US20110312972A1 - Substituted 3-benzofuranyl-indol-2-one-3-acetamididopiperazine derivatives, preparation thereof, and therapeutic use thereof - Google Patents

Substituted 3-benzofuranyl-indol-2-one-3-acetamididopiperazine derivatives, preparation thereof, and therapeutic use thereof Download PDF

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US20110312972A1
US20110312972A1 US13/201,141 US201013201141A US2011312972A1 US 20110312972 A1 US20110312972 A1 US 20110312972A1 US 201013201141 A US201013201141 A US 201013201141A US 2011312972 A1 US2011312972 A1 US 2011312972A1
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Marco Baroni
Letizia Puleo
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Sanofi SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to substituted 3-benzofuranyl-indol-2-one-3-acetamidopiperazine derivatives, to their preparation and to their therapeutic application.
  • Ghrelin is a 28 amino-acid peptide hormone produced mainly in the stomach by a post-translational process after cleavage of pre-pro-ghrelin (Kojima M., et al., Nature 1999; 402: 656-60). Ghrelin is an endogenous ligand of the growth hormone secretagogue pituitary receptor (GHSR1a).
  • GHS-R is encoded by two exons: exon 1 encodes the transmembrane domains (TMs) 1-5 and exon 2 encodes TM6 and 7 of the G-protein-coupled receptor (GPCR).
  • exon 1 encodes the transmembrane domains (TMs) 1-5
  • exon 2 encodes TM6 and 7 of the G-protein-coupled receptor (GPCR).
  • the two transcripts have been identified in the pituitary gland and the brain: one encoding the full-length GPCR (GHS-R1a) and the other encoding a truncated receptor (GHS-R1b) lacking TM6 and 7. Only the subtype GHS-R1a is activated by ghrelin and ghrelin mimetics. GHS-R1b is present in the liver and other peripheral tissues, but its function is unknown (Smith R. G. et al., Trends in Endocrinology and Metabolism, 2005, 16, No. 9).
  • the ghrelin receptor may also be coupled to the Gs/protein kinase A pathways in certain tissues (Ueno, N. et al., Endocrinology, 2004, 145, 4176-4184; Kim, M. S. et al., Int. J. Obes. Relat. Metab. Disord., 2004, 28: 1264-1271).
  • the ghrelin receptor has the relatively uncommon characteristic of having significant ligand-independent constitutive activity (Barazzoni, R. et al., Am. J. Physiol. Endocrinol. Metab., 2004, 288: E228-E235).
  • ghrelin Low levels of expression of ghrelin have been documented in various tissues, such as the intestines, the pancreas, the kidneys, the immune system, the placenta, the testicles, pituitary tissue and the hypothalamus ( Horm. Res. 2003; 59 (3): 109-17).
  • ghrelin is involved in hunger at mealtimes, and in the initiation of meals.
  • the circulating levels decreases with the intake of food and increase after meals, reaching concentrations that are sufficient to stimulate hunger and the intake of food.
  • Ingestion of ghrelin stimulates food intake rapidly and transiently, mainly by increasing the appetitive feeding behaviour and the number of meals.
  • Ghrelin stimulates the short-term taking of food more efficiently than any other molecule, with the exception of neuropeptide Y, with which it is approximately equipotent (Wren A. M. et al., J. Clin. Endocrinol. Metab., 2001; 86: 5992-5).
  • ghrelin is unique in its capacity to exert this effect, whether it is injected peripherally or centrally.
  • ghrelin Beyond its role in the initiation of meals, ghrelin also satisfies the established criteria of an adiposity-related hormone involved in regulating the long-term body mass.
  • the levels of ghrelin circulate as a function of the energy reserves and display compensatory changes in response to changes in body mass.
  • Ghrelin crosses the blood-brain barrier and stimulates the taking of food by acting on certain standard body mass-regulating centres, such as the hypothalamus, the hindbrain and the mesolimbic compensatory system.
  • ghrelin chronic administration of ghrelin increases the body mass via diverse concerted actions on the taking of food, energy expenditure and the utilisation of resources.
  • Congenital ablation of ghrelin or of the ghrelin receptor gene causes a resistance to feeding-induced obesity, and pharmacological blocking of ghrelin reduces the intake of food and the body mass.
