WO2006137791A1 - Nouveaux derives d'azetidine utiles en tant qu'antagonistes des recepteurs des neurokinines employes pour le traitement des maladies gastro-intestinales - Google Patents

Nouveaux derives d'azetidine utiles en tant qu'antagonistes des recepteurs des neurokinines employes pour le traitement des maladies gastro-intestinales Download PDF

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WO2006137791A1
WO2006137791A1 PCT/SE2006/000760 SE2006000760W WO2006137791A1 WO 2006137791 A1 WO2006137791 A1 WO 2006137791A1 SE 2006000760 W SE2006000760 W SE 2006000760W WO 2006137791 A1 WO2006137791 A1 WO 2006137791A1
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butyl
azetidin
fluorophenyl
methyl
cyano
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PCT/SE2006/000760
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Anders Johansson
Johan Johansson
Sverker Von Unge
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Astrazeneca Ab
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Priority to JP2008518082A priority Critical patent/JP2008546768A/ja
Priority to EP06747949A priority patent/EP1899318A4/fr
Publication of WO2006137791A1 publication Critical patent/WO2006137791A1/fr

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Definitions

  • the present invention relates to new compounds of formula I, to pharmaceutical compositions containing said compounds, and to the use of said compounds in therapy.
  • the present invention further relates to processes for the preparation of compounds of formula I and to new intermediates thereof.
  • the neurokinins also known as the tachykinins, comprise a class of peptide neurotransmitters which are found in the peripheral and central nervous systems.
  • the three principal tachykinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B
  • NKT neurokinin 1
  • NK 2 neurokinin 2
  • NK 3 neurokinin 3
  • NK receptor antagonist for the treatment of e.g. respiratory, cardiovascular, neuro, pain, oncology, inflammatory and/or gastrointestinal disorders.
  • respiratory, cardiovascular, neuro, pain, oncology, inflammatory and/or gastrointestinal disorders In order to increase the therapeutic index of such therapy it is desirable to obtain such a compound possessing no or minimal toxicity as well as being selective to said NK receptors.
  • said medicament has favourable pharmacokinetic and metabolic properties thus providing an improved therapeutic and safety profile such as lower liver enzyme inhibiting properties.
  • CYP cytochrome P450 3A4 is the most important enzyme in the human liver as a majority of oxidised drugs have been biotransformed by this enzyme. Accordingly, it is undesirable to employ a medication having a significant degree of such liver enzyme inhibiting properties.
  • NK receptor antagonists known in the art inhibit the CYP3A4 enzyme to a certain level and consequently there is a possible risk if high doses of those compounds are being used in therapy.
  • the present invention provides compounds with CYP3A4 enzyme inhibiting properties at a low level, as comparatively high IC 50 values are obtained in a CYP3A4 inhibiting assay. Said method for determining CYP3A4 inhibition is described in Bapiro et al; Drug Metab. Dispos. 29, 30-35 (2001).
  • the aperture-forming alpha sub-units are encoded by the human ether-a-go-go-related gene (hERG). Since IKr plays a key role in repolarisation of the cardiac action potential, its inhibition slows repolarisation and this is manifested as a prolongation of the QT interval. Whilst QT interval prolongation is not a safety concern per se, it carries a risk of cardiovascular adverse effects and in a small percentage of people it can lead to TdP and degeneration into ventricular fibrillation. Compounds of the present invention have particularly low activity against the hERG- encoded potassium channel. In this regard, low activity against hERG in vitro is indicative of low activity in vivo.
  • EP 0625509, EP 0630887, WO 95/05377, WO 95/12577, WO 95/15961, WO 96/24582, WO 00/02859, WO 00/20003, WO 00/20389, WO 00/25766, WO 00/34243, WO 02/51807 and WO 03/037889 disclose piperidinylbutylamide derivatives, which are tachykinin antagonists.
  • WO 96/05193, WO 97/27185 and EP 0962457 disclose azetidinylalkyllactam derivatives with tachykinin antagonist activity.
  • EP 0790248 discloses azetidinylalkylazapiperidones and azetidinylalkyloxapiperidones, which are stated to be tachykinin antagonists.
