WO2006087718A1 - Prolongement de duree de vie avec des medicaments - Google Patents

Prolongement de duree de vie avec des medicaments Download PDF

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WO2006087718A1
WO2006087718A1 PCT/IL2006/000205 IL2006000205W WO2006087718A1 WO 2006087718 A1 WO2006087718 A1 WO 2006087718A1 IL 2006000205 W IL2006000205 W IL 2006000205W WO 2006087718 A1 WO2006087718 A1 WO 2006087718A1
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compound
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aryl
lifespan
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Shimon Slavin
Aviv Gazit
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Yissum Research Development Company Of The Hebrew University Of Jerusalem
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/37—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by etherified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton

Definitions

  • the present invention is directed towards drugs which affect protein tyrosine kinases (PTKs) or steroid -related enzymes (SREs). More particularly the present invention relates to inhibiting PTKs and SREs activity, and to treating disorders related to PTKs or SREs activity in a subject. Specifically, the present invention is directed, inter alia, to encouraging apoptosis in malignant tissue, inhibiting apoptosis in non- malignant or healthy tissue, and elongating the lifespan of a subject while sustaining that subject in good health condition.
  • PTKs protein tyrosine kinases
  • SREs steroid -related enzymes
  • Aging research mainly deals with understanding the mechanism of aging, with little or no practical clinical use so far. Many of the genes involved in the aging process, also play crucial roles in early developmental stages in life. Therefore, gene manipulation of these genes may have very serious and unpredictable effects on health, and cannot be considered an option for clinical use in the foreseeable future, even if social, religious and political hurdles can be overcome.
  • Resveratrol was found to extend yeast lifespan by 70%, through the stimulation of histone deacetylase activity of Sir2 [Howitz, K.T. et al., (2003) Nature 425'- 191]. Resveratrol also extended nematode lifespan by 10% [Wood, J.G. et al., (2004) Nature 430: 686] and by 18% in flies [Bauer, J.H. et al., (2004) PNAS 10V 12980].
  • the following relates to the aging and small molecule inhibitors of crucially important enzymes, PTKs (protein kinases), and SREs (steroid related enzymes).
  • IGFs insulin-like growth factors
  • IGF-2 is thought to be a primary growth factor required for early development while IGF-I expression is seen in life later.
  • IGF-2 is primarily fetal in action and it is also essential for development and function of organs such as the brain, liver and kidney.
  • IGF-I Insulin-like growth factor 1
  • hGH growth hormone
  • IGF-I Insulin-like growth factor 1
  • IGF-I can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis.
  • IGF-I and its receptor play a key role in normal growth and development [Dupont, J. and Holzenberger, M. (2003) Birth Defects Res. 69: 257]. IGF-I plays an important role in childhood growth and continues to have anabolic effects in adults.
  • IGF axis While crucial in early life, overexpression of IGF axis seems to lead to a shorter lifespan in the aging organism. Reduction of IGF level expression in aging humans may thus be an attempt by the body to minimize this effect.
  • the hypothalamic activity of the GH-IGF network declines with age. An increased cardiovascular mortality in adults with GH deficiency can be found. Aging is accompanied by a progressive decline in circulating IGF-I, suggesting a continuing diminution of the GH-IGF axis throughout aging. Moreover, some studies suggest that GH might play an important role in lipid metabolism in healthy elderly subjects [Ceda G.P. et al., (1998) J. Clin. Endocrinol. Metab. 83-499].
  • the lifespan of Caenorhabditis elegans worm can be increased by more than 200 percent through genetic engineering. Mutations that result in loss or decrease of function of insulin-like signaling in worms, flies and mice are associated with extended lifespan.
  • mutations in the growth hormone-IGF-1 [Longo, V.D. and Finch, CE. (2003) Science 299- 1342; Liang, H. et al., (2003) Exper. Gerontology 3#1353; Hamet, P. and Tremblay, J.
  • PIK3 phosphatidyl inositol 3 kinase
  • AKT kinase a serine/threonine kinase, also called protein kinase B, PKB
  • FOXO Force transcription factor family
  • IGFs insulin-like growth factors
  • IGF-IR insulin-like growth factor 1 receptor
  • DAF-2 gene in Caenorhabditis elegans a homolog of the mammalian insulin/IGF 1 receptor, controls organism growth in response to poor nutrient conditions indirectly, by controlling formation of the long-lived, stress-resistant dauer stage during larval development, and the lifespan in the adult [Kimura et al., (1997) Science 277- 942].
  • RNA interference with the DAF-2 and laser zapping of gonad cells led to dramatic 500% increase in C. elegans lifespan without loss of vitality [Arantes-Oliveira, N. et al., (2003) Science 302: 611].
  • the insulin/IGF receptor homolog DInr controls organism growth directly by regulating cell size and cell number [Brogiolo, W. et al., (2001) Curr. Biol. IV- 213]. Furthermore, reduced insulin signaling causes female sterility and independently increases the lifespan [Tatar, M et al., (2001) 292'- 107; Clancy, D.J. et al., (2001) Science 292- 104].
  • Forkhead transcription factors belonging to the FOXO subfamily are negatively regulated by protein kinase B (PKB) in response to signaling by insulin and insulin-like growth factor in C. elegans and mammals.
  • PPKB protein kinase B
  • Loss-of- function mutations in daf-16 C. elegans only FOXO transcription factor completely suppress the dauer- constitutive and longevity phenotypes associated with reduced function of insulin-signaling components.
  • FOXO transcription factors mediate insulin resistance in diabetic mice [Nakae, J. et al., (2002) Nat. Genet. 32- 245] and have been proposed to be tumor suppressors, as several chromosomal translocations disrupting FOXO genes are found in cancers [Borkhardt, A. et al., (1997) Oncogene 14- 195,' Sublett, J.E. et al., (1995) Oncogene 11' 545], and overexpressed FOXO proteins can inhibit tumor growth [Ramaswamy, S. et al., (2002) Cancer Cell 2- 81].
  • IGF-I receptor and closely related insulin receptor by dominant negative mutants, antisense oligonucleotides, and peptides is well established. Dissimilarly, only few small chemical compounds molecules capable of inhibiting IGF-I receptor or related receptors are known [De Meytes, P. and Whittaker, J. (2002) Nature Reviews Drug Discovery 1- 769,” and Surmacz, E. (2003) Oncogene 22- 6589].
  • US 20040121407A1 publication relates to treatments and compositions that putatively alter the lifespan regulation and cellular responses to diseases and disorders by antagonizing the GH/IGF-1 axis.
  • This patent application offers theoretical discussion and speculative future uses of the GH/IGF-1 regulation, and does not exemplify neither proves the claimed use of any of the compounds described therein, in any living animal or even cells.
