WO2018146641A1 - Nouveaux inhibiteurs de signalisation cellulaire - Google Patents

Nouveaux inhibiteurs de signalisation cellulaire Download PDF

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WO2018146641A1
WO2018146641A1 PCT/IB2018/050839 IB2018050839W WO2018146641A1 WO 2018146641 A1 WO2018146641 A1 WO 2018146641A1 IB 2018050839 W IB2018050839 W IB 2018050839W WO 2018146641 A1 WO2018146641 A1 WO 2018146641A1
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acid
compound
cancer
composition
alcohol
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PCT/IB2018/050839
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Monideepa ROY
Goutam Biswas
Hemant SURYAVANSHI
Anubhab MUKHERJEE
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Invictus Oncology Pvt. Ltd.
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Publication of WO2018146641A1 publication Critical patent/WO2018146641A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/554—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6907—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
    • A61K47/6909—Micelles formed by phospholipids
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers

Definitions

  • the present disclosure relates generally to Cellular Signalling inhibitors, compositions and formulations comprising the same, and uses thereof.
  • the present disclosure provides CSF-IR inhibitors of BLZ-945-lipids conjugates, GW2580-lipid conjugates and PLX-3397-lipid conjugates demonstrating sustained inhibition of CSF/CSF-1R signalling pathway with decreased toxicity.
  • the present disclosure also provides supramolecular combinatorial therapeutics, wherein the CSF-IR inhibitor is combined with one or more of a chemotherapeutic agent, a kinase inhibitor, and an immunoregulator, each of which is optionally conjugated with a lipid.
  • Targeted therapies have been in the limelight as cancer therapeutics for the last few years. They have resulted in high response rates and improved overall survival in patients with cancer. However, consistent with other oncogene-targeted therapies, initial patient response is of limited durability and tumors eventually relapse. 1
  • the tumor microenvironment is increasingly recognized to play an important role in tumor proliferation, invasion, metastasis, and chemoresistance. It provides a conducive niche to the tumor through immunosuppression. Overcoming this immunosuppressive nature of the tumor microenvironment has been of particular interest in cancer therapy. Tumor cells manipulate the surrounding environment by producing cytokines that suppress cytolytic T-cells and recruit immunosuppressive cells.
  • Colony stimulating factor 1 is one such cytokine secreted by several cancer cell types. It induces the proliferation and differentiation of immunosuppressive myeloid cells such as M2 polarized macrophages and myeloid derived suppressor cells (MDSC) by binding to the CSF-1 receptor (CSF-IR) on cell surface.
  • CSF-1 receptor CSF-1 receptor
  • 111 Cellular signalling mediated by colony-stimulating factor 1 (CSF1) and its receptor CSF-IR plays a critical role in monocyte differentiation and generation and activity of tissue-resident macrophages. The overexpression of CSF1 is associated with poor prognosis in breast, ovarian, and prostate cancer.
  • TAMs tumor-associated macrophages
  • CSF1-CSF1R axis may have an important role towards activity of TAMs.
  • lv ' v vl The CSF1/CSF1R signalling pathway is targeted in the treatment against numerous malignancies, including breast, leukaemia, and glioblastoma.
  • CSF-IR regulates the functioning of macrophages impacting tumor progression
  • inhibiting the CSF-IR pathway has emerged as a major therapeutic goal in cancer.
  • some of the CSF-IR inhibitors had shown promising results in terms of potency, selectivity and bioavailability of cFMS kinase activity vu
  • some of the well-known inhibitors which are in the clinical phase trials are BLZ-945, GW2580, PLX-3397 etc. Although high in potency, these inhibitors fail to achieve a sustained inhibition of CSF-IR and are associated with toxicity to normal cells. Accordingly, there remains an urgent need for CSF-IR inhibitors with an improved activity profile while exhibiting decreased toxicity.
  • the present application describes the design of novel CSF-IR inhibitors that can preferentially accumulate in the tumor microenvironment and exert sustained inhibition of the target molecule, overcoming the dose-limiting toxic effects and achieving superior antitumor efficacy compared to currently available CSF-IR inhibitors.
  • the present invention is directed to hydrophobic, lipophilic prodrugs that lead to increased effective drug accumulation in tumor via enhanced permeability and retention (EPR) phenomenon leading to improved efficacy.
  • the lipids used in these prodrugs include phospholipids, cholesterol, fatty acids etc.
  • the present invention describes prodrugs of CSF-IR inhibitors that can assemble into supramolecular structure with improved pharmacokinetic profile such as long circulation time, enhanced uptake and sustained release of drug inside tumor.
  • compositions of prodrug of a CSF-IR inhibitor comprise a linker wherein CSF-IR is coupled through ester, ether, amide, or other covalent conjugation with the linker.
  • the lipid molecule can be cholesterol, oleic acid, alpha tocopherol, fatty acid or another naturally occurring lipid molecule which is conjugated to drug molecule through a suitable linker/spacer.
  • the spacer can be composed of aliphatic dicarboxylic acid, unsaturated dicarboxylic acid, aldaric acid, fumaric acid, propargylic acid, acetylene dicarboxylic acid, aromatic/hetero aromatic dicarboxylic acid, ethylene glycol, diethylene glycol, natural or unnatural amino acids individually or in any combinations.
  • Certain exemplary embodiments provide supramolecular combinatorial therapeutics, wherein a CSF-IR inhibitor is combined with one or more of a kinase inhibitor, or a chemotherapeutic drug, or a tumor-targeting antibody, each of which is optionally conjugated with a lipid.
  • the antibody can be useful for therapeutic purposes (i.e., a therapeutic antibody) or for targeting the supramolecular combinatorial therapeutic to a desired site (i.e., a targeting antibody).
  • the supramolecular combinatorial therapeutic further comprises an immunomodulator, which can include another CSF-IR inhibitor (s). Immunomodulators are active agents of immunotherapy, and can either activate or suppress an immune response.
  • the immunomodulator activates and stimulates an immune response against cancer cells, non-limiting examples of which include immune cells (e.g., natural killer cells, lymphokine-activated killer cells, cytotoxic T cells and dendritic cells), antibodies (e.g., anti-PD-Ll and anti-PD-1 antibodies, anti-CD52, anti-VEGF-A, anti- CD30, anti-EGFR, anti- CD33, anti-CD20, anti-CTLA4, and anti-HER-2 antibodies), and cytokines (e.g., interferons and interleukins).
  • the immunomodulator is conjugated with a lipid.
