SELECTIVE INHIBITORS OF SENESCENT CELLS AND USES THEREOF

FIELD AND BACKGROUND OF THE INVENTION

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. However, their fate in tissue is not well characterized. On one hand, benign melanocytic nevi (moles) are highly enriched for senescent cells yet can exist in skin throughout a lifetime, implying that senescent cells can be stably incorporated into tissues. On the other hand, it has been previously shown that 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 effort that the immune system invests in recognition and elimination of senescent cells suggests, although not directly, that senescent cells are deleterious for the organism and their elimination is beneficial. Additional background art includes WO2014/174511, Tchkonia T et al., Clin Invest. 2013 Mar 1; 123(3): 966-972; Zhu et al., Aging Cell, doi: 10.1111/acel.12344; and US Patent Application having Publication No. 2010/0310504.

SUMMARY OF THE INVENTION

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.

According to an aspect of some embodiments of the present invention there are provided compounds which are collectively represented by Formula I:

wherein:

each of Ar1, Ar2 and Ar3 is independently an aryl or heteroaryl;

j is 0, 1 or 2;

X is absent or is a linking group comprising one or more of amine, -S-, -S(=O) ₂ -, -C(=O)-, -O-C(=O)-, -NR'-C(=O)-, an alkyl, an alkenyl, an aryl and a heteroaryl;

Y is absent or is a linking moiety comprising one or more of amine, -S-, -

S(=O) ₂ -, -C(=O)-, -O-C(=O)-, -NR'-C(=O)-, an alkyl, an alkenyl, an aryl and a heteroaryl;

n, m and k are each independently 0, 1, 2, 3, 4 or 5; and R ₁ , R ₂ and R ₃ are each independently selected from nitro, alkoxy, nitrile, halo, hydroxy, oxo (=O), thiooxo (=S), an aryl, an alkyl, an alkenyl, a trihaloalkyl, and any combination thereof, or, alternatively, one of R ₁ and R ₂ and X form together a cyclic group, and/or one of R ₂ and R ₃ and Y form together a cyclic group,

for use in treating a disease associated with cell senescence.

According to some of any of the embodiments described herein, one or both of X and Y comprises a -S(=O) ₂ group.

According to some of any of the embodiments described herein, at least one of Ar1, Ar2 and Ar3 is aryl and the aryl is phenyl.

According to some of any of the embodiments described herein, 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.

According to some of any of the embodiments described herein, 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.

According to some of any of the embodiments described herein, 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.

According to some embodiments of Formula I described herein, Ar1 and Ar2 are each independently a heteroaryl.

According to some of these embodiments, X comprises or is -S-.

According to some of these embodiments, Ar3 is an aryl.

According to some of these embodiments, Y is absent.

According to some embodiments of Formula I described herein, Ar1 and Ar2 are each independently an aryl.

According to some embodiments of Formula I described herein, the aryl is phenyl.

According to some of these embodiments, J is 0.

According to some of these embodiments, X is absent.

According to some of these embodiments, n is 2, 3, 4 or 5.

According to some of these embodiments, at least one of the R ₁ substituents is an alkyl.

According to some of these embodiments, at least one of the R ₁ substituents is hydroxy. According to some of the embodiments wherein Ar1 and Ar2 are each independently an aryl, one of R ₁ and R ₂ , and X form together a cyclic group.

According to some of these embodiments, the cyclic group comprises a -NH- C(=O)- group.

According to some of these embodiments, n is other than 0, and at least one the R ₁ substituents is nitrile.

According to some of the embodiments wherein Ar1 and Ar2 are each independently an aryl, X comprises a -0-C(=O)- group.

According to some of these embodiments, n is other than 0, and one or more of the R ₁ substituents comprises a nitro group.

According to some of these embodiments, m is other than 0, and one or more of the R ₂ substituents comprises a trihaloalkyl.

According to some embodiments of Formula I described herein, Ar1 is aryl, Ar2 is heteroaryl, and j is 1.

According to some of these embodiments, the aryl is phenyl.

According to some of these embodiments, at least one of X and Y comprises a - S(=O) ₂ - group.

According to some of these embodiments, each of X and Y comprises the - S(=O) ₂ - group.

According to some of these embodiments, Ar3 is heteroaryl.

According to some of any of these embodiments, Ar3 is pyridine.

According to some of any of these embodiments, Ar2 is thiophene.

According to some of any of these embodiments, k is other than 0, and one or more of the R ₃ substituents comprises a trihaloalkyl.

According to some of any of these embodiments, k is other than 0, and one or more of the R ₃ substituents is halo.

According to some of any of these embodiments, n is other than 0, and one or more of the R ₁ substituents is alkoxy.

According to some of any of these embodiments, X is absent and Y is -S(=O) ₂ -. According to some of any of these embodiments, 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.

According to some of any of these embodiments, Ar3 is phenyl.

According to some of any of these embodiments, m is other than 0, and one or more of the R ₂ substituents is selected from amine and thioalkoxy.

According to some of any of these embodiments, k is other than 0, and one or more of the R ₃ substituents is halo.

According to some of any of these embodiments, n is other than 0, and one or more of the R ₁ substituents is halo.

According to some of any of the embodiments described herein, the compound is selected from Compounds 1-6 as presented in Table 2.

According to some of any of the embodiments described herein, the compound is selected from the compounds presented in Table 1.

According to some of any of the embodiments described herein, there is provided a compound represented by Formula II:

wherein:

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; and

R ₇ is alkyl, optionally substituted by one or more of hydroxy, alkoxy, thioalkoxy, sulfonyl, sulfonate and sulfoxide,

for use in treating a disease associated with cell senescence.

According to some of any of these embodiments, R ₄ and R5 are joined together to form a dioxolane ring.

According to some of any of these embodiments, R ₆ is sulfonyl. According to some of any of these embodiments, R ₇ is an alkyl substituted by one or more sulfonate groups.

According to some of any of these embodiments, R ₇ is -CH(OS(=O) ₂ -R ₈ ) ₂ , wherein R ₈ is alkyl.

According to some of any of the embodiments described herein, the disease associated with cell senescence is a fibrotic disease or an inflammatory disease.

According to some of any of the embodiments described herein, the disease is associated with cartilage degeneration.

According to some of any of the embodiments described herein, disease is selected from the group consisting of liver fibrosis, wound healing, skin fibrosis, pulmonary disease, kidney fibrosis, prostatitis, atherosclerosis, arthritis and pancreatitis.

According to some of any of the embodiments described herein, 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.

According to an aspect of some embodiments of the present invention there is provided 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.

According to some of any of the embodiments described herein, the pharmaceutical composition is formulated for topical administration.

According to some of any of the embodiments described herein, 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.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

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.

For example, hardware for performing selected tasks according to embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to exemplary embodiments of method and/or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, 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. Optionally, 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.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

In the drawings:

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. (9A) Growing and Etoposide treated (DIS) 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. (C) 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.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

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.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

In a search for novel compounds which are capable of directly and selectively eliminate senescent cells, the present inventors have developed an unbiased approach.

