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WO2001002386A1 - ANTAGONISTES SELECTIFS DU RECEPTEUR MUSCARINIQUE M2 PRESENTANT UNE STRUCTURE 5H-DIBENZ[b,f]AZEPINE - Google Patents

ANTAGONISTES SELECTIFS DU RECEPTEUR MUSCARINIQUE M2 PRESENTANT UNE STRUCTURE 5H-DIBENZ[b,f]AZEPINE Download PDF

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Publication number
WO2001002386A1
WO2001002386A1 PCT/EP2000/006020 EP0006020W WO0102386A1 WO 2001002386 A1 WO2001002386 A1 WO 2001002386A1 EP 0006020 W EP0006020 W EP 0006020W WO 0102386 A1 WO0102386 A1 WO 0102386A1
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Prior art keywords
dibenz
azepine
nch
diethylamino
compounds
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Inventor
Patrizia Maria Luisa Terni
Giacomina Roberta Mandelli
Stefano Maiorana
Bruno Pietro Imbimbo
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Mediolanum Farmaceutici SpA
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Mediolanum Farmaceutici SpA
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    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the present invention relates to novel pharmacologically active 5H-dibenz[b j ]azepine derivatives, the pharmaceutical compositions containing them and the use of such compounds/compositions for the treatment of cardiovascular disorders, more specifically bradycardia and brady arrhythmia and for treatment of cognitive disorders such as Alzheimer's disease.
  • Muscarine cholinergic receptors are present in a number of tissues. The activation of these receptors through their neurotransmitter, acetylcholine, can elicit different effects such as the increase in gastrointestinal motility, miosis, increase in the salivary and intestinal secretions, eminction stimulus, bradycardia. More particularly, M2 receptors are present in the cardiac tissue at post-synaptic level, and in hippocampus and cerebral cortex at pre-synaptic level (inhibitor autorececeptors).
  • Post-synaptic M2 receptors play a paramount role in the regulation of vagus nerve-mediated heart rate. Hyperstimulation of M2 receptors causes an increase in the parasympathetic activity and therefore is apparently an important risk factor in the sick sinus syndrome and in atrioventricular block. IV receptor antagonists may therefore be used in the treatment of atrial sinus functional disorders. Compounds with this type of activity are known, such as AF-DX 1 16
  • Pre-synaptic M2 receptors modify the acetylcholine release through a negative feedback mechanism.
  • the release of endogenous acetylcholine can be promoted by blocking these receptors with selective antagonists.
  • the increase in acetylcholine can improve cognitive performance under hypofunctionality conditions of the cholinergic system as is the case with Alzheimer's disease.
  • acetylcholinesterase inhibitors such as tacrine (New Engl. J. Med.
  • the present invention aimed at finding muscarine M2 receptors antagonists capable of promoting the cholinergic central transmission without inducing serious side effects.
  • the present invention relates to a novel class of 5H-dibenzo[b,fJazepine derivatives having high activity and selectivity for muscarine M2 receptors, long half-life, and without side effects.
  • the novel compounds are potentially useful in the treatment of cardiovascular disorders, in particular in the treatment of sinus bradycardia, sick sinus syndromes, disorders of atrio-ventricular conduction and bradyarrhythmias, or in the treatment of cognitive and neurodegenerative disorders such as Alzheimer's disease.
  • These novel derivatives have the general formula (I)
  • R ⁇ represents hydrogen or linear or branched C ⁇ _4 alkyl
  • R2 represents linear or branched C ⁇ _4 alkyl, phenyl, benzyl or phenethyl
  • R3 represents hydroxyl, linear or branched C 1.4 alkoxy, phenoxyl
  • m and n are independently an integer 1 to 10.
  • X-Y is CH2-CH2 and the alkylamino group is substituted at the piperidine at the 2- position.
  • X-Y is CH2-CH2 and the alkylamino group is substituted at the piperidine at the 3- position.
  • X-Y is CH2-CH2 and the alkylamino group is substituted at the piperidine at the 4- position.
  • the compounds of formula (I) can be salified with pharmacologically acceptable inorganic or organic acids selected, for example, from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, malonic acid, gluconic acid, salicylic acid, succinic acid, lactic acid and the like.
  • hydrochloric acid sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, malonic acid, gluconic acid, salicylic acid, succinic acid, lactic acid and the like.
