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WO2017052360A1 - Composés s'utilisant comme agents anticancéreux - Google Patents

Composés s'utilisant comme agents anticancéreux Download PDF

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Publication number
WO2017052360A1
WO2017052360A1 PCT/MY2016/050058 MY2016050058W WO2017052360A1 WO 2017052360 A1 WO2017052360 A1 WO 2017052360A1 MY 2016050058 W MY2016050058 W MY 2016050058W WO 2017052360 A1 WO2017052360 A1 WO 2017052360A1
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Prior art keywords
cancer
compound
cell
tumours
treatment
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Inventor
Chern Ein OON
Soo Choon Tan
Keng Yoon YEONG
Mohamed Ashraf Ali
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Universiti Sains Malaysia (USM)
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Universiti Sains Malaysia (USM)
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention is directed to the use of a compound (BZD9L1 ) that inhibits sirtuin enzymes.
  • S irtuins are NAD+ -dependent class ⁇ histone deacetylases (HDACs) that share extensive homologies with the yeast silent information regulator 2 (S IR2).
  • HDACs histone deacetylases
  • S IRTT7 seven proteins that possess NAD-dependent deacetylase, deacylase, and ADP-ribosyltransferase activities.
  • S irtuins have different subcellular localization, clearly reZecting the distinctive features of each sirtuin member.
  • S IRT1, S IRT6, and S IRT7 are mainly nuclear, S IRT2 is predominantly cytoplasmic, although nucleo- cytoplasmic shuttling has been reported, and S IRT3, S IRT4, and S IRT5 are largely localized to the mitochondria .
  • sirtuin inhibitors such as S irtinol, Tenovin-6, S alermide and Cambinol, which targets S IRT1 and/or S IRT2, have been associated with antitumour activities in vitro and in vivo.
  • sirtuin modulators usually vary in potency, depending on their chemical modifications, sirtuin expression and localization, cell-cycle phase and the complex roles of each sirtuin. Therefore the search for more potent and selective sirtuin modulators remains a significant area of pharmaceutical research. It is well established that cancer is an epigenetic as well as a genetic disease. Modifications in oncogenes or tumor suppressor genes are not only triggered by mutations, but they may also be due to post-translational modification that regulates the acetylation and deacetylation of histones and nonhistone proteins. S irtuins play a crucial role in the regulation of metabolism, differentiation, cell cycle progression, senescence and cell death.
  • S IRT1 and S IRT2 have been demonstrated to play a role in carcinogenesis, both as positive drivers and also negative regulators of tumourigenesis, as their functions are frequently altered in cancer cells.
  • S IRT1 and S IRT2 have been demonstrated to play a role in carcinogenesis, both as positive drivers and also negative regulators of tumourigenesis, as their functions are frequently altered in cancer cells.
  • S IRT1 and S IRT2 have found S IRT1 and S IRT2 to be implicated in tumorigenesis and drug resistance through deacetylation of numerous targets (Oon et al., unpublished).
  • S IRT1 and S IRT2 are involved in tumourigenesis through deacetylation of numerous histone and non-histone proteins.
  • S IRT1 and S IRT2 are implicated in growth regulation and tumourigenesis.
  • S IRT1 and S IRT2 provide a tumour cell survival advantage and resistance to therapy by inhibiting apoptosis, resisting senescence and allowing unchecked cell division.
  • S irtuin-2 (S IRT2), which acts as a G2 checkpoint mitotic regulator is crucial in cell cycle regulation, hence making it a potential target for cancer therapeutics.
  • Down-regulation of S IRT2 has been shown to impede cell cycle progression and induce cell-cycle arrest, while overexpression has been reported to cause prolongation of the mitotic phase of the cell cycle leading to the inhibition of cell proliferation.
  • the present invention is directed to the usefulness of compounds of formula I as an anti-cancer agent and in particular inhibition of sirtuin enzymes using said compounds.
  • R 1 represents hydrogen, halogen, hydroxyl, carboxyl, C 1-5 alkyl, imidazolyl, piperazinyl, morpholinyl, benzyl, R 4 OH or R 4 C OOH, where R 4 is (C l-h)TM and m is an integer of from 1 to 4;
  • R 2 represents hydrogen, phenyl or 3-(2-oxopyrrolidin-1 -yl)propyl
  • R 3 represents OR 5 or NR 6 R 7 ;
  • R 5 represents C 1-6 alkyl (e.g. ethyl).
  • R 6 and R 7 are independently H, N H2 (provided at least one is H), C i-e alkyl or, together with the N form a heterocyclic group having from 1 to 5 carbon atoms, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof,
  • the compound comprises a hydrogen at R 2 and/or an ethyl group at R 5 .
  • the invention also includes salts, solvates, prodrugs and metabolites of the compounds ethyl 2-phenyl-1 H-benzo[d]imidazole-5-carboxylate, ethyl 2-(4-bromophenyl)-1 H-benzo[d]imidazole- 5-carboxylate and ethyl 2-(4-(piperidin-1 -yl)phenyl-1 H-benzo[d]imidazole-5-carboxylate, and (BZD9L1 ) as disclosed herein.
  • the cancer to be treated may be selected from the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumours, C NS tumours, breast cancer, Castleman disease, cervical cancer, colon cancer, rectum cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIS T), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g.
  • acute lymphocytic acute myeloid, chronic lymphocytic, chronic myeloid, chronic myelomonocytic
  • liver cancer e.g. small cell or non-small cell
  • lung cancer e.g. small cell or non-small cell
  • lung carcinoid tumour e.g. lymphoma
  • malignant mesothelioma multiple myeloma, myelodys plastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumours, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (e.g.
  • basal and squamous cell basal and squamous cell, melanoma, Merkel cell
  • small intestine cancer stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumour.
