EP2403830A2 - Indolderivate zur behandlung neurodegenerativer krankheiten - Google Patents

Indolderivate zur behandlung neurodegenerativer krankheiten

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Publication number
EP2403830A2
EP2403830A2 EP10705616A EP10705616A EP2403830A2 EP 2403830 A2 EP2403830 A2 EP 2403830A2 EP 10705616 A EP10705616 A EP 10705616A EP 10705616 A EP10705616 A EP 10705616A EP 2403830 A2 EP2403830 A2 EP 2403830A2
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EP
European Patent Office
Prior art keywords
compound
formula
group
alkyl
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP10705616A
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English (en)
French (fr)
Inventor
Fanny Schmidt
Bruno Figadere
Rita Raisman-Vozari
Pierre Champy
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Centre National de la Recherche Scientifique CNRS
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Centre National de la Recherche Scientifique CNRS
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Publication of EP2403830A2 publication Critical patent/EP2403830A2/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • 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
    • 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

Definitions

  • the present invention relates to compounds having an aliphatic chain-substituted indole unit useful for the treatment of neurodegenerative diseases, as well as to a process for their preparation and their use.
  • neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.
  • a neurodegenerative disease is characterized by a progressive apoptotic death of particular neuronal subpopulations, related to a functional deficit of the affected transmission axes.
  • This type of disease affects the functioning of the central nervous system, especially the brain, in a progressive manner, the disease can evolve more or less rapidly (a few weeks to several years), and often irreversibly.
  • different functions may be affected such as motor skills, language, memory, perception or cognition.
  • Alzheimer's disease mention may in particular be made of Alzheimer's disease and Parkinson's disease.
  • Alzheimer's disease which affects approximately 24 million people worldwide, is a disease of brain tissue that results in the gradual and irreversible loss of mental function.
  • the first symptom is the loss of memory of recent events (amnesia), then the cognitive deficits extend to the domains of language (aphasia), movement organization (apraxia), visual recognition (agnosia) and functions. executives (such as decision making and planning).
  • Parkinson's disease affects the central nervous system and causes progressive motor disorders, including body tremors.
  • the therapeutic use of neurotrophins, described in the maintenance of various neuronal populations, has been proposed for curative purposes.
  • the administration of recombinant neurotrophins in injured animal models has shown a beneficial effect on neuronal survival, their initially encouraging use in humans has been rapidly limited. Indeed, the very high hydrophilicity of these compounds, prohibiting the passage of the blood-brain barrier and their rapid enzymatic degradation require repeated intracranial administration, generating dramatic side effects.
  • the indole nucleus is a motif found in many natural or non-natural compounds exhibiting various biological activities, antimicrobial, antiparasitic, antioxidant, neurotrophic, and anti-inflammatory activities having been reported.
  • X 2 represents a linear hydrocarbon chain, saturated or unsaturated, containing from 1 to 24, preferably from 8 to 22, carbon atoms, - R 1 represents a hydrogen atom or an OH or (C 1 -C 6) alkoxy group, such than methoxy, and
  • R 2 represents a group CH 3 or CH 2 OR 3 , with R 3 representing a hydrogen atom or a group (C 1 -C 6 ) alkyl, CO- (C 1 -C 6 ) alkyl or NH- (C 1 -C 6) ) alkyl.
  • R 3 representing a hydrogen atom or a group (C 1 -C 6 ) alkyl, CO- (C 1 -C 6 ) alkyl or NH- (C 1 -C 6) ) alkyl.
  • (C 1 -C 6) alkyl group is meant, in the sense of the present invention, a saturated hydrocarbon chain, linear or branched, having from 1 to 6 carbon atoms, in particular the methyl, ethyl, n-propyl groups. isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl. Preferably, it is a methyl group.
  • (C 1 -C 6) alkoxy group is meant, in the sense of the present invention, a (C 1 -C 6) alkyl group as defined above bonded to the molecule via an oxygen atom .
  • These are in particular methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy.
  • it is a methoxy group.
  • CO- (C 1 -C 6) alkyl is meant, within the meaning of the present invention, a (C 1 -C 6) alkyl group as defined above bonded to the molecule through a grouping CO.
