WO1998017636A1 - Derives de phenylalaninol pour le traitement de troubles du systeme nerveux central - Google Patents

Derives de phenylalaninol pour le traitement de troubles du systeme nerveux central Download PDF

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WO1998017636A1
WO1998017636A1 PCT/US1997/018683 US9718683W WO9817636A1 WO 1998017636 A1 WO1998017636 A1 WO 1998017636A1 US 9718683 W US9718683 W US 9718683W WO 9817636 A1 WO9817636 A1 WO 9817636A1
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phenyl
amino
alkyl
group
salkyl
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PCT/US1997/018683
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English (en)
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Scott L. Dax
Michael N. Greco
Michael J. Hawkins
Bruce E. Maryanoff
James Mcnally
Anna Vavouyios-Smith
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Ortho Pharmaceutical Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton

Definitions

  • PHENYLALANINOL DERIVATIVES FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS This invention relates to a series of phenylalaninol derivatives, pharmaceutical compositions containing them and intermediates used in their manufacture.
  • the compounds of the invention are ligands for the neuropeptide Y1 (NPY1 ) receptor, a receptor which is associated with a number of central nervous system disorders
  • select compounds of the invention exhibit anxiolytic activity in an animal model.
  • BACKGROUND OF THE INVENTION Regulation and function of the mammalian central nervous system is governed by a series of interdependent receptors, neurons, neurotransmitters, and proteins.
  • the neurons play a vital role in this system, for when externally or internally stimulated, they react by releasing neurotransmitters that bind to specific proteins.
  • neurotransmitters such as acetylcholine, adrenaline, norepinephrine, dopamine, serotonin, glutamate, and gamma-aminobutyric acid are as well known, as the specific receptors that recognize these compounds as ligands ("The Biochemical Basis of Neuropharmacology", Sixth Edition, Cooper, J. R.; Bloom, F.
  • Neuropeptides unlike small molecule neurotransmitters, are typically synthesized by the neuronal ribosome. In some cases, the active neuropeptides are produced as part of a larger protein which is enzymatically cleaved to yield the active substance. Compared to small molecule neurotransmitters, neuropeptide- based strategies may offer novel therapies for CNS diseases and disorders.
  • NPY neuropeptide Y
  • PP pancreatic polypeptide family
  • Neuropeptide Y is a single peptide protein that consists of thirty-six amino acids containing an amidated C-terminus.
  • NPY sequences from a number of animal species have been elucidated and all show a high degree of amino acid homology to the human protein (>94% in rat, dog, rabbit, pig, cow, sheep) (see Larhammar, D. in "The Biology of Neuropeptide Y and Related Peptides", Colmers, W. F. and Wahlestedt, C. Eds., Humana Press, Totowa, NJ 1993).
  • NPY is often co-localized with norepineph ⁇ ne (NE) rich neurons and NPY can regulate classic NE actions such as constriction of peripheral vascular beds, stimulation of sensory nerves as well as control of certain primary CNS functions (pituitary hormone release, behavior, central autonomic control).
  • NE norepineph ⁇ ne
  • Endogenous receptor proteins that bind NPY and related peptides as ligands have been identified and distinguished, and several such proteins have been cloned and expressed.
  • Six different receptor subtypes (Y1 , Y2, Y3, Y4(PP1 ), Y5, PYY) are recognized today based upon binding profile, pharmacology and / or composition if identify is known (Lundberg, J. M. et. al. Trends in Pharmaceutical Sciences 1996, 17, 301 ; Gerald, C. et. al. Nature 1996, 382, 168; Weinberg, D. H. et. al. Journal of Biological Chemistry 1996, 271, 16435; Gehlert, D. et. al. Current Pharmaceutical Design 1995, 1, 295)).
  • NPY receptor proteins belong to the family of so-called G-protein coupled receptors (GPCRs).
  • GPCRs G-protein coupled receptors
  • the neuropeptide Y1 receptor a known GPCR, is negatively coupled to cellular cyclic adenosine monophosphate (cAMP) levels via the action of adenylate cyclase (Westlind- Danielsson, A. et. al. Neuroscience Letter 1987, 74, 237; McDermott, B. J. et. al. Cardiovascular Research 1993, 27, 893).
