FR2637595A1 - Benzimidazole derivatives, their preparation and their application in therapeutics - Google Patents
Benzimidazole derivatives, their preparation and their application in therapeutics Download PDFInfo
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- FR2637595A1 FR2637595A1 FR8813323A FR8813323A FR2637595A1 FR 2637595 A1 FR2637595 A1 FR 2637595A1 FR 8813323 A FR8813323 A FR 8813323A FR 8813323 A FR8813323 A FR 8813323A FR 2637595 A1 FR2637595 A1 FR 2637595A1
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- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title claims description 4
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title abstract description 3
- 239000003814 drug Substances 0.000 title abstract 2
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- IZXWCDITFDNEBY-UHFFFAOYSA-N 1-(chloromethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCl)C=C1 IZXWCDITFDNEBY-UHFFFAOYSA-N 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- ZLAQATDNGLKIEV-UHFFFAOYSA-N 5-methyl-2-sulfanylidene-1h-pyrimidin-4-one Chemical compound CC1=CNC(=S)NC1=O ZLAQATDNGLKIEV-UHFFFAOYSA-N 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- -1 alkyl radical Chemical class 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000007815 allergy Effects 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003405 ileum Anatomy 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- FDFHVVHRBTXNIS-UHFFFAOYSA-O C[S+]=C(NC=C1)NC1=O Chemical compound C[S+]=C(NC=C1)NC1=O FDFHVVHRBTXNIS-UHFFFAOYSA-O 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000003033 spasmogenic effect Effects 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 0 *C(C(CC1)CCN1C1=Nc2ccc(*)cc2*1)=C Chemical compound *C(C(CC1)CCN1C1=Nc2ccc(*)cc2*1)=C 0.000 description 1
- XSXXYVYXFRZYSR-UHFFFAOYSA-N CCN(C1CCNCC1)C(N1)=NC=CC1=O Chemical compound CCN(C1CCNCC1)C(N1)=NC=CC1=O XSXXYVYXFRZYSR-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- QABXZSRBBWJIMH-UHFFFAOYSA-N Cc1ccc2NCC(Cl)=Nc2c1 Chemical compound Cc1ccc2NCC(Cl)=Nc2c1 QABXZSRBBWJIMH-UHFFFAOYSA-N 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 235000010676 Ocimum basilicum Nutrition 0.000 description 1
- 240000007926 Ocimum gratissimum Species 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000028004 allergic respiratory disease Diseases 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000001705 anti-serotonergic effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 231100000926 not very toxic Toxicity 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 201000004335 respiratory allergy Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- C07D401/14—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 three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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 (I) donnée en annexe dans laquelle R est un atome d'halogène, le radical hydroxy, un radical (C14)alkyle ou un radical (Cl,q)alcoxy. The compounds of the invention correspond to the formula (I) given in the annex in which R is a halogen atom, the hydroxyl radical, a (C 14) alkyl radical or a (Cl, q) alkoxy radical.
Les formes tautomères font partie de l'invention.The tautomeric forms are part of the invention.
Les composés de l'invention sont les métabolites d'un composé décrit dans le brevet français nO 85.13453 et les dérivés de ces métabolites.The compounds of the invention are the metabolites of a compound described in French Patent No. 85.13453 and the derivatives of these metabolites.
Les composés préférés de l'invention sont ceux pour lesquels
R est en position 5 ou 6 et représente un atome de chlore ou de fluor, le radical hydroxy, méthyle ou méthoxy.The preferred compounds of the invention are those for which
R is in position 5 or 6 and represents a chlorine or fluorine atom, the hydroxyl, methyl or methoxy radical.
Selon l'invention on peut préparer les composés (I) selon le schéma réactionnel donné en annexe 1.According to the invention, the compounds (I) can be prepared according to the reaction scheme given in Annex 1.
On fait réagir un composé (II), composé décrit dans le brevet français n" 85.13453 avec le composé (III), dans un solvant tel que l'alcool isoamylique, à une température de 1200C.A compound (II), a compound described in French Patent No. 85.13453, is reacted with the compound (III) in a solvent such as isoamyl alcohol at a temperature of 1200 ° C.
