FR2612928A1 - Hydroxylated imidazopyridine derivatives, their preparation and their application in therapeutics - Google Patents
Hydroxylated imidazopyridine derivatives, their preparation and their application in therapeutics Download PDFInfo
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- FR2612928A1 FR2612928A1 FR8704277A FR8704277A FR2612928A1 FR 2612928 A1 FR2612928 A1 FR 2612928A1 FR 8704277 A FR8704277 A FR 8704277A FR 8704277 A FR8704277 A FR 8704277A FR 2612928 A1 FR2612928 A1 FR 2612928A1
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- Prior art keywords
- chloro
- preparation
- hydroxylated
- therapeutics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Description
La présente invention a pour objet des dérivés hydroxylés d'imidazopyridines, leur préparation et leur application en thérapeutique.The present invention relates to hydroxylated derivatives of imidazopyridines, their preparation and their therapeutic application.
Les composés de l'invention répondent à la formule (I)
dans laquelle le radical OH se trouve
. soit sur le noyau phényle
. soit sur le noyau imidazo[l,2-apyridinyle. The compounds of the invention correspond to formula (I)
in which the OH radical is found
. either on the phenyl nucleus
. either on the imidazo [1,2-apyridinyl ring.
Le procédé de préparation du composé de l'invention pour lequel le radical OH est sur le noyau imidazopyridinyle est décrit ci-après et dans le schéma de l'annexe 1.The process for the preparation of the compound of the invention for which the OH radical is on the imidazopyridinyl ring is described below and in the diagram in Annex 1.
Exemple. Chloro-6 (chloro-4 phényl)-2 hydroxy-8 N,N-dipropylimidazo[1,2-a]pyridine-3-acétamide.Example. Chloro-6 (4-chloro-phenyl) -2 hydroxy-8 N, N-dipropylimidazo [1,2-a] pyridine-3-acetamide.
1. Chloro-6 (chloro-4 phényl)-2 méthoxy-8 imidazo[l,2a] pyridine.1. Chloro-6 (4-chloro-phenyl) -2 methoxy-8 imidazo [1,2a] pyridine.
On ajoute 10 g (29,4 mmoles) de bromo-8 chloro-6 (chloro-4 phényl)-2 imidazoC1,2-alpyridine, composé dont la préparation est décrite dans la demande de brevet déposée ce jour dérivés d'imidazopyridines, leur préparation et leur application en thérapeutique par la Demanderesse, en solution dans 60 ml d'hexaméthylphosphorotriamide à une solution de late de sodium préparé au moyen de 2,03 g de sodium et de 15 ml de méthanol, on porte le mélange réactionnel à 600C pendant 2 h 30, on ajoute de l'eau, extrait avec du CH2C12, lave la phase organique à l'eau, sèche sur MgSO4, filtre et concentre le filtrat sous pression réduite. On fait recristalliser le résidu d'évaporation dans un mélange acétate d'éthyle/hexane. 10 g (29.4 mmol) of 8-bromo-chloro-6 (4-chloro-phenyl) -2 imidazoC1,2-alpyridine, compound, the preparation of which is described in the patent application filed to date, derived from imidazopyridines, are added. their preparation and their therapeutic application by the Applicant, in solution in 60 ml of hexamethylphosphorotriamide in a sodium late solution prepared using 2.03 g of sodium and 15 ml of methanol, the reaction mixture is brought to 600C for 2 h 30, water is added, extracted with CH2Cl2, the organic phase is washed with water, dried over MgSO4, filtered and the filtrate is concentrated under reduced pressure. The evaporation residue is recrystallized from an ethyl acetate / hexane mixture.
F = 150-1510C.F = 150-1510C.
2. Chloro-6 (chloro-4 phényl)-2 a-hydroxy méthoxy-8 N,N dipropyl-imidazo[1,2-a]pyridine-3-acétamide. 2. Chloro-6 (4-chloro phenyl) -2 a-hydroxy methoxy-8 N, N dipropyl-imidazo [1,2-a] pyridine-3-acetamide.
