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IL280812B - Lyophilized preparation of cytotoxic dipeptides - Google Patents

Lyophilized preparation of cytotoxic dipeptides

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Publication number
IL280812B
IL280812B IL280812A IL28081221A IL280812B IL 280812 B IL280812 B IL 280812B IL 280812 A IL280812 A IL 280812A IL 28081221 A IL28081221 A IL 28081221A IL 280812 B IL280812 B IL 280812B
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IL
Israel
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group
independently selected
ring
hydrogen
alkyl
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IL280812A
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Hebrew (he)
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IL280812B2 (en
IL280812A (en
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Oncopeptides Ab
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Application filed by Oncopeptides Ab filed Critical Oncopeptides Ab
Priority claimed from PCT/EP2012/057577 external-priority patent/WO2012146625A1/en
Publication of IL280812A publication Critical patent/IL280812A/en
Publication of IL280812B publication Critical patent/IL280812B/en
Publication of IL280812B2 publication Critical patent/IL280812B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A61K38/105—Bombesin; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Emergency Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

FIELD AND BACKGROUND OF THE INVENTION 49 CLAIMED IS: 1. A lyophilized pharmaceutical preparation comprising (i) melphalan flufenamide, or a pharmaceutically acceptable salt thereof; and (ii) Trehalose. 2. A lyophilized pharmaceutical preparation according to claim 1, wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1). 3. A lyophilized pharmaceutical preparation according to claim 1 or 2, wherein the Trehalose has surfactant properties. 4. A lyophilized pharmaceutical preparation according to any one of claims 1-3, wherein the amount of Trehalose is about 10-100 % by weight of said melphalan flufenamide.
. A lyophilized pharmaceutical preparation according to claim 4, wherein the amount of the Trehalose is 10-50 % by weight of said melphalan flufenamide. 6. A lyophilized pharmaceutical preparation according to any one of claims 1-5, further comprising a physiologically acceptable solution. 7. A lyophilized pharmaceutical preparation according to claim 6, wherein said physiologically acceptable solution is a glucose solution. 8. A lyophilized pharmaceutical preparation according to claim 8, wherein the amount of glucose is 4.5-5.5 % by weight of the lyophilized preparation. 9. A lyophilized pharmaceutical preparation according to any one of claims 1-8, which is free, or substantially free from organic solvents.
. A kit of parts combination comprising (i) a lyophilized pharmaceutical preparation according to any one of claims 1-9; and (ii) a physiologically acceptable solution. 02785804\37-01 50 11. A kit of parts combination according to claim 10, wherein the physiologically acceptable solution is a glucose solution. 12. A kit of parts combination according to claim 11, wherein the amount of glucose is 4.5-5.5 % by weight. 13. A lyophilized pharmaceutical preparation according to any one of claims 1-9, for use as a medicament. 14. A lyophilized pharmaceutical preparation according to any one of claims 1-9, for use in the treatment and/or prevention of cancer.
. A lyophilized pharmaceutical preparation according to claim 14, wherein said cancer is any one of ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer or hematological cancer. 16. A kit of parts combination according to any one of claims 10-12, for use in the treatment of cancer. 17. A kit of parts combination according to claim 16, wherein said cancer is any one of ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer or hematological cancer. 18. A method for preparing a lyophilized pharmaceutical preparation according to any one of claims 1-9, whereby: a. melphalan flufenamide, or a pharmaceutically acceptable salt thereof, is dissolved in an organic solvent to obtain a melphalan flufenamide solution; b. water is added to the melphalan flufenamide solution in order to obtain an aqueous melphalan flufenamide solution, in a concentration of about 0.2-3.0 mg/ml; c. Trehalose is added to the melphalan flufenamide solution; and d. the aqueous melphalan flufenamide solution containing Trehalose is subjected to lyophilization. 19. A method according to claim 18, wherein the organic solvent is selected from any one of ethanol, ethanol containing acid, glycerin, propylene glycol, benzyl alcohol, 02785804\37-01 51 dimethylacetamide (DMA), N-methyl-2-pyrrolidone, isopropanol, n-butanol, tert­ butanol, methyl tert-butyl ether, propylene glycol, dimethylsulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, acetone, dimethylformamide, acetonitrile, dioxane, acetic acid, lactic acid, propionic acid, n-butanol, isopropanol, n-propanol, tert-butanol, sec-butanol, methanol, and a mixture of ethanol and water.
