FR2666582A1 - Benzimidazole derivatives, their preparation and their application to therapeutics - Google Patents
Benzimidazole derivatives, their preparation and their application to therapeutics Download PDFInfo
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Abstract
Description
La présente invention a pour objet des dérivés de benzimidazole, leur préparation et leur application en thérapeutique.The present invention relates to benzimidazole derivatives, their preparation and their therapeutic application.
Les composés de l'invention répondent à la formule
dans laquelle soit R1 est H, R2 est le radical 4-fluorobenzyle et R3 est le radical méthoxy, soit R1 est H, R2 est H et R3 est H, soit R1 est OH, R2 est H et R3 est H.The compounds of the invention correspond to the formula
wherein either R1 is H, R2 is the 4-fluorobenzyl radical and R3 is the methoxy radical, or R1 is H, R2 is H and R3 is H, or R1 is OH, R2 is H and R3 is H.
Les composés de l'invention sont préparés selon les modes opératoires décrits dans les exemples.The compounds of the invention are prepared according to the procedures described in the examples.
Exemple 1.Example 1.
C2-[1-C(4-fluorophényl)méthyll-l 1H-benzimidazol-2-yl]- pipéridin-4-yl]methylamino-5-méthoxy-pyrimidin-4-one. C2- [1-C (4-fluorophenyl) methyll-1 1H-benzimidazol-2-yl] - piperidin-4-yl] methylamino-5-methoxy-pyrimidin-4-one.
1.1. 2-Méthylthio-5-méthoxy-pyrimidinin-4-ol. 1.1. 2-Methylthio-5-methoxy-pyrimidinin-4-ol.
On prépare une solution d'éthylate de sodium à partir de 3,6 g (0,156 mole) de sodium dans environ 60 ml d'éthanol. A solution of sodium ethylate is prepared from 3.6 g (0.156 mole) of sodium in approximately 60 ml of ethanol.
Lorsque tout le sodium est consommé, on évapore l'excès d'éthanol. On ajoute 10 ml de toluène et ajoute lentement à la température ambiante un mélange de 10,3 ml (0,104 mole) de méthoxyacetate de méthyle et de 10,1 ml (0,125 mole) de formiate d'éthyle. A la fin de l'addition, on obtient une solution jaune pâle limpide. On laisse agiter la nuit à la température ambiante puis on refroidit et maintient la température à 10C en ajoutant lentement une solution de 18,8 g (0,100 mole) de sulfate de S-methylithiouronium dans environ 50 ml de soude à 10 %. Au cours de l'addition, du sulfate de sodium précipite dans le mélange. A la fin de l'addition, on laisse agiter à la température ambiante pendant 24 h.On filtre le sulfate de sodium, acidifie avec HC1 6N le filtrat. On ajuste à pH 6. Le produit précipite alors lentement. On le filtre et on le rince avec un peu d'eau puis avec un peu d'éther. On fait recristalliser le produit dans de l'éthanol. F = 234-2350C. When all the sodium is consumed, the excess ethanol is evaporated. 10 ml of toluene are added and a mixture of 10.3 ml (0.104 mole) of methyl methoxyacetate and 10.1 ml (0.125 mole) of ethyl formate is slowly added at room temperature. At the end of the addition, a clear pale yellow solution is obtained. The mixture is left to stir overnight at room temperature, then it is cooled and the temperature is maintained at 10C by slowly adding a solution of 18.8 g (0.100 mole) of S-methylithiouronium sulphate in approximately 50 ml of 10% sodium hydroxide. During the addition, sodium sulfate precipitates from the mixture. At the end of the addition, the mixture is left to stir at ambient temperature for 24 h. The sodium sulfate is filtered, the filtrate is acidified with 6N HCl. It is adjusted to pH 6. The product then precipitates slowly. It is filtered and rinsed with a little water and then with a little ether. The product is recrystallized from ethanol. F = 234-2350C.
1.2. [2-C1-[[(4-fluorophényl)méthyl]-l 1H-benzimidazol-2-yl]- pipéridin-4-yl]methylamino-5-méthoxy-pyrimidin-4-one.1.2. [2-C1 - [[(4-fluorophenyl) methyl] -1 1H-benzimidazol-2-yl] - piperidin-4-yl] methylamino-5-methoxy-pyrimidin-4-one.