  • the cancer to be treated may be selected from the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumours, C NS tumours, Castleman disease, cervical cancer, rectum cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIS T), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, liver cancer, malignant mesothelioma, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumours, prostate cancer, retinoblastoma, rhabdom
  • the cancer is selected from the group consisting of gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIS T), kidney cancer, pancreatic cancer, skin cancer (e.g. basal and squamous cell, melanoma, Merkel cell), small intestine cancer, and stomach cancer.
  • GIS T gastrointestinal stromal tumor
  • kidney cancer pancreatic cancer
  • skin cancer e.g. basal and squamous cell, melanoma, Merkel cell
  • small intestine cancer and stomach cancer.
  • the other compound when the use is as an adjuvant/neo-adjuvant therapeutic agent in the treatment of cancer, the other compound may be RO4929097 Notch inhibitor, 5- fluorouracil or cisplatin.
  • a pharmaceutical formulation comprising a compound of formula I as defined hereinbefore, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the compounds of formula l and conditions may be the same as the first aspect of the invention.
  • the other compound when the use is as an adjuvant/neo-adjuvant therapeutic agent in the treatment of cancer, the other compound may be R 04929097 Notch inhibitor, 5-fluorouracil or cisplatin.
  • R 1 is selected from the groups consisting of Hydrogen, halogen, hydroxyl, carboxyl, alkyl of up to 5 carbon atoms, imidazolyl, piperazinyl, morpholinyl, benzyl, R 4 OH or R 4 COOH, where R 4 is (C l-h)TM and m is an integer of from 1 to 4;
  • R 2 is selected from the group consisting of hydrogen, phenyl or 3-(2-oxopyrrolidin-1 -yl)propyl; and where R 3 is OR 5 or NR 6 R 7 .
  • R 5 can be C 1 -6 alkyl, preferably ethyl and R 6/7 are independently H, H2 (provided other one is H), C 1 -6 alkyl or, together with the N for a heterocyclic group having from 1 to 5 carbon atoms, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
  • R 2 is hydrogen.
  • angiogenesis is selected from one or more of the group consisting of leukemia, AIDS complications (e.g. Karposi S arcoma) or more particularly hemangioma, or, yet more particularly, inflammation (e.g. including rheumatoid arthritis), immunomodulation, retinal/blinding diseases (e.g. macular degeneration), skin diseases (e.g. psoriasis, keloids, rosacea, dermatitis), retinopathy, Alzheimer ' s disease, cerebral malaria, fibrosis, ischemic chronic wounds, endometriosis, obesity and other metabolic diseases.
  • leukemia e.g. Karposi S arcoma
  • inflammation e.g. including rheumatoid arthritis
  • immunomodulation e.g. macular degeneration
  • skin diseases e.g. psoriasis, keloids, rosacea, dermatitis
  • retinopathy e.g. psoriasis,
  • a method of treatment of a condition or disorder ameliorated by the inhibition of angiogenesis comprises the administration of an effective amount of a compound of formula l as defined in clause 1, or a pharmaceutically accepta ble salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment.
  • condition or disorder ameliorated by the inhibition angiogenesis is selected from one or more of the group consisting of leukemia, AIDS complications (e.g. Karposi S arcoma) or more particularly hemangioma, or, yet more particularly, inflammation (e.g. including rheumatoid arthritis), immunomodulation, retinal/blinding diseases (e.g. macular degeneration), skin diseases (e.g. psoriasis, keloids, rosacea, dermatitis), retinopathy, Alzheimer ' s disease, cerebral malaria, fibrosis, ischemic chronic wounds, endometriosis, obesity and other metabolic diseases.
  • leukemia e.g. Karposi S arcoma
  • inflammation e.g. including rheumatoid arthritis
  • immunomodulation e.g. macular degeneration
  • skin diseases e.g. psoriasis, keloids, rosacea, dermatitis
  • retinopathy e.g.
  • a pharmaceutical formulation including a compound of formula I as defined in any one of clauses 1 to 4, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • F igure 1 is the in vitro data showing BZD9L1 effectively reduced viability of leukemia (CC R F- C E M), colon (HCT-1 16) and breast (MDA-MB-468) cancer cell lines 72 hour post- treatment.
  • F igure 3 BZD9L1 reduced colony formation of HCT1 16, HT29, LIM1215 and Caco-2 colorectal cancer cells compared to control untreated. 5-F luorouracil was used as positive control.
  • BZD9L1 significantly reduced viability of breast cancer cell lines compared to MC F 10A normal breast cells. Data is normalized to untreated control.
  • B) IC50 of BZD9L1 in a panel of breast cell lines. Data is presented in the mean e S E M of duplicate (n 2) and ANOVA test f, P ⁇ 0.05, ** P ⁇ 0.01, ***, P ⁇ 0.001, ****, P ⁇ 0.0001 ).
  • F igure 7 is the in vitro data showing BZD9L1 and 5-fluorouracil (5-F U) significantly decreased cell viability of HCT116 colorectal cancer cell line with synergistic effect detected in combination treatment group 72 hour post- treatment.
  • F igure 10 A) data showing BZD9L1 in combination with 5-F luorouracil induced cell cycle arrest at S phase in HCT1 16 cell lines.
  • F igure 1 1 BZD9L1 induced expression of calreticulin as a marker for immunogenic cell death in MKN7, MKN28, MKN74, NUG-C3, NCI-N87 and MKN45 gastric cancer cell lines.
  • F igure 12 is the in vitro data showing BZD9L1 significantly reduced cell viability of EAHY 926 endothelial cells 72 hour post- treatment.
  • F igure 13 is the data showing dose dependent effect of BZD9L1 on apoptosis and necrosis cell death 72 hour post- treatment.
  • F igure 14 is the data showing BZD9L1 (50 ⁇ M) arrested EAHY 926 endothelial cells at G2/M phase 72 hour post-treatment.
  • F igure 15 is the data showing dose dependent effect of BZD9L1 on sprouting angiogenesis as depicted in the rat aortic ring assay (400x magnifications).
