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WO2004043947A1 - Novel pyridine derivatives, preparation method and pharmaceutical compositions containing same - Google Patents

Novel pyridine derivatives, preparation method and pharmaceutical compositions containing same Download PDF

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Publication number
WO2004043947A1
WO2004043947A1 PCT/FR2003/003275 FR0303275W WO2004043947A1 WO 2004043947 A1 WO2004043947 A1 WO 2004043947A1 FR 0303275 W FR0303275 W FR 0303275W WO 2004043947 A1 WO2004043947 A1 WO 2004043947A1
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group
alkyl
formula
compounds
hydrogen atom
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PCT/FR2003/003275
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French (fr)
Inventor
Sylvain Rault
Marina Kopp
Jean-Charles Lancelot
Stéphane Lemaitre
Bruno Pfeiffer
Jean-Guy Bizot-Espiard
Pierre Renard
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Les Laboratoires Servier
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Priority to AU2003292321A priority Critical patent/AU2003292321A1/en
Publication of WO2004043947A1 publication Critical patent/WO2004043947A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to new pyridine derivatives, their preparation process and the pharmaceutical compositions containing them.
  • pyridine derivatives are well known for their activity on nicotinic receptors, which gives them great interest in the treatment of pathologies linked to cerebral aging such as memory disorders or Alzheimer's disease ( Biol, Psychiatry, 2001, 49, 268 and Exp. Opin. Ther. Patents, 200,
  • Omeprazole are inhibitors of the gastric proton pump and used in therapy as an antiulcer.
  • Rosiglitazone are ligands for PPAR receptors and are used in the treatment of type 2 diabetes and more particularly insulin resistance.
  • Ri and R 2 identical or different, represent a hydrogen atom, an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl group or R a -C (Y) - with R a representing a hydrogen atom, a optionally substituted alkyl, alkoxy, aryl or optionally substituted heteroaryl group and Y representing an oxygen or sulfur atom or an NR group, where R b represents a hydrogen atom or an alkyl group, or alternatively: R 1 and R 2 together with the nitrogen atom which carries them form a heterocycle, aromatic or not, comprising from 5 to 8 links and from 1 to 3 heteroatoms chosen from the nitrogen, oxygen and sulfur atom, and optionally substituted by one or two substituents, identical or different, chosen from halogen atoms, and alkyl, polyhaloalkyl, alkoxy, hydroxy, cyano, nitro, amino groups (optionally substituted by one or two alkyl groups) and -C (Y
  • R 3 represents a hydrogen atom or a group chosen from alkyl, alkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or two alkyl groups) and -C (O) -R ⁇ ⁇ with Rd representing a group hydroxy, alkoxy or amino,
  • R 4 and R 5 identical or different, represent a hydrogen atom or an alkyl group
  • X represents an oxygen or sulfur atom or an NR e group with R e representing a hydrogen atom or an alkyl group
  • the compounds of formula (I) are different from 3- (4,5-dihydro-1H-imidazol-2-yl) -2-pyridinamine, from 3- (4,5-dihydro-1H- imidazol-2-yl) -N-phenyl-2-pyridinamine, 3- (4,5-dihydro-1H-imidazol-2-yl) -N-methyl-2-pyridinamine, and
  • alkyl denotes a hydrocarbon chain, linear or branched, containing from 1 to 6 carbon atoms
  • alkoxy denotes an alkyl-oxy group in which the alkyl chain, linear or branched, contains from 1 to 6 carbon atoms
  • polyhaloalkyl designates a carbon chain, linear or branched, containing from 1 to 3 carbon atoms and from 1 to 7 halogen atoms
  • heteroaryl denotes a group of 5 to 11 members, monocyclic or bicyclic, in which at least one of the rings is aromatic, comprising in the monocycle or in the bicycle 2 or 3 heteroatoms, chosen from nitrogen, oxygen and sulfur, and
  • cycloalkyle designates a hydrocarbon monocycle or bicycle containing 3 to 10 carbon atoms, and possibly unsaturated by lou 2 unsaturations.
  • aryl and heteroaryl means that the groups concerned can be substituted by one or two substituents, identical or different, chosen from halogen atoms and alkyl, alkoxy, polyhaloalkyl, hydroxy, cyano groups.
  • nitro, amino (optionally substituted by one or two alkyl groups) and -C (O) R e with Re representing a group chosen from hydroxy, alkoxy and amino, it being understood that the heteroaryl group may also be substituted by an oxo group on the non-aromatic part of the heteroaryl.
  • hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane sulfonic acids. , camphoric, etc ...
  • An advantageous aspect of the invention relates to the compounds for which R 3 represents a hydrogen atom or an alkyl group.
  • An advantageous aspect of the invention relates to the compounds for which, taken together or separately, R represents a hydrogen atom or an alkyl group, R and R 5 represent a hydrogen atom, and X represents a group NR e and more particularly NH.
  • the preferred alkyl group of the invention for the group R 3 is the methyl group.
  • the invention relates to the compounds of formula (I) for which Ri and R 2 form, together with the nitrogen atom which carries them, an optionally substituted heterocycle such as imidazoline, morpholine, piperidine or azepane.
  • a particularly advantageous aspect of the invention relates to the compounds of formula (I) for which, Ri and R 2 form together with the nitrogen atom which carries them a heterocycle, aromatic or not, with 5, 6 or 7 members, comprising 1 or 2 heteroatoms chosen from the nitrogen and oxygen atom, R 3 represents a hydrogen atom or an alkyl group, R4 and R 5 represent a hydrogen atom and X represents an NH group.
  • the group R 3 is an alkyl group located in position 6 of the pyridyl ring.
  • the invention also relates to the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material:
  • the carbonyl, thiocarbonyl, amino or alkylamino group (s) of the starting reagents (II) and (III) can be protected then, after condensation, deprotected for the needs of synthesis,
  • the compounds show in particular excellent activity in the reduction of blood glucose levels. These properties justify their therapeutic application in the treatment of type II non-insulin dependent diabetes, obesity, glucose intolerance.
  • the activity of these compounds is also recommended for the treatment and / or prophylaxis of other diseases including type I diabetes, metabolic syndrome and insulin resistance.
  • the present invention also relates to pharmaceutical compositions containing as active principle at least one compound of formula (I) alone or in combination with one or more inert non-toxic, pharmaceutically acceptable excipients or vehicles.
  • compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments , dermal gels, etc.
  • the useful dosage varies according to the age and weight of the patient, the nature and severity of the condition and the route of administration. This can be oral, nasal, rectal or parenteral. Generally, the unit dosage ranges from 0.1 to 500 mg for a treatment in 1 to 3 doses per 24 hours.
  • the starting materials used are known products or prepared according to known procedures.
  • a mixture of 0.04 mole (3.30 g) of 2-methylimidazole and 0.04 mole (5.50 g) of 2-chloronicotinonitrile is heated at 120 ° C. for 4 hours in DMF + in the presence of 0, 04 mole (5.52 g) of potassium carbonate. After cooling, the solution is extracted with 200 ml of ether and the organic phase is washed three times with water. After drying over magnesium sulfate, the ether is evaporated.
  • the experimental protocol is identical to that of Preparation 1, using azepane as the starting amine.
  • the experimental protocol is identical to that of preparation 1, starting from 2-chloro-6-methylnicotinonitrile and morpholine.
