(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION. TREATY (PCT)
`
`(19) World Intellectual Property Organiution
`international Bureau
`
`I 1111 DlllE ~ fillll 10011111111 fill I II Ill lllnllll lllll l~Hffll fill 11111~ ~111111 Ill
`
`(43) International Publication Date
`19 October 2006 (19.10.2006) .
`
`(51) International Patent ClasslflcaUon:
`. A61K 3114709 (2006.01)
`A61P 15/06 (2006.01)
`A61K 3114715 (2006.01)
`A61P ZSIZB (2006.01)
`A61P 11106 (2006.01)
`
`PCT
`
`(10) International Publication Number
`WO 2006/108666 Al .
`(81) Designated States (llllless otlre~ise '114ica1ed, ior every
`ki1u:I of national protection available): AE, AO, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR. BW,BY, BZ. CA, CH, CN,
`CO, CR. CU, CZ. DE, DK, DM, DZ. EC, EE, EO, ES, Fl,
`GB, GD, GE, GH, GM, HR. HU, ID, ll., IN; IS~ JP, KE,
`KG, KM, KN, KP, KR, Kz.·LC. LK, LR, LS, LT, LU, LV,
`LY. MA, MD, MG, MK, MN, MW, MX, Mz, NA, NO, Nl,
`NO, NZ. OM, PG, PH, PL. PT, Ro; RU, SC, so; SE; SG,
`SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, ·.uA, :uG, US,
`UZ. VC, VN, YU, ZA, ZM, 'ZW.
`.
`..
`
`(84) Designated States ( llllless o.tlrerwise indlcmed, ior evt!ry
`ki1u:I of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`'ZW), Eurasian (AM, AZ, BY. KO, Kz, MD. RU, TJ, TM),
`European (AT, BE, BO, CH,.CY, CZ, DE, DK, EE, ES, Fl,
`. FR, GB, GR, HU, IE, IS, IT, lJ', LU, LV. MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CP, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR. NE, SN, TD,TG).
`
`Published:
`with inlemalional search repon
`before the expiration of tire ·time !'unit for ame/uung tire
`claims and to be republished i~ the event of receipt of
`amendments
`
`For two-letter codes and other abbreviations, refer to the "Guhi(cid:173)
`ance Notes on Codes and Abbreviations" appearing al the begin(cid:173)
`ning of each regular issue of tire PCT Gatt!Ue.
`
`(21) International Applkatlon Number:
`PCTIBP2006/003437
`
`(22) Ioternatlonal.Flllng Date:
`
`13 April 2006 (13.04.2006)
`
`(25) FIUng Language:
`
`(26) Publication Language:
`
`English·
`
`English
`
`(30) Priority Data:
`60/670,648
`
`13 April 2005 (13.04.2005) US
`
`(71) Applicant (for all designated Stales eJCcept US): PRO·
`TEOSYS AG [DE/DE]; Carl-Zeiss-Strasse 51, 55129
`Mainz(DE).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): SCHRATTEN·
`HOLZ, Andre (DEIDEJ; Hinter der Kirche 43, 55129
`Mainz(DE).
`
`(74) Agent: WEICKMANN & WEICKMANN; Postfach 860
`820, 81635 Mllnchen (DE).
`
`--
`
`_
`_
`-
`
`=
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`::;;;;
`-
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`---
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`\C
`\C
`\C
`QO ________________________________________________________________________ ~
`
`e (54) Title: MEFLOQUINE, NELFINAVIR AND SAQUINAVIR AS NOVEL AGENTS FOR NEURODEGENERA11VE AND
`\0 (NEURO-) INFLAMMATORY DISEASES
`=
`.
`
`C'J (57) Abstract:· The present invention generally relates to the neuroprotective, anti-apoptotic and anti-inflammatory aetivity of
`N mefloquine, nelfinavir and saquinavir and derivatives thereof based on recently discovered interactions with prohibitin and estrogen
`0 receptors and the inhibition of mitochondrial voltage- dependent anion channel I. Thus, mefloquine, nelfinavir and saquinavir and
`
`:;;;;;... derivatives thereof may be used as medicaments for lhe prevention and/or ireaunent of neurodegenerative and inflammatory, partic-
`~ ularly neuroinflammatory diseases.