  • F igure 16 depicts data showing that the S IRT1 inhibitor EX527 increases C D34 vessel markers versus control groups.
  • F igure 17 is the synthetic scheme for the claimed novel anti-cancer compound (BZD9L1 ).
  • F igure 19 depicts data showing that BZD9L1 decreased HCT1 16 spheroid viability in a dose dependent manner through induction of cell death, as indicated by calcein AM (green) and P ropidium iodide (red) staining for live and dead cells respectively.
  • Cell nuclei were la bled with DAPI (blue).
  • E toposide was used as positive control for induction of cell death.
  • S pheroids were imaged using Zeiss live cells imaging fluorescent/phase microscope under 10x
  • F igure 20 is the data showing the effect of IC 50 BZD9L1 on the regulation of cancer pathways.
  • the data is a representation of mean e S E M determination using G raphPad P rism 6 software (* P ⁇ 0.05, ** P ⁇ 0.01 , ***, P .001, student s t-test).
  • F igure 21 is the data showing BZD9L1 induces reactive oxygen species (R OS ) in colorectal cancer cell line.
  • F igure 22 is the data showing that BZD9L1 reduces viability of stomach and renal cancer.
  • S tomach cancer cell line MKN74 and Kato3, and renal cancer cell line A498 and 786-0 were seeded with a density of 5000cells/well in 96-well plate and treated/untreated with BZD9L1 for 72h.
  • R 1 represents hydrogen, halogen, hydroxyl, carboxyl, C i- 5 alkyl, imidazolyl, piperazinyl, morpholinyl, benzyl, R 4 OH or R 4 C OOH, where R 4 is (C l-h)TM and m is an integer of from 1 to 4;
  • R 2 represents hydrogen, phenyl or 3-(2-oxopyrrolidin-1 -yl)propyl
  • R 3 represents OR 5 or NR 6 R 7 ;
  • R 5 represents C i-6 alkyl (e.g. ethyl).
  • R 6 and R 7 are independently H, H2 (provided at least one is H), C 1 -6 alkyl or, together with the N form a heterocyclic group having from 1 to 5 carbon atoms, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof,
  • references herein (in any aspect or embodiment of the invention) to compounds of formula I includes references to such compounds per se, to tautomers of such compounds, as well as to pharmaceutically acceptable salts or solvates, or pharmaceutically functional derivatives of such compounds.
  • P harmaceutically acceptable salts include acid addition salts and base addition salts.
  • S uch salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration).
  • S alts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • E xamples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, or preferably, potassium and calcium.
  • E xamples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulphonic acids (e.g. benzenesulphonic, naphthalene-2-sulphonic, naphthalene-1,5-disulphonic and p-toluenesulphonic), ascorbic (e.g.
  • L- glutamic L- glutamic
  • -oxoglutaric glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (e)-DL-lactic), lactobionic, maleic, malic (e.g.
  • salts are salts derived from mineral acids such as hydrochloric, hydrobromic, phosphoric, meta phosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, meta phosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids
  • metals such as sodium, magnesium, or preferably, potassium and calcium.
  • solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).
  • a non-toxic pharmaceutically acceptable solvent referred to below as the solvating solvent.
  • examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulphoxide.
  • S olvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent.
  • Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TG E ), differential scanning calorimetry (DS C) and X-ray crystallography.
  • TG E thermogravimetric analysis
  • DS C differential scanning calorimetry
  • X-ray crystallography X-ray crystallography
  • the solvates can be stoichiometric or non-stoic hiometric solvates.
  • Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.
  • prodrug of a relevant compound of formula I includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • P rodrugs of compounds of formula I may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • P rodrugs include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in a compound of formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N- Mannich bases.
  • General information on prodrugs may be found e.g. in Bundegaard, H. ' Design of P rodrugs, p. 1-92, E lsevier, New York-Oxford (1985).
  • Compounds of formula I may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a ichira I pool " method by reaction of the appropriate starting material with a ichira I auxiliary " which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • alkyl refers to an unbranched or branched, cyclic, saturated or unsaturated (so forming, for example, an alkenyl or alkynyl) hydrocarbyl radical, which may be substituted or unsubstituted (with, for example, one or more halo atoms).
  • alkyl refers to an acyclic group, it is preferably CMO alkyl and, more preferably, G-6 alkyl or, yet more particularly, Ci- 5 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), butyl (e.g.
  • alkyl is a cyclic group (which may be where the group “cycloalkyl” is specified), it is preferably C3-12 cycloalkyl and, more preferably, C 5 -io(e.g. C5-7) cycloalkyl.
  • alkylene refers to CMO (e.g. Ci- ⁇ ) alkylene and, preferably C 1-3 a Ikylene, such as pentylene, butylene (branched or unbranched), preferably, propylene (n-propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH2-).
  • CMO e.g. Ci- ⁇ alkylene
  • Ikylene such as pentylene, butylene (branched or unbranched), preferably, propylene (n-propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH2-).
  • halogen when used herein, includes fluorine, chlorine, bromine and iodine.
  • aryl when used herein includes C6-i 4 (such as C6-13 (e.g. C6-10)) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring. Ce-1 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Most preferred aryl groups include phenyl. Compounds of formula I that may be mentioned include those of the examples described hereinafter.
  • a particular compound of formula I that may be mentioned herein is the compound of formula la.
  • a method of treatment cancer which method comprises the administration of an effective amount of a compound of formula I as defined hereinbefore, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment;
  • a method of treatment cancer which method comprises the administration of an effective amount of a compound of formula I as defined hereinbefore, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, as an adjuvant/ neo-adjuvant therapeutic agent to a patient in need of such treatment.
  • cancer will be understood by those skilled in the art to relate to a group of different diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.
  • Cancers may include: hemangioma, leukemia, colon, breast, gastric and blood cancers and solid tumours.