  • PREPARATION 4 2- (l-Azépanyl) -6-méthyInicotinonitriIe
  • the experimental protocol is identical to that of preparation 3, using azepane as the starting amine.
  • the experimental protocol is identical to that of preparation 3, using morpholine as the starting amine.
  • PREPARATION 6 2- (4-MorphoIinyl) nicotinonitrile
  • the experimental protocol is identical to that of Preparation 1, using morpholine as the starting amine.
  • the experimental protocol is identical to that of Preparation 1, using azocane as the starting amine.
  • EXAMPLE A Hypoglycemic activity The hypoglycemic activity of the derivatives of the invention was sought in male Witsar rats of approximately 250 g aged three months. Experimental diabetes is obtained by iv injection of a low dose of streptozotocin (35 mg / kg iv) dissolved in a citrate buffer under anesthesia with Ketamine hydrochloride. These rats are called “STZ", they are characterized by a slight basal hyperglycemia, a clear intolerance or glucose and a frank alteration of the insulin secretion.
  • Glucose is administered orally (2g.kg _1 ) to alert rats. Blood samples are collected before and 10, 20, 30, 40, 60, 90 and 120 minutes after the administration of glucose. The processing of blood samples is identical to that described above.
  • the product to be tested is administered per os 1 hour before the OGTT.
  • the compounds of the invention very significantly lower blood sugar.
  • Example 5 very significantly decreases the glycemia of non-diabetic Wistar rats, Wistar STZ rats and Zucker rats (see Table 1).
  • Table 1 OGTT blood glucose values 1 hour after the glucose load and after oral administration of the compound of Example 5 at 10 and 30 mg / kg.
  • Three rats per dose are treated per os with one of the compounds of the invention (dispersed in 0.5% of carboxymethylcellulose in distilled water) and are observed at regular time intervals after 24 hours.
  • the presence or absence of symptoms are recorded: mortality, sedation, excitement, aggressiveness, tail shape, convulsions, pain, tremors, exophthalmos, salivation, piloerection, defecation, fear, etc., according to the criteria described by Irwin (Psychopharmacologia , 1968, 13, 222). This test allows an evaluation of the toxicity and the effect on behavior.
  • the compounds of the invention appear to be non-toxic, with in the case of Example 5 an absence of toxicity at the dose of 1024 mg / kg (maximum dose tested).

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention concerns compounds of formula (I) wherein: R1 and R2 are such as defined in the description; R3 represents a hydrogen atom or a group selected among alkyl, polyhalogenoalkyl, alkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or two alkyl groups) and -C(O)-Rd, Rd representing a hydroxy, alkoxy or amino group; R4 and R5, identical or different, represent a hydrogen atom or an alkyl group; X represents an oxygen atom, a sulphur atom or a NRe group, Re representing a hydrogen atom or an alkyl group, and their enantiomers, diastereoisomers, tautomers, as well as their addition salts to a pharmaceutically acceptable acid or base. The compounds exhibit an excellent activity in the reduction of blood glucose levels. Said properties makes them useful in the treatment of type II non-insulin-dependent diabetes, obesity, glucose intolerance. The activity of said compounds is also recommended for treating and/or preventing other diseases including type I diabetes, the metabolic syndrome and insulin resistance.

Description

NOUVEAUX DERIVES DE LA PYRIDINE, NEW PYRIDINE DERIVATIVES,
LEUR PROCEDE DE PREPARATIONTHEIR PREPARATION PROCESS
ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENTAND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
L'invention concerne de nouveaux dérivés de la pyridine, leur procédé de préparation ainsi que les compositions pharmaceutiques qui les contiennent.The invention relates to new pyridine derivatives, their preparation process and the pharmaceutical compositions containing them.
Sur le plan des structures chimiques, la littérature fournit de très nombreux exemples de dérivés de la pyridine.In terms of chemical structures, the literature provides numerous examples of pyridine derivatives.
Outre la nicotine elle même, des dérivés de la pyridine sont bien connus pour leur activité sur les récepteurs nicotiniques ce qui leur confère un grand intérêt dans le traitement de pathologies liées au vieillissement cérébral comme les troubles de la mémoire ou la maladie d'Alzheimer (Biol. Psychiatry, 2001, 49, 268 et Exp. Opin. Ther. Patents, 200,In addition to nicotine itself, pyridine derivatives are well known for their activity on nicotinic receptors, which gives them great interest in the treatment of pathologies linked to cerebral aging such as memory disorders or Alzheimer's disease ( Biol, Psychiatry, 2001, 49, 268 and Exp. Opin. Ther. Patents, 200,
10(10), 1561) ou de la douleur (Current Opinion in CPNS Investigational Drugs, 2000,10 (10), 1561) or pain (Current Opinion in CPNS Investigational Drugs, 2000,
2(2), 227).2 (2), 227).
D'autres comme l'Oméprazole sont inhibiteurs de la pompe à protons gastrique et utilisés en thérapeutique comme antiulcéreux.Others like Omeprazole are inhibitors of the gastric proton pump and used in therapy as an antiulcer.
D'autres enfin comme la Rosiglitazone sont ligands des récepteurs PPARs et sont utilisés dans le traitement du diabète de type 2 et plus particulièrement de l'insulino-résistanceOthers, such as Rosiglitazone, are ligands for PPAR receptors and are used in the treatment of type 2 diabetes and more particularly insulin resistance.
(Drugs of the Future, 1998, 23(9), 977).(Drugs of the Future, 1998, 23 (9), 977).
La demanderesse a présentement découvert de nouveaux dérivés de la pyridine de structure originale leur conférant des propriétés antidiabétiques.The Applicant has now discovered new pyridine derivatives with an original structure, which gives them anti-diabetic properties.
