WO2020065036A1 - Utilisation d'un inhibiteur d'un transporteur de la famille des ent dans le traitement du cancer et de la combinaison de ceux-ci avec un antagoniste du récepteur de l'adénosine - Google Patents

Utilisation d'un inhibiteur d'un transporteur de la famille des ent dans le traitement du cancer et de la combinaison de ceux-ci avec un antagoniste du récepteur de l'adénosine Download PDF

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Publication number
WO2020065036A1
WO2020065036A1 PCT/EP2019/076244 EP2019076244W WO2020065036A1 WO 2020065036 A1 WO2020065036 A1 WO 2020065036A1 EP 2019076244 W EP2019076244 W EP 2019076244W WO 2020065036 A1 WO2020065036 A1 WO 2020065036A1
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Prior art keywords
inhibitor
alkyl
receptor antagonist
adenosine receptor
ent
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PCT/EP2019/076244
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English (en)
Inventor
Stefano Crosignani
Erica Joke Katelijne Heleen HOUTHUYS
Olivier DE HENAU
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Iteos Therapeutics S.A.
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Priority claimed from BE20180115A external-priority patent/BE1026612B1/fr
Priority to KR1020217012382A priority Critical patent/KR20210086625A/ko
Priority to US17/281,156 priority patent/US20210338672A1/en
Priority to MX2021003500A priority patent/MX2021003500A/es
Priority to CA3113886A priority patent/CA3113886A1/fr
Priority to AU2019350454A priority patent/AU2019350454A1/en
Application filed by Iteos Therapeutics S.A. filed Critical Iteos Therapeutics S.A.
Priority to EP19780208.5A priority patent/EP3856181A1/fr
Priority to CN201980076736.8A priority patent/CN113164462A/zh
Priority to BR112021006033-2A priority patent/BR112021006033A2/pt
Priority to JP2021517484A priority patent/JP2022503879A/ja
Publication of WO2020065036A1 publication Critical patent/WO2020065036A1/fr
Priority to IL281802A priority patent/IL281802A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of an inhibitor of an ENT family transporter for the treatment of cancer.
  • the invention further relates to the combined use of such inhibitor of an ENT family transporter with an adenosine receptor antagonist, for the treatment of cancer.
  • the invention further relates to a pharmaceutical composition and a kit of parts comprising such combination.
  • ENT equilibrative nucleoside transporter family
  • SLC29 equilibrative nucleoside transporter
  • adenosine a potent physiological and pharmacological regulator of numerous functions.
  • Cellular signaling by adenosine occurs through four known G-protein-coupled adenosine receptors Al, A2A, A2B, and A3.
  • ENTs fulfil important regulatory roles in different physiological processes, such as modulation of coronary blood flow, inflammation, and neurotransmission (Griffith DA and Jarvis SM, Biochim Biophys Acta, 1996, 1286, 153-181; Shryock JC and Belardinelli L, Am J Cardiol, 1997, 79(12A), 2-10; Anderson CM et a , J Neurochem, 1999, 73, 867-873).
  • a variety of drugs such as dilazep, dipyridamole, and draflazine interact with ENTs and alter adenosine levels, and were developed for their cardioprotective or vasodilatory effects.
  • Adenosine is also a potent immunosuppressive metabolite that is often found elevated in the extracellular tumor microenvironment (TME) (Blay J et al., Cancer Res, 1997, 57, 2602-2605).
  • Extracellular adenosine is generated mainly by the conversion of ATP by the ectonucleotidases CD39 and CD73 (Stagg J and Smyth MJ, Oncogene, 2010, 2, 5346- 5358).
  • Adenosine activates four G-protein-coupled receptor subtypes (Al, A2A, A2B, and A3).
  • activation of the A2A receptor is believed to be the main driver of innate and adaptive immune cell suppression leading to suppression of antitumor immune responses (Ohta and Sitkovsky, Nature, 2001, 414, 916-920) (Stagg and Smyth, Oncogene, 2010, 2, 5346-5358) (Antonioli L et al., Nature Reviews Cancer, 2013, 13, 842-857) (Cekic C and Linden J, Nature Reviews, Immunology, 2016, 16, 177-192)
  • RNA expression levels of plasma membrane-localized ENT transporters (ENT1, ENT2 and ENT4) in human primary lymphocytes was checked in a publicly available RNA-seq database (Bonnal RJP et al., Nature, 2015, 2:150051).
  • the Applicant herein shows that adenosine as well as ATP profoundly suppress T cell proliferation and cytokine secretion (IL-2), and strongly reduce T cell viability. Adenosine- and ATP-mediated suppression of T cell viability and proliferation were successfully restored using ENTs inhibitors.
  • an ENT inhibitor in combination with an adenosine receptor antagonist enabled to restore not only adenosine- and ATP-mediated suppression of T cell viability and proliferation, but also restored T cell cytokine secretion.
  • the present invention provides the use of an inhibitor of an ENT family transporter for the treatment of cancer. It also provides the combined use of such inhibitor of an ENT family transporter with an adenosine receptor antagonist, for the treatment of cancer.
  • This invention thus relates to a method of treating cancer, comprising: administering, to a human subject in need thereof, an effective amount of an inhibitor of an ENT family transporter.
  • the ENT family transporter is ENT1
  • the inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a peptide, and an antibody.
  • the subject is treated with an additional therapeutic agent in combination with the inhibitor of the ENT family transporter, or has received the additional therapeutic agent within about fourteen days of administration of the inhibitor of the ENT family transporter.
  • the additional therapeutic agent comprises an adenosine receptor antagonist.
  • the subject has previously received at least one prior therapeutic treatment, and has progressed subsequent to the administration of the at least one prior therapeutic treatment and prior to administration of the inhibitor of an ENT family transporter.
  • the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
  • the invention also provides a dosage formulation, comprising: an ENT family transporter inhibitor in an amount effective to treat cancer in a human subject.
  • the ENT family transporter inhibitor is administered prior to, concomitant with, or subsequent to administration of an additional therapeutic agent comprising an adenosine receptor antagonist.
  • the invention also relates to a method of treating cancer, comprising: administering, to a patient in need thereof, a combination of an adenosine receptor antagonist and an inhibitor of an ENT family transporter.
  • the adenosine receptor antagonist is an A2A or A2B receptor antagonist. In one embodiment, the adenosine receptor antagonist is selected from:
  • the adenosine receptor antagonist is a compound of Formula (I), as defined hereafter.
  • the ENT family member is ENT1.
  • the A2A or A2B receptor antagonist and the ENT1 inhibitor are provided in the same formulation.
  • the invention further provides a formulation, comprising: an effective amount of an adenosine receptor antagonist in combination with an effective amount of an inhibitor of an ENT family member, along with a pharmaceutically acceptable excipient.
  • the adenosine receptor antagonist is an A2A or A2B receptor antagonist.
  • the adenosine receptor antagonist is selected from:
  • the adenosine receptor is a compound of Formula (I) as defined hereafter.
  • the ENT family member inhibitor is an ENT1 inhibitor.
  • the formulation further comprises an additional therapeutic agent.
  • aldehyde refers to a group -CHO.
  • alkenyl refers to unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.
  • alkoxy refers to a group -O-alkyl wherein alkyl is as herein defined.
  • alkyl refers to a hydrocarbyl radical of formula C n H 2n+i wherein n is a number greater than or equal to 1.
  • alkyl groups of this invention comprise from 1 to 8 carbon atoms, more preferably, alkyl groups of this invention comprise from 1 to 6 carbon atoms.
  • Alkyl groups may be linear or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl.
  • alkylaminoalkyl refers to a group -alkyl-NH-alkyl wherein alkyl is as herein defined.
  • alkylheteroaryl refers to any heteroaryl substituted by an alkyl group wherein alkyl is as herein defined.
  • alkylsulfonyl refers to a group -S0 2 -alkyl wherein alkyl is as herein defined.
  • alkylsulfonealkyl refers to a group -alkyl-S0 2 -alkyl wherein alkyl is as herein defined.
  • alkylsulfoxidealkyl refers to a group -alkyl-SO-alkyl wherein alkyl is as herein defined.
  • alkyne refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds.
  • Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkyl groups.
  • Non-limiting examples of alkynyl groups are ethynyl, 2- propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers and the like.
  • alkynealkyl refers to a group -alkyl-alkyne wherein alkyl and alkyne are as herein defined.
  • amino refers to a group -NH 2 .