  • cAMP cyclic adenosine monophosphate
  • NPY inhibits forskolin- induced cAMP production / levels in SK-N-MC neuroblastoma cell line.
  • a Y1 ligand that mimics NPY in this fashion is an agonist whereas one that competitively reverses the NPY inhibition of forskolin-induced cAMP production is an antagonist.
  • Neuropeptide Y itself is the archetypal substrate for the Y1 receptor and its binding can elicit a variety of pharmacological and biological effects in vitro and in vivo.
  • NPY When administered to the brain of live animals (intraventricularly (icv) or into the amygdala), NPY produces anxiolytic effects in established animal models of anxiety (e.g., the elevated plus-maze, Vogel punished drinking and Geller-Seifter's bar-pressing conflict paradigms) (Hilor, M. et. al.
  • Neuropeptide Y improves memory and performance scores in animal models of learning (Flood, J. F. et. al. Brain Research 1987, 421, 280) and therefore may serve as a cognition enhancer for the treatment of neurodegenerative diseases such as Alzheimer's Disease (AD) and AIDS-related and senile dementia.
  • AD Alzheimer's Disease
  • AIDS-related and senile dementia a cognition enhancer for the treatment of neurodegenerative diseases such as Alzheimer's Disease (AD) and AIDS-related and senile dementia.
  • NPY neoplasmic neuropeptide
  • Elevated plasma levels of NPY are present in animals and humans experiencing episodes of high sympathetic nerve activity such as surgery, newborn delivery and hemorrhage (Morris, M. J. et. al. Journal of Autonomic Nervous System 1986, 17, 143).
  • chemical substances that alter the NPY-ergic system may be useful in the treatment of stress.
  • the binding of NPY to the Y1 receptor also mediates endocrine functions such as the release of luteinizing hormone (LH) in rodents (Kalra, S. P. et. al. Frontiers in Neuroendrocrinology 1992, 13, 1 ).
  • LH luteinizing hormone
  • NPY neuropeptide Y1 receptor
  • NPY In the periphery, NPY inhibits pre-synaptic release of substance P from sensory neurons and such an effect can cause diminution of pain (analgesia) (Hua, X. Y. et. al. Journal of Pharmacological Experimental Therapy 1991 , 258, 243);. In animals, NPY produces dose-related antinociception (hot plate test) not associated with opioid (naloxone competition) or adrengeric (idazoxan) activities (Broqua, P. et. al. Brain Research 1996, 724, 25). Thus NPY receptor ligands may be useful for the treatment and relief of pain.
  • R is selected from the group consisting of hydrogen, d- ⁇ alkyl, C ⁇ cycloalkyl, Ci- ⁇ alkoxy, (RaJm- C j - * where m is 1-5, R 3 is selected from one or more or the group consisting of C ⁇ -5 alkyl, substituted C ⁇ . 5 alkyl (where the alkyl substituents are one or more of chlorine, bromine, iodine or fluorine), C ⁇ . 5 alkoxy, C ⁇ . 5 alkylthio, nitro, amino, C ⁇ -5 alkylamino, cyano, carboxylic acid C ⁇ -5alkoxycarbonyl, carboxaldehyde, carboxamide, phenyl, and halogen, and o
  • R 4 is aminoC ⁇ -9 alkyl or amino
  • Ri is selected form the group consisting of hydrogen, C ⁇ -5 aikyl, substituted Ci.salkyl (where the alkyl substituents are one or more of chlorine, bromine, iodine or fluorine), C ⁇ -5 alkoxy, C ⁇ -5 alkylthio, nitro, amino, C 1-5 alkylamino, cyano, carboxylic acid C ⁇ -5 alkoxycarbonyl, carboxaldehyde, carboxamide, phenyl, or halogen;
  • R 2 is selected form the group consisting of hydrogen, C 1-5 alkyl, substituted
  • Ci.salkyl (where the alkyl substituents are one or more of chlorine, bromine, iodine or fluorine), Ci-saikoxy, Ci.salkylthio, nitro, amino, C ⁇ . 5 alkylamino, cyano, carboxylic acid C ⁇ -5 alkoxycarbonyl, carboxaldehyde, carboxamide, phenyl, or halogen;
  • n 1-5
  • the compounds of Formula 1 are useful for treating central nervous system disorders such as anxiety, depression, cognition impairment, pain, and alcohol abuses.