On chauffe sous azote à la température du reflux 1,01 g (0,0030 mole) du composé C1-[(4-luoro-phényl)méthyl]iH- benzimidazol-2-yl]N-méthyl pipéridin-4-amine, 0,51 g (0,0030 mole) de 2-méthylthio-5-méthoxy pyrimidinol et 10 ml de xylène, dans un ballon. Après 140 heures de reflux, on arrête le chauffage. On évapore le xylène. On obtient un résidu noir que l'on fait passer sur colonne de silice en éluant avec
CH2Cl297/MeOH (97/3). On isole un produit qui cristallise par trituration dans l'éther. On le fait recristalliser dans 20 ml dlAcOBu. F = 229-2320C.1.01 g (0.0030 mol) of the compound C1 - [(4-luoro-phenyl) methyl] iH-benzimidazol-2-yl] N-methyl piperidin-4-amine is heated under nitrogen at the reflux temperature. 0.51 g (0.0030 mole) of 2-methylthio-5-methoxy pyrimidinol and 10 ml of xylene, in a flask. After 140 hours of reflux, the heating is stopped. The xylene is evaporated. A black residue is obtained which is passed through a silica column, eluting with
CH2Cl297 / MeOH (97/3). A product is isolated which crystallizes by trituration in ether. It is recrystallized from 20 ml of AcOBu. F = 229-2320C.
Exemple 2.Example 2.
[2-[1-[1H-benzimidazol-2-yl]-piperidin-4-yl]methylamino]- pyrimidin-4-one.[2- [1- [1H-benzimidazol-2-yl] -piperidin-4-yl] methylamino] - pyrimidin-4-one.
Dans un ballon de 500 ml, on introduit 1,52 g (0,007 mole) de 2-[(piperidin-4-yl)méthylamino]pyrimidin-4-one et 0,06 g (0,0063 mole) de chlorobenzimidazole dans 10 ml d'alcool isoamylique et on porte le mélange à 1200C au bain d'huile pendant 5 h.1.52 g (0.007 mole) of 2 - [(piperidin-4-yl) methylamino] pyrimidin-4-one and 0.06 g (0.0063 mole) of chlorobenzimidazole are introduced into a 500 ml flask ml of isoamyl alcohol and the mixture is brought to 1200C in an oil bath for 5 h.
On filtre le précipité et le lave avec un peu d'alcool isoamylique. On le dissout dans de l'eau, on ajoute 2 équivalents de soude 1N. On acidifie la solution obtenue à pH 8 avec de l'acide acétique. On essore, lave à l'eau et sèche le composé obtenu.The precipitate is filtered and washed with a little isoamyl alcohol. It is dissolved in water, 2 equivalents of 1N sodium hydroxide are added. The solution obtained is acidified to pH 8 with acetic acid. It is filtered, washed with water and the compound obtained is dried.
Le produit est recristallisé dans du méthanol.The product is recrystallized from methanol.
F = 2800C - Rendement : 17 %. F = 2800C - Efficiency: 17%.
ExemPle 3.EXAMPLE 3.
[2-[1-[6-hydroxy-1H-benzimidazol-2-yl]-pipéridin-4- yl]méthylamino]-pyrimidin-4-one. [2- [1- [6-hydroxy-1H-benzimidazol-2-yl] -piperidin-4-yl] methylamino] -pyrimidin-4-one.
3.1. El - E 6-methoxy-lH-benzimidazol-2-yl 1-4- (N-methyl-N- tertiobutylcarbonyloxy-pipéridine.3.1. El - E 6-methoxy-1H-benzimidazol-2-yl 1-4- (N-methyl-N- tertiobutylcarbonyloxy-piperidine.
On porte à 1200C, au bain d'huile, pendant 6 h, 22,5 g (0,123 mole) de 2-chloro-6-méthoxy-1H-benzimidazole, 29,3 g (0,136 mole) de 4-(N-méthyl N-tertiobutylcarbonyloxy pipéridine et 270 cm3 d'alcool isoamylique.Is brought to 1200C, in an oil bath, for 6 h, 22.5 g (0.123 mole) of 2-chloro-6-methoxy-1H-benzimidazole, 29.3 g (0.136 mole) of 4- (N- methyl N-tertiobutylcarbonyloxy piperidine and 270 cm3 of isoamyl alcohol.
On évapore le solvant sous vide. On reprend le précipité avec de l'éther, le filtre, le lave à l'éther et le sèche.The solvent is evaporated in vacuo. The precipitate is taken up with ether, the filter, washed with ether and dried.