  • Cancers that may be mentioned herein include those selected from the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumours, C NS tumours, breast cancer, Castleman disease, cervical cancer, colon cancer, rectum cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIS T), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g.
  • acute lymphocytic acute myeloid, chronic lymphocytic, chronic myeloid, chronic myelomonocytic
  • liver cancer e.g. small cell or non-small cell
  • lung cancer e.g. small cell or non-small cell
  • lung carcinoid tumour e.g. lymphoma
  • malignant mesothelioma multiple myeloma, myelodys plastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumours, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (e.g.
  • basal and squamous cell basal and squamous cell, melanoma, Merkel cell
  • small intestine cancer stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumour.
  • the cancer may be selected from the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumours, C S tumours, Castleman disease, cervical cancer, rectum cancer, endometrial cancer, esophagus cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIS T), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, liver cancer, malignant mesothelioma, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumours, prostate cancer, retinoblastoma, rhabdomyosarcoma
  • the cancer may be selected from the group consisting of gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIS T), kidney cancer, pancreatic cancer, skin cancer (e.g. basal and squamous cell, melanoma, Merkel cell), small intestine cancer, and stomach cancer.
  • GIS T gastrointestinal stromal tumor
  • kidney cancer pancreatic cancer
  • skin cancer e.g. basal and squamous cell, melanoma, Merkel cell
  • small intestine cancer and stomach cancer.
  • the cancer is not a blood cancer, a colon cancer, a breast cancer or a thyroid cancer.
  • a method of treatment of cancer which method comprises the administration of an effective amount of a compound of formula I, as hereinbefore defined, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof.
  • a method of treatment of cancer which method comprises the administration of an effective amount of a compound of formula I, as hereinbefore defined, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof as an adjuvant/ neo-adjuvant therapeutic agent.
  • the term ' treatment includes references to therapeutic or palliative treatment of patients in need of such treatment, as well as to the prophylactic treatment and/or diagnosis of patients which are susceptible to the relevant disease states.
  • patient and patients, include references to mammalian (e.g. human) patients.
  • subject or “patient” are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human.
  • the subject is a subject in need of treatment or a subject with a disease or disorder.
  • the subject can be a normal subject. T he term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.
  • the term effective amount refers to an amount of a compound, which confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease).
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • F urther embodiments of the invention that may be mentioned include those in which the compound of formula I is isotopically labelled. However, other, particular embodiments of the invention that may be mentioned include those in which the compound of formula I is not isotopically labelled.
  • isotopically labelled when used herein includes references to compounds of formula I in which there is a non-natural isotope (or a non-natural distribution of isotopes) at one or more positions in the compound. References herein to "one or more positions in the compound” will be understood by those skilled in the art to refer to one or more of the atoms of the compound of formula I. Thus, the term “isotopically labelled” includes references to compounds of formula I that are isotopically enriched at one or more positions in the compound.
  • the isotopic labelling or enrichment of the compound of formula I may be with a radioactive or non-radioactive isotope of any of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and/or iodine.
  • a radioactive or non-radioactive isotope of any of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and/or iodine.
  • Particular isotopes that may be mentioned in this respect include 2 H, 3 H,
  • compounds of formula I When the compound of formula I is labelled or enriched with a radioactive or nonradioactive isotope, compounds of formula I that may be mentioned include those in which at least one atom in the compound displays an isotopic distribution in which a radioactive or non- radioactive isotope of the atom in question is present in levels at least 10% (e.g. from 10% to 5000%, particularly from 50% to 1000% and more particularly from 100% to 500%) above the natural level of that radioactive or non- radioactive isotope.
  • Compounds of formula I may be administered by any suitable route, but may particularly be administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, trans mucosa lly (e.g. sublingually or buccally), rectally, transdermally, nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form.
  • Particular modes of administration that may be mentioned include oral, intravenous, cutaneous, subcutaneous, nasal, intramuscular or intraperitoneal administration.
  • Compounds of formula I will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutically acceptable adjuvant, diluent or carrier may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • pharmaceutical formulations may be found in, for example, Remington The S cience and P ractice of Pharmacy, 19th ed., Mack Printing Company, E aston, Pennsylvania (1995).
  • a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability.
  • S Amble solutions will be well known to the skilled person, with numerous methods being described in the literature. A brief review of methods of drug delivery may also be found in e.g. Langer, S cience (1990) 249, 1527.
  • any pharmaceutical formulation used in accordance with the present invention will depend on various factors, such as the severity of the condition to be treated, the pa rticular patient to be treated, as well as the compound(s) which is/are employed. In any event, the amount of compound of formula I in the formulation may be determined routinely by the skilled person.
  • a solid oral composition such as a tablet or capsule may contain from 0.001 to 99 % (w/w) active ingredient; from 0 to 99% (w/w) diluent or filler; from 0 to 20% (w/w) of a disintegrant; from 0 to 5% (w/w) of a lubricant; from 0 to 5% (w/w) of a flow aid; from 0 to 50% (w/w) of a granulating agent or binder; from 0 to 5% (w/w) of an antioxidant; and from 0 to 5% (w/w) of a pigment.
  • a controlled release tablet may in addition contain from 0 to 90 % (w/w) of a release-controlling polymer.
  • a parenteral formulation (such as a solution or suspension for injection or a solution for infusion) may conta in from 0.001 to 50 % (w/w) active ingredient; and from 50% (w/w) to 99% (w/w) of a liquid or semisolid carrier or vehicle (e.g. a solvent such as water); and 0-20% (w/w) of one or more other excipients such as buffering agents, antioxidants, suspension stabilisers, tonicity adjusting agents and preservatives.
  • a liquid or semisolid carrier or vehicle e.g. a solvent such as water
  • one or more other excipients such as buffering agents, antioxidants, suspension stabilisers, tonicity adjusting agents and preservatives.
  • compounds of formula I may be administered at varying therapeutically effective doses to a patient in need thereof.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
  • Administration may be continuous or intermittent (e.g. by bolus injection).
