WO2017002120A1 - Inhibiteurs sélectifs de cellules sénescentes et leurs utilisations - Google Patents

Inhibiteurs sélectifs de cellules sénescentes et leurs utilisations Download PDF

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WO2017002120A1
WO2017002120A1 PCT/IL2016/050702 IL2016050702W WO2017002120A1 WO 2017002120 A1 WO2017002120 A1 WO 2017002120A1 IL 2016050702 W IL2016050702 W IL 2016050702W WO 2017002120 A1 WO2017002120 A1 WO 2017002120A1
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compound
group
aryl
substituents
alkyl
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PCT/IL2016/050702
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English (en)
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Valery Krizhanovsky
Hilah GAL
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Yeda Research And Development Co. Ltd.
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Publication of WO2017002120A1 publication Critical patent/WO2017002120A1/fr

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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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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
    • A61K31/343—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 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • 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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    • A61K31/433—Thidiazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—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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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/14—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms
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    • C07C251/38—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Definitions

  • the present invention in some embodiments thereof, relates to therapy and, more particularly, but not exclusively, to a novel screening assay designed for identifying candidate compounds for eliminating senescent cells, to novel compounds that selectively eliminate senescent cells and to uses thereof in the treatment of a variety of diseases is which eliminating senescent cells is beneficial.
  • Cellular senescence a stable form of cell cycle arrest, is a mechanism limiting the proliferative potential of cells. Senescence can be triggered in many cell types in response to diverse forms of cellular stress. It is a potent barrier to tumorigenesis and contributes to the cytotoxicity of certain anti-cancer agents. While senescence limits tumorigenesis and tissue damage in a cell autonomous manner, senescent cells induce inflammation, tissue ageing, tissue destruction and promote tumorigenesis and metastasis in a cell non-autonomous manner in the sites of their presence. Therefore, their elimination might lead to tumor prevention and inhibition of tissue ageing. Indeed, elimination of senescent cells was shown to slow down tissue ageing in an animal model.
  • Organisms might have developed elaborate mechanisms to eliminate senescent cells in order to avoid their deleterious effects on the microenvironment.
  • their fate in tissue is not well characterized.
  • benign melanocytic nevi mofetil
  • senescent cells are highly enriched for senescent cells yet can exist in skin throughout a lifetime, implying that senescent cells can be stably incorporated into tissues.
  • components of the innate immune system specifically recognize and eliminate senescent cells in vitro and target senescent cells in vivo leading to tumor regression and reversion of liver fibrosis. Therefore, senescent cells can turn over in vivo and the immune system contributes to this turnover.
  • the present inventors have now devised a method for identifying compounds which selectively eliminate senescent cells. While practicing this method, the present inventors have uncovered numerous compounds which selectively eliminate senescent cells, and have identified common structural features which are assumed to account for the biological activity of these compounds. Based on these understandings, the present inventors were prompt to practice compounds which exhibit these structural features for eliminating senescent cells and for treating medical conditions associated with cell senescence.
  • each of Ar1, Ar2 and Ar3 is independently an aryl or heteroaryl
  • j 0, 1 or 2;
  • Y is absent or is a linking moiety comprising one or more of amine, -S-, -
  • At least one of Ar1, Ar2 and Ar3 is aryl and the aryl is phenyl.
  • At least one of n, m and k is other than 0, and at least one of R 1 , R 2 and R 3 is an electron-withdrawing group.
  • At least one of n, m and k is other than 0, and at least one of R 1 , R 2 and R 3 is halo.
  • At least one of n, m and k is other than 0, and at least one of R 1 , R 2 and R 3 is a trihaloalkyl.
  • Ar1 and Ar2 are each independently a heteroaryl.
  • X comprises or is -S-.
  • Ar3 is an aryl
  • Y is absent.
  • Ar1 and Ar2 are each independently an aryl.
  • the aryl is phenyl
  • J is 0.
  • X is absent.
  • n 2, 3, 4 or 5.
  • At least one of the R 1 substituents is an alkyl.
  • At least one of the R 1 substituents is hydroxy.
  • Ar1 and Ar2 are each independently an aryl, one of R 1 and R 2 , and X form together a cyclic group.
  • n is other than 0, and at least one the R 1 substituents is nitrile.
  • n is other than 0, and one or more of the R 1 substituents comprises a nitro group.
  • m is other than 0, and one or more of the R 2 substituents comprises a trihaloalkyl.
  • Ar1 is aryl
  • Ar2 is heteroaryl
  • j is 1.
  • the aryl is phenyl
  • Ar3 is heteroaryl
  • Ar3 is pyridine.
  • Ar2 is thiophene.
  • k is other than 0, and one or more of the R 3 substituents comprises a trihaloalkyl.
  • k is other than 0, and one or more of the R 3 substituents is halo.
  • n is other than 0, and one or more of the R 1 substituents is alkoxy.
  • Ar2 is pyrazolo[1,5- a]pyrimidine. According to some embodiments of Formula I described herein, wherein Ar1 is aryl, Ar2 is heteroaryl, and j is 1, Ar3 is aryl.
  • Ar3 is phenyl
  • m is other than 0, and one or more of the R 2 substituents is selected from amine and thioalkoxy.
  • k is other than 0, and one or more of the R 3 substituents is halo.
  • n is other than 0, and one or more of the R 1 substituents is halo.
  • the compound is selected from Compounds 1-6 as presented in Table 2.
  • the compound is selected from the compounds presented in Table 1.
  • R 4 and R 5 are each independently hydrogen, alkyl or cycloalkyl, or, alternatively, R 4 and R5 are joined together to form a dioxo-containing heteroalicyclic ring;
  • R 6 is hydrogen, alkyl, cycloalkyl, acyl, thioacyl, sulfonyl or sulfonate;
  • R 7 is alkyl, optionally substituted by one or more of hydroxy, alkoxy, thioalkoxy, sulfonyl, sulfonate and sulfoxide,
  • R 4 and R5 are joined together to form a dioxolane ring.
  • R 6 is sulfonyl.
  • R 7 is an alkyl substituted by one or more sulfonate groups.
  • the disease associated with cell senescence is a fibrotic disease or an inflammatory disease.
  • the disease is associated with cartilage degeneration.
  • disease is selected from the group consisting of liver fibrosis, wound healing, skin fibrosis, pulmonary disease, kidney fibrosis, prostatitis, atherosclerosis, arthritis and pancreatitis.
  • the disease associated with cell senescence is selected from the group consisting of atherosclerosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), arthritis and a premalignant disease.
  • atherosclerosis idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • a pharmaceutical composition comprising a compound as described herein in any of the respective embodiments and any combination thereof, as the active agent, and a pharmaceutically effective carrier.
  • the pharmaceutical composition is formulated for topical administration.
  • the pharmaceutical composition further comprises at least one agent selected from the group consisting of a sebum-regulating agent, an antibacterial and/or antifungal agent, a keratolytic agent and/or keratoregulating agent, an astringent, an anti-inflammatory and/or anti-irritant, an antioxidant and/or free-radical scavenger, a cicatrizing agent, an anti-aging agent and a moisturizing agent.
  • a sebum-regulating agent an antibacterial and/or antifungal agent
  • a keratolytic agent and/or keratoregulating agent an astringent
  • an anti-inflammatory and/or anti-irritant an antioxidant and/or free-radical scavenger
  • a cicatrizing agent an anti-aging agent and a moisturizing agent.
  • Implementation of the method and/or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.
  • a data processor such as a computing platform for executing a plurality of instructions.
  • the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data.
  • a network connection is provided as well.
  • a display and/or a user input device such as a keyboard or mouse are optionally provided as well.