Plus particulièrement, la présente invention concerne les composés de formule (I) :More particularly, the present invention relates to the compounds of formula (I):
Figure imgf000003_0001
dans laquelle :
Figure imgf000003_0001
in which :
• Ri et R2, identiques ou différents, représentent un atome d'hydrogène, un groupement alkyle, cycloalkyle, aryle éventuellement substitué, hétéroaryle éventuellement substitué ou Ra-C(Y)- avec Ra représentant un atome d'hydrogène, un groupement alkyle, alkoxy, aryle éventuellement substitué, ou hétéroaryle éventuellement substitué et Y représentant un atome d'oxygène, de soufre ou un groupement NR, où Rb représente un atome d'hydrogène ou un groupement alkyle, ou bien : Ri et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocycle, aromatique ou non, comportant de 5 à 8 chaînons et de 1 à 3 hétéroatomes choisis parmi l'atome d'azote, d'oxygène et de soufre, et éventuellement substitué par un ou deux substituants, identiques ou différents, choisis parmi les atomes d'halogène, et les groupements alkyle, polyhalogénoalkyle, alkoxy, hydroxy, cyano, nitro, amino (éventuellement substitué par un ou deux groupements alkyle) et -C(O)Rc avec Rc représentant un groupement choisi parmi hydroxy, alkoxy et amino,• Ri and R 2 , identical or different, represent a hydrogen atom, an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl group or R a -C (Y) - with R a representing a hydrogen atom, a optionally substituted alkyl, alkoxy, aryl or optionally substituted heteroaryl group and Y representing an oxygen or sulfur atom or an NR group, where R b represents a hydrogen atom or an alkyl group, or alternatively: R 1 and R 2 together with the nitrogen atom which carries them form a heterocycle, aromatic or not, comprising from 5 to 8 links and from 1 to 3 heteroatoms chosen from the nitrogen, oxygen and sulfur atom, and optionally substituted by one or two substituents, identical or different, chosen from halogen atoms, and alkyl, polyhaloalkyl, alkoxy, hydroxy, cyano, nitro, amino groups (optionally substituted by one or two alkyl groups) and -C (O) R c with R c representing a group chosen from hydroxy, alkoxy and amino,
• R3 représente un atome d'hydrogène ou un groupement choisi parmi alkyle, alkoxy, hydroxy, cyano, nitro, amino (éventuellement substitué par un ou deux groupements alkyle) et -C(O)-R<ι avec Rd représentant un groupement hydroxy, alkoxy ou amino,• R 3 represents a hydrogen atom or a group chosen from alkyl, alkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or two alkyl groups) and -C (O) -R < ι with Rd representing a group hydroxy, alkoxy or amino,
• R4 et R5, identiques ou différents, représentent un atome d'hydrogène ou un groupement alkyle,R 4 and R 5 , identical or different, represent a hydrogen atom or an alkyl group,
• X représente un atome d'oxygène, de soufre, ou un groupement NRe avec Re représentant un atome d'hydrogène ou un groupement alkyle,X represents an oxygen or sulfur atom or an NR e group with R e representing a hydrogen atom or an alkyl group,
à la condition que les composés de formule (I) soient différents de la 3-(4,5-dihydro-lH- imidazol-2-yl)-2-pyridinamine, de la 3-(4,5-dihydro-lH-imidazol-2-yl)-N-phényl-2- pyridinamine, de la 3-(4,5-dihydro-lH-imidazol-2-yl)-N-méthyl-2-pyridinamine, et de laprovided that the compounds of formula (I) are different from 3- (4,5-dihydro-1H-imidazol-2-yl) -2-pyridinamine, from 3- (4,5-dihydro-1H- imidazol-2-yl) -N-phenyl-2-pyridinamine, 3- (4,5-dihydro-1H-imidazol-2-yl) -N-methyl-2-pyridinamine, and
N-[3-(4,4-diméthyl-4,5-dihydro-l,3-oxazol-2-yl)-2-pyridinyl]-N-phénylamine,N- [3- (4,4-dimethyl-4,5-dihydro-l, 3-oxazol-2-yl) -2-pyridinyl] -N-phenylamine,
leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable,their enantiomers, diastereoisomers, tautomers, as well as their addition salts with an acid or a pharmaceutically acceptable base,
étant entendu que :Being heard that :
- le terme "alkyle" désigne une chaîne hydrocarbonée, linéaire ou ramifiée, contenant de 1 à 6 atomes de carbone, - le terme "alkoxy" désigne un groupement alkyle-oxy dont la chaîne alkyle, linéaire ou ramifiée, contient de 1 à 6 atomes de carbone,- the term "alkyl" denotes a hydrocarbon chain, linear or branched, containing from 1 to 6 carbon atoms, - the term "alkoxy" denotes an alkyl-oxy group in which the alkyl chain, linear or branched, contains from 1 to 6 carbon atoms,
- le terme "polyhalogénoalkyle" désigne une chaîne carbonée, linéaire ou ramifiée, contenant de 1 à 3 atomes de carbone et de 1 à 7 atomes d'halogène,the term "polyhaloalkyl" designates a carbon chain, linear or branched, containing from 1 to 3 carbon atoms and from 1 to 7 halogen atoms,
- le terme "hétéroaryle" désigne un groupement de 5 à 11 chaînons, monocyclique ou bicyclique, dans lequel au moins un des cycles est aromatique, comportant dans le monocycle ou dans le bicycle 2 ou 3 hétéroatomes, choisis parmi l'azote, l'oxygène et le soufre, etthe term "heteroaryl" denotes a group of 5 to 11 members, monocyclic or bicyclic, in which at least one of the rings is aromatic, comprising in the monocycle or in the bicycle 2 or 3 heteroatoms, chosen from nitrogen, oxygen and sulfur, and
- le terme cycloalkyle désigne un monocycle ou bicycle hydrocarboné comportant de 3 à 10 atomes de carbone, et éventuellement insaturé par lou 2 insaturations. - le terme "éventuellement substitué" associé aux expressions aryle et hétéroaryle signifie que les groupements concernés peuvent être substitués par un ou deux substituants, identiques ou différents, choisis parmi les atomes d'halogène et les groupements alkyle, alkoxy, polyhalogénoalkyle, hydroxy, cyano, nitro, amino (éventuellement substitué par un ou deux groupements alkyle) et -C(O)Re avec Re représentant un groupement choisi parmi hydroxy, alkoxy et amino, étant entendu que le groupement hétéroaryle peut être en plus substitué par un groupement oxo sur la partie non-aromatique de Phétéroaryle.- The term cycloalkyle designates a hydrocarbon monocycle or bicycle containing 3 to 10 carbon atoms, and possibly unsaturated by lou 2 unsaturations. - The term "optionally substituted" associated with the expressions aryl and heteroaryl means that the groups concerned can be substituted by one or two substituents, identical or different, chosen from halogen atoms and alkyl, alkoxy, polyhaloalkyl, hydroxy, cyano groups. , nitro, amino (optionally substituted by one or two alkyl groups) and -C (O) R e with Re representing a group chosen from hydroxy, alkoxy and amino, it being understood that the heteroaryl group may also be substituted by an oxo group on the non-aromatic part of the heteroaryl.
Parmi les acides pharmaceutiquement acceptables, on peut citer à titre non limitatif, les acides chlorhydrique, bromhydrique, sulfurique, phosphonique, acétique, trifluoroacétique, lactique, pyruvique, malonique, succinique, glutarique, fumarique, tartrique, maléïque, citrique, ascorbique, méthane sulfonique, camphorique, etc...Among the pharmaceutically acceptable acids, non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane sulfonic acids. , camphoric, etc ...
Parmi les bases pharmaceutiquement acceptables, on peut citer à titre non limitatif, l'hydroxyde de sodium, l'hydroxyde de potassium, la triéthylamine, etc...Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, etc.
Un aspect avantageux de l'invention concerne les composés pour lesquels R3 représente un atome d'hydrogène ou un groupement alkyle.An advantageous aspect of the invention relates to the compounds for which R 3 represents a hydrogen atom or an alkyl group.
Un aspect avantageux de l'invention concerne les composés pour lesquels, pris ensemble ou séparément, R représente un atome d'hydrogène ou un groupement alkyle, R et R5 représentent un atome d'hydrogène, et X représente un groupement NRe et plus particulièrement NH.An advantageous aspect of the invention relates to the compounds for which, taken together or separately, R represents a hydrogen atom or an alkyl group, R and R 5 represent a hydrogen atom, and X represents a group NR e and more particularly NH.
Le groupement alkyle préféré de l'invention pour le groupement R3 est le groupement méthyle.The preferred alkyl group of the invention for the group R 3 is the methyl group.
De façon avantageuse l'invention concerne les composés de formule (I) pour lesquels Ri et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocycle éventuellement substitué tel que l'imidazoline, la morpholine, la pipéridine ou l'azépane.Advantageously, the invention relates to the compounds of formula (I) for which Ri and R 2 form, together with the nitrogen atom which carries them, an optionally substituted heterocycle such as imidazoline, morpholine, piperidine or azepane.