  • aminoalkyl refers to a group -alkyl-NH 2 wherein alkyl is as herein defined.
  • aminosulfonyl refers to a group -S0 2 -NH 2 .
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl), typically containing 5 to 12 atoms; preferably 5 to 10; more preferably the aryl is a 5- or 6- membered aryl.
  • Non-limiting examples of aryl comprise phenyl, naphthalenyl.
  • cycloalkyl refers to a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures.
  • Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms; still more preferably more preferably the cycloalkyl is a 5- or 6-membered cycloalkyl. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • cycloalkyloxy refers to a group -O-cycloalkyl wherein cycloalkyl is as herein defined.
  • dialkylamino refers to a group -NR'R 2 wherein R 1 and R 2 are both independently alkyl group as herein defined.
  • dialkylaminoalkyl refers to a group -alkyl-NR'R 2 wherein R 1 and R 2 are both independently alkyl group, as herein defined.
  • dihydroxyalkyl refers to a group alkyl is as herein defined substituted by two hydroxyl (-OH) groups.
  • halo or“halogen” refers to fluoro, chloro, bromo, or iodo.
  • heteroaryl refers to an aryl group as herein defined wherein at least one carbon atom is replaced with a heteroatom. In other words, it refers to 5 to 12 carbon-atom aromatic single rings or ring systems containing 2 rings which are fused together, typically containing 5 to 6 atoms; in which one or more carbon atoms is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized.
  • Non limiting examples of such heteroaryl include: oxazolyl, thiazolyl, imidazolyl, furanyl and pyrrolyl.
  • the heteroaryl is a 5- or 6-membered heteroaryl, more preferably the 5- or 6-membered heteroaryl is a furyl.
  • heterocyclyl refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • the heterocyclyl is a 5- or 6-membered heterocyclyl.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • Non limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, l-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4
  • (heterocyclyl)(alkyl)aminoalkyl refers to a group -alkyl-NR'R 2 wherein R 1 is an alkyl group and R 2 is a heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined.
  • heterocyclylalkyl refers to a group -alkyl-heterocyclyl wherein alkyl and heterocyclyl are as herein defined.
  • heterocyclyloxy to a group -O-heterocyclyl wherein heterocyclyl is as herein defined.
  • heterocyclylsulfonyl refers to a group - SC -heterocyclyl wherein heterocyclyl is as herein defined.
  • hydroxyalkyl refers to a group -alkyl-OH wherein alkyl is as herein defined.
  • hydroxyalkylaminoalkyl refers to a group -alkyl-NH-alkyl-OH wherein alkyl is as herein defined.
  • sulfonylamino refers to a group -NH-SO2.
  • administration means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
  • an adenosine receptor antagonist includes any chemical entity that, upon administration to a patient, results in inhibition or down- regulation of a biological activity associated with activation of an adenosine receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to an adenosine receptor of its natural ligand.
  • adenosine receptor antagonists include any agent that can block activation of an adenosine receptor or any of the downstream biological effects of an adenosine receptor activation.
  • inhibitor refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of a gene and/or a protein or that has a biological effect to inhibit or significantly reduce the biological activity of a protein. Consequently, an“ENT inhibitor” or « inhibitor of an ENT family transporter” refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of ENT family transporter.
  • antibody as used herein includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity.
  • chemotherapy refers to a type of cancer treatment that uses one or more anti- cancer drugs (chemotherapeutic agents) as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to reduce symptoms. Chemotherapeutic agents are for example selected from anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds and any combination thereof.
  • hormone therapy refers to the use of hormones in medical treatment.
  • the hormone therapy is oncologic hormone therapy.
  • human refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult).
  • the term "patient” refers to a mammal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure.
  • the term“immunotherapy” refers to a therapy aiming at inducing and/or enhancing an immune response towards a specific target, for example towards cancer cells. Immunotherapy may involve the use of checkpoint inhibitors, checkpoint agonists (also called T-cell agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine-producing enzymes inhibitors, adoptive transfer, therapeutic vaccines, and combinations thereof.
  • nucleic acid refers to a polymer of nucleotides covalently linked by phosphodiester bonds, such as deoxyribonucleic acids (DNA) or ribonucleic acids (RNA), in either single- or double- stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
  • DNA deoxyribonucleic acids
  • RNA ribonucleic acids
  • peptide refers to a linear polymer of amino acids of less than 50 amino acids linked together by peptide bonds.
  • pharmaceutically acceptable refers to the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered.
  • pharmaceutically acceptable carrier refers to a substance that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all inactive substance such as for example solvents, cosolvents, antioxidants, surfactants, stabilizing agents, emulsifying agents, buffering agents, pH modifying agents, preserving agents (or preservating agents), antibacterial and antifungal agents, isotonifiers, granulating agents or binders, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, coating agents, bulking agents, release agents, absorption delaying agents, sweetening agents, flavoring agents and the like.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.
  • prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient’s risk of acquiring a condition or disease.
  • prodrug as used herein means the pharmacologically acceptable derivatives of compounds of Formula (I), such as for example esters or amides, whose in vivo biotransformation product generates the biologically active drug. Prodrugs are generally characterized by increased bio-availability and are readily metabolized into biologically active compounds in vivo.
  • radiation therapy refers to a method of treatment of cancer employing various radiations such as X-ray, gamma-ray, neutron ray, electron beam, proton beam and radiation sources. It is used as part of cancer treatment to control or kill malignant cells. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor.
  • the three main divisions of radiation therapy are: external beam radiation therapy (EBRT or XRT); brachytherapy or sealed source radiation therapy; and systemic radioisotope therapy (RIT) or unsealed source radiotherapy.
  • therapeutically effective amount or“effective amount” or“therapeutically effective dose” refer to the amount or dose of active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject, (1) delaying or preventing the onset of a cancer in the subject; (2) reducing the severity or incidence of a cancer; (3) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of a cancer affecting the subject; (4) bringing about ameliorations of the symptoms of a cancer affecting the subject; or (5) curing a cancer affecting the subject.
  • a therapeutically effective amount may be administered prior to the onset of a cancer for a prophylactic or preventive action. Alternatively, or additionally, a therapeutically effective amount may be administered after initiation of a cancer for a therapeutic action.
  • treating or“treatment” refer to therapeutic treatment; wherein the object is to prevent or slow down the targeted pathologic condition or disease.
  • a subject or mammal is successfully“treated” for a disease or affection or condition if, after receiving the treatment according to the present invention, the subject or mammal shows observable and/or measurable reduction in or absence of one or more of the following: reduction of the number of cancer cells; and/or relief to some extent, for one or more of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improvement in quality of life issues.
  • the above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.
  • stem cell transplant refers to a procedure in which a patient receives healthy blood-forming cells (stem cells) to replace their own that have been destroyed by disease or by the radiation or high doses of anticancer drugs that are given as part of the procedure.
  • the healthy stem cells may come from the blood or bone marrow of the patient, from a donor, or from the umbilical cord blood of a newborn baby.
  • a stem cell transplant may be autologous (using a patient’s own stem cells that were collected and saved before treatment), allogeneic (using stem cells donated by someone who is not an identical twin), or syngeneic (using stem cells donated by an identical twin).
  • subject refers to a mammal, preferably a human.
  • the subject is diagnosed with a cancer.
  • the subject is a patient, preferably a human patient, who/which is awaiting the receipt of, or is receiving, medical care or was/is/will be the subject of a medical procedure or is monitored for the development or progression of a disease, such as a cancer.
  • the subject is a human patient who is treated and/or monitored for the development or progression of a cancer.
  • the subject is a male.
  • the subject is a female.
  • the subject is an adult.
  • the subject is a child.
  • the invention relates to the use of an inhibitor of ENT family transporter for treating cancer.
  • ENT inhibitors inhibitors of an ENT family transporter are also referred to as ENT inhibitors.
  • the equilibrative nucleoside transporter (ENT) family also known as SLC29, is a group of plasmalemmal transport proteins which transport nucleoside substrates like adenosine into cells.
  • ENT1, ENT2, ENT3, and ENT4 There are four known ENTs, designated ENT1, ENT2, ENT3, and ENT4.
  • the ENT inhibitor is an inhibitor of ENT1.
  • the ENT inhibitor is an inhibitor which is selective of ENT1. In one embodiment, the ENT inhibitor is an inhibitor which is selective of ENT1 with respect to other ENTs inhibitors, especially with respect to ENT2 and ENT4.
