WO2013001490A1 - Nouveaux dérivés de dihydrochalcone anti-inflammatoires et leur utilisation - Google Patents

Nouveaux dérivés de dihydrochalcone anti-inflammatoires et leur utilisation Download PDF

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WO2013001490A1
WO2013001490A1 PCT/IB2012/053294 IB2012053294W WO2013001490A1 WO 2013001490 A1 WO2013001490 A1 WO 2013001490A1 IB 2012053294 W IB2012053294 W IB 2012053294W WO 2013001490 A1 WO2013001490 A1 WO 2013001490A1
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compound according
compound
treatment
disease
inflammatory
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PCT/IB2012/053294
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English (en)
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Anat ELMANN
Yoel Kashman
Rivka Ofir
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The State Of Israel - Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center)
Dead Sea & Arava Science Center
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Publication of WO2013001490A1 publication Critical patent/WO2013001490A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic

Definitions

  • the present invention relates to compounds, and pharmaceutical compositions containing them, that may be used in the treatment of inflammation and neurodegenerative diseases.
  • the present invention also relates to methods for treating inflammation using those compounds.
  • Astrocytes are the most abundant glial cell type in the brain, and play multiple roles in the protection of brain cells. Despite their high antioxidative activities, astrocytes exhibit a high degree of vulnerability, and are not resistant to the effects of reactive oxygen species ( OS). They respond to substantial or sustained oxidative stress with increased intracellular Ca , loss of mitochondrial potential, and decreased oxidative phosphorylation.
  • OS reactive oxygen species
  • Both astrocytes and microglial cells can produce proinflammatory cytokines (such as Tumor necrosis factor alpha, TNF ) and cytotoxic agents in response to ischemia, traumatic and infectious insults, chronic neurodegenerative diseases leading to deterioration of the disease processes.
  • proinflammatory cytokines such as Tumor necrosis factor alpha, TNF
  • cytotoxic agents in response to ischemia, traumatic and infectious insults, chronic neurodegenerative diseases leading to deterioration of the disease processes.
  • iNOS and NO generation have come to-be accepted as a marker and therapeutic target in neuroinflammatory conditions such as those observed in ischemia, multiple sclerosis, spinal cord injury, Alzheimer's disease and inherited peroxisomal (e.g. X-linked adrenoleukodystrophy; X-ALD) and lysosomal (e.g. Krabbe's disease) disorders.
  • ischemia multiple sclerosis
  • spinal cord injury e.g. X-linked adrenoleukodystrophy; X-ALD
  • lysosomal e.g. Krabbe's disease
  • Stroke is an important cause of mortality and morbidity worldwide but effective therapeutic strategy for the prevention of brain injury in patients with cerebral ischemia is lacking.
  • Stroke mediated cell death is a complex interplay of aberrant events involving inflammation, oxidative stress, excitotoxicity, acidosis, peri-infarct depolarization, and apoptosis.
  • Strokes can be subdivided into two categories, namely ischemic and hemorrhagic strokes. Ischemic strokes are more prevalent than hemorrhagic strokes making up approximately 87 % of all cases, and have been the target of most drug trials.
  • a thrombosis results in a restriction of blood flow to the brain and this result in insufficient oxygen and glucose delivery to support cellular homeostasis.
  • These processes share overlapping biochemical abnormalities causing injury to glia, neurons, and endothelial cells.
  • excitotoxic and necrotic cell death occurred within minutes. This elicits multiple processes that lead to brain injury, such as free radical production, oxidative stress, inflammation, excitotoxicity, ionic imbalance, apoptosis, and peri-infarct depolarization ( Front Biosci (Elite Ed). 2012 Jan 1 ;4:809-17.
  • Traditional Chinese herbal medicine and cerebral ischemia Traditional Chinese herbal medicine and cerebral ischemia.
  • Reactive oxygen species ROS
  • RNS reactive nitrogen species
  • Pulicaria incisa is a desert plant which belongs to the asteraceae family and has been used in traditional medicine for heart diseases (Mansour et al., FITOTERAPIA Volume LXI, No. 1, 1990, Nabiel Saleh, Phytochemistry 63, (2003), 239-241 (Editorial). Pulicaria incisa is commonly referred to as wild tea or desert fleabane and replaces tea for many of the Bedouins in Egypt (Mansour et al., 1990, Nabiel Saleh, Phytochemistry 63, (2003), 239-241 (Editorial).
  • Pi was also stated to decrease total lipid, total cholesterol and triglycerides and was proposed as a hypocholesterolemic agent (Amer et al., Manual Struktur-Rundschau, 103. Gonzgang. Heft 7, 2007, 320-327) and as hypoglycaemic (Shabana, Arch Exp Veterinarmed. 1990 44(J):389-94).