  • the compounds of the present invention have the following general formula:
  • R ⁇ represents hydrogen or a linear or branched C ⁇ _4 alkyl;
  • R2 represents a linear or branched Cj_4 alkyl, phenyl, benzyl or phenylethyl;
  • R3 represents hydroxyl, linear or branched Cj_4 alkoxyl, phenoxyl;
  • m and n are independently an integer 1 to 10.
  • novel 5H-dibenz[b j ]azepine derivatives having formula (I) can be prepared by reacting of haloacyl derivatives (II), wherein Hal can be chlorine, bromine or iodine, with an amine of formula (III), according to the following process:
  • the amination reaction is carried out in an inert solvent at a temperature between 0°C and the boiling temperature of the solvent.
  • the amine (II) is typically present in a two fold excess, or in one or two fold excess and in the presence of an auxiliary base.
  • the reaction may be carried out in chlorinated solvents such as dichloromethane, chloroform, dichloroethane; aromatic solvents such as benzene, toluene, chlorobenzene, pyridine; ketones such as acetone, acetonitrile, dimethylformarnide; alcohols such as methanol, ethanol, isopropanol.
  • the auxiliary base may be an organic base such as triethylamine, N,N-dimethylaniline, pyridine, 4-(dimethylamino)pyridine, or a organic base such as carbonate or hydrogen carbonate of alkali and alkaline earth metals.
  • the reaction may be accelerated by adding catalytic amounts of alkali metal iodides. The reaction is typically carried out for a period of 30 minutes to 10 hours, depending on the compound (I) and amine (III) used.
  • the other compounds of formula (II) may be prepared by reacting a
  • Hal and Hal' which are the same or different, can be chlorine, bromine or iodine.
  • the acylation is carried out in an inert solvent, at a temperature between room temperature and the boiling temperature of the solvent, preferably in the presence of an auxiliary base.
  • the reaction may be carried out in chlorinated solvents such as dichloromethane, chloroform, dichloroethane; aromatic solvents such as benzene, toluene, chlorobenzene; cyclic or acyclic ethers such as diisopropyl ether, tetrahydrofuran, dioxane.
  • the auxiliary base may be an organic base such as tnethylamine, N,N-dimethylaniline, pyridine, 4-(dimethylammo)pyridine, or an organic base such as carbonate or hydrogen carbonate of alkali and alkaline earth metals.
  • the methanesulfonyl derivative (XIII) is treated with methylamine 40% in water in acetonitrile at room temperature to give amino derivative (XVI).
  • This compound is benzoylated with benzoyl chloride and sodium hydroxide in acetone at room temperature to give amide (XVII).
  • the N-debenzylation of (XVII) with 10% palladium on activated carbon and ammonium formate in methanol at reflux gives (XVIII).
  • the reduction of (XVIII) with lithium aluminum hydride in tetrahydrofuran at reflux gives 4-[4-(N-benzyl-N-methylamino)butyl]piperidine (XIX).
  • the 4-[4-(diethylamino)heptyl]piperidine (XXIII) is prepared from 4-picoline and 6-bromohexanoyl chloride with the following procedure.
  • the amide (XX) is obtained by reacting 6-bromohexanoyl chloride and diethyl amine in acetonitrile at room temperature.
  • Compound (XX) is treated with 4-picolyl sodium, obtained from 4-picoline and sodium amide 50% in toluene, to give (XXI).
  • the hydrochloride of (XXI) obtained by treatment with a solution of hydrogen chloride in methanol, is hydrogenated with 5% platinum oxide under atmospheric pressure and room temperature, in acetic acid to give (XXII).
  • the reduction of (XXII) with lithium aluminum hydride in tetrahydrofuran under reflux gives 4-[4-(diethylamino)heptyl]piperidine (XXHl).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as active ingredient, in association with a pharmaceutical acceptable carrier, excipient or other additive, if necessary.
  • the pharmaceutical compositions containing a compound of formula (I) can be administered, for example, through the oral, parenteral, rectal, transdermal routes, in the form of capsules, tablets, solutions, suppositories, ointments and the like.
  • the daily dosage will depend on a number of factors, such as the type of disease and the conditions of the patient (weight, sex and age) and it will be determined according to standard procedures on the basis of the pharmacokinetic and toxicological characteristics of each compound. An average daily dosage will typically comprise 0.1 to 10 mg/kg.
