WO2014163622A1 - Multifunctional quinoline derivatives as anti-neurodegenerative agents - Google Patents

Multifunctional quinoline derivatives as anti-neurodegenerative agents Download PDF

Info

Publication number
WO2014163622A1
WO2014163622A1 PCT/US2013/034960 US2013034960W WO2014163622A1 WO 2014163622 A1 WO2014163622 A1 WO 2014163622A1 US 2013034960 W US2013034960 W US 2013034960W WO 2014163622 A1 WO2014163622 A1 WO 2014163622A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
hydrogen
formula
independently hydrogen
undecan
Prior art date
Application number
PCT/US2013/034960
Other languages
French (fr)
Other versions
WO2014163622A8 (en
Inventor
Ji-Wang Chern
Chen-Wei Huang
Pei-Teh Chang
Rahul Subhash TALEKAR
Original Assignee
Annji Pharmaceutical Co., Ltd.
Healthbanks Usa Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Annji Pharmaceutical Co., Ltd., Healthbanks Usa Inc. filed Critical Annji Pharmaceutical Co., Ltd.
Priority to AU2013385618A priority Critical patent/AU2013385618B2/en
Priority to CN201380075030.2A priority patent/CN105452224B/en
Priority to RU2015137621A priority patent/RU2642466C2/en
Priority to JP2016506301A priority patent/JP6153179B2/en
Priority to PCT/US2013/034960 priority patent/WO2014163622A1/en
Priority to BR112015024472A priority patent/BR112015024472A2/en
Priority to KR1020157026392A priority patent/KR101802048B1/en
Priority to EP13881032.0A priority patent/EP2981525A4/en
Publication of WO2014163622A1 publication Critical patent/WO2014163622A1/en
Publication of WO2014163622A8 publication Critical patent/WO2014163622A8/en
Priority to IL241295A priority patent/IL241295A0/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • US Patent Nos. 7,439.243 and 7,452.888 describe a series of quinolme derivatives useful for the treatment of CNS disorders, including Alzheimer ' s disease.
  • US Patent No. 7,009.053 describe a series of quinolme derivatives useful for treatment of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, ischemia, traumatic brain injury, spinal cord inj ury or osteoarthritis,
  • the invention relates to a compound of Formula (1.) or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof:
  • R 2 is hydrogen or halogen
  • .R:' is hydrogen, halogen, (CrCg kyl, or (CrCs)a1koxy;
  • R 4 is hydrogen, halogen, (C(-Cs)alkyl. (C r € 3 ⁇ 4 )aikoxy, or (CrC cramp)haioalkyl;
  • R 5 is hydrogen or (Cr €;3 ⁇ 4)alkanol
  • R 6 is hydrogen
  • R 7 is hydrogen, (Ci 1 ⁇ 2o)alkanol, (CrCs)alkylene iC 3 -Cs)heteroc d l(Cj ⁇ 2o) ⁇ anol, (C ' r Cs)alkylene (C3-Cs)heterocydyKCrC2(>)alkyl, ⁇ Ci !8)alk> : lene(CrC«)alkylan3 ⁇ 4no(Ci-C ⁇ >)a]kynyl, (C3 ⁇ 4- Cs)alkyleneamino(C j-C 3 ⁇ 4j)al kanol , or (C f - Cs)alky leneami no(C i-C a>)aikanol (C j -C «)alkylene
  • the invention relates to a method for preparing the compound as aforementioned, the method comprising:
  • R ⁇ R 4 , - . and R 6 are each independently hydrogen; or
  • R 4 , R , and R (> are each independently hydrogen and R* is Cl or
  • R '" , R ⁇ R “ ⁇ and R (> are each independeiitiv hydrogen and R 4 is CF , F ⁇ CI, or Br; or R 3 , R R 6 are each independently hydrogen, R ' ' is OCt . and R 4 is CI; or
  • R “ , R 4 is CI and R " ⁇ R 5 , * are each independently hydrogen
  • R 5 is CH 3 FbCH 3 . CH(CH 3 )2, or benzv l, and
  • R 3 , R 4 , R 5 , and R f> are each independently hydrogen and R' is C f?; or
  • R 2 , R ' R s , and R 6 are each independently hydrogen and R 4 is Cl , F ? CI, or Br; or
  • R" are each independently hydrogen, R 3 is OCH ? . and R 4 is CI; or
  • R z , R 4 is CI and R ' ⁇ R ⁇ R" are each independently hydrogen;
  • ' is CH 3 , CH 2 CH 3t CH ⁇ CJ3 ⁇ 4)2, CH 2 CH ⁇ CH 3 )2, or benzyl;
  • R 2 , R ' . R 4 , R' ; and R* are each independently hydrogen or
  • R 2 , R* R' ⁇ and R b are each independently hydrogen and R;' is CH3 ⁇ 4; or
  • R ⁇ . R ⁇ R ⁇ and R" are each independently hydrogen and R 4 is CH*, F, CL or Br; or