On prépare une solution de 9,46 g de diéthoxy-l,l N,N-dipropyl acétamide dans 135 ml d'acide acétique glacial et 0,46 ml d'acide chlorhydrique à 37 %.A solution of 9.46 g of diethoxy-1.1 N, N-N-dipropyl acetamide in 135 ml of glacial acetic acid and 0.46 ml of 37% hydrochloric acid is prepared.
On chauffe le mélange réactionnel à 60"C pendant 2 h.The reaction mixture is heated at 60 ° C for 2 h.
On ajoute 1,3 g d'acétate de sodium puis, après 10 mn, 4 g (13,6 mmoles) du composé obtenu sous 1.1.3 g of sodium acetate are added and then, after 10 min, 4 g (13.6 mmol) of the compound obtained under 1.
On chauffe le mélange réactionnel à 600C pendant 3 h puis on le refroidit et on évapore à sec.The reaction mixture is heated to 600C for 3 h, then cooled and evaporated to dryness.
On reprend le résidu avec du CH2Cl2, lave la phase organique à l'eau, sèche sur MgSO4, filtre et concentre le filtrat sous pression réduite. On purifie le produit obtenu par chromatographie avec l'éluant hexane/acétate d'éthyle 3/1. Le composé obtenu est utilisé tel quel pour l'étape suivante.The residue is taken up with CH2Cl2, the organic phase is washed with water, dried over MgSO4, filtered and the filtrate is concentrated under reduced pressure. The product obtained is purified by chromatography with the eluent hexane / ethyl acetate 3/1. The compound obtained is used as it is for the next step.
3. Chloro-6 (chloro-4 phényl)-2 méthoxy-8 N,N-dipropyl-imida zo[l ,2-a]pyridine-3-acétamide. 3. Chloro-6 (4-chloro phenyl) -2 methoxy-8 N, N-dipropyl-imida zo [1,2-a] pyridine-3-acetamide.
On mélange 2,75 g (6,12 mmoles) du composé obtenu précédemment, 50 ml de CH2C12 et 1,34 ml de SOC12. On porte le mélange réactionnel à 600C pendant 2 h, on évapore à sec puis sèche sous vide. On ajoute 30 ml de CH2Cl2 pur puis 2,82 g de
Rongalite. On laisse le mélange réactionnel à 200C pendant une nuit.2.75 g (6.12 mmol) of the compound obtained above, 50 ml of CH2Cl2 and 1.34 ml of SOC12 are mixed. The reaction mixture is brought to 600C for 2 h, evaporated to dryness and then dried under vacuum. 30 ml of pure CH2Cl2 are added and then 2.82 g of
Rongalite. The reaction mixture is left at 200C overnight.
On ajoute de l'eau au mélange, décante la phase organique, la lave à l'eau puis avec une solution de chlorure de sodium, sèche MgSO4, filtre et concentre le filtrat sous pression réduite. Water is added to the mixture, the organic phase is decanted, washed with water and then with a sodium chloride solution, dried MgSO4, filtered and the filtrate is concentrated under reduced pressure.
On purifie le résidu par chromatograhie (éluant : hexane 2/acétate d'éthyle 1).The residue is purified by chromatography (eluent: hexane 2 / ethyl acetate 1).
F = 162-1630C.F = 162-1630C.
4. Chloro-6 (chloro-4 phényl)-2 hydroxy-8 N,N-dipropyl-imidazo[1,2-a]pyridine-3-acétamide.4. Chloro-6 (chloro-4 phenyl) -2 hydroxy-8 N, N-dipropyl-imidazo [1,2-a] pyridine-3-acetamide.
A 0,15 mg (0,36 mmole) du produit obtenu sous 3 en solution dans 15 ml de dichlorométhane, on ajoute 0,2 ml (0,53 g, 2,11 mmoles) de BBr3 à -600C. On laisse le mélange revenir à la température ambiante, sous agitation, durant deux heures.To 0.15 mg (0.36 mmol) of the product obtained in 3 dissolved in 15 ml of dichloromethane, 0.2 ml (0.53 g, 2.11 mmol) of BBr3 at -600C is added. The mixture is allowed to return to room temperature, with stirring, for two hours.