On le redissout dans le mélange MEOH/H2O 20:80, en tiédissant. On ajoute du carbonate de sodium. On filtre le précipité, le lave à l'eau puis à l'éther. On fait recristalliser le composé dans du n-propanol. F = 2330C.
Rendement 57 %.It is redissolved in the MEOH / H2O 20:80 mixture, warming up. Sodium carbonate is added. The precipitate is filtered, washed with water and then with ether. The compound is recrystallized from n-propanol. F = 2330C.
Yield 57%.
3.2. [1-[6-methoxy-1H-benzimidazol-2-y]]-4-(N-methyl)- piperidine. 3.2. [1- [6-methoxy-1H-benzimidazol-2-y]] - 4- (N-methyl) - piperidine.
On porte à 600C dans un bain d'huile pendant 1 h, 10 g (0,0277 mole) du composé 3.1. en suspension dans 50 cm3 d'HCl 3N.Is brought to 600C in an oil bath for 1 h, 10 g (0.0277 mole) of compound 3.1. suspended in 50 cm3 of 3N HCl.
On refroidit le mélange, ajoute de la soude 10 N jusqu'à pH 7, puis du carbonate de potassium en poudre.The mixture is cooled, 10N sodium hydroxide is added to pH 7, then powdered potassium carbonate.
On extrait la solution au CH2Cl2 (5 x 400 ml), sèche sur sulfate de sodium, filtre et évapore. On obtient 6,6 g de produit - Rendement = 91,5 %.The solution is extracted with CH2Cl2 (5 x 400 ml), dried over sodium sulfate, filtered and evaporated. 6.6 g of product are obtained - Yield = 91.5%.
3.3. [2-[1-[6-methoxy-1H-benzimidazol-2-yl]-piperidin-4- yl]méthylamino]-pyrimidin-4-one.3.3. [2- [1- [6-methoxy-1H-benzimidazol-2-yl] -piperidin-4-yl] methylamino] -pyrimidin-4-one.
On porte au reflux, pendant deux semaines, 6,5 g (0,0249 mole) du composé 3.2, 3,5 g (0,0246 mole) de 2-méthylthiopyrimidin-4-one, 50 cm3 de toluène, 20 cm3 d'alcool isoamylique. On évapore le mélange à sec, purifie sur colonne de silice avec un mélange CH2C12/MEOH 90/10. On récupère 3,5 g de produit pur sous forme amorphe. On le dissout dans 20 cm3 d'alcool absolu. La base cristallise lentement. On l'essore, la lave à l'alcool et la sèche. Rendement = 31 % F = 198 C. 6.5 g (0.0249 mole) of compound 3.2 are brought to reflux for two weeks, 3.5 g (0.0246 mole) of 2-methylthiopyrimidin-4-one, 50 cm3 of toluene, 20 cm3 of isoamyl alcohol. The mixture is evaporated to dryness, purified on a silica column with a CH2Cl2 / MEOH 90/10 mixture. 3.5 g of pure product are recovered in amorphous form. It is dissolved in 20 cm3 of absolute alcohol. The base slowly crystallizes. It is wrung out, washed with alcohol and dried. Yield = 31% F = 198 C.
3.4. E2-El -E6-hydroxy-1H-benzimidazol-2-ylî-piperidin-4- yllméthylamino]-pyrimidin-4-one.3.4. E2-El -E6-hydroxy-1H-benzimidazol-2-ylî-piperidin-4-yllméthylamino] -pyrimidin-4-one.
Dans un ballon de 20 ml, on introduit 1,7 g (0,00480 mole) du composé 3.3 avec 5,6 g (0,0480 mole) de chlorure de pyridinium et on porte le mélange réactionnel à 1800C au bain d'huile pendant 4 h, en agitant, sous atmosphère d'argon. On ajoute 10 ml d'eau et alcalinise avec NaHCO3. On filtre le précipité, le lave à l'eau et le sèche. On le purifie sous forme de fumarate en présence de méthanol. On revient à la base en dissolvant le sel dans un mélange MEOH/H20 50/50. On neutralise avec 2 eq de NaHCO3 et évapore sous vide le méthanol. La base cristallise. On l'essore, la lave à l'eau et la sèche sous vide. F = 220-50C. Rendement = 25 %. 1.7 g (0.00480 mole) of compound 3.3 are introduced into a 20 ml flask with 5.6 g (0.0480 mole) of pyridinium chloride and the reaction mixture is brought to 1800 ° C. in an oil bath for 4 h, with stirring, under an argon atmosphere. 10 ml of water are added and basified with NaHCO3. The precipitate is filtered, washed with water and dried. It is purified in the form of fumarate in the presence of methanol. We return to the base by dissolving the salt in a MEOH / H2O 50/50 mixture. Neutralized with 2 eq of NaHCO3 and the methanol evaporated under vacuum. The base crystallizes. It is wrung, washed with water and dried under vacuum. F = 220-50C. Yield = 25%.
