WO2015087094A1 - Nouveaux dérivés arylalcénylpropargylamine faisant preuve d'action neuroprotectrice pour le traitement des maladies neurodégénératives - Google Patents

Nouveaux dérivés arylalcénylpropargylamine faisant preuve d'action neuroprotectrice pour le traitement des maladies neurodégénératives Download PDF

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WO2015087094A1
WO2015087094A1 PCT/HU2013/000122 HU2013000122W WO2015087094A1 WO 2015087094 A1 WO2015087094 A1 WO 2015087094A1 HU 2013000122 W HU2013000122 W HU 2013000122W WO 2015087094 A1 WO2015087094 A1 WO 2015087094A1
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prop
szv
methyl
nmr
mhz
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PCT/HU2013/000122
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Péter MÁTYUS
Paul HULEATT
Christina LL CHAI
Beáta SPERLÁGH
Mui Ling KHOO
Kálmán Magyar
Ágnes PAPP-BEHR
Ruth DEME
György TÚRÓS
Klára GYIRES
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Semmelweis Egyetem
Agency For Science, Technology And Research
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    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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Definitions

  • the invention relates to novel (hetero)aryl propargylamines and compositions containing thereof.
  • the compounds can be used in treating or preventing a disease or condition in a mammal related to monoamine oxidase dysfunction, especially in neurodegenerative diseases, e.g. Parkinson's disease, Alzheimer's disease or Huntington's disease.
  • Neurodegenerative diseases (Parkinson disease, Alzheimer's disease, stroke, etc.) are characterized by the progressive loss of neurons and typically occur in the elderly population, therefore, their incidence is continuously rising in industrialized countries.
  • Parkinson's disease (PD) is a chronic neurodegenerative disease, which is characterized by the progressive degeneration of nigrostriatal dopaminergic pathway of the brain. The disease is manifested in various motor symptoms such as bradykinesia, postural instability, resting tremor and muscle rigidity, appearing only at an advanced (70%) stage of degeneration.
  • the disease primarily affects the elderly population and during the progress of pathology, the degeneration extends to other cortical and subcortical non-dopaminergic pathways, which are responsible for non- motor symptoms such as depression, delusions and cognitive decline.
  • MAO-B mono-aminooxidase-B
  • MAO-B inhibitors inhibit the enzyme, responsible for the intracellular degradation of dopamine and thereby increase dopamine availability of the nigrostriatal pathway and they also prolong the action of L-DOPA replacement therapy.
  • MAO-B inhibitors such as selegiline or rasagiline, were thought to be neuroprotective against dopaminergic cell death.
  • rasagiline which is a selective and irreversible inhibitor of the MAO-B, increases cell survival in cell culture and animal models of PD (Zheng H et al, J. Neurochem., 2005, 95, 68-78; Bar- Am O et al, J. Neurochem., 2007, 103, 500-508); however, this protective effect is not translated to a clinically convincing neuroprotective action (Ahlskog JE et al, Neurology, 2010, 74, 1143-1148; Olanow CW et al, Neurology, 2010, 74, 1149-1150).
  • MAO inhibitors are used in the treatment of Parkinson's disease and depression, and these inhibitors provide symptomatic relief in patients as a result of higher concentrations of the neurotransmitters due to reduced metabolism.
  • Monoamine oxidases A and B are mitochondrial enzymes that metabolise neurotransmitters in the CNS. MAO B has long been relevant drug target for neurodegenerative and neurological diseases.
  • This invention outlines the synthesis, biological activities and potential applications of a novel series of compounds that demonstrates highly potent MAO-B inhibitory activity with remarkable selectivity over other types of monoamine oxidase enzymes as well as exhibits unexpectedly excellent neuroprotection properties.
  • the compounds of the invention may represent a real therapeutic breakthrough for neurodegenerative diseases, having the potential to provide both symptomatic relief and disease-modifymg action such that further degeneration is prevented.
  • one possible application area of the compounds described herein is the treatment of Parkinson's disease.
  • the compounds could be used to treat other neurodegenerative diseases.