  • the present disclosure relates to compounds of CSF-IR inhibitors and lipid conjugates of CSF- IR inhibitors of Formula I
  • 'Ligand' is selected from the group consisting of:
  • E C, O, NH, S;
  • G C, O, NH, S;
  • 'L' is a linker moiety connecting 'Ligand' and 'R' moieties; and 'R' is selected from the group consisting of a lipid, a lipid derivative, a lipid conjugate and combinations thereof;
  • CSF-IR inhibitors are the inhibitors which inhibits the CSFI/CSFIR signalling pathway.
  • CSF-IR inhibitors include compounds which target, decrease or inhibit the activity of Colony stimulating factor 1 receptor (CSF-IR).
  • lipid conjugates of CSF-IR inhibitors BLZ-945-lipid conjugate, GW2580-lipid conjugate and PLX3397-lipid conjugate.
  • the present invention is directed to lipid conjugates of CSF-IR inhibitors, such as BLZ-945, GW2580 and PLX3397, and that lipid conjugates of CSF-IR inhibitors.
  • CSF-IR inhibitors such as BLZ-945, GW2580 and PLX3397
  • the present disclosure relates to compounds of BLZ-945 series/Formula IA (BLZ-945-lipid conjugates), GW2580 series/ Formula IB (GW2580-lipid conjugates), PLX-3397 series/ Formula IC (PLX-3397-lipid conjugates).
  • A H, O, NH, S;
  • E C, O, NH, S;
  • G C, O, NH, S;
  • 'L' is a linker moiety connecting 'Ligand' and R' moieties
  • 'R' is selected from the group consisting of a lipid, a lipid derivative, a lipid conjugate and combinations thereof;
  • 'R' is selected from the group consisting of a lipid, a lipid derivative, a lipid conjugate and combinations thereof;
  • the linker group(s) in the BLZ-945 series (BLZ-945-lipid conjugates), GW2580 series (GW2580-lipid conjugates), PLX-3397 series (PLX-3397-lipid conjugates) of the present disclosure is selected from a group comprising a direct bond or an atom such as oxygen or sulfur, a unit such as R 1 , C(O), C(0)0, C(0) R ⁇ SO, SO2, SO2 H or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycly
  • the linker group(s) in the BLZ-945-lipids conjugates, GW2580-lipid conjugates, PLX-3397-lipid conjugates of the present disclosure is selected from a group comprising a direct bond, ester, ether, amide or other covalent conjugation with linker.
  • the linker group(s) in the BLZ-945-lipids conjugates, GW2580-lipid conjugates, PLX-3397-lipid conjugates of the present disclosure is selected from a group comprising one or more of succinic acid, fumaric acid, propargylic acid, ethylene glycol, diethylene glycol, and natural or unnatural amino acids.
  • the linker group(s) in the BLZ-945-lipids conjugates, GW2580-lipid conjugates, PLX-3397-lipid conjugates of the present disclosure is selected from a group comprising at least one of oxalic acid, malonic acid, succinic acid, glutaric acid, succinic acid, ethylene diamine, natural or unnatural amino acid, ethylene glycol, diethylene glycol, acetic acid, propionic acid, butyric acid, valeric acid, acrylic acid, but-2-enoic acid, pent-2-enoic acid, hex-2-enoic acid, 2-propynoic acid, but-2-ynoic acid, pent-2-ynoic acid, hex-2-ynoic acid, ethylene, propylene, 1-butene, 1-pentene, 1-hexene, acetylene, propyne, but-
  • the linker group(s) in the BLZ-945-lipids conjugates, GW2580-lipid conjugates, PLX-3397-lipid conjugates of the present disclosure is selected from a group comprising -C(0)CH 2 CH 2 C(0)-; -C(0)(CH 2 CH 2 ) m (C(0)CH 2 CH 2 )n- wherein 'n' is 1 to 10 and 'm' is 1 to 4; -C(0)(CH 2 ) x CH 2 C(0)NH(CH 2 CH 2 ) n -, wherein 'n' is 1 to 10 and 'x' is 0 to 3; -C(0)(CH 2 )mCH 2 C(0)NH(CH 2 CH 2 ) n HC(0)-, wherein 'n' is 1 to 10 and 'm' is 1 to 4; -C(0)CH 2 (CH 2 ) m C(0) H- wherein 'm' is 1 to 4; -C(0)(CH 2 )nCH 2 (R
  • the lipid(s) in the BLZ-945-lipids conjugates, GW2580-lipid conjugates, PLX-3397-lipid conjugates of the present disclosure is selected from a group comprising cholesterol, cholesterol derivatives, oleic acid, oleic acid derivative, alpha tocopherol, alpha tocopherol derivatives, phospholipid, phospholipid derivatives, fatty acid, naturally occurring lipid molecule which is conjugated to drug molecules, 1,3-Propanediol Dicaprylate/Dicaprate, 10-undecenoic acid, 1-dotriacontanol, 1-heptacosanol, 1-nonacosanol,
  • the lipid(s) or lipid derivative(s) in the BLZ-945-lipids conjugates, GW2580-lipid conjugates, PLX-3397-lipid conjugates of the present disclosure is selected from a group comprising cholesterol, cholesterol derivatives, oleic acid, oleic acid derivative, alpha tocopherol, alpha tocopherol derivatives, phospholipid, phospholipid derivatives, fatty acid or naturally occurring lipid molecule which is conjugated to drug molecules via a spacer, wherein the spacer is selected from a group comprising aliphatic dicarboxylic acid, unsaturated dicarboxylic acid, aldaric acid, fumaric acid, propargylic acid, acetylene dicarboxylic acid, aromatic/hetero aromatic dicarboxylic acid, ethylene glycol, diethylene glycol, natural or unnatural amino acids, or their derivatives individually or any combinations thereof.
  • the lipid conjugate(s) in the BLZ-945-lipids conjugates, GW2580-lipid conjugates, PLX-3397-lipid conjugates is the lipid or the lipid derivative conjugated with a compound selected from a group comprising a kinase inhibitor, a chemotherapeutic drug, an immunomodulator or an antibody or any combinations thereof.
  • the compound of Formula I is BLZ- 945-lipid conjugate(s).
  • the compound of Formula I is GW2580-lipid conjugate(s).
  • the compound of Formula I is PLX- 3397-lipid conjugate(s).
  • the supramolecular combinatorial therapeutic comprises a BLZ- 945-lipid conjugate.
  • the supramolecular combinatorial therapeutic comprises a GW2580-lipid conjugate.
  • the supramolecular combinatorial therapeutic comprises a PLX- 3397-lipid conjugate.
  • the supramolecular combinatorial therapeutic can further comprise a lipid conjugated kinase inhibitor.
  • the supramolecular combinatorial therapeutic further comprises an antibody (or an antigen binding fragment thereof), optionally conjugated with a lipid.