  • 4-phosphonocrotonate (25.63 g, 92.2 mmol) were dissolved in 60 mL of absolute ethanol and cooled to 0 - 5°C, under a nitrogen atmosphere.
  • Metal sodium (2.76 g, 119.9 mmol) dissolved in 150 mL of absolute ethanol was added dropwise to the cooled solution at below 5°C during 40 min. The solution was stirred at 5°C for 45 min and 1 h at room temperature.
  • the reaction mixture was diluted with 600 mL of brine and extracted with diethyl ether (5 x 100 mL).
  • Triethylamine (6.4 ml, 45.8 mmol) and (XII) (1 1.23 g, 45.4 mmol) were dissolved in 60 mL of tetrahydrofuran and cooled to 0°C.
  • Methanesulfonyl chloride (3.6 mL, 45.8 mmol) dissolved in 20 mL of tetrahydrofuran was added dropwise, while maintaining the reaction temperature below 5°C. The mixture was stirred for 45 min at this temperature and then warmed to room temperature. The resulting suspension was diluted with 60 mL of diethyl ether and the insoluble precipitate was filtered off.
  • the aqueous layer was basified with 40% aqueous NaOH and extracted with diethyl ether (3 x 80 mL). The combined organic phases were washed with water, dried over Na2S ⁇ 4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with petroleum ether-acetone-triethyl amine (16:4:0.5, v/v/v). After evaporating the solvent, the residue was dissolved in diethyl ether and washed with water (3 x 100 mL).
  • Membranes of Hamster ovarian cells (Receptor Biology, Beltsville, MD, USA) expressing human Mi , M 2 , M3 or M4 receptors were suspended in a 10 mM Tris- HCl solution at pH 7.2 containing 2 mM EDTA (plus 10% sucrose in the case of Mi , M3 and M4 receptors). Aliquots of the membrane fractions (0.02 mL) were incubated in duplicate with 10 increasing concentrations (from 10" 10 to 10"5 M) of the reference (4-DAMP) or test compounds.
  • the radioligand [3H]N-methylscopolamine ([3H]NMS) was added to the membrane preparations at the final concentration of 0.5 nM for Mi , M 2 , M4 receptors and 0.1 nM for M3 receptors.
  • the membrane preparations were incubated for 60 min at 25°C or 27°C.
  • Atropine 2.5 ⁇ M for M ⁇ receptors, 1 ⁇ M for M2 receptors, 0.5 ⁇ M for M3 and M4 receptors
  • the assay was terminated by rapid filtration under suction through Whatman GF/B glass fiber filters using a Tomtec 96 well harvester.
  • AF-DX 116 for M 2 receptors. Compared to AF-DX 116 the compounds of the
  • Examples 1 and 13 exhibit a better selectivity profile.
  • Guinea-Pig Atrium Isolated left atria were prepared from male or female Duncan Hartley derived guinea pigs weighing 325 ⁇ 25 g. Animals were sacrificed by C0 2 overexposure. Each atria was placed under 1 g tension in a 10 ml bath containing McEwen's solution at pH 7.4, bubbled with 95% 0 2 /5% C0 2 at 32 °C and subjected to field stimulation by 70% maximum voltage, 2.5 Hz at 0.5 msec pulse width. The left atria was connected to an isometric transducer and two pen recorders and allowed to equilibrate for 60 minutes before initiating the field stimulation. Each tissue was accepted for experimental use only if 1 g or more of tension was obtained.
  • Cumulative relaxation-response curve to methacholine was then generated with consecutive applications of 9 concentrations in 3 -fold increments ranging from 1 nM to 10 ⁇ M at 2 minutes intervals for a total of 18 minutes to establish the maximal response.
  • similar methacholine concentration-response were carried out in the presence of test compound concentration (low, middle and high), following a 15 minutes incubation period.
  • pA 2 values for test compounds were calculated by linear regression of the corresponding Schild plots. Table 2 reports the pA 2 values for the compounds of the Example 1, 6, 13.