  • WO 99/01451 and WO 97/25322 disclose azetidinylalkylpiperidine derivatives claimed to be tachykinin antagonists.
  • EP 0791592 discloses azetidinylaUcylglutarimides with tachykinin antagonistic properties.
  • WO2004/110344 A2 discloses dual NKl ,2 antagonists and the use thereof.
  • An object of the present invention was to provide novel neurokinin antagonists useful in therapy.
  • a further object was to provide novel compounds having improved pharmacokinetic and metabolic properties as well as limited interaction with the hERG channel.
  • the present invention provides a compound of the general formula (I)
  • Rl is hydrogen
  • R2 is Ci-C 4 alkyl, wherein one or more of the hydrogen atoms of the alkyl group may be substituted for a fluoro atom;
  • Het is selected from 2,5-diazabicyclo[2.2.1]heptane, octahydropyrrolo[3,4-c]pyrrole, 1,4- diazepane, octahydropyrrolo[l,2- ⁇ ]pyrazine, octahydro-2H-pyrido[l,2- ⁇ ]pyrazine, octahydropyrazino[2,l-c][l,4]oxazine; optionally substituted by C 1 -C 4 alkyl, wherein one or more of the hydrogen atoms of the alkyl group may be substituted for a fluoro atom; with the proviso that Het is connected to the azetidine ring at one of its nitrogen atoms; or Het is
  • X is CH 2 , O or NR6;
  • R3 is (CH 2 ) m NR4R5 or R3 is H if X is NR6;
  • R4 and R5 is each and independently selected from hydrogen, C 1 -C 4 alkyl or C 2 -C 4 hydroxyalkyl, wherein one or more of the hydrogen atoms of the alkyl group or hydroxyalkyl group may be substituted for a fluoro atom; or R4 and R5 may together form an azacycloalkane having 4 to 8 atoms, optionally substituted by one or more fluoro atoms; m is 0, 1, 2, 3 or 4 with the proviso that if m is 0 then X is CH 2 and R3 is attached to the 3- or 4-position of the ring;
  • R6 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, 2-(dimethylamino)-2-oxoethyl, wherein one or more of the hydrogen atoms of the alkyl group or hydroxyalkyl group may be substituted for a fluoro atom;
  • Ar is selected from
  • R7 is CN or F; as well as pharmaceutically and pharmacologically acceptable salts thereof, and enantiomers of the compound of formula I and salts thereof.
  • the present invention relates to compounds of formula I as defined above as well as to salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I.
  • the compounds of the present invention are capable of forming salts with various inorganic and organic acids and such salts are also within the scope of this invention.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclohexyl sulfamate, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2- hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, palmoate, persulfate, phenylacetate, phosphate, picrate, pivalate, propionate
  • Non-pharmaceutically-acceptable salts may be prepared from the corresponding acid in conventional manner.
  • Non-pharmaceutically-acceptable salts may be useful as intermediates and as such are another aspect of the present invention.
  • Acid addition salts may also be in the form of polymeric salts such as polymeric sulfonates.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is poorly soluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
  • Compounds of formula I have one or more chiral centres, and it is to be understood that the invention encompasses all optical isomers, enantiomers and diastereomers.
  • the compounds according to formula (I) can be in the form of the single stereoisomers, i.e. the single enantiomer (the i?-enantiomer or the iS-enantiomer) and/or diastereomer.
  • the compounds according to formula (I) can also be in the form of a racemic mixture, i.e. an equimolar mixture of enantiomers.
  • the compounds can exist as a mixture of conformational isomers.
  • the compounds of this invention comprise both mixtures of, and individual, conformational isomers. 0
  • alkyl includes straight as well as branched chain C1.4 alkyl groups, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t- butyl.
  • One or more of the hydrogen atoms of the alkyl group may be substituted for a fluoro atom, such as in difluoromethyl or trifluoromethyl. 5
  • C 1 -C 4 hydroxyalkyl is a hydroxyalkyl group comprising 1-4 carbon atoms and a hydroxyl group.
  • One or more of the hydrogen atoms of the hydroxyalkyl group may be substituted for a fluoro atom.