  • the supramolecular combinatorial therapeutic further comprises an antibody (or an antigen binding fragment thereof) conjugated with a lipid.
  • the antibody can be useful for thereaputic purposes (i.e., a therapeutic antibody) or for targeting the the supramolecular combinatorial therapeutic to a desired site (i.e., a targeting antibody).
  • the supramolecular combinatorial therapeutic further comprises an immunomodulator. Immunomodulators are active agents of immunotherapy, and can either activate or suppress an immune response.
  • the immunomodulator activates and stimulates an immune response against cancer cells, non-limiting examples of which include immune cells (e.g., natural killer cells, lymphokine-activated killer cells, cytotoxic T cells and dendritic cells), antibodies (e.g., anti-PD-Ll and anti-PD-1 antibodies, anti-CD52, anti-VEGF-A, anti- CD30, anti-EGFR, anti-CD33, anti-CD20, anti-CTLA4, and anti-HER-2 antibodies), and cytokines (e.g., interferons and interleukins).
  • the immunomodulator is conjugated with a lipid.
  • described herein is a method of treating cancer, comprising, administering a supramolecular combinatorial therapeutic as described herein to a patient in need of treatment for cancer.
  • the cancer is selected from the group consisting of: breast cancer; ovarian cancer; glioma; gastrointestinal cancer; prostate cancer; carcinoma, lung carcinoma, hepatocellular carcinoma, testicular cancer; cervical cancer; endometrial cancer; bladder cancer; head and neck cancer; lung cancer; gastro-esophageal cancer, and gynecological cancer.
  • the method further comprises co-administering one or more additional anti-cancer therapy to the patient.
  • the additional therapy is selected from the group consisting of surgery, chemotherapy, radiation therapy, thermotherapy, immunotherapy, hormone therapy, laser therapy, anti-angiogenic therapy, and any combinations thereof.
  • the additional therapy comprises administering an anti-cancer agent to the patient.
  • the method further comprises coadministration of one or more immunomodulators to the subject.
  • described herein is a method of treating allergy, comprising, administering a supramolecular combinatorial therapeutic as described herein to a patient in need of treatment for allergy, Systemic lupus erythematosus, Chronic Obstructive Pulmonary Disease and abnormal macrophage functions.
  • a composition comprises a compound of BLZ-945-lipid conjugate along with pharmaceutically acceptable excipient.
  • the composition comprises a compound of GW2580-lipid conjugate along with pharmaceutically acceptable excipient. In a non-limiting embodiment of the present disclosure, the composition comprises a compound of PLX-3397-lipid conjugate along with pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is selected from the group comprising adjuvant, diluent, carrier, granulating agents, binding agents, lubricating agents, disintegrating agent, sweetening agents, glidant, anti- adherent, anti-static agent, surfactant, anti-oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agent, and other conventionally known pharmaceutically acceptable excipient, or any combination of excipients thereof.
  • the composition inhibits colony stimulating factor-1 receptor (CSF-1R) and is administered to a subject in need thereof through modes selected from a group comprising intravenous administration, intramuscular administration, intraperitoneal administration, hepatoportal administration, intra articular administration and pancreatic duodenal artery administration, or any combination thereof.
  • CSF-1R colony stimulating factor-1 receptor
  • the present disclosure provides a method of treating cancer, comprising, administering the compounds of BLZ-945-lipid conjugate or derivative, salt, tautomeric form, isomer, polymorph, solvate, or intermediates thereof, or a composition to a subject in need of treatment for cancer.
  • the present disclosure provides a method of treating cancer, comprising, administering the compounds of GW2580-lipid conjugate or derivative, salt, tautomeric form, isomer, polymorph, solvate, or intermediates thereof, or a composition to a subject in need of treatment for cancer.
  • the present disclosure provides a method of treating cancer, comprising, administering the compounds of PLX-3397-lipid conjugate or derivative, salt, tautomeric form, isomer, polymorph, solvate, or intermediates thereof, or a composition to a subject in need of treatment for cancer.
  • the cancer is selected from the group consisting of breast cancer; ovarian cancer; glioma; gastrointestinal cancer; prostate cancer; carcinoma, lung carcinoma, hepatocellular carcinoma, testicular cancer; cervical cancer; endometrial cancer; bladder cancer; head and neck cancer; lung cancer; gastro-esophageal cancer, and gynecological cancer, or any combination thereof.
  • the method comprises coadministering one or more additional anti-cancer therapy to the subject.
  • the additional anti-cancer therapy is selected from the group consisting of surgery, chemotherapy, radiation therapy, thermotherapy, immunotherapy, hormone therapy, laser therapy, and anti-angiogenic therapy, or any combination thereof.
  • the additional anti-cancer therapy comprises administering a kinase inhibitor, a chemotherapeutic agent, an immunomodulator or any combination thereof, to the subject.
  • the supramolecular combinatorial therapeutic comprises a BLZ-945- lipid conjugate and a platinum-lipid conjugate.
  • the supramolecular combinatorial therapeutic comprises a BLZ-945- lipid conjugate and an antibody (or an antigen binding fragment thereof) lipid conjugate.
  • the antibody, or the antigen binding fragment thereof can be a therapeutic agent or a targeting ligand.
  • the supramolecular combinatorial therapeutic comprises a BLZ-945- lipid conjugate and an antibody (or an antigen binding fragment thereof) lipid conjugate, wherein the antibody is a therapeutic antibody or a targeting antibody or a combination thereof.
  • BLZ-945-lipid conjugate is compound of formula 23.
  • BLZ-945-lipid conjugate is compound of formula 24.
  • 'n' is 1 to 10 and 'x' is 0 to 3.
  • BLZ-945-lipid conj compound of formula 25 In yet another non-limiting embodiment of the present disclosure, BLZ-945-lipid conj compound of formula 25.
  • 'n' is 1 to 10 and 'm' is 1 to 4.
  • BLZ-945-lipid conjugate is compound of formula 26.
  • BLZ-945-lipid conjugate is compound of formula 27.
  • 'n' is 1 to 10;
  • R is H, alkyl, acid, amine, aryl or thiol;
  • Y is C, O, NH, S; and
  • X is C, O, NH, S.
  • the present disclosure further provides a BLZ-945 - lipid conjugate compound selected from:
  • GW-2580 is a potent and selective inhibitor of cFMS receptor kinase, inhibits cFMS in vitro at 60 nM with no activity against 26 other kinases. lx It also completely inhibits CSF-1 induced growth of mouse M- FS-60 myeloid cells and human monocytes (at 1 ⁇ ). GW-2580 completely inhibits bone degradation in human osteoclasts, rat calvaria and fetal long bone. x
  • GW-2580-lipid conjugate is compound of formula .