  • the ENT inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a peptide, and an antibody.
  • ENT inhibitors include dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, soluflazine, mioflazine, decynium-22, lopinavir, quinidine, 8MDP, TC-T 6000, 5-iodotubercidin, cilostazol, salts thereof and any mixture thereof.
  • the ENT inhibitor is selected from NBMPR, dipyridamole, dilazep, ticagrelor and salts thereof (including dilazep hydrochloride).
  • the ENT inhibitor is selected from dipyridamole, dilazep, ticagrelor and salts thereof (including dilazep hydrochloride).
  • the ENT inhibitor is NBMP or a salt thereof.
  • the ENT inhibitor is dipyridamole or a salt thereof.
  • the ENT inhibitor is dilazep or a salt thereof (including dilazep hydrochloride).
  • the ENT inhibitor is ticagrelor or a salt thereof.
  • ENT1 inhibitors include dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, 8MDP, 5- iodotubercidin, cilostazol, salts thereof and any mixture thereof.
  • selective ENT1 inhibitors include NBMPR, STI-571 (Gleevec), ticagrelor, salts thereof and any mixture thereof.
  • the invention thus relates to an inhibitor of an ENT family transporter for use in the treatment of cancer in a human subject.
  • the subject is treated with an additional therapeutic agent in combination with the inhibitor of the ENT family transporter, or has received the additional therapeutic agent within about fourteen days of administration of the inhibitor of the ENT family transporter.
  • the additional therapeutic agent comprises an adenosine receptor antagonist.
  • the ENT family transporter inhibitor is administered prior to, concomitant with, or subsequent to administration of the additional therapeutic agent comprising an adenosine receptor antagonist.
  • the subject has previously received at least one prior therapeutic treatment, and has progressed subsequent to the administration of the at least one prior therapeutic treatment and prior to administration of the inhibitor of an ENT family transporter.
  • the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
  • the invention thus relates to a method of treating cancer, comprising: administering, to a human subject in need thereof, an effective amount of an inhibitor of an ENT family transporter.
  • the subject in the method of the invention, is treated with an additional therapeutic agent in combination with the inhibitor of the ENT family transporter, or has received the additional therapeutic agent within about fourteen days of administration of the inhibitor of the ENT family transporter.
  • the additional therapeutic agent comprises an adenosine receptor antagonist. Further details regarding adenosine receptor antagonist are provided below.
  • the subject in the method of the invention, has previously received at least one prior therapeutic treatment, and has progressed subsequent to the administration of the at least one prior therapeutic treatment and prior to administration of the inhibitor of an ENT family transporter.
  • the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
  • the invention also relates to a dosage formulation, comprising an ENT family transporter inhibitor in an amount effective to treat cancer in a human subject.
  • the ENT family transporter inhibitor is administered prior to, concomitant with, or subsequent to administration of an additional therapeutic agent comprising an adenosine receptor antagonist.
  • the invention further relates to the combined use of an ENT inhibitor with an adenosine receptor antagonist.
  • the invention thus relates to a combination comprising:
  • an effective amount of an adenosine receptor antagonist preferably an effective amount of an adenosine receptor antagonist.
  • the term“combination” preferably means a combined occurrence of an ENT inhibitor and of an A2AR antagonist. Therefore, the combination of the invention may occur either as one composition, comprising all the components in one and the same mixture (e.g. a pharmaceutical composition), or may occur as a kit of parts, wherein the different components form different parts of such a kit of parts.
  • the administration of the ENT inhibitor and of the A2AR antagonist may occur either simultaneously or timely staggered, with similar or different timing of administration (i.e. similar or different numbers of administration of each component), either at the same site of administration or at different sites of administration, under similar of different dosage form.
  • the invention further relates to a method of treating cancer, comprising: administering, to a patient in need thereof, a combination of an adenosine receptor antagonist and an ENT inhibitor.
  • the ENT inhibitor is an inhibitor of ENT1.
  • the combination of the invention includes at least one adenosine receptor antagonist.
  • adenosine receptor antagonist refers to a compound that, upon administration to a patient, results in inhibition or down-regulation of a biological activity associated with activation of an adenosine receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to an adenosine receptor of its natural ligand.
  • adenosine receptor antagonists include any agent that can block activation of an adenosine receptor or any of the downstream biological effects of an adenosine receptor activation.
  • Adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as endogenous ligand. There are four known types of adenosine receptors in humans: Al, A2A, A2B and A3; each is encoded by a different gene (ADOARA1, ADORA2A, ADORA2B, and ADORA3 respectively).
  • the adenosine receptor antagonist is an antagonist of Al receptor, A2A receptor, A2B receptor, A3 receptor or of a combination thereof. In one embodiment, the adenosine receptor antagonist is an antagonist of A2A receptor, A2B receptor or of a combination thereof. In one embodiment, the adenosine receptor antagonist is an A2A or A2B receptor antagonist.
  • the adenosine receptor antagonist is an antagonist of A2A receptor (A2AR antagonist). In one embodiment, the adenosine receptor antagonist is an antagonist of A2B receptor (A2BR antagonist).
  • the adenosine receptor antagonist is an antagonist which is selective of A2A receptor with respect to other adenosine receptors. In one embodiment, the adenosine receptor antagonist is an antagonist which is selective of A2A receptor with respect to A2B receptor. In one embodiment, the adenosine receptor antagonist is an antagonist which is selective of A2B receptor with respect to other adenosine receptors. In one embodiment, the adenosine receptor antagonist is an antagonist which is selective of A2B receptor with respect to A2A receptor.
  • the combination of the invention comprises at least one A2A receptor antagonist as herein defined and at least one ENT inhibitor as defined above, such as for example at least one ENT1 inhibitor.
  • the combination of the invention includes at least one A2AR antagonist.
  • An“A2AR antagonist” refers to a compound that, upon administration to a patient, results in inhibition or down-regulation of a biological activity associated with activation of A2A receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to A2A receptor of its natural ligand.
  • Such A2AR antagonists include any agent that can block activation of A2A receptor or any of the downstream biological effects of A2A receptor activation.
  • A2AR antagonists include: Preladenant (SCH-420,8l4), Vipadenant (BIIB- 014), Tozadenant (SYK-l 15), ATL-444, Istradefylline (KW-6002), MSX-3, SCH-58261, SCH-4l2,348, SCH-442,4l6, ST-1535, Caffeine, VER-6623, VER-6947, VER-7835, ZM-24l,385, theophylline. It also includes A2AR antagonists disclosed in WO2018/178338, WO2011/121418, WO2009/156737, WO2011/095626 or W02018/136700.
  • the A2AR antagonist is a thiocarbamate derivative, especially a thiocarbamate derivative as those disclosed in WO2018/178338. More preferably the A2AR antagonist is a thiocarbamate derivative of formula (I) as described below.
  • the invention provides a combination comprising:
  • R 1 and R 2 are as defined below.
  • the A2AR antagonist is a compound of Formula (I):
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R 1 represents 5-membered heteroaryl; more preferably R 1 represents furyl;
  • R 2 represents 6-membered aryl or 6-membered heteroaryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl ; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkyla
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,
  • alkylaminoalkyl (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl alkylsulfonyl and alkylsulfonealkyl; or the heteroaryl or aryl groups are optionally substituted with two substituents that form together with the atoms to which they are attached a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,
  • alkylaminoalkyl (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
  • preferred compounds of Formula (I) are of Formula (la):
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R 1 represents 5-membered heteroaryl; more preferably R 1 represents furyl;
  • X 1 and X 2 represent each independently C or N;
  • R 1’ is absent when X 1 is N; or when X 1 is C, R 1 represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalky
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,
  • alkylaminoalkyl (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl;
  • R 2’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,
  • R 1 and R 2 form together with the atoms to which they are attached a 5- or 6- membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyal
  • alkylaminoalkyl (alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl;
  • R 3 is absent when X 2 is N; or when X 2 is C, R 3 represents H or halo, preferably H or F;
  • R 4 represents H or halo, preferably H or F; and R 5 represents H or halo, preferably H or F.
  • R 1 represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from C1-C6 alkyl (preferably methyl) and halo (preferably fhioro or chloro).
  • R 1 represents 5-membered heteroaryl; more preferably, R 1 represents furyl.
  • X 1 and X 2 represent each independently C or N. In another specific embodiment, X 1 and X 2 both represent C. In one specific embodiment of the invention, R 1 is absent when X 1 is N.