L'excès de BBr3 est alors détruit par du méthanol à -780C. On évapore le mélange réactionnel, purifie le résidu obtenu par chromatographie (éluant : dichlorométhane/méthanol 95/5). On obtient un produit que l'on fait cristalliser sous forme de base dans de l'acétate d'éthyle.The excess of BBr3 is then destroyed by methanol at -780C. The reaction mixture is evaporated, the residue obtained is purified by chromatography (eluent: dichloromethane / methanol 95/5). A product is obtained which is crystallized in the form of the base from ethyl acetate.
F = 190-191 C. F = 190-191 C.
Les composés de l'invention ont été soumis à des essais pharmacologiques qui ont montré leurs intéressantes propriétés pharmacologiques dans divers domaines.The compounds of the invention have been subjected to pharmacological tests which have shown their advantageous pharmacological properties in various fields.
La toxicité des composés a été déterminée chez les souris par voie intrapéritonéale.The toxicity of the compounds was determined in mice intraperitoneally.
La DL 50 va de 500 à 1000 mg/kg.The LD 50 ranges from 500 to 1000 mg / kg.
L'activité sédative ou hypnotique a été déterminée en observant l'action des composés sur l'ECoG du rat curarisé (Depoortere H., Rev. E.E.G. Neurophysiol., (1980) 10, 3, 207214). Chez le rat curarisé, les produits à étudier sont injectés par voie intrapéritonéale ou orale aux doses croissantes de 1 à 30 mg/kg. Ils induisent des tracés de sommeil aux doses égales ou supérieures à 0,3 mg/kg i.p.The sedative or hypnotic activity was determined by observing the action of the compounds on the ECoG of the curarized rat (Depoortere H., Rev. E.E.G. Neurophysiol., (1980) 10, 3, 207214). In the curarized rat, the products to be studied are injected intraperitoneally or orally at increasing doses from 1 to 30 mg / kg. They induce sleep patterns at doses equal to or greater than 0.3 mg / kg i.p.
L'activité anticonvulsivante des composés a été déterminée selon le test de l'inhibition des convulsions cloniques induites par le pentétrazol chez la souris selon la méthode de Worms et coll (J. Pharmacol. Exp. Ther., 220 : 660-671). The anticonvulsant activity of the compounds was determined according to the test for the inhibition of clonic convulsions induced by pentetrazol in mice according to the method of Worms et al (J. Pharmacol. Exp. Ther., 220: 660-671).
Chez des souris mâles (20-22 g) CD1 Charles River, les convulsions cloniques sont induites par injection i.v. de 35 mg/kg de pentetrazol, 30 mn après l'injection i.p. du produit a tester.In male mice (20-22 g) CD1 Charles River, clonic convulsions are induced by i.v. injection of 35 mg / kg of pentetrazol, 30 min after the i.p. of the product to be tested.
La D 50 est la dose qui protège 50 % des animaux des convulsions cloniques provoquées par le pentétrazol. La DA 50 des composés de l'invention va de 0,1 à 10 mg/kg.D 50 is the dose that protects 50% of animals from clonic convulsions caused by pentetrazol. The AD 50 of the compounds of the invention ranges from 0.1 to 10 mg / kg.
Effets sur la durée du "sommeil" induit par le hydroxy-4 butyrate de sodium.Effects on the duration of "sleep" induced by sodium hydroxy-4-butyrate.
Cette action a été déterminée par l'influence d'un composé sur la durée du "sommeil" induit par le hydroxy-4 butyrate de sodium (GBH) chez le rat curarisé.This action was determined by the influence of a compound on the duration of "sleep" induced by sodium hydroxy-4 butyrate (GBH) in the curarized rat.
Les animaux utilisés sont des rats mâles de souche Charles
River de 200 + 20 g. Les animaux, curarisés parl'alloférine à raison de lmg/kg par voiei.p., sont placés sous respiration artificielle à l'aide d'un masque appliqué sur le museau (fréquence respiratoire = 50/minute ; volume respiratoire = 14 ml).The animals used are male rats of the Charles strain.
River of 200 + 20 g. The animals, curarized by alloferin at a rate of 1 mg / kg by the oral route, are placed under artificial respiration using a mask applied to the muzzle (respiratory rate = 50 / minute; respiratory volume = 14 ml) .
