WO2018157232A1 - Compositions et combinaisons pharmaceutiques comprenant des inhibiteurs du récepteur d'androgène et leurs utilisations - Google Patents

Compositions et combinaisons pharmaceutiques comprenant des inhibiteurs du récepteur d'androgène et leurs utilisations Download PDF

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Publication number
WO2018157232A1
WO2018157232A1 PCT/CA2018/000039 CA2018000039W WO2018157232A1 WO 2018157232 A1 WO2018157232 A1 WO 2018157232A1 CA 2018000039 W CA2018000039 W CA 2018000039W WO 2018157232 A1 WO2018157232 A1 WO 2018157232A1
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prostate cancer
cancer
composition
pharmaceutically acceptable
acid
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PCT/CA2018/000039
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English (en)
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Marianne D. Sadar
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British Columbia Cancer Agency Branch
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    • 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
    • A61K38/08—Peptides having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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    • A61K31/12—Ketones
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    • 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, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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    • 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
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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    • C07C69/12—Acetic acid esters
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • This disclosure relates to therapeutic compounds and compositions thereof, as well as methods for the treatment of various indications, including cancer.
  • the disclosed compounds and compositions thereof find utility in therapy applications for treatment of prostate cancers including, but not limited to, primary/localized prostate cancer (newly diagnosed), locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
  • the compounds and compositions of the present disclosure can be useful in neoadjuvant and adjuvant therapies for various androgen-mediated or androgen-related diseases or conditions as well as in combination with different therapies, such as androgen ablation therapy.
  • the AR can be activated in the absence of androgen by stimulation of the cAMP-dcpcndcnt protein kinase (PKA) pathway, with interleukin-6 (1L-6) and by various growth factors (Culig et al. 1994 Cancer Res. 54, 5474-5478; Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; Sadar 1999 J. Biol. Chem. 21 A, 7777- 7783; Ueda et al 2002 A J. Biol. Chem. 211, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094).
  • PKA cAMP-dcpcndcnt protein kinase
  • compositions described herein can also be used to modulate the androgen receptor activity either in vivo or in vitro for both research and therapeutic uses.
  • the pharmaceutical compositions can be used in an effective amount so that androgen receptor activity can be modulated.
  • the androgen receptor can be mammalian.
  • the androgen receptor can be human.
  • the pharmaceutical compositions can be used to inhibit transactivau ' on of the AR N-tcrmmal domain (NTD).
  • composition comprising a compound having the structure of one or more of Formulae (I), (II), ( ⁇ ), (TV), (V), (VI), (VII), (VIII), (IX), or (X):
  • FIGS. 2A-F show inhibition of Pinl by compounds blocks AR transcriptional activity.
  • FIGS. 3A-I show Pinl interacts with the AR NTD and regulates transactivation.
  • the inhibitor of Pin 1 is a peptide.
  • the peptide is selected from: CRYPEVE1C, wherein the cysteine residues of said peptide are cyclized by a disulfide bond (SEQ ID NO: 1); Ac-Lys(N- biotinoyl>Ah-AU-Bth-I>Thr(P03H2)-Pip-Nal-Gln-NH2 (SEQ ID NO: 2); Ac-Phe-D- Thr(P03H2>Pip-Nal-Gln-NH2 (SEQ ID NO: 3); and Ac-Phe-Phe-pSer-T[(Z)CHdC-Pro-Arg- N3 ⁇ 4 (SEQ ID NO: 4).
  • Prodrugs can be prepared, for example, and without limitation, by converting appropriate functional groups (for example, a carboxylic acid functional group -COOH, an alcohol functional group - OH, or primary or secondary amine functional group) in the compounds as described herein with suitable moieties. Suitable moieties would be understood to and can be determined by those of ordinary skill in the art.
  • a prodrug can be formed by converting a primary or secondary amino functionality to an amide functionality.
  • a prodrug can be formed by converting a carboxylic acid functionality to an ester functionality, or converting an alcohol functionality to an ether functionality.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the disclosure.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation of pharmaceutical composition can be a self-emulsifying drug delivery system or a sclf- microemulsifying drug delivery system.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • a liquid or solid filler such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the disclosure, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the disclosure
  • the formulations arc prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure.
  • Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697, and 2005/004074; and U.S. Patent No. 6,583,124, the contents of which arc incorporated herein by reference.
  • liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids.
  • Some compounds and compositions of this disclosure can inhibit Rl 881 only and can interfere with a mechanism specific to ligand-dependent activation (e.g., accessibility of the ligand binding domain (LBD) to androgen).
  • Pin 1 Several known inhibitors of Pin I were tested in cell-based assays that measure proliferation or transcription mediated by AR. The results demonstrated that inhibition of Pin 1 interrupted the function of the AR NTD.
  • the Pin I inhibitor juglpne effectively and specifically blocked transcription mediated by AR induced by androgen, as well as transactivauon of the AR NTD in the presence of IL-6. It was found that Pin 1 predominantly interacted with a specific region of the AR NTD containing two Pin 1 binding sites, and by inhibiting Pin 1 the interactions between endogenous AR and STAT3 became attenuated. Furthermore, Pin 1 inhibitors were more effective than second-generation antiandrogens In blocking androgen-independent proliferation of LNCaP95 cells driven by AR variants. Without being bound by any one particular theory, Pin 1 seems to be a critical factor for transcription mediated by AR, regardless of ligand, by regulating the AR NTD.
  • FIG. 18B shows the dose-response of EPI-002 inhibition of androgen (R1881)-induced PSA-hiciferase activity in the presence of NAC (10 mM).
  • LNCap human prostate cancer cells were transiently transfected with the PSA(6.1kb)-luciferase reporter gene construct Bars represent the mean of 3 independent experiments each with 4 technical replicates per condition per experiment. The mean relative luciferase units/mg protein/minute was normalized to the control to determine fold-induction.

