WO2014170873A1 - Composés présentant une activité d'inhibition de la sirtuine - Google Patents
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- WO2014170873A1 WO2014170873A1 PCT/IB2014/060826 IB2014060826W WO2014170873A1 WO 2014170873 A1 WO2014170873 A1 WO 2014170873A1 IB 2014060826 W IB2014060826 W IB 2014060826W WO 2014170873 A1 WO2014170873 A1 WO 2014170873A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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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
- A61K31/425—Thiazoles
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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
- A61K31/435—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
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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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
- A61K31/435—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
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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
- A61K31/435—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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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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
- A61K31/495—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
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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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
- A61K31/495—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
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- 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]
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- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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 technical field of pharmaceutical industry and, in particular, concerns compounds with sirtuin inhibiting activity, which are useful in the treatment of different diseases, such as, for example, metabolic, inflammatory and tumor diseases.
- Sirtuins are NAD + -dependent enzymes, playing a role in ageing, metabolism, nutritional behavior, cancer and inflammation 1 . Due to their wide involvement in the physiopathology of highly prevalent diseases, sirtuins represent an interesting therapeutic target 2 .
- SIRT1-7 Seven sirtuins (SIRT1-7) are known, and activators of SIRT1 were described, with a potentially positive role in regulating metabolism and extending the duration of a healthy life ("healthspan"), although their mode of action is still controversial 2 . Inhibitors of SIRTl , SIRT2 and SIRT5 were reported too 3 .
- SIRT6 is involved in genome stability and its deficiency was associated to the development of a progeroid syndrome in mice 4 .
- SIRT6 promotes DNA repair by different mechanisms comprising deacetylation of histone H3 lysine 9 (H3K9) at telomeric chromatin with consequent association of WRN and telomere maintenance 5 , stabilization of DNA-dependent protein kinase (DNA-PK) at chromatin 6 , as well as poly(ADP- ribose) polymerase 1 (PARPl) mono-ADP-ribosylation and consequent promotion of its activity 7 .
- H3K9 histone H3 lysine 9
- PARPl poly(ADP- ribose) polymerase 1
- SIRT6 regulates glucose uptake by virtue of its capacity of co-repressing the transcription factor Hifla, a critical regulator of nutrient stress responses 8 .
- SIRT6 deficient cells exhibit increased Hifla activity, increased glucose uptake and glycolysis, and diminished mitochondrial respiration.
- SIRT6-deficient mice develop hypoglycaemia and exhibit a pronounced increase in glucose uptake in muscle and brown adipose tissue 4 - 8 .
- SIRT6 plays a role in inflammation, as shown by the immune defects of SIRT6-deficient mice 4 and by the ability to promote the expression of TNFa, IFN- ⁇ 10 and IL8 11 in response to activating stimuli.
- the immunogenic activity of SIRT6 reflects, at least in part, its propensity to increase intracellular ADP-ribose levels by virtue of its enzymatic activity 12 .
- SIRT6-derived ADP-ribose appears to promote Ca 2+ responses, cytokine gene transcription (via the transcription factor NFAT) and cell motility.
- SIRT6 inhibition appears as a viable strategy for the treatment of cancer (as a means to sensitize cancer cells to anticancer agents and radiotherapy and to reduce cancer-associated inflammation) 4 - 6 - 12 , metabolic disorders (by virtue of its capacity to increase tissue glucose uptake) and inflammation.
- Patent application WO 2008/ 138943 relates to a sirtuin inhibitor other than suramin for use in the reduction of TNF-alpha and/ or reduction of local or systemic inflammation in a subject and/ or treatment of TNF-alpha mediated diseases.
- the inhibitor in question is selected from sirtinol, m-sirtinol, p-sirtinol, splitomicin, dehydrosplitomicin, cambinol and dihydrocoumarin.
- Patent application WO 201 1 /0381 10 concerns the use of a SIRT6 inhibitor to reduce or inhibit hyperglycaemia or obesity in a subject.