  • R 1 represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalky
  • aminocarbonylalkyl (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
  • R 1 substituents are optionally substituted by one or more substituent selected from halo, hydroxy, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, (alky
  • R 2 represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (
  • aminocarbonylalkyl (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
  • R 2 substituents are optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.
  • substituents selected from oxo, halo, hydroxy, cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkylcarbony
  • R 1 and R 2 form together with the atoms to which they are attached a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamin
  • R 4 represents H or halo. In a preferred embodiment, R 4 represents H or F. In one specific embodiment of the invention, R 5 represents H or halo. In a preferred embodiment, R 5 represents H or F.
  • preferred compounds of Formula (la) are those of Formula (Ia-l):
  • preferred compounds of Formula (Ia-l) are those of Formula (la-la): (la- la) or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 and R 3 are as defined in Formula (la); and
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,
  • aminocarbonylalkyl (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,
  • aminocarbonylalkyl (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
  • R 1 represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.
  • preferred compounds of Formula (Ia-l) are those of Formula (la- lb):
  • R 1 represents H or halo, preferably H or F
  • R 2 represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,
  • R 1 represents H or halo. In a preferred embodiment, R 1 represents H or F.
  • R 2 represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,
  • aminocarbonylalkyl (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.
  • R 2 represents an alkyl or heterocyclyl group substituted by one or more group selected from hydroxy, cyano, heteroaryl, alkylheteroaryl, alkyne, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.
  • preferred compounds of Formula (Ia-l) are those of Formula (Ia-lc) or (Ia-ld): ) or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • R 1 and R 3 are as defined in Formula (la); R 1 represents H or halo, preferably H or F; R 2 represents H or halo, preferably H or F;
  • R and R lu represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,
  • aminocarbonylalkyl (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl; and
  • R 21 and R 2u represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,
  • aminocarbonylalkyl (alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl.
  • R 1 represents H or halo. In a preferred embodiment, R 1 represents H or F.
  • R 2 represents H or halo. In a preferred embodiment, R 2 represents H or F.
  • R and R lu represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
  • heterocyclyl (alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl
  • R and R lu represent each independently hydrogen, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl or heterocyclylalkylaminocarbonyl.
  • R 21 and R 2u represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkyl, heterocyclyl
  • R 21 and R 2u represent each independently hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl or heterocyclylalkylaminocarbonyl. In a preferred embodiment, R 21 and R 2u represent each independently hydrogen, alkyl or dialkylaminoalkyl.
  • preferred compounds of Formula (la) are those of Formulae (la-2) or (la-3):
  • R 1 , R 2’ , R 3 , R 4 and R 5 are as defined in Formula (la).
  • Particularly preferred compounds of Formula (I) of the invention are those listed in Table 1 hereafter.
  • the A2AR antagonist is selected from: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-
  • the A2AR antagonist is selected from: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-
  • the A2AR antagonist is (+)-5-amino-3-(2-(4-(2,4-difluoro-5- (2-(methylsulfinyl)ethoxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one (compound 8a).
  • the A2AR antagonist is (-)-5-amino-3-(2-(4-(2,4- difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-l-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][l,2,4]triazolo[l,5-c]pyrimidin-2(3H)-one (compound 8b).
  • the present invention also relates to enantiomers, salts, solvates, polymorphs, multi-component complexes and liquid crystals of compounds of Formula (I) and subformulae thereof.
  • the present invention also relates to polymorphs and crystal habits of compounds of Formula (I) and subformulae thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labeled compounds of Formula (I) and subformulae thereof.
  • the compounds of Formula (I) and subformulae thereof may contain an asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non-racemic mixtures as well.
  • a compound When a compound is desired as a single enantiomer, such may be obtained by stereo specific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be performed by any suitable method known in the art.
  • the compounds of the invention may be in the form of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the compounds of Formula (I) and subformulae thereof include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosy
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2- hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • Preferred, pharmaceutically acceptable salts include hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, tosylate, esylate and acetate.
  • the compounds of Formula (I) is under the form of a HC1 salt or esylate salt.
  • the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
  • the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH)
  • the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
  • Pharmaceutically acceptable salts of compounds of Formula (I) and subformulae thereof may be prepared by one or more of these methods:
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non- ionized.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N- methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate
  • pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N’-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethyl-amine, diethylamine, piperazine, tri sOiydroxymeth yl jam i nomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N’-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethyl-amine, die
  • salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, palmoate, esylate, tosylate, and the like, can be used as the dosage form.
  • a basic group such as amino
  • an acidic salt i.e. hydrochloride, hydrobromide, acetate, palmoate, esylate, tosylate, and the like, can be used as the dosage form.
  • salts of the compounds of the invention are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
  • non-pharmaceutically acceptable salts which may for example be used in the isolation and/or purification of the compounds of the invention.
  • salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula (I) above.
  • the compounds of the invention may be in the form of pharmaceutically acceptable solvates.
  • Pharmaceutically acceptable solvates of the compounds of Formula (I) and subformulae thereof contains stoichiometric or sub -stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol or water.
  • the term “hydrate” refers to when the said solvent is water.
  • pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the A2AR antagonist is an A2AR antagonist disclosed in WO2011/121418.
  • the A2AR antagonist is the compound of example 1 of WO2011/121418, namely 5-bromo-2,6-di-(lH-pyrazol-l-yl)pyrimidin-4-amine, also known as NIR178:
  • the A2AR antagonist is an A2AR antagonist disclosed in WO2009/156737.
  • the A2AR antagonist is the compound of example 1S of WO2009/156737, namely (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3- yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-amine, also known as CPI-444:
  • the A2AR antagonist is an A2AR antagonist disclosed in WO2011/095626.
  • the A2AR antagonist is the compound (cxiv) of WO2011/095626, namely 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)- 1,2,4- triazin-3-amine, also known as AZD4635:
  • the A2AR antagonist is an A2AR antagonist disclosed in W02018/136700.
  • the A2AR antagonist is the compound of example 1 of WO2018/136700, namely 3-(2-amino-6-(l-((6-(2-hydroxypropan-2-yl)pyridin-2- yl)methyl)-lH-l,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile, also known as AB928:
  • the A2AR antagonist is Preladenant (SCH-420,8l4), namely 2-
  • the A2AR antagonist is Vipadenant (BIIB-014), namely 3-(4- amino-3-methylbenzyl)-7-(2-furyl)-3H-(l,2,3)triazolo(4,5-d)pyrimidine-5-amine:
  • the A2AR antagonist is Tozadenant (SYK-115), namely 4- hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-l- carboxamide:
  • the adenosine receptor antagonist is selected from:
  • the adenosine receptor antagonist is 5-bromo-2,6-di-(lH-pyrazol-l- yl)pyrimidin-4-amine. In one embodiment, the adenosine receptor antagonist is (S)-7-(5- methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5-amine.
  • the adenosine receptor antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-l,2,4-triazin-3- amine. In one embodiment, the adenosine receptor antagonist is 3-(2-amino-6-(l-((6-(2- hydroxypropan-2-yl)pyridin-2-yl)methyl)- 1H- 1 ,2,3-triazol-4-yl)pyrimidin-4-yl)-2- methylbenzonitrile .
  • the combination of the invention includes at least one A2BR antagonist.
  • An“A2BR antagonist” refers to a compound that, upon administration to a patient, results in inhibition or down-regulation of a biological activity associated with activation of A2B receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to A2B receptor of its natural ligand.
  • Such A2BR antagonists include any agent that can block activation of A2B receptor or any of the downstream biological effects of A2B receptor activation.
  • A2BR antagonists include: Vipadenant (BIIB-014), CVT-6883, MRS-1706, MRS- 1754, PSB-603, PSB-0788, PSB-1115, OSIP-339, 391, ATL-801, theophylline, Caffeine,
  • the combination of the invention comprises:
  • an effective amount of an ENT inhibitor preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor and salts thereof (including dilazep hydrochloride), and
  • an effective amount of an adenosine receptor antagonist preferably an A2AR antagonist, preferably selected from:
  • the combination of the invention comprises:
  • an effective amount of an adenosine receptor antagonist preferably an A2AR antagonist, preferably selected from:
  • the combination of the invention comprises:
  • an effective amount of an ENT inhibitor preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor and salts thereof (including dilazep hydrochloride), and
  • the combination of the invention comprises:
  • an effective amount of an ENT inhibitor preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor and salts thereof (including dilazep hydrochloride), and
  • the invention further relates to formulation comprising the combination of the invention.
