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WO2012127030A1 - Arylpipérazines en tant qu'agents neuroprotecteurs - Google Patents

Arylpipérazines en tant qu'agents neuroprotecteurs Download PDF

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Publication number
WO2012127030A1
WO2012127030A1 PCT/EP2012/055212 EP2012055212W WO2012127030A1 WO 2012127030 A1 WO2012127030 A1 WO 2012127030A1 EP 2012055212 W EP2012055212 W EP 2012055212W WO 2012127030 A1 WO2012127030 A1 WO 2012127030A1
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phenyl
piperazin
ethyl
arh
compound
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PCT/EP2012/055212
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Vukic Soskic
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Proteosys Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention generally relates to novel arylpiperazines.
  • these arylpiperazines can be used as neuroprotective agents.
  • the invention also relates to a process for the manufacture of the novel compounds. Further, the invention relates to the use of the novel arylpiperazines in the treatment of diseases associated with, accompanied by or caused by mitochondrial stress.
  • Nitrogen monoxide (NO) also known as nitric oxide
  • NOS nitric oxide synthase
  • Endothelial NOS eNOS
  • nNOS neuronal NOS
  • eNOS Endothelial NOS
  • nNOS neuronal NOS
  • iNOS Inducible NOS
  • NO-mediated cell damage is a consequence of its highly reactive nature.
  • RNS reactive nitrogen species
  • N 2 O 3 dinitrogen trioxide
  • ONOO- peroxynitrite
  • toxicity through complexation with iron in iron-containing enzyme systems (Drapier 1988), oxidation of protein sulfhydryl groups (Radi 1991 ), nitration of proteins, nitrosylation of nucleic acids and DNA strand breaks (Wink 1991 ).
  • the main outcome of excessive NO production is apoptotic death of various cell types, including neurons (Heales 1999).
  • N-arylpiperazine subunit is part of a variety of pharmacologically interesting compounds, which act as dopamine and serotonine ligands, calcium blockers, antipsychotics, antihypertensive drugs or acetylcholinesterase inhibitors (Romero 2006).
  • Dopamine receptor ligands used for symptomatic therapy of Parkinson's disease show neuroprotective effects under a variety of neurodegenerative conditions (Chen 2008, Uberti 2002, Carvey 1997, Kitamura 1998; Yang 2008, Park 2009, Kato 2008) and the neuroprotective action of dopamine D1 antagonists has also been demonstrated (Cools 2002, Sonsalla 1986).
  • Non-receptor-mediated neuroprotection by dopaminergic ligands may include free radical scavenging activity against hydroxyl radicals and nitric oxide (Gomez-Vargas 1998, Pardo 1995) and subsequent prevention of neuronal mitochondrial damage and apoptosis (Gille 2002, Uberti 2004).
  • novel arylpiperazine-based dopamine receptor ligands were synthesized. It was found that these arylpiperazines show neuroprotective action in cell culture, with a significant selectivity for
  • a first aspect of the invention relates to a compound of the general formula I, II or III
  • R 1 is selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • R 3 is independently at each occurrence selected from the group consisting of: hydrogen, halogen, hydroxyl, d-C 2 -(halo)alkyl, and Ci-C 2 -(halo)alkoxy;
  • R 4 is independently at each occurrence selected from the group consisting of: hydrogen and C C 2 -alkyl;
  • n 1-10.
  • the inventive compounds have neuroprotective activity
  • the compounds according to the invention are capable of protecting human neuroblastoma cells from oxidative stress induced by nitric oxide (NO) as described in the Examples.
  • cells incubated with a compound of formula I, II, or III at a concentration of 2.5 ⁇ show a reduction in NO-induced cell damage of at least 15%, which may be determined using an acid phosphatase assay.
  • incubation of cells with a compound of formula I, II, or III at a concentration of 10 ⁇ leads to a reduction in NO-induced cell damage of at least 30%.
  • treatment of cells with a compound of formula I, II, or III at a concentration of 10 ⁇ reduces the amount of superoxide in e.g. SNP-treated cells by at least 2.5%.
  • treatment of cells with a compound of formula I, II, or III at a concentration of 10 ⁇ prevents changes of more than 30% in activation/inhibition of signalling molecules such as Akt, JNK, ERK, and AMPK in e.g. SNP-treated cells.
  • Activation/inhibition may be determined by analyzing phosphorylation of the respective signalling molecule by e.g. immunoblotting.
  • a compound according to the invention shows all biological effects described above.
  • a “pharmaceutically acceptable salt” refers to salts or complexes of a compound of formula I, II, or III.