  • FIGs. 1A-B present a flow chart (FIG. 1A) and a schematic illustration (FIG. IB) of a screening method for identifying candidate compounds that selectively inhibit senescent cells;
  • FIGs. 2A-B present comparative plots showing the effect of various concentrations of Compound 1 as described herein on the viability of IMR90 senescent cells (yellow curve) and of proliferating cells (green curve), as determined using the CellTiter-Glo Luminescent Cell Viability Assay, in two independent assays;
  • FIGs. 3A-B present comparative plots showing the effect of various concentrations of Compound 2 as described herein on the viability of IMR90 senescent cells (yellow curve) and of proliferating cells (green curve), as determined using the CellTiter-Glo Luminescent Cell Viability Assay, in two independent assays;
  • FIGs. 4A-B present comparative plots showing the effect of various concentrations of Compound 3 as described herein on the viability of IMR90 senescent cells (yellow curve) and of proliferating cells (green curve), as determined using the CellTiter-Glo Luminescent Cell Viability Assay, in two independent assays;
  • FIGs. 5A-B present comparative plots showing the effect of various concentrations of Compound 4 as described herein on the viability of IMR90 senescent cells (yellow curve) and of proliferating cells (green curve), as determined using the CellTiter-Glo Luminescent Cell Viability Assay, in two independent assays;
  • FIGs. 6A-B present comparative plots showing the effect of various concentrations of Compound 5 as described herein on the viability of IMR90 senescent cells (yellow curve) and of proliferating cells (green curve), as determined using the CellTiter-Glo Luminescent Cell Viability Assay, in two independent assays;
  • FIGs. 7A-B present comparative plots showing the effect of various concentrations of Compound 6 as described herein on the viability of IMR90 senescent cells (yellow curve) and of proliferating cells (green curve), as determined using the CellTiter-Glo Luminescent Cell Viability Assay, in two independent assays; and
  • FIGs. 8A-B present comparative plots showing the effect of various concentrations of Compound 7 as described herein on the viability of IMR90 senescent cells (yellow curve) and of proliferating cells (green curve), as determined using the CellTiter-Glo Luminescent Cell Viability Assay, in two independent assays;
  • FIGs. 9A-D present bar graphs validating the senescent cell inhibitory effect of Os007, Mb031, Mb041 compounds.
  • DIS Etoposide treated
  • IMR90 fibroblasts were seeded on 6 well plates (1.2x105 cells/well) and treated with increasing concentration of compound Os007 (1.5um, 3.12um, 6.25um, 12.5um and 25 um). Cells were cultured with the compound for 48 h followed by PrestoBlue viability analysis.
  • B Similarly, IMR90 growing and DIS cells were treated with increasing concentrations of compound Mb031 (5um, lOum and 25um) for 48 h before processing for PrestoBlue viability assays.
  • IMR90 cells were infected with either empty vector G(V) or with HRAS (RAS) to induce oncogene induced senescent population (OIS).
  • Cells were treated with increasing concentrations of compound Mb031 (2um, 5um and lOum) for 48 h before processing for PrestoBlue viability assays.
  • D Growing and DIS cell were treated with an increasing concentrations of compound Mb041 (5um, lOum, and 25 um) for 48 h before processing for PrestoBlue viability assays. Viability % of G, G(V), DIS or RAS cells was determined by comparison to their untreated related cultures.
  • the present invention in some embodiments thereof, relates to therapy and, more particularly, but not exclusively, to a novel screening assay designed for identifying candidate compounds for eliminating senescent cells, to novel compounds that selectively eliminate senescent cells and to uses thereof in the treatment of a variety of diseases is which eliminating senescent cells is beneficial.
  • the approach is built on a cell based, high-throughput screening assay in which the toxicity index of the compounds in measured in senescent versus dividing control cells.
  • the present inventors have uncovered exemplary compounds which selectively eliminate senescent cells.
  • the present inventors have identified some structural features which are common to the uncovered compounds, and have designed novel families of compounds which can be useful in selectively eliminating senescent cells and hence in the treatment of disorders and diseases which are associated with senescent cells, as described in further detail hereinunder.
  • a method of identifying candidate compounds which selectively eliminate senescent cells is generally effected by incubating senescent cells and proliferating cells with a tested compound, at a pre-determined concentration, in a suitable medium, and measuring a viability ratio of the senescent cells versus the proliferating cells, upon said incubation.
  • the method is effected using high- throughput methodologies, for simultaneously measuring and calculating the viability ratio for a plurality of compounds.
  • Such a method is also referred to herein as a screening method or a screening assay.
  • a compound for which the above-described calculated viability ratio is lower than 0.9, or lower than 0.8, or lower than 0.7 or, preferably, lower than 0.6, is determined as capable of selectively eliminating senescent cells.
  • compounds identified as exhibiting a viability ratio as described herein, which is lower than 1 are further tested for determining the IC50 value thereof for senescent vs. proliferating cells.
  • the method further comprises incubating senescent cells and growing cells with a tested compound, at various concentrations, in a suitable medium, and measuring the viability of the senescent cells and of the growing cells, upon said incubation. An IC50 ratio for a tested compound is then determined as a concentration at which 50% of the cells were no longer viable.
  • the relative IC50 values for growing cells versus senescent cells namely, an IC50 value determined for a compound for growing cells divided by an IC50 value determined for the same compound for senescent cells, are determined.
  • compounds exhibiting a relative IC50 value which is lower than 1 are identified as potent candidates for selectively eliminating senescent cells.
  • fluorescent cells refers to cells that are in cell cycle arrest, generally during the Gl transition of the cell cycle or in few cases in G2, elicited by replicative exhaustion due to telomere attrition or in response to stresses such as DNA damage, chemotherapeutic drugs, or aberrant expression of oncogenes.
  • the senescent cells are characterized by at least one or more of the following characteristics:
  • HAT histone acetyltransferase
  • HDAC histone deacetylase
  • DNMT DNA methyltransferase
  • demethylase histone ubiquitylase
  • deubiquitination enzyme histone chaperone
  • NAMPT nicotinamide phosphoribosyltransferase
  • glucose transporter inhibitor hexokinase 2
  • phosphofructokinase 2 inhibitor phosphofracto-2-kinase/fructose- 2,6-bisphosphatase 3 inhibitor
  • PK pyruvate kinase
  • M2 lactate dehydrogenase
  • the senescence inducing agent is Trazodone, etotifen, Cephalexin, Nisoldipme, CGS 15943, Clotrimazole, 5-Nonyltryptamine, Doxepin, Pergolide, Paroxetine, Resveratrol, Quercetin, Honokiol, 7-nitroindazole, Megestrol, Fluvoxamine, Etoposide, Veliparib, Rucaparib, Olaparib, Camptothecin, or Terbinafine.
  • proliferating cell refers to a cell that is undergoing cell division.
  • Figures 1A-B present a flow chart and a schematic illustration of the method and high throughput screening assay described herein.
  • a compound as described herein for use in treating a disease associated with cell senescence.
  • a method of treating a disease associated with cell senescence comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
  • Diseases associated with cell senescence include, but are not limited to fibrotic diseases, inflammatory diseases and pre-malignant disorders.
  • Senescent cells are present in fibrosis of many tissues including but not limited to skin, liver, lung, pancreas and prostate. Thus, the present inventors contemplate treating fibrotic diseases of such tissues.
  • Exemplary fibrotic diseases which may be treated using the agents described herein include but are not limited to eosinophilic esophagitis, hypereosinophilic syndromes (HES), Loeffler's endomyocarditis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and scleroderma.
  • HES hypereosinophilic syndromes
  • Loeffler's endomyocarditis endomyocardial fibrosis
  • idiopathic pulmonary fibrosis idiopathic pulmonary fibrosis
  • An exemplary pulmonary fibrotic disease contemplated by the present invention is chronic obstructive pulmonary disease (COPD) or Idiopathic pulmonary fibrosis.
  • COPD chronic obstructive pulmonary disease
  • Idiopathic pulmonary fibrosis Premalignant diseases:
  • the agents are used to treat pre-malignant lesions.
  • pre-malignant lesion refers to a mass of cells and/or tissue having increased probability of transforming into a malignant tumor.
  • pre-malignant lesions include, but are not limited to, adenomatous polyps, Barrett's esophagus, Pancreatic Intraepithelial Neoplasia (PanIN), IPMN (Intraductal Papillary Mucinus Neoplasia), DCIS (Ductal Carcinoma in situ) in the breast, leukoplakia and erythroplakia.
  • the pre-malignant lesion which is treated using the agents of this aspect of the present invention can transform into a malignant solid or non-solid (e.g., hematological malignancies) cancer (or tumor).
  • a malignant solid or non-solid e.g., hematological malignancies
  • the pre-malignant lesion which is treated using the agents of the present invention is an adenomatous polyp of the colon, an adenomatous polyp of the rectum, an adenomatous polyp of the small bowel and Barrett's esophagus.
  • Inflammatory diseases include, but are not limited to, chronic inflammatory diseases and acute inflammatory diseases.