  • a pharmaceutical formulation comprising a compound of formula I, as a single enantiomer, a racemate or a 5 mixture thereof as a free base or pharmaceutically acceptable salts thereof, for use in prevention and/or treatment of respiratory, cardiovascular, neuro, pain, oncology, imflammatory and/or gastrointestinal disorders.
  • compositions of this invention may be administered in standard o manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided s powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • composition of o this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
  • compositions of this invention will normally be administered to s humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received.
  • This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses.
  • a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of a compound of the formula (I) or a pharmaceutically o acceptable salt thereof may be used.
  • the present invention provides a method of treating or preventing a disease condition wherein antagonism of tachykinins acting at the NK receptors is beneficial which comprises administering to a subject an effective amount of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof.
  • the present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein antagonism of tachykinins acting at the NK receptors is beneficial.
  • the compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof may be used in the manufacture of a medicament for use in the prevention or treatment of respiratory, cardiovascular, neuro, pain, oncology and/or gastrointestinal disorders.
  • disorders are asthma, allergic rhinitis, pulmonary diseases, cough, cold, inflammation, chronic obstructive pulmonary disease, airway reactivity, urticaria,hypertension, rheumatoid arthritis, edema, angiogenesis, pain, migraine, tension headache, psychoses, depression, anxiety, Alzheimer's disease, schizophrenia, Huntington's disease, bladder hypermotility, urinary incontinence, eating disorder, manic depression, substance dependence, movement disorder, cognitive disorder, obesity, stress disorders, micturition disorders, mania, hypomania and aggression, bipolar disorder, cancer, carcinoma, fibromyalgia, non cardiac chest pain, gastrointestinal hypermotility, gastric asthma, Crohn's disease, gastric emptying disorders, ulcerative colitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), emesis, gastric asthma, gastric motility disorders, gastro-esophageal reflux disease (GERD) or functional dyspepsia.
  • Pharmacology irritable bowel syndrome (
  • CHO Kl cells obtained from ATCC were stably transfected with the human NK 2 receptor (hNK 2 R cDNA in pRc/CMV, Invitrogen) or the human NK 3 receptor (KNK 3 R in pcDNA 3.1/Hygro (+)ZIRESZCD8, Invitrogen vector modified at AstraZeneca EST-Bio UK, Alderley Park).
  • the cells were transfected with the cationic lipid reagent LIPOFECTAMINETM (Invitrogen) and selection was performed with Geneticin (G418, Invitrogen) at lmg/ml for the hNK 2 R transfected cells and with Hygromycin (Invitrogen) at 500 ⁇ g/ml for the KNK 3 R transfected cells.
  • Single cell clones were collected by aid of Fluorescence Activated Cell Sorter (FACS), tested for functionality in a FLIPR assay (see below), expanded in culture and cryopreserved for future use.
  • CHO cells stably transfected with human NK 1 receptors originates from AstraZeneca R&D, Wilmington USA.
  • Human NK 1 receptor cDNA obtained from RNA- PCR from lung tissue was subcloned into pRcCMV (Invitrogen). Transfection was performed by Calcium Phosphate and selection with lmg/ml G418.
  • the CHO cells stably transfected with !1NK 1 R, KNK 2 R and JiNK 3 R were cultured in a humidified incubator under 5% CO 2 , in Nut Mix F 12 (HAM) with Glutamax I, 10% Foetal Bovine Serum (FBS), 1% Penicillin/Streptomycin (PEST) supplemented with 200 ⁇ g/ml Geneticin for the KNKiR and KNK 2 R expressing cells and 500 ⁇ g/ml Hygromycin for the KNK 3 R expressing cells.
  • the cells were grown in Tl 75 flasks and routinely passaged when 70-80% confluent for up to 20-25 passages.
  • NK 1 ZNK 2 ZNK 3 receptor activation measured as NK 1 ZNK 2 ZNK 3 receptor mediated increase in intracellular Ca 2+ was assessed by the following procedure: CHO cells stably transfected with human NKj, NK 2 or NK 3 receptors were plated in black walled/clear bottomed 96-well plates (Costar 3904) at 3.5x10 4 cells per well and grown for approximately 24h in normal growth media in a 37 0 C CO 2 -incubator.