  • the invention provides a formulation, comprising: an effective amount of an adenosine receptor antagonist in combination with an effective amount of an inhibitor of an ENT family member, along with a pharmaceutically acceptable excipient.
  • the invention further relates to a pharmaceutical composition comprising the combination of the invention.
  • the pharmaceutical composition comprises:
  • the invention provides a pharmaceutical composition comprising:
  • an effective amount an ENT inhibitor such as for example an ENT1 inhibitor
  • an A2AR antagonist being a thiocarbamate derivative, more preferably a thiocarbamate derivative of Formula (I)
  • compositions of the invention further comprises an additional therapeutic agent.
  • the pharmaceutical composition of the invention can optionally contain such inactive substances that are commonly used in pharmaceutical formulations, such as for example cosolvents, lipid carrier, antioxidants, surfactants, wetting agents, emulsifying agents, buffering agents, pH modifying agents, preserving agents (or preservating agents), isotonifiers, stabilizing agents, granulating agents or binders, precipitation inhibitors, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, bulking agents, release agents, sweetening agents, flavoring agents, and the like.
  • inactive substances that are commonly used in pharmaceutical formulations, such as for example cosolvents, lipid carrier, antioxidants, surfactants, wetting agents, emulsifying agents, buffering agents, pH modifying agents, preserving agents (or preservating agents), isotonifiers, stabilizing agents, granulating agents or binders, precipitation inhibitors, lubricants,
  • the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable cosolvent.
  • cosolvents are selected from caprylic acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethylsulfoxide, dimethylacetamide, dimethylisosorbide and mixtures thereof.
  • the pharmaceutical composition of the invention comprises caprylic acid and/or PEG.
  • PEG polyethylene glycol
  • PEG400 polyethylene glycol
  • PEG polyethylene glycol
  • the composition comprises PEG, it is of a moderate molecular weight, preferably PEG 3350.
  • the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable lipid carrier.
  • the lipid carrier is lauroyl polyoxyl-32 glycerides.
  • This excipient corresponds to Gelucire ® 44/14 manufactured by Gattefosse (Saint-Priest - France). This excipient is also known under the following references: lauroyl polyoxyl-32 glycerides NF/USP (NF: National Formulary; USP: US Pharmacopeia); lauroyl macrogol-32 glycerides EP (European Pharmacopeia); hydrogenated coconut PEG-32 esters (INCI); CAS number 57107-95-6.
  • Gelucire ® 44/14 corresponds to a well-defined multi-constituent substance constituted of mono-, di- and triglycerides and PEG-32 mono- and diesters of lauric acid (C12).
  • Gelucire ® 44/14 has a melting point ranging from 42.5°C to 47.5°C (with a mean at 44°C) and an hydrophilic/lipophilic balance (HLB) value of 14.
  • the lipid carrier is Vitamin E TPGS.
  • Vitamin E TPGS Vitamin E TPGS.
  • This excipient is also known under the following references: D-a-Tocopherol polyethylene glycol-1000 succinate; Tocophersol n; Tocofersolan; VEGS; a-[4-[[(2R)-3,4-dihydiO-2,5,7,8-tetramethyl-2-
  • Vitamin E PEG succinate and is formed from Vitamin E which is conjugated to polyethylene glycol 1000 via a succinic acid linker.
  • Vitamin E TPGS has melting point in the range 37-41 °C and an hydrophilic/lipophilic balance (HLB) value of 13.
  • the pharmaceutical composition of the invention further comprises one or more antioxidant; preferably the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, sodium metabisulfite, ascorbic acid, methionine and vitamin E; more preferably the antioxidant is BHT.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • surfactants are added, such as for example polyethylene glycols, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, sodium docusate, sodium lauryl sulfate, polysorbates (20, 80, etc.), poloxamers (188, 407 etc.), pluronic polyols, polyoxyethylene sorbitan monoethers (TWEEN ® -20, TWEEN ® -80, etc.), vitamin E TPGS (Vitamin E polyethylene glycol succinate), cremophor RH40 (polyoxyl 40 hydrogenated castor oil), cremophor EL (polyoxyl 35 hydrogenated castor oil), polyethylene glycol 660 l2-monostearate, solutol HS15 (Polyoxyethylated 12- hydroxystearic acid), labrasol (caprylocaproyl polyoxyl-8 glycerides), labrafil M1944 (Oleoyl polyoxyl-6 glycerides), polyl
  • wetting agents are added, such as for example sodium lauryl sulphate, vitamin E TPGS, sodium docusate, polysorbate 80, poloxamer 407.
  • a preferred wetting agent is poloxamer 407.
  • emulsifying agents are added, such as for example carbomer, carrageenan, lanolin, lecithin, mineral oil, oleic acid, oleyl alcohol, pectin, poloxamer, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, triethanolamine, propylene glycol monolaurate, propylene glycol dilaurate, propylene glycol monocaprylate.
  • Preferred emulsifying agents are for example poloxamer, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprylate.
  • buffering agents are used to help to maintain the pH in the range that approximates physiological conditions
  • Suitable buffering agents include both organic and inorganic acids and salts thereof, such as citrate buffers (e.g., monosodium citrate- disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid- potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, fumaric acid-disodium fumarate mixture, monosodium fumarate-disodium fumarate mixture, etc
  • pH modifiers are added, such as for example sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, meglumine, sodium carbonate, citric acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid and malic acid;
  • preservatives agents are added to retard microbial growth.
  • Suitable preservatives for use with the present disclosure include phenol, benzyl alcohol, meta- cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalconium halides (e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.
  • isotonifiers sometimes known as“stabilizers” are added and include polyhydric sugar alcohols, for example trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the therapeutic agent or helps to prevent denaturation or adherence to the container wall or helps to inhibit the precipitation, particle growth or agglomeration of the active ingredient.
  • Typical stabilizers can be polyhydric sugar alcohols (enumerated above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol and the like, including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, a-monothioglycerol and sodium thio sulfate; low
  • Preferred stabilizers are for example glycerol; polyethylene glycol; polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate or hydroxypropylmethylcellulose acetate succinate; carboxymethylcellulose (Na/Ca); polyethylene glycol methyl ether-block-poly(D-L-lactide) copolymer; and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone polyvinylacetate copolymer.
  • granulating agent/binder(s) are added, such as for example starch, gums (inclusive of natural, semisynthetic and synthetic), microcrystalline cellulose, ethyl cellulose, methylcellulose, hydroxypropylcellulose, polymers such as povidone, polyvinylpyrrolidone polyvinylacetate copolymer and the like.
  • Preferred granulating agents are for example methylcellulose, hydroxypropylcellulose, povidone and polyvinylpyrrolidone polyvinylacetate copolymer.
  • precipitation inhibitors are added, such as for example water soluble derivatives of cellulose including hydroxypropylmethylcellulose and methylcellulose, and water soluble polymers such as polyvinylpyrrolidone, polyvinylpyrrolidone polyvinylacetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or poloxamer 407.
  • a preferred precipitation inhibitor is hydroxypropylmethylcellulose.
  • lubricants are added, such as for example magnesium stearate, glyceryl esters, behenoyl polyoxyl-8 glycerides Nf (Compritol HD5 ATO), sodium stearyl fumarate and the like.
  • disintegrants are added, such as for example synthetics like sodium starch glycolate, cross povidone, cross carmellose sodium, kollidon CL, and natural origin such as locust bean gum and the like.
  • glidants are added, such as for example talc, magnesium stearate, colloidal silicon dioxide, starch and the like.
  • diluents are added, such as for example dextrose, lactose, mannitol, microcrystalline cellulose, sorbitol, sucrose, dibasic calcium phosphate, calcium sulphate dehydrate, starch and the like.
  • adsorbents are added, such as for example silicon dioxide, purified aluminium silicate and the like.
  • the pharmaceutical composition of the invention is in the form of tablets and tableting excipients are added, such as for example granulating agents, binders, lubricants, disintegrants, glidants, diluents, adsorbents and the like.
  • the pharmaceutical composition of the invention is in the form of capsules, in which the capsule shells are constructed from gelatin or from non-animal derived products such as cellulose and its derivatives such as hydroxypropylmethylcellulose.