  • the dosage may also be determined by the timing and frequency of administration.
  • the dosage can vary from about 0.001 mg to about 1000 mg per day of a compound of formula I.
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • aspects of the invention described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic tha n, have better selectivity over, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise.
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • cancer therapies such as cytostatica, irradiation and photodynamic therapy, among others known to the physician.
  • the other therapeutic agent is a cytostatic (such as a taxane (e.g. docetaxel and, particularly, paclitaxel) or preferably, a platin (e.g. cisplatin and carboplatin) or an anthracycline (e.g. doxorubicin)) or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative of either of these.
  • cytostatic such as a taxane (e.g. docetaxel and, particularly, paclitaxel) or preferably, a platin (e.g. cisplatin and carboplatin) or an anthracycline (e.g. doxorubicin)) or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative of either of these.
  • a cytostatic such as a taxane (e.g. docetaxel and, particularly, paclitaxel) or preferably, a platin (e.g. cisp
  • an aromatase inhibitor i.e. a compound that blocks the production of estrogen from adrenal androgens via the aromatase pathway in peripheral tissues
  • a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof P referred AIs include anastrozole, letrozole and exemastane;
  • trastuzumab Herceptin
  • another antibody that is useful in the treatment of cancer such as bevacizumab, cetuximab or panitumumab;
  • a tyrosine kinase inhibitor i.e. a compound that blocks (or is capable of blocking), to a measurable degree, the autophosphorylation of tyrosine residues, thereby preventing activation of the intracellular signalling pathways in tumor cells
  • a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof i.e. a compound that blocks (or is capable of blocking), to a measurable degree, the autophosphorylation of tyrosine residues, thereby preventing activation of the intracellular signalling pathways in tumor cells
  • P referred TKIs include inhibitors of the vascular endothelial growth factor (VE G F) family, and/or the HE R-family of TKs, such as HE R- 1 /Human E pidermal G rowth Factor (E G F R; erbB1 ), H E R3 (erbB3), HE R4 (erbB4) and, more particularly, HE R2 (e toB2).
  • VE G F vascular endothelial growth factor
  • HE R-family of TKs such as HE R- 1 /Human E pidermal G rowth Factor (E G F R; erbB1 ), H E R3 (erbB3), HE R4 (erbB4) and, more particularly, HE R2 (e toB2).
  • P referred TKIs thus include imatinib, gefitinib, erlotinib, canertinib, sunitinib, zactima, vatalanib, sorafenib, leflunomide and, particularly, lapatinib; (v) a glitazone, such as troglitazone, pioglitazone and rosiglitazone, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • a biguanide such as phenformin, buformin, or, most preferably, metformin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • statin such as fluvastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin and, particularly, lovastatin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • rapamycin an inhibitor of activity of the mammalian target of rapamycin (mTOR), such as rapamycin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • an oligomycin such as oligomycin A, oligomycin B, oligomycin C, oligomycin D (rutamycin A), oligomycin E, oligomycin F, rutamycin B, 44-homooligomycin A and 44- homooligomycin B, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • AICAR aminoimidazole carboxamide ribonucleotide
  • a peroxisome proliferator-activated receptor (P PAR) agonist (which also include thiazolidinediones), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • AM251 (a C Bi receptor antagonist), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;
  • agonist we include direct and indirect-acting agonists
  • a notch inhibitor e.g. RO4929097
  • the compounds may be RO4929097 Notch inhibitor, 5-fluorouracil or cisplatin.
  • combination products according to the invention are particularly useful in the treatment of E R-positive cancers and/or early-stage breast cancers, for example in adjuvant therapy (i.e. reducing the risk of the cancer coming back after surgery), in neo-adjuvant therapy (before surgery, to shrink a large breast cancer so that a lumpectomy is possible), in the control of breast cancers that have come back after initial treatment, or in the control of breast cancers that cannot be removed when first diagnosed.
  • adjuvant therapy i.e. reducing the risk of the cancer coming back after surgery
  • neo-adjuvant therapy before surgery, to shrink a large breast cancer so that a lumpectomy is possible
  • S uch combination products according to the invention are also particularly useful in the treatment of patients at a high risk of breast cancer.
  • combination products according to the invention are particularly useful in the treatment of HE R2-positive cancers.
  • P harmaceutically-acceptable salts, solvates or pharmaceutically functional derivatives of any of the compounds listed in categories (i), (ii) and (iv) to (xvii) above are as described hereinbefore.
  • preferred pharmaceutically- acceptable salts include those of citric acid
  • preferred pharmaceutically-acceptable salts include mesylate salts
  • preferred pharmaceutically-acceptable salts include maleate salts.
  • F urther compounds that may be mentioned in combination with the compound of formula I include 5-flurouracil and R 04929097.
  • Combination products as described herein provide for the administration of compound of formula I in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of formula I, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of formula I and the other therapeutic agent).
  • compositions including a compound of formula I; another therapeutic agent useful in the treatment of cancer; and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • kits of parts comprising components: (a) a pharmaceutical formulation including a compound of formula I in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • a pharmaceutical formulation including another therapeutic agent useful in the treatment of cancer, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • Components (a) and (b) of the kits of parts described herein may be administered simultaneously or sequentially.
  • a method of making a kit of parts as defined above comprises bringing component (a), as defined above, into association with a component (b), as defined above, thus rendering the two components suitable for administration in conjunction with each other.
  • components (a) and (b) of the kit of parts may be:
  • kit of parts comprising: (I) one of components (a) and (b) as defined herein; together with (II) instructions to use that component in conjunction with the other of the two components.
  • kits of parts described herein may comprise more than one formulation including an appropriate quantity/dose of compound of formula I, and/or more than one formulation including an appropriate quantity/dose of the other therapeutic agent, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical compos ition(s) and/or physical form(s).