Un aspect particulièrement avantageux de l'invention concerne les composés de formule (I) pour lesquels, Ri et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocycle, aromatique ou non, à 5, 6 ou 7 chaînons, comportant 1 ou 2 hétéroatomes choisis parmi l'atome d'azote et d'oxygène, R3 représente un atome d'hydrogène ou un groupement alkyle, R4 et R5 représentent un atome d'hydrogène et X représente un groupement NH.A particularly advantageous aspect of the invention relates to the compounds of formula (I) for which, Ri and R 2 form together with the nitrogen atom which carries them a heterocycle, aromatic or not, with 5, 6 or 7 members, comprising 1 or 2 heteroatoms chosen from the nitrogen and oxygen atom, R 3 represents a hydrogen atom or an alkyl group, R4 and R 5 represent a hydrogen atom and X represents an NH group.
De façon tout à fait avantageuse, le groupement R3 est un groupement alkyle situé en position 6 du noyau pyridyle.Very advantageously, the group R 3 is an alkyl group located in position 6 of the pyridyl ring.
Parmi les composés préférés de l'invention, on peut citer particulièrement la 4-[3-(4,5- dihydro-lH-imidazol-2-yl)-6-méthyl-2-pyridinyl]morpholine.Among the preferred compounds of the invention, mention may be made especially of 4- [3- (4,5-dihydro-1H-imidazol-2-yl) -6-methyl-2-pyridinyl] morpholine.
L'invention concerne également le procédé de préparation des composés de formule (I), caractérisé en ce que l'on utilise comme produit de départ un composé de formule (II) :
Figure imgf000007_0001
The invention also relates to the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material:
Figure imgf000007_0001
dans laquelle Ri, R2 et R3 sont tels que définis dans la formule (I),in which Ri, R 2 and R 3 are as defined in formula (I),
que l'on condense à la diamine (III)that we condense to diamine (III)
Figure imgf000007_0002
Figure imgf000007_0002
dans laquelle R4 et R5 sont tels que définis dans la formule (I)in which R 4 and R 5 are as defined in formula (I)
pour conduire en présence de catalyseur approprié aux composés de formule (I),to lead, in the presence of a catalyst suitable for the compounds of formula (I),
- qui peuvent être, le cas échéant, purifiés selon une technique classique de purification,- which can be, if necessary, purified according to a conventional purification technique,
- dont on sépare, le cas échéant, les stéréoisomères selon une technique classique de séparation, - que l'on transforme, si on le souhaite, en leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable, étant entendu- from which the stereoisomers are separated, where appropriate, according to a conventional separation technique, - which, if desired, is converted into their addition salts with a pharmaceutically acceptable acid or base, it being understood
- qu'à tout moment jugé opportun au cours du procédé précédemment décrit, le ou les groupements carbonyles, thiocarbonyles, amino, alkylamino des réactifs de départ (II) et (III) peuvent être protégés puis, après condensation, déprotégés pour les besoins de la synthèse,- that at any time deemed appropriate during the process described above, the carbonyl, thiocarbonyl, amino or alkylamino group (s) of the starting reagents (II) and (III) can be protected then, after condensation, deprotected for the needs of synthesis,
- que les réactifs (II), et (III) sont préparés selon des modes opératoires connus, décrits dans la littérature.- that the reagents (II), and (III) are prepared according to known procedures, described in the literature.
Les composés montrent notamment une excellente activité dans la réduction des taux de glucose sanguin. Ces propriétés justifient leur application en thérapeutique dans le traitement des diabètes non insulino dépendants de type II, de l'obésité, de l'intolérance au glucose.The compounds show in particular excellent activity in the reduction of blood glucose levels. These properties justify their therapeutic application in the treatment of type II non-insulin dependent diabetes, obesity, glucose intolerance.
L'activité de ces composés est également recommandée pour le traitement et/ou la prophylaxie d'autres maladies incluant le diabète de type I, le syndrome métabolique et la résistance à l'insuline.The activity of these compounds is also recommended for the treatment and / or prophylaxis of other diseases including type I diabetes, metabolic syndrome and insulin resistance.
La présente invention a également pour objet les compositions pharmaceutiques renfermant comme principe actif au moins un composé de formule (I) seul ou en combinaison avec un ou plusieurs excipients ou véhicules inertes non toxiques, pharmaceutiquement acceptables.The present invention also relates to pharmaceutical compositions containing as active principle at least one compound of formula (I) alone or in combination with one or more inert non-toxic, pharmaceutically acceptable excipients or vehicles.
Parmi les compositions pharmaceutiques selon l'invention, on pourra citer plus particulièrement celles qui conviennent pour l'administration orale, parentérale, nasale, les comprimés simples ou dragéifiés, les comprimés sublinguaux, les gélules, les tablettes, les suppositoires, les crèmes, pommades, gels dermiques, etc..Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments , dermal gels, etc.
La posologie utile varie selon l'âge et le poids du patient, la nature et la sévérité de l'affection ainsi que la voie d'administration. Celle-ci peut être orale, nasale, rectale ou parentérale. D'une manière générale, la posologie unitaire s'échelonne entre 0,1 et 500 mg pour un traitement en 1 à 3 prises par 24 heures.The useful dosage varies according to the age and weight of the patient, the nature and severity of the condition and the route of administration. This can be oral, nasal, rectal or parenteral. Generally, the unit dosage ranges from 0.1 to 500 mg for a treatment in 1 to 3 doses per 24 hours.
Les exemples suivants illustrent l'invention et ne la limitent en aucune façon. Les structures des composés décrits ont été confirmées par des techniques spectroscopiques et spectrométriques usuelles.The following examples illustrate the invention and do not limit it in any way. The structures of the compounds described have been confirmed by standard spectroscopic and spectrometric techniques.
Les produits de départ utilisés sont des produits connus ou préparés selon des modes opératoires connus.The starting materials used are known products or prepared according to known procedures.
Les noms des composés exemplifiés ci après sous-entendent aussi leurs tautomères, par exemple la 4-[6-méthyl-3-(4-méthyl-4,5-dihydro-lH-imidazol-2yl)-2-pyridinyl] morpholine et son tautomère la 4-[6-méthyl-3-(5-méthyl-4,5-dihydro-lH-imidazol-2yl)-2- pyridinyl]morpholine. PREPARATION 1 : 2-(2-Méthyl-lH-imidazol-l-yI)nicotinonitriIeThe names of the compounds exemplified below also imply their tautomers, for example 4- [6-methyl-3- (4-methyl-4,5-dihydro-1H-imidazol-2yl) -2-pyridinyl] morpholine and its tautomer 4- [6-methyl-3- (5-methyl-4,5-dihydro-1H-imidazol-2yl) -2-pyridinyl] morpholine. PREPARATION 1: 2- (2-Methyl-1H-imidazol-1-yI) nicotinonitria
Un mélange de 0,04 mole (3,30 g) de 2-méthylimidazole, de 0,04 mole (5,50 g) de 2- chloronicotinonitrile est chauffé à 120°C pendant 4 heures dans le DMF+ en présence de 0,04 mole (5,52 g) de carbonate de potassium. Après refroidissement, la solution est extraite avec 200 ml d'éther et la phase organique est lavée trois fois à l'eau. Après séchage sur sulfate de magnésium, l'éther est évaporé.A mixture of 0.04 mole (3.30 g) of 2-methylimidazole and 0.04 mole (5.50 g) of 2-chloronicotinonitrile is heated at 120 ° C. for 4 hours in DMF + in the presence of 0, 04 mole (5.52 g) of potassium carbonate. After cooling, the solution is extracted with 200 ml of ether and the organic phase is washed three times with water. After drying over magnesium sulfate, the ether is evaporated.