  • the compounds compete with the natural ligands, NPY1 and PYY and bind to the NPY1 receptor.
  • the compounds demonstrate agonist activity by mimicking the activity of NPY1 in a cyclic adenosine monophosphate assay which uses human ceils.
  • the compounds exhibit anxiolytic activity in the rat although not in the monkey assay. The compounds appear to be selective for anxiolytic activity in the rat, for they do not exhibit anticonvulsant activity or general skeletal CNS activity in a comparable rodent model.
  • the compounds are ligands of the NPY receptor, but are not necessarily limited solely in their pharmacological or biological action due to binding to this or any neuropeptide, neurotransmitter or G-protein coupled receptor.
  • the described compounds may also undergo binding to adrengeric receptors.
  • the compounds described herein are potentially useful in the regulation of endocrine functions, particularly those associated with the pituitary and hypothalamic glands, and may be useful for the treatment of inovulation/infertility due to insufficient release of luteinizing hormone (LH).
  • the present invention comprises pharmaceutical compositions containing one or more of the compounds of Formula I.
  • the present invention comprises intermediates used in their manufacture of compounds of Formula I
  • alkyl and “alkoxy” whether used alone or as part of a substituent group, include straight and branched chains.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-methyl-3-butyl, 1- methylbutyl, 2-methylbutyl, neopentyl, hexyl, 1-methylpentyl, 3-methylpentyl.
  • Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups.
  • acid addition salts may be prepared and may be chosen from hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesuifonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, or saccharin, and the like.
  • Such salts can are made by reacting the free base of compounds of formula I with the acid and isolating the salt.
  • the compounds of formula I are prepared using the synthetic strategies depicted in Scheme I; more details are provided in subsequent schemes.
  • This chemistry allows for the production of carbamate, urea and amide derivatives.
  • Each approaches offer distinct advantages.
  • X is an oxygen atom
  • the phenylalaninol reacts efficiently with electron poor phenyl isocyanates; however a copper I salt is needed to catalyze reaction with some electron rich isocyanates.
  • activation of the phenylalaninol as a chloroformate allows for simple amines to be introduced, especially those difficult to activate as an isocyanate.
  • the methodology to construct urea, ether and carbonate derivatives has also been successfully developed.
  • a N-protected phenylalaninol a is reacted with a electron- poor phenylisocyanate b in an appropriate solvent.
  • the reaction can be carried out at ambient temperature or with heating; an amine base can be added but is not necessary. If the phenylisocyanate does not possess at least one (but preferably two or more) electron-withdrawing groups, then to the reaction is added copper (I) sulfate (not shown). With either method, the resultant carbamate adduct c is then subjected to removal of the nitrogen protecting group using conditions and methods known in the art (Scheme 2) to afford final product d
  • the choice of resin includes, but is not limited to, the Wang resin and the chlorotrityl and trityl resins.
  • the nitrogen center is joined via a carbamate linkage formed upon reaction of the phenylalaninol with the para- nitrophenyi carbonate derivative of the Wang resin (Scheme 3).
  • reaction with the phenylalaninol results in displacement of chloride; the resultant tritylated amine is reluctant to undergo further reaction at the nitrogen center due to steric hinderance.
  • the alcohol oxygen center is unperturbed and free to undergo reaction with isocyanates as described above.
  • a known advantage of solid-support-assisted organic synthesis is that large excesses of reagents can be used to improve yields and purity; the unused materials, as well as impurities are typically removed by washing the resin. Cleavage from the resin typically involves treatment with trifluoroacetic acid in an inert solvent. These operations are well known to those skilled in the art.
  • LG leaving group
  • reaction of the phenylalaninol precursor a with methanesulfonyl chloride in the presence of a base or alternatively, reaction of the same precursor with carbon tetrahalide in the presence of triphenylphosphine produces the mesylate or chloride or bromide respectively (Scheme 4).
  • the amine center is then introduced via displacement of the leaving group with an amine such as ammonia or with azide followed by reduction to the amine f.