  • R ' l R 5 , R" are each independently hydrogen, R* is OCI3 ⁇ 4, and R 4 is CI; or K" is CI, and R is oa-h or
  • R 2 , R 4 is CI and R:', R' R 6 are each independenily hydrogen: and
  • R 7 is (CH ⁇ OH, (CH ⁇ wOH, (CH 2 ) n OH ⁇ (CH 2 )i 2 OH, (CH 2 )uOH, iCH 2 ) ! 5 OH,
  • R ⁇ and ° are each independently hydrogen; or
  • R 2 , R 4 , R'êt and * are each independently hydrogen and R -> is CFI 3 ; or
  • R J , ⁇ R ' R 5 , and R" are each independently hydrogen and R* is C3 ⁇ 4 F, CI, or Br; or R ⁇ , R ' R ⁇ R" are each independently hydrogen, R-" is OCH 3 ⁇ 4 and R is CI; or
  • R ? R 4 is CI and R ! , K R ⁇ R 6 are each independently hydrogen;
  • R 7 is (CH 2 3 ⁇ 4 J OH 5 (CH 2 ) Kl OH ; (CH 2 ) n OH, (CH 2 ) 12 OH. (CH 2 )ijOH, (CH 2 ), $ OH; or
  • R Ul is methyl, ethyl, 2-propyl, methylenecyclopropyl, or benzyl
  • R is hydrogen, methyl ethyl, 2-propyl or inethySenecyclopropyi.
  • R 1 is hydrogen, methyl, ethy l, 2-propyl, or methylenecyclopropyl., with 2(piperazin-l-yl) ethanol to obtain a compound of Formula (1), wherein R 3 is hydrogen, CH h C3 ⁇ 4CH 3 , CHsCHgCti fe. Cl fcCHiClfek or CFi(CFi 3 )3 ⁇ 4 R 2 , R 3 , R R ⁇ and R 6 are each independently hydrogen: and R ' is CH 2 (N(CH 2 Ci-i 2 ) 2 )CH 2 CFi 2 0H; or
  • the invention reiates to a composition comprising a therapeutically effective amount of the compound as aforementioned, or a pharmaceutically acceptable salt a solvate or hydrate, a prodrug, or a metabolite thereof, and a pharmaceutically acceptable diluent or carrier.
  • the invention relates to a composition comprising a compound as aforementioned, or a pharmaceutically acceptable salt a solvate or hydrate, a prodrug, or a
  • the invention relates to a use of a compound as aforementioned in the manufacture of a medicament for treating a neurodegenerative disease.
  • the medicament is for treating Alzheimer's disease.
  • FiGs. lA-B show morphological analysis of the effects of compound C I 2 on fAf3 ⁇ 4 formation and dissociation of fAfis in the presence or absence of zinc ions.
  • FIG. 2 shows compound C12 inhibiting polymerization of ⁇ in the absence of zinc ions.
  • FiGs. 3A-B show compound C 1 2 acting as a neuroprotective agent targeting f ⁇ .
  • FIG. 4 shows qtii.noli.iie derivatives-induced neurite outgrowth.
  • FIG. 5 shows quinolme derivatives increased expression of GAP43 (a marker for neurite outgrowth).
  • FIG. 6 shows the results of rotarod test.
  • FiGs. 7A-.D show the results of Morris water maze test.
  • FIG. 8 shows an increase in GAP43 level and decrease in fAp level in memory-deficit fA
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a moiety or substituent
  • the moiety -CONH2 is attached through the carbon atom.
  • amino refers to -NHj.
  • the amino group can be optionally substituted as defined herein for the term “substituted.”
  • ' alkyiamino refers to -M 2 , wherein at least one R is alky i arid the second is alkyl or hydrogen.
  • ac i amino refers to N(R)C ⁇ ::: 0)R, wherein each R is independently hydrogen, alky I . or aryl.
  • alky refers to Cj-Ci3 ⁇ 4 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl, ethyl, 1 -propyl, 2-propyi, J -butyl, 2-methyl-l -propyl (iso- butyl -CH 2 CH(CH 3 )2), 2 ⁇ butyl (sec-butyl.
  • the a!kyi can be a monovalent hydrocarbon radical, as described arid exemplified above, or it can be a divalent hydrocarbon radical (i.e., alkylene).
  • the alky can optionally be substituted with one or more alkoxy, halo, haloalkyl, hydroxy, h droxy alkyl, ar iJieteroaryl heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylammo, acylamino, nitro, tri.fluoromethy.1,
  • alky lene 5" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 cai'bon atoms, and having two monovalent radical centers deri ved by the removal of two hydrogen atoms from the same or different carbon atoms of a parent alkane.