  • the invention relates to a compound of general formula (I)
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, optionally substituted Cue alkyl and optionally substituted C6-ioaryl;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, optionally substituted C
  • R 5 is selected from the group consisting of hydrogen, optionally substituted Ci_ 6 alkyl and optionally substituted C 6 .io aryl;
  • R 6 is hydrogen or halogen
  • Y is C 6 .i 0 aryl or heteroaryl, optionally substituted with one or more substituents selected from the group consisting of
  • Ci. 6 alkyl or C 2 . 6 alkenyl which is optionally substituted with one or more halogen, C 6- l oaryl, aminoC 6- i 0 aryl, C 6 _ioaryloxy or Cs.nheteroaryloxy,
  • Ci. 6 alkoxy which is optionally substituted with one or more halogen, C 6 -ioaryl or amino, which amino is optionally substituted with one or more Ci -6 alkyl,
  • n is an integer of 0 to 2
  • n is an integer of 1 to 5;
  • R 1 and R 2 is independently selected from hydrogen and C]. 4 alkyl
  • R 3 and R 4 is independently selected from hydrogen and
  • R 5 is selected from the group consisting of hydrogen optionally substituted with phenyl or with 1 to 3 halogen;
  • R 6 is hydrogen or halogen
  • n has the value of 0 or 1 ;
  • m has the value of 1 to 4.
  • R l and R 2 is independently selected from hydrogen and methyl
  • R 3 and R 4 is independently selected from hydrogen and methyl
  • R 5 is selected from the group consisting of hydrogen, methyl optionally substituted with phenyl, and ethyl optionally substituted with 1 to 3 halogen(s);
  • R 6 is hydrogen or halogen.
  • phenyl optionally substituted with one or more substituents selected the group consisting of halogen, nitro, cyano, benzyloxy, methoxy, 5-indolyloxymethyl, methyl optionally substituted with 1 to 3 halogen, benzyloxy optionally substituted with methyl- sulfanyl, halogen and methoxy, phenoxymethyl optionally substituted with methoxy or with 1 to 3 halogen, and
  • a pharmaceutical composition comprising a compound of general formula (I) or an enantiomer or diastereomer thereof or a salt, optionally a pharmaceutically acceptable salt or solvate according to any of above points 1 to 7 admixed with a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound according to the first aspect for the manufacture of a medicament for the treatment of neurodegenerative diseases.
  • a compound according to the first aspect in therapy in particular there is provided use of a compound according to the first aspect for the treatment of neurodegenerative diseases.
  • a composition in particular a pharmaceutical composition, comprising a compound according to the first aspect, or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, excipients or adjuvants.
  • the composition may be suitable for the treatment of cancer.
  • a method of treating neurodegenerative diseases comprising administering to a patient in need thereof a clinically effective amount of a compound according to the first aspect, or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, or of a composition according to the fourth aspect.
  • the present invention also encompasses enantiomers and diastereomers of the compounds described above. It also encompasses solvates, e.g. hydrates, of the compounds and of their enantiomers and diastereomers. It also encompasses salts of the compounds and of their enantiomers and diastereomers.
  • the salts may be clinically acceptable salts. They may pharmaceutically acceptable.
  • Figure 1 Effect of test compounds (10 nM) on oxidative stress induced pathological dopamine release in rat striatum slices.
  • Figure 2 Effect of test compounds (10 nM) on oxidative stress induced pathological dopamine release in rat striatum slices.
  • Figure 3 A and B Effect of test compounds (10 nM) on ischemic-like conditions induced pathological dopamine release in rat striatum slices.
  • [ H]dopamine release is expressed as fractional release (%) i.e. as percentage of the actual tritium content of the slices.
  • N 4-8 independent experiment/group.
  • Test compounds or their vehicle (CTRL) were administered (A) 15 min before the start of the ischemic-like conditions (B) 18 min before the second stimulation period (EFS2) and onwards.
  • Figure 4 Effect compounds of the invention (10 mg/kg i.p.) on endogenous dopamine content in the striatum and on the survival of animals after in vivo MPTP treatment. Symbols represent significant changes from saline treated ( +++ P ⁇ 0.001), MPTP treated (*P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001) and rasagiline (20 mg kg) treated animals, ( # P ⁇ 0.05, * *P ⁇ 0.001), respectively.
  • Statistical analysis one-way ANOVA followed by the Tukey test (dopamine content) and log rank test (survival). Number of independent experiments: 5-8/group.
  • Figure 5 Effect of compounds of the invention (10 mg/kg i.p.) on endogenous dopamine content in the striatum and on the survival of animals after in vivo MPTP treatment.