. A method according to claim 18 or 19, wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1). 21. A method according to any one of claims 18-20, wherein the organic solvent is ethanol. 22. Trehalose for use in a in a lyophilized preparation of melphalan flufenamide, or a pharmaceutically acceptable salt thereof, for decreasing the reconstitution time of the lyophilized preparation of melphalan flufenamide, or a pharmaceutically acceptable salt thereof, when reconstituted in an aqueous solvent. 23. The trehalose for use according to claim 22, wherein said melphalan flufenamide, or a pharmaceutically acceptable salt thereof, is melphalan flufenamide hydrochloride (J1). 24. The trehalose for use according to claim 22 or 23, wherein said melphalan flufenamide, or a pharmaceutically acceptable salt thereof, is dissolved in ethanol prior to subjecting said melphalan flufenamide to said excipient.
For the Applicants, BEINHOLD COHN AND PARTNERS 02785804\37-01 DynamicPDF for .NET v8.0.0.40 (Build 29393)

Claims (20)

CLAIMED IS:
1. A combination therapy comprising an effective amount of a chemotherapeutic agent and a nonsteroidal selective glucocorticoid receptor antagonist (SGRA), wherein said nonsteroidal selective glucocorticoid receptor antagonist binds to a glucocorticoid receptor (GR) and inhibits any biological response associated with the binding of the glucocorticoid receptor to an agonist, wherein said nonsteroidal selective glucocorticoid receptor antagonist preferentially binds to the glucocorticoid receptor rather than the progesterone receptor (PR), the mineralocorticoid receptor (MR) or the androgen receptor (AR), wherein the chemotherapeutic agent is selected from the group consisting of taxanes, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducing agents, antimetabolites, mitotic inhibitors and combinations thereof, the combination therapy being for use in treating a subject hosting a non-adrenocorticotrophic hormone (ACTH)-secreting pancreatic tumor, and is being for reducing the tumor load of the pancreatic tumor.
2. The combination therapy of claim 1, wherein said non- adrenocorticotrophic hormone (ACTH)-secreting pancreatic tumor is an exocrine pancreatic tumor.
3. The combination therapy of claim 1, wherein the chemotherapeutic agent is a taxane.
4. The combination therapy of claim 1, wherein the chemotherapeutic agent is selected from the group consisting of nab-paclitaxel, 5-fluorouracil (5-FU), gemcitabine, cisplatin and capecitabine.
5. The combination therapy of any of claims 1-4, wherein the nonsteroidal selective glucocorticoid receptor antagonist is a compound comprising a fused azadecalin structure.
6. The combination therapy of claim 5, wherein the nonsteroidal selective glucocorticoid receptor antagonist compound comprising a fused azadecalin structure is a compound having the following formula: 53 265217/5 1 R 1 L 2 2 L R N N N 5 R wherein 1 2 L and L are members independently selected from a bond and unsubstituted alkylene; 1 R is a member selected from unsubstituted alkyl, unsubstituted heteroalkyl, 1A 1C 1D 1C 1D 1A unsubstituted heterocycloalkyl, -OR , NR R , -C(O)NR R , and -C(O)OR , wherein 1A R is a member selected from hydrogen, unsubstituted alkyl and unsubstituted heteroalkyl, 1C 1D R and R are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl, 1C 1D wherein R and R are optionally joined to form an unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen; 2 has the formula: R 2G R t J X wherein 2G R is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, -CN, and -CF ; 3 J is phenyl; t is an integer from 0 to 5; X is -S(O )-; and 2 5 5A R is phenyl optionally substituted with 1-5 R groups, wherein 5A 5A1 5A2 5A3 R is a member selected from hydrogen, halogen, -OR , S(O )NR R , - 2 CN, and unsubstituted alkyl, wherein 5A1 R is a member selected from hydrogen and unsubstituted alkyl, and 5A2 5A3 R and R are members independently selected from hydrogen and unsubstituted alkyl, or salts thereof. 54 265217/5
7. The combination therapy of claim 5, wherein the nonsteroidal selective glucocorticoid receptor antagonist compound comprising a fused azadecalin structure is: O O O S N N N CF 3 F .
8. The combination therapy of claim 1, wherein the nonsteroidal selective glucocorticoid receptor antagonist is a compound comprising a heteroaryl ketone fused azadecalin structure or an octahydro fused azadecalin structure.