- SIRT6 inhibitors antibodies anti-SIRT6, interfering RNA molecules and antisense nucleic acids can be mentioned. Summary of the invention
- the problem underlying the present invention was that of providing compounds having inhibiting activity towards sirtuins, in particular, even if non exclusively, towards SIRT6, for the use in inducing glucose tissue uptake (and then in obtaining a reduction of glycaemic levels) and /or in reducing the production of TNF-alpha and other proinflammatory, chemotactic, or proangiogenic cytokines (such as IFN- ⁇ and IL8) and/ or in interfering with DNA repair in tumor cells, so as to be used as therapeutic agents in the treatment of type I or II diabetes-related diseases and/or inflammatory diseases and/or neoplastic diseases.
- R H, d-aalkyl, COOH, COOCi- 3 alkyl, halogen, NH-CO-d- salkyl, OH, Od- 3 alkyl, OCOd- 3 alkyl, SH, SC 1-3 alkyl, CF 3 , NO 2 , NR 4 R 5 ;
- R 4 , R 5 independently H, Ci- 3 alkyl
- R 1 OH, COOH
- R 6 Ci-6alkyl, optionally substituted C 3 -7cycloalkyl, in which 1 or 2 carbon atoms in the ring can be independently substituted with NH, S or O, optionally substituted 5-6 membered heteroaryl, containing 1 to 3
- R 6 C2-5alkyl, C3-scycloalkyl, 5-6 membered heteroaryl containing 1 or 2 N, O or S atoms in the ring,
- R 6 C2-5alkyl, C3-scycloalkyl, 5-6 membered heteroaryl containing 1 or 2 N, O or S atoms in the
- R 6 cyclopropyl, ethyl, pentyl, furyl, thienyl, pyrrolyl.
- compounds of formula (I) comprise the following compounds:
- R 7 H, C 1-3 alkyl, COOH, COOCi- 3 alkyl, halogen, NH-CO-Ci- salkyl, OH, OCi- 3 alkyl, OCOCi -3 alkyl, SH, SCi -3 alkyl, CF 3 , NO 2 , optionally substituted C 3- 7cycloalkyl, wherein 1 or 2 carbon atoms in the ring can be independently substituted with NH, S or O, optionally substituted 5-6 membered heteroaiyl, containing 1 to 3 N, O or S atoms in the ring, optionally substituted C6-ioaryl, NR 4 R 5 ;
- R 4 , R 5 independently H, C 1-3 alkyl;
- n 0-3;
- Y 5-6 membered heterocycle or phenyl optionally substituted with one or more substituents selected from Ci -3 alkyl, COOH, COOCi- salkyl, halogen, NH-CO-C 1- alkyl, OH, OC 1-3 alkyl, OCOC 1-3 alkyl, SH, SCi- salkyl, CF 3 , NO 2 , NR 4 R 5 ;
- R 4 , R 5 independently H, C 1-3 alkyl
- Ri6 Ri H, Ci-salkyl, COOH, COOCi- 3 alkyl, halogen, NH- CO-C 1-3 alkyl, OH, OC 1-3 alkyl, OCOCi- 3 alkyl, SH, SCi -3 alkyl, CF 3 , NO 2 , NR 4 R 5 , provided that at least one of R 15 , R 16 , R 17 is OH or COOH;
- R!8, Ri9 H, Ci-salkyl, COOH, COOC 1-3 alkyl, halogen, NH-CO- Ci- 3 alkyl, OH, OC 1-3 alkyl, OCOC 1-3 alkyl, SH, SC 1-3 alkyl, CF 3 , NO 2 , NR 4 R 5 ;
- R 4 , R 5 independently H, C 1-3 alkyl
- R 20 phenyl optionally bearing a substituent selected from the group consisting of CH 3 , CF 3 , CI, Br, OH, SH, OCH 3 , SCH 3 , NO 2 , NH 2 , NH- CH 3 , N(CH 3 ) 2 .
- the abovementioned compounds of formula (I), (Ila), (lib), (lie) and (III) can be used as inhibitors of one or more sirtuins, and in particular of SIRT6, to increase glucose tissue uptake in a subject.