  • Statistical analysis one-way ANOVA followed by the Tukey test (dopamine content) and log rank test (survival). Number of independent experiments: 5-8/group.
  • Figure 6 A Effect of compounds of the invention (10 mg/kg i.p.) on the basal locomotor activity, measured in the open field test . Symbols represent significant changes from saline ( +++ P ⁇ 0.001) and MPTP treated (***P ⁇ 0.001) animals, respectively.
  • Statistical analysis one-way ANOVA followed by the Tukey test.
  • Figure 6 B Effect of compounds of the invention (10 mg/kg i.p.) on the basal locomotor activity, measured in the rotarod test. Symbols represent significant changes from respective pretreatment values (**P ⁇ 0.01). Statistical analysis: one-way ANOVA followed by the Dunnett test. The time elapsed until the falling of the mice was expressed in sec.
  • Figure 7 Dose-dependent effect of compound SZV-1902 (0.1-10 mg/kg i.p.) on endogenous dopamine content in the striatum after in vivo MPTP (4x20 mg/kg) treatment. Dopamine content is expressed as pmol/mg protein. Symbols represent significant changes from saline treated ( +++ P ⁇ 0.001), MPTP treated (**P ⁇ 0.01, ***P ⁇ 0.001) treated animals, respectively. Statistical analysis: one-way ANOVA followed by the Tukey test. Number of independent experiments: 5-8/group.
  • Figure 8 A and B Effect of compounds of the invention (10 mg/kg i.p.) on endogenous dopamine metabolite (DOPAC, HVA) levels in mouse striatum 72 h after after in vivo MPTP treatment. Metabolite levels are expressed as pmol/mg protein. Symbols represent significant changes from saline treated ( + P ⁇ 0.05), MPTP treated (*P ⁇ 0.01, ***P ⁇ 0.001) and rasagiline (20 mg/kg) treated animals, ( # P ⁇ 0.05, ## P ⁇ 0.001), respectively.
  • Statistical analysis one-way ANOVA followed by the Tukey test. Number of independent experiments: 7-12/group.
  • Figure 9 The duration of action of compound SZV-1902 (10 mg/kg) i.p. and the effect on endogenous dopamine content in the striatum and on the survival of animals after in vivo MPTP treatment.
  • Figure 10 The effect of SZV-1902, SZV-2220 and rasagiline (10 mg/kg i.p for 21 days each) on MPTP depleted endogenous dopamine content in the mice striatum using the Tatton- ish model. Symbols represent significant changes from saline treated ( +++ P ⁇ 0.001), MPTP treated (***P ⁇ 0.001) and rasagiline treated animals, ( ff P ⁇ 0.05), respectively. Statistical analysis: one-way ANOVA followed by the Tukey test. Number of independent experiments: 8-12/group.
  • FIG. 11 A-F Hematoxylin-eosin staining on striatal sections of mice undergone subacute
  • A The control tissue show typical staining and round shape morphology of nuclei (black arrow). Damaged structure of striatal section in case of MPTP treatment (B). Similar morphology and nuclear staining in rasagiline (C), SZV-1902 (D) and SZV-2220 (E) treated mouse striatal sections.
  • Figure 12 Electron microscopic analyses of cell damage after striatal sections of mice undergone subacute MPTP treatment according to the Tatton-Kish model.
  • Figure 13 Effect of compounds of the invention (10 ⁇ ) on the survival of PC12 cells 24 h after 6-OHDA (200 ⁇ ) treatment. Survival data are expressed as percentage of 6-OHDA treated cells. Symbols represent significant changes from 6-OHDA treated (**P ⁇ 0.01, ***P ⁇ 0.001) cells. Statistical analysis: one-way ANOVA followed by the Tukey test. Each data are the average of at least 8 values measured in 2 independent plates
  • aryl means a monovalent mono- or bicyclic aromatic hydrocarbon moiety of 6 to 10 ring atoms ("C 6 .
  • aryl embraces such bicyclic rings where a linear hydrocarbon moiety of 3 to 4 carbon atoms is fused to a monocyclic aryl forming bicyclic ring system having an aromatic ring and a saturated or partially unsaturated ring, see e.g. dihydronaphtyl, tetrahydronaphtyl and indenyl.
  • the bicyclic ring comprising a saturated or partially unsaturated ring-forming moiety, see e.g. in indenyl.