  • examples of such salts include, but are not limited to, base addition salts formed by reaction of a compound of formula I, II, or III, with an organic or inorganic base, e.g. ammonia or a hydroxide, carbonate or bicarbonate of a metal cation, which is preferably selected from alkali metals (e.g. sodium, potassium or lithium), and alkaline earth metals (e.g. calcium or magnesium), or with an organic primary, secondary or tertiary alkyl amine.
  • alkali metals e.g. sodium, potassium or lithium
  • alkaline earth metals e.g. calcium or magnesium
  • acid addition salts formed with inorganic acids e.g.
  • hydrochloric acid hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid
  • organic acids e.g. aliphatic monocarboxylic and dicarboxylic acids, aromatic acids, and sulfonic acids.
  • Non-limiting examples of such acids are acetic acid, benzoic acid, (+)-camphor-10- sulfonic acid, citric acid, gluconic acid, lactic acid, methanesulfonic acid, propionic acid, oxalic acid, succinic acid, tartric acid, trifluoroacetic acid, and triphenylacetic acid.
  • a .pharmaceutically acceptable solvate may e.g. be a hydrate.
  • the term “suit(halo)alkyl” relates to an alkyl group which optionally contains at least one halo, e.g. F, CI, Br or I substituent up to perhalogenation.
  • the termticianalkyl means a monovalent linear or branched, saturated or unsaturated hydrocarbon moiety, consisting of carbon and hydrogen atoms, wherein the number of carbon atoms is defined by a subscript number, e.g. participatCi-Ci 2 ".
  • Non-limiting examples include methyl, ethyl, ethenyl, ethinyl, propyl, isopropyl, allyl, n-butyl, isobutyl, tert-butyl, butenyl, hexyl, octyl, and dodecyl.
  • ком ⁇ онент refers to an unsaturated aromatic carbocyclic group of from 6 to 10 carbon atoms having a single ring or two condensed rings.
  • Preferred aryl groups include phenyl and naphthyl.
  • the term “humanheteroaryl” as used herein refers to a monocyclic radical of 5 to 7 ring atoms containing one, two, or three ring heteroatoms selected from nitrogen, oxygen, and sulfur, the remaining ring atoms being carbon.
  • Preferred examples include, but are not limited to furanyl, imidazolyl, isoxazolyl, oxazolyl, pyridyl, pyridazinyl, pyrazinyl, thiazolyl, and thiophenyl.
  • "Alkoxy” means a moiety of the formula -OR, wherein R is an a Iky I moiety as defined herein. Non-limiting examples of alkoxy moieties include methoxy, ethoxy, and isopropoxy.
  • ..Substituted means that one or more functional groups (..substituents") are attached to one or more carbon atoms of an alkyl, cycloalkyi, aryl, or heteroaryl moiety as defined herein. Preferably, a given moiety is substituted with one, two, three, four, or five independently selected substituents.
  • the compound according to the invention has the general formula I or II.
  • R 1 , R 2 , R 3 , R 4 , and n may have a preferred meaning as defined herein.
  • the compound according to the invention has the general formula I.
  • the compound has the general formula I, II or III,
  • R 1 is selected from the group consisting of:
  • d-Ce-alkyl phenyl, and nitrogen-containing C 6 -heteroaryl, each unsubstituted or substituted with halogen, hydroxy, Ci-C 6 -(halo)alkyl, and/or Ci-C 6 -(halo)alkoxy, and
  • R 2 , R 3 , R 4 , and n may have preferred meaning as defined herein.
  • R 1 is phenyl, which is unsubstituted or substituted with halogen, hydroxyl, and/or CrC 6 -alkoxy, and
  • R 2 , R 3 , R ⁇ and n may have a preferred meaning as defined herein.
  • R 2 is selected from the group consisting of:
  • phenyl and Cs-Cr-heteroaryl each unsubstituted or substituted with halogen, hydroxyl, amino, CrC 6 -(halo)alkyl, and/or Ci-C 6 -(halo)alkoxy, and R 1 , R 3 , R 4 , and n may have a preferred meaning as defined herein.
  • R 2 is selected from the group consisting of:
  • phenyl 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyrazinyl, each unsubstituted or substituted with halogen, hydroxyl, amino and/or Ci-C 6 -alkoxy, and
  • R ⁇ R 3 , R 4 , and n may have a preferred meaning as defined herein.
  • the compound has the general formula I, wherein R 2 is selected from the group consisting of: phenyl, 2-pyridyl, 3-pyridyl, and pyridazinyl, each unsubstituted or substituted with halogen, hydroxy I, amino and/or Ci-Ce-alkoxy.