- such compounds can be used in the treatment of: type I and type II diabetes mellitus and complications thereof, such as ketoacidotic coma, hyperglycaemic hyperosmolar condition, atherosclerosis, ischaemic heart disease (angina and myocardial infarction), stroke, peripheral vasculopathy, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and diabetic foot.
- type I and type II diabetes mellitus and complications thereof such as ketoacidotic coma, hyperglycaemic hyperosmolar condition, atherosclerosis, ischaemic heart disease (angina and myocardial infarction), stroke, peripheral vasculopathy, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and diabetic foot.
- compounds of formula (I), (Ila), (lib), (lie) and (III) can be used as inhibitors of one or more sirtuins, and in particular of SIRT6, to reduce the production of TNF-alpha and other proinflammatory, chemotactic, or proangiogenic cytokines (such as IFN- ⁇ and IL8) in a subject and/ or to reduce local or systemic inflammation in a subject and/ or to treat a pathology mediated by TNF-alpha or other proinflammatory, chemotactic, or proangiogenie cytokines (such as IFN- ⁇ and IL8) in a subject having local or systemic excessive or dysregulated cytokine production.
- SIRT6 sirtuins
- inflammatory diseases comprising rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, Goodpasture syndrome, scleroderma, atherosclerosis, graft versus host disease (GVHD), organ transplant rejection, myocardial infarction, stroke, reperfusion injury after revascularization in heart and other organs.
- inflammatory diseases comprising rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, Goodpasture syndrome, scleroderma, atherosclerosis, graft versus host disease (GVHD), organ transplant rejection, myocardial infarction, stroke, reperfusion injury after revascularization in heart and other organs.
- GVHD graft versus host disease
- compounds of formula (I), (Ila), (lib), (lie) and (III) are used as inhibitors of one or more sirtuins, and in particular of SIRT6, to interfere with DNA repair in tumor cells, and then to exert an anticancer effect and sensitize said cells to antineoplastic agents and radiotherapy. Consequently, such compounds find an application in the treatment of neoplastic diseases comprising pancreatic cancer, breast cancer, colorectal cancer, prostatic cancer, ovarian cancer, melanoma, lung cancer, oesophageal cancer, hepatic carcinoma, lymphomas, leukaemias, myeloma, sarcomas, neoplastic cachexia.
- neoplastic diseases comprising pancreatic cancer, breast cancer, colorectal cancer, prostatic cancer, ovarian cancer, melanoma, lung cancer, oesophageal cancer, hepatic carcinoma, lymphomas, leukaemias, myeloma, sarcom
- the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of at least one compound of formula (I), (Ila), (lib), (lie) or (III) or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, as defined above and a pharmaceutically acceptable vehicle.
- pharmaceutically acceptable salts are those formed with organic acids such as oxalic, tartaric, maleic, succinic and citric and with inorganic acids such as nitric, hydrochloric, sulphuric and phosphoric.
- Compounds according to the invention haying one or more asymmetric carbon atoms can exist as pure enantiomers, pure diastereomers, racemic mixtures of enantiomers, racemates and mixtures of racemates.
- Compounds and compositions according to the invention can be administered through any available and efficient delivery system, comprising, but not limited to, oral, buccal, parenteral, inhalatory routes, topical application, injection, transdermal or rectal routes (e.g. suppositories), in unit dose formulations containing conventional, pharmaceutically acceptable and non-toxic supports, adjuvants and carriers.
- Administration by parenteral route includes subcutaneous, intravenous, intramuscular, intracisternal injection or infusion techniques.
- Solid dosage forms for administration by oral route comprise, for example, capsules, tablets, powders, granules and gels.
- the active compound can be mixed with at least one inert diluent, such as, for example, saccharose, lactose or starch.
- these dosage forms also comprise additional substances other than inert diluents, such as, for example, lubricating agents, like magnesium stearate.
- Injection preparations for example, sterile aqueous or oily solutions or suspensions for injection, can be formulated according to known art and optionally using suitable dispersing, wetting and /or suspending agents.
- compositions according to the present invention can be manufactured by using conventional pharmaceutical techniques, as described in various pharmacopoeias or handbooks in the field, such as for example "Remington's Pharmaceutical Sciences Handbook", Mack Publishing, New York, 18th Ed., 1990.