  • hypersensitivity examples include, but are not limited to, Type I hypersensitivity, Type II hypersensitivity, Type III hypersensitivity, Type IV hypersensitivity, immediate hypersensitivity, antibody mediated hypersensitivity, immune complex mediated hypersensitivity, T lymphocyte mediated hypersensitivity and DTH.
  • Type I or immediate hypersensitivity such as asthma.
  • Type II hypersensitivity include, but are not limited to, rheumatoid diseases, rheumatoid autoimmune diseases, rheumatoid arthritis (Krenn V. et al., Histol Histopathol 2000 Jul;15 (3):791), spondylitis, ankylosing spondylitis (Jan Voswinkel et al., Arthritis Res 2001; 3 (3): 189), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998; 17 (l-2):49), sclerosis, systemic sclerosis (Renaudineau Y.
  • paraneoplastic neurological diseases cerebellar atrophy, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff man syndrome, cerebellar atrophies, progressive cerebellar atrophies, encephalitis, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydenham chorea, Gilles de la Tourette syndrome, polyendocrinopathies, autoimmune polyendocrinopathies (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan; 156 (1):23); neuropathies, dysimmune neuropathies (Nobile-Orazio E.
  • Type IV or T cell mediated hypersensitivity include, but are not limited to, rheumatoid diseases, rheumatoid arthritis (Tisch R, McDevitt HO. Proc Natl Acad Sci U S A 1994 Jan 18;91 (2):437), systemic diseases, systemic autoimmune diseases, systemic lupus erythematosus (Datta SK., Lupus 1998;7 (9):591), glandular diseases, glandular autoimmune diseases, pancreatic diseases, pancreatic autoimmune diseases, Type 1 diabetes (Castano L. and Eisenbarth GS. Ann. Rev. Immunol. 8:647); thyroid diseases, autoimmune thyroid diseases, Graves' disease (Sakata S.
  • delayed type hypersensitivity examples include, but are not limited to, contact dermatitis and drug eruption.
  • T lymphocyte mediating hypersensitivity examples include, but are not limited to, helper T lymphocytes and cytotoxic T lymphocytes.
  • helper T lymphocyte-mediated hypersensitivity examples include, but are not limited to, T h l lymphocyte mediated hypersensitivity and T h 2 lymphocyte mediated hypersensitivity.
  • cardiovascular diseases include, but are not limited to, cardiovascular diseases, rheumatoid diseases, glandular diseases, gastrointestinal diseases, cutaneous diseases, hepatic diseases, neurological diseases, muscular diseases, nephric diseases, diseases related to reproduction, connective tissue diseases and systemic diseases.
  • autoimmune cardiovascular diseases include, but are not limited to atherosclerosis (Matsuura E. et al, Lupus. 1998;7 Suppl 2:S 135), myocardial infarction (Vaarala O. Lupus. 1998;7 Suppl 2:S 132), thrombosis (Tincani A. et al, Lupus 1998;7 Suppl 2:S 107-9), Wegener's granulomatosis, Takayasu's arteritis, Kawasaki syndrome (Praprotnik S. et al, Wien Klin Klin Klin Klin Klinschr 2000 Aug 25;112 (15-16):660), anti-factor VIII autoimmune disease (Lacroix-Desmazes S.
  • autoimmune rheumatoid diseases include, but are not limited to rheumatoid arthritis (Krenn V. et al, Histol Histopathol 2000 Jul;15 (3):791; Tisch R, McDevitt HO. Proc Natl Acad Sci units S A 1994 Jan 18;91 (2):437) and ankylosing spondylitis (Jan Voswinkel et al, Arthritis Res 2001; 3 (3): 189).
  • autoimmune glandular diseases include, but are not limited to, pancreatic disease, Type I diabetes, thyroid disease, Graves' disease, thyroiditis, spontaneous autoimmune thyroiditis, Hashimoto's thyroiditis, idiopathic myxedema, ovarian autoimmunity, autoimmune anti-sperm infertility, autoimmune prostatitis and Type I autoimmune polyglandular syndrome.
  • Diseases include, but are not limited to autoimmune diseases of the pancreas, Type 1 diabetes (Castano L. and Eisenbarth GS. Ann. Rev. Immunol. 8:647; Zimmet P. Diabetes Res Clin Pract 1996 Oct;34 Suppl:S 125), autoimmune thyroid diseases, Graves' disease (Orgiazzi J.
  • autoimmune gastrointestinal diseases include, but are not limited to, chronic inflammatory intestinal diseases (Garcia Herola A. et al, Gastroenterol Hepatol. 2000 Jan;23 (1): 16), celiac disease (Landau YE. and Shoenfeld Y. Harefuah 2000 Jan 16;138 (2): 122), colitis, ileitis and Crohn's disease.
  • autoimmune cutaneous diseases include, but are not limited to, autoimmune bullous skin diseases, such as, but are not limited to, pemphigus vulgaris, bullous pemphigoid and pemphigus foliaceus.
  • autoimmune hepatic diseases include, but are not limited to, hepatitis, autoimmune chronic active hepatitis (Franco A. et al., Clin Immunol Immunopathol 1990 Mar;54 (3):382), primary biliary cirrhosis (Jones DE. Clin Sci (Colch) 1996 Nov;91 (5):551; Strassburg CP. et al, Eur J Gastroenterol Hepatol. 1999 Jun;l l (6):595) and autoimmune hepatitis (Manns MP. J Hepatol 2000 Aug;33 (2):326).
  • autoimmune neurological diseases include, but are not limited to, multiple sclerosis (Cross AH. et al, J Neuroimmunol 2001 Jan 1 ; 112 (1-2): 1), Alzheimer's disease (Oron L. et al, J Neural Transm Suppl. 1997;49:77), myasthenia gravis (Infante AJ. And Kraig E, Int Rev Immunol 1999;18 (l-2):83; Oshima M. et al, Eur J Immunol 1990 Dec;20 (12):2563), neuropathies, motor neuropathies (Kornberg AJ. J Clin Neurosci.
  • autoimmune muscular diseases include, but are not limited to, myositis, autoimmune myositis and primary Sjogren's syndrome (Feist E. et al., Int Arch Allergy Immunol 2000 Sep; 123 (1):92) and smooth muscle autoimmune disease (Zauli D. et al, Biomed Pharmacother 1999 Jun;53 (5-6):234).
  • autoimmune nephric diseases include, but are not limited to, nephritis and autoimmune interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug; 1 (2): 140).
  • autoimmune diseases related to reproduction include, but are not limited to, repeated fetal loss (Tincani A. et al., Lupus 1998;7 Suppl 2:S 107-9).
  • autoimmune connective tissue diseases include, but are not limited to, ear diseases, autoimmune ear diseases (Yoo TJ. et al., Cell Immunol 1994 Aug; 157
  • autoimmune systemic diseases include, but are not limited to, systemic lupus erythematosus (Erikson J. et al., Immunol Res 1998; 17 (l-2):49) and systemic sclerosis (Renaudineau Y. et al., Clin Diagn Lab Immunol. 1999 Mar;6
  • infectious diseases include, but are not limited to, chronic infectious diseases, subacute infectious diseases, acute infectious diseases, viral diseases, bacterial diseases, protozoan diseases, parasitic diseases, fungal diseases, mycoplasma diseases and prion diseases.
  • diseases associated with transplantation of a graft include, but are not limited to, graft rejection, chronic graft rejection, subacute graft rejection, hyperacute graft rejection, acute graft rejection and graft versus host disease.
  • allergic diseases include, but are not limited to, asthma, hives, urticaria, pollen allergy, dust mite allergy, venom allergy, cosmetics allergy, latex allergy, chemical allergy, drug allergy, insect bite allergy, animal dander allergy, stinging plant allergy, poison ivy allergy and food allergy. Cancer:
  • Non-limiting examples of cancers which may be treated according to this aspect of the present invention include: adenocarcinoma, adrenal gland tumor, ameloblastoma, anaplastic, anaplastic carcinoma of the thyroid, angiofibroma, angioma, angiosarcoma, apudoma, argentaffmoma, arrhenoblastoma, ascites tumor cell, ascitic tumor, astroblastoma, astrocytoma, ataxia-telangiectasia, atrial myxoma, a basal cell carcinoma cell, bone cancer, brainstem glioma, brain tumor, breast cancer, Burkitt's lymphoma, cerebellar astrocytoma, cervical cancer, cherry angioma, cholangiocarcinoma, cholangioma, chondroblastoma, chondroma, chondrosarcoma, chori
  • the present compounds can be provided (e.g. as adjuvant therapy) along with other treatment modalities for cancers, which are selected based on cancer type, location, the cell type and the grade of malignancy.