  • the compound has the general formula II, wherein R 2 is selected from the group consisting of: phenyl, 2-pyridyl, and 3-pyridyl. The phenyl group may be unsubstituted or substituted with halogen, amino, and/or Ci-C 6 -alkoxy.
  • the 2-pyridyl or 3- pyridyl group may be unsubstituted or substituted, preferably monosubstituted in the ortho-position, with halogen, hydroxy, amino, and/or Ci-Ce-alkoxy.
  • R 3 is hydrogen, and R , R 2 , R 4 , and n may have a preferred meaning as defined herein.
  • R 4 is hydrogen, and R 1 , R 2 , R 3 , and n may have a preferred meaning as defined herein.
  • n is 1 -6. In a more preferred embodiment, n is 2.
  • the inventive compound has the general formula I, II, or III, wherein
  • R 1 is phenyl, which is unsubstituted or substituted with halogen, hydroxyl, and/or Ci-Ce-alkoxy;
  • R 2 is selected from the group consisting of:
  • phenyl 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyrazinyl, each unsubstituted or substituted with halogen, hydroxyl, amino and/or Ci-Ce-alkoxy; and
  • n 2.
  • R 1 is unsubstituted phenyl
  • R 2 is selected from the group consisting of:
  • R 3 and R 4 each are hydrogen; and n is 2.
  • the compound has the general formula II, wherein R 1 is unsubstituted phenyl;
  • R 2 is selected from the group consisting of:
  • phenyl, 2-pyridyl, and 3-pyridyl each unsubstituted or substituted with hydroxyl, with phenyl preferably being unsubstituted and 2-pyridyl and 3- pyridyl preferably being unsubstituted or monosubstituted in the ortho- position,
  • R 3 and R 4 each are hydrogen; and n is 2.
  • the compound has the general formula I, wherein R 1 is unsubstituted phenyl;
  • R 2 is selected from the group consisting of:
  • R 3 and R 4 each are hydrogen; and n is 2.
  • the compound according to the invention is selected from the group consisting of:
  • the compound according to the invention is selected from the group consisting of:
  • the compound according to the invention is N- ⁇ 4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl ⁇ -picolin- amide or a pharmaceutically acceptable salt or solvate thereof.
  • a further aspect of the invention relates to a process for the manufacture of a compound of the general formula I, II or 111, which comprises the steps of:
  • step (iv) reacting the product of step (iii) with a carboxylic acid of the general formula R 2 COOH, and
  • R 2 is selected from the group consisting of:
  • R 3 is independently at each occurrence selected from the group consisting of: hydrogen, halogen, hydroxyl, C 1 -C 2 -(halo)alkyl, and C C 2 -(halo)alkoxy;
  • R 4 is independently at each occurrence selected from the group consisting of: hydrogen and CrC 2 -alkyl; and wherein n is 0-9.
  • the aryicarboxyiic acid of step (i) has the general formula VII
  • the amine of step (i) has the general formula VIII
  • R 1 has the meaning as defined supra.
  • reaction product of step (i) has the general formula IX
  • R 1 and n have the meaning as defined supra.
  • R 1 is phenyl
  • R 2 is selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, and pyrazinyl, each unsubstituted or substituted with hydroxy I
  • R 3 and R 4 are hydrogen at each occurrence
  • n is 1.
  • Suitable reducing agents for use in the reduction step (ii) are e.g. diborane (B 2 H 6 ), lithium aluminium hydride (LAH; LiAIH 4 ), and diisobutyialuminium hydride (DIBAL).
  • diborane B 2 H 6
  • LAH lithium aluminium hydride
  • DIBAL diisobutyialuminium hydride
  • Suitable catalysts for hydrogenating the niiro group (N0 2 ) in step (iii) are transition metals of groups 8, 9, 10 and 11 of the periodic table, particularly nickel (e.g. Raney nickel), platinum, palladium, rhodium, and ruthenium.
  • the compound of formula I, II, or III is for use in medicine. Said use is preferably a use in human medicine, but the compounds may also be used for veterinary purposes. In specific embodiments, it may be preferred to use compounds of formula I.
  • the compound of formula I, II, or III is preferably administered to a subject in need thereof, e.g. a human subject, as a pharmaceutical composition.
  • a further aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I, II, or III, or a pharmaceutically acceptable salt or solvate thereof, and further comprising pharmaceutically acceptable excipients, adjuvants, diluents and/or carriers.
  • disintegrators examples include agar-agar, algins, calcium carbonate, cellulose, colloid silicon dioxide, gums, magnesium aluminium silicate, methylcellulose, and starch.
