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WO2006108666A1 - Mefloquine, nelfinavir et saquinavir utilises comme nouveaux agents dans les maladies neurodegeneratives et (neuro)inflammatoires - Google Patents

Mefloquine, nelfinavir et saquinavir utilises comme nouveaux agents dans les maladies neurodegeneratives et (neuro)inflammatoires Download PDF

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WO2006108666A1
WO2006108666A1 PCT/EP2006/003437 EP2006003437W WO2006108666A1 WO 2006108666 A1 WO2006108666 A1 WO 2006108666A1 EP 2006003437 W EP2006003437 W EP 2006003437W WO 2006108666 A1 WO2006108666 A1 WO 2006108666A1
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alkyl
halo
treatment
hydrogen
prevention
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PCT/EP2006/003437
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André SCHRATTENHOLZ
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Proteosys Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Mefloquine, Nelfinavir and Saquinavir as novel agents for neurodegenerative and (neuro-) inflammatory diseases
  • the present invention generally relates to the neuroprotective, anti-apoptotic and anti-inflammatory activity of mefloquine, nelfinavir and saquinavir and derivatives thereof based on recently discovered interactions with prohibitin and estrogen receptors and the inhibition of mitochondrial voltage- dependent anion channel 1.
  • mefloquine, nelfinavir and saquinavir and derivatives thereof may be used as medicaments for the prevention and/or treatment of neurodegenerative and inflammatory, particularly neuroinflammatory diseases.
  • Nelfinavir (Viracept ® ) and saquinavir (Invirase ® or Fortovase ® ) are known as anti-HI V drugs called HIV protease inhibitors.
  • Further HIV protease inhibitors of the same class of compounds are amprenavir (Agenerase ® ), indinavir (Crixivan ® ), lopinavir (Kaletra ® ), ritonavir (Norvir ® ) and atazanavir (Reyataz ® ). These compounds are used for treatment of HIV.
  • Nelfinavir is usually administered in the form of (3S-(2(2S*,3S*), 3 ⁇ ,4a ⁇ ,8a ⁇ ))-N-(1 , 1 -dimethylethyl)decahydro-2-(2-hydroxy-3-((3-hydroxy-2- methylbenzoyl)amino)-4-(phenylthio)butyl)-3-isoquinolinecarboxamide;
  • the compound, its manufacture, its mechanism of action and its clinical efficacy have been described in the state of the art.
  • Saquinavir is usually administered in the form of Saquinavir mesylate (S)-N- (( ⁇ SJ- ⁇ -CCIR ⁇ -CCSS ⁇ aS. ⁇ aSJ-a-Ctert-butylcarbamoyOoctahydro ⁇ CI H)- isoquinolyl)-1 -hydroxyethyl) phenethyl)-2-quinaldamidosuccinamide mono- methanesulfonate (salt); DRG-0164; Fortovase ® ; Invirase ® ; Ro 31-8959/003; Saquinavir monomethanesulfonate salt; butanediamide, N(sup 1)-(3-(3- (((1 ,1 -dimethylethyl)amino) carbonyl)octahydro-2(1 H)-isoquinolinyl)-2- hydroxy-1- (phenylmethyl)propyl)-2-((2-quinoliny
  • Mefloquine (Lariam ® ) is known as an anti-malaria drug which has high efficacy in treating the widespread chloroquine-resistant Plasmodium falciparum strains. Mefloquine is used both for prophylaxis and treatment of malaria and is relatively well tolerated.
  • Mefloquine is usually administered in the form of mefloquine hydrochloride CR*, S?)-(+-)- ⁇ -2- piperidinyl-2, 8-bis (trifluoromethyl)-4-quinolinemethanol- monohydrochloride; DL-erythro- ⁇ -2-piperidyl-2,8-bis(trifluoromethyl)-4- quinolinemethanol monohydrochloride; WR-142490; Ro-21-5998; Lariam ® . Ci 7 Hi 7 CIF 6 N 2 O; mol wt 414.78. C 49.23%, H 4.13%, Cl 8.55%, F 27.48%, N 6.75%, O 3.86%.
  • the relatively new antimalarial mefloquine (Lariam ® ) has become extremely popular due to its efficacy in treating the wide-spread chloroquine-resistant Plasmodium falciparum strains. Mefloquine is known both for severe neurologic and psychiatric adverse effects associated with its use.
  • the crucial molecular features correlated with neurotoxicity are under investigation and certain molecular features defining neurotoxicity are emerging.
  • VDA1 voltage-dependent anion selective channel-1
  • VDAC voltage dependent anion selective channel
  • VDAC proteins are tyrosine-phosphorylated under hypoxic conditions suggesting that tyrosine phosphorylation may then contribute to the modulation of VDAC protein function/conformation or interaction with other proteins (Liberatori S. et al., Proteomics 4, 1335-1340 (2004)). Also a role as redox sensor has been suggested recently (Baker M. A. et al., Biofactors 21, 215-221 (2004)). This relates very well to the experimental examples described below.
  • Prohibitins comprise a remarkably conserved protein family in eukaryotic cells with proposed functions in cell cycle progression, cancer, cellular stress management, senescence, apoptosis, and the regulation of mitochondrial activities (Liu H. et al., Proteomics 10, 3167-3176 (2004); Huang C. M. et al., Mass Spectrom. Rev. (2004); Wang K. J. et al., World of Gastroenterol. 10, 2179-2183, (2004); Wang S. et al. EMBO J. 23, 2293-2303 (2004); Gamble S. C. et al., Oncogene 23, 2996-3004 (2004); Joshi B. et al. Biochem. Biophys. Res. Commun.
  • Phb1 and Phb2 Two prohibitin homologues, Phb1 and Phb2, assemble into a high molecular weight complex of approximately 1.2 MDa in the mitochondrial inner membrane, but a nuclear localization of Phb1 and Phb2 also has been reported (Tatsuta T. et al., MoI. Biol. Cell. 16, 248- 259, (2005)).