  • NH- (C 1 -C 6) alkyl means a (C 1 -C 6) alkyl group as defined above bonded to the molecule via a grouping. NH.
  • unsaturated is meant, in the sense of the present invention, that the hydrocarbon chain may comprise one or more unsaturation (s).
  • unsaturation is meant, in the sense of the present invention, a double or triple bond and preferably a double bond.
  • the term "pharmaceutically acceptable” means that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither bio-logical nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical.
  • salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound.
  • Such salts include: (1) hydrates and solvates,
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • stereoisomers denotes diastereoisomers or enantiomers. It is therefore optical isomers. Stereoisomers that are not mirror images of each other are thus referred to as “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are referred to as "enantiomers”.
  • a carbon atom bonded to four nonidentical substituents is called a "chiral center”.
  • racemic mixture An equimolar mixture of two enantiomers is called a racemic mixture.
  • a compound according to the invention may meet the following formula (Ia):
  • R 1, R 2 and X 1 are as defined above, q represents an integer between 1 and 24, preferably between 8 and 22, and - m, n and p are as defined above.
  • R 1 represents a substituent of the indole ring, located on any of the carbon atoms of the indole unit. It will advantageously be a hydrogen atom.
  • R 2 will advantageously represent a CH 3 or CH 2 OH group.
  • Xi represents a CH 2 group.
  • the compounds of the invention may be chosen in particular from:
  • the present invention also relates to the use of a compound of formula (I) as defined above for the manufacture of a medicament, in particular a neurotrophic or neuroprotective drug, advantageously intended for the treatment or the prevention of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis or stroke.
  • a neurotrophic or neuroprotective drug advantageously intended for the treatment or the prevention of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis or stroke.
  • the present invention also relates to a method of treating or preventing neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis or stroke, including administering to a patient in need of an effective amount of a compound of formula (I) as defined above.
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis or stroke
  • the present invention also relates to a compound of formula (I) below:
  • X 2 represents a linear hydrocarbon chain, saturated or unsaturated, containing from 1 to 24, preferably from 8 to 22 carbon atoms,
  • R 1 represents a hydrogen atom or an OH or (C 1 -C 6) alkoxy group, such as methoxy, and
  • R 2 represents a CH 3 or CH 2 OR 3 group , with R 3 representing a hydrogen atom or a (C 1 -C 6 ) alkyl, CO- (C 1 -C 6) alkyl or NH- (C 1 -C 6 ) alkyl group; . excluding compounds of formula
  • a compound according to the invention may meet the following formula (Ia):
  • X 1, R 1 and R 2 are as defined above, and m represents an integer greater than or equal to 1, and n and p represent, independently of one of the other, an integer greater than or equal to 0 with m + n + p + 4 ⁇ 24 and preferably 8 ⁇ m + n + p + 4 ⁇ 22.
  • the compound of the invention may meet one of the following formulas (Ib) and (Ic):
  • R 1, R 2 and X 1 are as defined above, q represents an integer between 1 and 24, preferably between 8 and
  • R 1 will advantageously represent a hydrogen atom.
  • R 2 will advantageously represent a CH 3 or CH 2 OH group.
  • Xi represents a CH 2 group.
  • the compounds of the invention may be chosen in particular from:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I) as described above and a pharmaceutically acceptable vehicle.
  • the compounds according to the invention can be administered orally, sublingually, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally, and preferably orally.
  • the active ingredient may be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, animals or humans.
  • Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, parenteral forms of administration, - cutaneous, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.
  • the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.
  • a preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
  • a syrup or elixir preparation may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant.
  • Water-dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, as well as with taste correctors or sweeteners.
  • suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.
  • aqueous suspensions for parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible wetting agents are used.
  • the active ingredient may also be formulated as microcapsules, optionally with one or more additive carriers.
  • the compounds of the invention can be used at doses of between 0.01 mg and 1000 mg per day, given in a single dose once a day or administered in several doses throughout the day, for example twice per day. day in equal doses.
  • the dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses out of these ranges which the skilled person can realize himself.