  • the pharmaceutical composition of the invention is formulated as capsules, wherein the capsule shells are constructed from gelatin and wherein additional components are optionally included in the capsule shells, such as for example polyethylene glycol and sodium lauryl sulphate.
  • the pharmaceutical composition may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for rectal administration, for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • rectal administration for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.
  • compositions may be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
  • the pharmaceutical composition is in an adapted form for an oral administration.
  • Forms adapted to oral administration may be solid, semi-solid or liquid.
  • Some preferred, but non-limiting examples of such forms include liquid, paste or solid compositions, and more particularly tablets, tablets formulated for extended or sustained release, capsules (including soft and hard gelatin capsules), pills, dragees, lozenges, sachets, cachets, powder, liquids, gels, syrups, slurries, elixirs, emulsions, solutions, and suspensions.
  • the pharmaceutical composition is in an adapted form for an injection, especially to be injected to the subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion.
  • Sterile injectable forms of the pharmaceutical composition of the invention include sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration.
  • Sterile injectable forms of the pharmaceutical composition of the invention may be a solution or an aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic pharmaceutically acceptable diluent or solvent.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • the pharmaceutical composition of the invention is in an adapted form for a topical administration.
  • forms adapted for topical administration include, without being limited to, liquid, paste or solid compositions, and more particularly aqueous solutions, drops, dispersions, sprays, ointments, cremes, lotions, microcapsules, micro- or nanoparticles, polymeric patch, or controlled-release patch, and the like.
  • the pharmaceutical composition of the invention is in an adapted form for a rectal administration.
  • forms adapted for rectal administration include, without being limited to, suppository, micro enemas, enemas, gel, rectal foam, cream, ointment, and the like.
  • the pharmaceutical composition of the invention is in an adapted form for an administration by inhalation.
  • forms adapted for administration by inhalation include, without being limited to aerosols.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • the invention further relates to a kit of parts comprising the combination of the invention.
  • the kit of parts of the invention comprises:
  • the invention provides a kit of parts comprising:
  • the first and second parts of the kit may be under the form of pharmaceutical compositions.
  • Excipients, dosage form and administration route of such pharmaceutical compositions will be clear to the skilled person (reference is made to the latest edition of Remington’s Pharmaceutical Sciences), and especially may be those listed above with regards to the pharmaceutical composition of the invention.
  • the second part of the kit comprises a pharmaceutical composition comprising an A2AR antagonist, preferably a thiocarbamate derivative of Formula (I) as defined above, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • Pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant of the pharmaceutical composition of the second part of the kit of part may be those listed above with regards to the pharmaceutical composition of the invention.
  • the administration of the different parts of the kit may be made simultaneously or timely staggered, either at the same site of administration or at different sites of administration, under similar or different dosage forms.
  • kit of parts of the invention further comprises an additional therapeutic agent.
  • Administration regimen comprises an additional therapeutic agent.
  • the administration of the ENT inhibitor and the adenosine receptor antagonist may occur either simultaneously or timely staggered, either at the same site of administration or at different sites of administration, under similar or different dosage forms as further outlined below.
  • the ENT inhibitor is administered prior to, concomitant with, or subsequent to administration of an adenosine receptor antagonist.
  • the adenosine receptor antagonist and the ENT inhibitor may be administered separated in time (in a time- staggered manner), i.e. sequentially, and/or are administered at different administration sites.
  • the adenosine receptor antagonist may be administrated e.g. prior, concurrent or subsequent to the ENT inhibitor, or vice versa.
  • the adenosine receptor antagonist and the ENT inhibitor may be administered at different administration sites, or at the same administration site, preferably, when administered in a time staggered manner.
  • the adenosine receptor antagonist is to be administered prior to and/or concomitantly with an ENT inhibitor. In one embodiment, the adenosine receptor antagonist is to be administered prior to the day or on the same day that the ENT inhibitor is administered.
  • the ENT inhibitor is to be administered prior to and/or concomitantly with an adenosine receptor antagonist. In one embodiment, the ENT inhibitor is to be administered prior to the day or on the same day that the adenosine receptor antagonist is administered. In one embodiment, the adenosine receptor antagonist is to be administered prior to and/or concomitantly with an ENT inhibitor and continuously thereafter.
  • the ENT inhibitor is to be administered prior to and/or concomitantly with an adenosine receptor antagonist and continuously thereafter.
  • the ENT inhibitor and the adenosine receptor antagonist may be administered as a single daily dose, divided over one or more daily doses. It will be understood that the total daily usage of adenosine receptor antagonist and ENT inhibitor will be decided by the attending physician within the scope of sound medical judgment.
  • the specific dose for any particular subject will depend upon a variety of factors such as the cancer to be treated; the age, body weight, general health, sex and diet of the patient; and like factors well-known in the medical arts.
  • the subject is a mammal, preferably a human
  • the dose of adenosine receptor antagonist is a dose ranging from about 0.01 mg per kilo body weight (mg/kg) to about 5 mg/kg, preferably about 0.08 mg/kg to about 3.3 mg/kg, more preferably about 0.15 mg/kg to about 1.7 mg/kg.
  • the subject is a mammal, preferably a human
  • the dose of adenosine receptor antagonist is a dose ranging from about 0.01 mg per kilo body weight per day (mg/kg/day) to about 5 mg/kg/day, preferably about 0.08 mg/kg/day to about 3.3 mg/kg/day, more preferably about 0.15 mg/kg/day to about 1.7 mg/kg/day.
  • the subject is a mammal, preferably a human, and the dose of adenosine receptor antagonist, preferably a therapeutically effective dose, is a dose ranging from about 1 mg to about 500 mg, preferably about 5 mg to about 200 mg, more preferably from about 10 mg to about 100 mg.
  • the subject is a mammal, preferably a human, and the dose of adenosine receptor antagonist, preferably a therapeutically effective dose, is a dose ranging from about 1 mg to about 500 mg per administration, preferably about 5 mg to about 200 mg per administration, more preferably from about 10 mg to about 100 mg per administration.
  • the subject is a mammal, preferably a human, and the dose of adenosine receptor antagonist, preferably a therapeutically effective dose, is a daily dose ranging from about 1 mg to about 500 mg, preferably about 5 mg to about 200 mg, more preferably from about 10 mg to about 100 mg.
  • the subject is a mammal, preferably a human, and the dose of adenosine receptor antagonist, preferably a therapeutically effective dose, is a daily dose to be administered in one, two, three or more takes.
  • the subject is a mammal, preferably a human, and the dose of adenosine receptor antagonist, preferably a therapeutically effective dose, is a daily dose to be administered in one or two takes.
  • the subject is a mammal, preferably a human
  • the dose of ENT inhibitor preferably a therapeutically effective dose, is a dose ranging from about 0.01 mg per kilo body weight (mg/kg) to about 5 mg/kg.
  • the subject is a mammal, preferably a human
  • the dose of ENT inhibitor preferably a therapeutically effective dose, is a dose ranging from about 0.01 mg per kilo body weight per day (mg/kg/day) to about 5 mg/kg/day.
  • the subject is a mammal, preferably a human, and the dose of ENT inhibitor, preferably a therapeutically effective dose, is a dose ranging from about 1 mg to about 500 mg. In one embodiment, the subject is a mammal, preferably a human, and the dose of ENT inhibitor, preferably a therapeutically effective dose, is a dose ranging from about 1 mg to about 500 mg per administration.
  • the subject is a mammal, preferably a human, and the dose of ENT inhibitor, preferably a therapeutically effective dose, is a daily dose ranging from about 1 mg to about 500 mg.
  • the subject is a mammal, preferably a human, and the dose of ENT inhibitor, preferably a therapeutically effective dose, is a daily dose to be administered in one, two, three or more takes.
  • the subject is a mammal, preferably a human, and the dose of ENT inhibitor, preferably a therapeutically effective dose, is a daily dose to be administered in one or two takes.
  • Another object of this invention is the use of the combination as a medicament, i.e. for medical use.
  • the invention provides the use of the combination of the invention for the manufacturing of a medicament.
  • the invention provides the use of the pharmaceutical composition of the invention or the kit of the invention for the manufacturing of a medicament.
  • the invention provides the combination, the pharmaceutical composition or the kit of parts of the invention, for use in the treatment and/or prevention of cancer.
  • the invention further provides the use of the combination, pharmaceutical composition or kit of parts of the invention for the manufacture of a medicament for treating and/or preventing cancer.
  • the invention further provides a method of treating of cancer, which comprises administering to a mammal species in need thereof a therapeutically effective amount of the combination, pharmaceutical composition or kit of parts of the invention.