  • Prohibitin is also a tumor suppressor enriched in membrane microdomains, called lipid rafts and associated with viral infectious and inflammatory pathways, potentially via mitogen-activated protein kinase (e.g. Sharma A. et al., Proc. Natl. Acad. Sci. USA 101, 17492-17497 (2004)).
  • estrogen may exert neuroprotective effects against ⁇ -amyloid-induced toxicity by activation of estrogen receptor-mediated pathways in cholinergic neurons as a model for the pathology of Alzheimer's disease.
  • intracellular estrogen receptors are up-regulated by their cognate hormone even during exposure to neurotoxic agents, like ⁇ - amyloid1-40 (Marin R. et al., Neuroscience 121, 917-926 (2003)).
  • Estrogen appears to be an important neuromodulatory molecule.
  • REA repressor of estrogen receptor activity
  • REA is recruited to the hormone-occupied ER 1 decreases the transcriptional activity of ER, both when ER is acting directly through DNA response elements as well as when it is tethered to other transcription factors.
  • Estrogen antagonists are universally employed in the breast cancer therapy.
  • the molecular mechanisms by which these agents inhibit cellular proliferation in breast cancer cells are not fully defined.
  • E2F family of transcription factors
  • E2F repressor like prohibitin and the chromatin modifiers Brg1/Brm are required for estrogen antagonist-mediated growth suppression through the estrogen receptor, and that their recruitment to native promoter-bound E2F is induced via a JNK1 pathway.
  • HATs histone acetyltransferases
  • HDACs histone deacetylases
  • Histone acetyltransferases and deacetylases are recruited by transcription factors and adapter proteins to regulate specific subsets of target genes.
  • the repressor of estrogen receptor activity (REA) has been identified as a novel HDAC1 -associated protein. REA also associates with the class Il histone deacetylase HDAC5 (Kurtev V. et al., J. Biol. Chem 279, 24834- 24843, (2004)).
  • Estrogen and REA also appear to play a role in pathological processes in the eye: Despite the high prevalence of age-related cataracts, there are currently no known therapies to delay or prevent their occurrence. Studies in humans and rodent models suggest that estrogen may provide protection against age-related cataracts. The discovery of ocular estrogen receptors
  • estrogens indicates that estrogen protection may result from direct interactions with its receptors in the eye, instead an indirect consequence from effects on another tissue.
  • mefloquine, nelfinavir and saquinavir and related compounds interact with prohibitin and estrogen receptor repressor (REA) and inhibit VDAC-1. Based on these results it is demonstrated that mefloquine, nelfinavir and saquinavir and related compounds have cytoprotective and particularly neuro-protective efficacy.
  • REA estrogen receptor repressor
  • mefloquine, nelfinavir and saquinavir and related compounds are suitable for the prevention and/or treatment of diseases which are caused by, associated with or accompanied by calcium overload and inflammatory and/or apoptotic events.
  • a first aspect of the present invention relates to the use of a compound of formulae (1), (2), (3), (4) or (5)
  • cytoprotective medicament particularly a medicament for the prevention or treatment of a disease associated with an inflammatory component, e.g. a neurological or non-neurological inflammatory disease.
  • an inflammatory component e.g. a neurological or non-neurological inflammatory disease.
  • Ri, R 2 and R 4 are independently from each other hydrogen, Ci-C 6 -(halo)alkyl, or C3-C 8 -(halo)cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a five- or six-membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the ring is optionally monosubstituted up to polysubstituted with halo, Ci-C 4 -(halo)alkyl, CrC 4 -(halo)alkoxy, amino, Ci-C 4 - alkylamino, di(Ci-C 4 -alkyl)amino or Z, wherein Z is a Ci-C 6 -(halo)alkyl group (D-su bstituted with a group -NR 5 R 6 , wherein R 5 and R 6 are independently from each other hydrogen, Ci-C 8 -alkyl, or CO-d
  • R 3 is hydrogen, C 1 -C 6 -(halo)alkyl, C 3 -C 8 -(halo)cycloalkyl, or -NR 7 R 8 wherein R 7 and R 8 are independently from each other hydrogen, Ci-C 8 -alkyl, or
  • R 7 and R 8 together form a five- or six- membered ring optionally containing at least one further heteroatom selected from N 1 S and O 1 wherein the ring is optionally monosubstituted up to polysubstituted with halo, C 1 -C 4 -(halo)alkyl and Ci-C 4 -(halo)alkoxy.
  • Ri is hydrogen, Ci-C 6 -(halo)alkyl, or C 3 -C 8 -(halo)cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with a five- or six- membered ring optionally containing at least one heteroatom selected from N, S and O, and wherein the ring is optionally mono- or polysubstituted with halo, Ci-C 4 -(halo)alkyl, Ci-C 4 -(halo)alkoxy, amino, Ci- C 4 -alkylamino, di(d-C 4 -alkyl)amino or Z, wherein Z is a Ci-C 6 -(halo) alkyl group ⁇ -substituted with a group -NR 7 Re, wherein R 7 and R 8 are independently from each other hydrogen, Ci-C ⁇ -alkyI, or CO-Ci-C 8 -alkyl or wherein R 7 and R 8 together form
  • R 2 is hydrogen, halogen, Ci-C 6 -(halo)alkyl, or C 3 -C ⁇ -(halo)cycloalkyl, -NR9R10, wherein R 9 and R10 are independently from each other hydrogen, Ci-C ⁇ -alkyI, or CO-Ci-C 8 -alkyl or wherein R 9 and R10 together form a five- or six-membered ring optionally containing at least one further heteroatom selected from N, S and O, wherein the ring is optionally monosubstituted up to polysubstituted with halo, CrC 4 -(halo) alkyl and Ci-C 4 -(halo)alkoxy,
  • R 3 is hydrogen, Ci-C 6 -(halo)alkyl, or C 3 -C 8 -(halo)cycloalkyl, halogen, ORn, wherein Rn is d-C 6 -(halo)alkyl, or C 3 -C 8 -(halo)cycloalkyl,
  • R 4 is hydrogen, Ci-C 6 -(halo)alkyl, or C 3 -C 8 -(halo)cycloalkyl, CO-C r C 8 -alkyl,
  • R 5 is hydrogen, CrC 6 -(halo)alkyl, C 3 -C 8 -(halo)cycloalkyl or CO-Ci-C 8 -alkyl and
  • R 6 is hydrogen, Ci-C 6 -(halo)alkyl, C 3 -C 8 -(halo)cycloalkyl or C 2 -C 6 -alkylnyl.