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.

This approach enabled identification of compounds that are toxic for senescent but not dividing cells.

Using the screening assay, 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.

The Screening Assay:

According to an aspect of some embodiments of the present invention, there is provided a method of identifying candidate compounds which selectively eliminate senescent cells. The method 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. Preferably, 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.

In some embodiments, 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.

In some embodiments, 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.

In some of these embodiments, 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.

In some embodiments, 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.

In some embodiments, compounds exhibiting a relative IC50 value which is lower than 1 are identified as potent candidates for selectively eliminating senescent cells.

The term "senescent 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.

According to a particular embodiment, the senescent cells are characterized by at least one or more of the following characteristics:

1. activation of the p53/p21CIPl and/or pRb/pl6INK4A tumor suppressor pathways,

2. cells whose proliferation is irreversibly arrested,

3. shortening of telomere size,

4. expression of senescent-associated beta-galactosidase activity,

5. Specific chromatin modification,

6. Specific secretome,

7. Increase in reactive oxygen species and altered overall mitochondrial activity.

Methods of eliciting cell senescence are known in the art and include for example the use of a histone acetyltransferase (HAT), a histone deacetylase (HDAC), DNA methyltransferase (DNMT), demethylase, histone ubiquitylase, a deubiquitination enzyme, histone chaperone, histone exchange complex, chromatin remodeler, inhibitor of the NAHM- salvage pathway, inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), low glucose cell growth conditions (glucose limitation), a compound targeting glycolytic metabolism, a glucose transporter inhibitor, hexokinase 2, phosphofructokinase 2 inhibitor, phosphofracto-2-kinase/fructose- 2,6-bisphosphatase 3 inhibitor, pyruvate kinase (PK) inhibitor, pyruvate kinase M2 inhibitor, lactate dehydrogenase (LDH) inhibitor, LDH5 lactate dehydrogenase 5 inhibitor, carbonic anhydrase-9 inhibitor, activator of oxidative phosphorylation, and pyruvate dehydrogenase (PDH) complex activator, pyruvate dehydrogenase kinase inhibitor, membrane-bound V-ATPase inhibitor, monocarboxylate transporter 1 inhibitor, Adenosine Monophosphate- Activated Protein Kinase activator, or a hypoxia- inducible factor- 1 inhibitor.

In specific embodiments, 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. As used herein, the phrase "proliferating cell" refers to a cell that is undergoing cell division.

Referring now to the drawings, Figures 1A-B present a flow chart and a schematic illustration of the method and high throughput screening assay described herein.

The remaining figures present IC50 curves obtained for exemplary compounds according to some embodiments of the present invention.

Therapeutic Uses:

According to an aspect of some embodiments of the present invention there are provided a compound as described herein for use in treating a disease associated with cell senescence.

According to an aspect of some embodiments of the present invention there is provided a method of treating a disease associated with cell senescence, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.

According to an aspect of some embodiments of the present invention there is provided a use of any of the compounds described herein in the manufacture of a medicament for treating a disease associated with cell senescence.

Diseases associated with cell senescence include, but are not limited to fibrotic diseases, inflammatory diseases and pre-malignant disorders.

Fibrotic disease:

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.

An exemplary pulmonary fibrotic disease contemplated by the present invention is chronic obstructive pulmonary disease (COPD) or Idiopathic pulmonary fibrosis. Premalignant diseases:

According to a particular embodiment, the agents (and combinations thereof) are used to treat pre-malignant lesions.

As used herein, the phrase "pre-malignant lesion" refers to a mass of cells and/or tissue having increased probability of transforming into a malignant tumor. Examples of 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. Thus, 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). According to a particular embodiment, 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:

Inflammatory diseases, as used herein, include, but are not limited to, chronic inflammatory diseases and acute inflammatory diseases.

Inflammatory diseases associated with hypersensitivity:

Examples of hypersensitivity 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. et al., Clin Diagn Lab Immunol. 1999 Mar;6 (2): 156); Chan OT. et al, Immunol Rev 1999 Jun;169: 107), glandular diseases, glandular autoimmune diseases, pancreatic autoimmune diseases, diabetes, Type I diabetes (Zimmet P. Diabetes Res Clin Pract 1996 Oct;34 Suppl:S 125), thyroid diseases, autoimmune thyroid diseases, Graves' disease (Orgiazzi J. Endocrinol Metab Clin North Am 2000 Jun;29 (2):339), thyroiditis, spontaneous autoimmune thyroiditis (Braley-Mullen H. and Yu S, J Immunol 2000 Dec 15;165 (12):7262), Hashimoto's thyroiditis (Toyoda N. et al., Nippon Rinsho 1999 Aug;57 (8): 1810), myxedema, idiopathic myxedema (Mitsuma T. Nippon Rinsho. 1999 Aug;57 (8): 1759); autoimmune reproductive diseases, ovarian diseases, ovarian autoimmunity (Garza KM. et al., J Reprod Immunol 1998 Feb;37 (2):87), autoimmune anti-sperm infertility (Diekman AB. et al., Am J Reprod Immunol. 2000 Mar;43 (3): 134), neurodegenerative diseases, neurological diseases, neurological autoimmune diseases, 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), motor neuropathies (Kornberg AJ. J Clin Neurosci. 2000 May;7 (3): 191), Guillain-Barre syndrome, neuropathies and autoimmune neuropathies (Kusunoki S. Am J Med Sci. 2000 Apr;319 (4):234), myasthenic diseases, Lambert-Eaton myasthenic syndrome (Takamori M. Am J Med Sci. 2000 Apr;319 (4):204), 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. et al., Electroencephalogr Clin Neurophysiol Suppl 1999;50:419); neuromyotonia, acquired neuromyotonia, arthrogryposis multiplex congenita (Vincent A. et al, Ann N Y Acad Sci. 1998 May 13;841:482), cardiovascular diseases, cardiovascular autoimmune diseases, 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), granulomatosis, Wegener's granulomatosis, arteritis, Takayasu's arteritis and Kawasaki syndrome (Praprotnik S. et al, Wien Klin Wochenschr 2000 Aug 25;112 (15-16):660); anti-factor VIII autoimmune disease (Lacroix-Desmazes S. et al, Semin Thromb Hemost.2000;26 (2): 157);vasculitides, necrotizing small vessel vasculitides, microscopic polyangiitis, Churg and Strauss syndrome, glomerulonephritis, pauci-immune focal necrotizing glomerulonephritis, crescentic glomerulonephritis (Noel LH. Ann Med Interne (Paris). 2000 May; 151 (3): 178); antiphospholipid syndrome (Flamholz R. et al., J Clin Apheresis 1999; 14 (4): 171); heart failure, agonist-like beta- adrenoceptor antibodies in heart failure (Wallukat G. et al, Am J Cardiol. 1999 Jun 17;83 (12A):75H), thrombocytopenic purpura (Moccia F. Ann Ital Med Int. 1999 Apr- Jun; 14 (2): 114); hemolytic anemia, autoimmune hemolytic anemia (Efremov DG. et al, Leuk Lymphoma 1998 Jan;28 (3-4):285), gastrointestinal diseases, autoimmune diseases of the gastrointestinal tract, intestinal diseases, chronic inflammatory intestinal disease (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), autoimmune diseases of the musculature, myositis, autoimmune myositis, Sjogren's syndrome (Feist E. et al, Int Arch Allergy Immunol 2000 Sep; 123 (1):92); smooth muscle autoimmune disease (Zauli D. et al, Biomed Pharmacother 1999 Jun;53 (5-6):234), hepatic diseases, hepatic autoimmune diseases, autoimmune hepatitis (Manns MP. J Hepatol 2000 Aug;33 (2):326) and primary biliary cirrhosis (Strassburg CP. et al, Eur J Gastroenterol Hepatol. 1999 Jun;l l (6):595).