  • aryl also embraces such bicyclic rings where one of the rings is monocyclic aromatic ring and a saturated or partially unsaturated heterocyclyl is fused to said aromatic ring comprising one or more heteroatoms selected from N, O, or S and the remaining ring atoms are carbon.
  • the saturated or partially unsaturated ring-forming moiety comprises one or two heteroatoms selected from N or O, preferably said ring is of 5 or 6 ring atoms and comprises one or two O.
  • the bicyclic ring system comprising a heterocyclic ring is benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl or 2,3-dihidro-benzofuranyl.
  • substituted aryl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of aryl groups.
  • the substituted aryl groups carry one or more, preferably 1 to 4, e.g. 1 to 3 or 1 to 2 substituent(s), independently selected from the group of halogen, optionally substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, aralkyl, aryloxy, heteroaryloxy, hydroxyl, hydroxyalkyl, optionally substituted saturated heterocyclyls, optionally substituted carbamate, optionally substituted alkoxy, cycloalkoxy, carboxyl, alkoxycarbonyl, cyano, nitro, optionally substituted amino, aminoaryl, alkylsulfanyl, cycloalkylsulfanyl and alkylsulfonyl.
  • heteroaryl means a monovalent mono-, bi- or tricyclic aromatic hydrocarbon moiety of 5 to 14 ring atoms ("C 5 .i 4 heteroaryl”) , preferably of 5 to 13 (“Cs.nheteroaryl”) ring atoms where one or more, preferably one, two, or three, ring atom(s) is/are heteroatom(s) selected from N, O, or S, the remaining ring atoms being carbon.
  • Non-limiting examples are pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrirnidinyl, pyrazinyl, pyridazinyl, thiophenyl, benzo[b]thiophenyl, indazolyl, pyrazolyl, benzofuranyl, triazolyl, tetrazolyl, imidazolyl and naphtofuranyl, wherein pyrrolyl, thiazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, pyr
  • heteroaryl also embraces such bi- or tricyclic rings where at least one of the rings is aromatic, with the proviso that the aromatic ring is the one that comprises the heteroatom(s), such as 6,7-dihidro-benzofuranyl and dioxolo-indolyl.
  • substituted heteroaryl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of heteroaryl groups.
  • the substituted heteroaryl groups carry one or more, preferably 1 to 4 substituent(s), e.g. 1 to 3 or 1 to 2 substituent(s), independently selected from the group of halogen, alkyl, hydroxyl, hydroxyalkyl, carboxyl, alkoxy, nitro, amino, alkylsulfinyl, alkylsulfonyl and cyano, where alkyl (more preferably methyl), optionally substituted with halogen, alkoxy and halogen are preferred.
  • heterocyclyl are saturated or partially unsaturated mono- or bicyclic groups of 5 to 12 ring atoms (“Cs ⁇ heterocyclyl”) where one or more, preferably one, two, or three, ring atom(s) is/are heteroatom(s) selected from N, O, or S, the remaining ring atoms being carbon, such as pyrollidinyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl.
  • heterocyclyl is morpholinyl.
  • alkyl means a linear or branched saturated monovalent hydrocarbon moiety of one to six carbon atoms ("Ci -6 alkyP'), e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • alkyl (“Ci_ 4 alkyl”) is methyl, ethyl, /-propyl or i-butyl.
  • alkyl groups referring to alkyl moieties having one or more hydrogen atoms replaced by usual substituents of alkyl groups, preferably selected from the following group: halogen, optionally substituted amino, aryl, optionally substituted aryloxy and heteroaryloxy.
  • alkyl which is substituted is methyl or ethyl.
  • alkenyl means monovalent hydrocarbon chains of either linear or branched configuration comprising 2 to 6 carbon atoms and further comprising one or more carbon-carbon double bonds (“Ca ⁇ alkenyl”), preferably comprising 2 to 4 carbon atoms and one carbon-carbon double bond (“C 2 . 4 alkenyl”), more preferably alkenyl is ethenyl.
  • cycloalkyl means a non-aromatic monocyclic ring system of about 3 to about 7 carbon atoms ("C3 -7 cycloalkyl”), preferably monocyclic ring having 3 to 5 carbon atoms (“C 3- 5 cycloalkyl”), most preferably cyclopropyl.
  • _ 6 alkyr means a C6-io ryl group coupling via alkyl group of 1 to 6 carbon atoms. In a preferred embodiment is benzyl.