  • Guinea-Pig Ileum Guinea-Pig Ileum. Segments (2-3 cm) of proximal ileum were suspended in 30 mL Tyrode solution at 37 ⁇ 1 °C. The preparation was connected to an isometric strain gauge and was kept at a resting tension of 1 g. The changes in tension were registered through a polygraphic recorder. The ileum was stimulated with a sub-maximal concentration of acetylcholine (0.03 ⁇ M) every 4-5 minutes. The drugs were prepared in physiological saline solution. The activity of test compounds under investigation was expressed as a percent inhibition of the contraction induced by acetylcholine. The IC50 was calculated by non-linear regression. Table 2 reports the IC50 values for the compounds of the Example 1, 6, 13.
  • Antibradycardic activity of the Example 1 was evaluated in vivo in comparison to AF-DX 116.
  • the effects of these compounds on acetylcholine- induced bradycardia in rats were evaluated after intravenous and intraduodenal administration.
  • Heart rate and blood pressure were recorded and analyzed with the software HEM (Notocord, Croissy sur Seine, France).
  • Another catheter was introduced in the left jugular vein for acetylcholine perfusion.
  • a third catheter was introduced in the right jugular vein for vehicle, test or reference compound administration.
  • acetylcholine 50 ⁇ g/min/kg was continuously infused intravenously until stabilization of the blood pressure.
  • Vehicle sterile saline, 1 mL/kg
  • Test compounds were then injected as boluses at increasing concentration (10, 50, 250 ⁇ g/kg).
  • atropine (10 ⁇ g/kg) was injected intravenously.
  • mice were killed by urethane overdose. Four animals were used for each dose of the test compounds. ED50 values were estimated by non-linear regression and expressed as mean ⁇ SEM. Table 3 reports the ED50 values of the compounds of the Example 1 and AF-DX 116 for systolic blood pressure and heart rate.
  • Example 1 when administered intravenously in the rat, is able to antagonize an acetylcholine action mediated by M2 muscarinic receptor subtypes.
  • the effect of this compound was not significantly different
  • rats were killed by urethane overdose. Ten animals were used for each dose of test compounds. Five rats were employed for the vehicle administration. Statistical comparisons were carried out using one- way analysis of variance for completed randomized block. The test compounds were administered as maleate salts.
  • FIG. 1 represents the effects of the Example 1 and AF-DX 116 on the acetylcholine-induced bradycardia in the rat.
  • the compound of the Example 1 was able to counteract the acetylcholine-induced bradycardia in a dose — dependent fashion. At the dose of 15 mg/kg, this compound appeared more effective then AF-DX 116. HEMODYNAMIC EFFECTS IN CONSCIOUS DOGS.
  • Example 1 The effects of oral administration of the Example 1 on nocturnal bradycardia were investigated in conscious freely moving dogs. The effects of this compound on cardiac conduction times as well as on systolic and diastolic blood pressure were also evaluated. Experiments were performed on 8 beagle dogs, 4 males and 4 females, weighing between 11 kg and 13 kg.
  • Hemodynamic variables and electrocardiograms were recorded using a surgically implanted telemetric transmitter (model TL2M10-D70, Data Science Inc., St. Paul, Minnesota) in freely moving animals. Implantation was performed at least 10 days before the drug administrations under general anaesthesia (20 mg/kg i.v. thiopental followed by 1-1.5% i.v. halothane).
  • the telemetric transmitter was implanted in the left flank and the sensor catheter was introduced into the femoral artery of the animals.
  • the ECG leads of transmitters were placed in lead II, with one electrode on the right forelimb and one electrode on the left hindlimb. Measurements were done in the animal room.
  • Data were transmitted to an on-line-data acquisition system by means of a RLA2000 radio receivers (Data Science Inc., St. Paul, Minnesota).
  • a sampling rate of 500 Hz and an ART 1.0 telemetry data acquisition system (Data Science Inc., St. Paul, Minnesota) were used.
  • Heart rate, systolic and diastolic blood pressure were measured for 15 seconds every 5 minutes and averaged over 1-hour periods.
  • Electrocardiogram (lead II) was recorded for 15 seconds every 5 minutes and values of conduction times were determined at each time point. Measurements began at least one hour before drug administration and lasted for 12 (for QT and PR and QRS intervals) or 24 (for heart rate, systolic and diastolic blood pressure) hours after dosing. Any gross behavioural or autonomic changes, observed during the experiment, were recorded.
  • Placebo and the Example 1 (2, 4 and 8 mg/kg) were orally administered according to a randomised four-way, crossover design with a washout period of at least one week.
  • the drug was administered as a maleate salt and formulated in gelatine capsules. Administrations were done approximately at 10:00 p.m. by oral gavage.