  • GH growth hormone
  • DHEA dehydroepiandrosteron
  • E estradiol
  • elegans nematode and flies cannot synthesize sterols de novo, getting their supply of cholesterol from food, but they have an elaborate enzymatic machinery to modify sterols (ecdysone and related sterols are used in fly, see e.g. Kurzchalia T. and Ward S.: Nature Cell Biology (2003) 8-'684).
  • ecdysone and related sterols are used in fly, see e.g. Kurzchalia T. and Ward S.: Nature Cell Biology (2003) 8-'684
  • the mutants in daf-9 and daf-12, encoding cytochrome hydroxylase enzyme and nuclear hormone receptor respectively were found to prolong the lifespan.
  • a mutation involved in the biosynthesis of ecdysone caused 45% increase in the lifespan in flies [Simon A. et al: Science (2003) 299-1401].
  • Aromatase is a microsomal cytochrome P450 enzyme (CYP19 gene) that catalyzes the aromatization of ring A of androgen steroids to estrogen.
  • Aromatase inhibitors are in clinical use for breast cancer treatment, and since they proved to be better than long established tamoxifene (an estradiol receptor inhibitor), they were recently approved by the FDA as first line treatment.
  • Aromatase inhibitors were given for long periods of time (up to 4 years) with no serious adverse effects on bone metabolism, plasma lipids, and cardiovascular system. It is an object of this invention to provide pharmaceutical compositions for extending the lifespan of a subject comprising SREs, such as, e.g., aromatase inhibitors or estradiol receptor inhibitors.
  • PTKs and SREs are of fundamental importance for the biological regulation and signal transduction; and specifically IGF-I, aromatase, or estradiol receptor are found to affect nearly all aspects of cellular activities. It is therefore an object of the present invention to provide some known as well as novel compounds which are capable of inhibiting PTKs or SREs, such as IGF-I inhibitors, estradiol receptor inhibitors, or aromatase inhibitors, that may be used for treating disorders associated with PTKs or SREs. Further, it is an object of the present invention to provide pharmaceutical compositions comprising such compounds as the active components and methods for their preparation. Still another object of the present invention is to provide for methods of treating disorders associated with PTKs or SREs. Particularly, the compounds of the present invention are intended for elongating the lifespan in a subject.
  • the present invention relates to the use of protein tyrosine kinases (PTKs) inhibitors of formula (Ia) or (Ib), and steroid-related enzymes (SREs) inhibitors, such as aromatases inhibitors, in the preparation of a pharmaceutical composition for extending the lifespan of a subject, wherein said subject is particularly a mammal, most preferably a human.
  • PTKs protein tyrosine kinases
  • SREs steroid-related enzymes
  • Said steroid-related enzyme may be an aromatase, such as letrozole, anastrozole, fadrozole and vorozole, or estradiol receptor inhibitor selected from fulvestrant, tamoxifene and raloxifene, or a compound selected from AGS 308 and AGS 333, and said formulae have the structures:
  • Ri is H, OH, halogen, wherein the halogen may be F, Cl, Br, or I, nitro, CN, aldehyde, substituted ketone, COOH, trifluoromethyl, amide, substituted or unsubstituted alkyl, particularly isopropyl, or t-butyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkyloxy, preferably methoxy, haloalkyl or haloaryl comprising at least one substituent selected from F, Cl, Br, or I, aryloxy, preferably phenoxy, alkylamino, alkylamido, arylamino, arylamido?"
  • R2 is H, OH, alkyl, preferably t-butyl or isopropyl, aryl, arylalkyl, alkylaryl, alkyloxy, preferably methoxy, alkylthio, wherein the sulfur may replace any of the carbon atoms of the alkylthio, or arylthio, arylalkylthio, arylthioalkyl, particularly arylthiomethyl, heterocycloalkyl, alky lheterocyclo alkyl, heterocycloalkylalkyl, heteroaryl, hetroarylalkyl, alky lhetero aryl, preferably the heterocycloalkyl is one of cyclic urea, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxazolidonyl,
  • R3 is CN, amide, nitrileamido, aminothiol, amino, alkyl, alkenyl, alkynyl, alkylamino, alkylamido, alkyleneamino, alkyleneamido, particularly dicyanoethylene amino, wherein the alkyl, alkenyl, or alkynyl moieties in the above substituents may be substituted or unsubstituted, substituted or unsubstituted aryl, arylcarbonyl, arylalkylcarbonyl, arylalkylenecarbonyl, arylamido, particularly phenylamido, arylalkylamido, particularly phenylmethylamido, or phenylethylamido, arylalkyleneamido, arylamino, arylalkylamino, arylalkyleneamino arylsulfonyl, particularly phenylsulfonyl, aryl
  • R4 is H, aryl, arylalkyl, alkylaryl, he terocyclo alkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, hetroarylalkyl, alky lhetero aryl, preferably the heterocycloalkyl is one of cyclic urea, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxazolidonyl, isoxazolidonyl, pyrazolinyl, pyrazolidinyl, piperidyl, piperazine, morpholinyl, preferably the heteroaryl is one of pyrrolyl, thienyl, thiazolyl, benzothienyl, naphthothienyl, purinyl, iso
  • Het is a 5 or 6-membered hetero ring, preferably said ring selected from imidazoline, imidazolidine, carbostyryl, pyrrole, pyrroline, pyrrolidine, thiophene, thiazole, isothiazole, furan, furazan, oxazole, isoxazole, oxazolidine, isoxazolidone, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrazine, pyrimidine, pyridazine, piperidyl, piperazinyl, morpholinyl, particularly Het is either one of oxazolidone , cyclic urea, and pyrrolidone, and pharmaceutically acceptable salts thereof.
  • the present invention provides use of a compound, or a mixture of compounds, inhibiting a SRE or a PTK, in the preparation of a pharmaceutical composition for extending the lifespan of a subject, wherein said compound is selected from the group consisting of compounds of formula (Ia), compounds of formula (Ib), aromatase inhibitors, estradiol receptor inhibitors, and antilipolytic compounds AGS 308 and AGS 333.
  • the present invention provides a method of elongating the lifespan of a subject, particularly a mammal, most preferably a human, comprising administering to said subject an effective amount of a compound, or a mixture of compounds, inhibiting a SRE or a PTK, selected from the group consisting of compounds of formula (Ia), compounds of formula (Ib), aromatase inhibitors, estradiol receptor inhibitors, and antilipolytic compounds AGS 308 and AGS 333 as an active ingredient, and optionally further comprising a carrier, diluent, excipient and/or additive.
  • a SRE or a PTK selected from the group consisting of compounds of formula (Ia), compounds of formula (Ib), aromatase inhibitors, estradiol receptor inhibitors, and antilipolytic compounds AGS 308 and AGS 333 as an active ingredient, and optionally further comprising a carrier, diluent, excipient and/or additive.