  • kits of parts as described herein by “administration in conjunction with”, we include that respective formulations comprising compound of formula l and the other therapeutic agent are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition.
  • the term "administration in conjunction with” includes that the two components of the combination product (compound of formula I and the other therapeutic agent) are administered (optionally repeatedly), either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising compound of formula I, or a formulation comprising the other therapeutic agent, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.
  • the term "in conjunction with” includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component.
  • the terms “administered simultaneously” and “administered at the same time as” include that individual doses of compound of formula I and the other therapeutic agent are administered within 48 hours (e.g. 24 hours) of each other.
  • the compounds/combinations/methods/uses described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise.
  • 4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (10mL) by refluxing at 65 eC for 6 hours.
  • Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin (II) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour.
  • the resulting mixture was then treated with benzaldehyde (0.3 mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour.
  • the solution was cooled to room temperature and subsequently evaporated under reduced pressure.
  • This compound is prepared using the method as described above for ethyl 2-phenyl-1 H- benzo[d]imidazole-5-carboxylate except bromobenzaldehyde is used instead of benzaldehyde.
  • 4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (10mL) by refluxing at 65 eC for 6 hours.
  • Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin ( ⁇ ) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour.
  • T he resulting mixture was then treated with bromobenzaldehyde (0.3 mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour.
  • T he solution was cooled to room temperature and subsequently evaporated under reduced pressure.
  • Table 1 lists the half maximal inhibitory concentration (IC50) of BZD9L1 in inhibiting SIRT1 and SIRT2 activities compared to commercial sirtuin inhibitors.
  • BZD9L1 As shown in Table 1, the IC 5 o of BZD9L1 for SIRT1 is better than most commercial sirtuin inhibitors (AGK2, Cambinol, Salermide, Sirtinol and Tenovin-6). This is also true for the inhibitory effect of BZD9L1 on SIRT2, which is better than all of the commercial sirtuin inhibitors it was compared with, except AGK2. As inhibitors of sirtuin enzymes have been reported to have anti-cancer properties, BZD9L1 is a prospective anti-cancer agent.
  • BZD9L1 against three tumour cell lines derived from leukemia (CC R F-C E M), colon (HCT-116) and breast (MDA-MB-468) cancer were subsequently tested.
  • BZD9L1 showed significant cytotoxic effects against all three tumour cell lines, especially colon cancer cells.
  • CyQUANT ⁇ cell proliferation assay (Life Technology) was carried out to compare the effect of IC 50 BZD9L1 on LIM1215, HCT 116, HT29 colorectal cancer cells to CC D 18Co normal colon fibroblast cell line at 48 hr (F igure 2A).
  • the extent of Caco-2, LIM1215, HCT1 16 and HT29 colorectal cell proliferation was determined by quantifying the nucleic acids of viable cells 72hr post treatment with BZD9L1 , EX527, AG K2, Cambinol, Tenovin-6, 5-F luorouracil (positive control for cell death) or vehicle controls at 72h using CyQUANT ⁇ assay (Life Technologies) (F igure 5).
  • BZD9L1 significantly reduced cell viability and cell survival of HCT116, HT29 and LIM1215 colorectal cancer cells (F igure 2B).
  • BZD9L1 reduced colorectal cancer cell colony formation (F igure 3) and induced cell death in HT29 colorectal tumour spheroids to mimic the tumour microenvironment (F igure 4).
  • both BZD9L1 and Tenovin-6 reduced cell viability at a lower IC 50 ( Figure 5).
  • C lonogenic assay is an in vitro cell survival assay based on the ability of a single cell to grow into a colony after drug treatment. In our work, this assay serves as a useful tool to test whether BZD9L1 can reduce the clonogenic survival of tumour cells.
  • HCT116, HT29, Caco2 and LIM1215 cells were seeded out in appropriate dilutions. Cells were treated with respective IC 50, IC75 and IC90 of BZD9L1 for 3 days and left to form colonies for 10 days. Colonies were fixed with glutaraldehyde (6.0% v/v) and stained with crystal violet (0.5% w/v).
  • HT29 colorectal cancer spheroids were generated using the Perfecta3D ⁇ Hanging Drop Plates P rotocols (3D Biomatrix) according to manufacturer s standard protocol. S pheroids were treated with 25 I M of BZD9L1 for 3 days prior to staining with DAPI (blue) to label the nucleus and propidium iodide (red) to label dead cells. S pheroids treated with BZD9L1 exhibited apoptotic cell death compared to control untreated. MTT assay
  • CyQUANT ⁇ cell proliferation assay (Life Technology) was carried out to study the effect of BZD9L1 in combination with standard chemotherapy drugs such as 5-fluorouracil (F igure 7), C isplatin (F igure 8), and a new drug on clinical trial RO4929097 Notch inhibitor (Roche) (Gounder et al., 2012) (F igure 9) on HCT1 16 or LIM1215 colorectal cancer cells.
  • the extent of cell viability was determined by quantifying the nucleic acids of viable cells 72hr post treatment with BZD9L1 or vehicle control using CyQUANT ⁇ assay (Life Technologies) (F igure 7).
  • BZD9L1 and 5-fluorouracil (5-F U) (F igure 7), C isplatin (F igure 8) or R O4929097 Notch inhibitor (F igure 9) synergistically decreased HCT116/ LIM1215 cell viability compared to the use of either compound alone.
  • the synergistic effect of BZD9L1 and 5- fluorouracil was shown to be through increased cell cycle arrest (F igure 10a) and apoptotic cell death (Figure 10b). This suggests that BZD9L1 can be further exploited as an anti-cancer agent alone or as an adjuvant in combination with another therapeutic agent.
  • P ropidium iodide was used in conjunction with Annexin V to determine if cells were viable, apoptotic, or necrotic through differences in plasma membrane integrity and permeability.
  • HCT1 16 cells were treated with BDZ9L1 and/or 5-F luorouracil for 72hrs.
