EP2077837A2 - Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique. - Google Patents

Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique.

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Publication number
EP2077837A2
EP2077837A2 EP07848274A EP07848274A EP2077837A2 EP 2077837 A2 EP2077837 A2 EP 2077837A2 EP 07848274 A EP07848274 A EP 07848274A EP 07848274 A EP07848274 A EP 07848274A EP 2077837 A2 EP2077837 A2 EP 2077837A2
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EP
European Patent Office
Prior art keywords
trans
hydrochloride
chloro
trifluoromethylbenzamide
phenylmethyl
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.)
Withdrawn
Application number
EP07848274A
Other languages
German (de)
English (en)
French (fr)
Inventor
Gihad Dargazanli
Geneviève ESTENNE-BOUHTOU
Florence Medaisko
Maria Carmen Renones
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi Aventis France
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Filing date
Publication date
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP2077837A2 publication Critical patent/EP2077837A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyrrolizine derivatives, indolizine and quinolizine, their preparation and their therapeutic application.
  • Ar represents a group selected from phenyl, naphthyl-1, naphthyl-2, pyridinyl,
  • C1-C6 cycloalkyl (C1-C4) alkylthio, mono- or polyfluoro (C 1 -C 6 ) alkyl and mono- or polyfluoro (C 1 -C 6 ) alkyloxy,
  • R represents either a hydrogen atom or one or more substituents identical to or different from each other selected from halogen atoms and mono- or polyfluoro (C 1 -C 6 ) alkyl and mono- or polyfluoro (C 1 -C 6 ) alkyloxy, (C 1 -C 6 ) linear alkyl, (C 3 -C 7 ) branched or cyclic alkyl, (C 3 -C 7 ) cycloalkyl (C 1 -C 6 ) alkyl, ( C 1 -C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyloxy,
  • the compounds of general formula (I) have three asymmetric centers; they may exist as enantiomers or threo or erythro diastereoisomers with stereochemistry of the cis or trans bicycle substituent, or as a mixture of such isomers. They may also exist in the form of free bases, addition salts with acids and / or solvates or hydrates, namely in the form of combinations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
  • a first group of compounds consists of the compounds for which:
  • Ar represents a group selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thien-2-yl, thien-3-yl, this Ar group possibly being substituted with one or a plurality of substituents selected from halogen atoms and (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 5 -C 8 ) cycloalkyl-CCrC 1 alkyl, (C 1 -C 6 ) alkoxy,
  • C 3 -C 7) cycloalkylthio, (C 3 -C 7) cycloalkyl (Ci-C 6) alkylthio, mono- or polyfluoro (C 1 -C 6) alkyl and mono- or polyfluoro (C 1 -C 6) alkyloxy, m where n and R are as defined above.
  • a second group of compounds is constituted by the compounds for which:
  • Ar represents a group chosen from phenyl, pyridin-3-yl and thien-3-yl groups, this Ar group possibly being substituted with one or more substituents which are identical to or different from each other and are chosen from the atoms of halogen, m, n and R being as defined above.
  • a third group of compounds is constituted by the compounds for which: R represents either a hydrogen atom or one or more substituents identical to or different from each other selected from the atoms of halogen and mono- or polyfluoro (C 1 -C 6 ) alkyl and mono- (Ci-C 6) linear alkyl and pentafluorosulfanyl, m, n and Ar being as defined above.
  • a fourth group of compounds is constituted by the compounds for which:
  • n each represent, independently of one another, the number 1 or 2
  • Ar represents a group chosen from phenyl, pyridin-3-yl and thien-3-yl groups, this Ar group possibly being substituted with one or more halogen atoms;
  • R represents either a hydrogen atom or one or more substituents identical or different from each other selected from chlorine and methyl, trifluoromethyl, trifluoromethoxy and pentafluorosulfanyl groups.
  • a fifth group of compounds is constituted by the following compounds:
  • Amine coupling is then carried out between the diamine of general formula (V) and an activated acid or an acid chloride of general formula (VI), in which Y represents an activated OH group or a chlorine atom and R is such that defined above, using the methods known to those skilled in the art, to lead to the amide of general formula (I).
  • the chiral compounds of general formula (I) can be obtained by separation of the racemic compounds by high performance liquid chirography chromatography (HPLC) on a chiral column, or by resolution of the racemic amine of general formula (V) by use of a chiral acid, such as tartaric acid, camphorsulfonic acid, dibenzoyltartric acid, N-acetyleucine, by the fractional and preferential recrystallization of a diastereoisomeric salt in an alcohol-type solvent, or by enantioselective synthesis of using a chiral nitrile of general formula (II).
  • HPLC high performance liquid chirography chromatography