  • aryloxy means a C6-ioaryl group coupling via oxygen (“C6-ioaryloxy”).
  • the term is intended to include both unsubstituted and substituted aryloxy groups, the latter referring to aryloxy moieties having one or more hydrogen atoms replaced by usual substituents of aryl groups, preferably selected from the following group: halogen, cyano and alkoxy. In a preferred embodiment is phenoxy optionally substituted with halogen cyano or methoxy.
  • heteroaryloxy means a heteroaryl group coupling via oxygen (“C 5 . i 4 heteroaryloxy”).
  • heteroaryloxy is indolyloxy.
  • hydroxyalkyl means a C
  • hydroxyCi. 6 alkyl provided that if two hydroxyl groups are present they are not both on the same carbon atom. Examples include, but are not limited to hydroxymethyl, 2-hydroxyethyl, 2- hydroxypropyl and 3-hydroxypropyl, wherein hydroxymethyl is preferred.
  • alkoxy is intended to mean an alkyl group coupling via oxygen (“Ci -6 alkoxy”).
  • the term is intended to include both unsubstituted and substituted alkoxy groups, the latter referring to alkoxy moieties having one or more hydrogen atoms replaced by usual substituents of the alkyl groups, preferably selected from the following group: halogen, aryl, cycloalkyl and optionally substituted amino.
  • alkoxy is methoxy optionally substituted with 1 to 3 halogen, ethoxy optionally substituted with 1 to 3 halogen, dimethylamino-ethoxy, -propyloxy, cyclopropyl-methoxy and benzyloxy.
  • cycloalkoxy is intended to mean a cycloalkyl group coupling via oxygen (“C 3 . ycycloalkoxy”)- In a preferred embodiment cycloalkoxy is cyclopropyloxy.
  • carboxyl means a hydroxyl group coupling via carbonyl.
  • alkoxycarbonyl means an alkoxy group coupling via carbonyl ("Ci. 6 alkoxycarbonyl"). In a preferred embodiment alkoxycarbonyl is methoxicarbonyl.
  • amino means the monovalent group -NH 2 .
  • the term is intended to include both unsubstituted and substituted amino groups, the latter referring to amino moieties having one or more hydrogen atoms replaced by usual substituents preferably selected from the following group: alkyl, aryl, arylsulfonil, and alkylsulfonyl, more preferably methyl, ethyl, phenyl, tosyl and mesyl.
  • amino is dimethylamino, diethylamino, phenylamino, methylphenylsulfonamido or methanesulfonamido.
  • alkylsulfanyl means an alkyl group coupling via sulphur (“Ci ⁇ alkylsulfanyl”).
  • alkylsulfanyl is methylthio, ethylthio or z ' -propylthio.
  • alkylsulfonyl means an alkyl group coupling via -S0 2 -
  • alkylsulfonyl is methylsulfonyl or ethylsulfonyl.
  • arylsulfonyl means an aryl group coupling via -S0 2 - ("C 6 -ioarylsulfonyl”), preferably methylphenylsulfonyl.
  • benzyloxy means a methoxy group monosubstituted with phenyl.
  • general formula (I) includes all stereoisomeric forms of the compounds of the present invention.
  • stereoisomer as used herein includes all possible stereoisomeric forms, including all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure, unless the specific stereochemistry or isomer form is specifically indicated. Where the compounds of the present invention contain one or more chiral centers, all possible enantiomeric and diastereomeric forms, as well as the racemate, are included. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
  • salt means any ionic compound formed between one of the embodiments of the present invention and an acidic or basic molecule that can donate or accept ionic particle to/from its partner.
  • the quaternary amine salts are also included.
  • Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates.
  • Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,
  • Parkinson's disease is a chronic neurodegenerative disease, which is characterized by the progressive degeneration of nigrostriatal dopaminergic pathway of the brain.
  • Propenes of general formula (1) can be halogenated at the allylic position using N-bromo- or N-chlorosuccinimide under usual conditions to afford allyl halogenides of general formula (2).
  • the reaction can be carried out in an inert solvent such as chlorobenzene at reflux temperature, or by using a microwave method. This reaction may yield a mixture of the desired allyl bromide (2) and a vinyl bromide side product (2'), which could be conveniently separated by column chromatography.