  • Ramadan et al J. Verbr. Lebensm. (2009) 4:239-245, examined the antioxidant properties of the methanolic extracts of Pi.
  • Ramadan et al. did not demonstrate any specific active anti-oxidant compound existing in Pi.
  • Ramadan et al. showed a mere in vitro inhibition of the oxidation of linoleic acid by methanolic extract of Pi and not in vivo protection of living cells.
  • Calliste et al. ANTICANCER RESEARCH 21: 3949-3956 (2001) tested the anti- oxidative potential of substituted chalcones with different numbers and different positions of the hydroxy groups.
  • Calliste et al. establishes the importance of the ⁇ - ⁇ double bond of the chalcones.
  • Compounds of the present invention however, have ⁇ - ⁇ single bond structure, with the a and the ⁇ carbons being substituted, the a and the ⁇ carbons of the compounds of the present invention are those that appearing in formula I set forth below.
  • inhibition of the activated immune cells may provide an effective therapeutic intervention that might prevent or ameliorate various diseases.
  • This invention provides novel dihydrochalcone compounds, and prodrugs thereof, which are useful in the treatment of inflammatory diseases. It has been found that some trihydroxy-dihydrochalcones compounds having specific substituents as described herein are potent anti-inflammatory, anti-neuroinflammatory, and antioxidant drugs. [0023] More specifically, one aspect of the present invention provides compounds including tautomers, metabolites, resolved enantiomers, diastereomers, solvates, prodrugs and pharmaceutically acceptable salts thereof, said compound having the Formula I:
  • R 1 is Me, Et, MeO-, EtO, H0CH 2 CH 2 O, H0CH 2 C(Me) 2 O, (S)- -, cyclopropyl-CH 2 0-, H0CH 2 CH 2 - > HOCH 2 -,
  • R 2 , R 3 , R 4 and R 5 is H, Me, Et, OH, MeO-, EtO-, HOCH 2 CH 2 0-,
  • R 5 is H.
  • the invention relates to a compound selected from 1-propanone-
  • the present invention provides a composition comprising a compound as described herein.
  • this invention relates to the compounds of formula I, for the treatment or prevention of neuroinflammatory and inflammatory diseases.
  • this invention relates to the compounds of formula I, for the treatment or prevention of inflammatory CNS disease.
  • this invention relates to the compounds of formula I, for the treatment or prevention of oxidative stress.
  • this invention relates to the compounds of formula I, for reducing the amount of reactive oxygen species (ROS) in cells having oxidative stress condition.
  • ROS reactive oxygen species
  • these cells are glia cells.
  • the present invention provides a method of treating or preventing inflammation in a subject, the method comprising administering to the subject a therapeutically effecti ve amount of a compound as described herein.
  • the present invention provides a method of treating a disease or condition characterized by or associated with inflammation, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein.
  • the present invention provides a method of treating a disease or condition characterised by or associated with inflammation, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition as described herein.
  • the neuroinflammatory and inflammatory diseases are associated with increased oxidative stress.
  • the neuroinflammatory and inflammatory diseases are associated with excess amounts of reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • the oxidative stress is characterized by 3 ⁇ 4(3 ⁇ 4- induced cell death.
  • neuroinflammatory and inflammatory diseases are associated with production of cytokines selected from the group consisting of TNFa, IFNy, IL-6, IL-2, IL-4, IL-10, and IL-12.
  • An additional aspect of the invention is the use of compound of the present invention in the preparation of a medicament for the treatment or prevention of neuroinflammatory diseases a warm-blooded animal, preferably a mammal, more preferably a human, suffering from such disorder. More particularly, the invention includes the use of a compound of the invention in the preparation of a medicament for the treatment or prevention of a neuroinflammatory disorder or an inflammatory condition in a mammal.
  • Figure 5B shows induction of ROS production by H 2 0 2 in cultured astrocytes in a time dependent manner.
  • Figure 6 shows the effect of pre-treatment of astrocytes with 7-3028/9 on the ROS levels following treatment of the astrocytes with H2O2.
  • Figure 8 shows inhibition of peroxyl radical - induced oxidation of DCFH to DCF in primary microglial cells by 7-3028/9.
  • Figure 11 shows the effect of 7-3028/9 on LPS- induced cytokine secretion for different cytokines from naive splenocytes.
  • Figure 13 shows the no-effect of 7-3028/9 on cell viability of non-stimulated
  • Figure 14A shows the effect of 7-3028/9 on KLH-stimulated splenocyte proliferation.