  • nitriles of general formula (II) are described in Synlett, (1995), 519-522 when n and m represent 1 with cis and trans stereochemistry, in JOC, 55, (1990), 4688-4693 and JOC, 56, (1991), 4868-48741whenrepresented2 andrepresented 1 with stereochemistry trans, in Org. Letters, 2, (2000), 2085-2088 when n represents 1 and m represents 2 with trans and cis stereochemistry, and finally they can be prepared according to methods analogous to those described above when n and m represent 2 with trans stereochemistry. in racemic or chiral series.
  • lithiated derivatives of general formula (ni) are commercially available or they can be prepared according to methods known to those skilled in the art and analogous to those described in JOC, 62, (1997), 5484-5496 and Tetrahedron Letters, 35, (1994), 3673-3674.
  • Certain acids and chlorides of acids of general formula (VI) are commercially available or can be obtained by methods analogous to those described in patents EP-0556672, US-3801636, and in J Chem. Soc., (1927), 25, Chenu Pharm. Bull., (1992), 1789-1792, Aust. J. Chem., (1984), 1938-1950 and J. O., (1980), 527.
  • the invention also relates to the compounds of general formula (V):
  • n each represent, independently of one another, the number 1 or 2
  • Ar represents a group selected from phenyl, naphthyl-1, naphthyl-2, pyridinyl,
  • C 3 -C 7) cycloallcyl (CrC 6) alkylthio, mono- or polyfluoro (C 1 -C 6) alkyl and mono- or polyfluoro (C 1 -C 6) alkyloxy.
  • a first group of compounds is constituted by the compounds for which: m and n each represent, independently of each other, the number 1 or 2, Ar represents a group selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thien-2-yl, thien-3-yl, this Ar group possibly being substituted by one or more substituents chosen from halogen atoms and (C 1 -C 8 -alkyl) (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 ) cycloalkyl (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy groups, (C 1 -C 6 ) C 3 -C 7) cycloalkyloxy, (C 3 -C 7) cycloalkyloxy, (C 3 -C 7) cycloalkyloxy, (C 3 -C 7) cycloalkyloxy,
  • a second group of compounds is constituted by the compounds for which: Ar represents a group chosen from phenyl, pyridin-3-yl and thien-3-yl groups, this Ar group may be optionally substituted with one or more substituents selected from halogen atoms, m and n being as defined above.
  • n each represent, independently of one another, the number 1 or 2
  • Ar represents a group chosen from phenyl, pyridin-3-yl and thien-3-yl groups, this Ar group possibly being substituted by one or more halogen atoms.
  • trans-threo / erythro 1- (octahydroindolizin-5-yl) -1-phenylmethanamine; trans-threo 1- (octahydroindolizin-3-yl) -1-phenylmethanamine; ⁇ -erythro 1- (octahydroindolizin-3-yl) -1-phenylmethanamine; trans-tbeo / erythro 1- (octahydro-2H-quinolizin-4-yl) -1-phenylmethanamine; trans-erythro-1- (octahydro-2H-qumolizin-4-yl) -1- (4-fluorophenyl) niethananime; trans- ⁇ x- (octahydro-2H-qumolizin-4-yl) -1-pyridin-3-ylmethanam; trans-threo / cis-erythrox 1-
  • the mixture is treated with water and extracted several times with dichloromethane.
  • the combined organic phases are dried over sodium sulfate, filtered, the imine is concentrated under reduced pressure and taken up in a 50 ml flask with 25 ml of methanol.
  • the mixture was cooled to -5 ° C and 0.78 g (20.6 mmol) of sodium borohydride was added slowly. Stirring is continued, allowing the mixture to return to room temperature for 12 hours.
  • the mixture is concentrated under reduced pressure and taken up with water and ethyl acetate, the phases are separated and the aqueous phase is extracted with ethyl acetate. After washing the combined organic phases, drying over sodium sulfate, filtration and evaporation, 0.8 g of product is obtained in the form of a yellow oil which is used as it is in the next step.
  • the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol.
  • the mixture is treated with water and extracted several times with dichloromethane. After washing the organic phases with water and then with an aqueous solution of sodium hydroxide
  • This product is then converted into hydrochloride from a 0.1 N solution of hydrochloric acid in propan-2-ol.
  • C 6 H 5 is phenyl
  • ZXC 6 H 4 is X-substituted phenyl
  • C 5 H 4 N-3 is pyridin-3-yl
  • C 4 H 3 S-3 is thien-3-yl.
  • the compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their interest as substances with therapeutic activities.
  • [ 14 C] glycine uptake is studied in SK-N-MC cells (human neuroepithelial cells) expressing the native human glytl transporter by measuring the radioactivity incorporated in the presence or absence of the test compound.
  • the cells are cultured in monolayer for 48 h in 0.02% fibronectin pretreated plates.
  • the culture medium is removed and the cells are washed with a Krebs-HEPES buffer ([4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4.
  • a Krebs-HEPES buffer [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid
  • 10 mM glycine determination of non-specific uptake
  • 10 ⁇ M [ 14 C] glycine specific activity 112 mCi / mmol