  • the cells of each 96-well plate were loaded with the Ca 2+ sensitive dye Fluo-3 (TEFLABS 0116) at 4 ⁇ M in a loading media consisting of Nut Mix F12 (HAM) with Glutamax I, 22mM HEPES, 2.5mM Probenicid (Sigma P-8761) and 0.04% Pluronic F-127 (Sigma P-2443) for 1 h kept dark in a 37 0 C CO 2 -incubator.
  • the cells were then washed three times in assay buffer (Hanks balanced salt solution (HBSS) containing 2OmM HEPES, 2.5mM Probenicid and 0.1% BSA) using a multi-channel pipette leaving them in 150 ⁇ l at the end of the last wash.
  • assay buffer Hors balanced salt solution (HBSS) containing 2OmM HEPES, 2.5mM Probenicid and 0.1% BSA
  • K B IC50 / 1+ (EC 60 cone, of agonist used in assay / EC 50 agonist)
  • pK B - log K B
  • Membranes were prepared from CHO cells stably transfected with human NK 1 , NK 2 or NK 3 receptors according to the following method.
  • Cells were detached with Accutase® solution, harvested in PBS containing 5% FBS by centrifugation, washed twice in PBS and resuspended to a concentration of 1x10 8 cells/ml in Tris-HCl 50 mM, KCl 300 mM, EDTA-N 2 10 mM pH 7.4 (4 0 C).
  • Cell suspensions were homogenized with an UltraTurrax 30 s 12.000 rpm. The homogenates were centrifuged at 38.000 x g (4 0 C) and the pellet resuspended in Tris-HCl 50 mM pH 7.4. The homogenization was repeated once and the homogenates were incubated on ice for 45 min.
  • the radioligand binding assay is performed at room temperature in 96-well microtiter plates (No-binding Surface Plates, Corning 3600) with a final assay volume of 200 ⁇ l/well in incubation buffer (5OmM Tris buffer (pH 7.4 RT) containing 0.1 % BSA, 40 mg/L Bacitracin, complete EDTA-free protease inhibitor cocktail tablets 20 pills/L (Roche) and 3mM MnCl 2 ).
  • Competition binding curves were done by adding increasing amounts of the test compound. Test compounds were dissolved and serially diluted in DMSO, final
  • radioligand 50 ⁇ l radioligand, 3 ⁇ l test compound diluted in DMSO and 47 ⁇ l incubation buffer were mixed with 5-10 ⁇ g cell membranes in lOO ⁇ l incubation buffer and incubated for 30 min at room temperature on a microplate shaker. The membranes were then collected by rapid filtration on Filtermat B(Wallac), presoaked in 0.1 % BS A and 0.3% Polyethyleneimine (Sigma P-3143), using a Micro 96 Harvester (Skatron Instruments, Norway). Filters were washed by the harvester with ice-cold wash buffer (5OmM Tris-HCl, pH 7.4 at 4°C, containing 3mM MnCl 2 ) and dried at 5O 0 C for 30- 60 min.
  • ice-cold wash buffer 5OmM Tris-HCl, pH 7.4 at 4°C, containing 3mM MnCl 2
  • the compounds of the invention demonstrated statistically significant antagonistic activity at the NKi receptor within the range of 7-9 for the pKg .
  • the range for the pK ⁇ was 7-9.
  • the antagonistic activity at the NK3 receptor was 6-9 for the pK ⁇ .
  • the compounds of the invention demonstrated statistically significant CYP3A4 inhibition at a low level.
  • the IC50 values tested according to Bapiro et al; Drug Metab. Dispos. 29, 30-35 (2001) were generally greater than 2 ⁇ M.
  • the compounds of the invention which were tested, " demonstrated statistically significant hERG activity at a low level.
  • the IC50 values tested as described above were generally greater than 10 ⁇ M.
  • the metabolic stability of compounds according to formula I can be determined as described below:
  • the rate of biotransformation can be measured as either metabolite(s) formation or the rate of disappearance of the parent compound.
  • the experimental design involves incubation of low concentrations of substrate (usually 1.0 ⁇ M) with liver microsomes (usually 0.5 mg/ml) and taking out aliquotes at varying time points (usually 0, 5, 10, 15, 20, 30, 40 min.).