  • Ri is hydrogen, hydroxy or NHR 2 ,
  • R 2 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heterocyclylalkyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, arylalkylcarbonyl, heterocyclylalkylcarbonyl, alkoxycarbonyl, arylalkyl oxycarbonyl, heterocyclylalkoxycarbonyl, aryl, heterocyclyl, sulfonyl, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl or a group of the formula
  • R 7 and R 8 are independently from each other hydrogen, alkyl, aryl, heterocyclyl, arylalkyl, heterocyclyl alkyl or
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a saturated ring optionally containing a further heteroatom or a group
  • R 3 , R 4 are independently from each other hydrogen, alkyl, carbamido, or R 3 , R 4 form together with the carbon atom to which they are attached a carbocyclic ring,
  • R 5 is hydrogen or the residue of an inorganic or an organic ester and R 6 is alkyl, arylalkyl, heterocyclylalkyl, alkyloxyalkyl, hydroxyalkyl, amino alkyl, fluoroalkyl and Ri 3 is aryl, ⁇ -alkylaryl, ⁇ -alkylarylether or co-alkylarylthioether.
  • Ri is alkyl, arylalkyl, heterocyclylalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino, aminoalkyl, fluoroalkyl,
  • R 2 is hydrogen or the residue of an inorganic or an organic ester
  • R 3 is aryl, ⁇ -alkylaryl, ⁇ -alkylaryl ether or ⁇ -alkylaryl thioether and R 4 is aryl.
  • the compounds of formulae (1), (2) and (3) and its pharmaceutically acceptable salts may be prepared as described in the citations indicated in the Merck Index, 12 th edition, 1996 (cf. citations indicated on page 3 to 4).
  • Halo is, for example, fluorine, chlorine, bromine or iodine.
  • alkyl is related to saturated, straight-chain or branched hydrocarbon radicals having 1 to 4, 5, 6, 8, 9 or 10 carbon atoms, e.g. C 1 -C 6 alkyl such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1- methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1 -methyl butyl, 2- methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylbutyl, hexyl, 1 ,1- dimethylpropyl, 1 ,2- dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
  • Ci-C ⁇ -alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl or n-octyl, preferably Ci-C 4 -alkyl, especially methyl or ethyl, and more especially methyl.
  • ,Alkylcarbonyl are straight-chain or branched alkyl groups having 1 to 10 carbon atoms (as mentioned above), which are bonded to the structure via a carbonyl group (-CO-).
  • Alkylsulfonyl are straight-chain or branched alkyl groups having 1 to 10 carbon atoms (as mentioned above), which are bonded to the structure via a sulfonyl group (-SO 2 ).
  • alkenyl are unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 10 carbon atoms and a double bond in any desired position, e.g. C 2 -C 6 -alkenyl such as ethenyl, 1-propenyl, 2-propenyl.
  • Alkylnyl are straight-chain or branched hydrocarbon groups having 2 to 10 carbon atoms and a triple bond in any desired position, e.g. C 2 -C 6 -alkynyl.
  • alkyl are straight-chain or branched alkyl group having 1 to 4 carbon atoms (as mentioned above) which are optionally substituted by at least one halo, substituent up to perhalogenation.
  • ,Alkoxy are straight-chain or branched alkyl groups having 1 to 10 or 1 to 10 carbon atoms (as mentioned above), which are bonded to the structure via an oxygen atom (-O-).
  • alkoxycarbonyl are straight-chain or branched alkoxy groups having 1 to 10 carbon atoms (as mentioned above), which are bonded to the structure via a carbonyl group (-CO-).
  • ..Cycloalkyl are monocyclic alkyl groups having 3 to 12 carbon ring members, e.g. C 3 -C B -cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Cycloalkylcarbonyl is a monocyclic alkyl group having 3 to 12, e.g. 3 to 6, 8 to 12 carbon ring members (as mentioned above), which is bonded to the structure via a carbonyl group (-CO-).
  • C 3 -C 8 -(Halo)cycloalky1 are monocyclic alkyl groups with 3 to 8 carbon ring members, eg. C 3 -C 8 -cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl which are optionally substituted by at least one halo substitutent up to perhalogenation.
  • Ci-C 4 -(Halo)alkoxy are straight-chain or linear alkyl groups with 1 to 4, carbon atoms which are bound to the structure by an oxygen atom (-O-) and which are optionally substituted by at least one halo substitutent up to perhalogenation.
  • Alkylamino are straight-chain or branched alkyl groups with 1 to 4 carbon atoms, which are bound to the structure by an amino group (-NH-).
  • Ci-C4-Alkylamino or "di(Ci-C 4 )alkylamino” are straight-chain or branched alkyl groups with 1 to 4 carbon atoms, which are bound to the structure by an amino group (-NH-) or by the nitrogen atom (-N:) respectively.
  • Aryl or arylalkyl, arylsulfonyl, arylcarbonyl and arylalkoxycarbonyl are aromatic mono- or polycyclic hydrocarbon radicals which are bonded to the structure directly or (arylalkyl) via an alkyl group, (arylsulfonyl) via a sulfonyl group (-SO 2 -), (arylcarbonyl) via a carbonyl group (-CO-) and (arylalkoxycarbonyl) via an alkoxycarbonyl group, e.g. phenyl, naphthyl and phenanthryl and the corresponding radicals.
  • Heterocyclyl is a five- or six-membered ring optionally containing at least one heteroatom selected from N, S and O.