  • Typicai alk lene radicals include, but are not limited to: methylene ( ⁇ CHr-) -ethyiene (-CH 2 CH2-), U-propylene ( ⁇ CH 2 CH 2 CHr-X 1 ,4- butylene and the like.
  • the alkylene can optionally be substituted with one or more alkoxy, halo, haloalkyl, hydroxy, hydroxy alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxy carbon l, amino, imino, alkylamino, acylamino, nitro, trilluoromethyi,
  • each R x and R y are independently H, alkyl, alkenyl, aryl heteroar k heterocycle. cyc!oalkyl or hydroxy.
  • the aikykne can optionally be at least partially unsaturated, ⁇ hereby providing an alkenyierie.
  • alkynyl refers to a morsoradical branched or unbranched hydrocarbon chain, having a. point of complete unsaturauon (i.e., a carbon-carbon, sp triple bond), in one embodiment, the alkynyl group can have from 2 to 1 carbon atoms, or 2 to 6 carbon atoms. In another embodiment the alkynyl group can have from 2 to 4 carbon atoms. This term is exemplified by groups such as ethynyl, l-propynyl.
  • alkynyl can be unsubstituted or substituted.
  • alkoxy refers to the group alky 1-0-, where alky ) , is defined herein.
  • Preferred alkoxy groups include, e.g., methoxy, ethoxy, »-propoxy. .i'o-propoxy, ?i-buioxy, tert-bvtoxy, .ve -butoxy, n-penioxy, »-hexoxy, l ,2---dimethylbutoxy s and the like.
  • the alkoxy can optionally be substituted with one or more halo, haloalkyl, hydroxy, hydroxyalkyl. aryl, heteroaryl, heterocycle, cycloalkyL aikanoyl, alkoxycarbonyl, amino, imino, alkylamirto, acylamino, nitro, triffuoromethyJ,
  • benzenesidfonyianii.no benzoyl, benzo l amino, benzovioxv, benzyl, benzyloxy, benzyloxycarbonyl, benz lthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfa sulfoamino, thiosulfo, NR R y and'or COQR*, wherein each R* and R are independently H, alkyl, aikenyl, aryl, heteroaryl. heterocycle. cyc!oalkyl, or hydroxy .
  • alkanot refers to a compound of a general formula ROR where R is alkyl, as defined herein.
  • ary P refers to an unsaturated aromatic earbocycSic group of from 6 to 20 carbon atoms having a single ring (e.g. , phen l) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fiuorenyi, or anthryl ⁇ .
  • Preferred aryls include phenyl, naphihyi and the like.
  • the aryl can optionally be a divalent radical, thereby providing an arylene.
  • Tire ar l can optionally be substituted with one or more alkyl, aikenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl aikanoyl,
  • R x and W are independently H, alkyl alkenyl aryl, heteroaryf heterocycle, cycloalkyl or hydroxy.
  • aryloxy and ''arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alky! mostl . Examples include but are not limited to phenoxy, naphthyloxy, and benzyioxy.
  • Carbocyele refers to a saturated, unsaturated or aromatic ring having 3 to 8 carbon atoms as a raonocycle, 7 to 12 carbon atoms as a bicycle, and up to about 30 carbon atoms as a pot cycle.
  • Monocyclic carbocycles typically have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bieyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a icyclo [4,5], (5,5 ⁇ , ⁇ 5,6 ⁇ or [6,6] system, or 9 or 10 ring atoms arranged as a bicycio ⁇ 5.6 ⁇ or [6.6 ⁇ system.
  • carbocycles include eyclopropyl. cyclobutyl, cyclopenlyl, l-cyclopent-l-eoyk l - ydopent-2-enyl, 1- eyelopeni-3-enyl, eyctohexyl l-cyclohex-l-enyi, l-cye!ohex-2-enyi, 1 -cyclohex-3-enyl, phenyl, spiryi and naphthyi.
  • the carbocycle can be optionally substituted as described above for aikyl groups.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Such cycloalkyl groups include, by way of example, single ring structures such as eyclopropyl, cyclobutyl, cyclopenlyl. cyclooetyi. and the like, or multiple ring structures such as adamantanyl, and the like.
  • the cycloalkyl can optionally be substituted with one or more alkyl alkenyl, aJkoxy, halo, haloalkyl, hydroxy, hydroxy alkyl aryl, heteroary 1, heterocycle, cycloalkyl, alkanovl, aikoxycaxbony), amino, imino, alkylaroino, acyiarairio, riitro, triOuorometh l. trill norometho y, carboxy, earboxyalkyl, keto, ihioxo, alkylthio, a!k lsuifinyl, alkylsulfonyl, cyano.
  • cycloalkyl of hydroxy can optionally be at least partially unsaturated, thereby providing a cycioalkenyl. Additionally, the cycloalkyl can optionally be a divalent radical, thereb providing a cycloalky!ene.