Les composés (I) dans lesquels R est un radical (C1,4)alcoxy ou hydroxy-peuvent être préparés selon le schéma réactionnel donné en annexe 2 on fait réagir le compose (IV), décrit dans la littérature, avec le composé (V), puis on fait réagir le composé de condensation (VI) ainsi obtenu avec le chlorure de fluoro-4 benzyle et de l'hydrure de sodium, ce qui conduit à un mélange des deux composés (VII) portant le radical R soit en position 5, soit en position 6, que l'on peut séparer par cristallisation, puis on hydrolyse ces composés et enfin on fait réagir les composés (VIII), avec le S-méthylthiouracile pour obtenir les composés (I) dans lesquels R est un radical (C1,4)alcoxy, composés qui peuvent être hydrolysés avec de l'acide bromhydrique pour donner les composés (I) dans lesquels R est OH. The compounds (I) in which R is a (C 1 -C 4) alkoxy or hydroxy-radical can be prepared according to the reaction scheme given in Annex 2, the compound (IV), described in the literature, is reacted with the compound (V). ), and then the condensation compound (VI) thus obtained is reacted with 4-fluoro-benzyl chloride and sodium hydride, which leads to a mixture of the two compounds (VII) carrying the radical R in the position 5, or in position 6, which can be separated by crystallization, then these compounds are hydrolyzed and finally the compounds (VIII) are reacted with S-methylthiouracil to obtain the compounds (I) in which R is a radical (C1,4) alkoxy compounds which can be hydrolysed with hydrobromic acid to give the compounds (I) wherein R is OH.
Les exemples suivants illustrent l'invention.The following examples illustrate the invention.
Les analyses et les spectres IR et RMN confirment la structure des composés.Analyzes and IR and NMR spectra confirm the structure of the compounds.
Exemple 1; E EChloro-5E (f luoro-4 phényl)méthyl]-1 lH-ben- zimidazolyl-2]-1 pipéridinyl-43méthylamino]-2 pyrimidinol-4. Example 1; E-Chloro-5E (4-fluoro-phenyl) methyl] -1H-benzimidazol-2-yl] -1-piperidinyl-43-methylamino] -2-pyrimidinol.
1.1. Chloro-5[(fluoro-4 phényl)méthyl]-1 benzimidazolone.1.1. 5-Chloro [(4-fluorophenyl) methyl] benzimidazolone.
On chauffe à 140-1500C, pendant 2 h, un mélange de 20,9 g (0,083 mole) de N-[(fluoro-4 phényl)méthyl)-1 chloro-4 benzène diamine-1,2 et 6,5 g (0,11 mole) d'urée. On triture le mélange dans de l'éther, filtre. On obtient 4,7 g du produit recristallisé du toluène (F = 202-204 C).A mixture of 20.9 g (0.083 mol) of N - [(4-fluoro-phenyl) methyl) -1-chlorobenzene-1,2-diamine and 6.5 g is heated at 140-1500 ° C. for 2 hours. (0.11 moles) urea. The mixture is triturated in ether, filtered. 4.7 g of the recrystallized product of toluene (mp = 202-204 ° C.) are obtained.
De la même façon, on prepare la fluoro-5 E(fluoro-4 phényl)méthyl]-l benzimidazolone F = 155-1580C méthyl-5 E(fluoro-4 phényl)méthyl]-1 benzimidazolone
F = 175-183 C. Similarly, 5-fluoro-4- (4-fluoro-phenyl) methyl] -benzimidazolone F = 155-1580C methyl-5-E (4-fluoro-phenyl) methyl] -benzimidazolone is prepared.
M.p. 175-183 C.
1.2. Dichloro-2,5[(fluoro-4 phényl)méthyl]-1 lH-benzimidazole.1.2. 2,5-Dichloro [(4-fluorophenyl) methyl] -1H-benzimidazole.
On chauffe au reflux 3,9 g (0,014 mole) de chloro-5 ((fluoro4 phényl)méthyl]-1 benzimidazolone dans 60 ml de POCl3, cependant que l'on fait barboter du chlorure d'hydrogène gazeux dans le mélange, pendant environ 7 h.3.9 g (0.014 mol) of 5-chloro-1- (4-fluoro-phenyl) methyl benzimidazolone are refluxed in 60 ml of POCl 3, while gaseous hydrogen chloride is bubbled into the mixture for 30 minutes. about 7 pm
On évapore le mélange réactionnel, verse le résidu dans de la glace, alcalinise avec Na2CO3 extrait avec CH2Cl2. On lave la phase organique avec de l'eau, sèche, filtre, évapore.The reaction mixture was evaporated, the residue poured into ice, basified with Na2CO3 extracted with CH2Cl2. The organic phase is washed with water, dried, filtered and evaporated.