  • the invention further provides a subclass of compounds of formulae (Ia) and (Ib), novel compounds of formulae (Ha) and (lib):
  • Ri is hydroxy, R2 is hydrogen, R3 is cyano, and R4 forms a fused phenyl pyrrolidone with the main aromatic ring;
  • Ri is hydroxy, R2 is hydrogen, R3 is 3,4-dihydroxybenzoyl, and R 4 is hydrogen
  • Ri is bromide, R2 is t'butyl, R3 is cynao, and R4 is hydrogen; or
  • Het is oxazilidone, R2 and R 4 are hydrogen, and R3 is phenylmethylamido, or 3,4-dihydroxybenzoyl.
  • the present invention provides use of compounds of formulae (Ia), and (Ib) in the preparation of pharmaceutical composition for extending the lifespan in a subject, particularly mammalian, most preferably human.
  • the present invention provides use of compounds of formulae (Ha), and (lib) in the preparation of pharmaceutical composition for extending the lifespan in a subject, particularly mammalian, most preferably human.
  • the present invention provides use of aromatase inhibitors in the preparation of pharmaceutical composition for extending the lifespan in a subject, particularly mammalian, most preferably human.
  • the present invention provides use of estradiol receptor inhibitors in the preparation of pharmaceutical composition for extending the lifespan in a subject, particularly mammalian, most preferably human.
  • the present invention provides pharmaceutically acceptable compositions comprising a SRE inhibitor or a PTK inhibitor selected from compounds of formula (Ia) or (Ib), aromatase inhibitors, and estradiol receptor inhibitors, or mixtures thereof; optionally further comprising a carrier, diluent, excipient and/or additive.
  • the present invention provides a method of elongating the lifespan of a mammalian, preferably human subject, the method comprising the step of administering to that subject an effective amount of at least one compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising that compound.
  • the present invention provides a method for preventing and/or delaying the appearance of age-dependent and/or age- related disorders in a mammalian, preferably human subject, comprising the step of administering to that subject an effective amount of at least one compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising that compound.
  • the present invention provides an anti-aging method for a mammalian, preferably human subject, comprising the step of administering to that subject an effective amount of at least one compound of formula (Ia), or (Ib), or formula (Ha), or (lib), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • the present invention provides a method of elongating the lifespan of a mammalian, preferably human subject, the method comprising the step of administering to that subject an effective amount of at least one compound selected from compounds of formula (Ha) or (lib), aromatase inhibitors, and estradiol receptor inhibitors, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising that compound.
  • the present invention provides a method for preventing and/or delaying the appearance of age-dependent and/or age- related disorders in a mammalian, preferably human subject, comprising the step of administering to that subject an effective amount of at least one compound selected from compounds of formula (Ha) or (lib), aromatase inhibitors, and estradiol receptor inhibitors, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising that compound.
  • the administration of any of the compounds of formula (Ia) or (Ib) or (Ha) or (lib), or pharmaceutical compositions comprising the same delays aging symptoms and/or slows the aging process.
  • the subject is a mammalian subject afflicted with a premature aging disorder, the subject being the most preferably a human.
  • the present invention provides pharmaceutically acceptable glucose amine salt of a compound of formula (Ia) or (Ib), where that salt being preferably a combination, particularly at JUI ratio, of N-methyl glucose amine and the compound AG 1024, designated AGS 250.
  • the present invention provides a method for the manufacture of compounds as defined in formulae (Ha) and (lib), where this method comprises the following steps: a) mixing together a derivative of a hydroxybenzaldehyde, a derivative of acetonitrile, and ? -alanine in a solvent; b) renuxingJ c) evaporating; and d) triturating.
  • the present invention provides a method for the manufacture of the compound AGS 250, which comprises the steps of a) mixing together AGS 200 and N-methyl glucose amine; b) refhixing; c) evaporating; and d) triturating.
  • the solvent is ethanol in the manufacture of any of the novel compounds of the present invention, and the trituration is preferably carried-out in hexane, or in acetone -hexane mixture.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (Ha) or (lib), or mixtures thereof for the treatment of protein tyrosine kinase family (PTKs)- associated disorders in a mammalian subject in need.
  • PTKs protein tyrosine kinase family
  • the PTK is selected from the platelet- derived growth factor (PDGF), the epidermal growth factor (EGF), the insulin growth factor (IGF), and, preferably, the insulin-like growth factor- I (IGF-I) receptor.
  • PDGF platelet- derived growth factor
  • EGF epidermal growth factor
  • IGF insulin growth factor
  • IGF-I insulin-like growth factor- I
  • the PTK associated disorder is selected from (a) proliferative diseases, in particular sarcomas, carcinomas, lymphomas or melanomas; (b) fibrotic conditions, including pulmonary fibrosis, hepatic cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy! (c) metabolic diseases, in particular diabetes,' (d) other PTK-associated disorders such as arthritis, rheumatoid arthritis, psoriasis, neurodegenerative diseases; and (e) other abnormal conditions for example, transplant rejection, wound healing or inflammation.
  • the disorder comprises a malignant disorder selected from sarcomas, melanomas, lymphomas and carcinomas.
  • the present invention provides a method for the treatment and/ or prevention of PTK- associated disorders in a mammalian subject in need, comprising the step of administering to that subject a therapeutically effective amount of at least one of the compounds of formula (Ha), or (lib), or a therapeutically effective amount of a pharmaceutical composition comprising that compound, wherein the PTK associated disorder particularly includes PDGF, EGF, IGF and preferably IGF-I receptor related diseases.
  • the disorder is selected from (a) proliferative diseases, in particular sarcomas, carcinomas, lymphomas or melanomas," (b) fibrotic conditions, including pulmonary fibrosis, hepatic cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy; (c) metabolic diseases, in particular diabetes; (d) other disorders such as arthritis, rheumatoid arthritis, psoriasis, neurodegenerative diseases; and (e) other abnormal conditions for example, transplant rejection, wound healing or inflammation.
  • proliferative diseases in particular sarcomas, carcinomas, lymphomas or melanomas
  • fibrotic conditions including pulmonary fibrosis, hepatic cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy;
  • metabolic diseases in particular diabetes;
  • other disorders such as arthritis, rheumatoid arthritis, psoriasis, neurodegenerative diseases
  • Fig. 1. shows the lifespan extension in nematodes! the graph demonstrates the positive effect of compounds AGS- 199 and AGS-250 of the present invention on the extension of lifespan in C. elegansl
  • Fig. 2. shows the lifespan extension in fruit flies; the graph demonstrates the positive effect of compounds AGS-200 and AGS-250 of the present invention on the extension of lifespan in D. melanogaster, and
  • Fig. 3. shows the lifespan extension in nematodes.' the graph demonstrates the positive effect of an aromatase inhibitor, arimidex at 50 ?M, on the extension of the lifespan in C. elegans.