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`Mefloqulne, Nelfinavlr and Saqulnavtr as novel agents for·
`neurodegenerative and (neuro-)
`.
`Inflammatory diseases
`
`Description
`
`The present invention generally relates to the neuroprotective, anti-apoptotic
`and anti-inflammatory activity of mefloquine, nelfinavir and saquinavir and·
`derivatives thereof based on recenUy discovered interactions with prohlbltin
`and estrogen receptors and
`the
`inhibition of mitochondrial · voltage(cid:173)
`dependent anion channel" 1. Thus, mefloquine, nelfinavir and saquinavir and
`derivatives thereof may be used as medicaments for the prevention and/or
`of
`neurodegenerative
`and ·
`inflammatory.
`particularly
`treatment
`neuroinflammatory diseases.
`
`Nelfinavir (Viracepi®) and saquinavir (lnvirase® or Fortovase®) are k.nown as
`anti-HIV drugs called HIV protease inhibitors. Further HIV protease inhibitors
`of the same class of compounds are amprenavir (Agenerase®), indinavir
`(Crixivan®).
`loplnavir
`(Kaletra9),
`ritonavir
`(Norvire) and atazanavir
`(Reyataz8). These compounds are used for treatment of HIV.
`
`s
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`10
`
`1s
`
`Nelfinavir
`
`is usually administered
`
`in
`
`the
`
`form of (3S-(2(2S* ,35*),
`
`3a,4alJ,8alJ))-N-(1, 1-dimethylethyl)decahydro-2-(2-hydroxy-3-((3-hydroxy-2-
`20 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.
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`Nelfinavir .
`
`Saquinavir is us_ually administered in the form of Saquinavir mesylate (S)-N(cid:173)
`
`(( aS)-a-( ( 1 R)-2-( (3S,4aS,8aS )-3-(tert-butylcarbamoyl)octahydro-2( 1 H)-
`
`s
`
`isoquinolyl)-1-hydroxyethyl) phenethyl)-2-quinaldamidosuccinamide mono(cid:173)
`methanesulfonate (salt); DRG-0164; Fortovase8 ; lnvirase8 ; 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-quinolinylcarbonyl)amino )-.
`(35-(2
`
`10
`
`(1R*(R*),2S*),3a,4alJ,8aJ3))-. m~nomethanesulfonate (salt); N-[1-benzyl-2-
`
`6, 7,8,8a(cid:173)
`hydroxy-3-[[3-(tert-butylcarbamoyl)-1,2,3,4,4a,5,
`decahydroisoquinol-2-ympropyl)-2-(2-
`quinolylcarbonylamlno)succinamlde;
`methanesulfonlc acid. The compound, its manufacture, its mechanism of
`action and its clinical efficacy have been described in the state of the art.
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`Saquinavir
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`20
`
`The assumed antiapoptotic properties of this class of compounds have
`already been disclosed (Badley A. D. In vitro and in vivo effects of HIV ·
`protease inhibitors on apoptosis. Cell Death Differ. (2005) Mar 11; [Epub
`ahead of print]; Phenix B. N., Lum J.J., Nie Z., Sanchez-Dardon J.. and
`Badley A. D., Antiapoptotic mechanism of HIV protease
`inhibitors: .
`preventing mitochondrial transmembrane potential loss; Blood. 98, 1078- ·
`1085 (2001)).
`
`· -Mefloquine (Lariam®)--is- known as an anti-malaria drug which has high
`efficacy
`in treating
`the widespread chloroquine-resistant Plasmodium
`falciparom strains. Mefloqulne is used both for prophylaxis and treatment of
`malaria and is relatively well tolerated.
`
`Mefloquine is usually administered in the form of mefloquine hydrochloride
`
`(R*, S* )-(+-)-a-2~ piperldiny/-2, 8-bis
`
`(trifluoromethy/)-4-quinollnemethanol(cid:173)
`
`DL-erythro-a-2-piperidyl-2,8-bls(trifluorornethyl)-4-
`monohydrochlorlde;
`quinolinemethanol monohydrochloride; WR-142490; Ro-21-5998; Lariam•.