  • the pharmaceutical composition as defined above may also comprise another active ingredient, useful in particular in the treatment or prevention of neurodegenerative diseases, and advantageously chosen from acetylcholinesterase inhibitors such as the azeptile , galanthamine, rivastigmine, memantine and tacrine; monoamine oxidase inhibitors such as selegiline; catecholamine O-methyltransferase inhibitors such as entacapone; glutamatergic inhibitors such as amantadine and baclofen; cholinergic agonists such as sabcomelin; dopaminergic agonists such as pergolide, cabergoline, ropirinole and pramipexole; neurotransmitter analogs or precursors such as L-3,4-dihydroxyphenylalanine; and anticholinergics such as trihexyphenidyl and tropatepine.
  • acetylcholinesterase inhibitors such as the azeptile , galanthamine,
  • the subject of the present invention is also a pharmaceutical composition as defined above, for its use as a medicament, especially as a neurotrophic or neuroprotective medicament, advantageously intended for the treatment or the prevention of neurodegenerative diseases such as diabetic disease. Alzheimer's, Parkinson's disease, multiple sclerosis or stroke.
  • the present invention also relates to a method for preparing a compound of formula (I) as described above, characterized in that it comprises the following steps:
  • Step a By "carboxylic acid function in free form” means, within the meaning of the present invention, a CO 2 H group.
  • the term "carboxylic acid function in activated form” means a carboxylic acid function modified so as to render it more active with respect to a nucleophile.
  • activated forms are well known to those skilled in the art and may in particular be an acid chloride (COCl).
  • COCl acid chloride
  • Z will advantageously represent a CO 2 H or COCl group.
  • the compound of formula (II) may be obtained easily from corresponding carboxylic acid, commercially available by activation of the carboxylic acid function by techniques well known to those skilled in the art.
  • an acid chloride may be obtained in particular by reaction of the corresponding carboxylic acid with oxalyl chloride in the presence of a few drops of dimethylformamide (DMF). This reaction can be carried out in a solvent such as dichloromethane, especially at room temperature.
  • DMF dimethylformamide
  • the coupling reaction will be carried out in the presence of a coupling agent, such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), hydrochloride of 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide (EDC), carbonyldiimidazole (CDI), 2-H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU),
  • DIC diisopropylcarbodiimide
  • DCC dicyclohexylcarbodiimide
  • EDC hydrochloride of 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide
  • CDI carbonyldiimidazole
  • HBTU 2-H-benzotriazol-1
  • a coupling aid such as N-hydroxy succinimide (NHS), N-hydroxy benzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2, 3-benzotriazole (HOOBt), 1-hydroxy-7-azabenzotriazole
  • the compound of formula (II) used comprises a group Z in the form of an activated carboxylic acid function, and more particularly in the form of an acid chloride.
  • the coupling reaction will advantageously be carried out in the presence of a base such as triethylamine.
  • This reaction may be carried out in a solvent such as dichloromethane, especially at room temperature.
  • Step b
  • LiAlH 4 It may be implemented in a solvent such as tetrahydrofuran.
  • hydride is meant, in the sense of the present invention, a chemical compound capable of releasing hydride ions H " , making it possible to carry out a reduction reaction.
  • the separation of the final product from the reaction medium may be carried out by techniques well known to those skilled in the art, for example by extraction, evaporation of the solvent or by precipitation and filtration.
  • the compound of formula (I) thus obtained may also be purified if necessary by methods well known to those skilled in the art, such as by recrystallization if the compound is crystalline, by distillation, by column chromatography on silica gel or by high performance liquid chromatography
  • FIGURE
  • FIG. 1 represents photographs of fluorescent neurons obtained under the conditions of the DHR-123 test without treatment (control) or after treatment with
  • Figure 2 shows the 3-part brain section made in Example 2.3.
  • Figures 3 and 4 show the chromatograms (abscissa: time in minutes; ordinates: relative intensity in percent) obtained by HPLC-MS / MS from mouse brain extracts used in the experiments of Example 2.3. highlighting the presence or absence of the compound according to the invention 2c.
  • Figure 4 corresponds to the chromatograms obtained in the context of the oral treatment while Figure 5 corresponds to the chromatograms obtained in the context of intraperitoneal treatment.