  • Cell membranes were lysed with a hypotonic buffer (4mM S odium C itrate, 0.1 %T ritonX-100) containing 0.1 mM propidium iodide (PI), 2.5 ⁇ g/ml Annexin V and 50 mg/ml R NaseA (LifeTechnologies) for 20 min at 4 °C under mild agitation.
  • Dying tumour cells can elicit a potent anticancer immune response by exposing calreticulin on the cell surface prior to apoptosis cell death (see refs below). This can be targeted by the immune response to further activate a cascade of immunological response associated with T cells for effective tumour clearance.
  • MKN7, MKN28, MKN74, NUG-C3, NCI-N87 and MKN45 gastric cancer cell lines were treated with 100 ⁇ M BDZ9L1 for 72hrs.
  • F low cytometry was carried out to quantify the expression of calreticulin expression the cell surface according to Panaretakis et a I., 2009. S ee F igure 1 1.
  • BZD9L1 was examined for its effect on the growth of EAHY926 endothelial cells.
  • the extent of proliferation was determined by comparing EAHY926 endothelial cell counts for samples treated with different doses of BZD9L1 to that of untreated controls using CyQUANTs assay (LifeTechnologies). Cells were incubated with CyQUANT reagent according to the standard manufacturer's protocol. F luorescence intensities of samples were measured with a fluorescence microplate reader (Infinite 200TE CAN) using excitation at 485nm and fluorescence detection at 530nm.
  • EAHY926 cells were treated with different doses of BDZ9L1 for 72hrs.
  • Cell membranes were lysed with a hypotonic buffer (4mMS odiumC itrate, 0.1 %TritonX-100) containing 0.1 mM propidium iodide (PI), 2.5 ⁇ g/ml Annexin V and 50 mg/ml R NaseA (LifeTechnologies) for 20 min at 4 °C under mild agitation. Aggregates were removed by filtration trough a 40 mm cell strainer.
  • the total nuclei fluorescence F L2-A was measured under exclusion of debris/aggregates via the F L2-W versus F L2-A plot using the FACS Calibur (BDBiosciences). The data was analysed with the ModFIT Cell Cycle analysis software (Verity S oftwarehouse).
  • F igure 12 As shown in F igure 12, BDZ9L1 effectively impaired endothelial cell growth with increasing doses.
  • the data depicted in F igures 13 and 14 demonstrate that the mechanism of action appears to be through the induction of apoptosis (F igure 13) and cell cycle arrest at G2/M phase compared to Control (F igure 14).
  • Cell cycle arrest at G2/M phase has been associated with enhanced apoptosis in other studies and may improve the cytotoxicity of standard drugs.
  • the rat aortic ring assay was carried out according to Zhu et a I., 2002. Reference: Zhu WH, Nicosia R F .
  • the thin prep rat aortic ring assay a modified method for the characterization of angiogenesis in whole mounts.
  • the rat aortic ring assay allows analysis of cellular proliferation, migration, tube formation and microvessel branching in vitro, while mimicking the real-life environment in which angiogenesis occurs.
  • Rat aortic rings treated with BZD9L1 demonstrated inhibition of sprouting with increasing doses, suggesting that BZD9L1 is a potent a nti-angiogenic compound (F igure 15).
  • EX527 increased C D34 vessel number compared to the control P BS group in the pancreatic xenograft tumours (P ⁇ 0.01 ).
  • P rimary antibody omission was performed as negative control to demonstrate that the positive staining observed was not a result of high background staining. This shows that while EX527 is a S IRT 1 -selective inhibitor, it does not provide any a nti-angiogenic effects.
  • the aortic ring assay (Zhu et al, 2002, Blacher et al., 2001 ) and the spheroid sprouting assay (Blacher et al., 2014) are two established assays that have been widely accepted as in vitro models to study angiogenesis. These two assays allow the key steps of angiogenesis to be studied as the cell aggregates/ tissues mimic the native tissue/ microenvironment more accurately copmpared to 2D culture. Refs: Blacher S, Devy L, Burbridge MF, et al. Improved quantification of angiogenesis in the rat aortic ring assay. Angiogenesis 2001 ; 4: 133-42.
  • EAHY926 endothelial spheroids were generated according to modified protocol from Blacher et al., 2014. F ull Matrigel (BD Biosciences) rather than collagen was used as matrix for spheroid embedding.
  • HCT1 16, MKN74, Kato-3, A498 and 786-0 cancer cells were obtained from American Type C ulture Collection (ATCC) and maintained in Institute for Research in Molecular Medicine using R P MI medium (Nascalai Tesque) supplemented with 10% Fetal Bovine S erum (Biowest), 100 units/ml penicillin (Biowest) and 100 units/ml streptomycin (Biowest). Cells were kept at 37eC in a humidified 5% C O2 atmosphere.
  • ROS reactive oxygen species
  • HCT1 16 colorectal cancer or B16 melanoma spheroids were formed via the hanging drop method.
  • Cells were seeded at 5.0 B 10 3 cells per drop in R P MI media with 10% F BS and 0.24% methylcellulose.
  • S pheroids were placed into wells precoated with 0.75% agarose (Nacalai Tesque) and treated with BZD9L1 and E toposide with appropriate concentrations for 3 days.
  • S pheroid viability is accessed via live and dead staining using Propidium Iodide and/or Calcein AM according to protocol titled LIVE /DEAD ⁇ Assay to investigate Cell Viability and Toxicity (3D Biomatrix).
  • HCT1 16 cells were seeded with a density of 4.0 B 10 4 cells per well into an opaque bottom white 96-well plate and transfected with DNA constructs from 10-pathway profiler array (Qiagen, USA) using F ugene HD Transfection Reagent (P romega).
  • the cells were treated with BZD9L1 after 24h following determination of pathway activation/deactivation after another 24h using Dual G LO Luciferase Assay (P romega). The assay was performed according to the manufacturer s protocol.