  • Conventional therapies include surgery, radiation therapy, and chemotherapy.
  • combination therapy compounds may be administered by the same route of administration (e.g. intrapulmonary, oral, enteral, etc.) that the described compounds are administered.
  • the compounds for use in combination therapy with the herein described compounds may be administered by a different route of administration.
  • the additional agent can be administered immediately prior to (or after) the additional agent, on the same day as, one day before (or after), one week before (or after), one month before (or after), or two months before (or after) the described compounds, and the like.
  • the compounds described herein and the second reagent can be administered concomitantly, that is, where the administering for each of these reagents can occur at time intervals that partially or fully overlap each other.
  • the compounds described herein and second reagent can be administered during time intervals that do not overlap each other.
  • the compounds of the present invention and the at least one other cancer treatment modality are typically provided in combined amounts to achieve therapeutic, prophylactic and/or pain palliative effectiveness. This amount will evidently depend upon the particular compound selected for use, the nature and number of the other treatment modality, the condition(s) to be treated, prevented and/or palliated, the species, age, sex, weight, health and prognosis of the subject, the mode of administration, effectiveness of targeting, residence time, mode of clearance, type and severity of side effects of the pharmaceutical composition and upon many other factors which will be evident to those of skill in the art.
  • the other treatment modality will be used at a level at which therapeutic, prophylactic and/or pain palliating effectiveness in combination with the compound will be observed. Since the other treatment modality will generally be known pharmaceutical agents they will typically be used at a level between 10% of their normal minimum therapeutic dose and 500% of their maximum normal therapeutic dose. More preferably this range will be 25% of the normal minimum dose to 200% of the normal maximum dose.
  • the amount of the other treatment modality is below the minimum dose required for therapeutic, prophylactic and/or pain palliative effectiveness when used as a single therapy (e.g. 10-99%, preferably 25 to 75% of that minimum dose). This allows for reduction of the side effects caused by the other treatment modality but the therapy is rendered effective because in combination with the disclosed compounds, the combinations are effective overall.
  • the, or each of the, other treatment modalities is used at a level below the minimum normal therapeutic dose, for example 10-99% of the normal minimum therapeutic dose, preferably 25 to 75% of their normal therapeutic dose. This again serves to reduce the danger of side effects and allows a higher level of total effectiveness without exposing the subject to unacceptable side effects.
  • the compound and the at least one other treatment modality are synergistic with respect to their dosages. That is to say that the effect provided by the compound of the present invention is greater than would be anticipated from the additive effects of the compound and the at least one other treatment modality when used separately.
  • the compound of the present invention and the at least one other treatment modality are synergistic with respect to their side effects. That is to say that the side- effects caused by the other treatment modality in combination with the compound are less than would be anticipated when the equivalent therapeutic effect is provided by either the compound or by the at least one treatment modality when used separately.
  • anti-cancer drugs that can be co-administered with the agents of the invention include, but are not limited to Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adriamycin; Adozelesin; Aldesleukin; Altretamine;
  • Anthramycin Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat;
  • Bleomycin Sulfate Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin
  • Etoposide Phosphate Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Fluorocitabine; Fosquidone;
  • Interferon Alfa-nl Interferon Alfa-n3; Interferon Beta-I a; Interferon Gamma-I b;
  • Iproplatin Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride;
  • Mitogillin Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride;
  • Pegaspargase Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;
  • Porfimer Sodium Porfiromycin; Prednimustine; Procarbazine Hydrochloride;
  • Puromycin Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol;
  • Toremifene Citrate Trestolone Acetate; Triciribine Phosphate; Trimetrexate;
  • Trimetrexate Glucuronate Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine;
  • Vindesine Sulfate Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate;
  • Vinorelbine Tartrate Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin;
  • Zinostatin Zinostatin; Zorubicin Hydrochloride.
  • Additional antineoplastic agents include those disclosed in Chapter 52, Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner), and the introduction thereto, 1202-1263, of Goodman and Gilman's "The
  • the disease is associated with bone degeneration - e.g. osteoporosis.
  • the disease is not cancer.
  • the agents of the present invention selectively kill senescent cells, the present inventors contemplate that another use thereof is in cosmetic compositions as anti-aging agents for rejuvenating the skin.
  • the agents of the present invention may be formulated for cosmetics.
  • Such compositions typically comprise pharmaceutically acceptable excipient, notably dermatologically acceptable suitable for external topical application.
  • the cosmetic composition according to the present invention may further comprise at least one pharmaceutical adjuvant known to the person skilled in the art, selected from thickeners, preservatives, fragrances, colorants, chemical or mineral filters, moisturizing agents, thermal spring water, etc.
  • pharmaceutical adjuvant known to the person skilled in the art, selected from thickeners, preservatives, fragrances, colorants, chemical or mineral filters, moisturizing agents, thermal spring water, etc.
  • the composition may comprise at least one agent selected from a sebum- regulating agent, an antibacterial agent, an antifungal agent, a keratolytic agent, a keratoregulating agent, an astringent, an anti-inflammatory/anti-irritant, an antioxidant/free-radical scavenger, a cicatrizing agent, an anti-aging agent and/or a moisturizing agent.
  • a sebum-regulating agent an antibacterial agent, an antifungal agent, a keratolytic agent, a keratoregulating agent, an astringent, an anti-inflammatory/anti-irritant, an antioxidant/free-radical scavenger, a cicatrizing agent, an anti-aging agent and/or a moisturizing agent.
  • sodium-regulating agent refers, for example, to 5-a-reductase inhibitors, notably the active agent 5-a-Avocuta RTM sold by Laboratories Expanscience. Zinc and gluconate salts thereof, salicylate and pyroglutamic acid, also have sebum- suppressing activity. Mention may also be made of spironolactone, an anti-androgen and aldosterone antagonist, which significantly reduces the sebum secretion rate after 12 weeks of application. Other extracted molecules, for example from seeds of the pumpkin Cucurbita pepo, and squash seed oil, as well as palm cabbage, limit sebum production by inhibiting 5-a-reductase transcription and activity. Other sebum-regulating agents of lipid origin that act on sebum quality, such as linoleic acid, are of interest.
  • anti-bacterial agent and "antifungal agent” refer to molecules that limit the growth of or destroy pathogenic microorganisms such as certain bacteria like P. acnes or certain fungi (Malassezia furfur).
  • preservatives generally used in cosmetics or nutraceuticals, molecules with anti-bacterial activity (pseudo-preservatives) such as caprylic derivatives (capryloyl glycine, glyceryl caprylate, etc.), such as hexanediol and sodium levulinate, zinc and copper derivatives (gluconate and PCA), phytosphingosine and derivatives thereof, benzoyl peroxide, piroctone olamine, zinc pyrithione, selenium sulfide, econazole, ketoconazole, or local antibiotics such as erythromycin and clindamycin, etc.
  • keratoregulating agent and “keratolytic agent” refer to an agent that regulates or helps the elimination of dead cells of the stratum corneum of the epidermis.
  • the most commonly used keratoregulating/keratolytic agents include: alpha-hydroxy acids (AHAs) of fruits (citric acid, glycolic acid, malic acid, lactic acid, etc.), AHA esters, combinations of AHAs with other molecules such as the combination of malic acid and almond proteins (Keratolite RTM ), the combination of glycolic acid or lactic acid with arginine or the combination of hydroxy acid with lipid molecules such as LHA RTM (lipo-hydroxy acid), amphoteric hydroxy acid complexes (AHCare), willow bark (Salix alba bark extract), azelaic acid and salts and esters thereof, salicylic acid and derivatives thereof such as capryloyl salicylic acid or in combination with other molecules such as the combination of salicylic acid and polysaccharide (beta-hydroxy acid
  • astringent refers to an agent that helps constrict pores, the most commonly used being polyphenols, zinc derivatives and witch hazel.
  • anti-inflammatory/anti-irritant refers to an agent that limits the inflammatory reaction led by cytokines or arachidonic acid metabolism mediators and has soothing and anti-irritating properties.