`C11H11CIFeN20; mol wt 414.78. C 49.23%, H 4.13%, Cl 8.55%, F 27.48%, N
`6.75%, 0 3.86%. The compound, Its manufacture, its mechanism .of action
`and its clinical efficacy have been described extensively in C. J. Qhnm~cht
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`
`et al. J. Med. Chem. 14, 926 (1971); DE patent 28 06 909, CA. 90. 22838q
`(1979); U.S. patent 4,507,482; J. T. Blackwell, J. Med. Chem. , 17~ 210.
`(1974); M. W. Davidson et al, J. Med. Chem. 20, 1117 (1977); R. E. Brown.
`et al., Life Sci. 25, 1857 (1979); Photochemistry: G. A. Epling, U. C. Yoon,
`Chem. Letters 1982 (2), 211; Pharmacokinetics: D. E. SchwartZ ·.et. al.,:
`Chemotherapy (Basel) 28, 70
`(1982). HPLC determination: 1. M ..
`Kapetanovic et al, .1. Chromatog. 277, 209 (1983); G. M. Trenholme et al.,
`Science 190, 792 (1975); F. Tin et al. Bull. WHO 60, 913 (1982); J.M. Kofe: .
`Ekue et al., ibid. 61, 713 (1983); J.-M. de Souza ibid. 809, 815 and P. Lim In
`Analytical Profiles of Drug Substances vol. 14, K. Florey, Ed. (Academic
`Press, New York. 1985) pp 157-180 (all citations from Merck Index, 12"'
`edition, 1996).
`
`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 ...
`
`There have also been reports about neurotoxic effects of mefloquine at
`higher dosages (Rendi-Wagner P.· et al., Acta Trop. 81, 167-173 (2002).
`The mechanisms of these adverse effects are discussed controversially in
`_the_Jiterature. __ Joxic ~n~phalopatt)y _ ~pP-_e~r§. to_ b_e _on~_ of the serious
`neurological manifestations which
`is slowly reversible depending · on
`individual predisposition. Self-administration schemes can be therefore both
`most useful and dangerous due to expected benefits and poteniiai' risks.
`(Nicolas X. et al., Presse Med. 30, 1349-1350 (2001); Dow G. S. et al.,
`Antimicrob. Agents Chemother. 48, 2624-2632 (2004 ). There are indications
`that disruption of neuronal calcium homeostasis can induce an ER stress
`response at physiologically relevant concentrations, thus contributing to: the
`neurotoxicity of the drug in vitro (Dow G. S. et al., Malar. J. 2, 14 (2003).
`There are other indications, that mefloquine shows stereoselective brain
`uptake in humans and rats and is a substrate and an inhibitor of the efflux
`protein P-glycoprotein (Barraud de Lagerie S. et al., Br. J. Pharmacol. 141,
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`inhibits certain gap junction
`that mefloquine
`1214-1222 (2004)). Or,
`channels at concentrations between 1 and 100 µM (Cruikshank S. J. ·et al., .
`Proc. Natl. Acad. Sci. USA 101, 12364-12369 (2004)). Also,: it has ·been··
`reported that the (-)-(R,S)-enantiomer of mefloquine is a potent adei'losine
`A2A receptor antagonist (Weiss et al. ... (2003)) .. Moreover, other reports·
`
`show inhibition of volume-regulated and calcium-activated chloride channels .
`by mefloquine (Maertens et al., J. Pharmacol. Exp. Ther. 295, 2g.:.35 ,(2000)).
`
`The .crucial molecular features correlated with neurotoxicity are under. ·
`investigation and certain molecular features defining neurotoxicity are
`emerging. There is an important hydrogen bond acceptor (lipid) function, an
`aliphatic hydrophobic function, and a ring aromatic function specifically
`distributed in the 3D surface of the molecule. Mapping of the 3D structures
`of a series of structurally diverse quinolines to the pharmacophore allowed
`accurate qualitative predictions of neurotoxicity (or not) to be made (Dow G.