  • HCT1 16 cells were seeded at 2.5 B 10 3 cells per well in a 96-well microplate. MTT was added at the 72h time point following a 4h incubation time to yield formazan crystals and measured using a plate reader using wavelength of 570nm.
  • BZD9L1 affected HCT-116 cell viability by altering gene expression of cancer pathways.
  • Downregulation of the WNT, Notch, Tumour protein p53 (p53), myc- associated factor X (MYC/MAX) and Hypoxia-inducible factors (HIF) pathways were observed while NF kB up-regulation was demonstrated compared to control untreated (F igure 20).
  • the deregulation of the WNT pathway are known to be the precursor of colorectal cancer development [1].
  • WNT pathway is reported to be constitutively activated in most colorectal cancer cells due to f -catenin and APC gene mutation [2], and nuclear accumulation of f -catenin is observed in 80% of colorectal cancer [3].
  • f-catenin will be translocated into the nucleus and interacts with TC F/LE F transcription factors to activate genes for cellular processes resulting in cell proliferation, cell differentiation, cell migration and cell polarity [4]; and may causes metastasis due to its engagement in cadherin-based adheren junctions [5].
  • the downregulation of WNT pathway by BZD9L1 may explain the reduction of HCT1 16 cell viability.
  • Notch signaling pathway is overexpressed in many cancers including colorectal cancer [6].
  • the activation of Notch pathway is dependent on the cell-cell contact which is critical for mediating cell proliferation, differentiation and apoptosis.
  • aberrant activation of this pathway are often linked to the angiognesis and migration of cancer cells [7, 8], thus downregulation of Notch pathway in colorectal cancer by BZD9L1 could contribute to its activity as an anti-cancer agent.
  • MYC/MAX pathway increases biomass uptake, promote ribosomal biosynthesis and protein synthesis to accelerates cancer cell metabolism [10, 1 1].
  • BZD9L1 The downregulation of MYC/MAX by BZD9L1 may result in reduction of cell viability in HCT1 16.
  • HIF pathway plays important roles in regulating genes involved in cell proliferation, angiogenesis and apoptosis, metabolism, metastasis and resistance to chemotherapy [12].
  • HIF pathway has been shown to promote cell survival of the central core of tumors which are oxygen-deficient, thus enabling cancerous cells to be more resistant to less aerobic conditions [13]. Therefore, downregulation of this pathway by BZD9L1 may lower the survivability of HCT1 16 cancer cells.
  • NF kB pathway was found to be up-regulated by BZD9L1 compared to control untreated. T he NF kB pathways plays an important role in many physiological processes such as initiating immune responses, controlling cell proliferation, cell death and inducing inflammation [14]. NF kB plays an important role in maintaining cellular ROS levels, where R OS dysregulation subsequently cause an activation of this pathway. High amounts of ROS may trigger cellular apoptosis and necrosis via the NF kB pathway [15], as depicted in F igure 21.
  • BZD9L1 was shown to reduce cell viability of stomach and renal cancer cell lines, compared to untreated control (F igure 22). In 3 dimensional culture, BZD9L1 promoted cell death in mouse B16 F 10 melanoma tumour spheroids compared to control untreated (F igure 23).
  • Notch-1 signalling requires ligand- induced proteolytic release of intracellular domain. Nature, 1998.393(6683): p.382-6.

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Abstract

L'invention concerne un composé représenté par la formule I, dans laquelle R1 à R3 sont tels que définis dans la description, utilisé comme agent anticancereux ou son utilisation comme médicament adjuvant/néo-adjuvant dans le traitement du cancer.
PCT/MY2016/050058 2015-09-21 2016-09-21 Composés s'utilisant comme agents anticancéreux Ceased WO2017052360A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050137234A1 (en) * 2003-12-19 2005-06-23 Syrrx, Inc. Histone deacetylase inhibitors
WO2006094209A2 (fr) * 2005-03-03 2006-09-08 Sirtris Pharmaceuticals, Inc. Modulateurs de sirtuine a amide n-benzimidazolylalkyle substitue

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050137234A1 (en) * 2003-12-19 2005-06-23 Syrrx, Inc. Histone deacetylase inhibitors
WO2006094209A2 (fr) * 2005-03-03 2006-09-08 Sirtris Pharmaceuticals, Inc. Modulateurs de sirtuine a amide n-benzimidazolylalkyle substitue

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ARIENTI, K.L. ET AL.: "Checkpoint Kinase Inhibitors: SAR and Radioprotective Properties of a Series of 2-Arylbenzimidazoles", JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, no. 6, 2005, pages 1873 - 1885, XP002400069 *
SUZUKI, T. ET AL.: "2-Anilinobenzamides as SIRT Inhibitors", CHEMMEDCHEM, vol. 1, 2006, pages 1059 - 1062, XP008100962 *
YOON, Y.K. ET AL.: "Benzimidazoles as new scaffold of sirtuin inhibitors: Green synthesis, in vitro studies, molecular docking analysis and evaluation of their anti-cancer properties", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 83, 2014, pages 448 - 454, XP055371272 *
YOON, Y.K. ET AL.: "Discovery of a potent and highly fluorescent sirtuin inhibitor", MED. CHEM. COMMUN., vol. 6, 2015, pages 1857 - 1863, XP055371269 *
YOON, Y.K. ET AL.: "Structural Modifications of Benzimidazoles via Multi-Step Synthesis and Their Impact on Sirtuin-Inhibitory Activity", ARCH. PHARM. CHEM. LIFE SCI., vol. 349, 2016, pages 1 - 8, XP055371071, DOI: doi:10.1002/ardp.201500337 *
YOON, Y.K. ET AL.: "Synthesis and evaluation of antimycobacterial activity of new benzimidazole aminoesters", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 93, 2015, pages 614 - 624, XP029176745 *
YOON, Y.K. ET AL.: "Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 22, 2014, pages 703 - 710, XP028668777 *

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