  • the most traditional are glycyrrhetinic acid (licorice derivative) and salts and esters thereof, alpha-bisabolol, Ginkgo biloba, Calendula, lipoic acid, beta-carotene, vitamin B3 (niacinamide, nicotinamide), vitamin E, vitamin C, vitamin B 12, flavonoids (green tea, quercetin, etc.), lycopene or lutein, avocado sugars, avocado oleodistillate, arabinogalactan, lupin peptides, lupin total extract, quinoa peptide extract, Cycloceramide'.RTM.
  • anti- glycation agents such as carnosine, N-acetyl-cysteine, isoflavones such as, for example, genistein/genistin, daidzein/daidzin, spring water or thermal spring water (eau d'Avene, eau de la Roche Posay, eau de Saint Gervais, eau d'Uriage, eau de Gamarde), goji extracts (Lycium barbarum), plant amino acid peptides or complexes, topical dapsone, or anti-inflammatory drugs.
  • anti- glycation agents such as carnosine, N-acetyl-cysteine, isoflavones such as, for example, genistein/genistin, daidzein/daidzin, spring water or thermal spring water (eau d'Avene, eau de la Roche Posay, eau de Saint Gervais, eau d'Uriage, eau de Gamarde), goji
  • antioxidants/free-radical scavengers that may be used in combination are advantageously selected from the group comprised of thiols and phenols, licorice derivatives such as glycyrrhetinic acid and salts and esters thereof, alpha-bisabolol, Ginkgo biloba extract, Calendula extract, Cycloceramide RTM (oxazoline derivative), avocado peptides, trace elements such as copper, zinc and selenium, lipoic acid, vitamin B 12, vitamin B3 (niacinamide, nicotinamide), vitamin C, vitamin E, coenzyme Q10, krill, glutathione, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), lycopene or lutein, beta-carotene, the family of polyphenols such as tannins, phenol
  • the group of antioxidants further includes anti-glycation agents such as carnosine or certain peptides, N-acetyl-cysteine, as well as antioxidant or free-radical scavenging enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase, thioredoxin reductase and agonists thereof.
  • anti-glycation agents such as carnosine or certain peptides, N-acetyl-cysteine
  • antioxidant or free-radical scavenging enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase, thioredoxin reductase and agonists thereof.
  • the agents that cicatrize/repair the barrier function which may be used in combination are advantageously vitamin A, panthenol (vitamin B5), avocadofurane®, avocado sugars, lupeol, maca peptide extract, quinoa peptide extract, arabinogalactan, zinc oxide, magnesium, silicon, madecassic or asiatic acid, dextran sulfate, coenzyme Q10, glucosamine and derivatives thereof, chondroitin sulfate and on the whole glycosaminoglycans (GAGs), dextran sulfate, ceramides, cholesterol, squalane, phospholipids, fermented or unfermented soya peptides, plant peptides, marine, plant or biotechnological polysaccharides such as algae extracts or fern extracts, trace elements, extracts of tannin-rich plants such as tannins derived from gallic acid called gallic or hydrolysable tannins, initially found in oak gall
  • the anti-aging agents that can act in combination to treat acne in mature subjects are antioxidants and in particular vitamin C, vitamin A, retinol, retinal, hyaluronic acid of any molecular weight, Avocadofurane RTM , lupin peptides and maca peptide extract.
  • moisturizers/emollients are glycerin or derivatives thereof, urea, pyrrolidone carboxylic acid and derivatives thereof, hyaluronic acid of any molecular weight, glycosaminoglycans and any other polysaccharides of marine, plant or biotechnological origin such as, for example, xanthan gum, Fucogel.RTM., certain fatty acids such as lauric acid, myristic acid, monounsaturated and polyunsaturated omega-3, - 6, -7 and -9 fatty acids (linoleic acid, palmitoleic acid, etc.), sunflower oleodistillate, avocado peptides and cupuacu butter.
  • a compound as described herein can be used per se or in a pharmaceutical (or cosmetic) composition which further comprises a pharmaceutically (or cosmetically) acceptable carrier.
  • a "pharmaceutical composition” refers to a preparation of one or more of the active ingredients described herein with other chemical components such as physiologically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • the term "active ingredient” refers to the compounds described herein.
  • the pharmaceutical compositions may comprise additional active agents known to be useful in treating a particular disease.
  • the present inventors contemplate pharmaceutical compositions comprising the below described agents together with at least one sebum- regulating agent, an antibacterial agent, an antifungal agent, a keratolytic agent, a keratoregulating agent, an astringent, an anti-inflammatory/anti-irritant, an antioxidant/free-radical scavenger, a cicatrizing agent, an anti-aging agent and/or a moisturizing agent, as described herein above.
  • physiologically acceptable carrier and “pharmaceutically acceptable carrier” which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An adjuvant is included under these phrases.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the active ingredients of the pharmaceutical composition may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intracardiac, e.g., into the right or left ventricular cavity, into the common coronary artery, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • the route of administration is via topical delivery.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the active ingredients of the pharmaceutical composition may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the pharmaceutical composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used which may optionally contain gum Arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water based solution
  • compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredients (e.g. the compounds described herein) effective to prevent, alleviate or ameliorate symptoms of a disorder (e.g., fibrotic or inflammatory disease) or prolong the survival of the subject being treated.
  • a disorder e.g., fibrotic or inflammatory disease
  • the therapeutically effective amount or dose can be estimated from animal models (e.g. mouse models of liver fibrosis induced by CC1 4 , mouse model of pancreatitis induced by Caerulein, mouse model of COPD) to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans.
  • animal models e.g. mouse models of liver fibrosis induced by CC1 4 , mouse model of pancreatitis induced by Caerulein, mouse model of COPD.
  • Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in experimental animals.
  • the data obtained from these animal studies can be used in formulating a range of dosage for use in human.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. l).
  • Dosage amount and interval may be adjusted individually to provide cell numbers sufficient to induce normoglycemia (minimal effective concentration, MEC).
  • MEC minimum effective concentration
  • the MEC will vary for each preparation, but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. Detection assays can be used to determine plasma concentrations.
  • compositions to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • Compositions comprising a preparation of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, as if further detailed above.
  • Using the screening method as described herein enabled the present inventors to identify structural features which may be required for exhibiting selective elimination of senescent cells, and to devise accordingly a genus of compounds which can be useful in selectively eliminating senescent cells and hence in treating a disease associated with cell senescence, as described herein.
  • each of Ar1, Ar2 and Ar3 is independently an aryl or heteroaryl
  • j 0, 1 or 2;
  • n, m and k are each independently 0, 1, 2, 3, 4 or 5;
  • the compounds as described herein are comprised of 2 aryl and/or heteroaryl moieties, when j is 0; or of 3 aryl and/or heteraryl moieties, when j is 1, or of 4 aryl and/or heteroaryl moieties, when J is 2.
  • Each of the aryl or heteroaryl moieties can be substituted or unsubstituted.
  • the corresponding n, m or k variable is 0.
  • the corresponding n, m or k variable is other 0.
  • n represents the number of substituents R 1 of the Ar1 moiety
  • m represents the number of substituents R 2 of the Ar2 moiety
  • k represents the number of substituents R 3 of the Ar3 moiety.
  • n, m or k is 2, 3, 4 or 5
  • the corresponding 2 or more substituents can be the same or different.
  • Two aryl and/or heteroaryl moieties in the compounds described herein can be linked to one another via a linking moiety, denoted in Formula I as X or Y.
  • a linking moiety denoted in Formula I as X or Y.
  • X or Y is absent, the two aryl and/or heteroaryl moieties are linked to one another via a bond (yet are not to be regarded as fused to one another).
  • the bond is preferably a sigma saturated bond.
  • the X and Y linking groups may also comprise other groups, in addition to the above-listed groups.
  • X and/or Y linking moieties include: -
  • At least one of Ar1, Ar2 and Ar3 is aryl.
  • the aryl is phenyl.
  • j is 0.
  • both Ar1 and Ar2 are aryl, or both Ar1 and Ar2 are heteroaryl.
  • J is 1.
  • Ar1 is aryl and Ar2 is heteroaryl.
  • Ar1 and Ar3 are each aryl and Ar2 is heteroaryl.
  • the compound comprises at least one aryl or heteroaryl which is substituted by a halo substituent, such as a chloro substituent, namely, one or more of n, m and k is other than 0, and one or more of R 1 , R 2 and R 3 is halo.
