoid receptor agonist. In embodiments, the methods disclosed herein include methods for reducing catecholamine production and tumor volume in patients such as those with Cushing's syndrome who have metastatic or unresectable catecholamine-secreting tumors, the methods comprising administering an effective amount of mifepristone at a daily dose between 0.1 and 50 mg / kg / day for at least 5 weeks, provided that i) the patient does not require any further treatment with a glucocorticoid receptor antagonist, and ii) the patient is not simultaneously administered an exogenous glucocorticoid receptor agonist. In embodiments, these methods include administering an effective amount of mifepristone under the same conditions for at least 5 weeks at a daily dose between 0.1 and 100 mg / kg / day, or between 0.1 and 20 mg / kg / day, or between 0.1 and 15 mg / kg / day, or between 0.1 and 12 mg / kg / day, or between 0.1 and 10 mg / kg / day, or between 0.1 and 5 mg / kg / day, or between 0.1 and 3 mg / kg / day, or between 0.1 and 1 mg / kg / day. In embodiments, GRA is administered once daily. In embodiments, GRA is administered once daily with or immediately after a meal.

[0122] In some cases, the patient is administered a composition essentially consisting of mifepristone in an effective amount to reduce catecholamine secretion in a patient with a catecholamine-secreting tumor. In embodiments, the patient is a patient with Cushing's syndrome. In some cases, the patient is administered a composition essentially consisting of mifepristone in an effective amount to restore symptoms of catecholamine excess in a patient with a catecholamine-secreting tumor. In embodiments of the methods disclosed herein, the patient is administered a composition comprising mifepristone and other active agents in an effective amount to reduce catecholamine secretion in a patient with a catecholamine-secreting tumor. In embodiments of the methods disclosed herein, the patient is administered a composition comprising mifepristone and other active agents in an effective amount to restore symptoms of catecholamine excess in a patient with a catecholamine-secreting tumor. In embodiments, other active agents may include adrenergic blockers (e.g., alpha-adrenergic receptor blockers, beta-adrenergic receptor blockers, or adrenergic antagonists active at both alpha- and beta-adrenergic receptors); somatostatin; or somatostatin analogues; or combinations thereof. In embodiments, GRA is administered once daily. In embodiments, GRA is administered once daily with or immediately after a meal.

[0123] In some cases, the catecholamine-secreting tumor is a pheochromocytoma. In some cases, the catecholamine-secreting tumor is a paraganglioma. In some cases, the patient has a metastatic catecholamine-secreting tumor. In some embodiments, the patient has an unresectable non-malignant tumor. In some embodiments, the patient has an unresectable multifocal non-malignant tumor. In embodiments, the patient is a patient with Cushing's syndrome who has a tumor, and the tumor is a pheochromocytoma, or a paraganglioma, or a metastatic catecholamine-secreting tumor, or an unresectable non-malignant tumor, or an unresectable multifocal non-malignant tumor. In embodiments, the GRM, such as GRA, is administered once daily. In embodiments, the GRM, such as GRA, is administered once daily with or immediately after a meal.

[0124] composition

[0125] The applicant hereby discloses compositions comprising a glucocorticoid receptor antagonist (GRA) which may be used in the treatment of patients with catecholamine-secreting tumors. In embodiments, the compositions comprising GRA may be provided in an amount effective to reduce catecholamine secretion in patients with catecholamine-secreting tumors, or in an amount effective to restore symptoms of catecholamine excess in patients with catecholamine-secreting tumors, or both.

[0126] The applicant also discloses compositions comprising a glucocorticoid receptor antagonist (GRA) and other active agents, wherein the other active agent may be an adrenergic blocker (e.g., an alpha-adrenergic receptor blocker, or a beta-adrenergic receptor blocker, or an adrenergic antagonist active at both alpha- and beta-adrenergic receptors); or somatostatin; or a somatostatin analog; or a combination thereof. These compositions comprising GRA and other active agents may be used in the treatment of patients with catecholamine-secreting tumors. In embodiments, a composition comprising GRA and other active agents may contain an amount of GRA, the other active agent, or both that is effective in reducing catecholamine secretion in patients with catecholamine-secreting tumors. In embodiments, a composition comprising GRA and other active agents may contain an amount of GRA, the other active agent, or both that is effective in restoring symptoms of catecholamine excess in patients with catecholamine-secreting tumors.

[0127] The compositions disclosed herein can be prepared in various oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, cachets, gels, syrups, slurries, and suspensions, which are suitable for patient ingestion. The compositions of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. Furthermore, the compositions disclosed herein can be administered by inhalation, for example, intranasally. In addition, the compositions of the present invention can be administered transdermally. The compositions disclosed herein may also be administered via intraocular, intravaginal, and intrarectal routes, including suppositories, inhalants, powders, and aerosol formulations (see, for example, steroid inhalants, Rohatagi, J. Clin. Pharmacol. Vol. 35: pp. 1187-1193, 1995; Tjwa, Ann. AllergyAsthmaImmunol. Vol. 75: pp. 107-111, 1995).

[0128] Accordingly, in embodiments disclosed herein, the composition comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, a glucocorticoid receptor antagonist (GRA), and an adrenergic antagonist. The adrenergic antagonist may be an alpha-adrenergic antagonist, a beta-adrenergic antagonist, or an adrenergic antagonist having antagonist activity at both alpha-adrenergic and beta-adrenergic receptors. In further embodiments disclosed herein, the composition comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, a glucocorticoid receptor antagonist (GRA), and somatostatin. In other embodiments disclosed herein, the composition comprises a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, a glucocorticoid receptor antagonist (GRA), and a somatostatin analog.

[0129] With regard to the preparation of pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be either solid or liquid. Preparations in solid form include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances, which may act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials. Further details regarding formulation and administration techniques are described in detail in scientific literature and patent documents, for example, in the latest edition of Remington's Pharmaceutical Sciences, MackPublishing Co., Easton Pa. ("Remington's"). Please refer to the following.

[0130] In powders, the carrier is a micronized solid, which is present in the mixture along with the micronized active components. In tablets, the active components are mixed in a suitable proportion with a carrier having the required binding properties and compressed into the desired shape and size. Powders and tablets preferably contain 5% or 10% to 70% of other active agents and / or GRA.