  • 'n' is 1 to 10 and 'm' is 1 to 4.
  • GW-2580-lipid conj compound of formula 55 In another non-limiting embodiment of the present disclosure, GW-2580-lipid conj compound of formula 55.
  • 'n' is 1 to 10 and 'x' is 0 to 3.
  • GW-2580-lipid conj compound of formula 56 In yet another non-limiting embodiment of the present disclosure, GW-2580-lipid conj compound of formula 56.
  • 'n' is 1 to 10 and 'm' is 1 to 4.
  • GW-2580-lipid conjugate is compound of formula 57.
  • GW-2580-lipid conjugate is compound of formula 58.
  • 'n' is 1 to 10; R is H, alkyl, acid, amine, aryl or thiol; Y is C, O, H, S; and X is C, O, NH, S.
  • PLX3397 is an orally administered a small-molecule receptor tyrosine kinase (RTK) inhibitor of KIT, CSF-1R and FLT3, with anti-canecr potential.
  • RTK receptor tyrosine kinase
  • the FDA recently approved this molecule for patients with tenosynovial giant cell tumor (TGCT) for which surgical removal is contraindicated. It binds to and inhibits phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSFIR) and FMS-like tyrosine kinase 3 (FLT3), inhibiting tumor cell proliferation, down-modulation of macrophages, osteoclasts and mast cells involved in the metastatic disease. CSFIR and FLT3 are overexpressed or mutated in many cancer cell types and play major roles in tumor cell proliferation and metastasis 541
  • the present disclosure further provides a PLX-3397- lipid conjugate compound selected from:
  • 'n' is 1 to 10 and 'x' is 0 to 3;
  • 'n' is 1 to 10;
  • R is H, alkyl, acid, amine, aryl or thiol;
  • Y is C, O, NH or S; and
  • X is C, O, NH or S.
  • composition(s) comprising the compound of Formula I
  • 'Ligand' is selected from the group consisting of:
  • A H, O, NH, S;
  • E C, O, NH, S;
  • G C, O, NH, S;
  • 'L' is a linker moiety connecting 'Ligand' and 'R' moieties; and 'R' is selected from the group consisting of a lipid, a lipid derivative, a lipid conjugate and combinations thereof;
  • the composition comprises from about 1% to about 99% (w/w) of the compound of Formula I.
  • the composition further comprises a kinase inhibitor, a chemotherapeutic agent or an immunomodulator or any combination thereof.
  • the composition further comprises a co-lipid.
  • the co-lipid is selected from the group consisting of HSPC, DSPC, DPPC, DOPC, POPC, SOPC, Egg- PC, and DSPE-PEG, DPPE-PEG, DMPE-PEG or any combination thereof.
  • the composition comprises from about 1% to about 99% (w/w) of the kinase inhibitor.
  • the composition comprises from about 1%) to about 99% (w/w) of the chemotherapeutic agent.
  • the chemotherapeutic agent is selected from the group consisting of PI3K inhibitors; platinum compounds; inhibitors of topoisomerase I and II; alkylating agents; microtubule inhibitors; and angiogenesis inhibitors; or any combination thereof.
  • the chemotherapeutic agent is selected from the group consisting of germicitibine; Aldesleukin; Alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; Asparaginase; BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfanoral; calusterone; capecitabine; platinate; carmustine; carmustine with Polifeprosan Implant; celecoxib; chlorambucil; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D; Darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; Den
  • VM-26 testolactone
  • thioguanine (6-TG) thiotepa
  • topotecan toremifene
  • Tositumomab Tositumomab
  • trastuzumab tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; and zoledronate; or any mixture thereof
  • the PI3K inhibitor is selected from the group consisting of PI103; P1828; LY294002; wortmannin; demethoxyviridin; IC486068; IC87114; GDC-0941; perifosine; CALIOI; PX-866; IPI-145;
  • the chemotherapeutic agent is conjugated with a component of the composition.
  • the chemotherapeutic agent is conjugated with Polyethylene glycol (PEG).
  • PEG Polyethylene glycol
  • the composition comprises from about 1% to about 99% (w/w) of the immunomodulator.
  • the composition is a liposome, emulsion, or micelle.
  • the composition is a nanoparticle, wherein the nanoparticle is about 1 nm to about 400 nm in diameter.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the composition further comprises a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is selected from the group comprising adjuvant, diluent, carrier, granulating agents, binding agents, lubricating agents, disintegrating agent, sweetening agents, glidant, anti- adherent, anti-static agent, surfactant, anti-oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agent, and other conventionally known pharmaceutically acceptable excipient, or any combination of excipients thereof.
  • the composition inhibits colony stimulating factor or colony stimulating factor-1 receptor (CSF-1R) signaling pathway and is administered to a subject in need thereof through modes selected from a group comprising intravenous administration, intramuscular administration, intraperitoneal administration, hepatoportal administration, intra articular administration and pancreatic duodenal artery administration, or any combination thereof.
  • CSF-1R colony stimulating factor-1 receptor
  • the present disclosure also provides a method of treating cancer, comprising, administering the compound of Formula I or derivative, salt, tautomeric form, isomer, polymorph, solvate, or intermediates thereof, or a composition thereof to a subject in need of treatment for cancer.
  • the cancer is selected from the group consisting of breast cancer; ovarian cancer; glioma; gastrointestinal cancer; prostate cancer; carcinoma, lung carcinoma, hepatocellular carcinoma, testicular cancer; cervical cancer; endometrial cancer; bladder cancer; head and neck cancer; lung cancer; gastro-esophageal cancer, and gynecological cancer, or any combination thereof.
  • the method comprises coadministering one or more additional anti-cancer therapy to the subject.
  • the additional anti-cancer therapy is selected from the group consisting of surgery, chemotherapy, radiation therapy, thermotherapy, immunotherapy, hormone therapy, laser therapy, and anti-angiogenic therapy, or any combination thereof.
  • the additional anti-cancer therapy comprises administering a kinase inhibitor, a chemotherapeutic agent, an immunomodulator or any combination thereof, to the subject.
  • the immunomodulator activates an immune response against cancer cells, wherein the immunomodulator is selected from the group consisting of antibody, natural killer cells, lymphokine-activated killer cells, cytotoxic T cells and dendritic cells, anti-PD-Ll antibodies, anti-PD-1 antibodies, anti-CD52 antibodies, anti-VEGF-A antibodies, anti-CD30 antibodies, anti-EGFR antibodies, anti-CD33 antibodies, anti-CD20 antibodies, anti-CTLA4 antibodies, anti-HER-2 antibodies, interferons, and interleukins, or any combination thereof.