  • binders examples include hydroxymethyl cellulose, hydroxypropylcellulose, microcrystalline cellulose, and polyvinylpyrrolidone.
  • fillers include calcium carbonate, calcium phosphate, tribasic calcium sulfate, calcium carboxymethy!ce!lulose, cellulose, dextrin, dextrose, 1 fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol.
  • lubricants include agar, ethyl laureate, ethyl oleate, glycerin, glyceryl palmitostearate, glycols, hydrogenated vegetable oil, magnesium oxide, mannitol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl, sorbitol, stearates, and talc.
  • buffer substances colorants, consistency-improving agents, diluents, emollients, flavour-improving agents, preservatives, salts for varying the osmotic pressure, solubilizers, stabilizers, wetting and emulsifying agents, masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting-point wax, cocoa butter, water, alcohols, polyols, glycerol, vegetable oils and the like.
  • the pharmaceutical composition may also comprise at least one further active agent, e.g. one or more further organic or inorganic molecule.
  • the composition may be used alone, without further medication.
  • the composition may be used in combination with other medicaments, e.g. medicaments for treating neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, ALS, and stroke.
  • inventive compound of formula I, II, or III, or a pharmaceutical composition comprising a compound of formula I, II, or III is for use in the treatment of a disease, disorder or condition associated with, accompanied by or caused by mitochondrial stress.
  • the present invention also relates to a method for the treatment of a disease, disorder or condition associated with, accompanied by or caused by mitochondrial stress, comprising administering a pharmaceutically effective amount of a compound of formula I, II or III to a subject in need thereof.
  • Mitochondria are cellular organelles composed of two membranes.
  • An inner mitochondrial membrane (IMM) which is organized into so-called cristae, is surrounded by an outer membrane, which encloses the entire organelle.
  • the space surrounded by the IMM is called matrix and harbours the majority of the mitochondrial proteins, as well as the mitochondrial genome. Between the two membranes, there is an intermembrane space.
  • mitochondria The most prominent function of mitochondria is their role in the regulation of cellular metabolism and, most importantly, in the oxidative phosphorylation, a central step in the production of energy in the form of ATP.
  • the content of mitochondria differs according to the cell type. Cells which have high energy consumption, such as muscle and nerve cells, are particularly rich in mitochondria.
  • ROS reactive oxygen species
  • O 2 ⁇ - also known as superoxide
  • H 2 0 2 hydrogen peroxide
  • ROS lead to propagation of free radicals and can oxidize cellular lipids, nucleotide bases, and proteins.
  • O 2 " - can react with nitric oxide (NO) to form toxic compounds such as peroxy nitrite (ONOO ).
  • NO nitric oxide
  • ONOO peroxy nitrite
  • Inhibition of components of the mitochondrial respiratory chain may ultimately lead to apoptosis of cells.
  • oxidative or mitochondrial stress A state where cells, e.g. human ceils, produce increased amounts of oxidants, e.g. ROS, leading to an increased release of free radicals and resulting in cellular degeneration is referred to as oxidative or mitochondrial stress.
  • Mitochondrial stress seems to be involved in several disorders, including neurodegenerative and cardiovascular diseases.
  • the compound of formula I, II or III as described supra is for use in the treatment of a neurodegenerative disorder.
  • Another preferred embodiment of the invention is a method for the treatment of a neurodegenerative disorder.
  • said neurodegenerative disorder is selected from amyotrophic lateral sclerosis, Alzheimer's Disease, Parkinson's Disease and stroke.
  • said neurodegenerative disorder is amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig' s disease).
  • ALS amyotrophic lateral sclerosis
  • said neurodegenerative disorder is Alzheimer's Disease.
  • said neurodegenerative disorder is Parkinson's Disease.
  • said neurodegenerative disorder is stroke.
  • Figure 1 Synthetic route and chemical structures of the arylpiperazine dopaminergic ligands.
  • A Synthetic pathways for N- ⁇ 4-[2-(4-phenyl- piperazin-1-yl)-ethyl]-phenyl ⁇ -arylamides and N- ⁇ 3-[2-(4-phenyl-piperazin- 1 -yl)-ethyl]-phenyl ⁇ -arylamides.
  • B Synthetic pathways for 5-[2-(4-phenyl- piperazin-1 -yl)-ethy!]-2-pyridin-4-yl-1 H-benzoimidazole.
  • FIG. 1 The effect of arylpiperazines on SNP- and H 2 0 2 -induced toxicity in SH-SY5Y neuroblastoma cells.