[0131] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low-melting wax; cocoa butter; carbohydrates; sugars including lactose, sucrose, mannitol, or sorbitol; starches obtained from corn, wheat, rice, potato, or other plants; cellulose such as methylcellulose, hydroxypropyl methylcellulose, or sodium carboxymethylcellulose; and gums containing arabic and tragacanth; and proteins including gelatin and collagen, but are not limited to these. Disintegrants or solubilizers such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or salts thereof, such as sodium alginate, may be added as needed.

[0132] The core of the sugar-coated tablet is coated with a suitable coating such as a concentrated sugar solution, lacquer solution, or suitable organic solvent or solvent mixture, which may also contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention can also be used orally, for example, as push-fit capsules made from gelatin, and as sealed soft capsules made from gelatin with a coating such as glycerol or sorbitol. Push-fit capsules may contain other active agents and / or GRA mixed with fillers or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and stabilizers as needed. In soft capsules, other active agents and / or GRA may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol, with or without a stabilizer.

[0133] For the preparation of the suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and other active agents and / or GRA are homogeneously dispersed therein by stirring. The melted homogeneous mixture is then poured into a mold of a suitable size and cooled to solidify.

[0134] Liquid preparations include solutions, suspensions, and emulsions, such as aqueous solutions or water / propylene glycol solutions. For parenteral injections, liquid preparations can be formulated as solutions in aqueous polyethylene glycol solutions.

[0135] Aqueous solutions suitable for oral use can be prepared by dissolving other active agents and / or GRA in water and, if desired, adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions suitable for oral use can be prepared by dispersing a micronized active component in water containing a viscous material such as natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, and a dispersant or wetting agent such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of alkylene oxide with fatty acids (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with fatty acids and partial esters derived from hexitol (e.g., polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with fatty acids and partial esters derived from hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose, aspartame, or saccharin. The formulation can be adjusted according to osmotic pressure.

[0136] This also includes solid preparations intended to be converted into liquid preparations for oral administration immediately before use. Such liquid preparations include liquids, suspensions, and emulsions. These preparations may contain, in addition to the active ingredients, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0137] Oily suspensions can be formulated by suspending other active agents and / or GRA in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or in inorganic oils such as liquid paraffin; or in mixtures thereof. Oily suspensions may contain thickeners such as beeswax, solid paraffin, or cetyl alcohol. Sweeteners such as glycerol, sorbitol, or sucrose can be added to provide a palatable oral preparation. These formulations can be preserved by adding antioxidants such as ascorbic acid. For an example of an injectable oily vehicle, see Minto, J. Pharmacol. Exp. Ther. Vol. 281: pp. 93-102, 1997. The pharmaceutical formulations of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be the vegetable oils or inorganic oils described above, or mixtures thereof. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids such as sorbitan monooleate and hexitol anhydride, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings, as with syrup and elixir formulations. Such formulations may also contain lubricants, preservatives, or colorants.

[0138] The compositions of the present invention can also be delivered as microspheres for delayed release in the body. For example, the microspheres can be formulated for administration via intradermal injection of drug-containing microspheres released gradually under the skin (see Rao, J. Biomator Sci. Polym. 7th edition: pp. 623-645, 1995); as a biodegradable and injectable gel formulation (see, for example, GaoPharm. Res. Vol. 12: pp. 857-863, 1995); or as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. Vol. 49: pp. 669-674, 1997). Both transdermal and intradermal routes provide consistent delivery over several weeks or months.

[0139] In other embodiments, the compositions of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into body cavities or organ lumens. The formulation for administration will typically consist of a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that can be used include water and Ringer's solution and isotonic sodium chloride. Furthermore, sterile fixatives can be conventionally used as solvents or suspension media. Any sterile fixative can be used for this purpose, including synthetic mono or diglycerides. Furthermore, fatty acids such as oleic acid can similarly be used in injectable preparations. These solutions are sterile and generally free of undesirable substances. These formulations may be sterilized by conventional, well-known sterilization techniques. The formulations may optionally contain pH adjusters and buffers, toxicity adjusters, and pharmaceutically acceptable auxiliary substances to approximate physiological conditions, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate. The concentration of the composition of the present invention in these formulations can be varied over a wide range and will be selected according to the specific administration method and patient requirements, mainly based on the volume of body fluids, viscosity, body weight, etc. For IV administration, the formulation may be an injectable sterile preparation, such as an injectable sterile aqueous or oily suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The injectable sterile preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, such as a 1,3-butanediol solution.

[0140] In other embodiments, formulations of the compositions of the present invention can be delivered by using liposomes that fuse with or endocytose to cell membranes, i.e., by using ligands bound to liposomes, or by directly binding to oligonucleotides that bind to cell surface membrane protein receptors, thereby inducing endocytosis. By using liposomes, particularly if the liposome surface has ligands specific to target cells, or otherwise preferentially targeting specific organs, the compositions of the present invention can be focused on in vivo delivery to target cells (see, for example, Al-Muhammed, J. Microencapsul. Vol. 13: pp. 293-306, 1996; Chonn, Curr. Opin. Biotechnol. Vol. 6: pp. 698-708, 1995; Ostro, Am. J. Hosp. Pharm. Vol. 46: pp. 1576-1587, 1989).

[0141] Administration

[0142] In the embodiments, the composition is administered once daily. In the embodiments, the composition is administered once daily with or immediately after a meal.

[0143] The compositions disclosed herein can be delivered by any preferred means, including oral, parenteral, and topical methods. Topical transdermal administration methods can be formulated as applicator sticks, liquids, suspensions, emulsions, gels, creams, ointments, pastes, jellies, ointments, powders, and aerosols.

[0144] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is further divided into unit doses containing an appropriate amount of GRA and other active agents, the other active agents being selected from adrenergic antagonists, somatostatins, and somatostatin analogs. In embodiments, the adrenergic antagonist may be an alpha-adrenergic antagonist, a beta-adrenergic antagonist, or an adrenergic antagonist having activity at both alpha- and beta-adrenergic receptors. The unit dosage form may be a packaged preparation, the package containing individual amounts of the preparation, such as tablets, capsules, and powders packaged in vials or ampoules. Alternatively, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or an appropriate number of any of these in a packaged form.

[0145] GRA and other active agents can be administered concurrently or individually. Concurrent administration includes administering other active agents within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours after administering GRA. Concurrent administration also includes administering GRA and other active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Furthermore, GRA and other active agents can be administered once daily, or two, three, or more times per day, thereby achieving a preferred daily dosage level.