  • an effective amount refers to an amount sufficient to effect beneficial or desired results. Determination of an effective amount for a given administration is well within the ordinary skill in the pharmaceutical arts.
  • halo refers to fiuoro, chSoro, bromo, and iodo.
  • ''halogen refers to fluorine, chlorine, bromine, and iodine.
  • haioalky refers to alky! substituted by 1-4 halo groups, which may be the same or different.
  • Representative haloa!kyl groups include trill uoromethyl, 3-fluorododecyL 12,12,12- trifiuorododecyl, 2-brornooctyI, 3 --bromo---6--chioiOheptyl. and the like.
  • heteroaryP is a monocyclic, bicyclie, or tricyclic ring system containing one, two, or three aromatic rings aid containing at least one nitrogen, oxygen, or sulfur atom i an aromatic ring, and which can be unsubstituted or substituted.
  • the heteroaryl can optionally be a divalent radical, thereby providing heteroarylene.
  • heteroar l groups include, but are not limited to, 2H-pyrroiyl, 3H-indo ' lyI, 4H ⁇ qumoIizinyk 4nH---carbazolyl, acridinyl, benzo[d
  • benzothiazoS i ⁇ - arboiinyl, carbazoi l, chromen l, cinnaoiinyl, dibenzo ⁇ b,d)furanyl, furazanyl, fury I, imidazoiyl, imidizoi l, indazolyl, indoiisin l, indoiyl, isobenzofuranyl, isoindoiyl, isoquinolyl, isotliiazoly!, isoxazolyS, naphrayridinyl, napthoj 2,3-6], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolrayl, phenarsazin l, phenazinyl, phenothiazinyS, phenoxaihiim , phenoxa inyi,
  • phthalazinyl, pteridin l. purin l, pyranyl, pyrazinvL pyrazolyl, pyridazinyl, pyridyi. pyrimidinyl, pyrimddinyl, pyrroiyL qumazolmyl, quino!yl. quinoxaUnyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazoly ' l. and xaothenyl.
  • die terra "heteroary denotes a monocyclic aromatic ring containing fi e or six ring atoms containing carbon and 1 , 2, 3, or 4 heteroatoms independently selected from the group non-peroxide oxygen, sulfur, and ( ) wherein is absent or is H, O, alky I. phenyl, or benzyl
  • heteroaryl denotes an ortho-fused bicyclie heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz -derivative or one derived by fusing a propylene, or tefiramethylene diradieal thereto.
  • the heteroaryl can optionally be substituted with one or more alkyl, a!ken l, alkoxy, halo, haloalkyi, hydroxy, hydroxy alkyl, aryl heteroaryl, heterocycle, cycioalkyl, alkanoyi,
  • alkox earhonyl amino- iniino, alkylamino.
  • acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxya!kyl, keto, thioxo, alkylmio, alkylsulfinyl, alkylsulfonyl. cyano. acetamido.
  • benzenesulfoiiySaniino benzoyl, benzoyl amino, ben/.oyloxy, benzyl, benzyloxv. benzyloxy carbonyi, benzylthio, carbamoyl, carbamate, isoeyann&to. sulfamoyl, sulfinamoyl, suiiwo. sulfo, sulfoamino, thiosulfo, NR*R y and/or COOR ; , wherein each R s and R are independently H, alkyl, a!kenyl, and, heteroaryl heterocycle, cycioalkyl, or hydroxy.
  • heterocycle or '"heterocyclv * refers to a saturated or partially unsaturated ring system, containing at least one heteroatom selected from ihe group oxygen, nitrogen, and sulfur, and optionally substituted with alky I, or ⁇ , wherein R h is hydrogen or alfcyl.
  • heterocycle is a monocyclic, bicyclk, or tricyclic group containing one or more heteroatoms selected from the group oxygen, nitrogen, a d sulfur,
  • heterocycle groups include 1,3- dilrydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, l ,4-- 3ithiane, 2H--pyran, 2-py-raxoline, 4 /-p ran, chromanyl, imidazolidmyl, imidazolinyi, indolinyl, isochromanyl, isoindolinyl, morpholine, piperazinyi, piperidine, piperidyl, pyrazolidine, pyrazoiidinyi, pyrazoUnyl, pyrrolidine, pyrroiine, quinuclidine, and tliiomorpholine.
  • the heterocycle can optionally be a div alent radical, thereby providing a heterocyciene.