L'oesophage est préalablement ligaturé afin d'éviter l'entrée de l'air dans l'estomac.The esophagus is previously ligated to prevent the entry of air into the stomach.
Des électrodes corticales front-pariétales et occipitales permettent l'enregistrement de l'acitivité électrocorticographique sur un polygraphe Grass modèle 79 P à la vitesse de 6 mm/sec.Front-parietal and occipital cortical electrodes allow the recording of electrocorticographic activity on a Grass model 79 P polygraph at the speed of 6 mm / sec.
La préparation de l'animal est effectuée sous anesthésie locale (xylocaïne à 2 %). Les rats sont maintenus tout au long de l'expérience à température constante (37,50C). Dix minutes après la fin de la préparation du rat, une dose de 200 mg/kg de hydroxy-4 butyrate de sodium est injectée par voie intraveineuse au niveau de la queue.The preparation of the animal is carried out under local anesthesia (xylocaine 2%). The rats are maintained throughout the experiment at constant temperature (37.50C). Ten minutes after the end of the preparation of the rat, a dose of 200 mg / kg of sodium hydroxy-4 butyrate is injected intravenously into the tail.
Une dose de 10 mg/kg du composé à étudier est administrée par voie intrapéritonéale 3 minutes après l'administration du hydroxy-4 butyrate de sodium.A dose of 10 mg / kg of the compound to be studied is administered intraperitoneally 3 minutes after the administration of sodium hydroxy-4 butyrate.
L'évaluation des traces s'effectue par périodes de 15 minutes durant 75 minutes après l'injection de GHB. Durant cette période d'analyse, la durée totale du "sommeil" est déterminée. Une série de 15 témoins permet de préciser la durée du "sommeil GHB!'. The traces are evaluated in 15-minute periods for 75 minutes after the injection of GHB. During this analysis period, the total duration of "sleep" is determined. A series of 15 witnesses makes it possible to specify the duration of the "GHB sleep!".
L'analyse statistique des résultats est réalisée à l'aide du test "U" de Mann-Whitney.Statistical analysis of the results is carried out using the Mann-Whitney "U" test.
Certains composés réduisent les effets du GHB (jusqu'à 40 % de diminution de la durée du sommeil à la dose de 10 mg/kg), tandis que d'autres potentialisent ces effets (jusqu'à 40 % d'augmentation à la dose de 10 mg/kg). On constate également que les effets peuvent être opposés selon que les composés sont administrés à fortes doses ou à faibles doses.Certain compounds reduce the effects of GHB (up to 40% decrease in sleep duration at a dose of 10 mg / kg), while others potentiate these effects (up to 40% increase at dose 10 mg / kg). It is also noted that the effects can be opposed depending on whether the compounds are administered in high doses or in low doses.
Les résultats des essais pharmacologiques montrent que les composés de l'invention sont actifs dans le domaine du système nerveux central et possèdent des propriétés anxiolytiques, inductrices de sommeil, hypnotiques et anticonvulsivantes ; les composés de l'invention sont utiles pour le traitement des états d'anxiétés, des troubles du sommeil et autres affections neurologiques et psychiatriques.The results of the pharmacological tests show that the compounds of the invention are active in the field of the central nervous system and have anxiolytic, sleep-inducing, hypnotic and anticonvulsant properties; the compounds of the invention are useful for the treatment of anxiety states, sleep disorders and other neurological and psychiatric conditions.
Les composés de l'invention peuvent être présentés sous toute forme appropriée pour l'administration par voie orale, ou parentérale, par exemple sous forme de comprimés, de dragées, de gélules, de solutions buvables ou injectables etc.. avec tout excipient approprié.The compounds of the invention can be presented in any form suitable for oral or parenteral administration, for example in the form of tablets, dragees, capsules, oral or injectable solutions, etc. with any suitable excipient.