  • This chemistry can also be carried out using solid-support-assisted techniques.
  • Urea formation g ⁇ occurs upon treatment with phenylisocyanates and the final products t are obtained upon removal of the protecting group or cleavage from the resin.
  • protecting groups or resin linking groups that decrease the reactivity of the origin nitrogen center to avoid side reactions.
  • the Cbz (benzyloxycarbonyl) group is one such protecting group and the carbamate linkage is a suitable method of attachment to the Wang resin (see Scheme 5).
  • the leaving group can be displaced by sodium cyanate to produce the isocyanate j, and this intermediate can then be reacted with an amine such as an aniline j to produce the desired compounds (Scheme 6).
  • this chemistry is amenable to solid-support techniques.
  • LG OMs, Cl, Br
  • Grignard reagents and alkyllithiums species are suitable for this approach.
  • amine f can be coupled to phenylacetic acids using conventional peptide chemistry (DCC / HOBt, BOP, etc.) (Scheme 7).
  • DCC / HOBt, BOP, etc. conventional peptide chemistry
  • a pharmaceutical carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions made also be prepared utilizing aqueous carriers along with appropriate additives.
  • the pharmaceutical compositions described herein will typically contain from 1 to about 1000 mg of the active ingredient per dosage; one or more doses per day may be administered. Determination of optimum doses and frequency of dosing for a particular disease state or disorder is within the experimental capabilities of those knowledgeable in the treatment of central nervous system disorders. The preferred dose range is 50-100 mg/kg.
  • NPY1 neuropeptide receptor 1
  • SPA scintillation proximity technology
  • SK-N-MC expresses NPY1 and provides the receptor source.
  • the membranes were first trapped by wheat germ aggiutinin (WGA) coated SPA beads.
  • WGA wheat germ aggiutinin
  • Compounds were evaluated in terms of their ability to inhibit binding of the 125
  • Bacitracin Sigma, 10% stock solution
  • Leupeptin Sigma, 10 mg/ml
  • Homogenization buffer 10 mM HEPES, pH 7.4 containing 0.1 % bacitracin, 2 mM CaCl2, 2 mM MgCl2 and 0.3 M sucrose;
  • Wash buffer 10 mM HEPES, pH 7.4 containing 2 mM CaCl2, 2 mM MgCl2 and 0.1% bacitracin;
  • a) Cell culture The human neuroblastoma cell line, SK-N-MC, that expresses the NPY1 receptor, was obtained from ATCC. Cells were maintained in DMEM medium supplemented with 10%FCS, glutamate and antibiotics in 5%CO2 at 37°C. Cells were allowed to go to confluence before harvesting. They were either used immediately or frozen at -80 °C.
  • b) Cell membrane preparation P2 membrane preparations from SK-N-MC cells were used. Protein concentration was determined using the BioRad Protein assay performed in a microtitre plate with 0.1 % BSA as standard. Membranes were diluted to 5ug/ul in wash buffer. Each well would require 50ug of membranes.
  • 125l-neuropeptide Y ' Lyophilized powder (50 uCi) was dissolved in 1 ml of assay buffer.
  • the ligand solution was stored in 100 ul portions at -80°C and thawed only before use. Each well requires 0.5 ul of the stock ligand solution diluted into 76.25 ul in assay buffer.
  • Test compounds were dispensed into 96-well plate (3.75 ul of 1 mM).
  • Non-specific binding mean cpm in rows C,D of column 12
  • Putative hits are identified as compounds that give >50% inhibition at 25uM in the described assay, and confirmed by repeating the assay at least 2 times.
  • the inhibitory activity of the candidate compounds are scored as follows:
  • IC50 values are obtained by standard methods. Data for select compounds of the invention is listed in Tables A & B. IC ⁇ s are listed and if that number was not determined, the percentage of inhibition at a listed concentration is given. If a "#" is listed, that indicates that no data was obtained. Compoounds where " * " is indicated are the S-isomers, compounds where "**” is indicated are the R-isomers, compounds where " * **" is indicated are the racemic mixtures..
  • select compounds of the invention were evaluated in an cyclic adenosine monophosphate assay. This assay determines whether the compounds are agonists of NPY.