  • Ghrelin also exerts both physiological and pharmacological actions on the endocrine pancreas.
  • Acylated bioactive ghrelin is produced in the £ cells, recently described in the pancreatic islets (Prado, C. L., et al., 2004 , Proc. Natl Acad. Sci. USA, 101: 2924-2929), potentially providing a local source of ghrelin that acts on the ⁇ cells of the islets.
  • Blockage of this function of endogenous ghrelin by means of an antagonist for its receptors substantially reduced the fasted glucose concentrations, attenuated the glycaemic movement and increased the responses to insulin during glucose tolerance tests, suggesting an inhibitory role of ghrelin in the control of insulin secretion (Dezaki, K., et al. 2004 , Diabetes, 53: 3142-3151).
  • Ghrelin receptor antagonists could thus regulate hunger, the taking of meals and their frequency, and also, in the long-term, the weight, especially weight gain following diets or therapeutic regimens. Furthermore, in the context of an antidiabetic treatment, ghrelin antagonists could be useful for maintaining the equilibrium between insulin and glucose for controlling diabetic hyperphagia. Ghrelin antagonists could thus be used as anorexic and/or anti-obesity agents, or alternatively in the treatment of diabetes and its effects.
  • One subject of the present invention is compounds corresponding to formula (I):
  • R1 represents a hydrogen atom or a (C1-6)alkyl, —C( ⁇ O)(C1-6)alkyl or —C( ⁇ O)aryl group
  • the compounds of formula (I) comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers, These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.
  • the compounds of formula (I) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention.
  • salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (I) also form part of the invention.
  • one group of compounds is constituted by the compounds for which:
  • R1 represents a hydrogen atom or a (C1-6)alkyl, —C( ⁇ O)(C1-6)alkyl or —C( ⁇ O)aryl group
  • one group of compounds is constituted by the compounds for which:
  • R1 represents a hydrogen atom or a —C( ⁇ O)(C1-6)alkyl, —C( ⁇ O)aryl or (C1-6)alkyl group; and/or R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, more particularly chlorine or bromine, or a (C1-6)alkyl or trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H; and/or R5 and R6, which may be identical or different, represent a hydrogen atom or a group (C1-6)alkyl; and/or R7 represents a group (C1-C6)alkyl; and/or R8 and R9, which are located on positions 2 and 6 of the piperazine nucleus, represent a hydrogen atom, a group (C1-C6)alkyl, it being understood that at least one from among R8 and R9
  • R1 represents a hydrogen atom or a —C( ⁇ O)methyl, —C( ⁇ O)phenyl or methyl group; and/or R2, R3 and R4, which may be identical or different, located on any of the available positions of the phenyl nucleus, independently represent a hydrogen atom, a halogen atom, more particularly chlorine or bromine, or a methyl or trifluoromethyl group, it being understood that at least one from among R2, R3 and R4 is other than H; and/or R5 and R6, which may be identical or different, represent a hydrogen atom or a group (C1-6)alkyl; and/or R7 represents a methyl or ethyl group; and/or R8 and R9, which are located on positions 2 and 6 of the piperazine nucleus, represent a hydrogen atom or a methyl or ethyl group, it being understood that at least one from among R8 and R9 is other than H; and/or two from among R7, R8 and R
  • Compound No. 1 (+)-N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethyl-3,5-dimethylpiperazin-1-yl)acetamide;
  • Compound No. 2 (+)-N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)propionamide; in the form of the base or of an acid-addition salt.
  • protecting group Pg means a group that makes it possible firstly to protect a reactive function such as a hydroxyl or an amine during a synthesis, and, secondly, to regenerate the intact reactive function at the end of the synthesis. Examples of protecting groups and of protection and deprotection methods are given in Protective Groups in Organic Synthesis , Greene et al., 2nd edition (John Wiley & Sons, Inc., New York).
  • leaving group means a group that may be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group may thus be readily replaced with another group during a substitution reaction, for example.
  • Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. group. Examples of leaving groups and references for their preparation are given in Advances in Organic Chemistry , J. March, 3rd edition, Wiley Interscience, pp. 310-316.