  • a five- or six-membered ring optionally containing at least one heteroatom selected from N, S and O may be for example: a 5-membered heteroaryl, containing one to three nitrogen atoms: 5- membered ring heteroaryl groups, which in addition to carbon atoms can contain one to three nitrogen atoms as ring members, eg. 2-pyrrolyl, 3- pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 1 ,2,4-triazol-3-yl and 1 ,3,4-triazol-2-yl;
  • 5-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and a sulfur or oxygen atom or an oxygen or a sulfur atom
  • 5-membered ring heteroaryl groups which in addition to carbon atoms can contain one to four nitrogen atoms or one to three nitrogen atoms and a sulfur or oxygen atom or an oxygen or sulfur atom as ring members, eg.
  • 5-membered ring heteroaryl groups which in addition to carbon atoms can contain one to four nitrogen atoms or one to three nitrogen atoms and a sulfur or oxygen atom or an oxygen or a sulfur atom as ring members, and in which two adjacent carbon ring members or a nitrogen and an adjacent carbon ring member can be bridged to form an aromatic or heteroaromatic bicycle or polycycle, eg.
  • 6-membered heteroaryl containing one to three or one to four nitrogen atoms: 6-membered ring heteroaryl groups, which in addition to carbon atoms can contain one to three or one to four nitrogen atoms as ring members, eg. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3-yl and 1 ,2,4,5-tetrazin-3-yl; or
  • an aliphatic heterocyclyl such as piperidinyl and morpholinyl.
  • Heterocyclylalkyl, Heterocyclylsulfonyl, Heterocyclylcarbonyl and Heterocyclylalkoxycarbonyl are aromatic mono- or polycyclic hydrocarbon radicals which in addition to carbon ring members additionally can contain one to four nitrogen atoms or one to three nitrogen atoms and an oxygen or a sulfur atom or an oxygen or a sulfur atom and which are bonded to the structure (heterocyclylalkyl) via an alkyl group, (heterocyclylsulfonyl) via a sulfonyl group (-SO 2 -), (heterocyclylcarbonyl) via a carbonyl group (-CO-), and (heterocyclylalkoxycarbonyl) via an alkoxycarbonyl group.
  • the compounds of formulae (1), (2), (3), (4) and (5) may be present as an optical enantiomer or diastereomer or any mixture of enantiomers, such as racemates, or diastereomers.
  • ,salt preferably refers to pharmaceutically acceptable salts of compounds of formulae (1), (2), (3), (4) and (5) with suitable cations and/or anions.
  • suitable cations are alkaline metal cations such as Li + ; Na + and K + , alkaline earth metal cations such as Mg 2+ and Ca 2+ as well as suitable organic cations, e.g. ammoniums or substituted ammonium cations.
  • pharmaceutically acceptable anions are inorganic anions such as chloride, sulfate, hydrogensulfate, phosphate or organic anions such as acetate, citrate, tartrate, etc.
  • Derivatives of the compounds of formulae (1), (2), (3), (4) and (5) are any molecules which are converted under physiological conditions to a compound of formulae (1 ), (2), (3), (4) and (5) respectively, e.g. esters, amides etc. of compounds of formulae (1), (2), (3), (4) and (5) molecules which are products of metabolization reactions of a any compound of formulae (1 ), (2), (3), (4) and (5).
  • Preferred examples of the compounds of formulae (1), (2) and (3) include mefloquine and derivatives thereof, e.g. acetyl mefloquine, chloroquine, quenine, primquine, ablaquine and amodiaquine as well as derivatives thereof.
  • Preferred examples of the compounds of formulae (4) and (5) include nelfinavir/saquinavir and derivatives thereof, e.g. amprenavir (Agenerase ® ), indinavir (Crixivan ® ), lopinavir (Kaletra ® ), ritonavir (Norvir ® ) and atazanavir (Reyataz ® ).
  • the compounds of formulae (1) to (5) are used for the prevention or treatment of disorders associated with apoptotic or neuroinflammatory, or generally inflammatory disorders which are caused by and/or accompanied by mitochondrial dysfunction, particularly a dysfunctional mitochondrial transition pore, and/or disorders which are caused by and/or accompanied by HDAC-dysfunction, particularly a dysfunctional decrease in HDAC activity.
  • these disorders include neurodegenerative or neuroinflammatory diseases or pathological conditions, like M. Alzheimer, traumatic brain injury, M. Parkinson, amytrophic lateral sclerosis (ALS), stroke, migraine and multiple sclerosis.
  • At least one of the common lung diseases associated with a significant inflammatory component such as severe sepsis, acute lung injury, acute respiratory distress syndrome, cystic fibrosis, asthma, allergic rhinitis, or COPD or lung cancer, as well as any other cancer type.
  • a further preferred indication is the prevention or treatment of cystic fibrosis, particularly in persons with impaired function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl " channel or the prevention or treatment of ulcerative or other inflammatory conditions of the gastrointestinal system, particularly of persons with impaired function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl " channel.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Still a further preferred indication is for the prevention or treatment of inflammatory processes involved in cancer prevention or progression.
  • Still a further preferred indication is for the prevention or treatment of inflammatory processes involved in autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, especially for the treatment of patients identified by genetic or other markers to be more likely to be especially amenable to such treatment.
  • autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus
  • a further preferred indication is for the prevention or treatment of inflammatory or inflammation-associated ocular disorders, particularly macula degeneration, e.g. moist or dry macula degeneration, glaucoma, e.g. acute, primary, secondary or low angle glaucoma, diabetic retinopathy, anterior or posterior optical neuropathy, retinitis pigmentosa, neuritis nervi optici, or central artery obstruction.
  • macula degeneration e.g. moist or dry macula degeneration
  • glaucoma e.g. acute, primary, secondary or low angle glaucoma
  • diabetic retinopathy e.g. acute, primary, secondary or low angle glaucoma
  • anterior or posterior optical neuropathy retinitis pigmentosa
  • neuritis nervi optici e.g. central artery obstruction.