[0146] In some embodiments, co-administration can be achieved by simultaneous formulation, i.e., by preparing a single pharmaceutical composition containing both GRA and the other active agent. A preferred co-administered formulation is a single pharmaceutical composition containing GRA, the other active agent, and a pharmaceutically acceptable excipient. For example, a preferred co-administered formulation is a single pharmaceutical composition containing GRA, a pharmaceutically acceptable excipient, and an active agent selected from adrenergic receptor antagonists (e.g., alpha-adrenergic antagonists, beta-adrenergic antagonists, or adrenergic antagonists active at both alpha- and beta-adrenergic receptors), somatostatin, and somatostatin analogs.

[0147] In other embodiments, GRA and other active agents can be formulated individually.

[0148] Other active agents may be present in any suitable amount and may depend on various factors, including, but are not limited to, the subject's weight and age, disease status, etc. Suitable dosage ranges for other active agents in combination with GRA include approximately 0.1 mg to approximately 10,000 mg, or approximately 1 mg to approximately 1,000 mg, or approximately 10 mg to approximately 750 mg, or approximately 25 mg to approximately 500 mg, or approximately 50 mg to approximately 250 mg. Suitable dosages for other active agents in combination with GRA include approximately 0.1 mg, 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 mg.

[0149] Similarly, GRA can be present in any suitable amount in combination with other active agents. The amount of GRA may depend on various factors, including, but are not limited to, the patient's body weight and age, disease status, etc. Suitable dosage ranges for GRA in combination with other active agents include approximately 0.1 mg to approximately 10,000 mg, or approximately 1 mg to approximately 1,000 mg, or approximately 10 mg to approximately 750 mg, or approximately 25 mg to approximately 500 mg, or approximately 50 mg to approximately 250 mg. Suitable dosages for GRA in combination with other active agents, but are not limited to, include approximately 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or approximately 1,000 mg.

[0150] Other active agents and GRAs may be present in the compositions of the present invention in any suitable weight ratio, such as about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1 (w / w). Other active agents and GRAs may be present in any suitable weight ratio, such as about 1:100 (w / w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1, or 100:1 (w / w). Other dosages and dosage ratios of other active agents and GRAs are preferred in the compositions and methods disclosed herein.

[0151] The composition may also contain other suitable therapeutic agents. The compounds described herein may not be effective in combination with each other or alone, but may be used in combination with auxiliary agents that may contribute to the effectiveness of the active agent.

[0152] Exemplary Embodiments

[0153] Examples of the methods and compositions disclosed herein include, but are not limited to, the following exemplary embodiments. Patients treated according to these embodiments include, but are not limited to, patients with Cushing's syndrome having tumors as described in the following embodiments.

[0154] A method for reducing catecholamine excess in a patient with a catecholamine-secreting tumor, comprising administering an effective amount of a glucocorticoid receptor modulator to the patient, wherein the patient i) does not require further treatment with a glucocorticoid receptor antagonist, and ii) is not simultaneously administered an exogenous glucocorticoid receptor agonist. The glucocorticoid receptor modulator (GRM) may be a glucocorticoid receptor antagonist (GRA). In the method for reducing catecholamine excess in a patient with a catecholamine-secreting tumor disclosed herein, the GRM may be administered once daily. In embodiments of the method for reducing catecholamine excess in a patient with a catecholamine-secreting tumor disclosed herein, the GRM may be administered more than once daily.

[0155] In embodiments of a method for reducing catecholamine excess in patients with catecholamine-secreting tumors, the method comprises administering an effective amount of mifepristone at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist and is not concurrently administered an exogenous glucocorticoid receptor agonist. In embodiments, the daily dose of mifepristone is between 0.1 and 50 mg / kg / day for at least 5 weeks. In embodiments, the daily dose of mifepristone is between 1 and 10 mg / kg / day for at least 5 weeks.

[0156] A method for reversing symptoms of catecholamine excess in a patient with a catecholamine-secreting tumor, comprising administering an effective amount of GRM to the patient, wherein the patient does not require any other treatment using GRM such as GRA, and is not simultaneously administered an exogenous glucocorticoid receptor agonist. In embodiments of the method for reversing symptoms of catecholamine excess in a patient with a catecholamine-secreting tumor disclosed herein, GRM may be GRA. In embodiments, GRM may be administered once daily; in embodiments, GRM may be administered more than once daily.

[0157] In an embodiment of a method for reversing symptoms of catecholamine excess in patients with catecholamine-secreting tumors, the method comprises administering an effective amount of mifepristone at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist.

[0158] In embodiments of a method for restoring symptoms of catecholamine excess in patients with catecholamine-secreting tumors, the daily dose of mifepristone is once daily. In further embodiments of a method for restoring symptoms of catecholamine excess in patients with catecholamine-secreting tumors, mifepristone is administered more than once daily. In embodiments of a method for restoring symptoms of catecholamine excess in patients with catecholamine-secreting tumors, the daily dose of mifepristone is between 0.1 and 20 mg / kg / day for at least 5 weeks. In embodiments of a method for restoring symptoms of catecholamine excess in patients with catecholamine-secreting tumors, the daily dose of mifepristone is between 0.1 and 10 mg / kg / day for at least 5 weeks.

[0159] A method for improving the efficacy of chemotherapy in patients with catecholamine-secreting tumors, comprising administering an effective amount of a glucocorticoid receptor modulator to a patient receiving chemotherapy for treating a catecholamine-secreting neuroendocrine tumor, wherein the patient does not require further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist. In embodiments of the method for improving the efficacy of chemotherapy in patients with catecholamine-secreting tumors disclosed herein, the GRM may be GRA.

[0160] A method for improving the efficacy of chemotherapy in patients with catecholamine-secreting tumors, comprising administering an effective dose of mifepristone to a patient receiving chemotherapy for a catecholamine-secreting neuroendocrine tumor in the patient at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist and is not concurrently administered an exogenous glucocorticoid receptor agonist. In a further embodiment of the method for improving the efficacy of chemotherapy in patients with catecholamine-secreting tumors, mifepristone is administered more than once daily. In an embodiment of the method for improving the efficacy of chemotherapy in patients with catecholamine-secreting tumors, the daily dose of mifepristone is between 0.1 and 20 mg / kg / day for at least 5 weeks. In an embodiment of the method for improving the efficacy of chemotherapy in patients with catecholamine-secreting tumors, the daily dose of mifepristone is between 0.1 and 10 mg / kg / day for at least 5 weeks.