`S. et al., supra ·(2004)).
`
`In contrast to reports on neurotoxicity other reports cite· mild side effects
`(Wattanakoon Y. et al., Southeast Asia J. Trop. Med. Public Health 34, 542-
`545 (2003)) or even recommend use of mefloquine during pregnancy (Adam
`I. et al., Saudi Med. J. 25, 1400-1402 (2004) or in infants (Dubos F. et al.,
`Pedlatr. Infect. Dis. J. 23, 679-618 (2004)). Interestingly, there is a recent
`theoretical study coming to the conclusion that mefloquine, along with other
`approved heterocycllcs may have · neuroprotective properties, potentially
`acting on a mitochondrial target (Stavrovskaya I. G., et aL J. Exp. Med:. 200,
`214-222 (2004)). Moreover, a neuroprotective activity of mefloquiMe ·based
`on its activity as a purinergic receptor antagonist is suggested by Fletcher et
`al. (US Pat. 6,197,788), (-)-mefloquine is suggested to block purinergic
`receptors and
`is claimed
`for
`the
`treatment of movement or
`neurodegenerative disorders.
`
`Taken. together there are many suggestions of potential new targets of
`mefloquine and some controversy about the severity, nature and mechanism
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`of the neurotoxic side effects~ There are thus no proven findings at· present
`regarding the sphere of medical application for mefloquine.
`
`In the present application novel modes of adion and novel t~rgets for
`s . meftoqulne, nelfinavir and saquinavir and derivatives thereof are described, .
`thus_ establishing novel medical applications. These novel targets and their •
`implication
`for medical applications, particularly
`in
`the
`field
`. of
`neuroprotectlon, are described below.
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`The voltage-dependent anion selective channel-1 (VOA 1 ). is a constitutive
`mitochondrial protein which can
`induce pro-apoptotic mitochondrial
`membrane permeabilisation and thus a potential target for the design and
`development of therapeutic strategies.
`
`Since its introduction to clinical use in 1985, there have . been numerous
`reports of severe adverse neurological and psychiatric effeCts including
`acute psychosis, affective disorders, acute confuslonal states and seizures
`. (Le Bras M. et al., Histol. Histopathol. 20, 205-219 (2005)}.
`
`It has ·been showri that the voltage dependent anion seledive channel
`(VOA~) in the outer membrane is a specific benzodiazepine binding site :in
`mitochondrial membranes (Slocinska M. et al., Ada Biochim. Po. 54, 953-
`. 962 (2004 )). VDAC proteins have also been implicated In the pathology of
`models for amytrophlc lateral sclerosis. (ALS), a fatal neurodegenerative
`disease charaderized by progressive motor neuron death (Fukada ·K. et al.,
`Mol. Cell Proteomics 12, 1211-1223 (2004)). Moreover it has been shown
`· --that-VDAC-proteins-are-tyrosine-phosphorylated under .. hypoxic .c0nditions
`suggesting that tyrosine phosphorylation may then contribute to
`the
`modulation of VDAC protein fundion/conformation or interadion with other
`prot~ins (Liberatori S. et al., P~teomics 4, 1335-1340 (2004)). Also a rol~ as
`redox sensor has been suggested recently (Baker M. A. et al., Biofadors 21,
`215-221 (2004)). This relates very well to the experimental examples
`described below.
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`the context of potentially anti-apoptotic and cyto-/neuroprotective ·
`In
`properties of mefloquine, nelfinavir and saquinavlr described here it · Is -
`noteworthy that certain hydrophobic hormones like thyroid hormone exert . ·
`antiapoptotic effects via interaction with components of the mitochondrial -
`.
`.
`transition pore (Yehuda-Shnaidman E. et al., Endocrinology, (2005)). This:
`might_ re_late to the_ ~e_nt~?tion of the repressor of estrogen receptor related
`activity (REA) as a further protein labelled by the reactive mefloquine,
`nelflnavir and saqulnavir derivatives described in the examples below.
`
`.
`
`'
`
`Proh~bitins 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 ~I.,
`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.