  • the compounds of general formula (I) may be prepared according to the process that follows:
  • R1 which is other than H
  • Hal represents a halogen atom, for example chlorine, according to methods known to those skilled in the art, for example in the presence of a base such as K 2 CO 3 , NaH or t-BuO ⁇ K + , in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane or dimethyl sulfoxide (DMSO).
  • a base such as K 2 CO 3 , NaH or t-BuO ⁇ K +
  • a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane or dimethyl sulfoxide (DMSO).
  • the compound of general formula (I) may be prepared according to one or other of the following variants:
  • R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined in the general formula (I).
  • This reaction is generally performed using a halogenating agent, such as a chlorinating agent, for example phosphorus chlorides, especially PCl 5 , or alternatively PCl 3 or POCl 3 .
  • a halogenating agent such as a chlorinating agent, for example phosphorus chlorides, especially PCl 5 , or alternatively PCl 3 or POCl 3 .
  • the reaction is generally performed in the presence of pyridine or 4-dimethylaminopyridine, in a solvent such as dichloromethane or DMF.
  • R2, R3, R4, R7, R8, R9 and n are as defined in the general formula (I) and Hal′′ represents a halogen atom, preferably chlorine.
  • This reaction is generally performed using an organic or mineral base, such as K 2 CO 3 , Na 2 CO 3 , pyridine or 4-dimethylaminopyridine, in the presence of NaI or Kl, in an inert solvent such as DMF, dichloromethane, THF, dimethoxyethane or toluene.
  • the compound of general formula (III) may be prepared from a compound of general formula (V):
  • R2, R3 and R4 are as defined in the general formula (I) and Hal′ and Hal′′, which may be identical or different, independently represent a halogen atom, preferably chlorine.
  • This reaction is generally performed using pyridine or 4-dimethylaminopyridine in a solvent such as toluene, benzene or dichloromethane, preferentially at a temperature of between room temperature and the reflux point of the solvent.
  • a solvent such as toluene, benzene or dichloromethane
  • Room temperature is meant to be a temperature of between 5 and 25° C.
  • R3 and R4 are as defined in the general formula (I) and Hal represents a halogen atom, for example chlorine.
  • step c of Scheme 2 the compound of formula (V) is prepared from a compound of formula (VIII) by sparging with ammonia gas according to the method described in patent application FR 2 714 378.
  • R2, R3 and R4 are as defined in the general formula (I) and Hal represents a halogen atom, for example chlorine.
  • the compound of general formula (XIII) may be prepared by condensation of a compound of general formula (IV):
  • R7, R8, R9 and n are defined as in the general formula (I), with a corresponding halo compound, such as Hal′′′CH 2 COOAlk, in which Hal′′′ represents a halogen atom such as chlorine and Alk represents an alkyl group, such as ethyl.
  • a solvent such as toluene, benzene or dioxane.
  • the compound of general formula (XIII) may be prepared by condensation of a compound of general formula (XIV):
  • R5, R6, R8, R9 and n are defined as in the general formula (I) and Alk represents an alkyl group, with a compound R7-Hal′′′ in which Hal′′′ represents a halogen atom, such as chlorine, and R7 is defined as in the general formula (I).
  • This reaction is advantageously performed in a solvent such as toluene, benzene, dioxane or DMF in the presence of a base such as triethylamine or potassium carbonate.
  • the compounds of general formula (I) in which R1 represents an alkyl group and R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined in the general formula (I) may also be prepared according to Scheme 6 below:
  • a compound of formula (V) is reacted with a protecting group PG to give the compound of formula (XV).
  • protecting groups PG for the amine include benzimine and t-butyl carbamate. These protecting groups are introduced according to methods known to those skilled in the art, for example in the presence of a base such as K 2 CO 3 . NaOH or triethylamine, in a solvent such as dioxane. THF or DMSO.
  • the compound of general formula (XVI) may be prepared by reacting a compound of formula (XV) with a compound of formula ALK-Hal in which ALK represents a linear or branched saturated aliphatic group containing from 1 to 6 carbon atoms and Hal represents a halogen atom, for example chlorine.
  • the compound of general formula (XVII) is obtained from a compound of formula (XVI) by removing the protecting group according to well-known methods, for example in acidic medium with HCl or trifluoroacetic acid.
  • R2, R3, R4, R5, R6, R7, R8, R9 and n are as defined in the general formula (I).