  • an allylic chlorination reaction could be carried out using N-chlorosuccinimide, using diphenyl-diselenid, as a catalyst, in an inert solvent, such as dichloromethane, at temperature 20-30 °C for longer reaction time.
  • Nucleophilic substitution of the general formula (2) with a propargylamine affords the corresponding compounds of general formula (I).
  • the reaction can be conveniently carried out in a solvent, e.g.
  • dichoromethane acetonitrile, diethylether, preferably in an alcohol such as 2- propanol with one or two equivalents of propargylamine, in case of one equivalent of the amine in the presence of an acid acceptor, such as DEPE A, at room temperature or elevated temperature during 1 -24 h reaction time, or using microwave conditions.
  • an alcohol such as 2- propanol
  • propargylamine in case of one equivalent of the amine in the presence of an acid acceptor, such as DEPE A, at room temperature or elevated temperature during 1 -24 h reaction time, or using microwave conditions.
  • X represents halogen atom or a leaving group if m is 1 and n is 0.
  • the compounds of general formula (5) can be converted to the target compounds of general formula (I).
  • Nucleophilic substitution reaction of compounds of general formula (4) with a propargylamine affords the corresponding amino ketone compounds of the general formula (5).
  • These compounds can be converted to the requisite allylic amine target compounds of general formula (I) under mild conditions using a modified Wittig olefination reaction in dioxane, THF-2-propanol mixture using RhCl(Ph 3 )3 and Ph 3 P and trimethylsilyldiazomethan, at 60 °C.
  • Both of the aforementioned approaches involve either an allylic functionalisation step or a-functionalisation of a ketone to install a leaving group. Subsequent approaches were aimed at avoiding these functionalisation steps by direct formation of an allylic amine derivative or allylic alcohol.
  • compounds of general formula (I) - where R 1 , R 2 , R 3 , R 4 represent hydrogen, R 5 is an optionally substituted alkyl group, n is 0 and m is 1, Y has the same meaning as above, can be prepared from the aryl/heteroaryl-boronic acids, esters or salts with a vinyl bromide derivative, to give the coupling product of the general formula
  • the using (2-bromoallyl)methylcarbamate (6) is prepared from 2,3-dibromopropene with with methylamine solution followed by reaction with B0C2O.
  • the coupling reaction is carried out in microwave condition, using the catalyst of Palladium-acetate-XPhos or SPhos, and potassium triphosphate monohydrate as basis component, in alcohol-water solvent mixture.
  • the cleavage of the Boc group can be carried out using trifluoroacetic acid in dichloromethane and, upon neutralization.
  • the alkylation of the resulting amino compound with propargylbromide can be performed in the presence of a base, such as Na2CC>3 in an inert solvent, preferably DCM, at room temperature, for longer reaction time.
  • the compounds of the general formula (I) can be obtained in the first step by reaction of boronic acids (or derivatives thereof) with 2-bromoallyl alcohol resulted in the compounds of the general formula (9)
  • This intermediate can be used for the synthesis of compounds of general formula (I) by reaction with MsCl, followed by reaction with the appropriately substituted propargyalmine. This approach is advantageous for several reasons. First, both the coupling partners, boronic acids (or derivatives thereof) and the 2-bromoallyl alcohol are commercially available. Second, it can be used for the synthesis of compounds of general formula (I) bearing electron donating moieties at the para position of the aryl ring.
  • the reaction of the boronic acid with 2-bromoallyl alcohol can be carried out in microwave condition, using the catalyst of XPhos-[2-(2'-amino-l,l '- biphenyl)] -palladium II adduct, or Xphos-2,2-aminoethylphenyl-palladium II methy -butylether adduct, or Pd2(dba) 3 and PPh 3 and using potassium triphosphate monohydrate as a base component, in inert solvent, preferably THF, at 40-80 °C, for shorter or longer reaction time, depending on the substrate.
  • inert solvent preferably THF
  • the dioxaborolan derivative of the aryl/heteroaryl derivatives is used as starting material. It may be prepared from the aryl/hetaroaryl-bromide with pinacolborane, usig as catalyst PdCl 2 (dppf), or tris(dibenzylideneaceton) palladium-XPhos adduct, in the presence of triethyamine, as base in inert solvent such as dioxane.
  • the compounds of general formula (9) are readily converted to mesylate derivatives with MsCl, in an inert solvent, such as DCM, in the presence of a base. Its nucleophilic substitution with a propargylamine, affords the compounds of general formula (I).