`Blophys. Res. Commun. 312, 459-466 (2003); Fusaro G. et al.,' J. Biol.
`Chem. 278, 47853-47861 (2003)). 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., Mol. 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))·.
`
`_ -RecenLreports.Jist prohibitin-among __ the_secreted __ proteins ot_ adipocYtes
`(Wang P. et al., Cell. Mol. Life Sci. 61, 2405-2417, (2004) ), moreo~er it has
`been established as a vasc~lar marker of adipose tissue, which· was target
`of a· proapoptotic peptide as· an antiobesity experimental treatment (Kolonin
`M. G. et al. Nat. Med. 10, 625-632 (2004 )).
`
`Recent data suggest that estrogen may exert neuroprotective effects against
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`~-amyloid-lnduced toxicity by activation of estrogen . receptor-mediated
`
`-8-
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`
`.
`
`pathways in cholinergic neurons as a model for the pathology of Alzheimer's
`disease. In addition, Intracellular estrogen receptors are up-regulated ·by
`.
`their cognate hormone even during exposure to neurotoxlc agents, like P-
`amyloid1-40 (Marin R. et al., Neuroscience 121, 917-926 (2003)). Estrogen·
`appears to be an important neuromodulatory molecule. REA (repre~sor of. ·
`estrogen receptor activity) encodes a 37-kDa protein that is an .ER-~elective:
`.
`coregulator.
`Its competitive reversal of steroid receptor coactivator 1:
`enhancement of ER activity and Its direct interaction with llganded ER .
`suggest that it may play an important role in detennining the sensitivity of
`estrogen target cells to antiestrogens and estrogens, especially in cancer
`(Montano M. M. et al., Proc. Natl. Acad. ~ci. USA 96, 6947-6952~ (1999);
`Simon S. L. et al., Cancer Res. 60, 2796-2799, (2000)). REA is recruited to
`the hormone-occupied ER, decreases the tran~.criptional activity of ER, both
`when ER is acting directly through DNA response elements as well ;as. when
`it Is tethered to other transcription factors. Administration of antisense REA .
`increase
`in . ER transactivatlon, implyin~ that
`in a 2-4-fold
`resulted
`endogenous REA nonnally dampens the stimulatory response to estradiol
`(Delage-Mourroux R. et al., J. Biol. Chem. 275, 35848-35856, (2000)).·
`.
`.
`
`Estrogen antagonists are universally employed in the breast cancer therapy.
`The molecular mechanisms by which
`these agents
`inhibit eellular
`proliferation in breast cancer cells are not fully defined. Recent studies h~ve
`shown the involvement of the E2F (family of transcription factors) pathway in
`tamoxifen-induced growth arrest. E2F repressor, like prohibitin · and the
`chromatin modifiers Brg1/Brm are required for estrogen antagonist-mediated
`----growth-supp(ession through the-estrogen--receptor, a-ncf that-their recruitment
`to native promoter-bound E2F is induced via a JNK1 pathway. Collectively,
`these findings suggest that the prohibitin/Brg1/Brm node is a majcir cellular
`target
`for
`estrogen
`antagonists,
`and
`thereby
`also
`implicate
`prohibitin/Brg1/Brm as potentially important targets tor breast cancer therapy
`(Wang S. et al., supra, (2004 )).
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`Of particular interest Is the . recently discovered interaction of REA With
`histone deacetylases, which have drawn
`interest as potential
`neuroprotective targets (Langley B. et al., Curr. Drug Targets CNS Neurol. ·
`Dlsord. 4, 41-50, (2005)). Acetylation and deacetylatlon of hlstone protein,
`plays a critical role in regulating gene expression in a host of biological ·
`processes Including cellular proliferation, development, and differentiation.:
`Accordingly, aberrant acetylation and deacetylatlon resulting from the. ·
`misregulation of histone acetyltransferases
`(HATs) and/or histone
`deacetylases (HDACs) has been linked to clinical disorders ~uch as:
`Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, and various
`cancers. Aberrant HAT and HDAC activity may also be a common
`underlying mechanism contributing to neurodegeneration during acute and
`chronic neurological diseases,
`including stroke, Huntington's disease
`Amyotrophic Lateral Sclerosis and Alzheimer's disease (Langley B. et al.