Abstract

L'invention concerne des compositions comprenant des modulateurs de l'activation N-terminale du récepteur d'androgène, tels que EPI-002 et EPI-506 et un second agent thérapeutique. L'invention concerne également l'utilisation de telles compositions pour le traitement de diverses indications, en particulier le cancer de la prostate.
PCT/CA2018/000039 2017-02-28 2018-02-28 Compositions et combinaisons pharmaceutiques comprenant des inhibiteurs du récepteur d'androgène et leurs utilisations WO2018157232A1 (fr)

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US201762581477P 2017-11-03 2017-11-03
US201762581336P 2017-11-03 2017-11-03
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WO2020198712A1 (fr) * 2019-03-28 2020-10-01 Essa Pharma, Inc. Compositions et combinaisons pharmaceutiques comprenant des inhibiteurs du récepteur des androgènes et utilisations de celles-ci
US11242324B2 (en) 2020-04-17 2022-02-08 Essa Pharma, Inc. Solid forms of an n-terminal domain androgen receptor inhibitor and uses thereof
US11485713B2 (en) 2018-05-25 2022-11-01 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
US11779550B2 (en) 2015-03-12 2023-10-10 The University Of British Columbia Bisphenol ether derivatives and methods for using the same
US11919874B2 (en) 2016-04-15 2024-03-05 The University Of British Columbia Bisphenol derivatives and their use as androgen receptor activity modulators

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US11919874B2 (en) 2016-04-15 2024-03-05 The University Of British Columbia Bisphenol derivatives and their use as androgen receptor activity modulators
US11485713B2 (en) 2018-05-25 2022-11-01 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
WO2020198712A1 (fr) * 2019-03-28 2020-10-01 Essa Pharma, Inc. Compositions et combinaisons pharmaceutiques comprenant des inhibiteurs du récepteur des androgènes et utilisations de celles-ci
US11242324B2 (en) 2020-04-17 2022-02-08 Essa Pharma, Inc. Solid forms of an n-terminal domain androgen receptor inhibitor and uses thereof
US11358938B2 (en) 2020-04-17 2022-06-14 Essa Pharma, Inc. Solid forms of an N-terminal domain androgen receptor inhibitor and uses thereof
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