WO2009087395A1 - Composés de réduction du poids - Google Patents

Composés de réduction du poids Download PDF

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Publication number
WO2009087395A1
WO2009087395A1 PCT/GB2009/000064 GB2009000064W WO2009087395A1 WO 2009087395 A1 WO2009087395 A1 WO 2009087395A1 GB 2009000064 W GB2009000064 W GB 2009000064W WO 2009087395 A1 WO2009087395 A1 WO 2009087395A1
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WIPO (PCT)
Prior art keywords
alkyl
compounds
hal
compound according
methyl
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PCT/GB2009/000064
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English (en)
Inventor
Roger David Waigh
Alan Lang Harvey
Mark Hugh Mooney
Geoffrey Coxon
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University Of Strathclyde
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Publication of WO2009087395A1 publication Critical patent/WO2009087395A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/06—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • the present invention relates to compounds which find use as weight reducing agents, and find use in treating obesity and/or excess adiposity.
  • Dimethylallylguanidine also known as galegine
  • galegine was first isolated from the plant Galega officinalis in the late 1800s. The plant has a long history of use as an antidiabetic and galegine itself was used for a short time as a hypoglycemic.
  • Research in the 1950s resulted in the discovery of biguanides, rather than guanidines. These are known as the ' formin ' class of agents, and one of these, metformin, is still used for the treatment of type 2 diabetes .
  • NIDDM non-insulin dependent diabetes mellitus
  • the Applicant of the present invention has now unexpectedly found that a select group of compounds provide improved weight reducing effects in mammals.
  • R 1 , R 2 , R 3 and R 4 may be the same or different and are independently selected from H or Ci-C 6 alkyl;
  • R 5 and R 6 are independently selected at each position H, C x -C 6 alkyl or O-alkyl CF 3 or Hal or R 5 and R 6 are adjacent and together form a five or six membered hydrocarbon or heterocylic ring,
  • R 7 is H or Ci-C 6 alkyl
  • Hal is selected from F, Cl, Br and I; and n is 0 or 1; and excluding the following compounds and salts thereof: i) R 5 is H, n is 0, R 1 and R 2 are H, ii) R 5 is H, n is 1, R 1 and R 2 are H, R 3 and R 4 are methyl, iii) R 5 is H, n is 1, R 1 , R 2 , R 3 and R 4 are all H, and iv) R 5 is Hal which is Cl, n is 1, R 1 , R 2 , R 3 and R 4 are all H.
  • R 7 is H or methyl.
  • Preferred compounds for the stated use include those of formula (I) in which R 5 is Hal and n is 0.
  • Particularly preferred compounds of formula (I) for the stated use are those in which R 5 is Hal, n is 0 and R 1 , R 2 , R 3 and R 4 are all H.
  • Hal is chlorine or bromine
  • R 5 is chlorine or bromine
  • n is 0 and R 1 , R 2 , R 3 and R 4 are all H.
  • R 5 is H are those compounds of formula (I) in which n is 1, R 1 , R 2 , and R 3 are all H, and R 4 is Ci-C 6 alkyl.
  • R 4 is most preferably methyl or ethyl, particularly methyl.
  • the C ⁇ -Cg alkyl group includes methyl, ethyl, propyl, butyl, pentyl and hexyl, and includes geometric isomers and branched and cyclic versions as appropriate. For example, included are iso-propyl, sec-butyl, tert-butyl and cyclo-hexyl.
  • the Ci-C 6 alkyl group is a Ci-C 4 alkyl group.
  • the Ci-C 6 alkyl group can be optionally substituted, e.g. by carboxy, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted amide, nitro, thio, formyl, cyano, carbamoyl, halo (e.g. fluoro, chloro, bromo or iodo) , an ester, a ketone, -S(O)NR 12 R 13 or -S(O)R 14 , wherein R 12 , R 13 and R 14 each independently are Ci-C 6 alkyl.
  • the compounds according to formula (I) which are useful as described herein may be presented as a physiologically acceptable salt, ester or other physiologically functional derivative thereof, and the present invention also relates to the uses of those compounds of formula (I) for the preparation of a medicament for weight reduction.
  • the present invention also provides novel compounds. According to a second aspect of the present invention, there is provided a compound according to formula (II), or a physiologically acceptable salt thereof:
  • R 1 , R 2 , R 3 and R 4 may be the same or different and are independently selected from H or Ci-C 6 alkyl; R 5 and R 6 are independently selected at each position H, Ci-C 6 alkyl or O-alkyl CF 3 or Hal or R 5 and R 6 are adjacent and together form a five or six membered hydrocarbon or heterocylic ring,
  • R 7 is H or C 1 -C 6 alkyl, Hal is selected from F, Cl, Br and I; and n is 0 or 1; and excluding the following compounds and salts thereof: i) R 5 is H, n is 0, R 1 is H and R 2 is H, methyl or ethyl, ii) R 5 is H, n is 1, R 1 and R 2 are H, R 3 and R 4 are methyl, iii) R 5 is H, n is 1, R 1 , R 2 , R 3 and R 4 are all H, iv) R 5 is Hal and is Cl, n is 1, R 1 , R 2 , R 3 and R 4 are all H, and iv) Hal is F, Cl or Br, n is 0 and R 1 and R 2 are H.