  • the test compound is usually dissolved in DMSO.
  • the DMSO concentration in the incubation mixture is usually 0.1% or less since more solvent can drastically reduce the activities of some CYP450s.
  • Incubations are done in 100 mM potassium phosphate buffer, pH 7.4 and at 37 0 C. Acetonitrile or methanol is used to stop the reaction.
  • Male Mongolian gerbils (60-80g) are purchased from Charles River, Germany. On arrival, they are housed in groups often, with food and water ad libitum in temperature and humidity-controlled holding rooms. The animals are allowed at least 7 days to acclimatize to the housing conditions before experiments. Each animal is used only once and euthanized immediately after the experiment by heart punctuation or a lethal overdose of penthobarbital sodium.
  • Gerbils are anaesthetized with isoflurane.
  • Potential CNS-permeable NKl receptor antagonists are administered intraperitoneally, intravenously or subcutaneously. The compounds are given at various time points (typically 30-120 minutes) prior to stimulation with agonist.
  • the gerbils are lightly anaesthetized using isofluorane and a small incision is made in the skin over bregma.
  • 10 pmol of ASMSP a selective NKl receptor agonist
  • ASMSP a selective NKl receptor agonist
  • NK2 specific test model The in vivo effect (NK2) of the compounds of formula I can be determined by measuring NK2 receptor agonist-induced fecal pellet output using gerbil as described in e.g. The Journal of Pharmacology and Experimental Therapeutics (2001), pp. 559-564.
  • Colorectal distension (CRD) in gerbils is performed as previously described in rats and mice (Tammpere A, Brusberg M, Axenborg J, Hirsch I, Larsson H, Lindstr ⁇ m E. Evaluation of pseudo-affective responses to noxious colorectal distension in rats by manometric recordings. Pain 2005; 116: 220-226; Arvidsson S, Larsson M, Larsson H, Lindstr ⁇ m E 3 Martinez V. Assessment of visceral pain-related pseudo-affective responses to colorectal distension in mice by intracolonic manometric recordings. J Pain 2006; 7: 108-118) with slight modifications.
  • gerbils are habituated to Bollmann cages 30- 60 min per day for three consecutive days prior to experiments to reduce motion artefacts due to restraint stress.
  • a 2 cm polyethylene balloon (made in-house) with connecting catheter is inserted in the distal colon, 2 cm from the base of the balloon to the anus, during light isoflurane anaesthesia (Forene ® , Abbott Scandinavia AB, Solna, Sweden).
  • the catheter is fixed to the tail with tape.
  • the balloons are connected to pressure transducers (P-602, CFM-k33, 100 mmHg, Bronkhorst HI-TEC, Veenendal, The Netherlands).
  • Gerbils are allowed to recover from sedation in the Bollmann cages for at least 15 min before the start of experiments .
  • a customized barostat (AstraZeneca, Molndal, Sweden) is used to manage air inflation and balloon pressure control.
  • a customized computer software (PharmLab on-line 4.0) running on a standard computer is used to control the barostat and to perform data collection.
  • the distension paradigm used consists of 12 repeated phasic distensions at 80 mmHg, with a pulse duration of 30 sec at 5 min intervals.
  • Compounds or their respective vehicle are administered as intraperitoneal (i.p.) injections before the CRD paradigm.
  • Each gerbil receives both vehicle and compound on different occasions with at least two days between experiments. Hence, each gerbil serves as its own vehicle control.
  • the analog input channels are sampled with individual sampling rates, and digital filtering is performed on the signals.
  • the balloon pressure signals are sampled at 50 samples/s.
  • a highpass filter at 1 Hz is used to separate the contraction-induced pressure changes from the slow varying pressure generated by the barostat.
  • a resistance in the airflow between the pressure generator and the pressure transducer further enhances the pressure variations induced by abdominal contractions of the animal.
  • a customized computer software (PharmLab off-line 4.0) is used to quantify the magnitude of highpass-f ⁇ ltered balloon pressure signals.
  • the average rectified value (ARV) of the highpass-f ⁇ ltered balloon pressure signals is calculated for 30 s before the pulse (i.e baseline reponse) and for the duration of the pulse.
