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
  • C07D401/02—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
• • 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
• • 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
  • A61P1/12—Antidiarrhoeals
• • 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
• • 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
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • 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
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D249/12—Oxygen or sulfur atoms
• • 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 perazole derivatives, their preparation and their use in therapy.
• the first subject of the present invention is derivatives of perazoles (triazoles and tetrazoles) of general formula (I):
• the pair (A, B) represents (N, N), (N, C) or (C, N),
• R 2 and R 2 represent, independently of one another, a hydrogen atom, a group C l . 6 alkyl, C 2 _ 6 alkenyl or cyclo C 3 _ 6 alkyl,
• Ar 2 represents a phenyl radical or a pyridyl radical substituted by the groups R 3 , R ' 3 and R " 3 ,
• Ar 2 represents a phenyl radical substituted by the groups R 4 and R ' 4 ,
• R 3 , R ' 3 , R " 3 , R 4 and R' 4 represent, independently of one another, a hydrogen atom, a halogen atom, a C ⁇ alkyl, hydroxy, C ⁇ alkoxy, cyano, nitro, perfluoro-C ⁇ - 2 alkyl, amino, C x _ 4 alkyl-amino, d C ⁇ alkyl) - amino, C -, ..- alkoxycarbonyl-amino, alkoxycarbonyl) (C ... alkyl) -amino, aminosulfonyl, C ⁇ alkyl-aminosulfonyl or di (Ci. 4 alkyl) -aminosulfonyl, as well as their salts, N-oxides and hydrates.
• the preferred compounds according to the invention are chosen from the following subgroups, in which:
• R ⁇ and R 2 represent, independently of each other, a hydrogen atom, a C ⁇ alkyl, C 2 _ 4 alkenyl or cyclo C 3 _ 6 alkyl group, or
• R 3 ⁇ R ' 3 ⁇ R “ 3 , R 4 and R' 4 represent, independently of one another, a hydrogen atom, a halogen atom, a C ⁇ alkyl, hydroxy, C ⁇ alkoxy group , nitro, amino, C x _ 4 alkyl-amino, (C ⁇ alkoxycarbonyl) (C ⁇ alkyl) -amino, aminosulfonyl, more particularly R 3 R ' 3 and R " 3 represent a hydrogen when Ar x is a pyridine.
• a particularly preferred subgroup of compounds of formula (I) is that in which R 1r R 2 , R 3, R ' 3, R " 3 , R 4 and R' 4 are as defined above in the sub- groups of preferred compounds and A, B, Ar : and Ar 2 are as defined above.
• R 2 and R 2 represent, independently of one another, a hydrogen atom, a methyl, ethyl, propyl, isopropyl, vinyl, a cyclopropyl or cyclobutyl and R 3;
• R ' 3 and R " 3 represent, independently of one another, a hydrogen atom, a halogen atom, a C ⁇ alkyl group preferably a methyl, ethyl, propyl or isopropyl; hydroxy, ⁇ .
• R 4 and R ′ 4 represent, independently of one another, a hydrogen atom, a halogen atom, a hydroxy, a C x _ 2 alkoxy, nitro, amino group , (C 3 _ 4 alkoxycarbonyl) (C ⁇ alkyl) -amino, aminosulfonyl.
• z can take the values from 2 to 6, a carbon chain being able to have from 1 (2 or 3) to z carbon atoms,
• a group C ⁇ g alkyl represents a carbon chain of 1 to 6 carbon atoms, linear or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, etc; preferably methyl, ethyl, propyl, isopropyl, - perfluoroalkyl, an alkyl in which all the hydrogens have been replaced by fluorines,
• cycloalkyl a cyclic alkyl, for example, a C 3 _ 6 cycloalkyl group represents a cyclopropyl, cyclobutyl, cyclopentyl or a cyclohexyl, - alkenyl, a mono or polyunsaturated, linear or branched aliphatic group, preferably comprising 1 or 2 ethylenic unsaturations,
• leaving group is intended to mean a group which can be easily cleaved from a molecule, with the departure of an electronic pair, by breaking a heterolytic bond. This group can thus be easily replaced by another group during a nucleophilic substitution reaction for example.