`supra, (2005)).
`
`Hlstone acetyltransferases and deacetylases are recruited by transcription
`factors and adapter proteins to regulate specific subsets of targ~t genes ..
`The repressor of estrogen receptor activity (REA) has been ideritifled a~· a
`novel HDAC1-associated protein. REA also associates with the' clas5 II
`hlstone deacetylase HDACS (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. Stu.dies in
`-- humans- and ·rodent·-models ·suggest that ·estrogen may- provide- protection
`against age-related cataracts. The discovery of ocular estrogen receptors
`(ERs) indicates that estrogen protection may resuH from direct interactions
`with its receptors in the eye, instead an indirect consequence from effects on
`another tissue. (Davis V. L. et al., Proc. Natl. Acad. Sci. USA 99, 9427-9432,
`(2002)).
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`According to the results described in the examples of the present application ·
`it was found · that 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 demonstrate.d that
`mefloquine, nelfinavir and saquinavir and
`related compounds have
`cytoprotective and particularly neuro-protective efficacy. Since a ecimmon
`feature of the different cellular challenges described in the examples of the·
`present application
`is an
`initial cytotoxic calcium overload · which
`subsequently leads to inflammatory and apoptotlc events, mefloqulne,
`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.
`
`5
`
`10
`
`1s
`
`Thus, a first aspect of the present invention relates to the use of a oompound
`of formulae (1 ), (2), (3). (4) or (5)
`
`(1)
`
`(2)
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`- 11 -
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`(3)
`
`R.__ /'• •.. K
`R/
`(c\"-NH
`
`Offs
`
`4
`
`R
`1
`
`.
`
`13
`
`N
`
`0
`
`NH
`.
`~
`(4)
`
`5
`
`(5)
`or an optical isomer. a salt or derivative thereof for the manufacture of a
`cytoprotective medicament, particularly a medicament for the prevention or
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`..; 12-
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`treatment of a disease associated with an inflammatory component, e.g. a
`neurological or non-neurological inflammatory disease.
`
`5
`
`10
`
`1s
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`20
`
`25
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`30
`
`In the compounds of the formula (1)
`
`R1, ~and~ are independently from each other hydrogen, C,-Ce-(halo)alkyl,
`or ~-Cr(halo)cycloalkyl, wherein the alkyl or cycloalkyl group: is:
`optionally substituted with a five- or ·six-membered ring qptionally·
`containing at least one heteroatom selected from N, S and 0, and·
`wherein the ring is optionally monosubstituted up to polysubstituted
`with halo, C1-C4-(halo)alkyl, C1-C4-(halo)alkoxy, amino, C,-C4-
`alkylamino, di(C1-C4-alkyl)amino or Z, wherein Z Is a C1-Cr(halo)alkyl
`group (1)-Substituted with a group -NR&Re , wherein Rs and Re are
`independenUy from each other hydrogen, C1-Cralkyl, or CO-C,-Ca-alkyl
`or wherein Rs and Re together form a five- or six-membered ring
`optionally containing at least one further heteroatom selected from N, S
`and 0, wherein
`the ring
`Is optionally monosubstituted up
`to
`polysubstituted with halo, C1-C4-(halo)alkyl and C1-C4(halo)alkoxy and
`Ra is hydrogen, C1-Ce-(halo)alkyl, CrCa-(halo)cycloalkyl, or -NR1Rs wherein
`R1 and Ra are independently from each other hydrogen, C,-Ca-alkyl~ or
`CO-C1-Ca-alkyl or wherein R1 and Rs
`together form a five- or six(cid:173)
`membered ring optionally containing at least one further heteroatom.
`selected
`from N, S and 0, wherein
`the
`ring
`is optionally
`monosubstltuted up to polysubstituted with halo, C1-C4-(halo)alkyl and
`C1-C4-(halo)alkoxy.