9. The combination therapy of claim 8, wherein the nonsteroidal selective glucocorticoid receptor antagonist is a compound comprising a heteroaryl ketone fused azadecalin structure having the formula: 1 R O O O S 2 - N CH n J R ( ) 2 ( )1 4 N N 3 R wherein 1 R is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally 1a substituted with 1-4 groups each independently selected from R ; 1a each R is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C haloalkyl, C alkoxy, C haloalkoxy, CN, N-oxide, C cycloalkyl, and 1-6 1-6 1-6 3-8 C heterocycloalkyl; 3-8 ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S; 55 265217/5 2 each R is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C haloalkyl, C alkoxy, C haloalkoxy, C alkyl-C alkoxy, CN, OH, 1 6 1 6 1-6 1-6 1-6 2a 2b 2a 2a 2a 2b 2a 2a 2a NR R , C(O)R , C(O)OR , C(O)NR R , SR , S(O)R , S(O) R , C cycloalkyl, and C 2 3-8 3- 2c 8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R groups; 2 alternatively, two R groups linked to the same carbon are combined to form an oxo group (=O); 2 alternatively, two R groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally 2d groups; substituted with from 1 to 3 R 2a 2b R and R are each independently selected from the group consisting of hydrogen and C alkyl; 1-6 2c each R is independently selected from the group consisting of hydrogen, 2a 2b halogen, hydroxy, C alkoxy, C haloalkoxy, CN, and NR R ; 1-6 1-6 2d each R is independently selected from the group consisting of hydrogen and 2d C alkyl, or two R groups attached to the same ring atom are combined to form (=O); 1-6 3 R is selected from the group consisting of phenyl and pyridyl, each optionally 3a substituted with 1-4 R groups; 3a each R is independently selected from the group consisting of hydrogen, halogen, and C haloalkyl; and 1-6 subscript n is an integer from 0 to 3; or salts thereof. 56 265217/5
10. The combination therapy of claim 8, wherein the nonsteroidal selective glucocorticoid receptor antagonist is a compound comprising a heteroaryl ketone fused azadecalin structure having the formula: N O O O F C 3 S N N N N N F .
11. The combination therapy of claim 8, wherein the nonsteroidal selective glucocorticoid receptor antagonist compound comprising an octahydro fused azadecalin structure has the formula: 1 R O O O S N 2 - J R N ( ) 1 4 N a 3 R n ( ) wherein 1 R is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1a 1-4 groups each independently selected from R ; 1a each R is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C haloalkyl, C alkoxy, C haloalkoxy, N-oxide, and C cycloalkyl; 1-6 1-6 1-6 3-8 ring J is selected from the group consisting of an aryl ring and a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S; 2 each R is independently selected from the group consisting of hydrogen, C alkyl, 1-6 2a 2b halogen, C haloalkyl, C alkoxy, C haloalkoxy, C alkyl-C alkoxy, CN, OH, NR R , 1-6 1-6 1-6 1-6 1-6 57 265217/5 2a 2a 2a 2b 2a 2a 2a C(O)R , C(O)OR , C(O)NR R , SR , S(O)R , S(O) R , C cycloalkyl, and C 2 3-8 3-8 heterocycloalkyl having from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S; 2 alternatively, two R groups on adjacent ring atoms are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring 2c is optionally substituted with from 1 to 3 R groups; 2a 2b 2c R , R and R are each independently selected from the group consisting of hydrogen and C alkyl; 1-6 3a each R is independently halogen; and subscript n is an integer from 0 to 3, or salts thereof.
12. The combination therapy of claim 8, wherein the nonsteroidal selective glucocorticoid receptor antagonist is the compound comprising an octahydro fused azadecalin which has the following structure: N O O O F C 3 N S N N N N N H F .
13. A pharmaceutical composition for use in combination with a chemotherapeutic agent in treating a non- adrenocorticotrophic hormone (ACTH)-secreting pancreatic tumor, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a nonsteroidal glucocorticoid receptor antagonist compound comprising a fused azadecalin structure. 58 265217/5
14. The pharmaceutical composition for use of claim 13, wherein the nonsteroidal selective glucocorticoid receptor antagonist compound comprising a fused azadecalin structure is a compound having the following formula: 1 R 1 L 2 2 L R N N N 5 R wherein 1 2 L and L are members independently selected from a bond and unsubstituted alkylene; 1 R is a member selected from unsubstituted alkyl, unsubstituted heteroalkyl, 1A 1C 1D 1C 1D 1A unsubstituted heterocycloalkyl, -OR , NR R , -C(O)NR R , and -C(O)OR , wherein 1A R is a member selected from hydrogen, unsubstituted alkyl and unsubstituted heteroalkyl, 1C 1D R and R are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl, 1C 1D wherein R and R are optionally joined to form an unsubstituted ring with the nitrogen to which they are attached, wherein said ring optionally comprises an additional ring nitrogen; 2 R has the formula: 2G R t X J wherein 2G R is a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, -CN, and - CF ; 3 J is phenyl; t is an integer from 0 to 5; X is -S(O )-; and 2 5 5A R is phenyl optionally substituted with 1-5 R groups, wherein 59 265217/5 5A 5A1 5A2 5A3 R is a member selected from hydrogen, halogen, -OR , S(O )NR R , -CN, 2 and unsubstituted alkyl, wherein 5A1 R is a member selected from hydrogen and unsubstituted alkyl, and 5A2 5A3 R and R are members independently selected from hydrogen and unsubstituted alkyl, or salts thereof.