  • Preferred compounds include all those described above in relation to the stated use, excluding the compounds described in the above statements i) - ii) .
  • a pharmaceutical composition comprising a compound according to formula (I) as described hereinbefore, together with a pharmaceutically acceptable carrier therefor.
  • a compound as described according to the first aspect e.g. according to formula (I)
  • the weight reduction obtainable by means of the present invention includes both therapeutic and cosmetic weight reduction, and finds use in treating obesity and/or excess adiposity.
  • the weight reduction in accordance with the present invention may be applied to mammals which are obese through dietary intake or which are genetically predisposed to obesity. It is noted that an obese phenotype may be demonstrated as a consequence of failure to produce leptin, whereas diet-induced obesity is more typical of the presence of hyperleptinaemina and where excessive calorie intake interacts with particular genetic backgrounds to produce obesity.
  • Subjects include non-human animals, e.g. mammals especially domestic companion animals, such as dogs, cats rabbits and the like, and humans.
  • the compounds of the present invention may also be used to provide a hypoglycaemic effect.
  • a method of weight reduction comprising applying an effective amount of a compound according to the first or second aspects e.g. according to formulae (I) or (II) as described hereinbefore to an individual in need thereof.
  • physiologically acceptable salts of the compounds according to the invention include acid addition salts formed with organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Hydrogen sulfate salts are also included.
  • organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethan
  • the compounds described herein include a guanidine functional group which causes the compounds to become very strong bases and which may react with carbon dioxide (e.g. in the atmosphere) to form a molecule of a carbamic acid for each molecule of compound which then reacts with a second molecule of compound to form a salt.
  • carbon dioxide e.g. in the atmosphere
  • Such salts are also included within the term physiologically acceptable salts.
  • the present invention also includes physiologically functional derivatives of the described compounds.
  • Physiologically functional derivatives of compounds of the present invention are derivatives which can be converted in the body into the parent compound. Such physiologically functional derivatives may also be referred to as "pro-drugs” or “bioprecursors” .
  • Physiologically functional derivatives of compounds of the present invention include in vivo hydrolysable esters and amides .
  • the compounds of the present invention may exist in various stereoisomeric forms and the compounds of the present invention as hereinbefore defined include all stereoisomeric forms and mixtures thereof, including enantiomers and racemic mixtures.
  • the present invention includes within its scope the use of any such stereoisomeric forms or mixtures of stereoisomers, including the individual enantiomers of the compounds of formulae (I) and (II) as well as wholly or partially racemic mixtures of such enantiomers.
  • R 4 is C 1 -C 6 alkyl, preferably Ci-C 4 alkyl, most preferably methyl or ethyl, typically methyl.
  • the absolute stereochemistry about the carbon atom to which R 4 is attached may be S- or R-, and those compounds may be provided as enantiomers or racemic mixtures, or mixtures containing unequal amounts of the S- or R- forms.
  • the compounds of the present invention may be prepared using reagents and techniques readily available in the art and as described hereinafter. Novel intermediate compounds in the synthetic route for preparation of the compounds of the present invention may be important molecules for general application for the preparation of the molecules of the present invention.
  • the present invention extends to include those novel intermediate compounds.
  • the present invention further provides a treatment or prophylaxis of a disease, pathology or condition recited herein comprising administering a compound recited herein to a patient in need thereof.
  • the patient is typically an animal, e.g a mammal, especially a human.
  • the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof described herein may be presented as a pharmaceutical formulation, comprising the compound or physiologically acceptable salt, ester or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic and/or prophylactic ingredients.
  • the carrier (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the dose of compound described herein shall be determined by the skilled practitioner in accordance with well established pharmacological principles. A typical dose may be administered orally in the food of the recipient thereof, in amounts such as from about 1 mmol to about 25 mmol of compound per kg of food.
  • Preferable amounts being from about 2.5 mmol to about 10 mmol per kg of food, most preferably, about 3 mmol to about 5 mmol per kg of food.
  • a desirable amount is 3.25 - 3.75 mmol per kg of food.
  • the compounds may be added to a recipient animal in an amount of 0.05 - 5 mmol/kg body weight/day, such as 0.1 - 2 mmol/kg body weight/day.
  • compositions include those suitable for oral, topical (including dermal, buccal and sublingual) , rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous) , nasal and pulmonary administration e.g., by inhalation.
  • the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent.
  • Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored.
  • Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner.
  • Cachets are analogous to capsules wherein an active compound together with any accessory ingredient (s) is sealed in a rice paper envelope.
  • An active compound may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet.
  • Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.
  • Formulations for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release - controlling matrix, or is coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use.
  • Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of an active compound with the softened or melted carrier (s) followed by chilling and shaping in moulds.
  • compositions suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.
  • Injectible preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use.
  • an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.
  • An active compound may also be formulated as long- acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g. subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long- acting formulations are particularly convenient for prophylactic use.
  • Formulations suitable for pulmonary administration via the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient.
  • such formulations are in the form of finely comminuted powders ' which may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and/or a solid diluent.
  • suitable liquid propellants include propane and the chlorofluorocarbons
  • suitable gaseous propellants include carbon dioxide.
  • Self-propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension.
  • Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof.
  • an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation.
  • Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range 10 to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w/v of an active compound in aqueous or oily solution or suspension.
  • the pharmaceutical formulations described above may include, an appropriate one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of nonaqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • Therapeutic formulations for veterinary use may conveniently be in either powder or liquid concentrate form.
  • conventional water soluble excipients such as lactose or sucrose, may be incorporated in the powders to improve their physical properties.
  • suitable powders of this invention comprise 50 to 100% w/w and preferably 60 to 80% w/w of the active ingredient (s) and 0 to 50% w/w and preferably 20 to 40% w/w of conventional veterinary excipients.
  • These powders may either be added to animal feedstuffs, for example by way of an intermediate premix, or diluted in animal drinking water.
  • Liquid concentrates of this invention suitably contain the compound or a derivative or salt thereof and may optionally include a veterinarily acceptable water- miscible solvent, for example polyethylene glycol, propylene glycol, glycerol, glycerol formal or such a solvent mixed with up to 30% v/v of ethanol.
  • a veterinarily acceptable water- miscible solvent for example polyethylene glycol, propylene glycol, glycerol, glycerol formal or such a solvent mixed with up to 30% v/v of ethanol.
  • guanidine hemisulfate (galegine) for reference purposes and general procedure for synthesis of guanidine hemisulfates :
  • a mixture of 4-bromo-2-methyl-2-butene (19.4g, 1.0 eq, 130 mmol) and potassium phthalimide (29.8g, 1.2 eg, 161 mmol) were suspended in DMF (200 ml) and stirred at 12O 0 C for 1 hour before heating to 160 0 C and stirring for a further 18 hours.
  • the mixture was poured over ice and washed with dichloromethane (5 x 50 ml) , the organic phases separated and combined before washing with sodium hydroxide solution (0.1N) (2 x 100ml) and water (2 x 50ml) .
  • galegine (5.4g, 62%) as a white solid.
  • Mp 216-218 0 C (dec) .
  • Lit. 214-216 0 C (dec) (Desvages, G.; Olomucki, M. Research on the derivatives of guanidines from Galega officinalis .
  • L galegine and hydroxygalegine, Bull. Soc. Chim. Fr. 1969, 3229-3232.).
  • (+)-l- (2- phenylpropyl) guanidine hemisulfate (2.1g, 64%) was obtained as a white solid.
  • GDC 132 1- (naphthalene-2-ylmethyl) guanidine hemisulfate
  • IR (KBr, can "1 ) 3490 (m) , 3343 (br) , 3251 (br) , 3143 (br) , 288 (w) , 1671 (s) , 1107 (s) .
  • mice Male male BALB/c mice were obtained from stock at the Biological Procedures Unit within the University of Strathclyde.
  • a diet-induced obesity (DIO) mouse model was developed by feeding BALB/c mice on a synthetic high-fat (45 kcal%) diet (Research Diets, Inc., New Brunswick, NJ) post-weaning through to start of experimental procedures.
  • Homozygous obese ob/ob mice were purchased from Harlan UK (Bicester, UK) . All animals were housed individually in an air-conditioned environment maintained at 2 1+2 0 C with a 12h light/12h dark cycle. Animals were allowed continuous access to tap water and unless indicated otherwise were fed ad libitum on standard pellet diet (SDS, Cambridge, UK) . Before the initiation of feeding studies, mice were habituated to being housed individually and had their food intake and bodyweight monitored daily at 09.30.
  • Table 2 Effect of compounds in BALB/c mice Each compound administered in feed for 7 days.
  • MA 175 was toxic at the higher dose, the experiment was terminated at day 5.
  • Table 4 Effect of compounds in DIO mice

Abstract

La présente invention porte sur des composés qui trouvent utilisation en tant qu'agents de réduction du poids, et trouvent utilisation dans le traitement de l'obésité et/ou de l'adiposité en excès.
PCT/GB2009/000064 2008-01-10 2009-01-09 Composés de réduction du poids WO2009087395A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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