  • a halo substituent such as a chloro substituent
  • the compound comprises at least one aryl or heteroaryl which is substituted by one or more electron-withdrawing substituents, such as nitro, CF 2 , halo, nitrile, and the like), namely, one or more of n, m and k is other than 0, and one or more of R 1 , R 2 and R 3 is an electron-withdrawing substituent.
  • substituents such as nitro, CF 2 , halo, nitrile, and the like
  • one or more of Ar1, Ar2 and Ar3 is a chlorobenzene or a chloro-pyridine.
  • one or more of n, m and k is other than 0, and at least one of the R 1 , R 2 and R 3 substituents is a trihaloalkyl, for example, CF 3 .
  • one of Ar1, Ar2 and Ar3 is a heteroaryl.
  • two of Ar1, Ar2 and Ar3 are heteroaryls, which can be the same or different.
  • j is 1.
  • the heteroaryls can be the same or different.
  • j is 1, two of Ar1, Ar2 and Ar3 are each independently a heteroaryl, and one of Ar1, Ar2 and Ar3 is aryl, e.g., phenyl.
  • Ar1 and Ar2 are each independently a heteroaryl and Ar3 is aryl, e.g., phenyl.
  • Ar1 is aryl and Ar2 and Ar3 are each independently a heteroaryl.
  • Ar1 and Ar2 are each independently a heteroaryl, and X comprises or is -S-.
  • Ar3 is an aryl, for example phenyl.
  • Y is absent.
  • Ar1 and Ar2 are each independently a heteroaryl
  • Ar3 is an aryl, for example phenyl
  • X comprises or is -S-
  • Y is absent.
  • the one or both of Ar1 and Ar2 is a nitrogen- containing heteroaryl.
  • one or both of the nitrogen-containing heteroaryl comprises 2 or more nitrogen atoms.
  • examples include, without limitation, 4H- 1,2,4- triazole, 1H-1,2,4-triazole, 3H-pyrazole, 1H-pyrazole, 1H-imidazole, pyrazine, pyridazine, pyrimidine, 1,3,5-triazine, 1,2,4-triazine, and 1,2,3-triazine.
  • one of Ar1 and Ar2 is a triazole and one of Ar1 and Ar2 is pyrazine. In some of these embodiments, Ar1 is pyrazine and Ar2 is a triazole.
  • Ar1 and Ar2 are each independently a nitrogen-containing heteroaryl, as described herein, Ar3 is an aryl, for example phenyl, X comprises or is -S-, and Y is absent, one of n, m and k is other than 0. In some of these embodiments, n and m are other than 0.
  • n is 2 or more and two of the R 1 substituents are joined together to form a ring.
  • the ring is a heteroalicyclic ring, and in some embodiments, it is a thiazolidine ring.
  • the ring is a thiazolidine-2-thione.
  • the heteralicyclic ring is substituted by thiooxo and is further substituted by an alkyl, or alkenyl, for example, 2-propenyl.
  • m is 1 and R 2 is phenyl.
  • An exemplary compound according to these embodiments is Compound 6 in Table 1 hereinunder.
  • j is 1, Ar1 is aryl and Ar2 and Ar3 are each independently a heteroaryl.
  • one or both of Ar2 and Ar3 is independently a nitrogen- containing heteroaryl and Ar1 is aryl such as phenyl.
  • the heteroaryl comprises one nitrogen atom. Examples include, without limitation, pyrrole and pyridine.
  • Ar3 is pyridine.
  • Ar2 and Ar3 are independently a sulfur- containing heteroaryl such as a thiophene and Ar1 is aryl such as phenyl.
  • Ar2 is thiophene and Ar3 is pyridine.
  • Ar1 is aryl
  • Ar2 and Ar3 are each independently a heteroaryl
  • one or more of Ar1, Ar2 and Ar3 is substituted, such that one or more of n, m and k is other than 0.
  • one or more of R 1 , R 2 and R 3 is an electron- withdrawing group.
  • k is other 1, and R 3 is CF 3 .
  • Ar3 is pyridine, and k is 2.
  • the pyridine is substituted by a trihaloalkyl, e.g., CF 3 .
  • the pyridine is substituted by a halo such as chloro.
  • Ar3 is chloropyridine.
  • Ar3 is chloropyridine which is further substituted by an electron-withdrawing group such as a trihalolkyl, e.g., CF 3 .
  • n is other 0.
  • n is 1, and in some of these embodiments, n is alkoxy, for example methoxy.
  • Ar1 is aryl more specifically phenyl
  • Ar2 is thiophene
  • Ar3 is chloropyridine
  • Ar1 is substituted, for example, by alkoxy, and Ar3 is further substituted by an electron-withdrawing group such as a trihaloalkyl, e.g., CF 3 .
  • An exemplary such compound is Compound 2 in Table 2 hereinunder.
  • Ar1 is aryl
  • Ar2 is heteroaryl
  • j is 1.
  • the aryl is phenyl.
  • Ar3 is a heteroaryl, and in some embodiments it is a nitrogen-containing heteroaryl such as pyridine or pyrrole. In some of these embodiments, Ar3 is pyridine.
  • the heteroaryl is substituted such that k is other than 0.
  • one or more of the R 3 substituents comprises a trihaloalkyl, e.g., CF 3 and/or a halo, e.g., chloro.
  • Ar2 is thiophene.
  • n is other than 0, and one or more of the R 1 substituents is alkoxy.
  • Ar1 is aryl
  • Ar2 is heteroaryl
  • Ar2 is pyrazolo[l,5-a]pyrimidine.
  • Ar3 is aryl, e.g. phenyl.
  • Ar1 and Ar3 are each phenyl and Ar2 is pyrazolo[ 1 ,5-a]pyrimidine.
  • Ar1 is aryl
  • Ar2 is heteroaryl
  • Ar3 is aryl
  • m is other than 0, and one or more of the R 2 substituents is selected from amine and thioalkoxy.
  • m is 2 or more and the R 2 substituents include an amine and a thioalkoxy such as thiomethoxy.
  • Ar2 is pyrazolo[l,5-a]pyrimidine.
  • Ar1 is aryl
  • Ar2 is heteroaryl
  • Ar3 is aryl
  • k is other than 0, and one or more of the R 3 substituents is halo.
  • Ar1 is aryl
  • Ar2 is heteroaryl
  • Ar3 is aryl
  • n is other than 0, and one or more of the R 1 substituents is halo.
  • Ar1 is aryl
  • Ar2 is heteroaryl
  • j is 1
  • Ar3 is aryl or heteroaryl
  • at least one of n and k is other than 0, and at least one of the R 1 and R 3 substituents is halo, e.g., chloro.
  • Ar1 and Ar2 are each independently an aryl, such as phenyl, and j is 0.
  • X is absent, such that the two aryls are linked to one another via a bond.
  • Ar1 is a rearranged form of dihydroxyphenyl, and is 4-hydroxycyclohexa-2,5-dienone.
  • one or more of the two or more R 1 substituents is an alkyl, and in some of these embodiments, the alkyl is a bulky alkyl such as tert-butyl. In some embodiments, two of the R 1 substituents is an alkyl such as tert-butyl.
  • Ar1 and Ar2 are each independently phenyl
  • j is 0, and X is absent, and n is 2, 3, 4 or 5, one or more of the R 1 substituents is hydroxy.
  • An exemplary compound is Compound 5 in Table 2 hereinunder.
  • R 11 -R 19 are each independently selected from hydrogen, halo, alkyl, alkoxy, thioalkoxy, hydroxy, thiol, trihaloalkyl, carboxy, amine, nitrile, sulfonyl, sulfinyl, sulfate, and any one of the other substituents described herein.
  • R 11 -R 19 are each independently selected from hydrogen and alkyl.
  • R 11 -R 15 are each hydrogen.
  • one or more of R 16 -R 19 is alkyl, and in some embodiments, two or more of R 16 -R 19 is alkyl. In some of these embodiments, one or more of the alkyls is a bulky alkyl as described herein.
  • a compound as described herein features a structure corresponding to Formula la as described herein in any of the respective embodiments, in which the hydroxy is replaced by, for example, halo, alkoxy, thiol, thioalkoxy, or amine.
  • Ar1 and Ar2 are each independently phenyl, and j is 0, one of R 1 and R 2 , and X form together a cyclic group.
  • n is other than 0, and one or more of the R 1 substituents is or comprises a nitrile.