  • the known Y1 antagonist that was used in this test was BIBP-3226.
  • SK-N-MC American Tissue Culture Center
  • Wells were rinsed twice with Hank's solution (Gibco BRL, lot 9P6360) and the cells were incubated for 10 minutes at 37°C in 1 mM 3-isobutyl-1-methyl-xanthine (IBMX) (Sigma, lot 85H1331 ) dissolved in Hank's solution. Varying concentrations of test compounds or human neuropeptide Y (17 nM), or both, (Palomar Research Organics, lot 0496) were added to the appropriate wells and incubated for 1 minute at room temperature. Control wells received the same volume of DMSO in place of drugs.
  • IBMX 3-isobutyl-1-methyl-xanthine
  • Forskolin (Sigma, lot 102H78131 ) dissolved in DMSO was added to each well to a final concentration of 10uM. The cells were incubated at 37°C for 20 minutes. The supernatant in the wells was removed and rinsed once with Hank's solution. Ice cold 65% ethanol (0.5ml) was added to each well and incubated for 5 minutes at 0°C to extract cellular cAMP.
  • the ethanol extract was transferred into separate 1.8 mi microfuge tube and cleared by brief centrifugation for 30 seconds in a microfuge. The supernatant was transferred to a fresh microfuge tube.
  • cAMP content in separate extracts were determined using a cAMP Scintillation Proximity Assay System kit (Amersham) and cAMP standards according to the supplier's instructions. Effects on forskolin induced cAMP Ivels in SK-N-MCcells
  • IBMX is ATPase inhibitor; allows for accumulation of intracellular cAMP.
  • forskolin increases intracellular level of cAMP via adenylate cyclase.
  • Claimed compound (@ 10 uM) mimics NPY by reducing forskolin-enhanced cAMP levels.
  • the anxiolytic activity of selected compounds of the invention was assessed by determining their ability to encourage behavior that had been suppressed by punishment (Vogel, J.R. et al. Psychopharmacology 1971 , 21, 1 ).
  • Male rats were deprived of water for 48 hours and were deprived of food for 24 hours prior to testing. After the first 24 hours of water deprivation, they were placed in the conflict chamber for a training period; wherein, they were allowed 200 unpunished licks from a bottle containing tap water. The experiment was run the next day. At the expected time of peak activity, the animals were placed in the chamber and allowed access to tap water. If they failed to drink, the experiment was terminated in 5 min, and animals were evaluated for signs of CNS depression.
  • the biological assay is considered to be valid if the effects of a known anxiolytic (positive control) are detected, within the same experiment.
  • a compound was considered active if there is a significant difference in the median number of shocks tolerated between the drug-treated group and the control group.
  • the minimum effective doses (MED) for Cpd. 2 is 10 mg/kg where the median number of shocks tolerated was 4.5 in one experiment and 6 in another.
  • the critera for activity is 5.5 shocks.
  • the MED was defined as the minimum dose of the drug-treatment as analyzed using the Wilcoxon rank-sum test (SAS; Statistical Analysis System, version 5.16). If the MED value is greater than 10, an active dose of the compound being tested had not been determined.
  • SAS Wilcoxon rank-sum test
  • anti-pentylenetetrazol activity was evaluated by the subcutaneous administration of the CDgo dose of metrazol (the dose of metrazol was determined from the dose-response curve producing clonic convulsions in 90% of animals that received the corresponding vehicle for this experiment).
  • Metrazol was dissolved in 0.9% sodium chloride solution, and its dose volume was 10 ml/kg. Animals were housed individually for observation of clonic convulsions, tonic convulsions and death for a period of 30 min. Test compounds that blocked the clonic seizure component of the convulsion in at least 50% of the animals were considered active.
  • the biological assay was considered to be valid if the effects of a known anticonvulsant (positive control) were detected, within the same experiment. Activity was reported as percent reduction of clonic convulsions from the vehicle group.
  • the ED50 values of active compounds were calculated by the method of probits (Finney, D.J. 1971. Probit Analysis. London: Cambridge University Press) and are listed in Tables 1. An ED50 value of greater than 30 indicates that an active dose for the compound being tested had not been determined. Compounds active in this screen are considered active anticonvulsant / antiepileptic agents. Cpd. 2 was tested and was inactive in this assay.