- the average daily dose of the compounds according to the present invention depends on many factors, such as for example severity of the disease and state of the patient (age, weight, gender): the dose can generally range from 1 mg to 1500 mg/day of a compound according to the invention, optionally partitioned in more administrations.
- the present invention relates to a method for reducing the production of TNF-alpha and other proinflammatory, chemotactic, or proangiogenic cytokines in cells in vitro, comprising the step of exposing the cells to a compound as defined above, a method to increase glucose uptake in cells in vitro, comprising the step of exposing the cells to said compound, as well as a method to increase the antiproliferative and cytotoxic effect of antineoplastic drugs and of ionizing radiations in vitro, comprising the step of exposing tumor cells to said compound.
- compositions can be prepared with the compounds according to the present invention, for the treatment of different pathologic conditions mediated by sirtuins and, in particular, SIRT6.
- Some of these diseases such as type II diabetes mellitus, neoplastic diseases and inflammatory diseases, have very strong epidemiological impact and hence pharmaceutical formulations containing the compounds according to the present invention are susceptible of wide employment in different fields of medical therapy, with technical, economical and manufacturing advantages related to the fact of being based on stable and low molecular weight organic molecules.
- the formulations can comprise also further active substances, or can be used in combination with other formulations containing other active substances, such as for example antiinflammatory, blood glucose lowering agents, chemotherapies, or with radiotherapy.
- active substances such as for example antiinflammatory, blood glucose lowering agents, chemotherapies, or with radiotherapy.
- compounds of formula (I) can be prepared by methods described in Patent Application WO 2005/ 115374.
- Compounds of formula (Ha), (lib) or (lie) can be prepared according to the method described in Ueda S. et al., J Am Chem Soc. 2009 Oct 28; 131(42): 15080- 1 "Facile synthesis of 1 ,2,4-triazoles via a copper- catalyzed tandem addition-oxidative cyclization.”
- subject reference is made, in the present application, to animals, preferably mammals and, in a particularly preferred way, to human individuals.
- treating or “treatment” both a therapeutic treatment and a preventive, prophylactic treatment is meant, as well as a treatment achieving to prolong survival in comparison with what expected in the absence of a treatment.
- terapéuticaally effective amount refers to an amount able to determine a biological or therapeutic response in an animal or human tissue or system, pursued by a researcher, physician or veterinary and that, in particular, can prevent or alleviate at least one local or systemic symptom of the treated disease.
- the in vitro activity of the compounds according to the present invention in terms of sirtuin inhibition was determined using commercial kits for SIRT6, SIRT1 and SIRT2 available from the company Cayman, Ann Arbor, USA, following the instructions of the manufacturer.
- IC50 values were determined using the assays in commercial kits. All the compounds were dissolved at a 50mM concentration in DMSO. Concentrations of the compounds in the measurements for IC50 determination were in the 8 ⁇ to 5mM range. IC50 values were determined from non-linear logarithmic regression curves by GraphPad Prism (GraphPad Software, La Jolla, CA - USA). Three independent IC50 measurements were performed for each compound.
- BxPC-3 Cells overexpressing SIRT6 (Bauer I. et al., J. Biol. Chem. 2012 Oct 18) (3 x 10 5 cells/well) were seeded in 6-well plates and allowed to adhere for 24 hours before being incubated for 18 hours with various compounds ( ⁇ final concentration). Subsequently, to induce cytokine expression, cells were stimulated for 48 hours with 25 ng/ml of phorbol myristate acetate (PMA; Sigma Aldrich). Subsequently, supernatants were collected and assayed for IL8 and TNF using DuoSet ® ELISA kits available on the market (R&D Systems, Minneapolis, USA). Concentration in supernatants was normalized to cell density measured with sulforhodamine B.
- SIRT6 Brunauer I. et al., J. Biol. Chem. 2012 Oct 18
- Glucose uptake experiments 1 x 10 5 BxPC-3 cells engineered to express the pRETROSUPER vector (pRS) or a S I RT6- specific shRNA (sh2 SIRT6) (Bauer I, et al. J Biol Chem. 2012 Oct 18.) were plated in each well of a 12-well plate in 500 ⁇ of standard culture medium. 72 hours later, cells were incubated (or not incubated) in the presence of the compounds at a 200 ⁇ concentration for 18 h.