  • the heterocycle can optionally be substituted with one or more aJkyl, alkenyl, alkoxy, halo, haloalkyi, hydroxy, hydroxy alky I, ar l, heteroar l, heterocycle, cyeloalkyi, alkanoyl, a!koxycarbonyl, amino, imino. alkylamino, aeylaniino, nitro, triiluoromethyl,
  • benzenesulfonyiamino benzoyl, benzoyl amino, benzoyloxy, benzyl, benz loxy, teroyloxycarbonyl, benzy!thio, carbamoyl carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfmo, sulfo, snlfoammo, thiosu!fo, NR*R- V and/or COOR*, wherein each R and R 5 are independently !L alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
  • nitrogen heteroeycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole. pyridine, pyra ine, pyrimidme, pyridazine, indoiizine, isoindole, indole, indazoie, purine, quino!izioe, isoquinoline, quinoiine, phthalaane, naphthylpyridine. quinoxaline, quinazoline, cinnoiine, pteridine, carbazole. carboline, phenanthridine, acridine.
  • phenanthroline isothiazoie, phenazine, isoxazole, phenoxazme, phenothiazine, rmidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyL teirahydrofuranyl, and roe like as well as N-aikox -nitrogen containing heterocy cl es.
  • hydrate refers to the complex where the solvent molecule is water.
  • '"metabolite ' ' refers to any compound of the Formula.0) produced in vivo or in ' vitro from the parent drug, or its prodrugs.
  • the pharmaceutically acceptable salts of the compounds described herein can be synthesized from the parent compound, which contains a. basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid m water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of many suitable salts are found in Remington: The Science and Practice of Pharmacy. 21 st edition, Lippincott Williams & Wilkins, (2005).
  • prodrugs refer to a compound that is metabolized, for example hydroi zed or oxidized, in the host to form a compound of the Formula (I).
  • Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds thai can be oxidized, reduced, animated, deaminated, hydroxylated, dehydroxylaied. hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated. dephosphorylated to produce the active compound.
  • the prodrug can be readily prepared from the compounds of Formula (I) using methods known in the art. See, e.g. See Notari, R E., "Theory and Practice of Prodrug Kinetics," Methods in E ymo gy, 1 12:309 323 (1985); Bodor, N., “Novel Approaches in Prodrug Design/ * Drugs of (he Future, 6(3): 165 182 (1981 ); and Bundgaard, H., ' " Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities. '' in Design of Prodrugs (H. Bundgaard, ed. ),
  • solute refers to a complex of variable stoichiometry formed by a solut (in this invention, a compound of Formula I, or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention, should not interfere with the biological acti vity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid.
  • room temperature refers to a temperature in the range of about 20° C to about 30T.
  • substituted is intended to indicate thai one or more hydrogens on the atom indicated is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • Suitable indicated groups include, e.g., alky I, alkenyl, alkyiidenyi, alkenyiidenyl, aikoxy, halo, haloalkyl, hydroxy, hydroxy alky .1, arvl, heteroaryl, heterocycJe, cycloalkyl, alkanoyl, acyloxy, aikox carbonyl, amino, imino, alkylarnino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo.
  • treating or “treat” or “treatment” refer to obtaining a desired pharmacologic and or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease.
  • the invention relates to multifunctional quinoline derivatives having following properties: metal chelation, clearance of reactive oxygen species, anti-aggregation, neurite outgrowth and neuron proliferation. They are useful for treating neurondegeneratrve disease involving neuronal toxicity or dysfunction induced by oxidative stress and other disorders associated with misfokling protein aggregation, in animal model, quinoline derivatives (B3 or C I 2) at 1 to 100 mg/kg, preferable 1 to 10 mg/kg, i.p. daily) were found to improve memory of micewithout causing significant toxicit .
  • the invention relates to a compound of Formula (i) or a. pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof:
  • R 5 is hydrogen, (Ci-C 8 )alkyl_ (CrC s )ajkylene(C 3 'Cs)wcloalkyi, iC C s )teloalkyl, or (C Cs)alkylene(C6-C3 ⁇ 4))aiyi;
  • R' is hydrogen or halogen
  • R "! is hydrogen, halogen, (CVCs)aikyL or (Ci-Cs)alkoxy;
  • R 4 is hydrogen, halogen, (Cj-Cs)aikyL (Ci-Cs)alkoxy, or (CrCyjhaloalkyl;
  • R 5 is hydrogen or (C.t-C.3 ⁇ 4))aJkanol
  • R ft is hydrogen; and R 7 is hydrogen, ( Qjo)aikarioS, fC i-Cs ⁇ aikylerie (C ⁇ -C ⁇ etero ⁇ dyliCj-CaoJaikiaiol, (Cj- Cg)a!kylene (C j-Cs)heterocyc1 yi (C rCa aik l t (Cr g)alkyl ie(Ci- Cclalky iaminoCC 3 -C3 ⁇ 4)al kynyi, (C j - C1 ⁇ 2)a!kyleneamino(CrC2o ⁇ alkancsl 5 or (Cr 1 ⁇ 4)a!kyleneamsno ⁇ Ci-C2o)aIkaooI(CrCs)alk ⁇ 1eite Rintituted(C C 2 o)heteroaryi.