  • the present invention is directed towards the use of compounds of formula (Ia) or (Ib) in the preparation of a pharmaceutical composition for extending the lifespan of a subject,
  • Ri is H, OH, halogen, wherein the halogen may be F, Cl, Br, or I, nitro, CN, aldehyde, substituted ketone, COOH, trifluoromethyl, amide, substituted or unsubstituted alkyl, particularly isopropyl, or t -butyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkyloxy, preferably methoxy, haloalkyl or haloaryl comprising at least one substituent selected from F, Cl, Br, or I, aryloxy, preferably phenoxy, alkylamino, alkylamido, arylar ⁇ ino, arylamido;
  • R2 is H, OH, alkyl, preferably t-butyl or isopropyl, aryl, arylalkyl, alkylaryl, alkyloxy, preferably methoxy, alkylthio, wherein the sulfur may replace any of the carbon atoms of the alkylthio, or arylthio, arylalkylthio, arylthioalkyl, particularly arylthiomethyl, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, hetro arylalkyl, alkylheteroaryl, preferably the heterocycloalkyl is one of cyclic urea, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxazolidonyl, iso
  • R3 is CN, amide, nitrileamido, aminothiol, amino, alkyl, alkenyl, alkynyl, alkylamino, alkylamido, alkyleneamino, alkyleneamido, particularly dicyanoethylene amino, wherein the alkyl, alkenyl, or alkynyl moieties in the above substituents may be substituted or unsubstituted, substituted or unsubstituted aryl, arylcarbonyl, arylalkylcarbonyl, arylalkylenecarbonyl, arylamido, particularly phenylamido, arylalkylamido, particularly phenylmethylamido, or phenylethylamido, arylalkyleneamido, arylamino, arylalkylamino, aiylalkyleneamino arylsulfonyl, particularly phenylsulfonyl,
  • R4 is H, aryl, arylalkyl, alkylaryl, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, he tro arylalkyl, alkylheteroaryl, preferably the heterocycloalkyl is one of cyclic urea, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxazohdonyl, isoxazolidonyl, pyrazolinyl, pyrazolidinyl, piperidyl, piperazine, morpholinyl, preferably the heteroaryl is one of pyrrolyl, thienyl, thiazolyl, benzothienyl, naphthothienyl, purinyl, isothiazolyl,
  • Het is a 5 or 6-membered hetero ring, preferably said ring selected from imidazoline, imidazolidine, carbostyryl, pyrrole, pyrroline, pyrrolidine, thiophene, thiazole, isothiazole, furan, furazan, oxazole, isoxazole, oxazohdine, isoxazolidone, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrazine, pyrimidine, pyridazine, piperidyl, piperazinyl, morpholinyl, particularly Het is either one of oxazolidone , cyclic urea, and pyrrolidone, and pharmaceutically acceptable salts thereof.
  • alkyl throughout the specification and in the claims essentially refers to a saturated aliphatic hydrocarbon chain, straight or branched, that may contain between 1-20 carbon atoms, inclusive, preferably between 1-10 carbon atoms, and most preferably between 1-4 carbon atoms.
  • a substituted alkyl chain refers to an alkyl as defined herein above substituted with groups such as, but not limited to, cycloalkyl, substituted or unsubstituted aryl, heteroaryl, alkylhalide, haloaryl, alkylthio, arylthio, halogen, alkylamido, alkylamino, hydroxy, alkyloxy, aryloxy, nitro, and sulfonamido.
  • aryl throughout the specification in the claims essentially refers to at least one carbocyclic system having conjugated carbon-carbon double bonds, wherein when the aryl contains more than one ring then the rings are fused.
  • Non-limitative examples of aryl moieties are phenyl, naphthyl, and anthracyl.
  • Substituted aryl is therefore an aryl as defined hereinabove, bearing substituents selected from, but not limited to, substituted or unsubstituted alkyl, cycloalkyl, halogen, alkylhalide, alkylamido, alkylamino, alkylthio, hydroxy, alkoxy, nitro.
  • heteroaryl refers to any of the aryl rings defined hereinabove, where at least one of the carbon atoms of those rings may be substituted with an atom of a different element.
  • this element is at least one of oxygen, nitrogen, and sulfur.
  • heterocycloalkyl refers to a monocyclic or fused carbon atom chain which is in either saturated state or which has pi non- conjugated bonds, and where at least one of the carbon atoms of the ring is substituted with an atom of a different element.
  • this element is at least one of oxygen, nitrogen, and sulfur.
  • the invention provides a pharmaceutical preparation comprising at least one compound of formula (Ia) or (Ib) as the active component and may further comprise pharmaceutically acceptable carriers, diluents, vehicles, excipients and/or additives.
  • Said carriers, diluents, vehicles, excipients, or additives facilitate the consumption of the active component(s), are compatible with the latter, and do not carry any negative or inhibitory effect on the active component(s) performance and/or no side or negative effects on the recipient of the pharmaceutical preparation.
  • the pharmaceutical preparation of the invention may further comprise additional pharmaceutically active agents.
  • the invention provides a pharmaceutical preparation comprising at least one aromatase inhibitor.
  • Arimidex and femara are reversible synthetic aromatase inhibitors while formestane and exemestane, analogs of androstenedione, are irreversible inhibitors.
  • the lifespan was characterized by mean, median and maximal lifespan, and the extension was calculated relative to control + DMSO.
  • Arimidex increased the lifespan in worms, as measured by the mentioned three parameters, by 27%, 64% and 20%, respectively.
  • Aiitilipolytic compounds AGS 308 and AGS 333 also showed surprising effects on the lifespan extension! the former increasing the lifespan parameters by 36%, 33% and 22%, and the latter by 20%, 19% and 21% respectively.
  • the present invention is also directed to the use of SREs inhibitors, such as aromatase inhibitors, in the preparation of a pharmaceutical composition for extending the lifespan of a subject.
  • SREs inhibitors such as aromatase inhibitors
  • the pharmaceutical preparation of the invention comprises at least one aromatase inhibitor as the active component, and may further comprise pharmaceutically acceptable carriers, diluents, vehicles, excipients and/or additives.
  • Said carriers, diluents, vehicles, excipients, or additives facilitate the consumption of the active component(s), are compatible with the latter, and do not carry any negative or inhibitory effect on the active component(s) performance and/or no side or negative effects on the recipient of the pharmaceutical preparation.
  • the pharmaceutical preparation of the invention may further comprise additional pharmaceutically active agents.
  • the pharmaceutical formulation of the invention is intended to be used in the elongation of the lifespan of a subject, wherein said subject is particularly a mammal, and most preferably a human. While formulations include those suitable for topical, oral, rectal, nasal; preferred formulations are intended for parenteral administration, including intramuscular, intravenous, intradermal and subcutaneous administration.