- pRS pRETROSUPER vector
- sh2 SIRT6-specific shRNA S I RT6-specific shRNA
- Reactions were performed in a total volume of 10 ⁇ , containing 20 ⁇ g of recombinant SIRT6 (produced following published protocols 13 ) in 50mM Tris-HCl, pH 8.0, 150mM NaCl, lOmM dithiothreitol, and 0.4 ]iCi
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Abstract
Composés de formule (I) ou leurs énantiomères, leurs diastéréomères et leurs sels pharmaceutiquement acceptables, destinés à être utilisés en tant que médicament, en particulier en tant qu'inhibiteurs de sirtuines, avec une référence particulière à SIRT6. De tels composés augmentent l'absorption tissulaire du glucose et trouvent des utilisations dans le traitement du diabète de type I et le diabète sucré de type II et des complications de ceux-ci. Ils réduisent la production de TNF-alpha et d'autres cytokines inflammatoires, chimiotactiques ou pro-angiogéniques, trouvent des utilisations dans le traitement de maladies inflammatoires. Ils interfèrent avec la réparation de l'ADN dans des cellules tumorales, puis exercent un effet anticancéreux et sensibilisent ces cellules aux agents anticancéreux et à la radiothérapie, et trouvent ainsi des utilisations dans le traitement de maladies néoplasiques.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IT000647A ITMI20130647A1 (it) | 2013-04-19 | 2013-04-19 | Composti con attività inibente sulle sirtuine |
ITMI2013A000647 | 2013-04-19 |
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WO2014170873A1 true WO2014170873A1 (fr) | 2014-10-23 |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017201425A1 (fr) * | 2016-05-20 | 2017-11-23 | The Trustees Columbia University In The City Of New York | Activateurs anaboliques pour améliorer la neurodégénérescence |
CN112812077A (zh) * | 2019-11-18 | 2021-05-18 | 中国科学院上海药物研究所 | 苯甲酰胺类化合物及其制备方法、药物组合物和用途 |
WO2021113667A1 (fr) * | 2019-12-06 | 2021-06-10 | Wisconsin Alumni Research Foundation | Activateurs de la désacylase de protéine sirtuine 6 (sirt6) |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
US11497740B2 (en) | 2016-04-29 | 2022-11-15 | The Board Of Regents Of The University Of Texas System | Use of Jumonji C demethylase inhibitors for the treatment and prevention of chemotherapy resistance and radioresistance in cancer |
US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
WO2024005905A3 (fr) * | 2022-04-29 | 2024-03-14 | The Regents Of The University Of Michigan | Petites molécules inhibitrices de la sirtuine et leurs utilisations |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11497740B2 (en) | 2016-04-29 | 2022-11-15 | The Board Of Regents Of The University Of Texas System | Use of Jumonji C demethylase inhibitors for the treatment and prevention of chemotherapy resistance and radioresistance in cancer |
WO2017201425A1 (fr) * | 2016-05-20 | 2017-11-23 | The Trustees Columbia University In The City Of New York | Activateurs anaboliques pour améliorer la neurodégénérescence |
US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
CN112812077A (zh) * | 2019-11-18 | 2021-05-18 | 中国科学院上海药物研究所 | 苯甲酰胺类化合物及其制备方法、药物组合物和用途 |
CN112812077B (zh) * | 2019-11-18 | 2023-08-22 | 中国科学院上海药物研究所 | 苯甲酰胺类化合物及其制备方法、药物组合物和用途 |
WO2021113667A1 (fr) * | 2019-12-06 | 2021-06-10 | Wisconsin Alumni Research Foundation | Activateurs de la désacylase de protéine sirtuine 6 (sirt6) |
WO2024005905A3 (fr) * | 2022-04-29 | 2024-03-14 | The Regents Of The University Of Michigan | Petites molécules inhibitrices de la sirtuine et leurs utilisations |
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