  • a further aspect of the present invention relates to the use of a compound which is a MTP or REA inhibitor/modulator for the manufacture of a medicament for the prevention or treatment of airway diseases, preferably for the prevention or treatment of disorders as indicated above.
  • the compounds of formulae (1) to (5) may be used alone or together with other medicaments, e.g. oral asthma medications, antidiabetic or anticancer treatments.
  • the dual inhibitor compound is preferably a moderately strong VDAC-1 inhibitor, which has an IC 50 value for VDAC from 100 to 10000 ⁇ M, more preferably from 250 to 1000 ⁇ M.
  • the determination of the IC 50 value is carried out as indicated as in the Examples.
  • a further aspect of the present invention relates to the use of a compound which is a dual VDAC-1 /REA inhibitor or binding protein for the manufacture of a neuro- or cytoprotective medicament, preferably for the prevention or treatment of disorders as indicated above.
  • the compound is preferably a moderately strong VDAC-1 inhibitor as indicated above.
  • the IC 50 value is from 1 to 10,000 ⁇ M, more preferably from 5 to 1 ,000 ⁇ M. The determination of the IC 50 value is carried out as indicated in the Examples.
  • the compounds as indicated above are preferably administered to a subject in need thereof as a pharmaceutical composition, which may contain pharmaceutically acceptable carriers, diluents and/or adjuvants.
  • the pharmaceutical composition may be administered in the form of a tablet, capsule, solution, suspension, aerosol, spray etc (e.g. nasal or throat spray), gel, plaster etc.
  • the medicament may be administered according to any known means, wherein oral, pulmonal and intravenous administration is particularly preferred.
  • the dose of the active ingredient depends on the type and the variety of disease and usually is in the range from 1 to 2000 mg/day, preferably in the range from 10 to 200 mg/day.
  • the present application has applications in human and veterinary medicine, particularly in human medicine.
  • Fig. 1 Neuroprotective effect of mefloquine in the functional model outlined in the methods section.
  • Fig. 2 Neuroprotective effect of acetylmefloquine in the functional model outlined in the methods section.
  • Fig. 3 Silver stained gels of fractions enriched with Mefloquine-based affinity reagent (M: markers; RE: raw extract; F1-2, flow throughs, proteins not binding to affinity beads; E1-3: proteins binding to affinity beads and recovered by elutions of varying stringency): the numbered bands were identified by mass spectrometry.
  • M markers
  • RE raw extract
  • F1-2 flow throughs, proteins not binding to affinity beads
  • E1-3 proteins binding to affinity beads and recovered by elutions of varying stringency
  • the proteins in the specific mefloquine- associated fractions E1-3 are those with numbers 41-54: Beyond some structural and housekeeping proteins (e.g.
  • tubulin isoforms tubulin isoforms
  • mefloquine binding 45, 46 and 48
  • names and gene bank accession numbers are given in the following table: MWapp is the apparent molecular weight, pi is measured isoelectric point on 2D gels; MW 03 I is the calculated molecular weight.
  • Fig. 4 Structure of Nelfinavir-Sepharose 4B.
  • Fig. 5 Neuroprotective effect of nelfinavir and saquinavir in the functional model outlined in the methods section at concentrations of each 1 ⁇ M.
  • Fig. 6 Silver stained gels of fractions enriched with Nelfinavir/Saquinavir- based affinity reagent (1 ,2: raw extracts; 3-9, flow throughs, unspecific elutions, proteins not related to nelfinavir-part of affinity material beads;
  • 10,11 proteins binding to affinity beads and containing specific nelfinavir- related bands
  • the numbered bands were identified by mass spectrometry.
  • the proteins in the specific Nelfinavir/Saquinavir-associated fractions E1-3 are those with numbers 14-19: Beyond some structural and housekeeping proteins (e.g. tubulin isoforms), considered to be associated , but rather for anchoring than drug binding, the following bands appeared to be associated with Nelfinavir/Saquinavir binding: 14-10; names and gene bank accession numbers are given in the following table: MW ⁇ xp is the apparent molecular weight, pi is measured isoelectric point on
  • the compounds are suitable as cytoprotective drugs and new lead structures for the development and optimization of related compounds with this novel mode of action, generally for cytoprotection and, particularly for the treatment of disorders of the nervous system related to underlying apoptotic and/or inflammatory mechanisms.
  • ES cells D3 embryonic stem (ES) cells derived from 129/sv mice [Okabe et al., Mech. Dev. 59, 89-102 (1996)] were cultivated for 12 days, with passages on days 2, 4, 7 and 9 as described previously (Sommer S. et al., supra 2004). Insult conditions: Cells (24-well plates) were pre-incubated with or without 2OnM EPO in fresh medium for 24 hours at 37°C.
  • Image resolution was 168 x 129 pixels (binning 8 x 8, pixel size 6.8 x 6.8 ⁇ m). Only cells identified as neurons by morphological criteria and occasional immunostaining (not shown) and those whose calcium levels returned to the resting state after the first stimulation were taken into account. Controls included nominal zero calcium (negative) and 5 ⁇ M ionomycin (positive), 10 ⁇ M glutamate (positive) and depolarisation (55 mM K + ) (positive). Pharmacological agents were applied by a multi-valve, single-output focal drug application device (ALA Scientific) with the perfusion system DAD-12. Ratio images were displayed as a percentage of relative change in fluorescence over background fluorescence scale for comparison across experiments (as described in Sommer S. et al., supra (2004)). During each stimulation event, 20 image pairs were acquired.
  • ALA Scientific multi-valve, single-output focal drug application device
  • mefloquine HCI 200 mg
  • 10 ml of a 50% suspension of AffiGel 10 (BioRad) in isopropanol was added.
  • the suspension was shaken at room temperature for 16 hours whereupon 0.3 ml of ethanolamine was added.