Les composés ont été soumis à divers essais pharmacologiques montrant principalement leur activité antagoniste de l'histamine.The compounds have been subjected to various pharmacological tests mainly showing their histamine antagonistic activity.
1. Activité in vitro : iléon isolé de cobave
Le test a été effectué selon la méthode de Magnus modifiée par Savini (Arch. Int. Pharmacodyn., 1957, 113, 157), sur des cobayes tricolores mâles pesant environ 300 g, à jeun depuis 18 heures.1. In vitro activity: isolated guinea pig ileum
The test was carried out according to the Magnus method modified by Savini (Arch. Int. Pharmacodyn., 1957, 113, 157), on male tricolor guinea pigs weighing approximately 300 g, fasted for 18 hours.
Un fragment d'iléon est prélevé, placé à 390C dans un bain de tyrode traversé par un courant de carbogène (02 95 %, CO2 5 %) et relié à un capteur isotonique avec une tension maximale de 2,5 g. Les contractions sont enregistrées à l'aide d'un microdynamomètre Ugo Basile.A fragment of ileum is taken, placed at 390C in a tyrode bath crossed by a stream of carbogen (02 95%, CO2 5%) and connected to an isotonic sensor with a maximum voltage of 2.5 g. Contractions are recorded using a Ugo Basile microdynamometer.
Les contractions sont induites par les divers agents spasmogènes dont la concentration provoquant une réponse submaximale est déterminée (histamine : 1 à 8.10-8 g/ml).Contractions are induced by the various spasmogenic agents whose concentration causing a submaximal response is determined (histamine: 1 to 8.10-8 g / ml).
Les composés de l'invention dissous dans de l'eau distillée ou une solution 0,1 N d'acide méthanesulfonique sont mis en contact avec l'iléon pendant 1 mn avant l'introduction de la substance spasmogène. The compounds of the invention dissolved in distilled water or a 0.1 N solution of methanesulfonic acid are brought into contact with the ileum for 1 min before the introduction of the spasmogenic substance.
Les CA50 (concentration diminuant de 50 % les contractions induites par l'histamine) des composés les plus actifs de l'invention vont de 10 à 104 molaire.The CA50 (concentration decreasing by 50% the contractions induced by histamine) of the most active compounds of the invention range from 10 to 104 molar.
2. Activité in vivo : inflammation induite par l'histamine
L'injection intraplantaire dans une des pattes postérieures du rat d'histamine (2 mg) provoque un oedème mesuré, 1 heure après l'injection, à l'aide d'un pléthysmomètre à mercure Ugo
Basile.2. In vivo activity: histamine-induced inflammation
Intraplantar injection into one of the hind legs of the histamine rat (2 mg) causes a measured edema, 1 hour after the injection, using a Ugo mercury plethysmometer
Basil.
Les composés de l'invention, mis en suspension dans du tween en solution à 1 % dans de l'eau distillée sont administrés p.o; (0,5 ml/100 g) 1 heure avant l'injection de l'agent inflammatoire.The compounds of the invention, suspended in tween in 1% solution in distilled water are administered p.o; (0.5 ml / 100 g) 1 hour before injection of the inflammatory agent.
Les DA40 (dose qui diminue de 40 % le volume de l'oedème) des composés de l'invention varient de 0,2 à 10 mg/kg. The DA40 (dose which reduces the volume of edema by 40%) of the compounds of the invention vary from 0.2 to 10 mg / kg.
Les composés de l'invention sont peu toxiques. Leur DL 50 par voie orale est supérieure à 1000 mg/kg.The compounds of the invention are not very toxic. Their oral LD 50 is greater than 1000 mg / kg.
Les composés de l'invention peuvent donc être utilisés pour le traitement des allergies telles que allergies respiratoires, allergies cutanées, allergies oculaires et manifestations allergiques diverses.The compounds of the invention can therefore be used for the treatment of allergies such as respiratory allergies, skin allergies, eye allergies and various allergic manifestations.