  • the present invention provides a process for preparing a compound of the formula (I) or salts thereof which process comprises: a) reacting a compound of the formula (III) with a compound of the formula (IV):
  • R1-R2, Het, and Ar are as hereinbefore defined; and the conditions are such that reductive alkylation of the compounds of the formula (III) forms an N-C bond between the nitrogen atom of the azetidine group of the compounds of formula (III) and the carbon atom of the aldehyde group of the compounds of formula (FV); or b) reacting a compound of the formula (III) with a compound of the formula (V):
  • L is a group such that alkylation of the compounds of the formula (III) forms an N-C bond between the nitrogen atom of the azetidine group of the compounds of formula (III) and the carbon atom of the compounds of formula (V) that is adjacent to the L group; or c) reacting a compound of the formula (VI) with a compound of the formula (VH):
  • R1-R2, Het and Ar are as hereinbefore defined; and L' is a leaving group; wherein any other functional group is protected, if necessary, and: i) removing any protecting groups; ii) optionally oxidizing any oxidizeable atoms; iii) optionally forming a pharmaceutically acceptable salt.
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced and removed by conventional methods; see for example Protecting Groups in Organic Chemistry; Theodora W. Greene. Methods of removal are chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • the compounds of the formulae (III) and (IV) are reacted under conditions of reductive alkylation.
  • the reaction is typically performed at a non-extreme temperature, for example 0 - 40 °C, in a substantially inert solvent for example dichloromethane.
  • Typical reducing agents include borohydrides such as sodium cyanoborohydride.
  • the compounds of the formulae (III) and (V) are reacted under conditions of alkylation.
  • L is a leaving group such as halogen or alkylsulfonyloxy.
  • the reaction is typically performed at an elevated temperature, for example 30 - 130 °C, in a substantially inert solvent for example DMF.
  • the compounds of the formula (III) are known or may be prepared in conventional manner.
  • the compounds of the formula (IV) may be prepared, for example, by reacting a compound of the formula (VII) with a compound of the formula (VIII):
  • R1-R2 are as hereinbefore defined under conventional acylation conditions.
  • the compounds of the formula (V) may be prepared, for example, by reacting a compound of the formula (VII) with a compound of the formula (IX):
  • acylation reaction is performed in the presence of a non-nucleophilic base, for example N,N-diisopropylethylamine, in a substantially inert solvent such as dichloromethane at a non-extreme temperature.
  • a non-nucleophilic base for example N,N-diisopropylethylamine
  • the compounds of the present invention most often show highly complex NMR spectra due to the existence of conformational isomers. This is believed to be a result from slow rotation about the amide and/or aryl bond.
  • the following abbreviations are used in the presentation of the NMR data of the compounds: s-singlet; d- doublet; t-triplet; qt-quartet; qn-quintet; m-multiplet; b-broad; cm-complex multiplet, which may include broad peaks.
  • Ex 9 see Meth. 9
  • Ex 10 see Meth. 10
  • Ex 11 see Meth. 11
  • Ex 12 see Meth. 12
  • Ex 13 see Meth. 13
  • Ex 14 see Meth. 14
  • Ex 15 see Meth. 15
  • Ex 16 see Meth. 16
  • the starting materials for the examples above are either commercially available or are readily prepared by standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials.
  • the reaction mixture was stirred at RT for 40 min and then the solvent was removed by evaporation.
  • the residue was dissolved in ethyl acetate and the solution was washed with aqueous NaHCO 3 and then with brine.
  • the organic phase was separated by means of a phase separator column and then the solvent was removed by evaporation.
  • the product was purified by chromatography on silica gel (methanol - methylene chloride 2% to 20%). There was obtained 590 mg (73%) of the title compound as an oil.
  • the title compound was prepared by means of the reductive amination protocol described in Method 3 but using 3,5-dibromo-iV-[(2»S)-2-(4-fluorophenyl)-4-oxobutyl]-iV- methylbenzamide (see WO 04/110344) as the aldehyde starting material and fert-butyl (1- azetidin-3-ylpiperidin-4-yl)carbamate (see WO 96/05193) as the azetidine starting material (yield, 47%).