  • IR cm- 1 608, 671, 719, 739, 801, 847, 913, 1009, 1068, 1094, 1130, 1222, 1246, 1271, 1294, 1340, 1377, 1424, 1456, 1470, 1554, 1629, 1650. , 2851, 2918, 2955, 3089, 3264, 3387.
  • IR cm- 1 608, 718, 739, 801, 1011, 1094, 1225, 1293, 1340, 1377, 1456, 1553, 1630,
  • IR cm- 1 717, 739, 800, 1010, 1067, 1094, 1225, 1300, 1339, 1377, 1423, 1456, 1471, 1552, 1629, 1649, 2850, 2918, 3267, 3393.
  • IR cm- 1 609, 718, 739, 800, 1013, 1094, 1224, 1298, 1339, 1377, 1424, 1456, 1553, 1629, 1649, 2850, 2918, 3267, 3392.
  • IR cm. 1 669, 718, 739, 799, 913, 1012, 1066, 1095, 1222, 1299, 1339, 1377, 1424,
  • IR cm -1 560, 580, 608, 719, 739, 801, 931, 1011, 1069, 1094, 1126, 1225, 1269, 1299, 1340, 1377, 1425, 1456, 1555, 1629, 1650, 2851, 2920. , 3010, 3264, 3386.
  • IR cm. 1 606, 704, 727, 741, 758, 974, 1012, 1026, 1057, 1109, 1166, 1224, 1267, 1357, 1375, 1457, 1556, 1629, 1669, 1982, 2037, 2849, 2917. , 3275, 3394.
  • the mixture is filtered on celite, washed with ethyl acetate and then dried over anhydrous MgSO 4 and concentrated under reduced pressure.
  • IR cm- 1 565, 592, 611, 722, 739, 804, 842, 886, 914, 1010, 1078, 1104, 1221, 1309, 1341, 1358, 1376, 1453, 1467, 1504, 1553, 1622, 2849. , 2916, 3063, 3139, 3275, 3387.
  • IR cm- 1 592, 611, 721, 739, 805, 874, 1011, 1104, 1222, 1341, 1454, 1630, 2649,
  • IR cm- 1 565, 592, 611, 721, 739, 784, 803, 842, 886, 910, 1011, 1105, 1222, 1341,
  • IR cm- 1 563, 577, 600, 735, 805, 1010, 1125, 1223, 1339, 1455, 1619, 2848, 2916,
  • IR cm- 1 562, 572, 592, 609, 720, 740, 806, 868, 1011, 1104, 1221, 1341, 1455, 1626,
  • IR cm- 1 587, 669, 727, 740, 760, 974, 1010, 1024, 1044, 1108, 1149, 1216, 1355, 1374, 1457, 1466, 1668, 2848, 2923, 3299, 3425.
  • neurotrophic activity of neuronal growth factors is characterized by their capacity on the one hand to promote neuronal survival and on the other hand to stimulate their maturation.
  • neuritogenesis is a morphological criterion representative of the state of neuronal maturation.
  • antioxidant compounds also have a neuroprotective capacity. This is why it is also interesting to evaluate the antioxidant capacity of the compounds of the invention.
  • the dissection consists in extracting embryos from the uterus of a rat at fifteen days of gestation. The brain of each embryo is then dissected under a binocular microscope to extract the ventral mesencephalon.
  • the mesencephales are grouped in a falcon containing 2 ml of L15 medium and then dissociated mechanically (30 round trips), 5 ml of L15 medium are added. The suspension is allowed to stand for 8 minutes. The 5 ml of supernatant are recovered in a new falcon and the cells are dissociated again (30 round trips). 5 mL of L15 is added again and the suspension is left rest for 8 minutes. The 5 ml of supernatant are added to the previous ones. The cells thus extracted are then centrifuged for 5 minutes at 1000 rpm- 1 The cell pellet is taken up in Neurobasal medium supplemented with 1% B27, 1% glutamine and 1% penicillin / streptomycin mixture.
  • the cells are then seeded at the appropriate dilution (0.6 embryo per 24 well plate well and 0.4 per well of 48 well plate) .