  • the invention provides a method of treating cancer, comprising: administering, to a patient in need thereof, a combination of an adenosine receptor antagonist and an inhibitor of an ENT family transporter.
  • the specific embodiments relative to the adenosine receptor antagonists and inhibitors of an ENT family transporter recited above also applies in the context of the methods of treatment of the invention.
  • the invention also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of the combination, pharmaceutical composition or kit of parts of the invention to a patient in need thereof.
  • cancers that can be treated using the methods of the invention include solid cancers and non-solid cancers, especially benign and malignant solid tumors and benign and malignant non- solid tumors.
  • the cancer may be metastatic or non-metastatic.
  • the cancer may be may be familial or sporadic.
  • the cancer to be treated according to the present invention is a solid cancer.
  • solid cancer encompasses any cancer (also referred to as malignancy) that forms a discrete tumor mass, as opposed to cancers (or malignancies) that diffusely infiltrate a tissue without forming a mass.
  • solid tumors include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, carcinoid, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms (including Bowen’s disease and Paget’s disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin
  • the cancer to be treated according to the present invention is a non-solid cancer.
  • non-solid tumors include but are not limited to hematological neoplasms.
  • a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.
  • Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, non- Hodgkin’s lymphoma lymphomas, and lymphocytic lymphomas). Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.
  • the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.
  • the cancer is breast cancer. In a specific embodiment, the cancer is carcinoid cancer. In a specific embodiment, the cancer is cervical cancer. In a specific embodiment, the cancer is colorectal cancer. In a specific embodiment, the cancer is endometrial cancer. In a specific embodiment, the cancer is glioma. In a specific embodiment, the cancer is head and neck cancer. In a specific embodiment, the cancer is liver cancer. In a specific embodiment, the cancer is lung cancer. In a specific embodiment, the cancer is melanoma. In a specific embodiment, the cancer is ovarian cancer. In a specific embodiment, the cancer is pancreatic cancer. In a specific embodiment, the cancer is prostate cancer. In a specific embodiment, the cancer is renal cancer.
  • the cancer is gastric cancer. In a specific embodiment, the cancer is thyroid cancer. In a specific embodiment, the cancer is urothelial cancer. In another specific embodiment, the cancer is selected from the group consisting of: leukemia and multiple myeloma.
  • the patient is a warm-blooded animal, more preferably a human.
  • the subject receiving the ENT family transporter inhibitor is treated with an additional therapeutic agent in combination with the inhibitor of the ENT family transporter, or has received the additional therapeutic agent within about fourteen days of administration of the inhibitor of the ENT family transporter.
  • the additional therapeutic agent comprises an adenosine receptor antagonist.
  • the subject has previously received at least one prior therapeutic treatment, and has progressed subsequent to the administration of the at least one prior therapeutic treatment and prior to administration of the inhibitor of an ENT family transporter.
  • the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
  • the invention also relates to a pharmaceutical formulation for use in the treatment of a cancer, wherein the pharmaceutical formulation is administered to a human subject in an amount effective to treat the cancer, and wherein the formulation comprises:
  • the ENT family transporter is ENT1
  • the inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a peptide, and an antibody.
  • the pharmaceutical formulation further comprises an additional therapeutic agent.
  • the additional therapeutic agent comprises an adenosine receptor antagonist.
  • the pharmaceutical formulation for use of the invention he subject has previously received at least one prior therapeutic treatment.
  • the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
  • the pharmaceutical formulation is administered prior to, concomitant with, or subsequent to administration of the additional therapeutic agent comprising an adenosine receptor antagonist.
  • the invention also provides a pharmaceutical formulation for use in the treatment of a cancer, wherein the pharmaceutical formulation is administered to a human subject in an amount effective to treat the cancer, and wherein the formulation comprises:
  • the adenosine receptor antagonist comprises an A2A or A2B receptor antagonist.
  • the adenosine receptor antagonist is selected from:
  • the adenosine receptor antagonist comprises a compound of formula (I) as previously defined.
  • the invention also provides a method of treating a cancer comprising administering a pharmaceutical formulation to a human subject in an amount effective to treat the cancer, wherein the formulation comprises:
  • the ENT family transporter is ENT1
  • the inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a peptide, and an antibody.
  • the pharmaceutical formulation further comprises an additional therapeutic agent.
  • the additional therapeutic agent comprises an adenosine receptor antagonist.
  • the subject has previously received at least one prior therapeutic treatment.
  • the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery.
  • the pharmaceutical formulation is administered prior to, concomitant with, or subsequent to administration of the additional therapeutic agent comprising an adenosine receptor antagonist.
  • the invention also provides a method of treating a cancer comprising administering a pharmaceutical formulation to a human subject in an amount effective to treat the cancer, wherein the formulation comprises:
  • the adenosine receptor antagonist comprises an A2A or A2B receptor antagonist.
  • the adenosine receptor antagonist is selected from:
  • the adenosine receptor antagonist comprises a compound of formula (I) as previously defined.
  • Figures 1A, IB and 1C are graphs representing the expression of ENT1, ENT2 and ENT4, respectively, in human primary lymphocytes.
  • FPKMs Fragments Per Kilobase Million.
  • Source Bonnal RJP, Nature 2015.
  • Figure 2A and 2B are graphs representing viability of CD3+ T cells under different treatments and show the reversal of Adenosine/ ATP-mediated reduction in T cell viability by ENT inhibitors.
  • Human primary CD3+ T cells were stimulated with antiCD3/antiCD28 -coated microbeads, and treated with 25 mM adenosine (Figure 2A) or
  • Figures 3A, 3B, 3C and 3D are graphs representing proliferation of CD4+ T cells and CD8+ T cells under different treatments and show rescue of Adenosine/ATP-mediated suppression of T cell proliferation by ENT inhibitors.
  • Human primary CD3+ T cells were stimulated with antiCD3/antiCD28 -coated microbeads, and treated with 25 pM adenosine ( Figures 3A and 3C) or 200 pM ATP ( Figures 3B and 3D).
  • Proliferation of CD4+ ( Figures 3A and 3B) and CD 8+ ( Figures 3C and 3D) T cells was analysed by flow cytometry after a 3 days incubation period. Mean +/- SD of biological replicates are shown. Representative data for 1 healthy donor are shown.
  • Figures 4A and 4B are graphs representing IL-2 secretion by CD3+ T cells under different treatments and show rescue of Adenosine/ ATP-mediated suppression of T cell cytokine secretion by a combination treatment with ENT inhibitors and A 2A R antagonist Compound 8a.
  • CD3+ T cells were stimulated with antiCD3/antiCD28-coated microbeads, and treated with 25 mM adenosine ( Figure 4A) or 200 mM ATP ( Figure 4B).
  • IF-2 secretion in the supernatant was analysed by AlphaFISA after a 3 days incubation period. Mean +/- SD of biological replicates are shown. Representative data for 1 healthy donor are shown. Similar data were obtained in 2 healthy donors.
  • Figure 5A shows the viability of CD3+ T cells as determined by staining with a fixable viability dye.
  • Figure 5B shows the proportion of proliferating CD8+ T cells as determined by CFSE dilution.
  • Figure 5C shows the concentration of TNFa present in the cell culture supernatants.
  • Human primary CD3+ T cells were stimulated with antiCD3/antiCD28 -coated microbeads, and treated with 100 pM ATP or control medium.
  • Viability of CD3+ T cells ( Figure 5A) and proliferation of CD8+ T cells were analysed by flow cytometry after a 3 days incubation period. TNFa secretion in the supernatant was analysed by AlphaFISA.
  • Figure 6 shows in vivo EPS induced TNFalpha production in mouse, upon prior treatment with Compound 8b (A2AR antagonist) or NBMPR (ENT1 inhibitor) or the combination thereof.
  • BAFB/c mice were pretreated for lh before EPS (lmg/kg I.V) injection with NBMPR (20mg/kg p.o.) or vehicle. Thirty minutes prior mice were treated with a single dose of Compound 8b (3mg/kg p.o.) or vehicle.
  • Figure 7 shows the MCA205 tumor growth upon treatment with Compound 8b (A2AR antagonist) used in combination with NBMPR (ENT1 inhibitor).
  • Figure 7A is a graph representing the median tumor volume over time after subcutaneous inoculation of tumor cells.