  • beads were separated by filtration through glass sinter funnel and washed sequentially with 200 ml of DMF/isopropanol (1/1 ), 200 ml isopropanol, 200 ml 60% isopropanol, 500 ml 30% isopropanol and 1000 ml water.
  • the obtained mefloquine-AffiGel 10 beads were kept as 50% slurry in 30% isopropanol at 4 0 C until used.
  • the affinity beads (Meloquine-Affi-Gel 10) were used to bind the target(s) from fractionated crude cell extracts of D3 ES cells and other cell lines. Subsequently the affinity purified material was analysed by 1 D PAGE, immunostaining, and mass spectrometry.
  • Monoclonal anti-PARP antibody was purchased from BD BioScience (Cat# 556 362; clone C2-10). Secondary anti-mouse alkaline phosphatase conjugate was purchased from Sigma (Cat# A9316).
  • N BT/BC IP-western blot detection reagents came from Roche Diagnostics (Cat.# 1681451), Western Lightening CDP-Star chemiluminescence detection kit was supplied by Perkinelmer (Cat.# NEL616001 KT).
  • proteins were separated on 10% polyacryl amide gels and blotted onto nitrocellulose.
  • Blots were blocked with 5% skimmed milk powder in Tris buffered saline containing 0,1% Tween-20 (TBS-T).
  • anti-PARP antibody was incubated over night at 4°C using a 1:1000 dilution in milk powder TBS-T. Blots were subsequently washed 3 times using TBS-T. A second antibody was used at a dilution of 1 :1000 for NBT/BCIP detection and 1 :5000 for CDP-Star detection.
  • Cox-2 staining was obtained accordingly by using an antibody from Alexis, (ALX-210-711-1) anti-COX-2 (Cyclooxygenase-2); Rabbit, polyclonal; 1:1000 dilution; secondary antibody was anti-rabbit-AP (Sigma, A3937, 1 :1000)
  • iNOS staining was performed using a polyclonal anti-iNOS, Alexis, 1 :1000). Blots were washed in TBS/1.0 % Tween and incubated with the appropriate secondary antibody-horseradish peroxidase conjugate (anti-rabbit IgG, Sigma, 1 :2000).
  • CycLex® Sir2 Assay kit (Cat# CY- 1151) was used according to instructions of the manufacturer (CycLex Co., Ltd. 1063-103 Ohara, Tera-Sawaoka Ina, Nagano 396-0002 Japan). All substances tested in the SIR assay have to be cross-checked for their influence on the lysyl-endopeptidase. For this control an already deacetylated substrate peptide is used in order to measure directly lysyl- endopeptidase activity.
  • LPS challenge of 3T3 fibroblasts A 549 cells, V56 embryonic stem cells and neurally differentiated V56 embryonic stem cells was equally performed by exposing cells to 100 ng/ml lipopolysaccharide (LPS, E.coli 0111 :B4 LPS from Sigma) for 60 min in the presence or absence of mefloquine and related compounds. Cell pellets were further investigated by Western blot staining with anti cox-2 and anti iNOS antibodies of 1D polyacrylamide gels.
  • LPS lipopolysaccharide
  • PoIy-ADP ribosylated proteins were quantified from appropriate cellular protein extracts by Western blots using as primary antibody: Anti-poly(ADP- ribose); Antigen: mouse; Biomol, Cat Nr SA-216, Lot Nr. : P7482; and as secondary antibody: Anti mouse, AP; Sigma A 9316, Lot: 31 K 9205; both antibodies were used at 1 :2000 dilution.
  • apoptosis inducing factor AIF
  • mitochondria apoptosis inducing factor
  • mitochondrial fractions the cellular material was fractionated into cytosolic, nuclear and mitochondrial fractions according to Arnoult et al. (Damien Arnoult, Philippe Parone, Jean- Claude Martinou, Bruno Antonsson, Jerome Estaquier, and Jean Claude Ameisen Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli Journal of Cell Biology, Volume 159, Number 6, December 23, 2002 923-929).
  • AIF apoptosis inducing factor
  • Figure 1 shows the neuroprotective effect of mefloquine in the functional model outlined in the methods section and Figure 2 those of its derivative acetylmefloquine. Whereas control cells had a survival rate of 28.3 + 1.8%, mefloquine-treated cells had survival rates ranging from of 47.1 to 61.3 % with an EC50 of approx. 90 nM.
  • Mefloquine was used as a starting structure for the synthesis of the affinity reagent, which was used to bind the targets from fractionated crude cell extracts of D3 embryonic stem cells. Subsequently the affinity purified material was analysed by 1D PAGE ( Figure 3) and mass spectrometry. MALDI-TOF analysis of the silver stained gels indicated the presence of VDAC-1 , REA and prohibitin in enriched fractions.
  • VDAC-1 Homo sapiens prohibitin
  • PHB Homo sapiens prohibitin
  • VDAC-1 Homo sapiens voltage-dependent anion channel 1
  • HDAC histone deactylases
  • the cytoprotective properties of these and other related compounds are rather due to a hitherto unknown dual mode of action namely VDAC-1 and REA.
  • This novel mixed type of activity can be used for new high throughput screening of existing chemical libraries for identification of novel cytoprotective agents for the treatment of various indications as outlined above.
  • the invention relates to cytoprotective properties of compounds with a VDAC-1 modulating activity. 3. Cox-2 and iNOS expression in LPS challenge and chemical ischemia of neuronal and non-neuronal cells
  • a further preferred indication is for the prevention or treatment of inflammatory or inflammation-associated ocular disorders, particularly macula degeneration, e.g. moist or dry macula degeneration, glaucoma, e.g. acute, primary, secondary or low angle glaucoma, diabetic retinopathy, anterior or posterior optical neuropathy, retinitis pigmentosa, neuritis nervi optici, or central artery obstruction.
  • macula degeneration e.g. moist or dry macula degeneration
  • glaucoma e.g. acute, primary, secondary or low angle glaucoma
  • diabetic retinopathy e.g. acute, primary, secondary or low angle glaucoma
  • anterior or posterior optical neuropathy retinitis pigmentosa
  • neuritis nervi optici e.g., central artery obstruction.