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. et al, Mol Cell Endocrinol 1993 Mar;92 (1):77); ovarian diseases (Garza KM. et al, J Reprod Immunol 1998 Feb;37 (2):87), prostatitis, autoimmune prostatitis (Alexander RB. et al, Urology 1997 Dec;50 (6):893), polyglandular syndrome, autoimmune polyglandular syndrome, Type I autoimmune polyglandular syndrome (Hara T. et al, Blood. 1991 Mar 1;77 (5): 1127), neurological diseases, autoimmune neurological diseases, multiple sclerosis, neuritis, optic neuritis (Soderstrom M. et al, J Neurol Neurosurg Psychiatry 1994 May;57 (5):544), myasthenia gravis (Oshima M. et al, Eur J Immunol 1990 Dec;20 (12):2563), stiff-man syndrome (Hiemstra HS. et al, Proc Natl Acad Sci U S A 2001 Mar 27;98 (7):3988), cardiovascular diseases, cardiac autoimmunity in Chagas' disease (Cunha-Neto E. et al, J Clin Invest 1996 Oct 15;98 (8): 1709), autoimmune thrombocytopenic purpura (Semple JW. et al, Blood 1996 May 15;87 (10):4245), anti- helper T lymphocyte autoimmunity (Caporossi AP. et al, Viral Immunol 1998; 11 (1):9), hemolytic anemia (Sallah S. et al, Ann Hematol 1997 Mar;74 (3): 139), hepatic diseases, hepatic autoimmune diseases, hepatitis, chronic active hepatitis (Franco A. et al, Clin Immunol Immunopathol 1990 Mar;54 (3):382), biliary cirrhosis, primary biliary cirrhosis (Jones DE. Clin Sci (Colch) 1996 Nov;91 (5):551), nephric diseases, nephric autoimmune diseases, nephritis, interstitial nephritis (Kelly CJ. J Am Soc Nephrol 1990 Aug;l (2): 140), connective tissue diseases, ear diseases, autoimmune connective tissue diseases, autoimmune ear disease (Yoo TJ. et al, Cell Immunol 1994 Aug;157 (1):249), disease of the inner ear (Gloddek B. et al, Ann N Y Acad Sci 1997 Dec 29;830:266), skin diseases, cutaneous diseases, dermal diseases, bullous skin diseases, pemphigus vulgaris, bullous pemphigoid and pemphigus foliaceus.

Examples of delayed type hypersensitivity include, but are not limited to, contact dermatitis and drug eruption.

Examples of types of T lymphocyte mediating hypersensitivity include, but are not limited to, helper T lymphocytes and cytotoxic T lymphocytes.

Examples of helper T lymphocyte-mediated hypersensitivity include, but are not limited to, T _h l lymphocyte mediated hypersensitivity and T _h 2 lymphocyte mediated hypersensitivity.

Autoimmune 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.

Examples of 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 Wochenschr 2000 Aug 25;112 (15-16):660), anti-factor VIII autoimmune disease (Lacroix-Desmazes S. et al, Semin Thromb Hemost.2000;26 (2): 157), necrotizing small vessel vasculitis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune focal necrotizing and crescentic glomerulonephritis (Noel LH. Ann Med Interne (Paris). 2000 May; 151 (3): 178), antiphospholipid syndrome (Flamholz R. et al, J Clin Apheresis 1999; 14 (4): 171), antibody-induced heart failure (Wallukat G. et al, Am J Cardiol. 1999 Jun 17;83 (12A):75H), thrombocytopenic purpura (Moccia F. Ann Ital Med Int. 1999 Apr- Jun; 14 (2): 114; Semple JW. et al, Blood 1996 May 15;87 (10):4245), autoimmune hemolytic anemia (Efremov DG. et al, Leuk Lymphoma 1998 Jan;28 (3-4):285; Sallah S. et al, Ann Hematol 1997 Mar;74 (3): 139), cardiac autoimmunity in Chagas' disease (Cunha-Neto E. et al, J Clin Invest 1996 Oct 15;98 (8): 1709) and anti-helper T lymphocyte autoimmunity (Caporossi AP. et al, Viral Immunol 1998; 11 (1):9).

Examples of 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).

Examples of 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. Endocrinol Metab Clin North Am 2000 Jun;29 (2):339; Sakata S. et al, Mol Cell Endocrinol 1993 Mar;92 (1):77), spontaneous autoimmune thyroiditis (Braley-Mullen H. and Yu S, J Immunol 2000 Dec 15;165 (12):7262), Hashimoto's thyroiditis (Toyoda N. et al, Nippon Rinsho 1999 Aug;57 (8): 1810), idiopathic myxedema (Mitsuma T. Nippon Rinsho. 1999 Aug;57 (8): 1759), ovarian autoimmunity (Garza KM. et al, J Reprod Immunol 1998 Feb;37 (2):87), autoimmune anti-sperm infertility (Diekman AB. et al, Am J Reprod Immunol. 2000 Mar;43 (3): 134), autoimmune prostatitis (Alexander RB. et al, Urology 1997 Dec;50 (6):893) and Type I autoimmune polyglandular syndrome (Hara T. et al, Blood. 1991 Mar 1;77 (5): 1127). Examples of 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.

Examples of 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.

Examples of 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).

Examples of 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. 2000 May;7 (3): 191); Guillain-Barre syndrome and autoimmune neuropathies (Kusunoki S. Am J Med Sci. 2000 Apr;319 (4):234), myasthenia, Lambert-Eaton myasthenic syndrome (Takamori M. Am J Med Sci. 2000 Apr;319 (4):204); paraneoplastic neurological diseases, cerebellar atrophy, paraneoplastic cerebellar atrophy and stiff-man syndrome (Hiemstra HS. et al, Proc Natl Acad Sci units S A 2001 Mar 27;98 (7):3988); non-paraneoplastic stiff man syndrome, progressive cerebellar atrophies, encephalitis, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydenham chorea, Gilles de la Tourette syndrome and autoimmune polyendocrinopathies (Antoine JC. and Honnorat J. Rev Neurol (Paris) 2000 Jan; 156 (1):23); dysimmune neuropathies (Nobile-Orazio E. et al., Electroencephalogr Clin Neurophysiol Suppl 1999;50:419); acquired neuromyotonia, arthrogryposis multiplex congenita (Vincent A. et al, Ann N Y Acad Sci. 1998 May 13;841:482), neuritis, optic neuritis (Soderstrom M. et al, J Neurol Neurosurg Psychiatry 1994 May;57 (5):544) and neurodegenerative diseases. Examples of 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).