  • Another possible route for preparation of the compounds of general formula (I) is presented in Process E. - where the meanings of Y are defined above, R 5 is optionally substituted alkyl, R 1 , R 2 , R ' ⁇ R 4 are hydrogen, n can be 0, 1 or 2, the meanings of m can be 1,2,3 or 4.
  • Suzuki coupling methodologies may have limitations in certain cases (e.g. where the boronic acid coupling partners are unstable), therefore, a complementary method may be also used to access alcohols of general formula (12).
  • arylmagnesium bromides can add regioselectively to propargylic alcohols to afford allylic alcohols of compounds of general structure (12).
  • a palladium catalysed regioselective addition of boronic acids to alkynylols i.e. m > 2 can be used to access alkenylols of type (12).
  • the Suzuki reaction can be carried out in microwave vial, using Pd(PPhj) 4 as a catalyst in inert solvent, such as 1,4-dioxane, in presence of acetic acid.
  • Some alcohol intermediates of general formula (12) can be converted into the mesylate derivatives, in which the mesyloxy group can be substituted with propargylamines to afford the target compounds of general formula (I).
  • Another reaction route for preparation of compounds of general formula (I), where n is 0, m means 2, 3 or 4, is based on a reductive amination process. It starts from an alcohol of general formula (11), which is oxidized, using Dess-Martin periodinane (DMP) at room temperature, in inert solvent, such as DCM, then using NaBH(OAc) 3 for the reduction step. This method can be performed at room temperature, in an inert solvent, e.g. DCM as well.
  • DMP Dess-Martin periodinane
  • NaBH(OAc) 3 NaBH(OAc) 3
  • Analytical thin layer chromatography (TLC) separations were performed on Merck's silica gel 60 F254-precoated aluminum sheets. Visualization was accomplished with UV light (254 or 365 nm) and/or ninhydrin (200.0 mmol in ethanol) stain followed by heating. Solvent mixtures used for chromatography are always given in a vol/vol ratio. Flash column chromatography was generally performed using Silica Gel 60 (spherical, 40-100 ⁇ or 40-63 ⁇ ) purchased from Sigma- Aldrich, or Biotage SP1TM purification system by gradient. Melting points were determined on a Biichi-540 capillary melting point apparatus and are uncorrected.
  • Elemental analyses were performed on an Elementar VarioEL III apparatus. MW irradiation experiments were carried out in a monomode CEM-Discover MW reactor, using the standard configuration as delivered, including proprietary software. The experiments were executed in open vessel mode with control of the temperature by infrared detection. After completion of the reaction, the vial was cooled to 50 °C by air jet cooling.
  • ⁇ nuclear magnetic resonance (NMR) spectra was recorded at ambient temperature (if not indicated otherwise), in the solvent indicated, on a Bruker 400 Ultra Shield Spectrometer operating at 400 MHz and 101 MHz respectively or Varian Mercury Plus 400 spectrometer at frequency of 400 and 100 MHz or on a Varian Unity 600 spectrometer at frequency at 600 and 150 MHz or on a Bruker Avance III 500 spectrometer at frequency of 500 or 125 MHz respectively.
  • Chemical shifts for ⁇ NMR were recorded in parts per million (ppm) downfield from tetramethylsilane or proton signal of residual non-deuterated solvent ( ⁇ 7.26 ppm for CHC1 3 or ⁇ 4.87 ppm for CH 3 OH) as the internal signal.
  • RhCl(PPh 3 ) 3 and PPh 3 were weighed into a flame-dried 2-necked round-bottom flask before 1,4-dioxane was added under argon condition. To the stirred mixture at 60 °C was added dry isopropanol. The starting a-amino ketones were dissolved in 1,4-dioxane (10.0 ml) and introduced as a solution into the mixture before trimethylsilyldiazomethane (2.4 eq) was added dropwise to start the reaction. The reaction mixture was left to stir under argon at 60 °C for 16 h.
  • the flask was placed in an oil bath preheated to 160-170 °C upon stirring for 45 min (!: strongly effervescent, exothermic reaction), then the mixture was cooled down with an ice-water bath.
  • the succinimide precipitated upon cooling was filtered off and washed with chlorobenzene, the solvent was evaporated in vacuo.
  • the crude product was purified by vacuum distillation (1 Hgmm, main fraction: 103-106 °C) and subsequent flash chromatography on silica gel ( «-hexane).