PREPARATION 2 : 2-(l-Azépanyl)nicotinonitrilePREPARATION 2: 2- (l-Azépanyl) nicotinonitrile
Le protocole expérimental est identique à celui de la préparation 1 en utilisant comme aminé de départ l'azépane.The experimental protocol is identical to that of Preparation 1, using azepane as the starting amine.
PREPARATION 3 : 6-Méthyl-2-(4-morpholinyl)nicotinonitrilePREPARATION 3: 6-Methyl-2- (4-morpholinyl) nicotinonitrile
Le protocole expérimental est identique à celui de la préparation 1 en partant de la 2- chloro-6-méthylnicotinonitrile et de la morpholine.The experimental protocol is identical to that of preparation 1, starting from 2-chloro-6-methylnicotinonitrile and morpholine.
PREPARATION 4 : 2-(l-Azépanyl)-6-méthyInicotinonitriIePREPARATION 4: 2- (l-Azépanyl) -6-méthyInicotinonitriIe
Le protocole expérimental est identique à celui de la préparation 3 en utilisant comme aminé de départ l'azépane.The experimental protocol is identical to that of preparation 3, using azepane as the starting amine.
PREPARATION 5 : 6-Méthyl-2-(4-morpholinyl)nicotinonitriIePREPARATION 5: 6-Methyl-2- (4-morpholinyl) nicotinonitria
Le protocole expérimental est identique à celui de la préparation 3 en utilisant comme aminé de départ la morpholine.The experimental protocol is identical to that of preparation 3, using morpholine as the starting amine.
PREPARATION 6 : 2-(4-MorphoIinyl)nicotinonitrile Le protocole expérimental est identique à celui de la préparation 1 en utilisant comme aminé de départ la morpholine.PREPARATION 6: 2- (4-MorphoIinyl) nicotinonitrile The experimental protocol is identical to that of Preparation 1, using morpholine as the starting amine.
PREPARATION 7 : 2-(l-Azocanyl)nicotinonitrilePREPARATION 7: 2- (l-Azocanyl) nicotinonitrile
Le protocole expérimental est identique à celui de la préparation 1 en utilisant comme aminé de départ l'azocane.The experimental protocol is identical to that of Preparation 1, using azocane as the starting amine.
EXEMPLE 1 : 3-(4,5-Dihydro-lJH-imidazol-2-yl)-2-(2-méthyl-lH-imidazol-l- yl)pyridineEXAMPLE 1 3- (4,5-Dihydro-1 J H-imidazol-2-yl) -2- (2-methyl-1H-imidazol-1-yl) pyridine
Un mélange constitué de 25 ml d'éthane diamine, de 0,02 mole (3,70 g) du composé préparé dans la préparation 1 et d'une quantité catalytique de pentasulfure de phosphore (0,5 g, 0,05 eq) est chauffé à reflux pendant 4 heures. La solution refroidie est versée dansA mixture consisting of 25 ml of ethane diamine, 0.02 mole (3.70 g) of the compound prepared in preparation 1 and a catalytic amount of phosphorus pentasulfide (0.5 g, 0.05 eq) is heated at reflux for 4 hours. The cooled solution is poured into
50 ml d'eau additionnée de glace. Après extraction par 2 fois 50 ml de dichlorométhane, séchage sur sulfate de magnésium et évaporation du solvant, le produit est recristallisé dans un minimum d'acétonitrile. Point de fusion : 135°C.50 ml of water with ice added. After extraction with 2 times 50 ml of dichloromethane, drying over magnesium sulphate and evaporation of the solvent, the product is recrystallized from a minimum of acetonitrile. Melting point: 135 ° C.
EXEMPLE 2 : l-[3-(4,5-Dihydro-l r-imidazol-2-yl)-2-pyridinyI]azépaneEXAMPLE 2: l- [3- (4,5-Dihydro-l r-imidazol-2-yl) -2-pyridinyI] azepane
Le protocole expérimental est identique à celui de l'exemple 1, en partant du composé préparé dans la préparation 2. Point de fusion ; H4°C.The experimental protocol is identical to that of Example 1, starting from the compound prepared in Preparation 2. Melting point; H4 ° C.
EXEMPLE 3 : 4-[6-Méthyl-3-(4- éthyl-4,5-dihydro-l^-imidazol-2-yI)-2- pyridinyl] morpholineEXAMPLE 3 4- [6-Methyl-3- (4-ethyl-4,5-dihydro-1 ^ -imidazol-2-yI) -2-pyridinyl] morpholine
Le protocole expérimental est identique à celui de l'exemple 1, en partant de la 1,2- propanediamine et du composé de la préparation 3. Point de fusion : 147°C EXEMPLE 4 : l-[3-(4,5-Dihydro-li/-imidazol-2-yl)-6-méthyl-2- pyridinyl] azépaneThe experimental protocol is identical to that of Example 1, starting with 1,2-propanediamine and the compound of Preparation 3. Melting point: 147 ° C. EXAMPLE 4: 1- [3- (4,5-Dihydro-li / -imidazol-2-yl) -6-methyl-2-pyridinyl] azepane
Le protocole expérimental est identique à celui de l'exemple 1, en partant de la 1,2- propanediamine et du composé de la préparation 4. Point [ de fusion : 134°C.The experimental protocol is identical to that of Example 1, starting with 1,2-propanediamine and the compound of Preparation 4. Melting point: 134 ° C.
EXEMPLE 5 : 4-[3-(4,5-Dihydro-li7-iιιιidazol-2-yl)-6-méthyl-2- pyridinyl] morpholineEXAMPLE 5 4- [3- (4,5-Dihydro-li7-iιιιidazol-2-yl) -6-methyl-2-pyridinyl] morpholine
Le protocole expérimental est identique à celui de l'exemple 1, en partant de la 1,2- propanediamine et du composé de la préparation 5. Poini defusion : 147°C.The experimental protocol is identical to that of Example 1, starting with 1,2-propanediamine and the compound of Preparation 5. Poini defusion: 147 ° C.
EXEMPLE 6 : 4-[3-(4,5-Dihydro-l/-r-imidazol-2-yl)-2-pyridinyl]morpholineEXAMPLE 6 4- [3- (4,5-Dihydro-1 / - r -imidazol-2-yl) -2-pyridinyl] morpholine
Le protocole expérimental est identique à celui de l'exemple 1, en partant de la 1,2- propanediamine et du composé de la préparation 6. Point. de fusion : 133°CThe experimental protocol is identical to that of Example 1, starting with 1,2-propanediamine and the compound of preparation 6. Point . melting point: 133 ° C
EXEMPLE 7 : l-[3-(4,5-Dihydro-l /-imidazol-2-yl)-2-pyridinyl]azocaneEXAMPLE 7: 1- [3- (4,5-Dihydro-1 / -imidazol-2-yl) -2-pyridinyl] azocane
Le protocole expérimental est identique à celui de l'exemple 1, en partant de la 1,2- propanediamine et du composé de la préparation 7. Point de fusion : 226°C.The experimental protocol is identical to that of Example 1, starting with 1,2-propanediamine and the compound of Preparation 7. Melting point: 226 ° C.