  • Figure 2 shows the time course of heart rate for placebo and 3 doses of the Example 1 during the 24 hours post-treatment.
  • Example 1 antagonised the nocturnal bradycardia and shortened QT interval.
  • the effect of the drug reached statistically significance, compared to placebo, with the highest dose of 8 mg/kg (+19%» on heart rate and -4% on QT interval).
  • the effect on heart rate lasted for the entire 24-hour observation period.
  • Nocturnal systolic and diastolic blood pressure were not significantly affected by the Example 1.
  • No other signs of peripheral or central cholinergic block were observed at any dose.
  • the results of this study demonstrated that oral administration of the Example 1 produces long- lasting hemodynamic effects in the conscious dogs. IN VrVO FUNCTIONAL SELECTIVITY.
  • Example 1 and AF-DX 116 were examined at the dose of 15, 50 and 150 mg/kg by the oral route and administered to groups of 8 animals. Atropine (20 mg/kg) was used as positive control drug. Wistar rats (200 - 300 g) were used in this study. Animals were housed in cages of standard dimension with sawdust. The animal house was kept at a temperature of 19 - 23°C and a relative humidity of 45 - 65% with non-recycled filtered air changed approximately 10 times per hour.
  • the stomach was cut longitudinally and placed in 30 mL of a 0.9% NaCl solution. Twenty-four hours after, the stomach was removed and the volume adjusted to 36 ml with 0.9% NaCl and 4 mL of 1 M NaOH was added. After homogenization, the mixture was centrifuged at 3,000 rpm for 10 minutes. Phenol red concentrations were measured by spectrophotometry at 550 nM.
  • Intestinal Transit Time in Rats Intestinal transit time was evaluated by measuring the distance covered in the intestines by a suspension of vegetal charcoal orally administered. Compound of the Example 1 and AF-DX 116 were examined at the dose of 15, 50 and 150 mg/kg by the oral route and administered to groups of 8 animals. Atropine (20 mg/kg p.o.) was used as positive control drug. Wistar rats (200 -300 g) were used in this study. Animals were housed in cages of standard dimension with sawdust. The animal house was kept at a temperature of 19 - 23°C and a relative humidity of 45 - 65% with non-recycled filtered air changed approximately 10 times per hour. A 12-hour day-night cycle was adopted (7.30 a.m.
  • Salivary Secretion in Rats Salivary secretion was evaluated by measuring the weight gained by sublingual foam cubes after subcutaneous administration of oxotremorine. Compound of the Example 1 and AF-DX 116 were examined at the dose of 15, 50 and 150 mg/kg by the oral route and administered to groups of 8 animals. Atropine (10 mg/kg p.o.) was used as positive control drug. Male Sprague-Dawley rats (200 - 300 g) were randomly allocated to test treatments. Fifty minutes after test compounds or vehicle administration, rats were injected subcutaneously with oxotremorine (0.5 mg/kg).
  • Pupil Diameter in Rats Pupil diameter was evaluated under constant bright light with a dissecting microscope. Compound of the Example 1 and AF- DX 116 were examined at the dose of 15, 50 and 150 mg/kg by the oral route and administered to groups of 8 animals. Atropine (0.3 mg/kg p.o.) was used as positive control drug. Sprague-Dawley rats (200 - 250 g) were randomly allocated to test treatments. Pupil diameter was measured just before and 60 minutes after test compounds of vehicle administration.
  • a battery of 14 tests was carried out for compound of the Example 1 at Huntingdon Life Sciences (Huntingdon, U.K.) to explore a wide range of potential activities of the compound in a series of standardized in vivo and vitro models.
  • Pulmonary thromboembolism 100 mg/kg p.o. inactive
  • Example 1 The compound of the Example 1 was ineffective in all the activities explored, thus confirming a very selective pharmacological profile. In the Irwin test no abnormal signs were observed and no deaths occurred during the 7-day post-dose observation period at any of the doses tested. EFFECTS ON CORTICAL RELEASE OF ACETYLCHOLINE IN RATS An in vivo microdialysis study was carried out to examine the effects of the Example 1 on cortical release of acetylcholine in rats. A modified version of the microdialysis technique described by Cuadra et al. (7 Pharmacol Exper Ther 1994; 270: 277-284) was adopted.