Examples of 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).

Examples of 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).

Examples of autoimmune connective tissue diseases include, but are not limited to, ear diseases, autoimmune ear diseases (Yoo TJ. et al., Cell Immunol 1994 Aug; 157

(1) :249) and autoimmune diseases of the inner ear (Gloddek B. et al., Ann N Y Acad Sci 1997 Dec 29;830:266).

Examples of 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

(2) : 156); Chan OT. et al, Immunol Rev 1999 Jun;169: 107).

Infectious diseases:

Examples of 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.

Graft rejection diseases:

Examples of 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:

Examples of 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:

Many of existing and potential anti-cancer agents induce senescence of cancer cells, therefore the identified compounds can be used in combination with these agents to increase the efficacy of the anti-cancer treatment. Treatment by these agents can also reduce side effects of radiotherapy or chemotherapy with DNA-damaging agents.

Thus the compounds disclosed herein may be used to treat a cancerous disease. 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, chorioblastoma, choriocarcinoma, colon cancer, common acute lymphoblastic leukemia, craniopharyngioma, cystocarcinoma, cystofbroma, cystoma, ductal carcinoma in situ, ductal papilloma, dysgerminoma, encephaloma, endometrial carcinoma, endothelioma, ependymoma, epithelioma, erythroleukemia, Ewing's sarcoma, extra nodal lymphoma, feline sarcoma, fibro adenoma, fibro sarcoma, follicular cancer of the thyroid, ganglioglioma, gastrinoma cell, glioblastoma multiform, glioma, gonadoblastoma, haemangioblastoma, haemangioendothelioblastoma, haemangioendothelioma, haemangiopericytoma, haematolymphangioma, haemocytoblastoma, haemocytoma, hairy cell leukemia, hamartoma, hepatocarcinoma, hepatocellular carcinoma, hepatoma, histoma, Hodgkin' s disease, hypernephroma, infiltrating cancer, infiltrating ductal cell carcinoma, insulinoma, juvenile angioforoma, Kaposi sarcoma, kidney tumor, large cell lymphoma, leukemia, a leukemia, acute leukemia, lipoma, liver cancer, liver metastases, Lucke carcinoma, lymphadenoma, lymphangioma, lymphocytic leukemia, lymphocytic lymphoma, lymphoeytoma, lymphoedema, lymphoma, lung cancer, malignant mesothelioma, malignant teratoma, mastocytoma, medulloblastome., melanoma, meningioma, mesothelioma, Morton's neuroma, multiple myeloma, myeloblastoma, myeloid leukemia, myelolipoma, myeloma, myoblastoma, myxoma, nasopharyngeal carcinoma, neoplastic, nephroblastoma, neuroblastoma, neurofibroma, neurofibromatosis, neuroglioma, neuroma, non-Hodgkin's lymphoma, oligodendroglioma, optic glioma, osteochondroma, osteogenic sarcoma, osteosarcoma, ovarian cancer, Paget' s disease of the nipple, pancoast tumor, pancreatic cancer, phaeochromocytoma, pheoehromocytoma, plasmacytoma, primary brain tumor, progonoma, prolactinoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, rhabdo sarcoma, a solid tumor, sarcoma, a secondary tumor, seminoma, skin cancer, small cell carcinoma, squamous cell carcinoma, strawberry haemangioma, T-cell lymphoma, teratoma, testicular cancer, thymoma, trophoblastic tumor, Wilm's tumor.

Thus, 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.

In the context of a combination therapy, combination therapy compounds may be administered by the same route of administration (e.g. intrapulmonary, oral, enteral, etc.) that the described compounds are administered. In the alternative, 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. For example, the first reagent can be administered within the time frame of t=0 to 1 hours, while the second reagent can be administered within the time frame of t=1 to 2 hours. Also, the first reagent can be administered within the time frame of t=0 to 1 hours, while the second reagent can be administered somewhere within the time frame of t=2-3 hours, t=3-4 hours, t=4-5 hours, t=5-6 hours, t=6-7 hours, t=7-8 hours, t=8-9 hours, t=9-10 hours, and the like. Moreover, the second reagent can be administered somewhere in the time frame of t=minus 2-3 hours, t=minus 3-4 hours, t=minus 4-5 hours, t=5-6 minus hours, t=minus 6-7 hours, t=minus 7-8 hours, t=minus 8-9 hours, t=minus 9-10 hours.

The compounds of the present invention and the at least one other cancer treatment modality (i.e. second reagent) 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.

In one preferred embodiment, 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. In a further preferred embodiment 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.

In one preferred aspect of the present invention, 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. In an alternative but equally preferred embodiment, 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.

Exemplary 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;

Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole;

Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat;

Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin;

Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin

Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin;

Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine;

Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine;

Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate;

Duazomycin; Edatrexate; Eflornithine Hydrochloride; Elsamitrucin; Enloplatin;

Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin

Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Etoposide;

Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Fluorocitabine; Fosquidone;

Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Hydroxyurea; Idarubicin

Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a; Interferon Alfa-2b;

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;

Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate;

Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin;

Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride;

Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel;

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;

Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin;

Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Sulofenur; Talisomycin; Taxol; Tecogalan Sodium; Tegafur; Teloxantrone

Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine;

Thioguanine; Thiotepa; Tiazofuirin; Tirapazamine; Topotecan Hydrochloride;

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; 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

Pharmacological Basis of Therapeutics", Eighth Edition, 1990, McGraw-Hill, Inc.

(Health Professions Division).

Additional diseases:

According to still another embodiment, the disease is associated with bone degeneration - e.g. osteoporosis.

According to still another embodiment, the disease is not cancer.

Additional Uses:

Since 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. Thus, 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.

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.

The term "sebum-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.

The terms "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). The most traditional are 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.

The terms "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, or BHA), tazarotene, adapalene, as well as molecules of the retinoid family such as tretinoin, retinaldehyde, isotretinoin and retinol.

The term "astringent" refers to an agent that helps constrict pores, the most commonly used being polyphenols, zinc derivatives and witch hazel.

The term "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. (oxazoline derivative), 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.

The term "antioxidant" refers to a molecule that decreases or prevents the oxidation of other chemical substances. The 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, phenolic acids, anthocyanins, flavonoids such as, for example, extracts of green tea, of red berries, of cocoa, of grapes, of Passiflora incarnata or of Citrus, or isoflavones such as, for example, genistein/genistin and daidzein/daidzin. 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.