15. The pharmaceutical composition for use of claim 13, wherein the nonsteroidal selective glucocorticoid receptor antagonist compound comprising a fused azadecalin structure is: O O O S N N N F C 3 F .
16. The pharmaceutical composition for use of claim 13, wherein the nonsteroidal selective glucocorticoid receptor antagonist is a compound comprising a heteroaryl ketone fused azadecalin structure or an octahydro fused azadecalin structure.
17. The pharmaceutical composition for use of claim 16, wherein the nonsteroidal selective glucocorticoid receptor antagonist is a compound comprising a heteroaryl ketone fused azadecalin structure having the formula: 1 R O O O S 2 - N CH n J R ( ) 2 ( )1 4 N N 3 R wherein 60 265217/5 1 R is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1a 1-4 groups each independently selected from R ; 1a each R is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C haloalkyl, C alkoxy, C haloalkoxy, CN, N-oxide, C cycloalkyl, and C 1-6 1-6 1-6 3-8 3- heterocycloalkyl; 8 ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroaryl ring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S; 2 each R is independently selected from the group consisting of hydrogen, C alkyl, 1-6 2a 2b halogen, C haloalkyl, C alkoxy, C haloalkoxy, C alkyl-C alkoxy, CN, OH, NR R , 1 6 1 6 1-6 1-6 1-6 2a 2a 2a 2b 2a 2a 2a C(O)R , C(O)OR , C(O)NR R , SR , S(O)R , S(O) R , C cycloalkyl, and C 2 3-8 3-8 2c heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 1-4 R groups; 2 alternatively, two R groups linked to the same carbon are combined to form an oxo group (=O); 2 alternatively, two R groups are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with from 1 2d to 3 R groups; 2a 2b R and R are each independently selected from the group consisting of hydrogen and C alkyl; 1-6 2c each R is independently selected from the group consisting of hydrogen, halogen, 2a 2b hydroxy, C alkoxy, C haloalkoxy, CN, and NR R ; 1-6 1-6 2d each R is independently selected from the group consisting of hydrogen and C 1-6 2d alkyl, or two R groups attached to the same ring atom are combined to form (=O); 3 R is selected from the group consisting of phenyl and pyridyl, each optionally 3a substituted with 1-4 R groups; 3a each R is independently selected from the group consisting of hydrogen, halogen, and C haloalkyl; and 1-6 61 265217/5 subscript n is an integer from 0 to 3; or salts thereof.
18. The pharmaceutical composition for use of claim 16, wherein the nonsteroidal selective glucocorticoid receptor antagonist is a compound comprising a heteroaryl ketone fused azadecalin having the formula: N O O O F C 3 S N N N N N F .
19. The pharmaceutical composition for use of claim 16, wherein the nonsteroidal selective glucocorticoid receptor antagonist is a compound comprising an octahydro fused azadecalin structure having the formula: 1 R O O O S N 2 - J R N ( )1 4 N a 3 R n ( ) wherein 1 R is a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1a 1-4 groups each independently selected from R ; 1a each R is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, C haloalkyl, C alkoxy, C haloalkoxy, N-oxide, and C cycloalkyl; 1-6 1-6 1-6 3-8 ring J is selected from the group consisting of an aryl ring and a heteroaryl ring having from 5 to 6 ring members and from 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S; 62 265217/2 2 each R is independently selected from the group consisting of hydrogen, C alkyl, 1-6 2a 2b halogen, C haloalkyl, C alkoxy, C haloalkoxy, C alkyl-C alkoxy, CN, OH, NR R , 1-6 1-6 1-6 1-6 1-6 2a 2a 2a 2b 2a 2a 2a C(O)R , C(O)OR , C(O)NR R , SR , S(O)R , S(O) R , C cycloalkyl, and C 2 3-8 3-8 heterocycloalkyl having from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S; 2 alternatively, two R groups on adjacent ring atoms are combined to form a heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring 2c is optionally substituted with from 1 to 3 R groups; 2a 2b 2c R , R and R are each independently selected from the group consisting of hydrogen and C alkyl; 1-6 3a each R is independently halogen; and subscript n is an integer from 0 to 3, or salts thereof.
20. The pharmaceutical composition for use of claim 16, wherein the nonsteroidal selective glucocorticoid receptor antagonist is the compound comprising an octahydro fused azadecalin having the formula: N O O O F C 3 N S N N N N N H F . Dr. Revital Green Patent Attorney G.E. Ehrlich (1995) Ltd. 35 HaMasger Street, 13th Floor, Sky Tower 6721407 Tel Aviv
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