  • n is 1, and R 1 is nitrile.
  • An exemplary compound of these embodiments is Compound 3 in Table 2 hereinunder.
  • one or each of n and m is other than 0.
  • one or more of the R 1 and R 2 substituent(s) is an electron- withdrawing group.
  • n is other than 0, and one or more of the R 1 substituents comprises a nitro group.
  • m is other than 0, and one or more of the R 2 substituents comprises a trihaloalkyl.
  • An exemplary compound according to these embodiments is Compound 1 in Table 2 hereinunder.
  • R 4 and R5 are each independently hydrogen, alkyl or cycloalkyl, or, alternatively, R 4 and R5 are joined together to form a dioxo-containing heteroalicyclic ring;
  • R 6 is hydrogen, alkyl, cycloalkyl, acyl, thioacyl, sulfonyl or sulfonate;
  • R 7 is alkyl, optionally substituted by one or more of hydroxy, alkoxy, thioalkoxy, sulfonyl, sulfonate and sulfoxide.
  • R 4 and R5 are joined together to form a dioxolane ring.
  • the dioxolane ring is substituted and in some embodiments, it is substituted by e.g., one or more alkyls.
  • one or more of R 6 and R 7 is or comprises a slufonyl or sulfonate groups.
  • R 7 is an alkyl substituted by one or more sulfonate groups.
  • linking moiety describes a group (a substituent) that is attached to another moiety in the compound via two or more atoms thereof.
  • end group a group that is attached to another moiety in the compound via one atom thereof.
  • amine describes both a -NR'R" end group and a - NR'- linking group, wherein R' and R" are each independently hydrogen, alkyl, cycloalkyl, aryl, as these terms are defined hereinbelow.
  • the amine group can therefore be a primary amine, where both R' and R" are hydrogen, a secondary amine, where R' is hydrogen and R" is alkyl, cycloalkyl or aryl, or a tertiary amine, where each of R' and R" is independently alkyl, cycloalkyl or aryl.
  • R' and R" can each independently be hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, carbonyl, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, N-carbamate, O-carbamate, C- amide, N-amide, guanyl, guanidine and hydrazine.
  • amine is used herein to describe a -NR'R” group in cases where the amine is an end group, as defined hereinunder, and is used herein to describe a -NR'- group in cases where the amine is or forms a part of a linking group.
  • alkyl describes a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range; e.g., " 1-20", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted.
  • Substituted alkyl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, N-carbamate, O-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.
  • substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl
  • the alkyl group can be an end group, as this phrase is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, which connects two or more moieties via at least two carbons in its chain.
  • a linking group it is also referred to herein as "alkylene", e.g., methylene, ethylene, propylene, etc.
  • alkenyl describes an alkyl, as defined herein, in which at least one pair of carbon atoms are linked to one another via a double bond.
  • cycloalkyl describes an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system.
  • the cycloalkyl group may be substituted or unsubstituted.
  • Substituted cycloalkyl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O- carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, N-carbamate, O-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.
  • substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloal
  • the cycloalkyl group can be an end group, as this phrase is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moieties at two or more positions thereof.
  • heteroalicyclic describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • the heteroalicyclic may be substituted or unsubstituted.
  • Substituted heteroalicyclic may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, O-carbamate, N-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.
  • substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalky
  • the heteroalicyclic group can be an end group, as this phrase is defined hereinabove, where it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moieties at two or more positions thereof.
  • Representative examples are piperidine, piperazine, tetrahydrofurane, tetrahydropyrane, morpholino and the like.
  • aryl describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system.
  • the aryl group may be substituted or unsubstituted.
  • Substituted aryl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, N-carbamate, O-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.
  • substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl
  • the aryl group can be an end group, as this term is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this term is defined hereinabove, connecting two or more moieties at two or more positions thereof.
  • the aryl is phenyl.
  • heteroaryl describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • the heteroaryl group may be substituted or unsubstituted.
  • Substituted heteroaryl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, N-thiocarbamate, O-thiocarbamate, urea, thiourea, O-carbamate, N-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.
  • substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl
  • the heteroaryl group can be an end group, as this phrase is defined hereinabove, where it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moieties at two or more positions thereof.
  • Representative examples are pyridine, pyrrole, oxazole, indole, purine and the like.
  • alkaryl describes an alkyl, as defined herein, which is substituted by one or more aryl or heteroaryl groups.
  • An example of alkaryl is banzyl.
  • amine-oxide describes a -N(OR')(R") or a -N(OR')- group, where R' and R" are as defined herein. This term refers to a -N(OR')(R") group in cases where the amine-oxide is an end group, as this phrase is defined hereinabove, and to a - N(OR')- group in cases where the amine-oxime is an end group, as this phrase is defined hereinabove.
  • halide and "halo" describes fluorine, chlorine, bromine or iodine.
  • haloalkyl describes an alkyl group as defined above, further substituted by one or more halide.
  • dithiosulfide refers to a -S-SR' end group or a -S-S- linking group, as these phrases are defined hereinabove, where R' is as defined herein.
  • hydroxyl describes a -OH group.
  • alkoxy describes both an -O-alkyl and an -O-cycloalkyl group, as defined herein.
  • aryloxy describes both an -O-aryl and an -O-heteroaryl group, as defined herein.
  • thiohydroxy describes a -SH group.
  • thioalkoxy describes both a -S-alkyl group, and a -S-cycloalkyl group, as defined herein.
  • thioaryloxy describes both a -S-aryl and a -S-heteroaryl group, as defined herein.
  • cyano or "nitrile” describes a -C ⁇ N group.
  • nitro describes an -N0 2 group.
  • carboxylate as used herein encompasses C-carboxylate and O- carboxylate.
  • thiocarboxylate as used herein encompasses "C-thiocarboxylate and O-thiocarboxylate.
  • carbamate encompasses N-carbamate and O- carbamate.
  • thiocarbamate as used herein encompasses N-thiocarbamate and O- thiocarbamate.
  • dithiocarbamate encompasses N-dithiocarbamate and S-dithiocarbamate.
  • amide as used herein encompasses C-amide and N-amide.
  • hydrozine describes a -NR'-NR"R" ' end group or a -NR'-NR"- linking group, as these phrases are defined hereinabove, with R', R", and R'" as defined herein.
  • the compound described herein may be in a form of a salt, for example, a pharmaceutically acceptable salt, and/or in a form of a prodrug.
  • the phrase "pharmaceutically acceptable salt” refers to a charged species of the parent compound and its counter- ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound.
  • a pharmaceutically acceptable salt of the compounds described herein may optionally be a base addition salt comprising at least one acidic (e.g., phenol and/or carboxylic acid) group of the compound which is in a negatively charged form (e.g., wherein the acidic group is deprotonated), in combination with at least one counter-ion, derived from the selected base, that forms a pharmaceutically acceptable salt.
  • a base addition salt comprising at least one acidic (e.g., phenol and/or carboxylic acid) group of the compound which is in a negatively charged form (e.g., wherein the acidic group is deprotonated), in combination with at least one counter-ion, derived from the selected base, that forms a pharmaceutically acceptable salt.
  • the base addition salts of the compounds described herein may therefore be complexes formed between one or more acidic groups of the drug and one or more equivalents of a base.
  • the base addition salts may include a variety of organic and inorganic counter- ions and bases, such as, but not limited to, sodium (e.g., by addition of NaOH), potassium (e.g., by addition of KOH), calcium (e.g., by addition of Ca(OH) 2 , magnesium (e.g., by addition of Mg(OH) 2 ), aluminum (e.g., by addition of Al(OH) 3 and ammonium (e.g., by addition of ammonia).
  • sodium e.g., by addition of NaOH
  • potassium e.g., by addition of KOH
  • calcium e.g., by addition of Ca(OH) 2
  • magnesium e.g., by addition of Mg(OH) 2
  • aluminum e.g., by addition of Al(OH) 3
  • ammonium e.g
  • the acid or base additions salts can be either mono-addition salts or poly-addition salts.
  • addition salt refers to a salt in which the stoichiometric ratio between the counter- ion and charged form of the compound is 1: 1, such that the addition salt includes one molar equivalent of the counter-ion per one molar equivalent of the compound.