  • the radioactivity incorporated by the cells is then estimated after adding 100 ⁇ l of liquid scintillant and stirring for 1 h. Counting is performed on a Microbeta Tri-lux TM counter. The effectiveness of the compound is determined by the IC 50 concentration of the compound which decreases by 50% the specific uptake of glycine, defined by the difference in radioactivity incorporated by the control group and the batch that received glycine at 10 mM.
  • the compounds of the invention in this test, have an IC 50 of the order of 0.001 to 0.20 ⁇ M.
  • the compounds of the invention exhibit particular activity as inhibitors of glytl glycine transporters.
  • the compounds according to the invention can therefore be used for the preparation of medicaments, in particular inhibitory drugs for glycine transporters. glyti.
  • the compounds of the invention can be used for the treatment of behavioral disorders associated with dementia, psychoses, in particular schizophrenia (deficient form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptics.
  • behavioral disorders associated with dementia psychoses
  • psychoses in particular schizophrenia (deficient form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptics.
  • various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders for the treatment of various forms of depression, including psychotic depression, for the treatment of disorders due to abuse or alcohol withdrawal, sexual behavior disorders, eating disorders, for the treatment of migraine and for the treatment of primary and secondary generalized epilepsies, partial with simple or complex symptomatology, mixed forms and other syndromes epileptics, in addition to another antiepileptic treatment or monotherapy.
  • the subject of the present invention is also pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a base or a pharmaceutically acceptable salt or solvent, and in a mixture, where appropriate. with appropriate excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular administration.
  • the unit dosage forms may be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches, suppositories.
  • topical administration we can consider ointments, lotions and eye drops.
  • a pharmaceutical carrier which may be composed of diluents, such as, for example, lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders, (polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulphate may also be added.
  • diluents such as, for example, lactose, microcrystalline cellulose, starch, and formulation adjuvants such as binders, (polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.)
  • flow agents such as silica
  • lubricants such as magnesium stearate, stearic acid, glycerol tribehenate sodium stearyl fumarate.
  • Wetting agents or surfactants
  • the production techniques can be direct compression, dry granulation, wet granulation or hot melt.
  • the tablets may be bare, sugar-coated, for example with sucrose, or coated with various polymers or other suitable materials. It can be designed to allow rapid, delayed or sustained release of the active ingredient through polymer matrices or specific polymers used in the coating.
  • the active ingredient is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot melting), liquid or semi-solid.
  • the capsules may be hard or soft, film-coated or not, so as to have a rapid, prolonged or delayed activity (for example for an enteric form).
  • a composition in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.
  • a sweetener preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.
  • Water-dispersible powders and granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and taste-correcting agents.
  • dispersing agents or wetting agents or dispersing agents such as polyvinylpyrrolidone
  • sweeteners and taste-correcting agents for rectal administration, suppositories prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols, are used.
  • the active ingredient can be formulated also in the form of microcapsules, optionally with one or more carriers or additives, or with a polymer matrix or with a cyclodextrin (transdermal patches, sustained-release forms).
  • the topical compositions according to the invention comprise a medium compatible with the skin. They may be in the form of aqueous, alcoholic or aqueous-alcoholic solutions, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or gel, microemulsions, aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered.
  • the pharmaceutical compositions according to the invention may contain, besides a compound of general formula (I), other active ingredients which may be useful in the treatment of the disorders and diseases indicated above.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
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  • Obesity (AREA)
  • Nutrition Science (AREA)
  • Endocrinology (AREA)
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  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Indole Compounds (AREA)
EP07848274A 2006-09-22 2007-09-21 Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique. Withdrawn EP2077837A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0608348A FR2906251B1 (fr) 2006-09-22 2006-09-22 Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique
PCT/FR2007/001545 WO2008037881A2 (fr) 2006-09-22 2007-09-21 Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique.