  • l-chloro-4-(l,l,2,3-tetrabromopropan-2-yl)benzene recrystallized from anhydrous EtOH.
  • a suspension of l-chloro-4-(l,l,2,3-tetrabromopropan-2-yl)benzene (2.0 g, 4.3 mmol) and silica gel (20 mg) in CC1 4 (20.0 ml) was heated to reflux, while protected from light (tinfoil wrapping) (Suarez AR et al, J. Org. Chem., 1987, 52, 1145-1147).
  • the reaction was performed in microwave irradiation at 65 °C for 85 min, which included the time for the temperature to reach 65 °C ( ⁇ 2-3 min). After cooling to room temperature, the mixture was filtered using filter paper and the solid kept on the paper was washed several times with Et 2 0. The combined organic layers were concentrated to dryness, and re- dissolved in CHC1 3 (3.0 ml). To the solution was added CH 2 Br 2 (0.1 ml, 1.4 mmol) and a small amount of the resulted solution was taken for ⁇ -NMR to estimate the yield of the borylated product 3. After estimating the reaction yield (from 82-90%), the solution was concentrated to dryness and crude 3 was used directly in the next step without purification.
  • Acetone- ⁇ / 6 ⁇ 7.53-7.46 (m, 1H), 7.00-6.94 (m, 2H), 5.47 (s, 1H), 5.35 (s, 1H), 3.42 (s, 2H), 3.29 (d,
  • Acetone-i/ 6 ⁇ 7.27-7.23 (m, 1H), 7.17-7.1 1 (m, 2H), 5.53 (s, 1H), 5.44 (s, 1H), 3.43 (s, 2H), 3.31 (d,
  • R 1 H
  • R 2 C0 2 CH 3 (SZV-2407)
  • R 5-OCH j , 6 (SZV-2404)
  • Ci 5 Hi 6 N 2 x(COOH) 2 (314.36): C, 64.96%; H, 5.77%; N, 8.91%; O, 20.36%. Found: C, 61.98%; H, 5.57%; N, 8.45%; O, 20.65%.
  • R 4-S0 2 CH 3 (SZV-2245)
  • R 4-C(CH 3 ), (SZV-2421)
  • R 3-OCH j , 4-CH j (SZV-2422)
  • R 4-OCF 3 (SZV-2442)
  • Ci 3 H 13 FNx(COOH) 2 (311.28): C, 57.88%; H, 4.86%; N, 4.50%; O, 20.56%. Found: C, 58.01%; H, 5.07%; N, 4.21%; O, 20.83%.

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Abstract

L'invention concerne de nouveaux dérivés arylalcénylpropargylamine de formule générale (1) ou leurs énantiomères ou diastéréomères ou sels, éventuellement sels pharmaceutiquement acceptables, ou solvates de n'importe lequel d'entre eux. Les composés peuvent être utilisés dans le traitement ou la prévention d'une maladie ou d'un état chez un mammifère lié(e) à un dysfonctionnement de la monoamine oxydase, notamment dans les maladies neurodégénératives, par exemple la maladie de Parkinson, la maladie d'Alzheimer ou la maladie de Huntington.
PCT/HU2013/000122 2013-12-10 2013-12-10 Nouveaux dérivés arylalcénylpropargylamine faisant preuve d'action neuroprotectrice pour le traitement des maladies neurodégénératives WO2015087094A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022238507A1 (fr) * 2021-05-11 2022-11-17 Awakn Ls Europe Holdings Limited Composés et compositions thérapeutiques à base d'aminoindane

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4454158A (en) * 1981-06-01 1984-06-12 Merrell Toraude Et Compagnie Allyl amine MAO inhibitors
WO1985005617A1 (fr) * 1984-05-31 1985-12-19 Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. Derive de phenylisopropylamine et sa preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4454158A (en) * 1981-06-01 1984-06-12 Merrell Toraude Et Compagnie Allyl amine MAO inhibitors
US4454158B1 (fr) * 1981-06-01 1992-12-22 Merrell Toraude & Co
WO1985005617A1 (fr) * 1984-05-31 1985-12-19 Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. Derive de phenylisopropylamine et sa preparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022238507A1 (fr) * 2021-05-11 2022-11-17 Awakn Ls Europe Holdings Limited Composés et compositions thérapeutiques à base d'aminoindane

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