Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07D401/12—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 linked by a chain containing hetero atoms as chain links
• • 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

Definitions

• the present invention relates to and imidazole derivatives of general formula (I)
• A represents a heterocycle, saturated or unsaturated, comprising a nitrogen atom of formula (B), (D), (E) or (F):
• R and R 3 represent, independently of one another, hydrogen, a C .g alkyl group, or together form a polymethylene group - (CH) n -, n being able to take the values from 3 to 6,
• R 5 represents phenyl or 2-, 3- or _4-pyridine, the phenyl or pyridine being substituted by R 3 and R ' 3 , where R 3 and R' 3 represent, independently of one another, hydrogen, halogen, hydroxy, C x _ 4 alkyl or C ⁇ g alkoxy, R 6 represents phenyl or 2-, 3- or 4-pyridine, phenyl or pyridine being substituted by -R 4 and R ' 4 ( where R 4 and R' 4 represent, independently of one another, a hydrogen atom, a halogen, a hydroxy, an ammo, a cyano, a sulfonami e, an aminocarbonyl , a trifluoromethyl, a group C 1 _ 6 alkoxy, (di) hydroxy-C 1 . 6 alkoxy or C ⁇ _ 4 alkyl, and R 7 represents a hydrogen atom or a C _ 2 alkyl group.
• the preferred compounds according to the invention are the compounds for which:
• A represents a piperidine (B), more especially A represents a piperidine (B) and R 5 represents a phenyl.
• z can take the values between 2 and 6, a carbon chain being able to have from 1 to z carbon atoms,
• a C x _ ⁇ alkyl group represents a carbon chain of 1 to 6 carbon atoms, linear or branched, or preferably from 1 to 6, and more particularly consists of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc;
• the compounds of general formula (I) can be in the form of free base, N-oxide or of addition salts with pharmaceutically acceptable acids, which also form part of the invention.
• the compounds of general formula (I) have one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
• the compounds of the invention can be prepared by methods illustrated in the diagrams which follow, the operating conditions of which are conventional for a person skilled in the art.
• Hydroxyketone (III) is opposed to an arylurea (R 5 NHCONH2) at 180 ° C in hexanol, optionally in the presence of molecular sieve, to lead to imidazolone (IV).
• This imidazolone (IV) can also be obtained from 1 alphahaloketone (V), by successive reactions of potassium phthalimide (PhtalK) then of concentrated hydrous bro acid and acetic acid, to lead first to hydrobromide 1 aminoketone (VI) which by treatment with a phenylisocyanate (R 5 NCO) in pyridine or dimethylformamide leads to the compound (IV).
• the imidazolone (IV) can be prepared as indicated in diagram 2 according to the method described in patent US3432520.
• R 5 -NCO phenylisocyanate
• XVI phenylisocyanate
• the compounds of formula (I) can be obtained from alphahaloketone of formula (V) which is thermally condensed with formamide to give the imidazole (VIII).
• This imidazole (VIII) is then subjected to the action of a bismuth triaryl ((R 5 ) 3 Bi) in the presence of copper acetate and triethylamine in dichloromethane to lead to imidazole (IX).
• the isothiocyanate of formula (XVIII) is brought into contact in an organic solvent such as toluene or dichloromethane with an acetal dialkyl of formula (XIX) to intermediate lead to a thiourea which is cyclized to imidazolinethione of formula (XX) in an aqueous solution (0.01 to 12 N) of hydrochloric acid.
• the imidazolinethione of formula (XX) can be S-methylated by successive action of sodium hydride and methyl iodide in dimethylformamide at temperatures between -20 ° C and 60 ° C, to give the compound of formula (X), or else by the action of methanol in hydrochloric acid at temperatures between 20 ° C and reflux.
• the sulfide (X) is oxidized to the sulfone (XI) by the action of Oxone ® (potassium peroxymonosulfate) in the presence of wet alumina.
• Oxone ® potassium peroxymonosulfate
• other oxidants can be used such as hydrogen peroxide or potassium permanganate in acetic acid.
• (R 4 and / or R ' 4 ) and / or (R 3 and / or R' 3 ) is a derivatizable functional group, it may be optionally oxidized, reduced, alkyl or dealkylated by conventional methods known from one skilled in the art.
• the ethyl isonipecotate is alkylated with the compound of formula (XVII), as defined above, to lead to the ester (XIII) which is reduced by the mixed lithium and aluminum hydride to give alcohol (XIV), according to methods known to those skilled in the art.
• the mixture is left to return to ambient temperature and is stirred again for 2 hours.
• the compound is purified by flash chromatography on silica, eluting with a CH 2 C1 2 / CH 3 0H 95: 5 mixture.
• the filtrate is concentrated under reduced pressure and then purified on a silica column using a dichloromethane / methanol mixture 99/1 then 98/2. 0.65 g of product is obtained.
• Example 10 1-Phenyl-2 fumarate - [[1- (phenylmethyl) piperidin-4-yl] methoxy] -4,5,6,7-tetrahydro-1H-benzimidazole
• Example 11 1-phenyl -2- (piperidin-4-ylmethoxy) -4, 5, 6, 7- tetrahydro- IH-benzimidazole
• Example 12 1-Phenyl-2- [[[1- (3-hydroxyphenyl ethyl) piperidin-4-yl] methoxy] -4,5,6,7-tetrahydro-1H-benzimidazole fumarate.
• the mixture is brought to reflux temperature for 4 hours.
• the product precipitates, it is filtered, washed with a little acetone, dried under vacuum at 50 °.
• aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and then brine. It is dried over magnesium sulfate, filtered and concentrated.
• the compounds of the invention have been the subject of pharmacological tests which have shown their interest as active substances in therapy.
• Membranes of CHO cells, in solution in 10 m TRIS-HC1 buffer, 2 M EDTA pH 7.2, expressing the human muscarinic receptor M 3 subtype were supplied by the company Receptor Biology (Baltimore, USA).
• the filters were washed three times with 4 ml of cold phosphate buffer, dried and the radioactivity was measured by liquid scintillation (scintillant Ultima Gold). The concentration of compound displacing the specific binding by 50% (IC 50 ) was used to calculate the Ki values according to the Cheng-Prusoff equation. The effectiveness of each product studied is expressed by the negative logarithm of their Ki (pKi).
• the IC 50 values of the compounds of the invention vis-à-vis the M 3 receptors are between 1 and 350 nM.
• the compounds of the invention have also been studied as to their antagonistic effects with respect to the contractions of the female rabbit detrusor, mediated by the M 3 receptors.
• Female rabbits New Zealanders, 3-4 kg; ESD supplier
• Female rabbits aged around 20 weeks were sacrificed by cervical dislocation and then bloodless. After opening the abdomen, the bladders were removed and quickly put in a bicarbonate solution of Krebs of composition (mM): NaCl: 114; KC1: 4.7; CaCl 2 : 2.5; MgSO 4 : 1.2; KH 2 P0 4 : 1.2; NaHCO 3 : 25,; ascorbic acid: 1.1; glucose: 11.7.
• mM Krebs of composition
• Propranolol (1 ⁇ M), methylsergide (1 ⁇ M), 1 ondansetron (1 ⁇ M), GR113808 (1 ⁇ M) were added to Krebs in order to inhibit the ⁇ -adrenergic receptors and the various subtypes of serotoninergic receptors, respectively.
• -HT x / 5-HT 2 , 5-HT 3 and 5-HT 4 The bladders were cleaned, degreased and each side was cut into two longitudinal flaps about 4 mm wide and 15 mm long. The tissues were then placed in 20 ml tanks thermostated at 37 ° C under carbogenic aeration (95% 0 2 , 5% C0 2 ) and were subjected to a basal tension of 1 g.
• the voltage was measured using isometric gauges (Hugo Sacks, type 351) connected to couplers (Gould) which transform and amplify the responses which will be traced on 4-track potentiometric recorders (Gould) and connected to a system of data acquisition (Jad, Notocord). A balancing time of approximately 45 minutes was observed during which the Krebs is renewed and the basal tension rectified.
• the concentrations producing half of the maximum effect were calculated for each range (absence or presence of the compound to be studied), then the power of the compound to shift the response curve to carbachol was determined by a calculation of the affinity of the antagonist (pK b or apparent pA 2 ) according to the method of Furchgott (Handbook of Experimental Pharmacology, 1972, 283-335).
• the pK b of the compounds of the invention are between 7 and 9.5.
• the compounds of the invention have also been studied as to their affinity for 5-HT 4 receptors in the guinea pig striatum, according to the method described by Grossman et al., In Br. J. Pharmacol., 109 , 618-624 (1993).
• the specific binding represents 90% of the total radioactivity recovered on the filter.
• the IC 50 values of the compounds of the invention are between 1 and 350 nM.
• the compounds of the invention were studied as regards their antagonistic effects with respect to the 5-HT 4 receptors in one rat esophagus.
• mice Male Sprague-Dawley rats weighing 300 to 450 g are used. We quickly remove a fragment of about 1.5 cm from the end part of the esophagus, we eliminate the muscular layer, we open the inner muscular mucous membrane longitudinally, we mount it in a tank with isolated organ containing a Krebs solution -Henseleit at 32 ° C oxygenated by a carbogenic current (95% 0 2 and 5% C0), and it is connected to an isometric transducer under a basal voltage of 0.5 g. The compounds are studied at a concentration of 1 ⁇ M. We measure their ability to displace the relaxation introduced by 5-HT (at concentrations of 0.1 nM) from the esophageal tissue pre-contracted to the P ⁇ M substance. The compounds of the invention are active in this test.
• the compounds of the invention in combination with suitable, pharmaceutically acceptable excipients, can be presented in all forms suitable for oral or parenteral administration, such as tablets, dragees, capsules, capsules, suspension or solutions for oral or injection injection, and dosages to allow administration of 0.1 to 50 mg / kg per day.

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• 1997
  • 1997-11-19 FR FR9714486A patent/FR2771093B1/fr not_active Expired - Fee Related
• 1998
  • 1998-11-17 US US09/554,138 patent/US6200991B1/en not_active Expired - Fee Related
  • 1998-11-17 EP EP98955672A patent/EP1032569A1/fr not_active Withdrawn
  • 1998-11-17 AU AU12433/99A patent/AU1243399A/en not_active Abandoned
  • 1998-11-17 JP JP2000521093A patent/JP2001523679A/ja not_active Withdrawn
  • 1998-11-17 WO PCT/FR1998/002446 patent/WO1999025710A1/fr not_active Application Discontinuation
  • 1998-11-18 AR ARP980105841A patent/AR023292A1/es not_active Application Discontinuation
  • 1998-11-18 CO CO98067821A patent/CO4990949A1/es unknown
  • 1998-11-18 ZA ZA9810558A patent/ZA9810558B/xx unknown
  • 1998-11-18 TW TW087119098A patent/TW448170B/zh not_active IP Right Cessation

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