  • the cultures are incubated at 37 ° C in a humid atmosphere enriched with 5% CO 2 in 24-well plate or 48 wells.
  • Immunohistochemistry At 8 days of culture, the cells are fixed with a 4% formaldehyde solution and then washed three times with PBS. The cells are then subjected to immunohistochemistry anti-tyrosine hydroxylase (TH) revealed by a secondary antibody coupled to a fluorochrome emitting in the red (Cy3). Analyzes. Neuroprotection is assessed by counting 10 field positive TH neurons per well directly under an inverted fluorescence microscope, reported as a percentage of the untreated control. The experiments are carried out at the rate of three wells per condition. Three independent experiments are performed under these conditions. The total neuritic length per cell is calculated by the Neurite Outgrowth software by Explora Nova on 60 to 100 neurons photographed independently by condition. • Results
  • ventral mesencephalon contains dopaminergic neurons from the substantia nigra which degenerate in Parkinson's disease, as well as those present in the ventral tegmental area.
  • Primary cultures of embryonic ventral mesencephalon can be performed after extraction and dissection of embryos, collection and dissociation of ventral mesencephalons and seeding of the cell suspension in multiwell plates.
  • GABAergic ⁇ 94%)
  • dopaminergic ⁇ 3%
  • serotonergic ⁇ 3%
  • Glia is essentially astrocytic, we also find oligodendrocytes and microglia ( ⁇ 3%) in smaller proportions.
  • Other non-neural cell types are also present in very small proportions such as erythrocytes, fibroblasts and endothelial cells.
  • the different cell populations can be identified by immunocytochemistry of specific markers.
  • Dopaminergic neurons are identified by labeling tyrosine hydroxylase.
  • TH + neurons dopaminergic neurons
  • This observation has been exploited as an in vitro model of neuronal death in Parkinson's disease for the search for neuroprotective compounds. Under these same conditions, the fibers of the remaining neurons are not altered and neuritogenesis can be observed and quantified.
  • This model is therefore particularly interesting in our study since it makes it possible in the same experiment to obtain the two expected results, namely the quantification of neuroprotection and neuritogenesis.
  • the neurotrophic potential of our compounds could be evaluated by carrying out a double screening including the estimation of the neuroprotective potential and the capacity to stimulate the neuritic growth.
  • the neuroprotective potential of each compound is then estimated by counting the number of remaining neurons (TH + neurons) under a fluorescence microscope. The results for the different treatments are expressed as a percentage of the number of neurons remaining relative to the untreated cultures (Control). Neuritogenesis is quantified by measuring the total neuritic length reported by dopaminergic neuron (neuritic length / TH + neuron) using an image analyzer on at least sixty conditionally photographed neurons (10-30% of dopaminergic neurons). total). All experiments were performed by comparison with a positive control, dibutyryl-AMPcyclic (db-cAMP) (Mourlevat S. et al Mol Pharmacol 2003, 64 (3), 578-586).
  • db-cAMP dibutyryl-AMPcyclic
  • Ic C O (CH 2 ) 14 CH 3 121.3 ⁇ 3.2 ** 168.6 ⁇ 11.5 **
  • ABTS 2,2'-azino- ⁇ - (3-ethylbenzthiazoline-6-sulfomic acid)
  • ABTS is a colored indicator of the presence of hydroxyl radicals in solution. Indeed, the attack of a hydroxyl radical on the ABTS generates the formation of an ATBS + 'cation radical (Equation 1). This colored entity gives the solution an absorbance (Abs) at 450 nm.
  • the antioxidant capacity of a compound can then be expressed as IC 50, reflecting the concentration at which 50% of the hydroxyl radicals were reduced by the test compound.
  • test compounds and the Trolox ® were dissolved in ethanol to obtain solutions of 1 mM.
  • concentrations ranging from 1 mM to 10 nM.
  • 90 ⁇ l of a 1-1 ethanol-water mixture was added on a 96-well ELISA plate, followed by 15 ⁇ l of a 1 mM aqueous ABTS solution, 15 ⁇ l of an aqueous Fe 2 solution.
  • the ABTS test was therefore performed by comparison with Trolox ® .