Certains composés de l'invention sont très sélectifs pour les récepteurs de l'histamine (H1) et sont dénués d'activité anticholinergique et antisérotoninergique aux doses thérapeutiques. Ils possèdent une longue durée d'action et leur disponibilité par voie orale est très élevée.Certain compounds of the invention are very selective for histamine receptors (H1) and are devoid of anticholinergic and antiserotoninergic activity at therapeutic doses. They have a long duration of action and their availability by the oral route is very high.
L'invention comprend, par conséquent, toutes compositions pharmaceutiques renfermant les composés et/ou leurs sels comme principes actifs, en association avec tous excipients appropriés à leur administration par voie orale ou parentérale.The invention therefore includes all pharmaceutical compositions containing the compounds and / or their salts as active ingredients, in combination with any excipients suitable for their oral or parenteral administration.
La posologie quotidienne peut aller de 1 à 100 mg par voie orale The daily dosage can range from 1 to 100 mg orally
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2693194A1 (en) * | 1992-07-03 | 1994-01-07 | Synthelabo | New alkanamide cpds. are serotoninergic receptor, type 5-HT3, ligands - useful in treating e.g. nausea, schizophrenia, anxiety, depression, Alzheimer's disease, pain, migraine and gastrointestinal disorders |
EP0958820A1 (en) * | 1998-05-19 | 1999-11-24 | Sanofi-Synthelabo | Use of an imidazol derivative for the manufacture of a medicament for treating auto-immunodiseases |
WO2004031170A1 (en) * | 2002-10-02 | 2004-04-15 | Ragactives, S.L. | Method and intermedia used to obtain derivatives of 1-(1h- benzimidazole-2-il)-4-(2-aminopyrimidine)piperidine |
CN103814024A (en) * | 2011-09-26 | 2014-05-21 | 默克专利股份公司 | Benzyl piperidine compounds as lysophosphatidic acid (LPA) receptor antagonist |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0217700A1 (en) * | 1985-09-11 | 1987-04-08 | Synthelabo | Benzimidazole derivatives, their preparation and their therapeutical use |
FR2637595A1 (en) * | 1988-10-11 | 1990-04-13 | Synthelabo | Benzimidazole derivatives, their preparation and their application in therapeutics |
-
1990
- 1990-09-07 FR FR9011100A patent/FR2666582B1/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0217700A1 (en) * | 1985-09-11 | 1987-04-08 | Synthelabo | Benzimidazole derivatives, their preparation and their therapeutical use |
FR2637595A1 (en) * | 1988-10-11 | 1990-04-13 | Synthelabo | Benzimidazole derivatives, their preparation and their application in therapeutics |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2693194A1 (en) * | 1992-07-03 | 1994-01-07 | Synthelabo | New alkanamide cpds. are serotoninergic receptor, type 5-HT3, ligands - useful in treating e.g. nausea, schizophrenia, anxiety, depression, Alzheimer's disease, pain, migraine and gastrointestinal disorders |
EP0958820A1 (en) * | 1998-05-19 | 1999-11-24 | Sanofi-Synthelabo | Use of an imidazol derivative for the manufacture of a medicament for treating auto-immunodiseases |
WO2004031170A1 (en) * | 2002-10-02 | 2004-04-15 | Ragactives, S.L. | Method and intermedia used to obtain derivatives of 1-(1h- benzimidazole-2-il)-4-(2-aminopyrimidine)piperidine |
ES2208098A1 (en) * | 2002-10-02 | 2004-06-01 | Ragactives, S.L. | Process and intermediates for obtaining 1-(1h-benzimidazol-2-yl)-4-(pyrimidin-2-ylamino)piperidine derivatives |
CN103814024A (en) * | 2011-09-26 | 2014-05-21 | 默克专利股份公司 | Benzyl piperidine compounds as lysophosphatidic acid (LPA) receptor antagonist |
US20150011557A1 (en) * | 2011-09-26 | 2015-01-08 | Merck Patent Gmbh | Benzyl Piperidine Compounds as Lysophosphatidic Acid (LPA) Receptor Antagonist |
US9527850B2 (en) * | 2011-09-26 | 2016-12-27 | Merck Patent Gmbh | Benzyl piperidine compounds as lysophosphatidic acid (LPA) receptor antagonist |
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