  • Rats Male Sprague-Dawley rats (250-330 g) were used. Rats were anesthetized with sodium pentobarbital (50 mg/kg i.p.) and mounted in a Kopf stereotaxic frame, with the incisor bar at 3.3 mm below intramural zero. Animals were implanted with a dialysis fiber inserted transversally in the cortex ( coordinates vs. bregma: A + 1.0 and V — 2.0). The probe was secured to the skull with screws and dental cement and the skin was sutured. Rats were placed into individual acrylic bowls and left to recover for at last 16 hours without perfusion. The experiment was commenced the following day.
  • the microdialysis probe was connected to a 2-channel swivel and perfused with Ringer's solution (147 mM NaCl; 4.0 mM KC1; 4.0 mM CaCl 2 ) at the constant flow rate of 3 ⁇ L/min. Donepezil 3 ⁇ M was added to the Ringer's solution to prevent the hydrolysis of acetylcholine.
  • the compound of the Example 1 was administered at time 0 after collecting baseline samples 90, 60 and 30 minutes prior to the administration. The compound was administered as maleate salt at the final concentrations of 3, 15 and 50 ⁇ M. It was dissolved in Ringer's solution and administered intracortically via the dialysis probe.
  • the mobile phase (100 mM Na 2 HP04; 0.5 mM tetramethyammonium chloride; 0.005%) Reagent MB microbicide; 2.0 mM 1-octanesulfonic acid salt and 150 ⁇ M EDTA; pH 8.0) was filtered before passing trough a Prodigy ODS3 analytical column (C18 reverse phase, 5 ⁇ m, 150 x 3.2 mm, Phenomenex) at a flow rate of 0.600 mL/min. The column was coupled to an immobilized enzyme reactor containing acetylcholinesterase to convert acetylcholine to choline and acetic acid.
  • the enzyme reactor also contained choline oxidase, which converts choline to betaine and hydrogen peroxide. Electrochemical detection of the latter was performed using an ECD with a platinum electrode set a +300 mV. The columns were maintained at the constant temperature of 35° C. The peaks of ACh in brain dialysates were displayed, integrated and stored by means of a Kontron Instrument 450. Quantification was made by comparing peak heights of the samples to a standard curve.
  • Figure 3 reports mean cortical acetylcholine concentrations after intracortical administration of the Example 1. The results of this study demonstrated that the compound of the Example 1, intracortical administered, was able to increase the acetylcholine concentrations in the rat cortex in a dose-response fashion. ANALGESIC ACTIVITY IN MICE.
  • mice Male Swiss albino mice (20 - 30 g) were used. Animals were kept at 22 ⁇ 1 C° with a 12-hour light- dark cycle, with food and water ad libitum. Mice were placed on a stainless steel thermostat plate set at 50 ⁇ 0.1 C°. A plastic cylinder was used to confine the mice to the heated surface of the hot-plate.
  • the licking latency was defined as the time elapsing from thermal exposure and the licking of the fore or hind paws.
  • a cut-off time of 75 seconds was adopted for licking latency in order to avoid unethical suffering and injury of animals.
  • Mean baseline licking latency was determined with three measurements before test compounds administration. Test compounds were administered by subcutaneous route to groups of 12 - 17 animals. Compound of the Examples 1, 6, 13 and AF-DX 116 were evaluated at the doses of 5 mg/kg. Oxotremorine (0.2 mg/kg s.c.) was used as positive control drug. After test compounds administration, licking latencies were measured at 15-min intervals for 150 min. Statistical comparisons were carried out using repeated measures analysis of variance.
  • Figure 4 reported the licking latencies (mean ⁇ SEM) after subcutaneous administration of oxotremorine (0.2 mg/kg), AF-DX 116 (5 mg/kg) and compounds of the Example 1, 6 and 13 (5 mg/kg) to groups of 12-17 mice. Compounds of the Example 1, 6, 13 and AF-DX 116 produced weak and transient effects on licking latencies suggesting a poor penetration of the blood brain barrier.