[0161] A method for improving the effectiveness of alpha- and beta-adrenergic receptor blockade in patients with catecholamine-secreting neuroendocrine tumors, comprising administering an effective amount of GRM to a patient who has received an alpha-adrenergic receptor blocker, a beta-adrenergic receptor blocker, or both for the treatment of a catecholamine-secreting neuroendocrine tumor, wherein the patient does not require any further treatment with GRM such as GRA, and is not simultaneously administered an exogenous glucocorticoid receptor agonist. In embodiments of the method for improving the effectiveness of alpha- and beta-adrenergic receptor blockade in patients with catecholamine-secreting tumors, GRM is GRA.

[0162] A method for improving the efficacy of alpha- and beta-adrenergic receptor blockade in patients with catecholamine-secreting neuroendocrine tumors, comprising administering an effective amount of mifepristone to patients who have received an alpha-adrenergic receptor blocker, a beta-adrenergic receptor blocker, or both for the treatment of a catecholamine-secreting neuroendocrine tumor in the patient, at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist.

[0163] A method for improving the efficacy of somatostatin and somatostatin analog treatment in patients with catecholamine-secreting neuroendocrine tumors, comprising administering an effective amount of a glucocorticoid receptor modulator to the patient, wherein somatostatin or a somatostatin analog is administered to the patient to treat the catecholamine-secreting neuroendocrine tumor in the patient, and the patient does not require further treatment with a glucocorticoid receptor antagonist, and is not simultaneously administered an exogenous glucocorticoid receptor agonist. In embodiments of the method for improving the efficacy of somatostatin and somatostatin analog treatment in patients with catecholamine-secreting tumors disclosed herein, GRM may be GRA.

[0164] A method for improving the efficacy of somatostatin and somatostatin analog treatment in patients with catecholamine-secreting neuroendocrine tumors, comprising administering an effective amount of a glucocorticoid receptor modulator to the patient, wherein somatostatin or a somatostatin analog is administered to the patient to treat the catecholamine-secreting neuroendocrine tumor, and an effective amount of mifepristone is administered to the patient who received somatostatin or a somatostatin analog for treatment of the catecholamine-secreting neuroendocrine tumor at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist.

[0165] A method for improving the effectiveness of somatostatin analog imaging in patients with catecholamine-secreting neuroendocrine tumors, comprising administering an effective amount of a glucocorticoid receptor modulator to a patient who has received somatostatin analog imaging for the diagnosis or treatment of a catecholamine-secreting neuroendocrine tumor, wherein the patient does not require further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist. In embodiments of the method for improving the effectiveness of somatostatin analog imaging in patients with catecholamine-secreting neuroendocrine tumors, the GRM may be GRA.

[0166] A method for improving the effectiveness of somatostatin analog imaging in patients with catecholamine-secreting tumors, comprising administering an effective amount of mifepristone to a patient who has received somatostatin analog imaging for the diagnosis or treatment of a catecholamine-secreting neuroendocrine tumor at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist.

[0167] A method for improving the effectiveness of somatostatin analog imaging in patients with catecholamine-secreting tumors, comprising administering an effective amount of mifepristone to a patient who has received somatostatin analog imaging for the diagnosis or treatment of a catecholamine-secreting neuroendocrine tumor at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist.

[0168] A method for improving the efficacy of peptide receptor radionuclide therapy (PRRT) in patients with catecholamine-secreting neuroendocrine tumors, comprising administering an effective amount of glucocorticoid receptor modulator to a patient receiving peptide receptor radionuclide therapy (PRRT) to treat the catecholamine-secreting neuroendocrine tumor, wherein the patient does not require further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist.

[0169] A method for improving the efficacy of peptide receptor radionuclide therapy (PRRT) in patients with catecholamine-secreting tumors, comprising administering an effective amount of mifepristone to patients receiving peptide receptor radionuclide therapy (PRRT) for the treatment of catecholamine-secreting neuroendocrine tumors at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patients do not require any further treatment with a glucocorticoid receptor antagonist and are not simultaneously administered an exogenous glucocorticoid receptor agonist.

[0170] For example, in any or all of the methods disclosed herein, including methods for reducing catecholamine excess in patients with catecholamine-secreting tumors; methods for reversing symptoms of catecholamine excess in patients with catecholamine-secreting tumors; methods for improving the effectiveness of chemotherapy in patients with catecholamine-secreting tumors; methods for improving the effectiveness of alpha and beta-adrenergic receptor blockade in patients with catecholamine-secreting tumors; methods for improving the effectiveness of somatostatin and somatostatin analog treatment in patients with catecholamine-secreting neuroendocrine tumors; methods for improving the effectiveness of somatostatin analog imaging in patients with catecholamine-secreting neuroendocrine tumors; and methods for improving the effectiveness of peptide receptor radionuclide therapy (PRRT) in patients with catecholamine-secreting neuroendocrine tumors, GRM may be mifepristone. In embodiments, GRM may be GRA, which binds to type II glucocorticoid receptors (GR-II) with higher affinity than type I glucocorticoid receptors (GR-I). In the embodiments, the GRM may be a GRA that binds to GR-II with higher affinity than GR-I and further binds to the progesterone receptor (PR). In the embodiments, the GRM is a GRA that binds to GR-II with a binding constant of less than approximately 10 nanomolars (nM). In the embodiments, the GRM is a GRA that binds to GR-II with a binding constant of less than approximately 5 nM. In the embodiments, the GRM is a GRA that binds to GR-II with a binding constant of less than approximately 2 nM. In the embodiments, the GRM is a GRA that binds to GR-II with a binding constant of less than approximately 1 nM. In the embodiments, the GRM is a GRA that binds to GR-II with a binding constant of less than approximately 10 nanomolars (nM) and further binds to PR with a binding constant of less than approximately 10 nM. In the embodiments, the GRM is a GRA that binds to GR-II with a binding constant of less than approximately 10 nanomolars (nM) and further binds to PR with a binding constant of more than approximately 500 nM. In this embodiment, GRM is a GRA that binds to GR-II with a binding constant of less than approximately 10 nanomolar concentration (nM) and further binds to PR with a binding constant of more than approximately 1000 nM.In embodiments in which GRM binds to PR with a binding constant greater than approximately 500 nM or greater than approximately 1000 nM, GRM may also be GRA that binds to GR-II with a binding constant of less than approximately 5 nM, less than approximately 2 nM, or less than approximately 1 nM.