  • A SH-SY5Y cells were incubated with different concentrations of SNP or H 2 0 2 and the cell viability was determined by acid phosphatase assay after 24 h.
  • B Cells were pretreated with different arylpiperazines (10 ⁇ ) for 30 min and then exposed to SNP (2 mM) or H 2 O z (100 ⁇ ). The cell viability was determined by acid phosphatase assay after 24 h.
  • FIG. 3 The inhibitory effect of compound 6a on SNP-induced depolarization of mitochondrial membrane and apoptosis in SH-SY5Y cells.
  • A, B, C, D SH-SY5Y cells were pretreated with compound 6a (10 ⁇ ) for 30 minutes and then exposed to SNP (2 mM). After 24 h, cells were stained with annexin V-FITC/Pl (A), PI (B), ApoStat (C) or JC-1 (D), and phosphatidylserine externalization (A), DNA fragmentation (B), caspase activation (C) or mitochondrial membrane potential (D) was examined by flow cytometry.
  • the representative dot plots and histograms (A, B, C) or mean + SD values (D) from three independent experiments are presented ( * p ⁇ 0.05 and # p ⁇ 0.05 refer to untreated and SNP-treated cells, respectively).
  • FIG. 4 The effect of compound 6a on superoxide and NO levels in SH- SY5Y cells following exposure to chemically or cell-derived NO.
  • A, B SH- SY5Y cells were pre-incubated with compound 6a (10 ⁇ ) for 30 minutes and then treated with SNP (2 mM). After 24 h, flow cytometry was used to determine intracellular levels of superoxide anion in DHE-stained cells (A) or NO in DAF-stained cells (B).
  • C, D Rat peritoneal macrophages were incubated without or with LPS (5 pg/ml) and rat interferon- ⁇ (10 ng/ml), in the absence or presence of different concentrations of compound 6a.
  • Nitrite accumulation was measured after 24 h and 48 h using Griess reaction (C), while intracellular NO content in DAF-stained cells was determined after 24 h by flow cytometry (D).
  • E, F SH-SY5Y cells were co-incubated with LPS + IFN-y-stimulated rat peritoneal macrophages in the absence or presence of different concentrations of compound 6a. After 24 h and 48 h, nitrite concentrations were measured using Griess method (E), while the cell viability was determined by acid phosphatase assay (F).
  • the representative histogram (A) or mean + SD values (B-F) from three independent experiments are presented ( * p ⁇ 0.05 and *p ⁇ 0.05 refer to untreated and SNP-treated cells, respectively).
  • FIG. 5 The effect of compound 6a on SNP-induced cell death- regulating signalling pathways in SH-SY5Y cells.
  • SH-SY5Y cells were treated with compound 6a (10 ⁇ ) for 30 minutes before addition of SNP (2 mM).
  • Activation (phosphorylation) of Akt, JNK, ERK and AMPK was analyzed by immunoblotting after 8 h (the data from one of two experiments with similar results are shown).
  • Figure 6. The effect of compound 6a is not dopamine receptor-mediated.
  • SH-SY5Y cells were first incubated with D1/D2 receptor blocker (+)butac!amol (10 ⁇ ), then with compound 6a (10 ⁇ ) after 30 minutes and then with SNP (2 mM) after additional 30 min. Cell viability was assessed by acid phosphatase assay after 24 h. The data are presented as mean + SD of triplicates from one of two experiments with similar results ( " p ⁇ 0.05 refers to cells treated with SNP alone).
  • Target compounds 4a,b- 12a,b were obtained by condensation of anilines 3a,b with corresponding aromatic carboxylic acid in presence of propylphosphonic acid anhydride (PPAA) in N-Dimethylformamide (DMF). All compounds were characterized by NMR spectroscopy and mass spectroscopy.
  • PPAA propylphosphonic acid anhydride
  • DMF N-Dimethylformamide
  • Ra-Ni (0.4-0.5 g) was added in small portions to a stirred solution of the nitro compounds 2a,b (6.0 g, 20 mmol), 7.2 ml (90 mmol) hydrazine hydrate, 20 ml ethanol and 20 ml 1 ,2-dichloroethane at 30 °C.
  • the reaction temperature was increased to 40-45 °C by external heating.
  • the reaction mixture was filtered through celite. Amines 3a,b were recovered from filtrate after solvent was removed in vacuo and recrystallization from ethyl acetate.
  • isonicotinic acid (393 mg, 3.3 mmol), diamine 13 (890 mg, 3.0 mmol) and 4.0 ml 4 N HCI were heated in an autoclave to 180 °C for 6 h. After cooling to ambient temperature, 15 ml of 10% NaHC0 3 was added and the obtained product was extracted with chloroform. The solvent was removed in vacuo and crude benzimidazole 14 was purified by silica gel column chromatography using a gradient of methanol (0-2%) in dichloromethane and recrystallized from EtOH.