  • Figures 15A-D shows the effect of 7-3028/9 on KLH-induced cytokine secretion in different cytokines from splenocytes.
  • Figure 16 shows the effect of 7-3028/9 on LPS-induced cytokine secretion from splenocytes.
  • the present invention relates to novel trihydroxy-dihydrochalcone compounds according to Formula I.
  • the a and ⁇ carbons are linked by a single covalent bond and are both substituted with hydroxyl groups.
  • Certain compounds of this invention can exist as two or more tautomeric forms.
  • tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another, such as structures formed by the movement of a hydrogen from one site to another within the same molecule.
  • Other tautomeric forms of the compounds may interchange, for example, via enolization/de-enolization and the like. Accordingly, the present invention includes the preparation of all tautomeric forms of compounds of this invention.
  • Reagents useful for synthesising compounds may be obtained or prepared according to techniques known in the art. For example, approaches to synthesising the core decalin structure of the compounds of the present invention are provided in Ley et al. (Chem. Soc, Chem. Commun., 1983, 503 - 505) and references cited therein.
  • the compound may be isolated from a natural source.
  • the compound may be isolated from a plant, in some embodiments, the compound may be isolated from the plant Pulicaria incisa.
  • a "prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
  • Prodrugs include free hydroxy groups that may be derivatized as prodrugs by converting the hydroxy group to a phosphate ester, hemisucci nates dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy) ethyl ethers.
  • each cc-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , -P(0)(0(C r C 6 )alkyl)2 or glycosyl (the radical resulting from, the removal, of a hydroxyl group of the hemiacetal form of a carbohydrate).
  • Prodrugs of a compound of the present invention may be identified using routine techniques known in the art.
  • Various forms of prodrugs are known in the art.
  • prodrug derivatives see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by rogsgaard- Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs, " by H. Bundgaard p. 113-191 (1991); c) H.
  • Inflammation is intended to mean the process by which a subject's immune system coordinates a response to tissue damage, infection, antigenic challenge, etc. Inflammation may be associated with overproduction of reactive oxygen species (ROS). Inflammation may be associated with any one or more of a H 2 0 2 -oxidative stress induced cell death, overproduction of NO, overproduction of cytokines and MPO activity.
  • ROS reactive oxygen species
  • MPO Myeloperoxidase
  • HOCl hypochlorous acid
  • CI " chloride anion
  • Oxidative stress is defined as pathologic change seen in living organisms in response to excessive levels of cytotoxic oxidants and free radicals in the environment
  • Diagnosis of inflammatory or neuroinflammatory condition in a subject, wherein said inflammatory or neuroinflammatory condition is associated with overproduction of ROS, H 2 0 2 -oxidative stress induced cell death, overproduction of NO, overproduction of cytokines and MPO activity is a process well known in the art.
  • treating as used herein in relation to inflammation in a subject is intended to mean that the compound or pharmaceutical composition reduces or abrogates the symptoms and/or cause of the inflammation.
  • prevention in relation to inflammation in a subject is intended to mean that the compound or pharmaceutical composition substantially prevents an inflammatory response and/or reduces the symptoms of the inflammatory response that would otherwise occur had the subject not been treated with the compound or pharmaceutical composition.
  • the compound may be prepared into a variety of pharmaceutical compositions in the form of, e.g., an aqueous solution, an oily preparation, a fatty emulsion, an emulsion, a gel, etc., and these preparations may be administered as intramuscular or subcutaneous injection or as injection to an organ, or as an embedded preparation or as a transmucosal preparation through nasal cavity, rectum, uterus, vagina, lung, etc.
  • the composition may be administered in the form of oral preparations (for example solid preparations such as tablets, capsules, granules or powders; liquid preparations such as syrup, emulsions or suspensions).
  • Compositions containing the compound may also contain a preservative, stabiliser, dispersing agent, pH controller or isotonic agent.
  • suitable preservatives are glycerin, propylene glycol, phenol or benzyl alcohol.
  • suitable stabilisers are dextran, gelatin, a-tocopherol acetate or alpha- thioglycerin.
  • suitable dispersing agents include polyoxyethylene (20), sorbitan mono-oleate (Tween 80), sorbitan sesquioleate (Span 30), polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68) or polyoxyethylene hydro genated castor oil 60.