  • the same ranges from 10 nm to 1 mM indoles Ic, Ic, Ig, Ii, 2a, 4c, 2g, 2h, and 2i were tested.
  • the results are shown in Table 2 below.
  • the amine compounds of the invention tested 2a, 2c, 2g, 2h and 2i have IC50 close to that of Trolox ® highlighting the interest of the amine function in the antioxidant activity of these compounds.
  • the presence of intrachain double bonds improves the antioxidant activity leading to a lower IC50 than Trolox ® (see 2h).
  • Dihydrorhodamine 123 or DHR123 is used as an indicator of reactive oxygen species (ROS). Unloaded and non-fluorescent, it passively crosses the cell membrane before being oxidized, on contact with free radicals, rhodamine 123 emitting a green fluorescence. Free radicals
  • the cells When the cells are treated with an antioxidant, the amount of intracellular ROS is decreased. This decrease is reflected, in the presence of DHR123, by a quantifiable decrease in the fluorescence emitted.
  • the cultures were placed strictly under the same conditions as for the neuroprotection / neuritogenesis test. Thus the cultures were maintained for eight days in the presence of a concentration of 10 nM each of the tryptamine derivatives tested. The 8 th day in vitro (DIV 8), 50 .mu.m DHR-123 (Sigma) were added and the cells were incubated 30 minutes at 37 ° C.
  • FIG. 1 illustrates the decrease of the intensity of fluorescence emitted in neurons after treatment with the compound Ih at 10 nM, the compound showing the highest antioxidant activity, as compared to Trolox ® and the untreated control.
  • BBB blood-brain barrier
  • the purpose of this study is to verify by HPLC coupled to mass spectrometry, the presence of the molecule 2c according to the invention in the cerebral parenchyma after a sub-chronic treatment of the hydrochloride of the molecule 2c (2c / HCl) by Oral or intraperitoneal (IP).
  • mice During the acclimation and study period, mice have free access to food and drink. All the experiments were carried out in accordance with the conditions of the decree n ° 2001-464 of May 29th, 2001 relating to the experiments practiced on the animals.
  • Treatments Two sub-chronic (oral or intraperitoneal) treatments of
  • IP Intraperitoneal
  • mice R1, R2 and R3 received the same treatments as the previous mice except for the Thursday when they did not receive the second treatment:
  • the solution of 2c hydrochloride to be administered is prepared in the vehicle (0.5% Tween80 + 99.5% carboxymethyl cellulose 1%, in NaCl 0.9% in water) at a concentration of 15, 0 g / L. Three groups were formed:
  • mice All mice are treated twice a day for 4 days. The 5 th day they receive final treatment and were euthanized between 3:00 ET 7:30 after the last treatment according to the following scheme: between 13:30 and 18:00
  • mice are anesthetized with an injection of 0.1 ml of a 6% sodium pentobarbital solution and the mice are then infused to remove traces of blood from the brain with 0.9% NaCl solution.
  • % which contains heparin (200 ⁇ l of heparin choay at 5000 IU / ml in a liter of 0.9% NaCl).
  • Each animal is infused with at least 50 mL of this solution.
  • the mouse is decerebrated. The cerebellum, brain stem and olfactory bulbs are eliminated.
  • the brain is dissected into 3 parts according to the scheme shown in FIG. 2.
  • the 3 parts of the brain are frozen in isopentane at -30 ° C. for one minute and then stored separately at -80 ° C.
  • Positive and Negative Controls The brains of vehicle mice are used for positive and negative controls.
  • 10 ⁇ l of a hydrochloride solution of 2c at 1 ⁇ g / ml are added to the supernatant and diluted half in MeOH before transfer into a HPLC vial.
  • Preparation of the daughter of 2c A stock solution of 2c hydrochloride is prepared extemporaneously in MeOH at a concentration of 1.0 mg / ml. All the other solutions are prepared by dilution of this stock solution in MeOH and then stored at -40 ° C.
  • Instrumentation and conditions for the analysis of compound 2c Detection and quantification, based on peak area, are carried out by HPLC-MS / MS, in MRM mode.
  • the HPLC system consists of a Dionex Ultimate 3000 pump equipped with an automatic Dionex WPS-3000PL sample injector.