  • Aryl carboxylic acids (2.2 mmol), amines 3a,b (560 mg, 2.0 mmol), 1 .0 ml triethyl amine, and 1 .8 ml 50% PPAA, were stirred in 7 ml DMF at room temperature for 16 h, subsequently diluted with 200 ml ethyl acetate and extracted 2 times with 50 ml 8% NaHCO 3 and 50 ml H 2 O, each. Organic phase was dried over MgSO 4 , filtered and concentrated in vacuo. Obtained products were purified by silica gel column chromatography using a gradient of methanol (0-5 %) in dichloromethane. Most amides crystallized from ethyl acetate as free bases.
  • the human neuroblastoma cell line SH-SY5Y was obtained from American Type Culture Collection. Rat peritoneal macrophages were isolated from Albino Oxford rats as previously described (Harhaji 2006), in accordance with the Declaration of Helsinki. The neuroblastoma cell line was grown in Modified Eagle Medium and F12 cell culture medium (1 :1) supplemented with 10% fetal calf serum, 2 mM L-glutamine, nonessential amino acids and penicillin/streptomycin.
  • rat peritoneai macrophages were initially grown in a HEPES (25 mM)-buffered RPMI 1640 cell culture medium supplemented with 5% fetal calf serum, 2 mM L-glutamine, 10 mM sodium pyruvate and penicillin/streptomycin.
  • the cells were maintained at 37°C in a humidified atmosphere with 5% C0 2 .
  • the SH-SY5Y cells were prepared for experiments using the conventional trypsinization procedure with trypsin/EDTA.
  • peritoneal macrophages (1 x 10 5 cells per well, 24-well plate) were initially grown in a HEPES (25 mM)-buffered RPMl 1640 cell culture medium supplemented with 5% fetal calf serum, 2 mM L-glutamine, 10 mM sodium pyruvate and penicillin/streptomycin.
  • SH-SY5Y cells were differentiated using phorbol 2-myristate 13-acetate (PMA). Cells were seeded in 96-well flat-bottom plates (2 x 10 3 cells per well) and PMA (80 nM) was added 24 h after seeding. Medium was changed every 3 days and cultures were allowed to differentiate for 6 days. Undifferentiated cells were rested for 24 h and treated with NO-releasing chemical sodium nitroprusside (SNP) and/or other agents, as described below and in Figure legends.
  • PMA phorbol 2-myristate 13-acetate
  • Cell viability was determined after 24-hour treatment by measuring the activity of a lysosomal enzyme acid phosphatase (Connolly 1986). At the end of incubation, cultivating medium was removed, and the acid phosphatase substrate p-nitrophenyl phosphate (10 mM) was added. The reaction was stopped after 1 h of incubation at 37°C by addition of 0.1 M NaOH. The color development, corresponding to the number of viable cells, was monitored by automated microplate reader at 405 nm. After subtracting the background value of NaOH alone, the results were presented as a percentage of the viability of untreated cells, which were regarded as 100% viable.
  • Apoptotic cell death was assessed by flow cytometry analysis of DNA fragmentation in cells stained with the DNA-binding dye propidium iodide (PI; BD Pharmingen, San Diego, CA) as previously described (Harhaji- Trajkovic 2009). Red PI fluorescence (FL2) was analyzed with a FACSCalibur flow cytometer (BD, Heidelberg, Germany), using a peak fluorescence gate to exclude cell aggregates. Cell distribution among cell cycle phases was determined with Cell Quest Pro software and hypodiploid cells in the sub-G 0 /Gi compartment were considered apoptotic.
  • PI propidium iodide
  • Apoptosis was also analyzed by double staining with f!uoresceinisothiocyanate (FITC)-conjugated annexin V and PI, in which annexin V binds to the apoptotic cells with exposed phosphatidylserine, while PI labels the late apoptotic/necrotic cells with a damaged membrane. Staining was performed according to the manufacturer's instructions (BD Pharmingen), and flow cytometry was performed on a FACSCalibur flow cytometer. The percentage of early apoptotic (annexin PI ⁇ ) and late apoptotic/necrotic (annexin7PI + ) cells was determined using Cell Quest Pro software.
  • FITC f!uoresceinisothiocyanate
  • caspases apoptosis executioner enzymes
  • flow cytometry after labeling the cells with a cell-permeable, FITC- conjugated pan-caspase inhibitor (ApoStat; R&D Systems, Minneapolis, MN) according to the manufacturer's instructions.