[0171] For example, in any or all of the methods disclosed herein, including methods for reducing catecholamine excess in patients with catecholamine-secreting tumors; methods for reversing symptoms of catecholamine excess in patients with catecholamine-secreting tumors; methods for improving the effectiveness of chemotherapy in patients with catecholamine-secreting tumors; methods for improving the effectiveness of alpha and beta-adrenergic receptor blockade in patients with catecholamine-secreting tumors; methods for improving the effectiveness of somatostatin and somatostatin analog treatment in patients with catecholamine-secreting neuroendocrine tumors; methods for improving the effectiveness of somatostatin analog imaging in patients with catecholamine-secreting neuroendocrine tumors; and methods for improving the effectiveness of peptide receptor radionuclide therapy (PRRT) in patients with catecholamine-secreting neuroendocrine tumors, GRM may be administered once daily. In further embodiments, GRM may be administered more than once daily. In embodiments, GRM may be administered in a daily dose between 1 and 1000 mg / kg / day. In an embodiment, GRM may be administered daily for at least 5 weeks. In an embodiment, GRM may be administered in a daily dose between 1 and 100 mg / kg / day. In an embodiment, GRM may be administered in a daily dose between 1 and 100 mg / kg / day for at least 5 weeks. In an embodiment, GRM may be administered in a daily dose between 1 and 50 mg / kg / day. In an embodiment, GRM may be administered in a daily dose between 1 and 50 mg / kg / day for at least 5 weeks. In an embodiment, GRM may be administered in a daily dose between 1 and 20 mg / kg / day. In an embodiment, GRM may be administered in a daily dose between 1 and 20 mg / kg / day for at least 5 weeks.

[0172] In embodiments, the method comprises administering an effective amount of mifepristone at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist and is not simultaneously administered an exogenous glucocorticoid receptor agonist. In embodiments, the daily dose of mifepristone is between 0.1 and 50 mg / kg / day for at least 5 weeks. In embodiments, the daily dose of mifepristone is between 1 and 10 mg / kg / day for at least 5 weeks.

[0173] In further embodiments, the applicant discloses pharmaceutical compositions herein.

[0174] For example, the applicant discloses a pharmaceutical composition comprising a glucocorticoid receptor antagonist in an effective amount for treating a patient having a catecholamine-secreting tumor; a pharmaceutical composition comprising a glucocorticoid receptor antagonist in an effective amount for reducing the effects of catecholamine excess in a patient having a catecholamine-secreting tumor. In embodiments of the pharmaceutical composition, treatment of a patient with the composition is effective for reducing catecholamine production in the patient's tumor, for reducing the effects of catecholamine excess in the patient, or both. In embodiments of the pharmaceutical composition, GRA is selected from a steroidal glucocorticoid receptor antagonist, GRA having a cyclohexyl-pyrimidine skeleton; GRA having a condensed azadecalin skeleton; GRA having a heteroarylketone condensed azadecalin skeleton; or GRA having an octahydro-condensed azadecalin skeleton. In embodiments of the pharmaceutical composition, GRA is mifepristone.

[0175] The applicant also discloses a pharmaceutical composition comprising a glucocorticoid receptor antagonist (GRA) and other active agents, wherein the GRA and other agents are present in an effective amount to reduce catecholamine production in the patient's tumor, to reduce the effects of catecholamine excess in the patient, or for both purposes. In embodiments, the GRA is selected from a steroidal glucocorticoid receptor antagonist, a GRA having a cyclohexyl-pyrimidine backbone; a GRA having a fused azadecalin backbone; a GRA having a heteroaryl ketone fused azadecalin backbone; or a GRA having an octahydro fused azadecalin backbone. In an embodiment, the GRA is mifepristone.

[0176] In embodiments, the other agent is an adrenergic antagonist. In embodiments, the other agent is an adrenergic antagonist selected from an alpha-adrenergic receptor blocker, or a beta-adrenergic receptor blocker, or an adrenergic antagonist that is active at both alpha- and beta-adrenergic receptors.

[0177] In embodiments, the other agent comprises an adrenergic antagonist in an effective amount to reduce catecholamine production in the patient's tumor, to reduce the effects of catecholamine excess in the patient, or for both purposes.

[0178] In embodiments, the other agent is somatostatin or a somatostatin analog. In embodiments, the composition comprises somatostatin or a somatostatin analog in an effective amount to reduce catecholamine production in the patient's tumor, to reduce the effects of catecholamine excess in the patient, or for both purposes.

Examples

[0179] The following examples are provided to illustrate embodiments of the methods disclosed herein and are helpful in the explanation, but do not limit the methods for treating patients with catecholamine-secreting tumors.

[0180] (Example 1)

[0181] A 53-year-old woman with metastatic pheochromocytoma associated with ectopic ACTH secretion unresponsive to conventional chemotherapy with CVD (cyclophosphamide, vincristine, and dacarbazine) and sunitinib (tyrosine kinase inhibitor) was enrolled in a phase 2 trial using a somatostatin analog. Three months into treatment, the subject's metanephrine levels remained significantly elevated, and she continued to experience marked catecholamine excess symptoms (palpitations, tremors, and panic attacks) despite the use of high doses of atenolol (beta-blocker) and phenoxybenzamine (alpha-blocker). Simultaneously, she was diagnosed with Cushing's syndrome, and mifepristone 300 mg was added to her regimen, with the dose further increased to 600 mg daily two weeks later. One week after starting mifepristone, the subject noticed a dramatic improvement in her symptoms associated with cortisol excess and catecholamine excess. Two weeks after treatment with mifepristone, plasma epinephrine levels decreased by 50%, and nine weeks after treatment, plasma metanephrine levels decreased by 25%. Three months after treatment with mifepristone, the subject's catecholamine excess symptoms were controlled, and metanephrine levels were slightly elevated, but the subject developed vaginal bleeding, and mifepristone was temporarily discontinued. One week after discontinuing mifepristone, the subject experienced a worsening of catecholamine excess symptoms. Metanephrine levels were four times higher compared to the levels obtained during mifepristone administration.