  • the antibody is a therapeutic antibody or a targeting antibody or a combination thereof.
  • the present disclosure also provides a method for inhibition of CSF or CSF-1R signalling pathway in a cell, wherein said method comprises act of contacting the cell with the compound of formula I, derivative, salt, tautomeric form, isomer, polymorph, solvate, or intermediates thereof, or a composition thereof.
  • the technology described herein relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a supramolecular combinatorial therapeutic and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers and diluents include saline, aqueous buffer solutions, solvents and/or dispersion media. The use of such carriers and diluents is well known in the art.
  • materials which can serve as pharmaceutically- acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters, such as ethylene glycol;
  • wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservative and antioxidants can also be present in the formulation.
  • the terms such as “excipient”, “carrier”, “pharmaceutically acceptable carrier” or the like are used interchangeably herein.
  • the carrier inhibits the degradation of the active agent, e.g. a composition as described herein.
  • the pharmaceutical composition comprising a supramolecular combinatorial therapeutic can be a parenteral dose form. Since administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. In addition, controlled- release parenteral dosage forms can be prepared for administration of a patient, including, but not limited to, DUROS ® -type dosage forms and dose-dumping.
  • Suitable vehicles that can be used to provide parenteral dosage forms of a composition as described herein are well known to those skilled in the art. Examples include, without limitation: sterile water; water for injection USP; saline solution; glucose solution; aqueous vehicles such as but not limited to, sodium chloride injection, Ringer's injection, dextrose Injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water- miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Compounds that alter or modify the solubility of a pharmaceutically acceptable salt can also be incorporated into the parenteral dosage forms of the disclosure, including conventional and controlled-release parenteral dosage forms.
  • compositions can also be formulated to be suitable for oral administration, for example as discrete dosage forms, such as, but not limited to, tablets (including without limitation scored or coated tablets), pills, caplets, capsules, chewable tablets, powder packets, cachets, troches, wafers, aerosol sprays, or liquids, such as but not limited to, syrups, elixirs, solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion.
  • Such compositions contain a predetermined amount of the pharmaceutically acceptable salt of the disclosed compounds, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005).
  • the present disclosure further provides a formulation comprising the compound of Formula I
  • A H, O, H, S;
  • E C, O, NH, S;
  • G C, O, NH, S;
  • 'L' is a linker moiety connecting 'Ligand' and 'R' moieties
  • 'R' is selected from the group consisting of a lipid, a lipid derivative, a lipid conjugate and combinations thereof;
  • the phospholipid or PEGylated phospholipid is selected from a group comprising HSPC, DSPC, DPPC, DOPC, POPC, SOPC, Egg PC , DPPE-PEG, DMPE-PEG and DSPE-PEG or any combination thereof; wherein the composition comprises about 1% to about 99% (w/w) of these phospholipid and PEGylated phospholipid or any combination thereof.
  • the formulation comprises the compound along with HSPC, POPC and DSPE-PEG in a ratio 5 :55 :35 :5.
  • the formulation comprises the compound along with HSPC, POPC and DSPE-PEG in a ratio 10:50:35 :5.
  • the formulation comprises the compound along with HSPC, POPC and DSPE-PEG in a ratio 15 :50:30:5.
  • compositions and methods described herein can be administered to a subject having or diagnosed as having cancer.
  • the methods described herein comprise administering an effective amount of compositions described herein to a subject in order to alleviate a symptom of a cancer.
  • "alleviating a symptom of a cancer” is ameliorating any condition or symptom associated with the cancer. As compared with an equivalent untreated control, such reduction is by at least 5%, 10%, 20%, 40%, 50%, 60%, 80%), 90%), 95%), 99% or more as measured by any standard technique.
  • a variety of means for administering the compositions described herein to subjects are known to those of skill in the art.
  • Such methods can include, but are not limited to oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, cutaneous, topical, injection, or intratumoral administration. Administration can be local or systemic.
  • an effective amount refers to the amount of a composition described herein needed to alleviate at least one or more symptom of the disease or disorder, and relates to a sufficient amount of pharmacological composition to provide the desired effect.
  • the term "therapeutically effective amount” therefore refers to an amount of a composition described herein that is sufficient to provide a particular anti-tumor effect when administered to a typical subject.
  • An effective amount as used herein, in various contexts, would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact "effective amount”. However, for any given case, an appropriate "effective amount” can be determined by one of ordinary skill in the art using only routine experimentation.
  • an effective dose of a composition as described herein can be administered to a patient once. In certain embodiments, an effective dose of a composition as described herein can be administered to a patient repeatedly.
  • subjects can be administered a therapeutic amount of a composition as described herein, such as, e.g. 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or more.
  • the treatments after an initial treatment regimen, the treatments can be administered on a less frequent basis.
  • treatment can be repeated once per month, for six months or a year or longer.
  • Treatment according to the methods described herein can reduce levels of a marker or symptom of a condition, e.g. tumor size and/or growth by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80 % or at least 90% or more.
  • the dosage of a composition as described herein can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment, or make other alterations to the treatment regimen.
  • the dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity a composition as described herein.
  • the desired dose or amount of activation can be administered at one time or divided into subdoses, e.g., 2-4 subdoses and administered over a period of time, e.g., at appropriate intervals through the day or other appropriate schedule.
  • administration can be chronic, e.g., one or more doses and/or treatments daily over a period of weeks or months.
  • dosing and/or treatment schedules are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, or more.
  • a composition as described herein can be administered over a period of time, such as over a 5 minute, 10 minute, 15 minute, 20 minute, or 25 minute period.
  • the dosage ranges for the administration of a composition as described herein, according to the methods described herein depend upon, for example, the form of a composition as described herein, its potency, and the extent to which symptoms, markers, or indicators of a condition described herein are desired to be reduced, for example the percentage reduction desired for tumor growth.
  • the dosage should not be so large as to cause adverse side effects.
  • the dosage will vary with the age, condition, and sex of the patient and can be determined by one of skill in the art.
  • the dosage can also be adjusted by the individual physician in the event of any complication.
  • Efficacy of a composition as described herein in, e.g. the treatment of a condition described herein, or to induce a response as described herein can be determined by the skilled clinician. However, a treatment is considered "effective treatment," as the term is used herein, if one or more of the signs or symptoms of a condition described herein are altered in a beneficial manner, other clinically accepted symptoms are improved, or even ameliorated, or a desired response is induced e.g., by at least 10% following treatment according to the methods described herein. Efficacy can be assessed, for example, by measuring a marker, indicator, symptom, and/or the incidence of a condition treated according to the methods described herein or any other measurable parameter appropriate, e.g. tumor size and/or growth.