  • nelfinavir, saquinavir and related compounds have a previously unknown and neuroprotective mode of action via binding to VDAC-1 , REA and prohibitin. Due to these previously unknown neuroprotective effects, the compounds are suitable as cytoprotective drugs and new lead structures for the development and optimization of related compounds with this novel mode of action, generally for cytoprotection and, particularly for the treatment of disorders of the nervous system related to underlying apoptotic and/or inflammatory mechanisms.
  • D3 embryonic stem (ES) cells derived from 129/sv mice [Okabe et al., 1996, supra] were cultivated for 12 days, with passages on days 2, 4, 7 and 9 as described previously (Sommer S. et al., supra 2004).
  • Insult conditions Cells (24-well plates) were pre-incubated with or without 2OnM EPO in fresh medium for 24 hours at 37°C. Cells were rinsed once with low K + solution (140 mM NaCI 1 4.7 mM KCI, 1.2 mM KH 2 PO 4 , 2.5 mM CaCI 2 , 1.2 mM MgSO 4 , 11 mM glucose, 15 mM Hepes-NaOH, pH 7.35).
  • Excitation wavelengths ( ⁇ i, ⁇ 2 ) and the emission wavelength were 340, 380 and 510 nm, respectively. Acquisition and analysis of data after appropriate stimulation were performed by using MetaFluor software (Universal Imaging Corporation). Image resolution was 168 x 129 pixels (binning 8 x 8, pixel size 6.8 x 6.8 ⁇ m). Only cells identified as neurons by morphological criteria and occasional immunostaining (not shown) and those whose calcium levels returned to the resting state after the first stimulation were taken into account. Controls included nominal zero calcium (negative) and 5 ⁇ M ionomycin (positive), 10 ⁇ M glutamate (positive) and depolarisation (55 mM K + ) (positive).
  • Pharmacological agents were applied by a multi-valve, single-output focal drug application device (ALA Scientific) with the perfusion system DAD-12. Ratio images were displayed as a percentage of relative change in fluorescence over background fluorescence scale for comparison across experiments (as described in Sommer S. et al., supra (2004)). During each stimulation event, 20 image pairs were acquired.
  • ALA Scientific multi-valve, single-output focal drug application device
  • nelfinavir free base or saquinavir
  • 20 ml of 90% DMF 200 ⁇ l of ethyldiisopropylamine was added.
  • the solution was cooled on ice.
  • This solution was mixed with a suspension of 5 g sucked dried p-diazoniumbenzoylamido Sepharose 4B and shaked for 2 hours at room temperature. Then 0.2 ml of aniline was added and shaking was continued for another 60 min.
  • Nelfinavir Sepharose 4B was separated by filtration and washed with 80% DMF (200 ml), 40% DMF (200 ml), water (200 ml), 0.1 M HCI (200 ml) water 500 ml. Finally it was resuspended in 30% 2-propanol and kept in fridge until used.
  • Nelfinavir-Sepharose 4B The structure of Nelfinavir-Sepharose 4B is depicted in Figure 4.
  • the affinity beads (nelfinavir/saquinavir-Affi-Gel 10) were used to bind the target(s) from fractionated crude cell extracts of D3 ES cells and other cell lines. Subsequently the affinity purified material was analysed by 1 D PAGE, immunostaining, and mass spectrometry.
  • NBT/BCIP-westemblot detection reagents came from Roche Diagnostics (Cat.# 1681451)
  • Western Lightening CDP-Star chemiluminescence detection kit was supplied by Perkinelmer (Cat.# NEL616001 KT).
  • Perkinelmer Cat.# NEL616001 KT
  • proteins were separated on 10% polyacryl amide gels and blotted onto nitrocellulose. Blots were blocked with 5% skimmed milk powder in Tris buffered saline containing 0,1% Tween-20 (TBS-T).
  • anti-PARP antibody was incubated over night at 4 0 C using a 1 :1000 dilution in milk powder TBS-T. Blots were subsequently washed 3 times using TBS-T. A second antibody was used at a dilution of 1:1000 for NBT/BCIP detection and 1 :5000 for CDP-Star detection.
  • Cox-2 staining was obtained accordingly by using an antibody from Alexis, (ALX-210-711-1) anti-COX-2 (Cyclooxygenase-2); Rabbit, polyclonal; 1 :1000 dilution; secondary antibody was anti-rabbit-AP (Sigma, A3937, 1 :1000).
  • iNOS staining was performed using a polyclonal anti-iNOS, Alexis, 1 :1000). Blots were washed in TBS/1.0 % Tween and incubated with the appropriate secondary antibody-horseradish peroxidase conjugate (anti-rabbit IgG, Sigma, 1 :2000).
  • LPS challenge of 3T3 fibroblasts A 549 cells, V56 embryonic stem cells and neurally differentiated V56 embryonic stem cells was equally performed by exposing cells to 100 ng/ml lipopolysaccharide (LPS, E.coli 0111 :B4 LPS from Sigma) for 60 min in the presence or absence of nelfinavir or saquinavir and related compounds respectively. Cell pellets were further investigated by Western blot staining with anti cox-2 and anti iNOS antibodies of 1 D polyacrylamide gels.
  • LPS lipopolysaccharide
  • PoIy-ADP ribosylated proteins were quantified from appropriate cellular protein extracts by Western blots using as primary antibody: Anti-poly(ADP- ribose); Antigen: mouse; Biomol, Cat Nr SA-216, Lot Nr. : P7482; and as secondary antibody: Anti mouse, AP; Sigma A 9316, Lot: 31 K 9205; both antibodies were used at 1 :2000 dilution.
  • apoptosis inducing factor AIF
  • mitochondrial fractions were fractionated into cytosolic, nuclear and mitochondrial fractions according to Arnoult et al. (Damien Arnoult, Philippe Parone, Jean- Claude Martinou, Bruno Antonsson, Jerome Estaquier, and Jean Claude Ameisen Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli Journal of Cell Biology, Volume 159, Number 6, December 23, 2002 923-929).