[0182] (Example 2)

[0183] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment should be administered an effective dose of mifepristone at a daily dose of 50 mg / kg / day. Measurements will show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0184] (Example 3)

[0185] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment should be administered an effective dose of mifepristone at a daily dose of 20 mg / kg / day. Measurements will show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0186] (Example 4)

[0187] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment should be administered an effective dose of mifepristone at a daily dose of 15 mg / kg / day. Measurements will show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0188] (Example 5)

[0189] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment should be administered an effective dose of mifepristone at a daily dose of 10 mg / kg / day. Measurements will show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0190] (Example 6)

[0191] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment should be administered an effective dose of mifepristone at a daily dose of 5 mg / kg / day. Measurements will show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0192] (Example 7)

[0193] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 50 mg / kg / day, along with chemotherapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0194] (Example 8)

[0195] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 20 mg / kg / day, along with chemotherapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0196] (Example 9)

[0197] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective amount of mifepristone at a daily dose of 15 mg / kg / day, and chemotherapy is also administered. Measurement shows that the blood levels of catecholamines 5 weeks after treatment are lower compared to the initial levels.

[0198] (Example 10)

[0199] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective amount of mifepristone at a daily dose of 10 mg / kg / day, and chemotherapy is also administered. Measurement shows that the blood levels of catecholamines 5 weeks after treatment are lower compared to the initial levels.

[0200] (Example 11)

[0201] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective amount of mifepristone at a daily dose of 5 mg / kg / day, and chemotherapy is also administered. Measurement shows that the blood levels of catecholamines 5 weeks after treatment are lower compared to the initial levels.

[0202] (Example 12)

[0203] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, an effective dose of mifepristone is administered at a daily dose of 50 mg / kg / day, along with an adrenergic antagonist. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0204] (Example 13)

[0205] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, an effective dose of mifepristone is administered at a daily dose of 20 mg / kg / day, along with an adrenergic antagonist. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0206] (Example 14)

[0207] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, an effective dose of mifepristone is administered at a daily dose of 10 mg / kg / day, along with an adrenergic antagonist. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0208] (Example 15)

[0209] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, an effective dose of mifepristone is administered at a daily dose of 5 mg / kg / day, along with an adrenergic antagonist. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0210] (Example 16)

[0211] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 20 mg / kg / day, along with chemotherapy and an adrenergic antagonist. Measurements show that serum catecholamine levels 5 weeks after treatment are lower than initial levels.

[0212] (Example 17)

[0213] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 20 mg / kg / day, along with somatostatin. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0214] (Example 18)

[0215] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 10 mg / kg / day, along with somatostatin. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0216] (Example 19)

[0217] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 5 mg / kg / day, along with somatostatin. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0218] (Example 20)

[0219] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 1 mg / kg / day, along with somatostatin. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0220] (Example 21)

[0221] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 20 mg / kg / day, along with chemotherapy and somatostatin. Measurements show that serum catecholamine levels 5 weeks after treatment are lower than initial levels.

[0222] (Example 22)

[0223] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, an effective dose of mifepristone is administered at a daily dose of 20 mg / kg / day, along with a somatostatin analog. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0224] (Example 23)

[0225] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, an effective dose of mifepristone is administered at a daily dose of 15 mg / kg / day, along with a somatostatin analog. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0226] (Example 24)

[0227] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, an effective dose of mifepristone is administered at a daily dose of 10 mg / kg / day, along with a somatostatin analog. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0228] (Example 25)

[0229] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, an effective dose of mifepristone is administered at a daily dose of 5 mg / kg / day, along with a somatostatin analog. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0230] (Example 26)

[0231] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 20 mg / kg / day, along with chemotherapy and somatostatin analogs. Measurements show that serum catecholamine levels 5 weeks after treatment are lower than initial levels.

[0232] (Example 27)

[0233] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 20 mg / kg / day, along with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0234] (Example 28)

[0235] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 15 mg / kg / day, along with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0236] (Example 29)

[0237] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 10 mg / kg / day, along with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0238] (Example 30)

[0239] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily rate of 5 mg / kg / day, along with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0240] (Example 31)

[0241] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered an effective dose of mifepristone at a daily dose of 20 mg / kg / day, along with an adrenergic antagonist, and further treated with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0242] (Example 32)

[0243] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a GRA selected from the following: glucocorticoid receptor antagonists with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, at a daily dose of 100 mg / kg / day. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0244] (Example 33)

[0245] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a GRA selected from the following: a glucocorticoid receptor antagonist with a cyclohexyl-pyrimidine skeleton; a GRA with a condensed azadecalin skeleton; a GRA with a heteroarylketone condensed azadecalin skeleton; and a GRA with an octahydro condensed azadecalin skeleton, at a daily dose of 50 mg / kg / day. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0246] (Example 34)

[0247] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a GRA selected from the following: glucocorticoid receptor antagonists with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, at a daily dose of 20 mg / kg / day. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0248] (Example 35)

[0249] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a GRA selected from the following: glucocorticoid receptor antagonists with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, at a daily dose of 15 mg / kg / day. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0250] (Example 36)

[0251] For patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, a glucocorticoid receptor antagonist (GRA) selected from those with a cyclohexyl-pyrimidine skeleton; a GRA with a condensed azadecalin skeleton; a GRA with a heteroarylketone condensed azadecalin skeleton; and a GRA with an octahydro condensed azadecalin skeleton is administered at a daily dose of 10 mg / kg / day. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0252] (Example 37)

[0253] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 100 mg / kg / day, along with chemotherapy. The GRAs selected from those with a cyclohexyl-pyrimidine skeleton, GRAs with a condensed azadecalin skeleton, GRAs with a heteroarylketone condensed azadecalin skeleton, and GRAs with an octahydro condensed azadecalin skeleton are also administered. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0254] (Example 38)

[0255] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 50 mg / kg / day, along with chemotherapy. The GRAs selected from those with a cyclohexyl-pyrimidine skeleton, GRAs with a condensed azadecalin skeleton, GRAs with a heteroarylketone condensed azadecalin skeleton, and GRAs with an octahydro condensed azadecalin skeleton are also administered. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0256] (Example 39)

[0257] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 20 mg / kg / day, along with chemotherapy. The GRAs selected from those with a cyclohexyl-pyrimidine skeleton, GRAs with a condensed azadecalin skeleton, GRAs with a heteroarylketone condensed azadecalin skeleton, and GRAs with an octahydro condensed azadecalin skeleton are also administered. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0258] (Example 40)

[0259] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 15 mg / kg / day, along with chemotherapy. The GRAs selected from those with a cyclohexyl-pyrimidine skeleton, GRAs with a condensed azadecalin skeleton, GRAs with a heteroarylketone condensed azadecalin skeleton, and GRAs with an octahydro condensed azadecalin skeleton are also administered. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0260] (Example 41)