• a leaving group is for example a halogen, a mesylate group (-S0 2 CH 3 ), triflate or tosylate
• the compounds of general formula (I) may contain one or more asymmetric carbons. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and their mixtures, including racemic mixtures, form part of the invention.
• the compounds of general formula (I) can be in the form of free base or of addition salts with acids, which also form part of the invention.
• These salts include those with mineral or organic acids which allow proper separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, by example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphosulfonic acid, and those which form physiologically acceptable salts, such as hydrochloride, hydrobromide, citrate, sulfate, hydrogen sulfate, dihydrogen phosphate, maleate, fumarate, pa oate, 2-naphthalenesulfonate, paratoluenesulfonate.
• salts are preferred, the other salts are part of the present invention.
• These salts can be prepared, according to methods known to a person skilled in the art, for example, by reaction of the compound of formula (I) in base form with the acid in an appropriate solvent, such as an alcoholic solution or a organic solvent, then separation of the medium which contains it by evaporation of the solvent or by filtration.
• the compounds of general formula (I) can also be in the form of N-oxide derivatives which form part of the present invention. These derivatives are obtained by oxidation reaction of the compound of formula (I) according to methods known to those skilled in the art.
• a second subject of the present invention is processes for preparing the compounds of formula (I).
• these compounds 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.
• the alcoholate is preformed by the action of a non-nucleophilic base such as sodium hydride, in an organic solvent such as dimethylformamide (DMF) or 1-methyl-2-pyrrolidinone (NMP) and at temperatures between -10 and 120 ° C.
• a non-nucleophilic base such as sodium hydride
• organic solvent such as dimethylformamide (DMF) or 1-methyl-2-pyrrolidinone (NMP)
• X will preferably be a mesylate group.
• X will preferably be a chlorine atom or a mesylate.
• X will preferably be a chlorine atom or a mesylate group.
• Diagram 2
• a compound of formula Ar 1 NHNH 2 in which rj is as defined above, is reacted with an aldehyde of formula RiCHO, in which R x is as defined above, in an acid medium such as hydrochloric acid and in the presence of sodium thiocyanate, to obtain a compound of formula (V) which is then oxidized by the action of oxygen in the presence of sodium hydroxide, to give a compound of formula (VI) (Bull Soc. Chim. Jpn., 46 (7), 2215-18, (1973)).
• an oxidant such as hydrogen peroxide, metachloroperbenzoic acid (MCPBA) or Oxone®
• a nitrile of formula (XV), in which R ⁇ is as defined in formula (I), is reacted with absolute ethanol in the presence of gaseous hydrochloric acid to lead to the alkylimidate of formula (XVI) according to the method described in J. Am. Chem. Soc, 1825, (1942).
• the alkylimidate of formula (XVI) thus obtained is N-carbethoxylated, according to the method described in J. Med. Chem., 36, 2558, 1993, with ethyl chloroformate in dichloromethane in the presence of triethylamine.
• This N-carbethoxyalkylimidate is then reacted with a hydrazine of formula (XVIII), in which Ar x is as defined above, (according to Angel. Chem. 75, 918 (1963)) in toluene at a temperature of approximately 50 ° C and then in the presence of triethylamine at a temperature of approximately 90 ° C to yield the triazolone of formula (XIX).
• the amine of formula Ar x NH 2 in which Ar x is as defined above is amidified by formic acid (Organic Syntheses, Coll. Vol. 3, 479-83) to obtain a compound of formula (X).
• the arylisocyanate of formula Ar x NCS is reacted with activated sodium triazide, at reflux of water according to the method described in Can. J. Chem., 37 . , 101-109 (1959), to obtain a compound of formula (XII).
• the compounds of formula (I), in which Ar 2 represents a phenyl radical as defined for the compounds of formula (I), but preferably where R 4 or R ′ 4 represent a hydrogen atom or an electron donor group can be modified to lead to other derivatives of formula (I) as indicated in scheme 7.