Publications (1)

Publication Number Publication Date
EP2077837A2 true EP2077837A2 (fr) 2009-07-15

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EP07848274A Withdrawn EP2077837A2 (fr) 2006-09-22 2007-09-21 Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique.

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US (2) US7776880B2 (pt)
EP (1) EP2077837A2 (pt)
JP (1) JP2010504311A (pt)
KR (1) KR20090080947A (pt)
CN (1) CN101573113A (pt)
AR (1) AR062896A1 (pt)
AU (1) AU2007301880A1 (pt)
BR (1) BRPI0717100A2 (pt)
CA (1) CA2663080A1 (pt)
CL (1) CL2007002732A1 (pt)
CO (1) CO6160309A2 (pt)
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FR2842804B1 (fr) 2002-07-29 2004-09-03 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
FR2861074B1 (fr) * 2003-10-17 2006-04-07 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
UY32397A (es) * 2009-01-28 2010-08-31 Astrazeneca Ab Compuestos de 2-aza-biciclo [2,2,1] heptano y sus usos
WO2010087761A1 (en) * 2009-01-28 2010-08-05 Astrazeneca Ab 2-aza-bicyclo[2.2.2]octane compounds and uses thereof
US8338441B2 (en) 2009-05-15 2012-12-25 Gilead Sciences, Inc. Inhibitors of human immunodeficiency virus replication
US8143273B2 (en) * 2010-06-22 2012-03-27 Hoffman-La Roche Inc. Quinolizidine and indolizidine derivatives

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JP2004510712A (ja) * 2000-09-22 2004-04-08 オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド オクタヒドロ−インドリジンおよびキノリジンおよびヘキサヒドロ−ピロリジン
FR2861073B1 (fr) * 2003-10-17 2006-01-06 Sanofi Synthelabo Derives de n-[heteroaryl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
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WO2008037881A3 (fr) 2008-05-22
PE20081376A1 (es) 2008-11-07
NZ575573A (en) 2011-12-22
KR20090080947A (ko) 2009-07-27
AU2007301880A1 (en) 2008-04-03
NO20091351L (no) 2009-06-22
MX2009003083A (es) 2009-04-02
US20090258899A1 (en) 2009-10-15
IL197500A0 (en) 2009-12-24
JP2010504311A (ja) 2010-02-12
ZA200901850B (en) 2010-06-30
TN2009000082A1 (en) 2010-08-19
FR2906251B1 (fr) 2008-11-07
US20100267766A1 (en) 2010-10-21
MEP10109A (en) 2011-12-20
CL2007002732A1 (es) 2008-04-18
UY30604A1 (es) 2008-05-02
CO6160309A2 (es) 2010-05-20
TW200819455A (en) 2008-05-01
EA015974B1 (ru) 2012-01-30
EA200970312A1 (ru) 2009-12-30
CA2663080A1 (fr) 2008-04-03
GT200900061A (es) 2010-06-21
US7776880B2 (en) 2010-08-17
SV2009003191A (es) 2009-10-27
WO2008037881A2 (fr) 2008-04-03
HN2009000504A (es) 2011-10-20
MA30790B1 (fr) 2009-10-01
CN101573113A (zh) 2009-11-04
BRPI0717100A2 (pt) 2013-10-15
FR2906251A1 (fr) 2008-03-28
AR062896A1 (es) 2008-12-10
CR10658A (es) 2009-06-24

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