[0261] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 10 mg / kg / day, along with chemotherapy. The GRA selected from the following is used: a glucocorticoid receptor antagonist with a cyclohexyl-pyrimidine skeleton; a GRA with a condensed azadecalin skeleton; a GRA with a heteroarylketone condensed azadecalin skeleton; and a GRA with an octahydro condensed azadecalin skeleton. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0262] (Example 42)

[0263] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 50 mg / kg / day, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, along with an adrenergic antagonist. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0264] (Example 43)

[0265] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 20 mg / kg / day, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, along with an adrenergic antagonist. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0266] (Example 44)

[0267] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 15 mg / kg / day, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, along with an adrenergic antagonist. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0268] (Example 45)

[0269] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 10 mg / kg / day, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, along with an adrenergic antagonist. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0270] (Example 46)

[0271] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 50 mg / kg / day, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, along with chemotherapy and adrenergic antagonists. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0272] (Example 47)

[0273] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 50 mg / kg / day, along with somatostatin. The GRA selected from those with a cyclohexyl-pyrimidine skeleton, a condensed azadecalin skeleton, a heteroarylketone condensed azadecalin skeleton, and an octahydro condensed azadecalin skeleton is also administered. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0274] (Example 48)

[0275] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 20 mg / kg / day, along with somatostatin. The GRA selected from those with a cyclohexyl-pyrimidine skeleton, GRA with a condensed azadecalin skeleton, GRA with a heteroarylketone condensed azadecalin skeleton, and GRA with an octahydro condensed azadecalin skeleton is also administered. Measurements show that serum catecholamine levels 5 weeks after treatment are lower than initial levels.

[0276] (Example 49)

[0277] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 15 mg / kg / day, along with somatostatin. The GRA selected from those with a cyclohexyl-pyrimidine skeleton, GRA with a condensed azadecalin skeleton, GRA with a heteroarylketone condensed azadecalin skeleton, and GRA with an octahydro condensed azadecalin skeleton is also administered. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0278] (Example 50)

[0279] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 10 mg / kg / day, along with somatostatin. The GRA selected from those with a cyclohexyl-pyrimidine skeleton, GRA with a condensed azadecalin skeleton, GRA with a heteroarylketone condensed azadecalin skeleton, and GRA with an octahydro condensed azadecalin skeleton is also administered. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0280] (Example 51)

[0281] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 50 mg / kg / day, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, along with chemotherapy and somatostatin. Measurements show that serum catecholamine levels 5 weeks after treatment are lower than initial levels.

[0282] (Example 52)

[0283] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 50 mg / kg / day, along with a somatostatin analog. This GRA is selected from glucocorticoid receptor antagonists with a cyclohexyl-pyrimidine skeleton (GRA), GRA with a condensed azadecalin skeleton, GRA with a heteroarylketone condensed azadecalin skeleton, and GRA with an octahydro condensed azadecalin skeleton. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0284] (Example 53)

[0285] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 20 mg / kg / day, along with a somatostatin analog, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0286] (Example 54)

[0287] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 15 mg / kg / day, along with a somatostatin analog, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0288] (Example 55)

[0289] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 10 mg / kg / day, along with a somatostatin analog, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0290] (Example 56)

[0291] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 20 mg / kg / day, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, along with chemotherapy and somatostatin analogs. Measurements show that serum catecholamine levels 5 weeks after treatment are lower than initial levels.

[0292] (Example 57)

[0293] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 50 mg / kg / day with a glucocorticoid receptor antagonist (GRA) selected from those with a cyclohexyl-pyrimidine skeleton, GRA with a condensed azadecalin skeleton, GRA with a heteroarylketone condensed azadecalin skeleton, and GRA with an octahydro condensed azadecalin skeleton, along with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0294] (Example 58)

[0295] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 20 mg / kg / day with a glucocorticoid receptor antagonist (GRA) selected from those with a cyclohexyl-pyrimidine skeleton, GRA with a condensed azadecalin skeleton, GRA with a heteroarylketone condensed azadecalin skeleton, and GRA with an octahydro condensed azadecalin skeleton, along with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0296] (Example 59)

[0297] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 15 mg / kg / day with a glucocorticoid receptor antagonist (GRA) selected from those with a cyclohexyl-pyrimidine skeleton, GRA with a condensed azadecalin skeleton, GRA with a heteroarylketone condensed azadecalin skeleton, and GRA with an octahydro condensed azadecalin skeleton, along with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0298] (Example 60)

[0299] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 10 mg / kg / day with a glucocorticoid receptor antagonist (GRA) selected from those with a cyclohexyl-pyrimidine skeleton, GRA with a condensed azadecalin skeleton, GRA with a heteroarylketone condensed azadecalin skeleton, and GRA with an octahydro condensed azadecalin skeleton, along with peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0300] (Example 61)

[0301] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered at a daily dose of 50 mg / kg / day, selected from glucocorticoid receptor antagonists (GRAs) with a cyclohexyl-pyrimidine skeleton; GRAs with a condensed azadecalin skeleton; GRAs with a heteroarylketone condensed azadecalin skeleton; and GRAs with an octahydro condensed azadecalin skeleton, along with an adrenergic antagonist and further peptide receptor radionuclide therapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0302] (Example 62)

[0303] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, a single pharmaceutical composition containing mifepristone 300 mg and an adrenergic antagonist is administered daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0304] (Example 63)

[0305] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 100 mg and an adrenergic antagonist daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0306] (Example 64)

[0307] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, a single pharmaceutical composition containing mifepristone 300 mg and an adrenergic antagonist is administered daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0308] (Example 65)

[0309] In patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment, a single pharmaceutical composition containing mifepristone 300 mg and an adrenergic antagonist is administered daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0310] (Example 66)

[0311] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 100 mg and an adrenergic antagonist daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0312] (Example 67)

[0313] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 300 mg and an adrenergic antagonist daily for 5 weeks, along with chemotherapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0314] (Example 68)

[0315] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 100 mg and an adrenergic antagonist daily for 5 weeks, along with chemotherapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0316] (Example 69)

[0317] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 300 mg and an adrenergic antagonist daily for 5 weeks, along with chemotherapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0318] (Example 70)

[0319] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 100 mg and an adrenergic antagonist daily for 5 weeks, along with chemotherapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0320] (Example 71)

[0321] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 50 mg and an adrenergic antagonist daily for 5 weeks, along with chemotherapy. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0322] (Example 72)

[0323] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 300 mg and somatostatin daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0324] (Example 73)

[0325] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 100 mg and somatostatin daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0326] (Example 74)

[0327] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 50 mg and somatostatin daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0328] (Example 75)

[0329] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 300 mg and a somatostatin analog daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0330] (Example 76)

[0331] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 100 mg and a somatostatin analog daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0332] (Example 77)

[0333] Patients with metastatic or unresectable catecholamine-secreting tumors who do not require treatment with glucocorticoid receptor antagonists and have not received exogenous glucocorticoid receptor agonist treatment are administered a single pharmaceutical composition containing mifepristone 50 mg and a somatostatin analog daily for 5 weeks. Measurements show that blood catecholamine levels 5 weeks after treatment are lower than initial levels.