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Abstract

L'invention concerne de nouveaux dérivés de la 5H-dibenzo[b,f]azépine représentés par la formule (I) dans laquelle X-Y représente CH2-CH2, CH=CH, CH=CR3; R1 représente hydrogène ou alkyle C1-4 linéaire ou ramifié; R2 représente alkyle C1-4 linéaire ou ramifié, phényle, benzyle ou phénéthyle; R3 représente hydroxyle, alcoxy C1-4 linéaire ou ramifié, phénoxyle; m et n valent indépendamment un entier compris entre 1 et 10. Ces composés sont capables de bloquer sélectivement les récepteurs muscariniques M2 et peuvent être utilisé dans le traitement de troubles cardio-vasculaires, notamment les bradycardies et les bradyarythmies, et dans le traitement de troubles cognitifs, tels que la maladie d'Alzheimer.
PCT/EP2000/006020 1999-07-01 2000-06-28 ANTAGONISTES SELECTIFS DU RECEPTEUR MUSCARINIQUE M2 PRESENTANT UNE STRUCTURE 5H-DIBENZ[b,f]AZEPINE Ceased WO2001002386A1 (fr)

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AU59796/00A AU5979600A (en) 1999-07-01 2000-06-28 Selective m2 muscarinic receptor antagonists having 5h-dibenz[b,f]azepine structure

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ITMI99A001452 1999-07-01
IT1999MI001452A ITMI991452A1 (it) 1999-07-01 1999-07-01 Antagonisti selettivi per i recettori m2 con struttura 5h-dibenzo b,fazepinica

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021545A3 (fr) * 2006-08-18 2008-04-03 Vertex Pharma Modulateurs des récepteurs muscariniques
WO2009015897A1 (fr) * 2007-08-02 2009-02-05 Recordati Ireland Limited Nouveaux composés hétérocycliques servant d'antagonistes du mglu5
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
US7858635B2 (en) 2005-12-22 2010-12-28 Vertex Pharmaceuticals Incorporated Spiro compounds as modulators of muscarinic receptors
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7879834B2 (en) 2004-08-19 2011-02-01 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7973162B2 (en) 2007-10-03 2011-07-05 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
EP3324966A4 (fr) * 2015-07-20 2019-04-10 Chase Pharmaceuticals Corporation Combinaison muscarinique d'un antagoniste sélectif du récepteur m2 et d'un antagoniste non sélectif périphérique pour le traitement de troubles hypocholinergiques
CN115448871A (zh) * 2022-08-30 2022-12-09 中国药科大学 一种盐酸替罗非班的制备方法

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Cited By (20)

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Publication number Priority date Publication date Assignee Title
US7879834B2 (en) 2004-08-19 2011-02-01 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US8497295B2 (en) 2004-08-19 2013-07-30 Vertex Pharmaceuticals Incorporated Spiroindoline modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
US8367691B2 (en) 2004-08-19 2013-02-05 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8258148B2 (en) 2004-08-19 2012-09-04 Vertex Pharmaceutical Incorporated Spiroindoline modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7858635B2 (en) 2005-12-22 2010-12-28 Vertex Pharmaceuticals Incorporated Spiro compounds as modulators of muscarinic receptors
US8304423B2 (en) 2006-02-22 2012-11-06 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786107B2 (en) 2006-08-18 2010-08-31 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2008021545A3 (fr) * 2006-08-18 2008-04-03 Vertex Pharma Modulateurs des récepteurs muscariniques
CN101821256A (zh) * 2007-08-02 2010-09-01 瑞蔻达蒂爱尔兰有限公司 作为mGlu5拮抗剂的新型杂环化合物
WO2009015897A1 (fr) * 2007-08-02 2009-02-05 Recordati Ireland Limited Nouveaux composés hétérocycliques servant d'antagonistes du mglu5
EA018328B1 (ru) * 2007-08-02 2013-07-30 Рекордати Айерленд Лимитед Новые гетероциклические соединения в качестве антагонистов метаботропных глутаматных рецепторов 5-го подтипа (мглу5)
US8518916B2 (en) 2007-08-02 2013-08-27 Recordati Ireland Limited Heterocyclic derivatives as M-GLU5 antagonists
US7973162B2 (en) 2007-10-03 2011-07-05 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
EP3324966A4 (fr) * 2015-07-20 2019-04-10 Chase Pharmaceuticals Corporation Combinaison muscarinique d'un antagoniste sélectif du récepteur m2 et d'un antagoniste non sélectif périphérique pour le traitement de troubles hypocholinergiques
CN115448871A (zh) * 2022-08-30 2022-12-09 中国药科大学 一种盐酸替罗非班的制备方法

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