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, and catechin tannins resulting from the polymerization of flavan units whose model is provided by the catechu (Acacia catechu). The trace elements that may be used are advantageously selected from the group comprised of copper, magnesium, manganese, chromium, selenium, silicon, zinc and mixtures thereof.

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.

The most commonly used 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.

Pharmaceutical compositions:

In any of the method and uses described herein, 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.

As used herein 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.

Herein the term "active ingredient" refers to the compounds described herein. It will be appreciated that the pharmaceutical compositions may comprise additional active agents known to be useful in treating a particular disease. Thus, for example for treatment of skin fibrotic diseases, 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.

Hereinafter, the phrases "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.

Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

Pharmaceutical 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.

Pharmaceutical 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.

For injection, 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.

According to a particular embodiment, the route of administration is via topical delivery.

Alternately, one may administer the pharmaceutical composition in a local rather than systemic manner, for example, via injection of the pharmaceutical composition directly into a tissue region of a patient.

Pharmaceutical 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.

Pharmaceutical 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.

For injection, 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. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, 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). If desired, 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. For this purpose, concentrated sugar solutions 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.

Pharmaceutical 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. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by nasal inhalation, 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. In the case of a pressurized aerosol, 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.

The pharmaceutical composition 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.

Pharmaceutical 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. Optionally, 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.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use.

The pharmaceutical composition of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides. Pharmaceutical 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.

Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

For any preparation used in the methods of the invention, 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.

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). 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.

The amount of a composition 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.

The compounds:

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.

According to some embodiments of the present invention, the compounds described herein are collectively represented by Formula I:

wherein:

each of Ar1, Ar2 and Ar3 is independently an aryl or heteroaryl;

j is 0, 1 or 2;

X is absent or is a linking group comprising one or more of amine, -S-, -S(=O) ₂ -, -C(=O)-, -O-C(=O)-, -NR'-C(=O)-, an alkyl, an alkenyl, an aryl and a heteroaryl; Y is absent or is a linking moiety comprising one or more of amine, -S-, - S(=O) ₂ -, -C(=O)-, -O-C(=O)-, -NR'-C(=O)-, an alkyl, an alkenyl, an aryl and a heteroaryl;

n, m and k are each independently 0, 1, 2, 3, 4 or 5; and

R ₁ , R ₂ and R ₃ are each independently selected from nitro, alkoxy, nitrile, halo, hydroxy, oxo (=O), thiooxo (=S), an aryl, an alkyl, an alkenyl and a trihaloalkyl, or, alternatively, one of R ₁ and R ₂ and X form together a cyclic group, and/or one of R ₂ and R ₃ and Y form together a cyclic group.

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.

When j is 2, the Ar3 moiety, the Y moiety, the number k of substituent R ₃ and the nature of substituent R ₃ can be the same or different in each of the two [Y-Ar3] units.

Each of the aryl or heteroaryl moieties can be substituted or unsubstituted. For an unsubstituted moiety, the corresponding n, m or k variable is 0. For a substituted moiety, the corresponding n, m or k variable is other 0.

Thus, n represents the number of substituents R ₁ of the Ar1 moiety; m represents the number of substituents R ₂ of the Ar2 moiety; and k represents the number of substituents R ₃ of the Ar3 moiety.

For each of the Ar1, Ar2 or Ar3 moieties, when 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. When 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.

Each of the X and Y linking moieties, when other than a bond, can independently comprise any one of the above-listed amine, -S-, -S(=O) ₂ -, -C(=O)-, -O- C(=O)-, -NR'-C(=O)-, an alkyl, an alkenyl, an aryl and a heteroaryl groups, and any combination thereof. The X and Y linking groups may also comprise other groups, in addition to the above-listed groups. For example, X and/or Y can be an alkyl or alkenyl, for example, methylene or ethylene, or ethenyl, conjugated to -O-, -S-, -S(=O) ₂ -, -C(=O)-, -O-C(=O)-, and/or - NR'-C(=O)-; or -S- conjugated to -C(=O)-, -O-C(=O)-, -NR'-C(=O)-, an alkyl, and/or an alkenyl.

Exemplary, non-limiting, examples of the X and/or Y linking moieties include: -

S-, -CH=CH-C(=O)-NH-C(=O)-, -S(=O) ₂ -, -CH-CH ₂ -O-C(=O)-, -CH-O-C(=O)-, or absent.

Additional examples include: -C(=O)-NH-, -CH=C(CN)-, -NH-C(=O)-CH ₂ -S-, - NH-C(=O)-CH ₂ -, -S(=O) ₂ -NH-, and -S-C(=CH-CH=C(CN) ₂ )-.

In some of any of the embodiments described herein, at least one of Ar1, Ar2 and Ar3 is aryl. In some of these embodiments, the aryl is phenyl.

In some of any of the embodiments described herein, j is 0. In some of these embodiments, both Ar1 and Ar2 are aryl, or both Ar1 and Ar2 are heteroaryl.

In some of any of the embodiments described herein, J is 1. In some of these embodiments, Ar1 is aryl and Ar2 is heteroaryl. In some of these embodiments, Ar1 and Ar3 are each aryl and Ar2 is heteroaryl.

In some of any of the embodiments described herein, 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.

In some of any of the embodiments described herein, 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.

In some embodiments, one or more of Ar1, Ar2 and Ar3 is a chlorobenzene or a chloro-pyridine.

In some of any of the embodiments described herein, 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 .

In some of any of the embodiments described herein, one or both of X and Y is or comprises a -S(=O) ₂ - group. In some of any of the embodiments described herein, one of Ar1, Ar2 and Ar3 is a heteroaryl. In some of these embodiments, two of Ar1, Ar2 and Ar3 are heteroaryls, which can be the same or different.

In some of any of the embodiments described herein, when two of Ar1, Ar2 and Ar3 are heteroaryls, j is 1. The heteroaryls can be the same or different.

In some of any of the embodiments described herein, 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.

In some of these embodiments, Ar1 and Ar2 are each independently a heteroaryl and Ar3 is aryl, e.g., phenyl. Alternatively, Ar1 is aryl and Ar2 and Ar3 are each independently a heteroaryl.

In some embodiments of Formula I as presented herein, Ar1 and Ar2 are each independently a heteroaryl, and X comprises or is -S-.

In some of these embodiments, Ar3 is an aryl, for example phenyl.

In some of these embodiments, Y is absent.

In some embodiments of Formula I as presented herein, Ar1 and Ar2 are each independently a heteroaryl, Ar3 is an aryl, for example phenyl, X comprises or is -S-, and Y is absent.

In some of these embodiments, the one or both of Ar1 and Ar2 is a nitrogen- containing heteroaryl.

In some of these embodiments, 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.

In some embodiments, 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.

In some of any of the embodiments described herein for Formula I, in which 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.