[0334] All references discussed in this application, including all patents, patent applications, and publications cited herein, are expressly incorporated by reference in their entirety. In certain embodiments, for example, the following items are provided: (Item 1) A method for reducing catecholamine excess in patients with catecholamine-secreting tumors, A method comprising administering an effective amount of a glucocorticoid receptor modulator to the patient. (Item 2) The method according to item 1, wherein the glucocorticoid receptor modulator is a glucocorticoid receptor antagonist that binds to type II glucocorticoid receptors with higher affinity than type I glucocorticoid receptors. (Item 3) The method according to item 1 or 2, wherein the glucocorticoid receptor modulator is administered at a daily dose between 1 and 1000 mg / kg / day. (Item 4) The method according to any one of items 1 to 3, wherein the glucocorticoid receptor modulator is mifepristone. (Item 5) The method according to any one of items 1 to 4, wherein the patient is not simultaneously administered an exogenous glucocorticoid receptor agonist. (Item 6) The method according to any one of items 1 to 5, wherein the patient is a patient with Cushing's syndrome, and the method is for treating Cushing's syndrome in the patient. (Item 7) A method for reducing catecholamine excess in a patient with a catecholamine-secreting tumor, comprising administering an effective amount of a glucocorticoid receptor modulator at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist. (Item 8) The method according to item 7, wherein the glucocorticoid receptor modulator is a glucocorticoid receptor antagonist that binds to type II glucocorticoid receptors with higher affinity than type I glucocorticoid receptors. (Item 9) The method according to item 7 or 8, wherein the glucocorticoid receptor modulator is administered at a daily dose between 1 and 1000 mg / kg / day. (Item 10) The method according to any one of items 7 to 9, wherein the glucocorticoid receptor modulator is mifepristone. (Item 11) The method according to item 10, wherein the daily dose of mifepristone is between 0.1 and 50 mg / kg / day for at least 5 weeks. (Item 12) The method according to any one of items 7 to 11, wherein the patient is not simultaneously administered an exogenous glucocorticoid receptor agonist. (Item 13) The method according to any one of items 7 to 12, wherein the patient is a patient with Cushing's syndrome, and the method is for treating Cushing's syndrome in the patient. (Item 14) A method for improving the effectiveness of chemotherapy in patients with catecholamine-secreting tumors, A method comprising administering an effective amount of a glucocorticoid receptor modulator to a patient undergoing chemotherapy for a catecholamine-secreting neuroendocrine tumor, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist. (Item 15) The method according to item 14, wherein the glucocorticoid receptor modulator is a glucocorticoid receptor antagonist that binds to the type II glucocorticoid receptor with higher affinity than the type I glucocorticoid receptor. (Item 16) The method according to item 14 or 15, wherein the glucocorticoid receptor modulator is administered at a daily dose between 1 and 1000 mg / kg / day. (Item 17) The method according to any one of items 14 to 16, wherein the glucocorticoid receptor modulator is mifepristone. (Item 18) The method according to any one of items 14 to 17, wherein the patient is not concurrently administered an exogenous glucocorticoid receptor agonist. (Item 19) The method according to any one of items 14 to 18, wherein the patient is a patient with Cushing's syndrome, and the method is for treating Cushing's syndrome in the patient. (Item 20) A method for improving the effectiveness of alpha and beta-adrenergic receptor blockade in patients with catecholamine-secreting tumors, A method comprising administering an effective amount of a glucocorticoid receptor modulator to a patient who has received an alpha-adrenergic receptor blocker, a beta-adrenergic receptor blocker, or both, for the treatment of a catecholamine-secreting neuroendocrine tumor, at a daily dose between 0.1 and 100 mg / kg / day for at least 5 weeks, wherein the patient does not require any further treatment with a glucocorticoid receptor antagonist. (Item 21) The method according to item 20, wherein the glucocorticoid receptor modulator is a glucocorticoid receptor antagonist that binds to type II glucocorticoid receptors with higher affinity than type I glucocorticoid receptors. (Item 22) The method according to item 20 or 21, wherein the glucocorticoid receptor modulator is administered at a daily dose between 1 and 1000 mg / kg / day. (Item 23) The method according to any one of items 20 to 22, wherein the glucocorticoid receptor modulator is mifepristone. (Item 24) The method according to any one of items 20 to 23, wherein the patient is not concurrently administered an exogenous glucocorticoid receptor agonist. (Item 25) The method according to any one of items 20 to 24, wherein the patient is a patient with Cushing's syndrome, and the method is for treating Cushing's syndrome in the patient. (Item 26) A method for improving the efficacy of somatostatin analogs in patients with catecholamine-secreting neuroendocrine tumors, A method comprising administering an effective amount of a glucocorticoid receptor modulator to the patient, wherein a somatostatin analog is administered to the patient to treat a catecholamine-secreting neuroendocrine tumor in the patient, and the patient does not require any further treatment with a glucocorticoid receptor antagonist. (Item 27) The method according to item 26, wherein the glucocorticoid receptor modulator is a glucocorticoid receptor antagonist. (Item 28) The method according to item 26 or 27, wherein the glucocorticoid receptor modulator is mifepristone. (Item 29) The method according to any one of items 26 to 28, wherein the patient is not concurrently administered an exogenous glucocorticoid receptor agonist. (Item 30) The method according to any one of items 26 to 29, wherein the patient is a patient with Cushing's syndrome, and the method is for treating Cushing's syndrome in the patient.

Claims

[Claim 1] A composition comprising mifepristone as described in the specification.

Images