  • poly- addition salt refers to a salt in which the stoichiometric ratio between the counter-ion and the charged form of the compound is greater than 1: 1 and is, for example, 2: 1, 3: 1, 4: 1 and so on, such that the addition salt includes two or more molar equivalents of the counter-ion per one molar equivalent of the compound.
  • prodrug refers to a compound which is converted in the body to an active compound (e.g., the compound of the formula described hereinabove).
  • a prodrug is typically designed to facilitate administration, e.g., by enhancing absorption.
  • a prodrug may comprise, for example, the active compound modified with ester groups, for example, wherein any one or more of the hydroxyl groups of a compound is modified by an acyl group, optionally (C 1 _ 4 )acyl (e.g., acetyl) group to form an ester group, and/or any one or more of the carboxylic acid groups of the compound is modified by an alkoxy or aryloxy group, optionally (C 1 _ 4 )alkoxy (e.g., methyl, ethyl) group to form an ester group.
  • an acyl group optionally (C 1 _ 4 )acyl (e.g., acetyl) group to form an ester group
  • carboxylic acid groups of the compound is modified by an alkoxy or aryloxy group, optionally (C 1 _ 4 )alkoxy (e.g., methyl, ethyl) group to form an ester group.
  • each of the compounds described herein, including the salts thereof, can be in a form of a solvate or a hydrate thereof.
  • solvate refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the heterocyclic compounds described herein) and a solvent, whereby the solvent does not interfere with the biological activity of the solute.
  • hydrate refers to a solvate, as defined hereinabove, where the solvent is water.
  • the compounds described herein can be used as polymorphs and the present embodiments further encompass any isomorph of the compounds and any combination thereof.
  • the present embodiments further encompass any enantiomers and diastereomers of the compounds described herein.
  • enantiomer refers to a stereoisomer of a compound that is superposable with respect to its counterpart only by a complete inversion/reflection (mirror image) of each other. Enantiomers are said to have "handedness” since they refer to each other like the right and left hand. Enantiomers have identical chemical and physical properties except when present in an environment which by itself has handedness, such as all living systems.
  • a compound may exhibit one or more chiral centers, each of which exhibiting an R- or an S-configuration and any combination, and compounds according to some embodiments of the present invention, can have any their chiral centers exhibit an R- or an S-configuration.
  • diastereomers refers to stereoisomers that are not enantiomers to one another. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more, but not all of the equivalent (related) stereocenters and are not mirror images of each other. When two diastereoisomers differ from each other at only one stereocenter they are epimers. Each stereo-center (chiral center) gives rise to two different configurations and thus to two different stereoisomers.
  • embodiments of the present invention encompass compounds with multiple chiral centers that occur in any combination of stereo-configuration, namely any diastereomer.
  • compositions, methods or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating refers to inhibiting, preventing or arresting the development of a pathology (disease, disorder or condition, as described herein in any of the respective embodiments) and/or causing the reduction, remission, or regression of a pathology.
  • pathology disease, disorder or condition, as described herein in any of the respective embodiments
  • Those of skill in the art will understand that various methodologies and assays can be used to assess the development of a pathology, and similarly, various methodologies and assays may be used to assess the reduction, remission or regression of a pathology.
  • the term "preventing” refers to keeping a disease, disorder or condition from occurring in a subject who may be at risk for the disease, but has not yet been diagnosed as having the disease.
  • the term "subject” includes mammals, preferably human beings at any age which suffer from the pathology. Preferably, this term encompasses individuals who are at risk to develop the pathology.
  • Human IMR90 fibroblasts obtained from ATCC ⁇ CCL186TM, were grown in a DMEM + 10 % FBS medium up to a 60 % confluency. Etoposide (Sigma, Cat. No.: E1383) was added to the cell medium to achieve a final concentration of 100 ⁇ . After 48 hours, Etoposide-containing media was removed and cells were washed with PBS (x 3) and seeded in 384-well plates (1000 cells per well). Plated cells were then incubated for 7 days prior to the screening assay, to obtain the senescent phenotype (DIS). EVIR90 growing (proliferating) cells were also seeded under the same conditions (384-well plates, 1000 cells per well), one day prior to assay.
  • the tested compounds were then added at a concentration of 10 ⁇ , to the growing and DIS cells for a period of 48 hours of further incubation under the same conditions.
  • the rate of growth inhibition for each compound was calculated as the mean absorbency of senescent cells/mean absorbency of growing cells, which corresponds to the viability ratio of senescent to growing cells.
  • IC50 experiments were performed using 5 different inhibitory concentrations of compounds: 25 ⁇ , 8.33 ⁇ , 3.33 ⁇ , 1.33 ⁇ and 0.53 ⁇ . All experiments were repeated three times and performed in duplicates.
  • ABT-737 served as a positive control, and Staurosporin as a negative control, for all experiments.
  • IMR90 cells were seeded in 384-well plates (1000 cells per well) after the initial 48 hours treatment with etoposide. The cells were then incubated for 7 days prior to the IC50 assay, to obtain the senescent phenotype (DIS). IMR90 growing (proliferating) cells were seeded one day prior to the assay. The tested compounds were then added at the 5 inhibitory concentrations mentioned, for a period of 48 hours, followed by viability measurements, using the CellTiter-Glo Luminescent Cell Viability Assay. The rate of growth inhibition was calculated for each compound at each concentration as described hereinabove for the screening assay. EXAMPLE 2
  • IC50 values for these compounds were determined as described in Example 1. Based on the IC50 curves generated in these assays, 7 compounds were identified as most potent. These compounds, along with the negative and positive controls, and the determined IC50 values are presented in Table 2 below.
  • Figures 2A-B, 3A-B, 4A-B, 5A-B, 6A-B, 7A-B and 8A-B present the representative IC50 viability curves for Compounds 1, 2, 3, 4, 5, 6 and 7, respectively.
  • Table 3 presents the CTG ratios of senescent / growing cells, as measured at 5 different concentrations (in duplicates) for an IC50 experiment.
  • the uncovered compounds have a preferential cytotoxicity for senescent cells, compared to growing cells.
  • each of these compounds inhibited senescent cells to a greater degree than they inhibited the dividing control cells.

Abstract

L'invention concerne des composés utiles pour l'élimination sélective de cellules sénescentes, des compositions les comprenant et leurs utilisations dans le traitement de maladies et de troubles dans lesquels une élimination sélective de cellules sénescentes est bénéfique. Les composés sont sélectivement représentés par les formules (I) et (II) suivantes ; les variables étant telles que définies dans la description. L'invention concerne également un dosage de criblage pour identifier des composés qui inhibent sélectivement des cellules sénescentes.
PCT/IL2016/050702 2015-07-02 2016-06-30 Inhibiteurs sélectifs de cellules sénescentes et leurs utilisations WO2017002120A1 (fr)

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US11731977B2 (en) 2016-09-02 2023-08-22 Cyclerion Therapeutics, Inc. SGC stimulators
US10472363B2 (en) 2016-09-02 2019-11-12 Cyclerion Therapeutics, Inc. SGC stimulators
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US10570145B2 (en) 2017-07-28 2020-02-25 Nimbus Lakshimi, Inc. TYK2 inhibitors and uses thereof
US10577373B2 (en) 2017-07-28 2020-03-03 Nimbus Lakshimi, Inc. TYK2 inhibitors and uses thereof
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US10508120B2 (en) 2017-07-28 2019-12-17 Nimbus Lakshimi, Inc. TYK2 inhibitors and uses thereof
US10562907B2 (en) 2017-07-28 2020-02-18 Nimbus Lakshimi, Inc. TYK2 inhibitors and uses thereof
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11160805B2 (en) 2018-06-15 2021-11-02 Handa Onocology, Llc Kinase inhibitor salts and compositions thereof
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US11911372B2 (en) 2018-06-28 2024-02-27 Ctxt Pty Ltd Compounds
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11814386B2 (en) 2018-10-05 2023-11-14 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11492346B2 (en) 2019-06-18 2022-11-08 Pfizer Inc. Benzisoxazole sulfonamide derivatives
WO2021167478A1 (fr) * 2020-02-19 2021-08-26 Ibmc - Instituto De Biologia Molecular E Celular 4-pyrrolidin-1-yl-5-p-tolyl-thiéno[2,3-d] pyrimidine destinée à être utilisée dans le traitement de maladies associées au vieillissement et au vieillissement prématuré par la stabilité chromosomique restaurée et l'inhibition de la sénescence cellulaire

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