  • Treatment includes any treatment of a disease in an individual or an animal (some non-limiting examples include a human or an animal) and includes: (1) inhibiting the disease, e.g., preventing a worsening of symptoms (e.g. pain or inflammation); or (2) relieving the severity of the disease, e.g., causing regression of symptoms.
  • An effective amount for the treatment of a disease means that amount which, when administered to a subject in need thereof, is sufficient to result in effective treatment as that term is defined herein, for that disease.
  • Efficacy of an agent can be determined by assessing physical indicators of a condition or desired response, (e.g. tumor size and/or growth). It is well within the ability of one skilled in the art to monitor efficacy of administration and/or treatment by measuring any one of such parameters, or any combination of parameters. Efficacy can be assessed in animal models of a condition described herein, for example treatment of cancer. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant change in a marker is observed, e.g. a decreased in tumor size and/or growth.
  • a "subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters.
  • Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
  • the subject is a mammal, e.g., a primate, e.g., a human.
  • the terms, "individual,” “patient” and “subject” are used interchangeably herein.
  • the subject is a mammal.
  • the mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of cancer.
  • a subject can be male or female.
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment (e.g. cancer) or one or more complications related to such a condition, and optionally, have already undergone treatment for cancer or the one or more complications related to cancer.
  • a subject can also be one who has not been previously diagnosed as having cancer or one or more complications related to cancer.
  • a subject can be one who exhibits one or more risk factors for cancer or one or more complications related to cancer or a subject who does not exhibit risk factors.
  • a "subject in need" of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.
  • agent refers generally to any entity which is normally not present or not present at the levels being administered to a cell, tissue or subject.
  • An agent can be selected from a group including but not limited to: polynucleotides; polypeptides; small molecules; and antibodies or antigen-binding fragments thereof.
  • a polynucleotide can be RNA or DNA, and can be single or double stranded, and can be selected from a group including, for example, nucleic acids and nucleic acid analogues that encode a polypeptide.
  • a polypeptide can be, but is not limited to, a naturally-occurring polypeptide, a mutated polypeptide or a fragment thereof that retains the function of interest.
  • agents include, but are not limited to a nucleic acid aptamer, peptide-nucleic acid (PNA), locked nucleic acid (LNA), small organic or inorganic molecules; saccharide; oligosaccharides; polysaccharides; biological macromolecules, peptidomimetics; nucleic acid analogs and derivatives; extracts made from biological materials such as bacteria, plants, fungi, or mammalian cells or tissues and naturally occurring or synthetic compositions.
  • PNA peptide-nucleic acid
  • LNA locked nucleic acid
  • An agent can be applied to the media, where it contacts the cell and induces its effects.
  • an agent can be intracellular as a result of introduction of a nucleic acid sequence encoding the agent into the cell and its transcription resulting in the production of the nucleic acid and/or protein environmental stimuli within the cell.
  • the agent is any chemical, entity or moiety, including without limitation synthetic and naturally-occurring non-proteinaceous entities.
  • the agent is a small molecule having a chemical moiety selected, for example, from unsubstituted or substituted alkyl, aromatic, or heterocyclyl moieties including macrolides, leptomycins and related natural products or analogues thereof. Agents can be known to have a desired activity and/or property, or can be selected from a library of diverse compounds.
  • small molecule can refer to compounds that are "natural product-like,” however, the term “small molecule” is not limited to "natural product-like” compounds. Rather, a small molecule is typically characterized in that it contains several carbon— carbon bonds, and has a molecular weight more than about 50, but less than about 5000 Daltons (5 kD). Preferably the small molecule has a molecular weight of less than 3 kD, still more preferably less than 2 kD, and most preferably less than 1 kD. In some cases it is preferred that a small molecule have a molecular mass equal to or less than 700 Daltons.
  • the term "inhibitor” refers to an agent which can decrease the expression and/or activity of the targeted expression product (e.g. mRNA encoding the target or a target polypeptide), e.g. by at least 10% or more, e.g. by 10% or more, 50% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 98 % or more.
  • the efficacy of an inhibitor of, for example, PI3K e.g. its ability to decrease the level and/or activity of PI3K can be determined, e.g.
  • PI3K polypeptide by measuring the level of a PI3K polypeptide (and/or mRNA encoding such a polypeptide) and/or the activity of PI3K.
  • Methods for measuring the level of a given mRNA and/or polypeptide are known to one of skill in the art, e.g. RTPCR with primers can be used to determine the level of RNA and Western blotting with an antibody can be used to determine the level of a polypeptide.
  • the activity of, e.g. PI3K can be determined using methods known in the art and described above herein. .
  • the terms “treat,” “treatment,” “treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with a disease or disorder, e.g. cancer.
  • the term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder associated with a cancer.
  • Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a disease is reduced or halted.
  • treatment includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and/or decreased mortality, whether detectable or undetectable.
  • treatment also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).
  • composition or “pharmaceutical composition” are used interchangeably and refers to the active agent in combination with a pharmaceutically acceptable carrier e.g. a carrier commonly used in the pharmaceutical industry.
  • a pharmaceutically acceptable carrier e.g. a carrier commonly used in the pharmaceutical industry.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • administering refers to the placement of a compound as disclosed herein into a subject by a method or route which results in at least partial delivery of the agent at a desired site.
  • Pharmaceutical compositions comprising the compounds disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject.
  • amphiphilic refers to a molecule that has both a hydrophobic portion and a lipophobic portion, i.e. at least one a polar, water-soluble group and at least one a nonpolar, water- insoluble group.
  • an amphiphilic molecule will partition to the interface of the two phases.
  • an amphiphile is a molecule that is soluble in both an aqueous environment and a non-aqueous environment.
  • the term "amphiphile" refers to an amphiphilic molecule.
  • compositions, methods, and respective component(s) thereof are used in reference to compositions, methods, and respective component(s) thereof, that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not.
  • the amine salt (16- 20) thus produced was treated with freshly prepared sulphoxide derivative (Scheme 7) using diisopropyl ethyl amine in N-methyl morpholine at elevated temperature for 3 days.TM The compound formation was monitored by using TLC method. (Scheme 8) The crude reaction mixture was then evaporated and then purified by column chromatography to get the final compound.
  • R alkyl groups, acids, amines, aromatic, thiols
  • R cholesterol acid, saturated fatty acid, unsaturated fatty acid, branched unsaturated fatty acid.