  • the pharmaceutical formulation of the invention used in the elongation of the lifespan of a subject, particularly a mammal, and most preferably a human, may comprise, in a preferred embodiment of the invention, a pharmaceutically acceptable known compound, e.g. antineoplastic or entiestrogen, such as triazole derivatives letrozole and anastrozole, imidazole derivative fadrozole, pyrazole derivative AGS 308, antiestrogens fulvestrant or raloxifene, etc.
  • a pharmaceutically acceptable known compound e.g. antineoplastic or entiestrogen, such as triazole derivatives letrozole and anastrozole, imidazole derivative fadrozole, pyrazole derivative AGS 308, antiestrogens fulvestrant or raloxifene, etc.
  • compositions comprising at least one aromatase inhibitor as the active component, are intended to be used for the treatment of aromatase activity related diseases, disorders, or conditions in a subject in need, particularly a mammal, and most preferably a human.
  • Another aspect of the invention relates to a method of elongating the lifespan of a subject, particularly a mammal, most preferably a human, comprising administering to said subject an effective amount of an aromatase inhibitor or estradiol receptor inhibitor, specifically any one of fadrozole, letrozole, anastrozole, 3,5-dimethylpyrazole, and raloxifene, or mixtures thereof, or pharmaceutically acceptable salts thereof.
  • an aromatase inhibitor or estradiol receptor inhibitor specifically any one of fadrozole, letrozole, anastrozole, 3,5-dimethylpyrazole, and raloxifene, or mixtures thereof, or pharmaceutically acceptable salts thereof.
  • the present invention is directed to the use of the following compounds :
  • said pharmaceutical composition may comprise any of the compounds AG 336, AG 2262, AG 2263, AG 538 (AGS 199) and AG 1024 (AGS 200) or mixtures thereof.
  • the present invention is directed towards selected compounds of formulae (Ia) and (Ib) of the present invention which form a subclass of novel compounds ⁇
  • Ri is hydroxy
  • R2 is hydrogen
  • R3 is cyano
  • R 4 forms a fused phenyl pyrrolidone hetero ring with the main aromatic ring;
  • Ri is hydroxy, R2 is hydrogen, R3 is 3,4-dihydroxybenzoyl, and R 4 is hydrogen; or
  • Ri is bromide, R2 is t-butyl, R3 is cyano, and R 4 is hydrogen; or
  • Het is oxazilidone, R2 and R 4 are hydrogen, and R3 is phenylmethylamido, or 3,4-dihydroxybenzoyl; and to pharmaceutically acceptable salts thereof.
  • the present invention is directed to the following compounds of formulae (Ha) and (lib):
  • the present invention is directed to a pharmaceutically acceptable glucose amine salt of a compound of formula (Ia) designated AGS 250, wherein said salt is preferably a combination, particularly at 1 ⁇ 1 ratio, of N-methyl glucose amine and the compound AGS 200 (AG 1024).
  • AGS 200 (AG 1024) N-methyl D-glucose amine
  • the invention in another embodiment, relates to a method for the manufacture of a compound of formula (Ha) or (lib).
  • Said method comprises the steps of- (a) mixing together a derivative of a hydroxy benzaldehyde, a derivative of acetonitrile, and beta-alanine in a solvent; b) refluxing; c) evaporating)" and d) triturating, as described in Examples 1 to 4.
  • said solvent is ethanol and the evaporation and trituration processes are carried out in hexane.
  • the invention relates to pharmaceutical preparations comprising as active ingredient at least one compound of formula (Ha) or (Hb), and optionally further comprising a carrier, diluent, vehicle, excipient and/or additive.
  • the present invention is directed to the use of at least one compound of the compounds of formula (Ha) or (lib), preferably any of the said compounds AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, and AGS 323 in the manufacture of a pharmaceutical composition.
  • the present invention is directed to the use of a salt of compound AG 1024 (AGS 200), particularly the novel N-methyl glucose amine salt (designated AG 250, and synthesized according to Example 5 in the preparation of a pharmaceutical composition.
  • AZA 200 novel N-methyl glucose amine salt
  • This pharmaceutical preparation is particularly intended to be used in the elongation of the lifespan of a subject.
  • synthesis of the salt designated AGS 250 comprises the steps oi- a) mixing together AGS 200 and N-methyl glucose amine; b) refluxing; c) evaporating; and d) triturating.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated.
  • a carrier should be both pharmaceutically and physiologically acceptable in the sense of being compatible with the other ingredients and not injurious to the patient.
  • Pharmaceutical preparations comprising the active component(s) with one or more acceptable carriers may be provided in either solid, liquid, sol-gel, aerosol, spread, cream, lotion, ointment spray, suspension, drops, solution, or powder form, and administration may therefore take the various corresponding oral, gastrointestinal, rectal, subcutaneous, parenteral, nasal, respiratory, or topical routes. Oral administration may be followed by adsorption of the active components through the sidewalls of different sections of the alimentary tract, whereas by subcutaneous or parenteral administration is meant, inter alia, subdermally, intravenously, arterially, or intramuscularly.
  • Topical administration of the active component(s), or corresponding pharmaceutical preparations may take place through any exposed surface of the recipient's organs, and the nasal or respiratory routes may be implemented with the use of a suitable inhalator dispenser device, the active component(s) being accompanied with a dense pharmaceutically acceptable propellant.
  • formulations include those suitable for topical, oral, rectal, nasal, preferred formulations are intended for parenteral administration, including intramuscular, intravenous, intradermal and subcutaneous administration.
  • the pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringe ability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the pharmaceutical preparations for the lifespan extension of the present invention may be administered in the form of solid tablets, a gelatin capsules or elixirs.
  • the pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the art of pharmacy. It is understood by the skilled artisan, that the preferred dosage would be individualized to the patient following good laboratory practice and standard medical practice.
  • compositions comprising at least one of the compounds of formula (Ha) or (lib) as the active component(s), are intended to be used for the treatment of PTKs activity related diseases, disorders, or conditions in a subject in need, particularly a mammal, and most preferably a human.
  • said compound of formula (Ha) or (lib) is any of the compounds AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, AGS 323, and mixtures thereof.
  • said PTK associated disorder or condition is related to the platelet-derived growth factor (PDGF), the epidermal growth factor (EGF), the insulin growth factor (IGF), and particularly the insulin-like growth factor-I (IGF- 1) receptor activities.
  • growth factor relates to a complex family of polypeptide hormones or biological factors that are produced by the body to control growth, division and maturation of blood cells by the bone marrow. They regulate the division and proliferation of cells and influence the growth rate of some cancers. Perturbation of growth factor production or of the response to growth factor is important in neoplastic transformation.
  • IGF Insulin like Growth Factor
  • IGF factors I and II are polypeptides with considerable sequence similarity to insulin.
  • IGF- 1 Insulin-like growth factor- 1
  • IGF-I also acts as potent survival factor in numerous cell lines exposed to environmental stresses, primary through activation of the AKT signal pathway.