In some of these embodiments, n is 2 or more and two of the R ₁ substituents are joined together to form a ring. In some of these embodiments, the ring is a heteroalicyclic ring, and in some embodiments, it is a thiazolidine ring. In some embodiments, the heteroalicylic ring is substituted by thiooxo (=S). In some of these embodiments, the ring is a thiazolidine-2-thione. In some embodiments, the heteralicyclic ring is substituted by thiooxo and is further substituted by an alkyl, or alkenyl, for example, 2-propenyl.

In some embodiments, m is 1 and R ₂ is phenyl.

An exemplary compound according to these embodiments is Compound 6 in Table 1 hereinunder.

In some of any of the embodiments described herein for Formula I, j is 1, Ar1 is aryl and Ar2 and Ar3 are each independently a heteroaryl.

In some of these embodiments, one or both of X and Y is or comprises -S(=O) ₂ -. In some embodiments, each of X and Y is or comprises -S(=O) ₂ -. In some embodiments, X is -NH-S(=O) ₂ - and Y is -S(=O) ₂ .

In some embodiments, one or both of Ar2 and Ar3 is independently a nitrogen- containing heteroaryl and Ar1 is aryl such as phenyl. In some of these embodiments, the heteroaryl comprises one nitrogen atom. Examples include, without limitation, pyrrole and pyridine.

In some of these embodiments, Ar3 is pyridine.

In some embodiments, one or both of Ar2 and Ar3 is independently a sulfur- containing heteroaryl such as a thiophene and Ar1 is aryl such as phenyl. In some of these embodiments, Ar2 is thiophene and Ar3 is pyridine.

In some of any of the embodiments of Formula I as presented herein, Ar3 is pyridine, Ar2 is thiophene, Ar1 is aryl and one or both of X and Y is or comprises - S(=O) ₂ -. In some of these embodiments, X is -NH-S(=O) ₂ - and Y is -S(=O) ₂ .

In some of any of the embodiments described herein for Formula I, in which Ar1 is aryl, Ar2 and Ar3 are each independently a heteroaryl, and one or both of X and Y is or comprises -S(=O) ₂ -, one or more of Ar1, Ar2 and Ar3 is substituted, such that one or more of n, m and k is other than 0. In some of these embodiments, one or more of R ₁ , R ₂ and R ₃ is an electron- withdrawing group.

In some of these embodiments, k is other 1, and R ₃ is CF ₃ . In some of these embodiments, Ar3 is pyridine, and k is 2. In some embodiments, the pyridine is substituted by a trihaloalkyl, e.g., CF ₃ . In some embodiments, the pyridine is substituted by a halo such as chloro.

In some of any of the embodiments described herein or Formula I, in which Ar1 is aryl, Ar2 and Ar3 are each independently a heteroaryl, and one or both of X and Y is or comprises -S(=O) ₂ -, Ar3 is chloropyridine. In some of these embodiments, Ar3 is chloropyridine which is further substituted by an electron-withdrawing group such as a trihalolkyl, e.g., CF ₃ .

In some of any of the embodiments described herein for Formula I, in which Ar1 is aryl, Ar2 and Ar3 are each independently a heteroaryl, one or both of X and Y is or comprises -S(=O) ₂ -, and one or more of Ar1, Ar2 and Ar3 is substituted, n is other 0. In some of these embodiments, n is 1, and in some of these embodiments, n is alkoxy, for example methoxy.

In some of any of the embodiments described herein for Formula I, Ar1 is aryl more specifically phenyl, Ar2 is thiophene, Ar3 is chloropyridine, X is -NH-S(=O) ₂ - and Y is -S(=O) _2i 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.

In some of any of the embodiments described herein for Formula I, Ar1 is aryl, Ar2 is heteroaryl, and j is 1. In some of these embodiments, the aryl is phenyl. In some of these embodiments, one or both of X and Y is or comprises a -S(=O) ₂ - group.

In some of these embodiments, each of X and Y independently is or comprises said -S(=O) ₂ - group.

In some of these embodiments, 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.

In some of the embodiments in which Ar3 is a nitrogen-containing heteroaryl, the heteroaryl is substituted such that k is other than 0. In some of these embodiments, one or more of the R ₃ substituents comprises a trihaloalkyl, e.g., CF ₃ and/or a halo, e.g., chloro.

In some of these embodiments, Ar2 is thiophene.

In some of these embodiments, n is other than 0, and one or more of the R ₁ substituents is alkoxy. In some of any of the embodiments described herein for Formula I, in which Ar1 is aryl, Ar2 is heteroaryl, j is 1, and one or both of X and Y is or comprises a -S(=O) ₂ - group, X is absent and Y is -S(=O) ₂ -.

In some of these embodiments, Ar2 is pyrazolo[l,5-a]pyrimidine.

In some of these embodiments, Ar3 is aryl, e.g. phenyl.

In some of these embodiments, Ar1 and Ar3 are each phenyl and Ar2 is pyrazolo[ 1 ,5-a]pyrimidine.

In some of any of the embodiments described herein for Formula I, in which Ar1 is aryl, Ar2 is heteroaryl, Ar3 is aryl, and one or both of X and Y is or comprises a - S(=O) ₂ - group, m is other than 0, and one or more of the R ₂ substituents is selected from amine and thioalkoxy.

In some of these embodiments, X is absent and Y is -S(=O) ₂ -.

In some of these embodiments, m is 2 or more and the R ₂ substituents include an amine and a thioalkoxy such as thiomethoxy.

In some of these embodiments, Ar2 is pyrazolo[l,5-a]pyrimidine.

In some of any of the embodiments described herein for Formula I, in which Ar1 is aryl, Ar2 is heteroaryl, Ar3 is aryl, and one or both of X and Y is or comprises a - S(=O) ₂ - group, k is other than 0, and one or more of the R ₃ substituents is halo.

In some of any of the embodiments described herein for Formula I, in which Ar1 is aryl, Ar2 is heteroaryl, Ar3 is aryl, and one or both of X and Y is or comprises a - S(=O) ₂ - group, n is other than 0, and one or more of the R ₁ substituents is halo.

In some of any of the embodiments described herein for Formula I, in which Ar1 is aryl, Ar2 is heteroaryl, j is 1, Ar3 is aryl or heteroaryl, and one or both of X and Y is or comprises a -S(=O) ₂ - group, 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.

Exemplary compounds in which Ar1 is aryl, Ar2 is heteroaryl, j is 1, Ar3 is aryl or heteroaryl, and one or both of X and Y is or comprises a -S(=O) ₂ - group are Compounds 2 and 4 in Table 2 hereinunder.

In some of any of the embodiments described herein for Formula I, Ar1 and Ar2 are each independently an aryl, such as phenyl, and j is 0.

In some of these embodiments, X is absent, such that the two aryls are linked to one another via a bond. In some of these embodiments, Ar1 is a rearranged form of dihydroxyphenyl, and is 4-hydroxycyclohexa-2,5-dienone.

In some of the embodiments in which Ar1 and Ar2 are each independently phenyl, j is 0, and X is absent, n is 2, 3, 4 or 5. In some of these embodiments, 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.

In some of the embodiments in which 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.

Other exemplary compounds according to these embodiments can be represented by Formula la:

wherein:

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.

