EP-4736953-A2 - THERAPEUTIC AGENTS AND METHODS

Abstract

The invention provides glucocorticoid receptor antagonists for treatment of infection, neoplasia , and fatty liver disease.

Inventors

• ALTSCHUL, RANDICE LISA
• THEISE, NEIL DAVID
• KESEL, ANDREAS J.
• RAPKIN, MYRON
• O'BRIEN, REBECCA
• ARMENT, ANTHONY R.

Assignees

• Pop Test Oncology LLC

Dates

Publication Date

20260506

Application Date

20171003

Claims (15)

1. A compound selected from the group consisting of: - PT162, or a pharmaceutically acceptable salt thereof; - PT163, or a pharmaceutically acceptable salt thereof; - PT164, or a pharmaceutically acceptable salt thereof; - PT165, or a pharmaceutically acceptable salt thereof; - PT166, or a pharmaceutically acceptable salt thereof; - PT167, or a pharmaceutically acceptable salt thereof, - TCY1, or a pharmaceutically acceptable salt thereof - KM-1, or a pharmaceutically acceptable salt thereof; and combinations thereof.
2. A pharmaceutical composition comprising a therapeutically effective amount of at least one active agent, wherein the active agent is selected from the group consisting of: PT162, PT163, PT164, PT165, PT166, PT167, OR-1, MR-1, TCY1, PT150, and pharmaceutically acceptable salts thereof, or a combination thereof; and at least one pharmaceutically acceptable excipient.
3. The pharmaceutical composition of claim 2 in a dosage form selected from the group consisting of a minicapsule, a capsule, a tablet, an implant, a troche, a lozenge, a minitablet, a temporary or permanent suspension, an injectable, an ovule, a suppository, a wafer, a chewable tablet, a quick or fast dissolving tablet, an effervescent tablet, a buccal or sublingual solid, a granule, a film, a sprinkle, a pellet, a topical formulation, a patch, a bead, a pill, a powder, a triturate, a smart pill, a smart capsule, a platelet, a strip, and a sachet.
4. The pharmaceutical composition of claim 2 in a dosage form for topical application, and at least one pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 2 in a dosage form for topical application wherein said formulation is in a form selected from the group consisting of: cream, lotion, gel, oil, ointment, suppository, spray, foam, liniment, aerosol, buccal and sublingual tablet or a transdermal device or patch for absorption through the skin or mucous membranes.
6. A kit for treating or preventing a condition in a patient, the kit comprising: (a) the pharmaceutical composition of any one of claims 2 to 5 in a therapeutically effective amount; and (b) at least one blister package; a lidded blister; a blister card or packet; a clamshell; an intravenous (IV) package, IV packette or IV container; a tray or a shrink wrap comprising the pharmaceutical composition.
7. An active agent selected from the group consisting of PT162, PT163, PT164, PT165, PT166, PT167, TPR-1, OR-1, MR-1, TCY1, PT150, PT155, PT156, PT157, PT158, PT159, PT160, and pharmaceutically acceptable salts thereof, or a combination thereof, for use in a method of treating and/or preventing neoplasia in a patient, wherein the neoplasia prevented or treated is selected for the group consisting of hepatocellular carcinoma, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, squamous cell cancer or adenocarcinoma of the head and neck, colorectal cancer, renal cancer, brain cancer, prostate cancer, small and non-small cell lung cancer, bladder cancer, bone or joint cancer, uterine cancer, cervical cancer, multiple myeloma, hematopoietic malignancies, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, skin cancer, melanoma, squamous cell carcinoma, leukemia, lung cancer, ovarian cancer, stomach cancer, Kaposi's sarcoma, laryngeal cancer, endocrine carcinomas, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the pituitary gland, cancer of the adrenal gland, and combinations thereof.
8. The active agent or combination for use of claim 7, wherein the neoplasia is chemo-resistant ER/GR+ breast cancer.
9. The active agent or combination for use of claim 7 or claim 8, wherein the administration of the active agent or combination reduces toxicities and side effects when given systemically.
10. The active agent or combination for use of any one of claims 7 to 9, wherein the active agent or comnbination is given systemically through oral or intravenous routes.
11. The active agent or combination for use of any one of claims 7 to 10, wherein the active agent or combination is targeted to tumor by intra-arterial infusion to reduce systemic side effects of GR blockade.
12. The active agent or combination for use of any one of claims 7 to 11, wherein the active agent or combination is given to accomplish cure or remission of tumor.
13. The active agent or combination for use of any one of claims 7 to 12, wherein the active agent or combination is given to accomplish reduction of tumor burden to enhance effectiveness of subsequent surgical resection.