On obtient 3,2 g (F = 164-1670C) de produit recristallisé de l'acétate d'éthyle. 3.2 g (mp = 164 ° -1670 ° C.) of recrystallized product of ethyl acetate are obtained.
En utilisant la même technique, on prépare le chloro-2 fluoro-5[(fluoro-4 phényl)méthyl]-1 lH-benzimidazole (F = 117-120 C) et le chloro-2 méthyl-5 (fluoro-4 phényl)methyl]- 1 lH-benzimidazole. F = 144-146 C. Using the same technique, 2-chloro-5-fluoro-5- [(4-fluorophenyl) methyl] -1-benzimidazole (F = 117-120 ° C.) and 2-chloro-methyl-5 (4-fluorophenyl) are prepared. ) methyl] -1H-benzimidazole. Mp = 144-146C.
1.3. EftChloro-5 t(fluoro-4 phényl)méthyl]-1 1H-benzimidazo- lyl-23-1 pipéridinyl-4]méthylamino]-2 pyrimidinol-4. 1.3. EftChloro-5- (4-fluoro-phenyl) methyl] -1H-benzimidazolyl-23-1-piperidinyl-4-methylamino] -2-pyrimidinol-4.
on porte au reflux 26 h un mélange de 3,4 g (0,115 mole) du dérivé chloré précédent avec 2,4 g (0,115 mole) de [(pipéridinyl-4) méthylamino]-2 1H-pyrimidinone-4 et 1,7 g de carbonate de potassium dans 20 ml de méthyl-3 butanol-1. On évapore à-.sec, reprend le résidu avec cH2c12 et de l'eau, décante, sèche, filtre, évapore.refluxed for 26 hours a mixture of 3.4 g (0.115 mol) of the above chlorinated derivative with 2.4 g (0.115 mol) of [(4-piperidinyl) methylamino] -1H-pyrimidinone-4 and 1.7 g of potassium carbonate in 20 ml of 3-methyl-1-butanol. Evaporate to -sec, take up the residue with cH2c12 and water, decant, dry, filter, evaporate.
Après purification du produit par chromatographie on obtient 4,4 g de produit recristallisé de l'éthanol. (F = 236-238 C)
En procédant de façon identique avec les mêmes quantités on obtient les dérivés fluoro-5 et méthyl-5 correspondants.After purification of the product by chromatography, 4.4 g of product recrystallized from ethanol are obtained. (Mp = 236-238 ° C)
By proceeding in the same manner with the same amounts, the corresponding fluoro-5 and methyl-5 derivatives are obtained.
Exemple 2. [[[EMethoxy-5[(fluoro-4 phényl)méthyl]-1 1H-ben- zimidazolyl-2]-1 pipéridinyl-4]méthylamino]-2 pyrimidinol-4.Example 2 [[[5-Emethoxy-4 - [(4-fluorophenyl) methyl] -1H-benzimidazolyl] -1-piperidinyl] methylamino] -2-pyrimidinol-4.
2.1. [EMéthoxy-5 lH-benzimidazolyl-2]-1 pipéridinyl-4] méthyl carbamate de diméthyl-1,1 éthyle.2.1. [1,1-Ethyl-1-methoxy-1-piperidinyl] -1-dimethyl-1,1-methyl-1,1-dimethyl-1,1-dimethylformate.
On chauffe au reflux pendant 6 h, 29,3 g (0,136 mole) de (pipéridinyl-4) N-méthyl carbamate de tertiobutyle, 22,5 g (0,123 mole) de chloro-2 méthoxy-5 lH-benzimidazole dans 270 ml de méthyl-3 butanol-l.29.3 g (0.136 mol) of tert-butyl (4-piperidinyl) -N-methyl carbamate, 22.5 g (0.123 mol) of 2-chloro-methoxy-1H-benzimidazole in 270 ml are refluxed for 6 hours. of 3-methyl-1-butanol.