  • BSA bovine serum albumin
  • EDTA ethylenediaminetetraacetic acid
  • FACS fluorescence-activated cell sorting
  • FBS fetal bovine serum
  • PBS phosphate buffered saline
  • Reagents and compounds used in the following assays have the following sources:
  • CD3 + T cells were isolated by immunomagnetic negative selection, using the EasySep Human T Cell Isolation Kit as per manufacturer’s instructions. CD3 + T cells were stored in heat inactivated FBS and 10% DMSO in liquid nitrogen.
  • Human primary T cell culture Human purified CD3 + T cells were thawed and washed twice with RPMI1640 medium, UltraGlutamine, supplemented with lx non-essential amino acids (Lonza), and lmM Sodium Pyruvate (Gibco) (complete media), containing 10% hiFBS. After the final wash, cells were resuspended in PBS containing 10% FBS, and labeled using 3 mM CFSE during 5 min at room temperature, followed by two wash steps in complete media. After the last wash, cells were suspended at I.bcIO 6 cells/mL in X-Vivol5 medium.
  • 50 pL of cell suspension (8xl0 4 T cells) was added to wells of sterile round-bottom 96-well plates.
  • Cells were activated by adding 50 pL of anti-CD3 anti- CD28 coated microbeads (Dynabeads human T-activator CD3/CD28), suspended in X- Vivol5 medium, at a ratio of one microbead per two cells.
  • Adenosine stock solution of 75mM in DMSO
  • ATP powder
  • A2AR antagonist Compound 8a received either the A2AR antagonist Compound 8a at a final concentration of 300 nM, NIR178 at a final concentration of 5 pM, CPI-444 at a final concentration of 5 pM, AZD4635 at a final concentration of 1 pM, or AB928 at a final concentration of 1 pM, or a matched concentration of DMSO.
  • some wells received the ENT-l inhibitor dipyridamole at a final concentration of 1 pM, or a combination of dipyridamole and A2AR antagonist.
  • the final concentration of DMSO in the assay was 0.05%, and the final assay volume was 200 pL.
  • FACS buffer PBS containing 2mM EDTA and 0.1% BSA
  • surface marker antibodies and viability dye for 20 min on ice.
  • Cells were washed twice with FACS buffer and data acquired using an LSRFortessa (BD biosciences). Analysis was performed using FlowJo software (Treestar).
  • CD3 + T cells were stimulated with anti-CD3/CD28-coated microbeads, and treated with adenosine or ATP.
  • Adenosine as well as ATP profoundly suppressed T cell proliferation and cytokine secretion (IL-2), and strongly reduced T cell viability ( Figures 2-4).
  • Extracellular adenosine is taken up by cells by Equilibrative Nucleoside Transporters (ENTs).
  • ENTs Equilibrative Nucleoside Transporters
  • Figure 5A-C illustrates that the inhibition of T cells in the presence of ATP may be reversed by a combination of the ENT-l inhibitor dipyridamole and the A2A receptor antagonists Compound 8a, AB928, CPI-444, NIR178 and AZD4635. More specifically, ATP significantly inhibited CD8+ T cell proliferation and reduced T cell viability which was completely reversed by the ENT-l inhibitor dipyridamole. ATP also significantly inhibited the production of TNFa. Both the A2AR and the ENT-l inhibitors individually could partially restore cytokine production. The combination of both inhibitors further increased the restoration of cytokine secretion compared to either treatment alone.
  • ENT inhibitors regulate the import and export of nucleosides for example, adenosine across cell membranes such that inhibition of the equilibrative nucleoside transport may decrease the concentration of adenosine inside the cell and allow accumulation of adenosine extracellularly.
  • High intracellular adenosine has been shown to lead to suppression of proliferation, survival and function of immune cells.
  • extracellular adenosine by binding to the adenosine receptor 2 A decreases activation and function, such as for example pro-inflammatory cytokine production and cytotoxicity of immune cells.
  • A2AR adenosine receptor 2 A
  • Inhibition of equilibrative transporters therefore aims to decrease intracellular adenosine and thereby improving immune cell survival, proliferation and function, while A2AR inhibition aims to restore pro- inflammatory activity, cytotoxicity and immune cell activation by inhibiting extracellular adenosine.
  • NBMPR (6-S-[(4-Nitrophenyl)methyl]-6-thioinosine) is a specific ENT1 inhibitor and has similar activity in humans and mice. NBMPR is therefore used in mouse models to specifically inhibit the activity ENT1.
  • LPS Lipopolysaccharides
  • A2AR antagonist Compound 8b
  • ENT1 inhibitor NBMPR
  • MCA205 tumor cells were inoculated subcutaneously into the right flank of C57BL/6 mice. When tumors reached an average size of about 50 mm 3 , mice were randomly allocated into groups. Mice were administered vehicle p.o. (2.5% DMSO, 10% Solutol HS15 in dH 2 0 pH3) as control or NBMPR at 20 mg/kg p.o. BIDx22 (day7-29) as single agent or in combination with Compound 8b p.o. at 3 mg/kg QDx22 (day7-29).

Abstract

La présente invention concerne l'utilisation d'un inhibiteur d'un transporteur de la famille des ENT pour le traitement du cancer. L'invention concerne en outre l'utilisation combinée d'un tel inhibiteur d'un transporteur de la famille des ENT avec un antagoniste du récepteur de l'adénosine, pour le traitement du cancer. L'invention concerne en outre une composition pharmaceutique et un kit d'éléments comprenant une telle combinaison.
PCT/EP2019/076244 2018-09-27 2019-09-27 Utilisation d'un inhibiteur d'un transporteur de la famille des ent dans le traitement du cancer et de la combinaison de ceux-ci avec un antagoniste du récepteur de l'adénosine WO2020065036A1 (fr)

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JP2021517484A JP2022503879A (ja) 2018-09-27 2019-09-27 がん治療におけるｅｎｔファミリートランスポーター阻害剤の使用及びそのアデノシン受容体アンタゴニストとの組み合わせ
US17/281,156 US20210338672A1 (en) 2018-09-27 2019-09-27 Use of an inhibitor of an ent family transporter in the treatment of cancer and combination thereof with an adenosine receptor antagonist
MX2021003500A MX2021003500A (es) 2018-09-27 2019-09-27 Uso de un inhibidor de un transportador de la familia ent en el tratamiento del cáncer y su combinación con un antagonista del receptor de adenosina.
CA3113886A CA3113886A1 (fr) 2018-09-27 2019-09-27 Utilisation d'un inhibiteur d'un transporteur de la famille des ent dans le traitement du cancer et de la combinaison de ceux-ci avec un antagoniste du recepteur de l'adenosine
AU2019350454A AU2019350454A1 (en) 2018-09-27 2019-09-27 Use of an inhibitor of an ENT family transporter in the treatment of cancer and combination thereof with an adenosine receptor antagonist
KR1020217012382A KR20210086625A (ko) 2018-09-27 2019-09-27 암 치료에서 ent 계열 운반체 억제제의 용도 및 아데노신 수용체 길항제와 이의 조합물
EP19780208.5A EP3856181A1 (fr) 2018-09-27 2019-09-27 Utilisation d'un inhibiteur d'un transporteur de la famille des ent dans le traitement du cancer et de la combinaison de ceux-ci avec un antagoniste du récepteur de l'adénosine
CN201980076736.8A CN113164462A (zh) 2018-09-27 2019-09-27 Ent家族转运蛋白的抑制剂在癌症治疗中的用途及其与腺苷受体拮抗剂的组合
BR112021006033-2A BR112021006033A2 (pt) 2018-09-27 2019-09-27 Uso de um inibidor de um transportador da família ent no tratamento de câncer e combinação do mesmo com um antagonista do receptor de adenosina
IL281802A IL281802A (en) 2018-09-27 2021-03-25 Use of an inhibitor of an ent family transporter in the treatment of cancer and combination thereof with an adenosine receptor antagonist

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WO2021110697A1 (fr) * 2019-12-02 2021-06-10 Astrazeneca Ab Formulations pharmaceutiques solides de 6- (2-chloro-6-méthylpyridin-4-yl)-5-(-4-fluorophényl)-1,2,4-triazin-3-amine
WO2022178135A1 (fr) 2021-02-17 2022-08-25 Iteos Belguim Sa Composés, compositions et procédés de traitement de ces derniers
WO2023059739A1 (fr) * 2021-10-06 2023-04-13 iTeos Belgium SA Composés macrocycliques ayant une activité d'inhibition de l'ent1
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