  • Increase in green fluorescence (FL1) is a measure of caspase activity within individual cells of the treated population. The results are expressed as the percentage of cells containing active caspases.
  • DHE dihydroethidium
  • DAF diaminofluorescein
  • FL2 fluorescence (DHE) or green (FL1 ) fluorescence (DAF), corresponding to ROS or RNS levels, respectively, was determined using a FACSCalibur flow cytometer (BD). Nitrite accumulation, which reflects NO production, was measured using Griess reaction as previously described (Harhaji 2006).
  • the mitochondrial depolarization was assessed using JC-1 (R&D Systems), a lipophilic cation susceptible to changes in mitochondrial membrane potential with property of aggregating upon membrane polarization, forming an orange-red fluorescent compound. If the potential is disturbed, the dye cannot access the transmembrane space and remains or reverts to its green monomeric form.
  • the cells were stained with JC-1 as described by the manufacturer, and the green monomer and the red aggregates were detected by flow cytometry. The results are presented as a green/red fluorescence ratio (geomean FL1/FL2), the decrease and increase of which reflect mitochondrial hyperpolarization and depolarization, respectively.
  • Example 2 Arylpyperazines protect neuroblastoma cells from NO- mediated toxicity
  • arylpiperazines were investigated in neuron-like SH-SY5Y cells treated for 24 h with NO donor SNP or hydrogen peroxide. Both toxins in a dose dependent manner decreased cell viability, as demonstrated by acid phosphatase activity assay (Fig 2A). The compounds were screened at the highest non-toxic concentration, which was 10 ⁇ - at 20 ⁇ , several ligands have demonstrated a slight reduction in cell numbers (data not shown). While none of the investigated ligands showed protective effects on H 2 O 2 induced toxicity, the ligands reduced SNP-induced cell damage (Fig 2B).
  • Apoptotic events in SH-SY5Y cells treated with SNP were determined using double staining with annexin V-FITC and propidium iodide, which detect phosphatidylserine externalization and cell membrane damage, respectively.
  • Compound 6a significantly decreased the number of annexin + PI ⁇ (early apoptotic) and annexin + PI + (late apoptotic/necrotic) cells in SNP-treated SH-SY5Y cultures (Fig 3A).
  • Example 4 Arylpyperazines reduce superoxide production in neuroblastoma cells exposed to NO
  • compound 6a influenced SNP-generated intracellular production of reactive oxygen and nitrogen species in SH- SY5Y cells.
  • the increase in superoxide anion and NO/peroxynitrite content in SNP-exposed cells was demonstrated using fluorescent dyes DHE and DAF, respectively (Fig. 4A, B).
  • Fig. 4A, B While treatment with 6a markedly reduced the amount of superoxide in SNP-treated cells, we observed only a slight non-significant decrease in NO/peroxynitrite concentration (Fig. 4A, B).
  • rat peritoneal macrophages stimulated for NO production with LPS and IFN- ⁇ .
  • Example 5 Arylpyperazines modulate apoptosis-associated signalling pathways in NO-treated neuroblastoma cells
  • Oxidative stress including that induced by NO, triggers various intracellular signalling pathways involved in regulation of cell death.
  • Oxidative stress including that induced by NO, triggers various intracellular signalling pathways involved in regulation of cell death.
  • Immunoblot analysis of enzyme phosphorylation (activation) demonstrated that the treatment with SNP for 8 h inhibited Akt and activated JNK, ERK and AMPK in SH-SY5Y cells (Fig. 5).
  • arylpiperazine treatment diminished SNP-triggered activation of pro- apoptotic signalling pathways (Jun-N-terminal kinase, extracellular signal- regulated kinase, AMP-activated protein kinase) and prevented SNP- mediated down-regulation of anti-apoptotic Akt activity.
  • Neuroprotective effect of arylpiperazines was apparently independent of binding to dopamine receptors, as it was not affected by pretreatment with butaclamol, a high-affinity D1/D2 receptor blocker.
  • arylpiperazine dopaminergic ligands plausible candidates for development as potential therapeutics for neurodegenerative disorders.
  • the above examples demonstrate the neuroprotective action of novel arylpiperazine-based dopamine receptor ligands in NO-exposed SH-SY5Y neuroblastoma cells.
  • the most effective compound, 6a prevented NO- induced depolarization of mitochondrial membrane, oxidative stress and alterations of intracellular signalling pathways involved in apoptotic cell death.
  • the observed effects were apparently not due to a direct scavenging of NO and were independent of dopamine receptor binding.