  • R alkyl groups, acids, amines, aromatic, thiols
  • R alkyl groups, acids, amines, aromatic, thiols
  • R alkyl groups, acids, amines, aromatic, thiols
  • the PLX-3397 series of compound was also prepared in two steps starting from the same acids 4, 8 11, 14 and 15. Initially it was treated with N-Boc protected 5-((5-chloro-lH-pyrrolo[2,3- b]pyridin-3-yl)methyl)pyridin-2-amine to form the coupled at the indole -NH position. Then the N-Boc was deprotected using the TFA condition followed by reductive amination with 6- (trifluoromethyl)nicotinaldehyde to get the final compound.
  • Scheme 19 Scheme 19
  • R cholesterol acid, saturated fatty acid, unsaturated fatty acid, branched unsaturated fatty acid.
  • R alkyl groups, acids, amines, aromatic, thiols
  • R alkyl groups, acids, amines, aromatic, thiols
  • lipid conjugates of CSF1R inhibitor lipid conjugates are prepared using the process described above for BLZ-945-lipids conjugates, GW2580-lipid conjugates, PLX-3397-lipid conjugates.
  • IO-801_01 3 ⁇ 4 NMR (500 MHz, CDCh) ⁇ 8.45-8.31 (d, 1H), 8.12-7.95 (m, 1H), 7.77-7.66 (m 1H), 7.63-7.51 (d, 1H), 7.36-7.30 (d, 1H), 7.13-7.02 (m, 1H), 6.98-6.90 (m, 1H), 5.38-5.34 (m, 1H), 4.89-4.79 (m, 1H), 4.24-4.17 (t, 2H), 3.74-3.60 (m, 3H), 3.26-3.14 (m, 1H), 3.05-2.98 (d, 3H), 2.69-2.49 (m, 4H), 2.40-2.30 (m, 2H), 2.27-1.77 (m, 12H), 1.60-1.41 (m, 10H), 1.40- 1.31 (m, 4H), 1.27-1.26 (m, 2H), 1.20-1.03(m, 7H), 1.01 (s, 3H), 0.94-0.91 (
  • IO-801_02 ⁇ NMR (500 MHz, CDCh) ⁇ 8.50-8.38 (d, 1H), 8.10-8.01 (m, 1H), 7.73-7.67 (m 1H), 7.41-7.33 (m, 1H), 7.22-7.15 (m,lH), 7.03-6.95 (m, 1H), 5.39-5.33 (m, 1H), 4.91-4.81 (m, 1H), 3.62-3.52 (t, 2H), 3.44-3.33 (m, 2H), 3.23-3.11 (m, 1H), 3.06-2.98 (d, 3H), 2.67-2.55 (m, 2H), 2.54-2.45 (m, 2H), 2.39-2.28 (m, 2H), 2.25-2.12 (m, 3H), 2.10-1.93 (m, 3H), 1.92- 1.79 (m, 5H), 1.60-1.39 (m, 12H), 1.35 (m, 4H), 1.21-1.03 (m, 10H), 1.01 (s, 3H
  • IO-801_03 3 ⁇ 4 NMR (500 MHz, CDCh) ⁇ 8.47-8.37 (d, 1H), 8.11-8.01 (m, 1H), 7.83-7.60 (m
  • IO-803_01 3 ⁇ 4 MR (500 MHz, CDCb) ⁇ 8.49-8.37 (d, 1H), 8.10-7.97 (m, 1H), 7.81-7.62 (m 2H), 7.64-7.52 (d, 1H), 7.35(s, 1H), 7.19-7.10 (m, 1H), 7.05-6.92 (m, 1H), 6.01-5.77 (m, 1H), 5.38-5.28 (m, 1H), 4.95-4.78 (m, 1H), 3.87-3.43 (m, 2H), 2.63-2.54 (m, 2H), 2.50-2.33 (m, 4H), 2.31-2.24 (m, 1H), 2.21-2.06 (m, 2H), 2.04-1.91 (m, 2H), 1.90-1.80 (m, 5H), 1.65-1.31 (m, 15H), 1.29-1.25 (m, 2H), 1.21-1.03 (m, 8H), 1.00 (s, 3H), 0.95-0.91 (d, 3
  • IO-806_01 3 ⁇ 4 NMR (500 MHz, CDCb) ⁇ 8.45-8.33 (d, 1H), 8.09-7.96 (m, 1H), 7.76-7.66 (m 1H), 7.65-7.55(m, 1H), 7.36-7.31 (m, 1H), 7.09-7.05 (m, lH), 6.98-6.92 (m, 1H), 5.38-5.32 (m, 1H), 4.89-4.76 (m, 1H), 4.24-4.17 (m, 2H), 3.85-3.75 (m,lH), 3.71-3.60 (m, 14H) , 3.24- 3.11 (m, 1H), 3.05-2.94 (d, 3H), 2.70-2.49 (m, 4H), 2.41-2.32 (m, 2H), 2.25-2.16 (m, 1H), 2.15-2.07 (m, 1H), 2.05-1.74 (m, 7H), 1.68-1.40(m, 11H), 1.38-1.31 (m, 4H
  • IO-806_02 3 ⁇ 4 NMR (500 MHz, CDCb) ⁇ 8.44-8.36 (d, 1H), 8.09-7.96 (m, 1H), 7.75-7.56 (m, 2H), 7.37-7.30 (m, 1H), 7.10-7.03 (m, 1H), 7.00-6.93 (m, 1H), 5.42-5.21 (m, 2H), 4.87- 4.74 (m, 1H), 4.52-4.38 (m, 1H), 3.91-3.73 (m, 1H), 3.49-3.24 (m, 2H), 3.07-2.94 (d, 3H), 2.52-2.42 (m, 2H), 2.41-2.30 (m, 2H), 2.27-2.10 (m, 2H), 2.04-1.90 (m, 2H), 1.88-1.78 (m, 5H), 1.60-1.41 (m, 10H), 1.38-1.32 (m, 3H), 1.31-1.21 (m, 6H), 1.19-1.05 (m, 7H), 0.99
  • IO-806_03 3 ⁇ 4NMR (500 MHz, CDCh) ⁇ 8.44-8.34 (d, 1H), 8.10-7.95 (m, 1H), 7.75-7.66 (d, 1H), 7.64-7.52 (d, 1H), 7.39-7.30 (m, 1H), 7.13-7.02 (m, 1H), 6.99-6.91 (m, 1H), 5.41-5.27 (m, 1H), 5.00-4.89 (m, 1H), 4.16-4.01 (m, 2H), 3.89-3.75 (m, 1H), 3.67-3.54 (m, 8H), 3.23- 3.11 (m, 1H), 3.06-2.97 (d, 3H), 2.41-2.27 (m, 2H), 2.24-2.08 (m, 2H), 2.06-1.93 (m, 2H), 1.92-1.79 (m, 5H), 1.62-1.41 (m, 11H), 1.40-1.32 (m, 3H), 1.29-1.26 (m, 5H), 1.20
  • Supramolecular nanostructures were formulated using thin film hydration method with varying mole ratios of phospholipids (such as HSPC, POPC, SOPC, Egg PC, etc.), PEGylated- phospholipids (such as DSPE-PEG) and CSF1R inhibitor conjugates.