  • R' is hydrogen, €H 3 , CH-2CH3, CH(CH ⁇ , ClfeCitfCHsfe, CF 3 , or benzyl;
  • R 2 is hydrogen, F, or CI
  • R 3 is hydrogen, F. CI, CH 3f or OCH ;
  • R 4 is hydrogen. F, CI, Br, C3 ⁇ 4, OC3 ⁇ 4. or CF 3 ;
  • R 5 is hydrogen. (CH 2 ) repeatGH, or (CH 2 ) l2 0H;
  • R ft is hydrogen
  • R 7 is hydrogen, (CH 2 )90H ? (CH 2 )u>OH 5 ((3 ⁇ 4) ⁇ ⁇ , ⁇ C3 ⁇ 4)» 2 OH, (CH 2 ) 13 OH, (CH ⁇ OH,
  • R ! is hydrogen, CH S , CH 2 CH 3 , C.H(C3 ⁇ 4> 2 , CB 2 CH(CH,) 2 , C3 ⁇ 4CH(CH 2 ) 3 ⁇ 4 C 3 ⁇ 4 or benzyl;
  • R “ , R 4 , R ⁇ and R" are each independently hydrogen;
  • R 7 is (OfefeOH, (CH 2 ) u >OH, (CH 2 ) n OH 5 (CH 2 )i 2 OH, ⁇ CH 2 )iiOH, (CH 2 ) l4 0H,
  • R' is hydrogen, O F, CH 2 CHs, CrfjCf!fCHsk C%CBiCB 2 ) 3 ⁇ 4 or CH(CH 3 >2;
  • R "? , R 3 , R', and R e are each independently hydrogen
  • R* is CHj, F. CI, Br, Cf 3 , or OCH 3 ;
  • R 7 is (CH 2 )i>OH, (CB 2 )K' ( OH, (CH ⁇ nOH, (CH 2 ⁇ J2 OB, (C ⁇ DOH. (CH 2 ) ls OH ⁇
  • R* is hydrogen, CB 3 , CH 2 C3 ⁇ 4, CH(CH 2 > 2 , or C3 ⁇ 4CH(CH2) 2 ;
  • R , R 4 are each independently CI
  • R.”', R' and R" are each independently hydrogen;
  • R 7 is (CH 2 )uOH, CH 2 NH(CH 2 )sOH. or C3 ⁇ 4N(C3 ⁇ 4)CH 2 C-CH.
  • R J is hydrogen, ⁇ 3 ⁇ 4, CH 2 CH. CHsCHiCH a, CB 2 CH(CH 2 ) 2 , CH(CH 3 ⁇ 2 , or benzyl;
  • R' " , R ⁇ R 4 , R (> . and R' are each independently hydrogen; and ' is «3 ⁇ 4)uGH or (CH 2 ⁇ I2 OH.
  • R* is C3 ⁇ 4
  • R ⁇ R 5 , and R 6 are each independently hydrogen
  • R "1 and R4 are each independently OCH3 or CI;
  • the compound is selected from the group consisting of 9-( 8-(benzy I oxy )q uinolin-2-yj)n onan- 1 -oL 10-(8-(benzy loxy)q uinol in-2-y !decatv 1 -ol, 1 1 -(8 - (benzy!oxy)qninolin-2-y!ur)decan-t -ol.
  • the invention relates to a composition
  • a composition comprising a compound as
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, amyotrophic lateral scierosis (ALS), cataract cognitive disorder, cerebral ischaemia stroke, cerebral palsy; stroke, haemorrhagie stroke, Creotzfeldt-Jacob disease, spongiform encephalopathy, Mad Cow disease, dementia, depression. Down's syndrome, epilepsy, post- traumatic epilepsy, frontolemporal dementia.. Gilles de ia Tourette's syndrome, Haiierhoden- Spaiz disease, Huntington's disease, Levvy body disease, Parkinson ' s disease, cognitive impairment, learning deficit, macular degeneration, memory deficit, multiple sclerosis, multiple system atrophy, motor neuron disease. Pick's disease, progressive supranuclear palsy, pseudo dementia, retinopathy, senile dementia, schizophrenia transient anoxial induced neurodegeneration, pain, brain traumatic- injury, and spinal cord injury.
  • ALS amyotrophic lateral scierosis
  • Reagents and conditions (a) Mel, K 2 CO acetone, r.t 10 h.; (b) 1 ) LHMDS, THF, 0 D C, 1 h.;
  • Reagents and conditions (a) Ethyl iodide or 2-bronropropan.e, 3 ⁇ 4Ci3 ⁇ 4, DMF, 60 '" 'C. 14 h. (b) 1) LHMDS, THE 0 1 h.; 2) RT, 12 - 30 h.
  • N-chlorosuccini raids (0.3 g, 2.25 mmoi) was added to a stirred solution of compounds B in CHCI 3 (20 ml) for 48 h.