  • the neuroprotective action of novel arylpiperazines was relatively selective for NO, as they were unable to protect SH-SY5Y cells from the toxic effect of hydrogen peroxide.
  • the NO donor SNP has previously been used for induction of apoptosis in a number of neuron-like cell lines (Pytlowany 2008; Lim 2009). NO and its toxic metabolite, peroxynitrite (ONOO ⁇ ), inhibit components of the mitochondrial respiratory chain, thus leading to depolarization of mitochondrial membrane and subsequent release of small molecules such as cytochrome c, which activate caspases, the main apoptosis-executing enzyme family (Heaies 1999). Accordingly, the compounds of the present invention, e.g. compound 6a, exerted neuroprotective effect through mitochondrial membrane stabilization, causing repolarization of mitochondrial membrane and subsequent decrease in caspase activation and DNA fragmentation.
  • the compounds of the present invention e.g. compound 6a, exerted neuroprotective effect through mitochondrial membrane stabilization, causing repolarization of mitochondrial membrane and subsequent decrease in caspase activation and DNA fragmentation.
  • neuroprotective dopamine receptor ligands such as pramipexole and talipexole
  • display similar mode of action accumulating in the mitochondria and restoring their membrane potential following MPP + induced apoptotic damage in SHSY5Y cells (Abramova 2002; Kakimura 2001 ).
  • inventive compounds such as compound 6a remains to be pinpointed, it is nevertheless evident that the protective effect occurs as a consequence of reducing superoxide, rather than NO content, following exposure of cells to SNP.
  • the latter points to a potential therapeutic value of the arylpiperazines in preventing CNS damage in neurodegenerative/neuroinflammatory diseases in which macrophage-like microglial cells are major source or neurotoxic inflammatory mediators, including NO (Brown 2010).
  • arylpiperazine dopaminergic ligands prevent NO-induced modulation of cell death-associated signalling pathways, mitochondrial damage, oxidative stress and subsequent apoptosis of neuron-like SH-SY5Y cells. Having in mind the role of mitochondrial aberrations, metabolic imbalance and resulting oxidative stress in development of Alzheimer's and Parkinson's disease (Andersen 2004; Sayre 2001 ; Halliwell 2006), arylpiperazine dopaminergic ligands may be suitable candidates for development as potential therapeutics for these and other neurodegenerative conditions.
  • Strosznajder JB Involvement of multiple protein kinases in cPLA2 phosphorylation, arachidonic acid release, and cell death in in vivo and in vitro models of 1-methyl-4-phenylpyridinium-induced parkinsonism- the possible key role of PKG. J Neurochem. 2009 Jul;110(1 ):307-17. 7. Chen L, Xu B, Liu L, Luo Y, Yin J, Zhou H, Chen W, Shen T, Han X,
  • SKF 83959 is an antagonist of dopamine D1 -like receptors in the prefrontal cortex and nucleus accumbens: a key to its antiparkinsonian effect in animals? Neuropharmacology, 42, 237-245.
  • SKF 83959 is an antagonist of dopamine D1 -like receptors in the prefrontal cortex and nucleus accumbens: a key to its antiparkinsonian effect in animals? Neuropharmacology, 42, 237-245.
  • neurodegenerative diseases an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Radical Biol. Med. 26, 1346-1355.
  • Taniguchi T. (2001 ) Release and aggregation of cytochrome c and a- synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole. Eur . J. Pharmacol. 417, 59-67.
  • Lam PY Cadenas E. Compromised proteasome degradation elevates neuronal nitric oxide synthase levels and induces apoptotic cell death.
  • Nerve growth factor-induced PKB/Akt activity is sustained by phosphoinositide 3-kinase dependent and independent signals in sympathetic neurons. Brain Res 837, 127-142.
  • OPC14857 reduce, through a presynaptic mechanism, glutamate release in rat prefrontal cortex: possible relevance to neuroprotective interventions in schizophrenia. Synapse. 62(11 ):804-18.

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Abstract

La présente invention concerne en général de nouvelles arylpipérazines. En particulier, ces arylpipérazines peuvent être utilisés en tant qu'agents neuroprotecteurs. L'invention concerne également un procédé de fabrication de nouveaux composés. En outre, l'invention concerne l'utilisation de nouvelles arylpipérazines dans le traitement de maladies associées à un stress mitochondrial, accompagnées par un stress mitochondrial ou provoquées par un stress mitochondrial.
PCT/EP2012/055212 2011-03-23 2012-03-23 Arylpipérazines en tant qu'agents neuroprotecteurs WO2012127030A1 (fr)

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