  • suitable pH controllers include hydrochloric acid, sodium hydroxide and the like.
  • suitable isotonic agents are glucose, D- sorbitol or D- mannitol.
  • the composition may also contain other constituents or additives such as a pharmaceutically acceptable carrier, diluent, excipient, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbent, preservative, surfactant, colorant, fiavorant or sweetener, taking into account the physical and chemical properties of the compound being administered.
  • composition may be administered orally, parenterally, by inhalation spray, adsorption, absorption, topically, rectally, nasally, bucally, vaginally, ocularly, intraventricularly, via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, or by any other convenient dosage form.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrastemal, and intracranial injection or infusion techniques.
  • the composition When administered parenterally, the composition may be in a unit dosage, sterile injectable form (solution, suspension or emulsion) which is preferably isotonic with the blood of the recipient with a pharmaceutically acceptable earner.
  • sterile injectable forms are sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable forms may also be sterile injectable solutions or suspensions in non-toxic parenteral ly-acceptable diluents or solvents, for example, as solutions in 1,3-butanediol.
  • any fixed oil may be employed including synthetic mono- or di-glycerides, com, cottonseed, peanut, and sesame oil.
  • Fatty acids such as ethyl oleate, isopropyl myristate, and oleic acid and its glyceride derivatives, including olive oil and castor oil, especially in their polyoxyethylated versions, are useful in the preparation of injectables.
  • oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.
  • the carrier may contain minor amounts of additives, such as substances that enhance solubility, iso tonicity, and chemical stability, for example anti-oxidants, buffers and preservatives.
  • the anti-neuroinflammatory, anti-inflammatory and antioxidant properties of l-(2,4-dihydroxy-6-methoxyphenyl)-3-(3 J 4-dihydroxyphenyl) ⁇ 2,3- dihydroxypropan-l-one in primary cultures of rat brain glial cells and in vivo in mice have been assessed.
  • this active compound might be developed as a drug or food additive for the prevention and/or amelioration of various diseases that involve inflammation and oxidative stress, e.g. inflammatory, autoimmune and neurodegeneratrive diseases.
  • compounds of the present invention are used to inspire a protective effect on an oxidative stress condition.
  • 7-3028/9 prevents the induced increase in ROS levels following H2O2 -induced oxidative stress.
  • Astrocytes were preloaded with DCF-DA for 30 min and washed.
  • 7-3028/9 (6 g ml) was added to astrocytes before (-2 h, -1 h), concomitant (0) or after (1 h, 2 h) the addition of H2O2 (175 ⁇ ).
  • ROS production was measured at the indicated time points.
  • the inventors have used primary cultures of rat brain astrocytes and microglial cells in the following experimental system:
  • Figure 1 shows that H 2 0 2 induced astrocytic cell death in a dose dependent manner.
  • Astrocytes 100,000 cells/well of 24 wells plate
  • cell death was quantified 24 hr later using a method based on the measurements of the enzyme Lactate Dehydrogenase (LDH).
  • LDH Lactate Dehydrogenase
  • Extract of Achillea fragrantissima downregulates ROS production and protects astrocytes from oxidative-stress-induced cell death.
  • Negative-stress-induced cell death ISBN 978-953-307-485-6, (Raymond Chuen-Chung Chang, ed).
  • a reduction of at least 70% of ROS levels are indication for anti-oxidant activity in the cellular anti-oxidant assay (See Wolfe, .L., & Liu R.H. (2007) Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. Journal of Agriculture and Food Chemistry, Vol.55, No. 22, pp.8896-8907.).
  • LPS lipopolyscaccharide
  • DTH delayed type hypersensitivity
  • mice (6 weeks old, female, balb/c) with domitor and shave their abdomen. Paint on the abdomen with 150 microliters of 3% oxazolone (4:1) in olive oil;
  • mice either subcutaneously (s.c, 100 microliters) or intra-peritoneally (i.p., 100 microliters) with the compound of the invention.
  • s.c 100 microliters
  • intra-peritoneally i.p., 100 microliters
  • mice Thirty minutes later - challenge mice by applying to one ear a total of 20 microliters/ear of 1% oxazolone (in 4:1 aceton/olive oil) onto both sides of one ear topically (10 microliters/side);
  • mice Two hr after the challenge repeat the injection of the compound of the invention 5.
  • Dexamethasone in acetone, topically, 50 micrograms/20 microliter s/ear, 10 microliters/each side of challenged ear) 1 hr after oxazolone challenge;
  • MPO myeloperoxidase