  • the pharmaceutical compositions comprising compound (Ha) or (lib) as active agent may be used for the treatment of protein tyrosine kinase family (PTKs) associated disorders selected from (a) proliferative diseases, in particular sarcomas, carcinomas, lymphomas or melanomas; (b) fibrotic conditions, including pulmonary fibrosis, hepatic cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy! (c) metabolic diseases, for instance diabetes; (d) other disorders such as arthritis, rheumatoid arthritis, psoriasis, neurodegenerative diseases; and (e) other abnormal conditions for example, transplant rejection, wound healing or inflammation.
  • PTKs protein tyrosine kinase family
  • associated disorder and "related disorder” are used similarly throughout the present description and they relate to disorders associated with a malfunction of PTK or SRE or a receptor related to them.
  • a “disorder” is a condition in which there is a disturbance of normal functioning.
  • a “disease” is any abnormal condition of the body or mind that causes discomfort, dysfunction, or distress to the person affected or those in contact with the person. Sometimes the term is used broadly to include injuries, disabilities, syndromes, symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts these may be considered distinguishable categories.
  • Disease, disorder, condition and illness are equally used herein, and they refer, but do not limit to ⁇ neoplastic or proliferative disorders, nonneoplastic disorders, neurological disorders, metabolic disorders, skeletal muscle disorders, diseases caused by protein misfolding or protein aggregation, cardiovascular disorder, dermatological disorder, fibrotic conditions, inflammatory disorders, geriatric disorder, age related and/or associated disorders.
  • a "neoplastic or proliferative disorder” is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication! an abnormal state or condition characterized by proliferative cell growth.
  • a “neurological disorder” is a disease or disorder characterized by an abnormality or malfunction of neuronal cells or neuronal support cells.
  • the disorder can affect the central and/or peripheral nervous system.
  • Exemplary neurological diseases include- neuropathies, skeletal muscle atrophy and neurodegenerative diseases.
  • Exemplary neurodegenerative diseases include"- Alzheimer's, Amyotrophic lateral sclerosis (ALS) and Parkinson's disease.
  • cardiovascular disorder is a disease or disorder characterized by an abnormality or malfunction of the cardiovascular system.
  • cardiovascular diseases include : cardiac dysrhythmias, chronic congestive heart failure, ischemic stroke, coronary artery disease and car diomy op athy .
  • a “metabolic disorder” is a disease or disorder characterized by an abnormality or malfunction of metabolism.
  • One category of metabolic disorders are disorders of glucose or insulin metabolism.
  • a "dermatological disorder” is a disease or disorder characterized by an abnormality or malfunction of the skin and/or its appearance.
  • diseases caused by protein misfolding or protein aggregation include among others : Parkinson's disease, prion diseases, familial amyeloid polyneuropathy, tauopathies, polyglutamine aggregation disorders, Fragil-X syndrome, myotonic dystrophy and Alzheimer's disease.
  • the compounds of formula (Ha) or (lib), particularly the compounds specifically disclosed above, are effective in treating disorders, diseases, and conditions related with PTKs activity in a subject, particularly a mammal, most preferably a human in need of such treatment. Therefore the present invention is directed to the use of compounds of formula (Ha) or (lib) in the treatment of diseases, disorders, and conditions, related with PTKs activity, by administering an effective amount of at least one compound of the compounds of formula (Ha) or (lib) to a subject, particularly a mammal, most preferably a human, in need of such treatment.
  • the present invention is directed to the compounds designated AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, and AGS 323, for use in the treatment of diseases, disorders, and conditions, related with PTKs activity, by administering an effective amount of at least one compound of the compounds of formula (Ha) or (lib) to a subject, particularly a mammal, most preferably a human, in need of such treatment.
  • a subject particularly a mammal, most preferably a human
  • PTKs signal pathways include a series of extracellular and intracellular signaling components that have a downstream target, for example a transcription factor.
  • the IGF-I axis includes the IGF-I receptor and intracellular signaling components including Pl(3) kinase, PTEN phosphatase, PI(3,4)P 2 , 14-3-3 protein and PI(3,4,5)P 3 phosphatidyl inositol kinases, AKT serine/threonine kinase (e.g. AKT-I, 2, or 3) or a Forkhead transcription factor (e.g. FOXO-I, 3 or 4).
  • Pl(3) kinase PTEN phosphatase
  • PI(3,4)P 2 14-3-3 protein
  • PI(3,4,5)P 3 phosphatidyl inositol kinases e.g. AKT serine/threonine kinase (e.g. AKT-I, 2, or 3) or a For
  • IGF-1 Insulin-like growth factor 1
  • IGF-1 activates upstream kinases, important for the survival of various cell types.
  • This enzyme called phosphoinositide 3-kinase (PI3-K)
  • PI3-K phosphoinositide 3-kinase
  • IGF-I axis members play important roles in many different biological processes such as cell death and survival, insulin metabolism, cytoprotective response, radiation resistance, promotion of neuronal survival and inhibition of neorodegeneration, may prevent cancers and also be involved in metastases of breast and colon cancer cells.
  • the present invention is also directed to the use of compounds of formula (Ha) or (lib) in the treatment of malignant disorders such as sarcomas, melanomas, lymphomas or carcinomas, by administering an effective amount of at least one compound of formula (Ha) or (lib) to a subject, particularly a mammal, most preferably a human subject in need of such treatment.
  • the present invention is directed to the compounds designated AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, and AGS 323, for use in the treatment malignant disorders, by administering an effective amount of at least one compound of formula (Ha) or (lib) to a mammalian subject in need, most preferably a human.
  • An additional aspect of the present invention is directed to the use of compounds of formula (Ha) or (lib), preferably any of the compounds AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, AGS 323 and mixtures thereof, or pharmaceutical preparation comprising them, for elongating the lifespan of a mammal subject, particularly a human.
  • compounds of formula (Ha) or (lib) preferably any of the compounds AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, AGS 323 and mixtures thereof, or pharmaceutical preparation comprising them, for elongating the lifespan of a mammal subject, particularly a human.
  • Lifespan used herein, relates to ⁇ a lifetime! the average or maximum length of time an organism can be expected to survive or last.
  • Maximum lifespan corresponds to the age at which the survival curves touch the age-axis (0%); it represents the age at which the oldest known member of the species has died. (In animal studies, maximum lifespan is typically taken to be the mean lifespan of the most long-lived 10%). "Mean lifespan” or average lifespan, corresponds to the age at which the horizontal line for 50% survival intersects the survival curve. Mean lifespan varies with susceptibility to disease, accident and homicide/suicide, whereas maximum lifespan is determined by "rate of aging”.
  • maximum lifespan is regarded as a proxy for aging. Chemicals, calorie restriction with adequate nutrition, or other interventions which increase maximum lifespan are said to have slowed the aging process.
  • Life extension consists of attempts to extend life beyond the maximum natural lifespan. So far none has been proven successful in humans.