On évapore le solvant sous vide, reprend le résidu avec de l'éther, filtre le précipité que l'on dissout dans le méthanol aqueux, alcalinise avec Na2CO3, filtre le précipité et le sèche. On obtient 29 g de produit recristallisé du propanol1. (F = 2380C).The solvent is evaporated in vacuo, the residue is taken up with ether, the precipitate is filtered off, dissolved in aqueous methanol, basified with Na2CO3, the precipitate is filtered off and dried. 29 g of recrystallized product of propanol are obtained. (F = 2380C).
2.2. { E EMéthoxy-5 [(fluoro-4 phénylXméthyl]-1 lH-benzimidazolyl-2]-1 pipéridinyl-4] N-méthyl carbamate de diméthyl-l,l éthyle.2.2. {E-5-ethoxy-5 - [(4-fluorophenyl) methyl] -1H-benzimidazol-2-yl] -1-piperidinyl] N-methyl-dimethyl-1,1-ethyl carbamate.
On ajoute par portions 17,2 g (0,05 mole) du dérivé précédent à une suspension de 2,75 g de NaH à 50 % dans 50 ml de DMF.17.2 g (0.05 mol) of the above derivative are added in portions to a suspension of 2.75 g of 50% NaH in 50 ml of DMF.
On porte le mélange à 450C pendant 1/2 h, refroidit avec de la glace puits additionne 62 ml (0,057 mole) de chlorométhyl-l fluoro-4 benzène, en solution dans 10 ml de DMF. On laisse le mélange revenir à 200C, agite 3 h. On verse le mélange dans de l'eau, extrait avec CH2C12. On lave la phase organique avec de l'eau, sèche, filtre et évapore. On reprend le résidu avec de l'éther, filtre le produit cristallisé.The mixture is heated at 450 ° C. for 1/2 h, cooled with ice, and 62 ml (0.057 mole) of 1-chloromethyl-4-fluoro-benzene, dissolved in 10 ml of DMF, are added. The mixture is allowed to return to 200 ° C. and stirred for 3 hours. The mixture is poured into water and extracted with CH 2 Cl 2. The organic phase is washed with water, dried, filtered and evaporated. The residue is taken up in ether and the crystalline product is filtered off.
On obtient le produit (F = 167 C) recristallisé de l'éthanol. The product (F = 167 ° C.) recrystallized from ethanol is obtained.
2.3. [[[Méthoxy-6 E (f luoro-4 phényl)méthyl]-l 1H-benzimidazo- lyl-2]-1 pipéridinyl-4]-méthyl carbamate de diméthyl-l,l éthylé. 2.3. Ethyl dimethyl-1-ethyl-6-methoxy-6-fluoro-4-fluoro-4-phenyl-4-methyl-1H-benzimidazol-1-yl] piperidin-4-yl] carbamate.
Le filtrat éthéré obtenu sous 2.2. est évaporé à sec et le résidu purifié par chromatographie sur colonne de silice
(éluant CH2Cl2-acétate d'éthyle 50/50).The ether filtrate obtained under 2.2. is evaporated to dryness and the residue purified by chromatography on a silica column
(eluent CH2Cl2-ethyl acetate 50/50).
On obtient le composé F = 127 C. The compound F = 127C is obtained.
2.4. [Méthoxy-5 [(Eluoro-4 phényl)méthyl]-1 lH-benzimidazo- lyl-2]-1 N-méthyl pipéridinamine-4.2.4. [5-Methoxy-5- [4- (4-fluoro-phenyl) methyl] -1H-benzimidazol-2-yl] -N-methylpiperidinamine.
On agite à 50 C, pendant 4 h, 9,7 g (0,02 mole) de produit obtenu sous 2.2. dans 50 ml d'HCl 3N. On refroidit la solution résultante, alcalinise avec de la soude, extrait avec
CH2Cl2, sèche, filtre, évapore. On obtient 7,7 g d'huile que l'on utilise brute pour la suite de la synthèse.0.07 g (0.02 mol) of product obtained under 2.2 are stirred at 50 ° C. for 4 hours. in 50 ml of 3N HCl. The resulting solution is cooled, rendered alkaline with sodium hydroxide, extracted with
CH2Cl2, dry, filter, evaporate. 7.7 g of crude oil are obtained for the rest of the synthesis.