  • the reaction mixture was poured into crushed ice and extracted with CH 2 CI 2 (20ml X 2).
  • the extract was purified by column, chromatography with Hex/EA (3: 1) and recrystai Sized to gi ve compound (0.1 g, 49%).
  • Reagents and conditions (a) HQ. iCI. ? , glacial HOAe, 1 i; ; 0. 6 h, rt.
  • Reagents and conditions (a) methyl vinyl ketone, HCL reflux, (b) Mel. sCCh, acetone, rt 8h; Elf or 2 ⁇ bromopropane or methylenecyclopropyl bromide, K2CO3, DMF, 60 6 C, (c) I) LH.MDS, THF, 0 °C, 1 h.: 2) Br(CH 2 )»..i H, rt. (d) BnBr. KOM, EtOH, reflux, (e) H 3 ⁇ 4 Pd/C, MeOH, rt 24 h.
  • T3 ⁇ 4e intermediate INT was synthesized through ring closure from 2-arninophenol reacted with methyl vin l ketone.
  • INT I was reacled with various aJkyl halides to afford 8-alkoxy- 4methylquino.)me derivatives as intermediates.
  • Corresponding Brt ' CHs iOH was reacted with intermediates to synthesize series of compounds 3 and I.
  • the protective group J was removed by hydrogenaiiori (method iliustraied in example I) to obtain compound K.
  • TSie intermediate was synthesized through ring closure from 2 rifluoromethoxy aniline reacied with crotoiialdehyde. Intermediate was reacted with corresponding Br(Ci3 ⁇ 4) tl .,iOH (as illustrated above) to synthesize series compounds L.
  • Reagents and conditions (a) SeO3 ⁇ 4 dioxane, 50 to 80 °C; (b) N-methy!propagylaraine or 2- (pipera .in-1 -yl) ethano! or NHaiCHa )n-i OH, NaBH(OAc);;, l,2 ⁇ dkhloroeihane, rt.
  • FIG. lA shows C12 inhibited ⁇ aggregation in the presence or absence of zinc ions using a microscopy analysis after Congo red staining.
  • FIG. IB and F1G.2 show that C1.2 dissolved preformed ⁇ aggregates.
  • HQs. 3A-B show that compounds C I 2, CQ and €12 intermediate protected neuron cells from zinc-induced ⁇ ' ⁇ . Only compound C 12 was effective toward zinc-tree aggregates (FIG, 3B).
  • FIG. 4 shows induction of neurite outgrowth triggered by compound C 12 on undifferentiated PCI 2 cells.
  • FIG, 5 shows quinoline derivatives increased expression of GAF43.
  • FIG, 6 shows compound C 12 and B3 improved performance of learning in ⁇ -induced memor -deficit mice.
  • FIG. 8 shows an increase in GAP43 level and decrease in fAp level in memory-deficit fAp-lesioned mice by compound CI 2.

Abstract

Novel quinolone derivatives are disclosed. Also disclosed are synthesis and use thereof for treating neurodegenerative diseases. In an aspect, the invention relates to a composition comprising a therapeutically effective amount of the compound as aforementioned, or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof and a pharmaceutically acceptable diluent or carrier. Further in another aspect, the invention relates to a composition comprising a compound as aforementioned, or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof, and a pharmaceutically acceptable diluent or carrier tor use in treating a neurodegenerative disease. Yet in another aspect, the invention relates to a use of a compound as aforementioned in the manufacture of a medicament for treating a neurodegenerative disease. In one embodiment, the medicament is for treating.Alzheimer's disease.

Description

MULTIFUNCTIONAL QUI.NOLI.NE DERIVATIVES AS ATSTI-NEURODEGENE ATIVE
AGENTS
BACKGROUND OF THE INVENTION'
US Patent Nos. 7,439.243 and 7,452.888 describe a series of quinolme derivatives useful for the treatment of CNS disorders, including Alzheimer 's disease. US Patent No. 7,009.053 describe a series of quinolme derivatives useful for treatment of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, ischemia, traumatic brain injury, spinal cord inj ury or osteoarthritis,
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a compound of Formula (1.) or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof:
Figure imgf000003_0001
Formula (Ϊ)
wherein
l is hydrogen, (CrCs)aikyk (C^^alkyleneiCg-C^doalk l^C '^h loalk l, or (C Cs)alky lene(CVC ¾>)ai ! ;
R2 is hydrogen or halogen,
.R:' is hydrogen, halogen, (CrCg kyl, or (CrCs)a1koxy;
R4 is hydrogen, halogen, (C(-Cs)alkyl. (C r€¾)aikoxy, or (CrC„)haioalkyl;
R5 is hydrogen or (Cr€;¾)alkanol;
R6 is hydrogen, and
R7 is hydrogen, (Ci ½o)alkanol, (CrCs)alkylene iC3-Cs)heteroc d l(Cj^2o)^ anol, (C'r Cs)alkylene (C3-Cs)heterocydyKCrC2(>)alkyl, <Ci !8)alk>:lene(CrC«)alkylan¾no(Ci-C{>)a]kynyl, (C¾- Cs)alkyleneamino(C j-C ¾j)al kanol , or (C f- Cs)alky leneami no(C i-C a>)aikanol (C j -C«)alkylene
substituted(C¾-C2())heteroaryl.