  • the present invention provides a method for the prevention and treatment of diseases, disorders, and conditions related with PTKs activity in a subject, particularly a mammal, most preferably a human, in need of such treatment by administering to that subject an effective amount of at least one compound of the compounds of formula (Ha) or (lib), specifically any of the compounds AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, and AGS 323 disclosed hereinabove, or of a pharmaceutical preparation comprising one of said compounds as the active component(s).
  • Treatment refers to therapeutic treatment. Those in need of treatment are mammal subjects suffering from any PTK activity related disorder, or SRE activity related dosorder.
  • patient or “subject in need” is meant any mammal for which administration of any of the compounds of the invention or any pharmaceutical composition comprising any of said compounds or mixes thereof, is desired in order to overcome or slow down such infliction.
  • a “preventive treatment” or “prophylactic treatment” is acting in a protective manner; to defend against or prevent something, especially a condition or disease.
  • the term "effective amount” or “sufficient amount” means an amount necessary to achieve a selected result.
  • the “effective treatment amount” is determined by the severity of the disease in conjunction with the preventive or therapeutic objectives, the route of administration and the patient's general condition (age, sex, weight and other considerations known to the attending physician).
  • mammal for purposes of treatment refers to any animal classified as a mammal including, human, research animals, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc.
  • the mammal is human.
  • the compounds of formula (Ha) or (lib) of the present invention are directed towards the treatment of proliferative disorders, diseases, and conditions selected from solid tumors, soft tissue tumors, hematopoietic cancers and metastatic cancers.
  • cancers examples include- sarcomas, adenocarcinomas, lymphomas and carcinomas affecting lungs, breast, gastrointestinal (colon, rectal, small intestine), liver, genitourinary tract (renal, bladder, urothelial cells), pharynx, prostate and ovary.
  • prolifereative disorders may include papillomas, blastoglioma, Kaposi's sarcoma, melanoma, squamous cell carcinoma, astrocytoma, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease, Burkitt's disease, arthritis, rheumatoid arthritis, diabetic retinopathy, angiogenesis, restenosis, in- stent restenosis and vascular graft restenosis.
  • the compounds of formula (Ha) or (lib), specifically any of the compounds AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, and AGS 323 disclosed above, are directed towards the treatment of fibrotic disorders, diseases, and conditions selected from pulmonary fibrosis, hepatic cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy, thrombic microangiopathy syndromes and transplant rejection.
  • the compounds of formula (Ha) or (lib), specifically any of the compounds AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, and AGS 323 disclosed above, are directed towards the treatment of conditions selected from metabolic disorders, inflammation, neurodegenerative diseases, psoriasis, diabetes, and wound healing.
  • Another aspect of the invention relates to a method of elongating the lifespan of a subject, particularly a mammal, most preferably a human, comprising administering to said subject an effective amount of any of the compounds of formula (Ia) or (Ib), specifically any of the compounds AG 336, AG 2262, AG 2263, AG 538, AG 1024, mixtures thereof, pharmaceutically acceptable salts or a pharmaceutical preparation comprising at least one of such compounds.
  • administration of compounds of formula (Ia) or (Ib) to nematodes and flies resulted in elongation of their lifespan.
  • the present invention provides a method of elongating the lifespan of a subject, particularly a mammal, most preferably a human, by administering to that subject an effective amount of at least one compound of the compounds of formula (Ha) or (lib), specifically any of the compounds AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, and AGS 323.
  • the present invention provides a method of elongating the lifespan of a subject, particularly a mammal, most preferably a human, by administering to that subject a pharmaceutical preparation comprising an effective amount of at least one compound selected from the group consisting of a compound having formula (Ia), a compound having formula (Ib), a compound having formula (Ha), a compound having formula (lib), an aromatase inhibitor, an estradiol receptor inhibitor, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of said compounds.
  • a pharmaceutical preparation comprising an effective amount of at least one compound selected from the group consisting of a compound having formula (Ia), a compound having formula (Ib), a compound having formula (Ha), a compound having formula (lib), an aromatase inhibitor, an estradiol receptor inhibitor, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of said compounds.
  • the present invention provides a method of elongating the lifespan of a subject, particularly a mammal, most preferably a human, by administering to that subject a pharmaceutical preparation comprising an effective amount of at least one compound selected from the group consisting of a AG 336, AG 2262, AG 2263, AG 538, AG 1024, AGS 192, AGS 195, AGS 206, AGS 244, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, AGS 323, letrozole, anastrozole, forme stane, exemestane, fulvestrant, raloxifene, tamoxifene, AGS 308, and AGS 333, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of said compounds.
  • a pharmaceutical preparation comprising an effective amount of at least one compound selected from the group consisting of a AG 336, AG 2262, AG 2263, AG 538, AG 1024,
  • an effective amount of the composition of the invention useful for the lifespan elongation, will be an amount sufficient to prolong the lifespan beyond expectancy.
  • an effective amount of the composition of the invention will confer longevity by extending the mean and maximum lifespan values of a certain population treated with said compositions by delaying the appearance of aging symptoms.
  • the method of the invention is intended to prevent and/or delay the appearance of age dependent disorders in a mammalian subject, most preferably a human, by administering to that subject an effective amount of at least one compound selected from the group consisting of formula (Ia), formula (Ib), AG 336, AG 2262, AG 2263, AG 538, AG 1024, formula (Ha), formula (lib), AGS 192, AGS 195, AGS 5
  • Age-dependent means definitely occurring with age, age eventually causes the disease. Eye cataracts, eye macular degeneration, osteoporosis, osteoarthritis, vulvovaginal atrophy (women), nodular prostate hyperplasia (men), senile emphysema, wrinkled skin, poor vision (presbyopia), brain cell loss, weak immune system (monoclonal gammopathy) are examples of age dependent disorders.
  • the invention is directed to a method of preventing and/or delaying the appearance of age related disorders in a mammalian subject, preferably human.
  • the method comprises the step of administering to said subject an effective amount of at least one compound selected from the group consisting of a compound having formula (Ia), a compound having formula (Ib), a compound having formula (Ha), a compound having formula (lib), and an aromatase inhibitor, estradiol receptor inhibitor, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of said compounds.
  • the method of the invention comprises the step of administering to said subject an effective amount of at least one compound selected from the group consisting of a AG 336, AG 2262, AG 2263, AG 538, AG 1024, AGS 192, AGS 195, AGS 206, AGS 244, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, AGS 323, letrozole, anastrozole, formestane, exemestane, fulvestrant, raloxifene, tamoxifene, AGS 308, and AGS 333, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising any of said compounds.
  • Age-related means increasing in prevalence with age, age just raises its prevalence.