  • the title compound was prepared by means of the reductive amination protocol described in Method 3 but using 3-cyano-iV-[(2 J S)-2-(4-fluorophenyl)-4-oxobutyl]-iV-methyl-l- naphthamide (see WO 04/110344) as the aldehyde starting material and tert-butyl (1- azetidin-3-ylpiperidin-4-yl)methylcarbamate (see Method 7c) as the azetidine starting material (yield, 78%).
  • the title compound was prepared by means of the reductive amination protocol described in Method 3 but using 3-cyano-iV-[(2 1 S)-2-(4-fluorophenyl)-4-oxobutyl]-iV-methyl-5,6,7,8- tetrahydronaphthalene-1-carboxamide (see WO 04/110344) as the aldehyde starting material and fer/-butyl (l-azetidin-3-ylpiperidin-4-yl)methylcarbamate (see Method 7c) as the azetidine starting material (yield, 25%).
  • the title compound was prepared by means of the reductive amination protocol described in Method 3 but using 3-cyano-N-[(2 1 S)-2-(4-fluorophenyl)-4-oxobutyl]-iV-methyl-l- naphthamide (see WO 04/110344) as the aldehyde starting material and tert-butyl (1- azetidin-3-ylpiperidin-4-yl)carbamate (see WO 96/05193) as the azetidine starting material (yield, 60%).
  • the title compound was prepared by means of the reductive amination protocol described in Method Ic but using 3,5-dibromo-iV-[(25 ⁇ -2-(4-fluorophenyl)-4-oxobutyl]-N- s methylbenzamide (see WO 04/110344) as the aldehyde starting material and tert-butyl ⁇ 2- [(3i?)-4-azetidin-3-ylmorpholin-3-yl]ethyl ⁇ carbamate (see Method 12g) as the azetidine starting material (yield, 35%).
  • a reaction vessel was loaded with platinum (IV) oxide (80%, 33 mg), an ethanol (3 mL) solution of tert-b ⁇ xty ⁇ methyl(2-pyridin-2-ylethyl)carbamate (0.51 g, 2.2 mmol) and acetic acid (0.1 mL). The mixture was stirred under hydrogen (1.6 bar) at RT for 57 h. The catalyst was filtered off by means of Celite® and the solvent was removed by evaporation. There was obtained 0.58 g (94%) of tert-butyl methyl(2-piperidin-2-ylethyl)carbamate.
  • a reaction vessel was loaded with palladium hydroxide (20% on carbon, 165 mg) and a mixture of tert-butyl (2- ⁇ 1 -[I -(diphenylmethyl)azetidin-3-yl]piperidin-2- yl ⁇ ethyl)methylcarbamate (0.55 g, 1.2 mmol), acetic acid (0.3 mL) and methanol (4 mL). 0
  • the mixture was stirred under hydrogen for 20 h at 1.6 bar and RT.
  • the catalyst was filtered off by means of Celite® and the filter cake was washed with methanol. The solvent was removed by evaporation and the residue was dissolved in HCl (2M).
  • the mixture was washed with toluene and the pH of the aqueous solution was adjusted to pH 11 by the addition of aqueous NaOH (5M).
  • the mixture was extracted twice with methylene chloride 5 and the combined organic solutions were dried over MgSO 4 .
  • the solvent was removed by evaporation and the residue re-dissolved in methylene chloride.
  • the mixture was filtered through a cation exchange column (Isolute SCX-2, 2 g). The column was first washed with THF and then with methylene chloride. The product was eluted with a mixture of ammonia-saturated methanol and methylene chloride (1:9).
  • the solvent was removed by evaporation and the residue was partitioned between methylene chloride and diluted aqueous HCl. The two phases were separated and the aqueous solution was then extracted twice with methylene chloride. The pH of the aqueous solution was made alkaline by adding K 2 CO 3 . An effort to extract the product over to an organic solution by means of methylene chloride was unsuccessful.
  • the aqueous solution was rendered acidic by adding HCl and then the mixture was filtered through a cation exchange column (Isolute SCX-2, 10 g). The column was washed with water and ethanol and then the product was eluted with ammonia-saturated methanol.