In some embodiments of Formula la, R ₁₁ -R ₁₉ are each independently selected from hydrogen and alkyl.

In some embodiments of Formula la, R ₁₁ -R ₁₅ are each hydrogen. In some embodiments of Formula la, 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.

In alternative embodiments, 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.

In alternative embodiments, a compound as described herein features a structure corresponding to Formula la as described herein in any of the respective embodiments, in which the oxo (=O) is replaced by, for example, thiooxo (=S), or imine (=NR').

In alternative embodiments, 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, and the oxo (=O) is replaced by, for example, thiooxo (=S), or imine (=NR').In some of the embodiments in which 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. In some of these embodiments, the cyclic group comprises a -NH-C(=O)- group. In some of these embodiments, the cyclic group comprises a =C(=O)-NH-C(=O)- group, and in some of these embodiments, the cyclic group is piperidine-2,6-dione. In some of these embodiments, R ₂ and X form together the cyclic ring.

In some of these embodiments, n is other than 0, and one or more of the R ₁ substituents is or comprises a nitrile.

In some embodiments, n is 1, and R ₁ is nitrile.

An exemplary compound of these embodiments is Compound 3 in Table 2 hereinunder.

In some of any of the embodiments of Formula I as described herein, in which Ar1 and Ar2 are each phenyl, and j is 0, X comprises a -O-C(=O)- group. In some of these embodiments, X is -R-O-C(=O)- group, wherein R is alkyl, e.g., ethylene.

In some of these embodiments, one or each of n and m is other than 0. In some of these embodiments, one or more of the R ₁ and R ₂ substituent(s) is an electron- withdrawing group. In some embodiments, n is other than 0, and one or more of the R ₁ substituents comprises a nitro group.

In some embodiments, 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.

Alternatively, according to some embodiments of the present invention, the compounds as described herein are collectively represented by Formula II:

wherein:

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; and

R ₇ is alkyl, optionally substituted by one or more of hydroxy, alkoxy, thioalkoxy, sulfonyl, sulfonate and sulfoxide.

In some of these embodiments, R ₄ and R5 are joined together to form a dioxolane ring. In some embodiments, the dioxolane ring is substituted and in some embodiments, it is substituted by e.g., one or more alkyls.

In some of any of the embodiments of Formula II as presented herein, one or more of R ₆ and R ₇ is or comprises a slufonyl or sulfonate groups.

In some of any of these embodiments, R ₆ is sulfonyl, such that OR ₆ is -O- S(=O) ₂ -R ₈ , and R ₈ is alkyl, e.g., methyl.

In some of any of these embodiments, R ₇ is an alkyl substituted by one or more sulfonate groups.

In exemplary embodiments, R ₇ is -CH(OS(=O) ₂ -R ₈ ) ₂ , wherein R ₈ is alkyl.

An exemplary compound according to embodiments of Formula II as described herein in Compound 7 in Table 2 hereinunder. Definitions:

Herein throughout, the phrase "linking moiety" describes a group (a substituent) that is attached to another moiety in the compound via two or more atoms thereof. In order to differentiate a linking group from a substituent that is attached to another moiety in the compound via one atom thereof, the latter will be referred to herein and throughout as an "end group".

As used herein, the term "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.

Alternatively, 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.

The term "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.

The term "alkyl" describes a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, 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.

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. When an alkyl is a linking group, it is also referred to herein as "alkylene", e.g., methylene, ethylene, propylene, etc.

The term "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.

The term "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. 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.

The term "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. 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.

The term "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. 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. Preferably, the aryl is phenyl.

The term "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. Examples, without limitation, of 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. 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.

The term "alkaryl" describes an alkyl, as defined herein, which is substituted by one or more aryl or heteroaryl groups. An example of alkaryl is banzyl.

The term "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.

The term "halide" and "halo" describes fluorine, chlorine, bromine or iodine.

The term "haloalkyl" describes an alkyl group as defined above, further substituted by one or more halide.

The term "sulfate" describes a -O- S(=O) ₂ -OR' end group, as this term is defined hereinabove, or an -O- S(=O) ₂ -O- linking group, as these phrases are defined hereinabove, where R' is as defined hereinabove.

The term "thiosulfate" describes a -O-S(=S)(=O)-OR' end group or a -O- S(=S)(=O)-O- linking group, as these phrases are defined hereinabove, where R' is as defined hereinabove.

The term "sulfite" describes an -O- S(=O)-O- R' end group or a -O-S(=O)-0- group linking group, as these phrases are defined hereinabove, where R' is as defined hereinabove.

The term "thiosulfite" describes a -O-S(=S)-0-R' end group or an -O-S(=S)- O- group linking group, as these phrases are defined hereinabove, where R' is as defined hereinabove.

The term "sulfinate" or "sulfinyl" describes a -S(=O)-OR' end group or an - S(=O)-O- group linking group, as these phrases are defined hereinabove, where R' is as defined hereinabove.

The term "sulfoxide" describes a -S(=O)R' end group or an -S(=O)- linking group, as these phrases are defined hereinabove, where R' is as defined hereinabove. The term "sulfonate" or "sulfonyl" describes a -S(=O)2-R' end group or an - S(=O) ₂ - linking group, as these phrases are defined hereinabove, where R' is as defined herein.

The term "S- sulfonamide" describes a -S(=O) ₂ -NR'R" end group or a -S(=O) ₂ - NR'- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "N- sulfonamide" describes an R'S(=O) ₂ -NR"- end group or a -S(=O) ₂ -NR'- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

The term "disulfide" 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.

The term "phosphonate" describes a -P(=O)(OR')(OR") end group or a -P(=O)(OR')(0)- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "thiophosphonate" describes a -P(=S)(OR')(OR") end group or a

-P(=S)(OR')(0)- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "carbonyl" or "carbonate" as used herein, describes a -C(=O)-R' end group or a -C(=O)- linking group, as these phrases are defined hereinabove, with R' as defined herein.

The term "thiocarbonyl " as used herein, describes a -C(=S)-R' end group or a - C(=S)- linking group, as these phrases are defined hereinabove, with R' as defined herein.

The term "oxo" as used herein, described a =0 end group.

The term "thiooxo" as used herein, described a =S end group.

The term "oxime" describes a =N-OH end group or a =N-O- linking group, as these phrases are defined hereinabove.

The term "hydroxyl" describes a -OH group.

The term "alkoxy" describes both an -O-alkyl and an -O-cycloalkyl group, as defined herein.

The term "aryloxy" describes both an -O-aryl and an -O-heteroaryl group, as defined herein. The term "thiohydroxy" describes a -SH group.

The term "thioalkoxy" describes both a -S-alkyl group, and a -S-cycloalkyl group, as defined herein.

The term "thioaryloxy" describes both a -S-aryl and a -S-heteroaryl group, as defined herein.

The term "cyano" or "nitrile" describes a -C≡N group.

The term "isocyanate" describes an -N=C=0 group.