ETUDE PHARMACOLOGIOUEPHARMACOLOGICAL STUDY
EXEMPLE A : Activité hypoglycémiante L'activité hypoglycemiante des dérivés de l'invention a été recherchée sur des rats mâles Witsar d'environ 250 g âgés de trois mois. Un diabète expérimental est obtenu par injection iv d'une faible dose de streptozotocine (35 mg/kg iv) dissoute dans un tampon citrate sous anesthésie au chlorhydrate de Kétamine. Ces rats sont appelés "STZ", ils sont caractérisés par une légère hyperglycémie basale, une nette intolérance ou glucose et une franche altération de la sécrétion d'insuline.EXAMPLE A: Hypoglycemic activity The hypoglycemic activity of the derivatives of the invention was sought in male Witsar rats of approximately 250 g aged three months. Experimental diabetes is obtained by iv injection of a low dose of streptozotocin (35 mg / kg iv) dissolved in a citrate buffer under anesthesia with Ketamine hydrochloride. These rats are called "STZ", they are characterized by a slight basal hyperglycemia, a clear intolerance or glucose and a frank alteration of the insulin secretion.
L'homeostasie a été évaluée par un test de tolérance au glucose, réalisée deux semaines après injection de streptozotocine. Enfin l'activité hypoglycémiant a été évalué sur des rats "Zucker". Les rats "Zucker fatty" fa/fa sont apparus à la suite d'une mutation spontanée dans la souche 13 M (Zucker &Homeostasis was assessed by a glucose tolerance test, performed two weeks after injection of streptozotocin. Finally the hypoglycemic activity was evaluated on "Zucker" rats. The "Zucker fatty" fa / fa rats appeared following a spontaneous mutation in the 13 M strain (Zucker &
Zucker, 1961), et sont génétiquement insulinorésistants et obèses.Zucker, 1961), and are genetically insulin resistant and obese.
Leur obésité est observable dès l'âge de quatre semaines, elle s'accompagne donc d'insulinorésistance, et d'une hyperinsulinémie. Ce modèle est prédictifs des états diabétiques présentant des désordres métaboliques associés tel que l'obésité. L'homeostasie a été évaluée également par un test de tolérance au glucose.Their obesity is observable from the age of four weeks, so it is accompanied by insulin resistance, and hyperinsulinemia. This model is predictive of diabetic conditions with associated metabolic disorders such as obesity. Homeostasis was also assessed by a glucose tolerance test.
. Test de tolérance au glucose par voie orale (OGTT). Oral glucose tolerance test (OGTT)
Le glucose est administré per os (2g.kg_1) à des rats vigiles. Les échantillons de sang sont collectés avant et 10, 20, 30, 40, 60, 90 et 120 minutes après l'administration du glucose. Le traitement des échantillons sanguins est identique à celui décrit précédemment.Glucose is administered orally (2g.kg _1 ) to alert rats. Blood samples are collected before and 10, 20, 30, 40, 60, 90 and 120 minutes after the administration of glucose. The processing of blood samples is identical to that described above.
Le produit à tester est administré per os 1 heure avant l'OGTT.The product to be tested is administered per os 1 hour before the OGTT.
Les composés de l'invention diminuent très significativement la glycémie.The compounds of the invention very significantly lower blood sugar.
Par exemple, le composé de l'Exemple 5 diminue très significativement la glycémie des rats Wistar non diabétique, des rats Wistar STZ et des rats Zucker (voir tableau 1).For example, the compound of Example 5 very significantly decreases the glycemia of non-diabetic Wistar rats, Wistar STZ rats and Zucker rats (see Table 1).
Tableau 1 : OGTT valeurs de glycémie 1 heures après la charge en glucose et après administration per os du composé de l'Exemple 5 à 10 et 30mg/kg.
Figure imgf000013_0001
Table 1: OGTT blood glucose values 1 hour after the glucose load and after oral administration of the compound of Example 5 at 10 and 30 mg / kg.
Figure imgf000013_0001
EXEMPLE B : Etude de toxicité aiguë - Test dTr inEXAMPLE B: Acute toxicity study - dTr in test
Trois rats par dose sont traités per os avec un des composés de l'invention (dispersé dans 0,5 % de carboxyméthylcellulose dans l'eau distillée) et sont observés à des intervalles de temps réguliers après 24 heures. La présence ou l'absence des symptômes sont enregistrés : mortalité, sédation, excitation, agressivité, forme de la queue, convulsions, douleurs, tremblements, exophtalmie, salivation, piloérection, défécation, peur, etc, suivant les critères décrits par Irwin (Psychopharmacologia, 1968, 13, 222). Ce test permet une évaluation de la toxicité et de l'effet sur le comportement.Three rats per dose are treated per os with one of the compounds of the invention (dispersed in 0.5% of carboxymethylcellulose in distilled water) and are observed at regular time intervals after 24 hours. The presence or absence of symptoms are recorded: mortality, sedation, excitement, aggressiveness, tail shape, convulsions, pain, tremors, exophthalmos, salivation, piloerection, defecation, fear, etc., according to the criteria described by Irwin (Psychopharmacologia , 1968, 13, 222). This test allows an evaluation of the toxicity and the effect on behavior.
Les composés de l'invention s'avèrent être non toxiques, avec dans le cas de l'exemple 5 une absence de toxicité à la dose de 1024 mg/kg (dose maximale testée).The compounds of the invention appear to be non-toxic, with in the case of Example 5 an absence of toxicity at the dose of 1024 mg / kg (maximum dose tested).