La posologie quotidienne peut aller de 0,5 à 2000 mg. Annexe 1
Claims (4)
Priority Applications (19)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8704277A FR2612928B1 (en) | 1987-03-27 | 1987-03-27 | HYDROXYL DERIVATIVES OF IMIDAZOPYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| EP88400666A EP0289371B1 (en) | 1987-03-27 | 1988-03-21 | Imidazopyridine derivatives, their preparation and therapeutical use |
| DE8888400666T DE3865073D1 (en) | 1987-03-27 | 1988-03-21 | IMIDAZOPYRIDINE DERIVATIVES, THEIR PRODUCTION AND THERAPEUTIC USE. |
| ES198888400666T ES2026666T3 (en) | 1987-03-27 | 1988-03-21 | PROCEDURE FOR PREPARING IMIDAZOPYRIDINE DERIVATIVES. |
| AT88400666T ATE67765T1 (en) | 1987-03-27 | 1988-03-21 | IMIDAZOPYRIDE DERIVATIVES, THEIR PRODUCTION AND THERAPEUTIC USE. |
| IL85840A IL85840A (en) | 1987-03-27 | 1988-03-23 | Substituted 2-phenylimidazo(1,2-a)pyridine-3-acetamides and pharmaceutical compositions containing them |
| NZ224032A NZ224032A (en) | 1987-03-27 | 1988-03-25 | Imidazo(1,2-a)pyridine derivatives and pharmaceutical compositions |
| HU881526A HU198048B (en) | 1987-03-27 | 1988-03-25 | Process for production of derivatives of imidazo-piridine and medical preparatives containing these substances |
| KR1019880003233A KR880011155A (en) | 1987-03-27 | 1988-03-25 | Imidazopyridine derivatives, their preparation and application to treatment |
| FI881434A FI881434A (en) | 1987-03-27 | 1988-03-25 | FOERFARANDE FOER FRAMSTAELLNING AV IMIDAZOPYRIDINDERIVAT VILKA AER TERAPEUTISKT ANVAENDBARA. |
| DK167388A DK167388A (en) | 1987-03-27 | 1988-03-25 | IMIDAZO (1,2-A) PYRIDINE DERIVATIVES AND MEDICINALS CONTAINING SUCH DERIVATIVES |
| PT87090A PT87090B (en) | 1987-03-27 | 1988-03-25 | METHOD FOR PREPARING IMITAZOPYRIDINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| NO881333A NO881333L (en) | 1987-03-27 | 1988-03-25 | PROCEDURE FOR THE PREPARATION OF IMIDAZOPYRIDINE DERIVATIVES. |
| AU13736/88A AU597809B2 (en) | 1987-03-27 | 1988-03-25 | Imidazopyridine derivatives and compositions containing them |
| JP63073036A JP2733492B2 (en) | 1987-03-27 | 1988-03-25 | Imidazopyridine derivatives |
| CA000562556A CA1324139C (en) | 1987-03-27 | 1988-03-25 | 2-phenyl-3-acylaminomethyl-imidazo[1,2-a]pyridine derivatives |
| AR88310427A AR243523A1 (en) | 1987-03-27 | 1988-03-28 | Imidazopyridine derivatives, their preparation and therapeutical use |
| US07/173,813 US4847263A (en) | 1987-03-27 | 1988-03-28 | Imidazopyridine derivatives and compositions containing them |
| GR91401761T GR3003145T3 (en) | 1987-03-27 | 1991-11-14 | Imidazopyridine derivatives, their preparation and therapeutical use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8704277A FR2612928B1 (en) | 1987-03-27 | 1987-03-27 | HYDROXYL DERIVATIVES OF IMIDAZOPYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2612928A1 true FR2612928A1 (en) | 1988-09-30 |
| FR2612928B1 FR2612928B1 (en) | 1989-06-16 |
Family
ID=9349492
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8704277A Expired FR2612928B1 (en) | 1987-03-27 | 1987-03-27 | HYDROXYL DERIVATIVES OF IMIDAZOPYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Country Status (1)
| Country | Link |
|---|---|
| FR (1) | FR2612928B1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0050563A1 (en) * | 1980-10-22 | 1982-04-28 | Synthelabo | Imidazo(1,2-a)pyridine derivatives, process for their preparation and their therapeutical use |
-
1987
- 1987-03-27 FR FR8704277A patent/FR2612928B1/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0050563A1 (en) * | 1980-10-22 | 1982-04-28 | Synthelabo | Imidazo(1,2-a)pyridine derivatives, process for their preparation and their therapeutical use |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2612928B1 (en) | 1989-06-16 |
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