The term "nitro" describes an -N0 ₂ group.

The term "carboxylate" as used herein encompasses C-carboxylate and O- carboxylate.

The term "C-carboxylate" describes a -C(=O)-OR' end group or a -C(=O)-O- linking group, as these phrases are defined hereinabove, where R' is as defined herein.

The term "O-carboxylate" describes a -OC(=O)R' end group or a -OC(=O)- linking group, as these phrases are defined hereinabove, where R' is as defined herein.

The term "thiocarboxylate" as used herein encompasses "C-thiocarboxylate and O-thiocarboxylate.

The term "C-thiocarboxylate" describes a -C(=S)-OR' end group or a -C(=S)-O- linking group, as these phrases are defined hereinabove, where R' is as defined herein.

The term "O-thiocarboxylate" describes a -OC(=S)R' end group or a -OC(=S)- linking group, as these phrases are defined hereinabove, where R' is as defined herein.

The term "carbamate" as used herein encompasses N-carbamate and O- carbamate.

The term "N-carbamate" describes an R"OC(=O)-NR'- end group or a -OC(=O)-NR'- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "O-carbamate" describes an -OC(=O)-NR'R" end group or an - OC(=O)-NR'- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "thiocarbamate" as used herein encompasses N-thiocarbamate and O- thiocarbamate. The term "O-thiocarbamate" describes a -OC(=S)-NR'R" end group or a -OC(=S)-NR'- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "N-thiocarbamate" describes an R"OC(=S)NR'- end group or a -OC(=S)NR'- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "dithiocarbamate" as used herein encompasses N-dithiocarbamate and S-dithiocarbamate.

The term "S-dithiocarbamate" describes a -SC(=S)-NR'R" end group or a -SC(=S)NR'- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "N-dithiocarbamate" describes an R"SC(=S)NR'- end group or a -SC(=S)NR'- linking group, as these phrases are defined hereinabove, with R' and R" as defined herein.

The term "urea", which is also referred to herein as "ureido", describes a -NR'C(=O)-NR"R" ' end group or a -NR'C(=O)-NR"- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein and R'" is as defined herein for R' and R".

The term "thiourea", which is also referred to herein as "thioureido", describes a -NR'-C(=S)-NR"R" ' end group or a -NR'-C(=S)-NR"- linking group, with R', R" and R" ' as defined herein.

The term "amide" as used herein encompasses C-amide and N-amide.

The term "C-amide" describes a -C(=O)-NR'R" end group or a -C(=O)-NR'- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

The term "N-amide" describes a R'C(=O)-NR"- end group or a R'C(=O)-N- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

The term "guanyl" describes a R'R"NC(=N)- end group or a -R'NC(=N)- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein. The term "guanidine" describes a -R'NC(=N)-NR"R' " end group or a - R'NC(=N)- NR"- linking group, as these phrases are defined hereinabove, where R', R" and R'" are as defined herein.

The term "hydrazine" 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.

As used herein, the term "hydrazide" describes a -C(=O)-NR'-NR"R"' end group or a -C(=O)-NR'-NR"- linking group, as these phrases are defined hereinabove, where R', R" and R'" are as defined herein.

As used herein, the term "thiohydrazide" describes a -C(=S)-NR'-NR"R"' end group or a -C(=S)-NR'-NR"- linking group, as these phrases are defined hereinabove, where R', R" and R'" are as defined herein.

As used herein, the term "methyleneamine" describes a -NR'-CH ₂ -CH=CR"R"' end group or a -NR'-CH ₂ -CH=CR"- linking group, as these phrases are defined hereinabove, where R', R" and R'" are as defined herein.

For any of the embodiments described 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.

As used herein, 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.

In the context of some of the present embodiments, 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.

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). Each of these acid addition salts can be either a mono-addition salt or a poly-addition salt, as these terms are defined herein.

Depending on the stoichiometric proportions between the charged group(s) in the compound and the counter-ion in the salt, the acid or base additions salts can be either mono-addition salts or poly-addition salts.

The phrase "mono-addition salt", as used herein, 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.

The phrase "poly- addition salt", as used herein, 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.

As used herein, the term "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.

Further, each of the compounds described herein, including the salts thereof, can be in a form of a solvate or a hydrate thereof.

The term "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.

The term "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.

As used herein, the term "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. In the context of the present embodiments, 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.

The term "diastereomers", as used herein, 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. In the context of the present invention, embodiments of the present invention encompass compounds with multiple chiral centers that occur in any combination of stereo-configuration, namely any diastereomer.

As used herein the term "about" refers to ± 10 %.

The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to".

The term "consisting of means "including and limited to". The term "consisting essentially of" means that the composition, method 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.

As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in 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.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

As used herein the term "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.

The term "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. 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.

As used herein, 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.

As used herein, 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.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion.

EXAMPLE 1

Design of a Screening Assay

Schematic illustrations of an exemplary screening assay as described herein are presented in Figures 1A-B.

Human IMR90 fibroblasts, obtained from ATCC© CCL186™, 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 μΜ. 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 μΜ, to the growing and DIS cells for a period of 48 hours of further incubation under the same conditions.

Cell viability was measured using the CellTiter-Glo Luminescent Cell Viability

Assay (Promega).

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.

Compounds which exhibited a viability ratio lower than 0.6 were determined as those that exhibit selective toxicity towards senescent cells.

These compounds were further tested for determining their IC50 towards senescent cells. IC50 experiments were performed using 5 different inhibitory concentrations of compounds: 25 μΜ, 8.33 μΜ, 3.33 μΜ, 1.33μΜ and 0.53 μΜ. 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.

In the IC50 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

Identification of Senescent Cells Inhibitors

Overall 3 libraries of compounds were screened using the assay described in Example 1 hereinabove, 384 different compounds in each plate, with multiple plates per run, as follows:

The 26 compounds for which viability ratio was determined as lower than presented in Table 1 below.

Table 1

The 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.

Table 2

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 below presents the CTG ratios of senescent / growing cells, as measured at 5 different concentrations (in duplicates) for an IC50 experiment. Table 3

As shown, the uncovered compounds have a preferential cytotoxicity for senescent cells, compared to growing cells. These compounds are representative examples of a novel class of compounds that are useful for specific elimination of senescent cells, similarly to ABT-737 and ABT-263 or known molecular players like p21(CDKNlA). It is noted that some of the uncovered compounds exhibit structural features similar to known senescent inhibitors such as ABT-737, such as, for example, a presence of an -S(=O) ₂ group and/or chlorobenzene groups. Some of the uncovered compounds present a structural feature that was not previously associated with compounds capable of selective elimination of senescent cells; the presence of fluoro substituents on an aromatic ring.

EXAMPLE 3

Validation of Senescent Cells Inhibitors

Three compounds that were identified using the screen described in Example 2 were validated - namely Os007, Mb031 and Mb041.

As shown in Figures 9A-D, each of these compounds inhibited senescent cells to a greater degree than they inhibited the dividing control cells.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.