  • cytokine measurement collect conditioned media from the cells plated at the 24 wells plates after 24 hr (for IL-2 and TNFa), 48 hr (for !FNy) or 72 hr (IL-10);
  • the astro-protective compounds were purified from Pi by activity guided fractionation using the bioassay of protection of astrocytes from H 2 0 2 -induced cell death (as described in Fig. IB).
  • the wild plant Pi 56 gr was homogenized and extracted with ethyl acetate (EA) (3x250 fflL, overnight).
  • EA crude extract (1.08 gr) was chromatographed on a Sephadex LH-20 column, eluting with Hexane/MeOH/CH 2 Cl 2 (2:1 :1) to afford compound 7-3028/9 (described hereinbelow) (16.7 mg) and compound 7-3028/6 (described hereinbelow) (3.5 mg).
  • the cultivated Pi was found also to contain compounds 7-3028/9 and 7-3028/6 in varying yields.
  • the dose response of the purified chalcones 7-3028/6 and 7-3028/9 is presented in Figure 3 and shows that these molecules exhibit astroprotective activity at 0.5 or 3 ⁇ ( ⁇ 1 or 6 ⁇ ) respectively.
  • Astrocytes were preincubated for 2 hr with the indicated concentrations of the pure compounds. ⁇ 2 0 2 (200 ⁇ ) was then added and cytotoxicity was measured 20 hr later.
  • Peroxyl radicals are generated by thermolysis of 2 ; 2'-Azobis(amidinopropane) (ABAP) at physiological temperature. ABAP decomposes at approximately 1.36xlO ⁇ V l at 37°C, producing at most IxlO 12 radicals/ml/s.
  • the experiment was carried out with ABAP 0.6 mM, and increasing doses of 7-3028/9.
  • the kinetics of DCFH oxidation in astrocytes and microglial cells by peroxyl radicals generated from ABAP is shown in Figures 7 and 8, respectively. In the experiment shown in Figure 7, astrocytes were incubated with 7-3028/9 (12 microg/ml, A; or with the indicated concentrations, B).
  • Compound 7-3028/9 reduced the degree of oxazolone-induced ear edema in mice, as was measured by both ear weight ( Figure 9) and thick ( Figure 9).
  • the anti-inflammatory effect of this compound was also demonstrated by the reduction of myeloperoxidase (MPO) activity and the levels of various inflammatory factors (TNFa, IFNy, IL-6, IL-2, IL-4, IL-10, IL-12) secreted by different immune cells, in ear homogenates of the experimental mice ( Figure 10).
  • MPO myeloperoxidase
  • cytokine levels were measured in duplicates by ELISA.
  • MPO activity 3 different experiments.
  • 7-3028/9 is not toxic to none-stimulated and LPS-stimulated splenocytes.
  • Figure 13 demonstrates that 7-3028/9 is not toxic to none-stimulated and. LPS- stimulated splenocytes.
  • Splenocytes were prepared from naive (none- immunized mice). Cell viability was measured at the indicated time points by Crystal violet. Data represent the mean ⁇ SEM from two experiments (10 mice), performed in quadriplicates.
  • Figure 14 demonstrate that 7-3028/9 down-regulates the proliferative response of splenocytes to each of the stimulators.
  • the inventors have also determined the cytokine profile secreted from splenocytes obtained from the different in vivo experimental groups that were activated by either LPS or KLH and treated (or not) with 7-3028/9. It can be deduced that 7-3028/9 down-regulates the proliferative response of splenocytes.
  • mice (6 mice per group for each experiment) were immunized with KLH in CFA, and treated (s.c.) with 7-3028/9. Eight days later, spleens were removed from mice, pooled and splenocytes were stimulated with either KLH or LPS in the presence or absence of 7-3028/9. Cytokine levels in supernatants were measured in duplicates by ELISA, and the results are presented as MeaniSEM of different in vivo experiments.
  • IL-2 100 ⁇ , collected after 24 h, 2 experiments
  • IFNy and TNFa 100 ⁇ L J collected after 48 h, 2 experiments

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Abstract

Cette invention concerne des dérivés de dihydrochalcone utiles dans le traitement des maladies inflammatoires et neuro-inflammatoires telles que la maladie d'Alzheimer ou de Parkinson ou autres affections telles que l'AVC. Les α- et β-carbones de la dihydrochalcone sont tous deux hydroxylés. Cette invention concerne également des procédés d'utilisation desdits composés dans le traitement des maladies inflammatoires chez les mammifères et des compositions pharmaceutiques les contenant.
PCT/IB2012/053294 2011-06-28 2012-06-28 Nouveaux dérivés de dihydrochalcone anti-inflammatoires et leur utilisation WO2013001490A1 (fr)

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WO2024127401A1 (fr) * 2022-12-16 2024-06-20 The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) Infusion de pulicaria incisa pour réduire la mort cellulaire neuronale et traiter des pathologies neuronales liées à l'âge

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WO2024127401A1 (fr) * 2022-12-16 2024-06-20 The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) Infusion de pulicaria incisa pour réduire la mort cellulaire neuronale et traiter des pathologies neuronales liées à l'âge

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