  • Atherosclerosis stroke, heart attack, etc. temporal arteritis, myelodysplastic syndrome, chronic lymphocytic leukemia, plasma cell myeloma, ("multiple” myeloma), hypertension, type II diabetes, Alzheimer's disease (controversy), idiopathic Parkinson's disease, prostate cancer, skin cancer, breast cancer, colon cancer, "atrophic gastritis” (stomach cancer precursor), calcific aortic stenosis, Paget's disease of bone, glaucoma, iatrogenic disease and polypharmacy ("vulnerability to infections”) are some examples of age related disorders.
  • the invention is also related to an anti-aging method for treating a mammalian subject, preferably a human, comprising the step of administering to said subject an effective amount of at least one compound of formula (Ia) or (Ib) or formula (Ha) or (lib) or a pharmaceutically acceptable salt or a pharmaceutical composition comprising an effective amount of any compound of the invention.
  • said compounds are specifically selected from the groups AG 336, AG 2262, AG 2263, AG 538 or AG 1024; and AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322, or AGS 323 .
  • Aging is the progressive loss of physiological functions that increases the probability of death; the organic process of growing older and showing the effects of increasing age. 5
  • Anti-aging are strategies, programs, and supplements that reduce, prevent, and reverse the decline of physiological functions and age-related dysfunction, disorders, and diseases.
  • Aging changes are frequently associated with an increase in likelihood of mortality, but this is not necessarily the case. For example, graying of hair is a symptom of aging, but graying does not increase likelihood of mortality. Aging changes which are not associated with a specific disease, but which are associated with a generalized increase in mortality would qualify as “biomarkers" of aging and would distinguish "biological age” from "chronological age”. Biomarkers would be better predictors of the increased likelihood of mortality (independent of specific disease) than the passage of time (chronological age).
  • the anti-aging method is intended to delay aging symptoms or slow the aging process.
  • Aging symptoms are changes that typically occur with age. These age changes include : loss of hearing ability, decline in the ability to taste salt and bitter, reduction of the thymus, increased levels of antibodies, some form of arthritis, teeth loss, twice higher insulin requirements to achieve the glucose uptake of the young, reduced sensitivity to growth factors and hormones due to fewer receptors and dysfunctional post-receptor pathways, decline in body weight, increase in body fat, decline in muscle strength, decline in reaction time, drop in degree of saturation of fats in the brains of old animals, diminution of the sleeping time and quality sleep, presbyopia (reduced ability to focus on close-up objects), physical disability (defined as the inability to use public transportation) and appearance of various pathological conditions. 5
  • the invention is also directed to a method for delaying aging symptoms in a mammalian subject, preferably a human, afflicted with a premature aging disorder by employing the compounds of the invention, namely compounds of formula (Ia) or (Ib) and of formula (Ha) or (lib).
  • the invention is also directed to the treatment of such disorders by employing any of the compounds of formula (Ia) or (Ib) and formula (Ha) or (lib).
  • Said compounds are selected from the groups AG 336, AG 2262, AG 2263, AG 538 or AG 10241; and AGS 192, AGS 195, AGS 206, AGS 244, AGS 250, AGS 317, AGS 318, AGS 319, AGS 320, AGS 321, AGS 322 or AGS 323; respectively.
  • Tyrphostins synthesis and assays for IGF-I and insulin tyrosine kinases activity inhibition are described in'- Parrizas, M. et al., (1997) Endocrinology 138- 1427; Blum, G., Gazit, A. and Levitski, A. (2000) Biochemistry 39: 15705; Blum, G., Gazit, A. and Levitski, A. (2003) JBC 278- 40442 and USP 3,331,738.
  • the following assays demonstrate in a non-limitative way the positive life- extending effect of the compounds of the present invention in several organisms. It will be appreciated that such illustrations of the inhibitory effect of the compounds of the present invention on PTKs activity, particularly that of IGF-I receptor kinase, may be further broadened and implemented to other species, particularly mammalians, and most preferably humans.
  • C. elegans nematodes were grown at 25° C on agar and fed E. coli, in 20x3 cohorts. The inhibitors were added after L4 stage of the larvae. Nematodes were transferred and fresh inhibitor added every 3 days. Three criteria were used to measure the lifespan extension, with mean lifespan considered the most important. a. Mean lifespan - sum of all days lived divided by number of nematodes b. Maximum lifespan - day when the last survivor died. c. Median lifespan - day when half the nematodes were alive.
  • Table 1 and Figure 1 demonstrate the significant life -extension effect experienced after the administration of some of the compounds of the present invention in identical concentrations. Total sum of days, and mean as well as the maximal lifespan were all increased, although more extensively for some compounds than others, and particularly for AGS 199.
  • D. melanogaster flies were grown at 29°C, in 20x3 cohorts. Flies were transferred and fresh inhibitor added every 3 days. Three criteria were used to measure the lifespan extension, with mean lifespan considered the most important. a. Mean lifespan - sum of all days lived divided by number of flies. b. Maximum lifespan ⁇ day the last survivor died. c. Median lifespan ⁇ day half the flies were alive.
  • mice for each experiment group were injected 5 days a week for a period of 6 weeks with AGS 199 (25 mg/Kg ), AGS 200 (12.5 mg/Kg ) and AGS 250 ( 25 mg/Kg).
  • Glucose level was tested twice a week. Glucose level was normal (80 vs. 90-100 normally) and no signs of diabetes developed.
  • Administration of 25 mg/Kg of AGS 200 and 50 mg/Kg of AGS 250 were toxic to the mice (died within 24 hours).
  • the lifespan extension was calculated relative to control+DMSO. 60 worms cohorts were used for each experiment.

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Abstract

La présente invention a trait à de nouveaux composés inhibiteurs des protéines tyrosine kinases (PTK) ou des enzymes associées aux stéroïdes (SRE), qui affectent l'apoptose dans des tissus malins, et peuvent être utilisés dans la préparation de médicaments pour le traitement de divers troubles, et pour le prolongement de la durée de vie d'un sujet tout en maintenant ce sujet en bonne santé. L'invention a également trait à un procédé et des compositions anti-vieillissement pour le prolongement de la durée de vie.
PCT/IL2006/000205 2005-02-17 2006-02-16 Prolongement de duree de vie avec des medicaments WO2006087718A1 (fr)

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DE102006054205A1 (de) * 2006-11-15 2008-05-29 Rheinische Friedrich-Wilhelms Universität Verwendung von Cytohesin-Inhibitoren zur chemischen Induktion von Langlebigkeit
CN102211200A (zh) * 2011-06-14 2011-10-12 东华大学 一种一步合成茄子状Ag-Ag2S纳米异质结的方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006054205A1 (de) * 2006-11-15 2008-05-29 Rheinische Friedrich-Wilhelms Universität Verwendung von Cytohesin-Inhibitoren zur chemischen Induktion von Langlebigkeit
CN102211200A (zh) * 2011-06-14 2011-10-12 东华大学 一种一步合成茄子状Ag-Ag2S纳米异质结的方法

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