  • This reaction is generally performed using a halogenating agent, such as a chlorinating agent, for example phosphorus chlorides, especially PCl 5 or PCl 3 or POCl 3 .
  • the reaction is generally performed in the presence of pyridine or 4-dimethylaminopyridine, in a solvent such as dichloromethane or DMF.
  • the compound of formula (I) is converted into an acid-addition salt thereof.
  • the process according to the invention may optionally include the step that consists in isolating the desired product of general formula (I).
  • the melting points were measured using a Büchi B-540 machine.
  • the products are detected by UV at 220 nm.
  • the ⁇ D measurements were recorded on a Perkin-Elmer model PE341 polarimeter using a cell with a 1 dm optical path length.
  • the organic phase is separated out, dried over Na 2 SO 4 , filtered and evaporated under vacuum. The residue is taken up in ethyl acetate and washed with 1N sodium hydroxide solution. The organic phase is dried over Na 2 SO 4 , filtered and evaporated under vacuum. The solid is taken up in ethyl ether and filtered off. 4.2 g of expected product are obtained.
  • the organic phase is washed with 1N hydrochloric acid solution.
  • the aqueous phases are combined, brought to basic pH with aqueous NH 3 solution and extracted with dichloromethane.
  • the organic phase is dried, filtered and concentrated to give 870 mg of solid white product.
  • reaction mixture is poured into water and extracted with ethyl acetate.
  • organic phase is washed with saturated NaHCO 3 solution, dried over Na 9 SO 4 , filtered and evaporated under vacuum. 500 mg of an orange-coloured solid are obtained, which product is purified on a column by flash chromatography using 1/1 ethyl acetate/methanol as eluent, to obtain the title product.
  • the compounds according to the invention underwent in vivo studies.
  • mice Male Crl CD BR rats (Charles River, Italy) weighing 150-175 g were housed in a chamber at regulated temperature (22 ⁇ 1° C.) and humidity (55 ⁇ 10%) and with a 12-hour lightness-darkness cycle, for at least 7 days before their use. Feed and water were available ad libitum. The feed was removed 18 hours before sacrificing the animals. The rats were sacrificed by cervical dislocation, and the stomach was removed surgically, opened along the shorter curvature and placed in a Krebs solution (of composition (mM): 118.4 NaCl; 4.7 KCl; 2.5 CaCl 2 ; 3.7 NaH 2 PO 4 ; 1.2 MgSO 4 ; 25 NaHCO 3 ; 5.6 glucose).
  • mM composition
  • the strips were maintained at a resting load of 1 g and, after washing, 10 ⁇ M of choline (acetylcholine precursor) and 10 ⁇ M of indomethacin (prostaglandin synthetase inhibitor) were added to the medium, to reduce the spontaneous phasic contractions (Depoortere et al., Eur. J. Pharmacol. 515, 1-3, 160-168, 2003; Dass et al., Neurosciences 120, 443-453, 2003). Isotonic contractions were initiated by stimulation with an electric field.
  • Two platinum wire electrodes were placed at the surface and at the bottom of the organ bath, and the electric-field stimulation was performed with a Power Lab stimulator (AD Instruments Pty Ltd, Castle Hill, Australia) coupled to a multiplex pulse propeller (Ugo Basile, Varese, Italy) (Fukuda et al., Scand. J. Gastroenterol. 12, 1209-1214, 2004).
  • the supramaximal stimulation was applied to create maximum contractions (20 Hz, pulse width: 2 milliseconds; 5 volts; batch trains every 2 minutes, 150 mA).
  • the current was reduced to obtain a submaximal stimulation (50% reduction of the maximum contractile response).
  • the contractions were recorded by computer with a data recording and analysis system (Power Lab, Chart 5) connected to isotonic transducers (Ugo Basile, Varese, Italy) via preamplifiers (Octal Bridge Amp). After stabilization, concentration-response cumulative curves for ghrelin (0.1 nM-1 ⁇ M) were plotted, with and without incubation (contact time: 30 minutes) of the antagonist molecules. Supramaximal electric-field stimulation was used for each strip as reference (100%) to classify the responses per test substance.