EXEMPLE C : Composition pharmaceutiqueEXAMPLE C Pharmaceutical composition
Formule de préparation pour 1000 comprimés dosés à 10 mg :Preparation formula for 1000 tablets dosed at 10 mg:
Composé de l'exemple 5 10 gCompound of example 5 10 g
Hydroxypropylcellulose 2 g Amidon de blé 10 gHydroxypropylcellulose 2 g Wheat starch 10 g
Lactose 100 gLactose 100 g
Stéarate de magnésium 3 gMagnesium stearate 3 g
Talc 3 g Talc 3 g

Claims

REVENDICATIONS
1. Composés de formule (I)1. Compounds of formula (I)
Figure imgf000014_0001
Figure imgf000014_0001
dans laquelle : • Ri et R2, identiques ou différents, représentent un atome d'hydrogène, un groupement alkyle, cycloalkyle, aryle éventuellement substitué, hétéroaryle éventuellement substitué ou Ra-C(Y)- avec Ra représentant un atome d'hydrogène, un groupement alkyle, alkoxy, aryle éventuellement substitué, ou hétéroaryle éventuellement substitué et Y représentant un atome d'oxygène, de soufre ou un groupement NRb où R représente un atome d'hydrogène ou un groupement alkyle, ou bien :in which: • Ri and R 2 , identical or different, represent a hydrogen atom, an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl group or R a -C (Y) - with R a representing an atom of hydrogen, an optionally substituted alkyl, alkoxy, aryl, or optionally substituted heteroaryl group and Y representing an oxygen or sulfur atom or a group NR b where R represents a hydrogen atom or an alkyl group, or alternatively:
Ri et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocycle, aromatique ou non, comportant de 5 à 8 chaînons et de 1 à 3 hétéroatomes choisis parmi l'atome d'azote, d'oxygène et de soufre, et éventuellement substitué par un ou deux substituants, identiques ou différents, choisis parmi les atomes d'halogène et les groupements alkyle, polyhalogénoalkyle, alkoxy, hydroxy, cyano, nitro, amino (éventuellement substitué par un ou deux groupements alkyle) et -C(O)Rc avec Rc représentant un groupement choisi parmi hydroxy, alkoxy et amino,Ri and R 2 form together with the nitrogen atom which carries them a heterocycle, aromatic or not, comprising from 5 to 8 links and from 1 to 3 heteroatoms chosen from the atom of nitrogen, oxygen and sulfur , and optionally substituted by one or two substituents, identical or different, chosen from halogen atoms and alkyl, polyhaloalkyl, alkoxy, hydroxy, cyano, nitro, amino groups (optionally substituted by one or two alkyl groups) and -C (O) R c with R c representing a group chosen from hydroxy, alkoxy and amino,
R3 représente un atome d'hydrogène ou un groupement choisi parmi alkyle, alkoxy, hydroxy, cyano, nitro, amino (éventuellement substitué par un ou deux groupements alkyle) et -C(O)-Rd avec Rd représentant un groupement hydroxy, alkoxy ou amino, • R4 et R5, identiques ou différents, représentent un atome d'hydrogène ou un groupement alkyle,R 3 represents a hydrogen atom or a group chosen from alkyl, alkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or two alkyl groups) and -C (O) -Rd with R d representing a hydroxy group, alkoxy or amino, R 4 and R 5 , identical or different, represent a hydrogen atom or an alkyl group,
• X représente un atome d'oxygène, de soufre, ou un groupement NRe avec Re représentant un atome d'hydrogène ou un groupement alkyle,X represents an oxygen or sulfur atom or an NR e group with R e representing a hydrogen atom or an alkyl group,
à la condition que les composés de formule (I) soient différents de la 3-(4,5-dihydro-lH- imidazol-2-yl)-2-pyridinamine, de la 3-(4,5-dihydro-lH-imidazol-2-yl)-N-phényl-2- pyridinamine, de la 3-(4,5-dihydro-lH-imidazol-2-yl)-N-méthyl-2-pyridinamine, et de la N-[3-(4,4-diméthyl-4,5-dihydro-l,3-oxazol-2-yl)-2-pyridinyl]-N-phénylamine,provided that the compounds of formula (I) are different from 3- (4,5-dihydro-1H-imidazol-2-yl) -2-pyridinamine, from 3- (4,5-dihydro-1H- imidazol-2-yl) -N-phenyl-2-pyridinamine, 3- (4,5-dihydro-1H-imidazol-2-yl) -N-methyl-2-pyridinamine, and N- [3 - (4,4-dimethyl-4,5-dihydro-l, 3-oxazol-2-yl) -2-pyridinyl] -N-phenylamine,
leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable,their enantiomers, diastereoisomers, tautomers, as well as their addition salts with a pharmaceutically acceptable acid or base,
étant entendu que :Being heard that :
- le terme "alkyle" désigne une chaîne hydrocarbonée, linéaire ou ramifiée, contenant de 1 à 6 atomes de carbone,the term "alkyl" designates a hydrocarbon chain, linear or branched, containing from 1 to 6 carbon atoms,
- le terme "alkoxy" désigne un groupement alkyle-oxy dont la chaîne alkyle, linéaire ou ramifiée, contient de 1 à 6 atomes de carbone,the term "alkoxy" denotes an alkyl-oxy group in which the linear or branched alkyl chain contains from 1 to 6 carbon atoms,
- le terme "polyhalogénoalkyle" désigne une chaîne carbonée, linéaire ou ramifiée, contenant de 1 à 3 atomes de carbone et de 1 à 7 atomes d'halogène,the term "polyhaloalkyl" designates a carbon chain, linear or branched, containing from 1 to 3 carbon atoms and from 1 to 7 halogen atoms,
- le terme "hétéroaryle" désigne un groupement de 5 à 11 chaînons, monocyclique ou bicyclique, dans lequel au moins un des cycles est aromatique, comportant dans le monocycle ou dans le bicycle 2 ou 3 hétéroatomes, choisis parmi l'azote, l'oxygène et le soufre, etthe term "heteroaryl" denotes a group of 5 to 11 members, monocyclic or bicyclic, in which at least one of the rings is aromatic, comprising in the monocycle or in the bicycle 2 or 3 heteroatoms, chosen from nitrogen, oxygen and sulfur, and
- le terme cycloalkyle désigne un monocycle ou bicycle hydrocarboné comportant de 3 à 10 atomes de carbone, et éventuellement insaturé par lou 2 insaturations.- The term cycloalkyle designates a hydrocarbon monocycle or bicycle containing 3 to 10 carbon atoms, and possibly unsaturated by lou 2 unsaturations.
- le terme "éventuellement substitué" associé aux expressions aryle et hétéroaryle signifie que les groupements concernés peuvent être substitués par un ou deux substituants, identiques ou différents, choisis parmi les atomes d'halogène et les groupements alkyle, alkoxy, polyhalogénoalkyle, hydroxy, cyano, nitro, amino (éventuellement substitué par un ou deux groupements alkyle) et -C(O)Re avec Re représentant un groupement choisi parmi hydroxy, alkoxy et amino, étant entendu que le groupement hétéroaryle peut être en plus substitué par un groupement oxo sur la partie non-aromatique de l 'hétéroaryle.- The term "optionally substituted" associated with the expressions aryl and heteroaryl means that the groups concerned can be substituted by one or two substituents, identical or different, chosen from halogen atoms and alkyl, alkoxy, polyhaloalkyl, hydroxy, cyano groups. , nitro, amino (optionally substituted by one or two alkyl groups) and -C (O) R e with R e representing a selected group among hydroxy, alkoxy and amino, it being understood that the heteroaryl group may be additionally substituted by an oxo group on the non-aromatic part of the heteroaryl.
2. Composés de formule (I) selon la revendication 1 pour lesquels R3 représente un atome d'hydrogène ou un groupement alkyle, leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou une base pharmaceutiquement acceptable.2. Compounds of formula (I) according to claim 1 for which R 3 represents a hydrogen atom or an alkyl group, their enantiomers, diastereoisomers, tautomers, as well as their addition salts with a pharmaceutically acceptable acid or base.
3. Composés de formule (I) selon une quelconque des revendications 1 ou 2 pour lesquels R4 représente un atome d'hydrogène, leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou une base pharmaceutiquement acceptable.3. Compounds of formula (I) according to any one of claims 1 or 2 for which R 4 represents a hydrogen atom, their enantiomers, diastereoisomers, tautomers, as well as their addition salts with a pharmaceutically acceptable acid or base.
4. Composés de formule (I) selon une quelconque des revendications 1 à 3 pour lesquels R représente un atome d'hydrogène, leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou une base pharmaceutiquement acceptable.4. Compounds of formula (I) according to any one of claims 1 to 3 for which R represents a hydrogen atom, their enantiomers, diastereoisomers, tautomers, as well as their addition salts with a pharmaceutically acceptable acid or base.