  • AIF apoptosis inducing factor
  • Figure 5 shows the neuroprotective effect of nelfinavir and saquinavir in the functional model outlined in the methods section at concentrations of each 1 ⁇ M.
  • control cells here had a survival rate of 5.9 ⁇ 3.3%
  • nelfinavir (1 ⁇ M)-treated cells had a survival rate of 91.0 + 3.8%
  • saquinavir (1 ⁇ M)- treated cells had a survival rate of 59.5 % ⁇ 5.5%, with EC50 of approx. 100 nM (nelfinavir) and 950 nM (saquinavir) under ischemic conditions.
  • Nelfinavir was used as a starting structure for the synthesis of the affinity reagent, which was used to bind the targets from fractionations of crude cell extracts of D3 embryonic stem cells. Subsequently the affinity purified material was analysed by 1 D PAGE (Fig. 6) and mass spectrometry. MALDI-TOF analysis of the silver stained gels indicated the presence of VDAC-1 in specifically enriched fractions.
  • VDAC-1 Homo sapiens prohibitin
  • PHB Homo sapiens prohibitin
  • VDAC-1 Homo sapiens voltage-dependent anion channel 1
  • the cytoprotective properties of these and other related compounds are rather due to a hitherto unknown second mode of action on namely VDAC-1.
  • This novel mixed type of activity can be used for new high throughput screening of existing chemical libraries for identification of novel cytoprotective agents for the treatment of various indications as outlined above.
  • the invention relates to cytoprotective properties of compounds with a VDAC-1 modulating activity.
  • a further preferred indication is for the prevention or treatment of inflammatory or inflammation-associated ocular disorders, particularly macula degeneration, e.g. moist or dry macula degeneration, glaucoma, e.g. acute, primary, secondary or low angle glaucoma, diabetic retinopathy, anterior or posterior optical neuropathy, retinitis pigmentosa, neuritis nervi optici, or central artery obstruction.
  • macula degeneration e.g. moist or dry macula degeneration
  • glaucoma e.g. acute, primary, secondary or low angle glaucoma
  • diabetic retinopathy e.g. acute, primary, secondary or low angle glaucoma
  • anterior or posterior optical neuropathy retinitis pigmentosa
  • neuritis nervi optici e.g. central artery obstruction.
  • VDAC1 As a plasma membrane NADH-oxidoreductase. Biofactors. 2004;21(1-4):215-21
  • estradiol prevents amyloid-beta peptide-induced cell death in a cholinergic cell line via modulation of a classical estrogen receptor. 49: Neuroscience. 2003;121 (4):917-26.

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Abstract

L'invention concerne généralement l'activité neuroprotectrice, antiapoptotique et anti-inflammatoire de la mefloquine, du nelfinavir et du saquinavir et de dérivés de ces derniers, basée sur les interactions découvertes récemment avec les récepteurs de la prohibitine et des oestrogènes et sur l'inhibition du canal anionique mitochondrial voltage dépendant 1. On peut par conséquent utiliser la mefloquine, le nelfinavir et le saquinavir et les dérivés de ces derniers comme médicaments dans la prévention et/ou le traitement de maladies neurodégénératives et inflammatoires et, en particulier, de maladies neuroinflammatoires.
PCT/EP2006/003437 2005-04-13 2006-04-13 Mefloquine, nelfinavir et saquinavir utilises comme nouveaux agents dans les maladies neurodegeneratives et (neuro)inflammatoires WO2006108666A1 (fr)

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WO2012088305A1 (fr) * 2010-12-22 2012-06-28 The Feinstein Institute For Medical Research Procédés pour traiter le lupus érythémateux disséminé utilisant des inhibiteurs de protéase du vih
WO2014187225A1 (fr) * 2013-05-21 2014-11-27 华东师范大学 Utilisation de méfloquine dans la préparation d'un médicament préventif contre la douleur neuropathique
CN104173348B (zh) * 2013-05-21 2017-10-31 华东师范大学 左旋甲氟喹在制备预防神经病理性疼痛药物中的应用
CN104173347A (zh) * 2013-05-21 2014-12-03 华东师范大学 甲氟喹在制备预防神经病理性疼痛药物中的应用
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WO2014187226A1 (fr) * 2013-05-21 2014-11-27 华东师范大学 Utilisation de méfloquine lévogyre dans la préparation d'un médicament préventif contre la douleur neuropathique
CN104173348A (zh) * 2013-05-21 2014-12-03 华东师范大学 左旋甲氟喹在制备预防神经病理性疼痛药物中的应用
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CN103961684A (zh) * 2014-05-23 2014-08-06 滨州医学院 沙奎拉韦在制备预防或治疗急性肺损伤/急性呼吸窘迫综合征和肺纤维化的药物中的应用
CN103989689A (zh) * 2014-05-28 2014-08-20 滨州医学院 地瑞那韦乙醇盐在制备预防或治疗急性肺损伤/急性呼吸窘迫综合征和肺纤维化的药物中的应用
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CN104083373A (zh) * 2014-07-08 2014-10-08 滨州医学院 洛匹那韦在制备预防或治疗急性肺损伤/急性呼吸窘迫综合征和肺纤维化的药物中的应用
WO2017059122A1 (fr) * 2015-09-29 2017-04-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Méthodes de traitement et de prévention d'une sclérose latérale amyotrophique
WO2018081624A1 (fr) 2016-10-27 2018-05-03 The United States Government As Represented By The Department Of Veterans Affairs Micro-arn dans l'activation de lymphocytes t
RU2810301C2 (ru) * 2022-04-08 2023-12-26 федеральное государственное бюджетное образовательное учреждение высшего образования "Волгоградский государственный медицинский университет" Министерства здравоохранения Российской Федерации Применение производного коричной кислоты при болезни Альцгеймера как церебропротекторного средства, регулирующего функцию VDAC1

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