  • the agonist concentration producing 50% of the maximum effect was calculated using a four-parameter logistic model according to Ratkovsky and Reedy ( Biometrics, 42, 575-582, 1986), with adjustment by non-linear regression using the Levenberg-Marquard algorithm in the Everstat software.
  • the pKb values for the antagonists were calculated according to the Cheng-Prusoff equation (Kenakin et al., Competitive Antagonism, Pharmacologic Analysis of Drug - Receptor Interaction, 3rd edition, 331-373, Philadelphia, New York; Raven: Lippincott, 1997).
  • the compounds of formula (I) show antagonist activity towards the ghrelin receptor with IC 50 values ranging from 5 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 9 M.
  • the compound of Example No. 2 has an IC 50 value of 1.2 ⁇ 10 ⁇ 8 M.
  • the compounds of formula (I) demonstrated advantageous pharmacological properties for the development of a medicament, in particular medicaments for preventing or treating any pathology in which the ghrelin receptor is involved.
  • a subject of the invention is medicaments comprising a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid.
  • the compounds according to the invention may be used, for man and animals, in the treatment or prevention of various ghrelin-dependent complaints.
  • the compounds according to the invention may be used as anorexic agents, for regulating the appetite, the taking of meals and their frequency, and also, in the long-term, the weight, especially weight gain following diets or therapeutic regimens.
  • the compounds according to the invention are thus particularly useful for preventing or treating obesity, appetite disorders, diabetes, excess weight and/or the effects thereof.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
  • excipients are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration may be administered in unit administration form, as a mixture with standard pharmaceutical excipients, to animals and human beings, for the prophylaxis or treatment of the above disorders or diseases.
  • the appropriate unit administration forms include oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions
  • sublingual, buccal, intratracheal intraocular or intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • the compounds according to the invention may be used in creams, gels, ointments or lotions.
  • a unit administration form of a compound according to the invention in tablet form may comprise the following components:
  • the dose of active principle administered per day may be from 0.1 to 100 mg/kg in one or more dosage intakes. Via the parenteral route, it may be from 0.01 to 10 mg/kg/day
  • the dosage that is appropriate to each patient is determined by the practitioner according to the mode of administration, and the weight and response of the said patient.
  • the present invention also relates to combinations of one or more compound(s) according to the invention of general formula (I) with one or more active ingredient(s).
  • active ingredient(s) that is (are) suitable for the said combinations, mention may be made especially of anti-obesity and antidiabetic agents, and also rimonabant, metformin or sulfonylureas.
  • the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration to a patient of an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for treating the pathologies indicated above.

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US13/201,141 2009-02-12 2010-02-09 Substituted 3-benzofuranyl-indol-2-one-3-acetamididopiperazine derivatives, preparation thereof, and therapeutic use thereof Abandoned US20110312972A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0900620A FR2941946B1 (fr) 2009-02-12 2009-02-12 Derives de 3-benzofuranyl-indol-2-one-3-acetamidopiperazines substitues, leur preparation et leur application en therapeutique
FR09/00620 2009-02-12
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KR20110118157A (ko) 2011-10-28
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TW201041877A (en) 2010-12-01
US9889130B2 (en) 2018-02-13
EP2396319A1 (fr) 2011-12-21
WO2010092288A1 (fr) 2010-08-19
AU2010212704A1 (en) 2011-09-01
BRPI1008562A2 (pt) 2017-06-06
FR2941946B1 (fr) 2011-03-25
CN102361864B (zh) 2015-11-25
UY32448A (es) 2010-09-30
CN102361864A (zh) 2012-02-22
CA2752198C (fr) 2017-05-30
AU2010212704B2 (en) 2015-11-12
JP2012517460A (ja) 2012-08-02
MX2011008546A (es) 2011-11-18
JP5694958B2 (ja) 2015-04-01
IL214544A0 (en) 2011-09-27
RU2011137408A (ru) 2013-03-20
AR075398A1 (es) 2011-03-30
MY152069A (en) 2014-08-15
EP2396319B1 (fr) 2013-07-17
US20170119761A1 (en) 2017-05-04
HK1164861A1 (en) 2012-09-28
TWI461421B (zh) 2014-11-21
FR2941946A1 (fr) 2010-08-13
JO2851B1 (en) 2015-03-15
RU2542980C2 (ru) 2015-02-27

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