Abstract

La présente invention concerne de nouveaux dérivés d'azétidine représentés par la formule (I), des compositions pharmaceutiques contenant lesdits composés et l'utilisation de ces composés en tant qu'antagonistes des récepteurs des neurokinines (NK) dans le traitement des maladies gastro-intestinales. Cette invention porte également sur des processus de préparation des composés de formule (I) et sur les nouveaux intermédiaires utilisés dans la préparation de ces mêmes composés. Formule (I)
PCT/SE2006/000760 2005-06-23 2006-06-21 Nouveaux derives d'azetidine utiles en tant qu'antagonistes des recepteurs des neurokinines employes pour le traitement des maladies gastro-intestinales WO2006137791A1 (fr)

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EP06747949A EP1899318A4 (fr) 2005-06-23 2006-06-21 Nouveaux derives d'azetidine utiles en tant qu'antagonistes des recepteurs des neurokinines employes pour le traitement des maladies gastro-intestinales

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WO2007136324A1 (fr) * 2006-05-18 2007-11-29 Albireo Ab Dérivés de 1-[(4-[benzoyl(méthyl)amino]-3-(phényl)butyl]azétidine destinés au traitement de troubles gastro-intestinaux 1
WO2007136325A1 (fr) * 2006-05-18 2007-11-29 Astrazeneca Ab Dérivés de 1-[(4-[benzoyl(méthyl)amino]-3-(phényl)butyl]azétidine destinés au traitement de troubles gastro-intestinaux 2
WO2007136326A2 (fr) * 2006-05-18 2007-11-29 Astrazeneca Ab Nouveaux composés 302
WO2008076041A1 (fr) * 2006-12-19 2008-06-26 Albireo Ab Dérivés de l'azetidinazabicyclo [3.2.1] octane qui sont des antagonistes du récepteur de la neurokinine (nk) et utilisation de ces derniers
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
US8288370B2 (en) 2005-09-29 2012-10-16 Albireo Ab Substituted azetidine compounds of formula (I) useful in the treatment of functional gastrointestinal disorders, IBS, and functional dyspepsia
US8785681B2 (en) 2007-03-08 2014-07-22 Albireo Ab 2-substituted-3-phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease

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RU2727022C2 (ru) * 2013-10-01 2020-07-17 Сфинготек Гмбх Способ прогнозирования риска возникновения тяжелых нежелательных сердечных явлений

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Cited By (13)

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US8288370B2 (en) 2005-09-29 2012-10-16 Albireo Ab Substituted azetidine compounds of formula (I) useful in the treatment of functional gastrointestinal disorders, IBS, and functional dyspepsia
AU2007253666B2 (en) * 2006-05-18 2012-03-15 Albireo Ab 1- [ (4- [benzoyl (methyl) amino] -3- (phenyl) butyl] azetidine derivatives for the treatment of gastrointestinal disorders 1
WO2007136326A2 (fr) * 2006-05-18 2007-11-29 Astrazeneca Ab Nouveaux composés 302
WO2007136326A3 (fr) * 2006-05-18 2008-01-24 Astrazeneca Ab Nouveaux composés 302
WO2007136324A1 (fr) * 2006-05-18 2007-11-29 Albireo Ab Dérivés de 1-[(4-[benzoyl(méthyl)amino]-3-(phényl)butyl]azétidine destinés au traitement de troubles gastro-intestinaux 1
WO2007136325A1 (fr) * 2006-05-18 2007-11-29 Astrazeneca Ab Dérivés de 1-[(4-[benzoyl(méthyl)amino]-3-(phényl)butyl]azétidine destinés au traitement de troubles gastro-intestinaux 2
WO2008076041A1 (fr) * 2006-12-19 2008-06-26 Albireo Ab Dérivés de l'azetidinazabicyclo [3.2.1] octane qui sont des antagonistes du récepteur de la neurokinine (nk) et utilisation de ces derniers
US8785681B2 (en) 2007-03-08 2014-07-22 Albireo Ab 2-substituted-3-phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease
US9181181B2 (en) 2007-03-08 2015-11-10 Albireo Ab 2-substituted-3-phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf

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