  • a compound of the invention was tested for its ability to alleviate the anxiety of rat in a behavioral model of trait anxiety.
  • This behavioral assay is qualitatively unique in that it is based on the innate behavior of the animal and may model human anxiety traits (Pellow, S. et al. J. Neurosci. Methods 1985, 14, 149). It is thought to be a model for short term anxiolytic events where the Vogel model is thought to represent chronic anxiety.
  • Adult male Long-Evans hooded rates (Charles River Laboratories were used. Animals had unlimited accss to food and water except during the experiment but were deprived of food but not wateer for 18 hours before use. Test compounds were evaluated by the oral route of administration.
  • Each black plastic maze had two open arms and two arms with 40 cm high walls (enclosed arms), of equal length (50 cm), extending rom the center at right angles, suh that arms of similar type were opposite each other.
  • Each plus-maze was elevated approximately 60 cm above the floor. Infrared photo-beams that crossed the entrance of each arm and the center of the maze detected the exploratory activity of an animal in the maze. At one hour after treatment, animals were placed on an open arm of the plus-maze facing the center. The 10-min test was initiated when the animal entered the center of the apparatus. Data collection was automated and was obtained while the investigator was outside of the laboratory.
  • mice Male CDi mice, fasted for at least 16 hours but allowed access to water except during the period of observation, were placed on a horizontally- held screen (mesh size 1/4", wire diameter approximately 1.0 mm). The screen was inverted and mice which successfully climb to the top side of the screen within one minute were selected for testing. Selected mice were weighed and divided into equal groups. Test compounds or vehicle were administered to those mice parenterally. At a pre-determined interval (or intervals) after administration, the animals were tested for their ability to climb to the top side of the inverted screen (pass the test). Activity is reported as the percent reduction in the number of animals that pass the test in each treatment group relative to the corresponding vehicle-treated group.
  • Percent Reduction 100 X ([Percent Pass in Vehicle Group] - [Percent Pass in Test Group]/Percent Pass in Vehicle Group). Test compounds which produce a 50% or greater reduction in the number passing the test were considered active. Cpd. 2 was tested and had no affect upon the six tested mice.
  • Examples of preferred compounds of Formula I include compounds where R are hydrogen or 4-aminomethylbenzoyl; R-i is hydrogen; n is 0; R 2 is trifluoromethyl or chloro; p is 2; X is O; Y is NH; q is 1.
  • Examples of particularly preferred compounds of formula I include: O-(N-3,5-bis(trifluoromethyl)phenyl)carbamoyl-D-phenylalaninol
  • N-(f-Butoxycarbonyl)-D-phenylalaninol (2.51 g, 10 mmol) was dissolved in dichloroethane (50 mL) at ambient temperature. To this solution was added 3,5- bis(trifluoromethyl)phenyl isocyanate (1.90 mL, 11 mmol) and the mixture was stirred overnight. A white solid formed, most of the solvent was removed via rotary evaporation and hexanes (60 mL) was added.
  • the white solid was filtered off and washed with fresh hexanes to afford the desired product (5.5 g, >100%) of approximately 85-90% purity. This material could be carried forward as described below or purified in the following manner.
  • the solid was dissolved in a minimum amount of hot toluene (approx. 30 mL) and let cool to form a viscous white sludge. Hexanes (approx.
  • Ethyl ether was added to the resultant oil and then removed by rotary evaporation. Fresh ether was added (mimium amount to free oil from vessel walls) and again removed by evaporation. The resultant white solid, the TFA salt of the desired product, was neutralized via dissolution into a minimum amount of 90:10:1 CH 2 CI 2 /CH 3 OH/NH 4 OH and passed through a short silica gel column.
  • This resin was shown to have incorporated the phenylalaninol substrate via the displacement of 4-nitrophenol (which could be used to monitor the progress of the reaction).
  • the bulk of this resin (referred to as resin-bound phenylalaninol) was then used in subsequent reactions as described below.
  • an aliquot of the derivatized resin was removed to confirm the attachment of the desired substrate onto the resin and to quantify the substrate to resin ratio (mmol substrate / g resin).