• the compounds of formula (I), in which A, B, R ,, R 2 , Ar lr n and m are as defined in formula (I) and Ar 2 is as defined above are debenzylated by the action of ammonium formate at the reflux of methanol in the presence of a catalytic amount of palladium on carbon to lead to the derivatives of formula (XIV).
• the debenzylation reaction can be carried out by the action of hydrogen in a solvent such as methanol or ethanol in the presence of a catalytic amount of palladium on carbon and optionally hydrochloric acid.
• Ar x , n and m are as defined above, are new and form part of the invention.
• the starting compounds in particular the compounds (XV), (XVI) (XVII), (XVIII), Ar ! NH 2 , Ar ⁇ NCS, A ⁇ NCO, Ar 2 CHO, Ar 2 CH 2 X are commercially available or described in the literature, or can be prepared by methods described therein or which are known to man of career.
• the following examples illustrate the methods and techniques used for the preparation of this invention, without however limiting the scope of the claim.
• Elementary micro-analyzes and NMR, IR or mass spectra confirm the structures of the compounds obtained.
• Example 3 5- (Methylsulfonyl) -1-phenyl-1H-1,2,4-triazole.
• Example 6 3-Methyl-5- (methylthio) -1-phenyl-1H-1,2,4-triazole.
• Example 7 3-Methyl-5- (methylthio) -4-phenyl-4H-1,2,4-triazole.
• Example 8 4- [[(3-Methyl-1-phenyl-1H-1,2,2,4-triazol-5-yl) oxy] methyl] -1- (phenylmethyl) piperidine.
• Example 10 4- [[(1-Phenyl-ltf-tetrazol-5-yl) oxy] methyl] piperidine.
• Example 12 3-Hydroxyphenyl) -3-methyl-5- [[1- (phenylmethyl) piperidin-4-yl] methoxy] - 1H-1, 2, 4-triazole.
• the pH of the solution obtained is brought to 8 with 1M sodium hydrogen carbonate.
• the mixture is purified by chromatography on silica gel, eluting with a gradient of the dichloromethane: methanol: ammonia mixture of 99: 1: 0.1 to 98: 2: 0.2. 0.33 g of solid is thus obtained.
• Example 14 Azide (-methylphenyl) carbamic.
• N- (4-methylphenyl) hydrazinecarboxamide in 26 ml of IN hydrochloric acid a solution of 1.82 g of sodium nitrate in 11 ml of water is slowly added at 15 ° C. After 1 hour of stirring, it is filtered, washed with water, dried at 30 ° C. and under vacuum with phosphorus pentoxide. 4.04 g of ocher crystals are obtained.
• Example 16 4- [[[1- (4-Methylphenyl) -1H-tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine.
• Example 17 1- (4-Fluorophenyl) -liT-tetrazole-5-thiol.
• a solution of 15 g of sodium triazide in 45 ml of water is added with 1.5 ml of hydrazine hydrate. After crystallization from acetone, filtration, washing with acetone, drying under vacuum under a stream of nitrogen, 11.95 g of activated nitrogen triazide are obtained.
• Example 18 1- (4-Fluorophenyl) -5- (methylthio) -1H- tetrazole.
• Example 19 1- (4-Fluorophenyl) -5- (methylsuifonyl) -1H-tetrazole.
• Example 20 4- [[[1- (-Fluorophenyl) -ltf- tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine,
• Example 21 5-Methyl-2-phenyl-2,4-dihydro-3tf-1,2,4-triazole -3-one.
• Example 22 5-chloro-3-Methyl-1-phenyl-ltf-1,2,4-triazole.
• Example 23 1- (2-fluorophenyl) -3-methyl-5- [[1- [(3-methoxyphenyl) ethyl] -piperidin-4-yl] methoxy] - Itf-triazole.
• the aqueous phase is exhausted with ethyl acetate, and the combined organic phases washed with water, with brine, dried over sodium sulfate, filtered and concentrated.
• the crude is purified by chromatography on silica gel, eluting with a methanol gradient of 5 to 10% in dichloromethane. After concentration and drying under vacuum, 6.93 g of oil are thus recovered.