14. The active agent or combination for use of any one of claims 7 to 13, wherein the active agent or combination is given to accomplish reduction of tumor burden to make an unresectable tumor resectable.
15. The active agent or combination for use of any one of claims 7 to 14, wherein the neoplasia is hepatocellular carcinoma (HCC).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benfit under 35 USC § 119(e) of U.S. Provisonal Patent Application No. 62/404,036, filed October 4, 2016; U.S. Provisonal Patent Application No.62/412,414, filed October 25, 2016; U.S. Provisonal Patent Application No.62/433,988, filed December 14, 2016; U.S. Provisonal Patent Application No. 62/440,636, filed December 30, 2016; U.S. Provisonal Patent Application No. 62/441,076, filed December 30, 2016; U.S. Provisonal Patent Application No. 62/420,578, filed November 11, 2016; U.S. Provisonal Patent Application No.62/442,478, filed January 5, 2017; U.S. Provisonal Patent Application No. 62/449,195, filed January 23, 2017; U.S. Provisonal Patent Application No. 62/474,738, filed March 22, 2017; U.S. Provisonal Patent Application No.62/501,811, filed May 5, 2017; U.S. Provisonal Patent Application No. 62/517,289, filed June 9, 2017; the disclosures of which are incorporated herein by reference in their entireties. BACKGROUND OF THE INVENTION Two categories of diseases affect plants and animals and have significant costs in terms of societal function, economics, and health and well-being: neoplasia and infection. Neoplasia is the abnormal growth of tissues from epigenetic or genetic changes in once normal cells which then produce benign or malignant proliferations, mass forming, or more generally spreading patterns, or both. Infections involve the invasion of a plant or animal by microorganisms such as bacteria, viruses, fungi, yeasts and parasites which then, with multiplication, lead to disease/injury. Together, these easily comprise the majority of human diseases requiring clinical care and attention, diseases involving animals (inclusive of pets and livestock), and diseases of plants, both decorative and agricultural. The most common treatments of infections involve anti-microbial compounds given locally, topically, or systemically. Neoplasia may be treated surgically, chemotherapeutically, radiotherapeutically or, more recently, through manipulation of the immune system. This application covers a set of compounds that function as anti-microbial therapeutic agents or as anti-neoplastic agents or as both. They may function as single agents, paired together in combinations of two or three or more, or in combination with unrelated compounds, also in combinations of two or three or more. The invention provides glucocorticoid receptor antagonists for treatment of infection, neoplasia, and fatty liver disease. For example, the molecules PT150, PT155, PT156 and PT157 are potent glucocorticoid receptor (GR) antagonists. PT150 is a steroidal hormone with high binding affinity for the human GR and comparatively low affinities for other hormonal receptors (e.g. progesterone, estrogen, mineralocorticoid, androgen). Its binding yields significant biological antagonism. PT155, PT156 and PT157 are varying organization of the PT150 molecule with a phenylsemithiocarbazone modification - this modification can lead to binding to other PT150 molecules or co-crystallization with them. All these compounds, PT150 and its derivatives, have some degree of anti-bacterial, anti-viral, anti-fungal and anti-neoplastic affects, relating to the ubiquity of cortisol or cortisol-like receptor binding in mammals (human and non-human) and in pathogens which have evolved to exploit the cortisol "stress hormone" response to infection and resultant inflammation. (Reynolds AR Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic-pituitary-adrenal axis activation. Drug Alcohol Depend. 2015 Sep 1;154:100-4). In particular, binding of these compounds to form GR-compound complexes which then bind to glucocorticoid response elements in viral genomes leads to inactivation or suppression of viral gene function and, thereby, to inhibition of viral physiology, including inactivation of viral replication, viral encoating, viral shedding and elimination of pro-virus of chronic latent viral infections. Other mechanisms for viral suspicion are suspected to include binding to cytoplasmic molecules important for processing and shepherding of viral particles. In addition, the GR antagonists (PT150, PT155, PT156 and PT157) also affect non-alcoholic fatty liver disease (NAFLD), a progressive chronic disease in the setting of metabolic syndrome (indicated by obesity, diabetes mellitus, hyperlipidemia, and hypertension). Hepatic metabolic dysfunction in this setting has been shown to be related to GR modulation of Hes1 gene expression. The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene. Genetic restoration of hepatic Hes1 levels in steatotic animals normalizes hepatic triglyceride (TG) levels. Increased glucocorticoid action leads to inhibition of Hes1 and may be a central mediator in the