`
`In the compounds of the formulae (2) and (3)
`R, is hydrogen, C1-Cr(halo)alkyl, or CrCr(halo)cycloalkyl, wherein the alkyl
`or cycloalkyl group is optionally substituted with a five- or six-
`membered ring optionally containing at least one heteroatoi'n' selected
`from N,. S and 0, and wherein the ring is optionally mono- or pt>ly(cid:173)
`substituted with halo, C,-C,-(halo)alkyl, CrC4-(halo)alkoxy, amino, C1-
`C4-alkylamino, dl(C,-C4-alkyl)amino or Z, wherein Z is a CrC6-(halo)
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`-13-
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`-
`
`Rz
`
`alkyl group w-substituted with a group -NR,Ra; wherein R, and Ra are •
`.
`.
`independently from each other hydrogen, C1-Ce-alkyl, or CO-C,.;..~s-alkyl .
`or wherein R, and Ra together -form a five- or six-membered ring
`C?Ptionally c0ntalning at least one further heteroatom selected from N, S .
`and 0, wherein
`the ring
`is optionally ·monosubstituted up
`to
`polysubstitut~d with halo, C1-C4-(halo)alkyl and C1-C4-(halo)alk~xy.
`is hydrogen, halogen, C1-Ca-(halo)alkyl, or CrCa-(halo)cycloalkyl, _
`-NRaR10, wherein Ra and R1o are Independently from ea~h other :
`_hydrogen, C1-Ce-alkyl, or CO-C1-Cralkyl or wh~rein Ra and R,o -
`together form a five- or .six-membered ring optionally containing at least
`one further heteroatom selected from N, S and 0, wherein the ring is
`optionally monosubstituted up to polysubstituted with halo, C,-C4-(halo) .
`alkyl and C,-C4·(halo)alkoxy,
`~is hydrogen, C,-Ca-(halo)alkyl, or CrCa-(halo)cycloalkyl, halogen, OR11,
`wherein R11 is C,-Ca-(halo)alkyl, or ~-Ca-(halo)cycloalkyl,
`~ is hydrogen, C,-Ca-(halo)alkyl, or ~-Ca-(halo)cycloalkyl, CO-C1-C8-alkyl,
`Rs Is hydrogen, C1-Ca-(halo)alkyl, CrCa-(halo)cycloalkyl or CO-C1-Ca-alkyl
`and
`Ra is hydrogen, C1-Ca-(halo)alkyl, C3-Ca-(halo)cycloalkyl or CrCa-alkYlnyl.
`
`In the compounds of the formula (4)
`
`R, is hydrogen, hydroxy or NHRz,
`~ is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heterocyclylalkyl, cycloalkyl,
`alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl,
`arylalkylcarbonyl, heterocyclylalkylcarbonyl, alkoxycarbonyl, · arylalkyl
`oxycarbonyl, heterocyclylalkoxycarbonyl, aryl, heterocyclyl, · suifonyl,
`alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl or a group of the formula
`
`5
`
`10
`
`15
`
`20
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`25
`
`. fa
`,....Ny
`
`R7
`
`x
`
`30
`
`wherein X is 0 or S and
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`R1 and Ra are independently from each other hydrogen, alkyl, aryl,
`heterocyclyl~ arylalkyl, heterocyclyl alkyl or
`R1 and Ra together witti the nitrogen atom to which they are attached
`form a saturated ring optionally containing a further heteroatom. or
`a group
`
`wherein R1o is hydrogen, alkyl, arylalkyl, heterocyclylalkyl, aryl,
`heterocyclyl when n=O and Y is 0 or S or
`R,o is hydrogen, alkyl, arylalkyl, heterocyclylalkyl, aryl, heterocyclyl
`when n=1, Y Is N, Re is hydrogen or alkyl or
`Rg and R1o form together with the heteroatom to which they are
`attached a heterocyclic ring when n=O and Y Is N, 0 or S, ·and
`R11 and R,2 independently are hydrogen or alkyl or
`R,, and R12 form together with the carbon atom to which they are
`attached a ring,
`R:i, ~ are independently from each other hydrogen, alkyl, carbamido, or
`~. ~ form together with the carbon atom to which they are attached a
`carbocyclic ring,
`Rs is hydrogen or the residue of an inorganic or an organic ester and
`Ra Is alkyl, arylalkyl, heterocyclylalkyl, alkyloxyalkyl, hydroxyalkyl, amino
`alkyl, fluoroalkyl and
`R13 is aryl, oralkylaryl, oralkylarylether or co-alkylarylthloether.