  • each product was readily obtained via cleavage from the resin by treating the resin for 10 to 20 min with TFA/water (95:5). The resultant solution was filtered and evaporated. The residue was analyzed by HPLC and MS and shown to be desired product. Specific examples follow and illustrate the usefulness of this methodology.
  • the product was cleaved from the resin by treatment with TFA:CH2Cl2 (80:20, 100mL); the organics were removed in vacuo to isolate the desired phenylalaninol-derived carbamate trifluoroacetate salt.
  • the phenylalaninol-derived carbamate could be also be obtained as the corresponding free base or as the hydrochloride salt as described here.
  • This resin which contained the appropriate mesylated phenylalaninol was dried at room temperature under a flow of nitrogen.
  • This resin-bound mesylate (9 g, 4.5 mmol) was suspended in DMF (100 mL), treated with lithium azide (8 g, 0.163 mol) and heated to 70 °C for 18 h.
  • the resultant resin-bound azide was collected by filtration washed successively with DMF (3x), water (3x), MeOH (3x), THF (3x) and DCM (3x) and dried under a flow of nitrogen.
  • This material (approx. 4.5 mmol) was suspended in THF (90 mL), treated with triphenylphosphine (8.26 g, 31.5 mmol) and heated to 60 °C for 2 h. The solution was filtered from the resin, and the resin was washed with three portions of THF. This material was suspended in THF (100 mL), treated with water (10 mL) and heated to 60 °C for 2 h. The resin was collected by filtration and washed successively with THF (3x), MeOH (3x) and DCM (3x) and dried under a flow of nitrogen. At this point the resin, independently shown to contain the corresponding phenylalaninol-derived amine, was divided into portions for derivatization into the corresponding ureas, amides etc. as described below.
  • the above resin (1.0 g, 0.54 mmol) was suspended in DCM (10 mL) and treated with 3,5-bis(thfiuoromethyl)phenylisocyanate (1.0 mL, 5.79 mmol). The mixture was shaken at room temperature for 2.5 h. The resin was collected by filtration, and washed successively with DCM (3x), DMF (3x), MeOH (3x), THF (3x) and DCM (3x). The resin was treated twice with TFA/water (95/5) for 15 min and 5 min, filtered and washed with DCM. The solutions were combined, and the solvent was evaporated at 60 °C, under a flow of nitrogen.
  • the resin was collected by filtration, and washed successively with DMF (3x), MeOH (3x), THF (3x) and DCM (3x). The resin was treated twice with TFA/water (95/5) for 10 and 5 min, then washed with DCM.
  • the resin was collected by filtration and washed with DMF (3x), MeOH (3x), THF (3x) and DCM (3x), then treated twice with TFA/water (95/5) for 10 and 5 min.
  • the resin was washed with DCM and the combined solutions were evaporated under a flow of nitrogen at 60 °C.

Abstract

L'invention concerne une série de dérivés de phénylalaninol de la formule (I) dont les composants X, R, R1, R2, Y, q, n et p sont définis dans le descriptif. L'invention concerne également des compositions pharmaceutiques contenant ces dérivés et des intermédiaires utilisés dans leur fabrication. Les composés de l'invention sont des modulateurs du récepteur NPY1 et présentent une activité anxiolytique chez des modèles animaux.
PCT/US1997/018683 1996-10-22 1997-10-20 Derives de phenylalaninol pour le traitement de troubles du systeme nerveux central WO1998017636A1 (fr)

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WO2001046152A1 (fr) * 1999-12-21 2001-06-28 Monsanto Technology Llc Derives diacyl herbicides de propylenediamine
EP2445489A2 (fr) * 2009-06-26 2012-05-02 SK Biopharmaceuticals Co., Ltd. Compositions de traitement de la dépendance aux drogues et d amélioration du comportement lié aux dépendances
US8877806B2 (en) 2005-06-08 2014-11-04 Sk Biopharmaceuticals Co., Ltd. Treatment of sleep-wake disorders
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US11439597B2 (en) 2016-09-06 2022-09-13 Axsome Malta Ltd. Formulations of (R)-2-amino-3-phenylpropyl carbamate
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