  • the mass spectrometer used is a Water-Micromass Quattro Ultima equipped with an electrospray ionization source and a triple quadrupole analyzer. Data acquisition and analysis is done via Masslynx 3.5.
  • the liquid chromatography is performed in isocratic mode with an XBridge TM (Waters) C18 column, 150 x 2.1 mm, having a particle size of 3.5 ⁇ m.
  • the mobile phase is composed of a mixture of two phases A and B, in proportions 3/97.
  • Phase B is composed of 0.2% triethylamine in MeOH (v / v).
  • the flow rate is set at 0.2 mL / min and the injection volume is 10 ⁇ L.
  • the mass spectrometer is connected to the HPLC system using an electrospray ionization source.
  • a switching valve is programmed to send the first three minutes of the chromatography to the trash in order to avoid salt accumulation at the capillary of the source.
  • the voltage of the capillary is set at 3000 V and the voltage of the cone at 50 V
  • the temperature of the source is set at 120 0 C
  • the desolvation gas (N 2 ) is set at a flow rate of 463 L / h and the temperature at 35O 0 C.
  • the mass spectra are obtained in positive mode.
  • the parameters are optimized to obtain the maximum molecular ion at m / z 385.66, corresponding to compound 2c.
  • the collision is obtained with an inert gas (argon) and the energy is set at 22eV in MS / MS mode to detect the mass transitions: m / z 385.66 ⁇ 254.23 and 385.66 ⁇ 144.17.
  • the calibration line is made from a standard range of 7 concentrations (0.5 ⁇ g / mL, 0.1 ⁇ g / mL, 20 ng / mL, 4 ng / mL, 0.8 ng / mL; 0.16 ng / mL and 0.08 ng / mL). • Results
  • the area of the HPLC peaks is a function of the concentration of the compound 2c in the range of 0.16 to 500.00 ng / mL with an R 2 of 0.9997.
  • the limit of detection is 0.08 ng / mL with a S / N ratio (signal / noise) of 3: 1.
  • the retention time of compound 2c is 5.3 minutes and the acquisition time is 8 minutes. minutes.
  • Compound 2c is capable of crossing in vivo the BBB after IP administration and per os of 2c / HCl.
  • Oral treatment at 300 mg / kg / day achieves concentrations approximately 1.5 times higher than those obtained after IP treatment at 20 mg / kg / day.

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FR0951303A FR2942625B1 (fr) 2009-03-02 2009-03-02 Derives indoliques pour le traitement de maladies neurodegeneratives
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US9744155B2 (en) 2012-03-28 2017-08-29 Ixcela, Inc. IPA as a therapeutic agent, as a protective agent, and as a biomarker of disease risk
CN106309436A (zh) * 2016-07-25 2017-01-11 宁波大学 可用作乙酰胆碱酯酶抑制剂的色胺衍生物及其用途
CN106565588A (zh) * 2016-11-10 2017-04-19 徐州工程学院 一种从坚果中提取食物源二十烷酸‑5‑羟色胺的方法
KR101874594B1 (ko) * 2016-12-07 2018-07-05 한국한의학연구원 아떼모야 잎 추출물 또는 이의 분획물을 포함하는 인지기능 장애의 예방 또는 치료용 조성물
CN107118146B (zh) * 2017-04-13 2019-09-03 宁波大学 一种6-溴色胺衍生物及其制备方法和用途
CN107814787A (zh) * 2017-11-13 2018-03-20 济南大学 一种他克林‑吲哚乙酸杂联体化合物及其制备方法和应用
US11041847B1 (en) 2019-01-25 2021-06-22 Ixcela, Inc. Detection and modification of gut microbial population
CA3229361A1 (en) * 2021-08-20 2023-02-23 Abdelmalik Slassi 3-cycloamino-indole compounds as serotonergic agents useful for the treatment of disorders related thereto

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US8614246B2 (en) 2013-12-24
US20110319387A1 (en) 2011-12-29
FR2942625B1 (fr) 2013-11-22
CA2754283A1 (fr) 2010-09-10
WO2010100133A3 (fr) 2010-11-18
CN102369185A (zh) 2012-03-07

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