De la même façon et avec les mêmes quantités on obtient le [tméthoxy-6[(fluoro-4 phényl)méthyl]-l 1H-benzimidazolyl-2]-1
N-méthyl pipéridinamine-4 sous forme d'huile.In the same way and with the same amounts we obtain [tmethoxy-6 [(4-fluorophenyl) methyl] -1 H -benzimidazolyl-2] -1
N-methyl piperidinamine-4 as an oil.
2.5. [[[Méthoxy-5 [(fluoro-4 phényl)méthylJ-l 1H-benzimida- zolyl-2]-1 pipéridinyl-4]méthylamino]-2 pyrimidinol-4.2.5. [[[5-Methoxy-5- [(4-fluorophenyl) methyl] -1H-benzimidazolyl] -1-piperidinyl] methylamino] -2-pyrimidinol.
Une solution de 7,6 g (0,02 mole) de méthoxy-5 [(fluoro-4 phényl)méthyl]-l lH-benzimidazolyl-2]-1 N-méthyl pipéridinamine-4 et de 2,7 g (0,19 mole) de S-méthyl-thiouracile dans 50 ml de toluène est chauffée au reflux 168 h. On refroidit, filtre le précipité.A solution of 7.6 g (0.02 mol) of 5-methoxy [(4-fluorophenyl) methyl] -1H-benzimidazolyl-2] -1 N-methylpiperidinamine-4 and 2.7 g 19 mol) of S-methyl-thiouracil in 50 ml of toluene is refluxed for 168 h. Cool, filter the precipitate.
On obtient le composé recristallisé du propanol-l. F = 247 C. The recrystallized propanol-1 compound is obtained. Mp = 247 C.
De la même façon, avec les mêmes quantités, on obtient le [[[méthoxy-6[(fluoro-4 phényl)méthyl]-l lH-benzimidazolyl 23-1 pipéridinyl-4]méthylamino]-2 pyrimidinol-4. F = 2250C.In the same way, with the same amounts, [[6-methoxy-4- [4-fluoro-phenyl] methyl] -1H-benzimidazolyl-1-piperidinyl-4-methylamino] -2-pyrimidinol-4 is obtained. F = 2250C.
ExemPle 3. [[[[Hydroxy-5[fluoro-4 phényl)méthyl]-l îH-ben- zimidazolyl-2]-1 pipéridinyl-4jméthylamino]-2 pyrimidinol-4.Example 3 [[[[5- (4-Fluoro-4-phenylphenyl) methyl] -1H-benzimidazol-2] -1-piperidinyl-4-methylamino] -2-pyrimidinol-4.
On chauffe à 1300C pendant 7 h, 1,75 g (0,0038 mole) du composé obtenu dans l'exemple 2 en solution dans 32 ml d'acide acétique et 4 ml d'HBr à 48 %.1.75 g (0.0038 mol) of the compound obtained in Example 2 dissolved in 32 ml of acetic acid and 4 ml of 48% HBr are heated at 1300C for 7 hours.
On évapore à sec, reprend le résidu avec du méthanol, ajoute du bicarbonate de sodium jusqu'à pH 8, évapore, triture le résidu dans de l'eau, filtre. On purifie le produit par chromatographie sur colonne. On obtient le composé recristallise du méthanol F = 267OC . It is evaporated to dryness, the residue is taken up in methanol, sodium bicarbonate is added until pH 8, the mixture is evaporated and the residue is triturated in water, filtered. The product is purified by column chromatography. The recrystallized compound of methanol F = 267OC is obtained.
On obtient, de la même façon, lrEtEthydroxy-6t(fluoro-4 phényl)méthyl]-l 1H-benzimidazolyl-2]-1 pipéridinyl-4]méthylamino]-2 pyrimidinol-4, recristallisé du propanol-l. F = 2560C.In the same way, 4-ethyl-6-tetrahydro-4-phenyl-methyl-1H-benzimidazol-2-yl] -4-piperidinyl] methylamino] -2-pyrimidinol is obtained, recrystallized from propanol-1. F = 2560C.
Les composés, préparés à titre d'exemples, sont représentés dans le tableau suivant. The compounds prepared by way of example are shown in the following table.