`
`In the compounds of the formula (5)
`
`R, is alkyl, arylalkyl, heterocyclylalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino,
`aminoalkyl, fluoroalkyl,
`R2 is hydrogen or th.a residue of an inorganic or an organic ester,
`~ is aryl, co-alkylaryl, co-alkylaryl ether or co-alkylaryl thioether and
`
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`~is aryl.
`
`- 15-
`
`s
`
`10
`
`The use of mefloquine for the manufadure of a medicamenf f~>r the
`prevention or treatment of a disorder which is disclosed· in US. 6, 197 ,788 is :
`exempted from the use according to the present invention.
`
`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, 121t1 edition, 1996 (cf; citations indicated on page 3 to 4).
`
`The compounds of formulae (4) and (5) and its pharmaceutically acceptable
`salts may be prepared as described in the state of the art.
`
`The general terms according· to the present invention used herein above and
`below preferably have the following meanings:
`
`15
`
`"Halon is, for example, fluorine, chlorine, bromine or iodine.
`
`20
`
`If not indicated differently, •alkyl" is related to s~turated, stralght.:.chaln' or
`branched hydrocarbon radicals having 1 to 4, 5, 6, 8, 9 or 10 carbon atoms,
`e.g. C1-Cs alkyl such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-
`methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-
`methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylbutyl,' hexyl, 1, 1-
`dimethylpropyl, 1,2- dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-
`25 methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
`1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and· 1-
`ethyl-2-methylpropyl. -
`
`30
`
`·crCa-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 CrC4-alkyl, especially methyl or ethyl, and more especially
`methyl.
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`.,Alkylcarbonyla are straight-chain or branched alkyl groups having 1 to 10 ·.
`carbon atoms (as mentioned above), which are bonded to the ~tructure via a
`carbonyl group (-CO-).
`
`s
`
`10
`
`. 15
`
`20
`
`25
`
`30
`
`.,Alkylsulfonyl• are straight-chain or branched alkyl groups having • 1 · to 10
`carbon atoms (as mentioned above), which are bonded to the structure v1a·a
`sulfonyl group (-SOz).
`
`,,Alkeny1• are unsaturated, straight-chain or branched hydrocarbon· radicals
`having 2 to 10 carbon atoms and a double bond in any desired position, e.g.
`CrCralkenyl such as ethenyl, 1-propenyl, 2-propenyl.
`
`,,Alkylnyla are straight-chain or branched hydrocarbon groups having 2·to 10
`carbon atoms and a triple bond in ~ny desired position, e.g. CrCa-alkynyl.
`
`.(Halo)alkyl° are straight-chain or branched alkyl group having 1 to 4 carbon
`atoms (as mentioned above) which are optionally substituted by at lt:tast 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 (-0-).
`
`,,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. Ca-Ca-eycloalkyl such as cyclopropyl, cyclobutyl~ cyclopentyl,
`cyclohexyl, cycloheptyl and cyclooctyl.
`
`"CycloalkylcarbonylD 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
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`structure via a carbonyl group (-CO-).
`
`- 17-
`
`s
`
`10
`
`15
`
`20
`
`2s
`
`30
`
`"~-Cr(Halo)cycloalkyl• are monocyclic alkyl groups with 3 to 8 ca~o.n ring·
`members, eg. CrCa-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyt,:
`cyclohexyl, cycloheptyl and cyclooctyl which are optionally substituted by at
`least one halo substitutent up to perhalogenation.
`
`"C1-C4-(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 (-0-) and:
`which are optionally substituted by at least one halo substitutent up to
`perhalogenatlon.
`
`"Alkylamino• are straight-chain or branched alkyl groups with 1 to 4 carbon
`atoms, which are bound to the s