  • % Encapsulation efficiency of the CSF1R inhibitors in the supramolecules was determined by UV spectrophotometry. Average size, polydispersity index (PDI) and surface potential of the nanoparticles were measured by Dynamic light scattering (DLS).
  • phospholipids such as HSPC, POPC, SOPC, Egg PC, etc.
  • PEGylated- phospholipids such as DSPE-PEG
  • CSF1R inhibitor conjugates % Encapsulation efficiency of the CSF1R inhibitors in the supramolecules was determined by UV spectrophotometry. Average size, polydispersity index (PDI) and surface potential of the nanoparticles were measured by Dynamic light scattering
  • HSPC, POPC, IO-806 03 and DSPE-PEG taken in 55:35:5:5 mol% ratio, were dissolved in Chloroform. All lipid solutions were mixed homogeneously in round bottom flask and organic solvent was evaporated by rotary evaporator resulting in a thin lipid film. The lipid film was kept under high vacuum for 3-4 hr. It was, then, hydrated (by adding 5% Lactose solution to it) for 1.0 h at 60°C in hot water bath. Next, hydrated nanoparticles were sequentially extruded through 400nm, 200nm and lOOnm pore size membrane held by filter support for 11 times at 60°C using Avanti extruder supported over hot plate.
  • HSPC, POPC, IO-806 02 and DSPE-PEG taken in 55:35:5:5 mol% ratio, were dissolved in Chloroform. All lipid solutions were mixed homogeneously in round bottom flask and organic solvent was evaporated by rotary evaporator resulting in a thin lipid film. The lipid film was kept under high vacuum for 3-4 hr. It was, then, hydrated (by adding 5% Lactose solution to it) for 1.0 h at 60°C in hot water bath. Next, hydrated nanoparticles were sequentially extruded through 400nm, 200nm and lOOnm pore size membrane held by filter support for 11 times at 60°C using Avanti extruder supported over hot plate.
  • hydrated nanoparticles were sequentially extruded through 400nm, 200nm and lOOnm pore size membrane held by filter support for 11 times at 60°C using Avanti extruder supported over hot plate. It is evident from UV measurement that 4.1 mol% of IO-803_01was encapsulated in the supramolecule. DLS measurement reveals average size of the nanoparticles to be 137.9 nm, PDI 0.058 and surface potential -24.5 mV. The resulting solution was lyophilized and stored at 4°C.
  • HSPC, POPC, IO-801 02 and DSPE-PEG taken in 50:30: 15:5 mol% ratio, were dissolved in Chloroform. All lipid solutions were mixed homogeneously in round bottom flask and organic solvent was evaporated by rotary evaporator resulting in a thin lipid film. The lipid film was kept under high vacuum for 3-4 hr. It was, then, hydrated (by adding 5% Lactose solution to it) for 1.0 h at 60°C in hot water bath. Next, hydrated nanoparticles were sequentially extruded through 400nm, 200nm and lOOnm pore size membrane held by filter support for 11 times at 60°C using Avanti extruder supported over hot plate.

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Abstract

La présente invention concerne de manière générale des inhibiteurs de signalisation cellulaire du composé de formule I, des compositions et des préparations les comprenant, des procédés, des processus et des utilisations associés. La présente invention concerne particulièrement, des inhibiteurs CSF-IR de conjugués BLZ-945-lipides, de conjugués GW2580-lipide et de conjugués PLX-3397-lipide présentant une inhibition prolongée de la voie de signalisation CSF/CSFIR avec une toxicité réduite. La présente invention concerne également des agents thérapeutiques combinatoires supramoléculaires, un inhibiteur CSF-IR étant combiné à un ou plusieurs parmi, un agent chimiothérapique, un inhibiteur de kinase et un immunorégulateur, chacun d'entre eux étant éventuellement conjugué avec un lipide. La présente invention concerne également un procédé de traitement du cancer, des allergies, du lupus érythémateux systémique, de la néphrite, de la bronchopneumopathie chronique obstructive, et des fonctions macrophages anormales ou toute combinaison de ceux-ci.
PCT/IB2018/050839 2017-02-11 2018-02-12 Nouveaux inhibiteurs de signalisation cellulaire WO2018146641A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110054660A (zh) * 2018-12-25 2019-07-26 四川大学 一种果糖修饰的乳腺癌靶向脂质材料的制备和应用
CN115381817A (zh) * 2022-08-15 2022-11-25 北京中医药大学 Sotuletinib在制备治疗新月体肾炎的药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007121484A2 (fr) * 2006-04-19 2007-10-25 Novartis Ag Composés à base de benzoxazole et de benzothiazole 6-0 substitués et procédés d'inhibition de signalisation csf-1r
WO2013188763A1 (fr) * 2012-06-15 2013-12-19 The Brigham And Women's Hospital, Inc. Compositions pour le traitement du cancer et leurs procédés de préparation
WO2017137958A1 (fr) * 2016-02-11 2017-08-17 Invictus Oncology Pvt. Ltd. Inhibiteurs de signalisation cellulaire, leurs formules et leurs procédés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007121484A2 (fr) * 2006-04-19 2007-10-25 Novartis Ag Composés à base de benzoxazole et de benzothiazole 6-0 substitués et procédés d'inhibition de signalisation csf-1r
WO2013188763A1 (fr) * 2012-06-15 2013-12-19 The Brigham And Women's Hospital, Inc. Compositions pour le traitement du cancer et leurs procédés de préparation
WO2017137958A1 (fr) * 2016-02-11 2017-08-17 Invictus Oncology Pvt. Ltd. Inhibiteurs de signalisation cellulaire, leurs formules et leurs procédés

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110054660A (zh) * 2018-12-25 2019-07-26 四川大学 一种果糖修饰的乳腺癌靶向脂质材料的制备和应用
CN115381817A (zh) * 2022-08-15 2022-11-25 北京中医药大学 Sotuletinib在制备治疗新月体肾炎的药物中的应用
CN115381817B (zh) * 2022-08-15 2023-09-05 北京中医药大学 Sotuletinib在制备治疗新月体肾炎的药物中的应用

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