Tableau
<tb> Composé <SEP> - <SEP> R <SEP> F( C) <SEP>
<tb> <SEP> 1- <SEP> 5-Cl <SEP> 236-238
<tb> <SEP> 2 <SEP> 5-F <SEP> 236-238
<tb> <SEP> 3 <SEP> 5-CH3 <SEP> 219-221
<tb> <SEP> 4 <SEP> 5-OCH3 <SEP> 247
<tb> <SEP> 5 <SEP> 5-OH <SEP> 267
<tb> <SEP> 6 <SEP> 6-OCH3 <SEP> 225
<tb> <SEP> 7 <SEP> 6-OH <SEP> 256
<tb>
Les composés ont été soumis à divers essais pharmacologiques montrant principalement leur activité antagoniste de l'hìsta- mine et pour quelques uns de la sérotonine.<tb> Compound <SEP> - <SEP> R <SEP> F (C) <SEP>
<tb><SEP> 1- <SEP> 5-Cl <SEP> 236-238
<tb><SEP> 2 <SEP> 5-F <SEP> 236-238
<tb><SEP> 3 <SEP> 5-CH3 <SEP> 219-221
<tb><SEP> 4 <SEP> 5-OCH3 <SEP> 247
<tb><SEP> 5 <SEP> 5-OH <SEP> 267
<tb><SEP> 6 <SEP> 6-OCH3 <SEP> 225
<tb><SEP> 7 <SEP> 6-OH <SEP> 256
<Tb>
The compounds have been subjected to various pharmacological tests showing mainly their antihistamine and some serotonin antagonist activity.
l. Activité in vitro : iléon isolé de cobaye
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.l. In vitro activity: isolated guinea pig ileum
The test was carried out according to the method of Savini-modified Magnus (Arch Int Pharmacodyn, 1957, 113, 157) in male tricolor guinea pigs weighing about 300 g, fasting 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 %, C02 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.An ileum fragment is removed, placed at 390C in a tyrode bath traversed by a carbogen stream (02 95%, CO2 5%) and connected to an isotonic sensor with a maximum voltage of 2.5 g. The 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 8.1Q-8 g/ml).The contractions are induced by the various spasmogenic agents whose concentration causing a submaximal response is determined (histamine: 1 to 8.1 × 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.Compounds of the invention dissolved in distilled water or 0.1 N solution of methanesulfonic acid are contacted with the ileum for 1 min before introduction of the spasmogenic substance.
Les CA50 (concentration diminuant de 50 % les contractions induites par l'histamine) des composés de l'invention vont de 10-s à 10-8 molaire.CA50 (concentration decreasing by 50% histamine-induced contractions) of the compounds of the invention range from 10 -5 to 10-8 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
The intraplantar injection in one of the posterior 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 0,5 à 10 mg/kg. DA40 (a dose that decreases the volume of edema by 40%) of the compounds of the invention ranges from 0.5 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, cutaneous allergies, ocular allergies and various allergic manifestations.
Ils sont très sélectifs pour les récepteurs de l'histamine (H1) et sont dénués d'activité anticholinergique et antisérotoninergique aux doses thérapeutiques.They are highly selective for histamine receptors (H1) and lack anticholinergic and antiserotoninergic activity at therapeutic doses.
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 any 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.
Annexe 1
formes tautomères
Annexe 2
tautomeric forms
Annex 2
Claims (6)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2666582A1 (en) * | 1990-09-07 | 1992-03-13 | Synthelabo | Benzimidazole derivatives, their preparation and their application to therapeutics |
| 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 |
| CN120441547A (en) * | 2025-05-06 | 2025-08-08 | 大连医科大学附属第二医院 | A novel fatty acid amide hydrolase (FAAH) inhibitor and its application in disease treatment |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2587029A1 (en) * | 1985-09-11 | 1987-03-13 | Synthelabo | BENZIMIDAZOLE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF |
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| FR2587029A1 (en) * | 1985-09-11 | 1987-03-13 | Synthelabo | BENZIMIDAZOLE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2666582A1 (en) * | 1990-09-07 | 1992-03-13 | Synthelabo | Benzimidazole derivatives, their preparation and their application to therapeutics |
| 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 |
| CN120441547A (en) * | 2025-05-06 | 2025-08-08 | 大连医科大学附属第二医院 | A novel fatty acid amide hydrolase (FAAH) inhibitor and its application in disease treatment |
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