• Example 25 1- (2-fluorophenyl) -3-methyl-5- [[1- [(3-hydroxyphenyl) methyl] -piperidin-4-yl] methoxy] - ltf-triazole hydrochloride
• the aqueous phase is made alkaline and then extracted with ethyl acetate.
• the organic phases are combined and dried over sodium sulfate and concentrated.
• the crude product is purified by chromatography on silica gel, eluting with ethyl acetate / methanol / ammonia 99 / 0.5 / 0.5.
• Example 27 1-phenyl-3-methyl-5- [[1- [3-aminophenylmethyl] -piperidin-4-yl] methoxy] -ltf-triazole.
• Example 28 1-phenyl-3-methyl-5- [[1- [2,3-dihydroxyphenylmethyl] -piperidin-4-yl] methoxy] -ltf-triazole.
• Ar x phenyl group (or pyridyle when indicated by “*" next to the number) substituted by R 3 , R ' 3 and R “ 3 ;
• R ' 3 and R " 3 are hydrogen atoms unless otherwise indicated in parentheses,
• Ar 2 phenyl group substituted with R 4 and R ' 4 ;
• R ' 4 is a hydrogen atom unless otherwise indicated in parentheses
• the compounds of the invention have been the subject of pharmacological tests which have shown their interest as active substances in therapy.
• 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 50% the specific bond (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 pKi of the compounds of the invention vis-à-vis the M 3 receptors are between 6 and 9.5.
• 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 then quickly placed 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.
• l ⁇ M GR113808
• 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
• the pK b of the compounds of the invention are between 6 and 9.5.
• the compounds of the invention have also been studied as regards their affinity with respect to 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).
• Guinea pigs (Hartley, Charles River) weighing 300 to 400 g are euthanized and their brains removed.
• the striata are excised and frozen at -80 ° C.
• the homogenate is centrifuged for 10 minutes at 48000 ⁇ g, the pellet is recovered, it is resuspended and it is again centrifuged under the same conditions.
• the final pellet is suspended in Hepes-NaOH buffer (30 mg of fresh tissue / ml). This membrane suspension is used as it is.
• the incubation is stopped by filtration on hatman GF / B® filters, previously treated with 0.1% polyethyleneimine, each tube is rinsed with 4 ml of buffer at 0 ° C. and filtered again.
• the radioactivity retained on the filters is measured by liquid scintigraphy.
• the non-specific binding is determined in the presence of 30 ⁇ M serotonin.
• 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 3500 nM.
• the compounds of the invention were studied as regards their antagonistic effects with respect to the 5-HT 4 receptors in the rat esophagus.
• a 5-HT 4 and M 3 receptor antagonist can therefore be used in the treatment of pathologies where a 5-HT 4 and M 3 receptor antagonist provides a therapeutic benefit.
• they can be used in the treatment of irritable bowel syndrome, memory impairment, airway obstruction and bladder instability, especially emergency urinary incontinence.
• the present invention relates to pharmaceutical compositions containing, as active principle, a compound according to the invention.
• these pharmaceutical compositions contain an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt, N-oxide or hydrate thereof, and one or more suitable pharmaceutical excipients.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration
• the active principle of formula (I) above, its salt or hydrate, if any can be administered in unit administration form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
• Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal administration forms, subcutaneous, intramuscular or intravenous administration and forms of rectal administration.
• the compounds according to the invention can be used in creams, ointments or lotions.
• the dose of active principle can vary between 0.1 mg and 50 g per kg of body weight per day. Although these dosages are examples of an average situation, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.
• Each unit dose can contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, of active ingredient in combination with one or more pharmaceutical excipients. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 0.5 to 2500 mg.
• the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• a pharmaceutical excipient such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• the tablets can be coated with sucrose, a cellulose derivative, or other materials.
• the tablets can be produced by different techniques, direct compression, dry granulation, wet granulation or hot melting.
• a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
• aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
• the present invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of a compound according to the invention or one of its salts or hydrates.

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