5. Composés de formule (I) selon une quelconque des revendications 1 à 4 pour lesquels5. Compounds of formula (I) according to any one of claims 1 to 4 for which
X représente un groupement NRe, leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou une base pharmaceutiquement acceptable.X represents a group NR e , their enantiomers, diastereoisomers, tautomers, as well as their addition salts with a pharmaceutically acceptable acid or base.
6. Composés de formule (I) selon une quelconque des revendications 1 à 5 pour lesquels Ri et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocyle, aromatique ou non, comportant de 5 à 8 chaînons et de 1 à 3 hétéroatomes choisis parmi l'atome d'azote, d'oxygène et de soufre, et éventuellement substitué par un groupement alkyle, leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou une base pharmaceutiquement acceptable.6. Compounds of formula (I) according to any one of claims 1 to 5 for which Ri and R 2 form, together with the nitrogen atom which carries them, a heterocyle, aromatic or not, comprising from 5 to 8 members and from 1 with 3 heteroatoms chosen from the nitrogen, oxygen and sulfur atom, and optionally substituted by an alkyl group, their enantiomers, diastereoisomers, tautomers, as well as their addition salts with a pharmaceutically acceptable acid or base.
7. Composés de formule (I) selon une quelconque des revendications 1 à 6 pour lesquels Ri et R2 forment ensemble avec l'atome d'azote qui les porte un hétérocyle, aromatique ou non, comportant de 5 à 7 chaînons, et 1 ou 2 hétéroatomes choisis parmi l'atome d'azote et d'oxygène, R3 représente un atome d'hydrogène ou un groupement alkyle, R4 et R5 représentent un atome d'hydrogène et X représente un groupement NH, leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou une base pharmaceutiquement acceptable.7. Compounds of formula (I) according to any one of claims 1 to 6 for which Ri and R 2 form together with the nitrogen atom which carries them a heterocyle, aromatic or not, comprising from 5 to 7 members, and 1 or 2 heteroatoms chosen from the atom of nitrogen and oxygen, R 3 represents a hydrogen atom or an alkyl group, R 4 and R 5 represent a hydrogen atom and X represents an NH group, their enantiomers, diastereoisomers, tautomers, as well as their salts of addition to a pharmaceutically acceptable acid or base.
8. Composés de formule (I) selon la revendication 7 pour laquelle R3 représente un groupement alkyle en position 6, leurs énantiomères, diastéréoisomères, tautomères, ainsi que leurs sels d'addition à un acide ou une base pharmaceutiquement acceptable.8. Compounds of formula (I) according to claim 7 for which R 3 represents an alkyl group in position 6, their enantiomers, diastereoisomers, tautomers, as well as their addition salts with a pharmaceutically acceptable acid or base.
9. Composé de formule (I) selon une quelconque des revendications 1 à 8 qui est la 4-[3- (4,5-dihydro-lH-imidazol-2-yl)-6-méthyl-2-pyridinyl]morpholine, ainsi que ses sels d'addition à un acide pharmaceutiquement acceptable.9. Compound of formula (I) according to any one of claims 1 to 8 which is 4- [3- (4,5-dihydro-1H-imidazol-2-yl) -6-methyl-2-pyridinyl] morpholine, as well as its addition salts with a pharmaceutically acceptable acid.
10. Procédé de préparation des composés de formule (I) selon la revendication 1, caractérisé en ce que l'on utilise comme produit de départ un composé de formule (II) :10. Process for preparing the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) is used as starting material:
Figure imgf000017_0001
Figure imgf000017_0001
dans laquelle Ri, R2 et R3 sont tels que définis dans la formule (I),in which Ri, R 2 and R 3 are as defined in formula (I),
que l'on condense à la diamine (III)that we condense to diamine (III)
Figure imgf000017_0002
Figure imgf000017_0002
dans laquelle R4 et R5 sont tels que définis dans la formule (I) pour conduire en présence de catalyseur approprié aux composés de formule (I),in which R 4 and R 5 are as defined in formula (I) to lead, in the presence of a catalyst suitable for the compounds of formula (I),
- qui peuvent être, le cas échéant, purifiés selon une technique classique de purification,- which can be, if necessary, purified according to a conventional purification technique,
- dont on sépare, le cas échéant, les stéréoisomères selon une technique classique de séparation, - que l'on transforme, si on le souhaite, en leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable, étant entendu- from which the stereoisomers are separated, where appropriate, according to a conventional separation technique, - which, if desired, is converted into their addition salts with a pharmaceutically acceptable acid or base, it being understood
- qu'à tout moment jugé opportun au cours du procédé précédemment décrit, le ou les groupements carbonyles, thiocarbonyles, amino, alkylamino des réactifs de départ (II) et (III) peuvent être protégés puis, après condensation, déprotégés pour les besoins de la synthèse,- that at any time deemed appropriate during the process described above, the carbonyl, thiocarbonyl, amino or alkylamino group (s) of the starting reagents (II) and (III) can be protected then, after condensation, deprotected for the needs of synthesis,
- que les réactifs (II), et (III) sont préparés selon des modes opératoires connus, décrits dans la littérature.- that the reagents (II), and (III) are prepared according to known procedures, described in the literature.
11. Composition pharmaceutique contenant comme principe actif au moins un composé selon une quelconque des revendications 1 à 9, seul ou en combinaison avec un ou plusieurs excipients ou véhicules inertes, non toxiques, pharmaceutiquement acceptables.11. Pharmaceutical composition containing as active principle at least one compound according to any one of claims 1 to 9, alone or in combination with one or more excipients or inert, non-toxic, pharmaceutically acceptable vehicles.
12. Composition pharmaceutique selon la revendication 11 contenant au moins un principe actif selon l'une quelconque des revendications 1 à 9 utiles pour la fabrication de médicaments traitant le diabète et l'obésité.12. Pharmaceutical composition according to claim 11 containing at least one active principle according to any one of claims 1 to 9 useful for the manufacture of medicaments treating diabetes and obesity.
13. Composition pharmaceutique selon la revendication 11 contenant au moins un principe actif selon l'une quelconque des revendications 1 à 9 utiles pour la fabrication de médicaments traitant le diabète. 13. Pharmaceutical composition according to claim 11 containing at least one active principle according to any one of claims 1 to 9 useful for the manufacture of medicaments treating diabetes.
PCT/FR2003/003275 2002-11-05 2003-11-04 Novel pyridine derivatives, preparation method and pharmaceutical compositions containing same WO2004043947A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4052510A (en) * 1974-12-18 1977-10-04 Sandoz, Inc. 4-alkyl-2,6-di(secondary or tertiary alkylamino) pyridines, compositions thereof and methods for treating diabetes and obesity
WO2001044201A1 (en) * 1999-12-16 2001-06-21 Schering Corporation Substituted imidazole neuropeptide y y5 receptor antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4052510A (en) * 1974-12-18 1977-10-04 Sandoz, Inc. 4-alkyl-2,6-di(secondary or tertiary alkylamino) pyridines, compositions thereof and methods for treating diabetes and obesity
WO2001044201A1 (en) * 1999-12-16 2001-06-21 Schering Corporation Substituted imidazole neuropeptide y y5 receptor antagonists

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