In another aspect, the invention relates to a method for preparing the compound as aforementioned, the method comprising:
( ί ) reacting the compound of Formula (11 )
Figure imgf000004_0001
Formula (11) wherein:
κ R\ R4, - . and R6 are each independently hydrogen; or
R4, R , and R(> are each independently hydrogen and R* is Cl or
R'", R\ R"\ and R(> are each independeiitiv hydrogen and R4 is CF , F\ CI, or Br; or R3, R R6 are each independently hydrogen, R'' is OCt . and R4 is CI; or
R", R4 is CI and R"\ R5, * are each independently hydrogen,
with benzyl bromide, methyl iodide, eth l iodide, 2-bramopropane, or methyl enecyxlopropyl bromide in a basic solution at about room temperature io about 80¾C to obtain the compound of Formula (111)
Figure imgf000004_0002
Formula ( I I I )
wherein:
R5 is CH3 FbCH3. CH(CH3)2,
Figure imgf000004_0003
or benzv l, and
R2, R\ R4, R*, and are each independently hydrogen: or
R3, R4, R5, and Rf> are each independently hydrogen and R' is C f?; or
R2, R' Rs, and R6 are each independently hydrogen and R4 is Cl , F? CI, or Br; or
R", Rs, R" are each independently hydrogen, R3 is OCH?. and R4 is CI; or
Rz, R4 is CI and R'\ R\ R" are each independently hydrogen;
(2) reacting the compound of Formula (Hi) with iithium bisitrimethy lsilyl)amide and z bromo(CiCjo)alkanol in tetrabydrofuran at ( C to obtain the compound of Formula (I)
7
Figure imgf000005_0001
Formula (I) wherein:
' is CH3, CH2CH3t CH<CJ¾)2, CH2CH{CH3)2, or benzyl;
R2, R '. R4, R'; and R* are each independently hydrogen or
R2, R* R'} and Rb are each independently hydrogen and R;' is CH¾; or
R^. R\ R\ and R" are each independently hydrogen and R4 is CH*, F, CL or Br; or
R'l R5, R" are each independently hydrogen, R* is OCI¾, and R4 is CI; or K" is CI, and R is oa-h or
R2, R4 is CI and R:', R' R6 are each independenily hydrogen: and
R7 is (CH^OH, (CH^wOH, (CH2)nOH} (CH2)i2OH, (CH2)uOH, iCH2)! 5OH,
(3) reacting the compound of Formula (I), wherein R! is benzyl with hydrogen gas under pressure with palladium on carbon at room temperature in methanol Of with boron trichloride in dicMoromethane at 0°C to obtain the compound of Formula (1)
Figure imgf000005_0002
Formula (D
R1, R2. R-\ R4. R\ and ° are each independently hydrogen; or
R!. R2, R4, R'„ and * are each independently hydrogen and R-> is CFI3; or
R J, ^ R' R5, and R" are each independently hydrogen and R* is C¾ F, CI, or Br; or R}, R' R\ R" are each independently hydrogen, R-" is OCH¾ and R is CI; or
R? R4 is CI and R!, K R \ R6 are each independently hydrogen; and
R7 is (CH2¾JOH5 (CH2)KlOH; (CH2)nOH, (CH2)12OH. (CH2)ijOH, (CH2),$OH; or
(4) reacting the compound of Formula (I), wherein Rl, R'l R:\ R*, R3, and R* are each independently hydrogen and R' is (CH )nOH, with -chlof osuccinimide in methylene chloride at room temperature to afford the compound of Formula (L), wherein. R1, R"\ R5. and R are each independently hydrogen, R2 and R4 are each independently chlorine, and R! is (CMiiuOM; or <5) reacting the compound of Formula (1), wherein R! is methyl, R2 f R3, R4, R'S arid are each independeiitiy hydrogen and R' is (t¾)n.OH,
Figure imgf000006_0001
with concentrated hydrochloric acid, lt¾. and glacsal acetic acid io afford the compound of Formula {!), wherein R! is methyl R?, R:', RS, and R" are each independently hydrogen, R4 is CI, and R ' is {CH OH,
(C¾)UO:H, (Ο¾)] 20Η5 (CH2)i.<OH,
Figure imgf000006_0002
(CH )U)OCOCHs, iC¾)„OCOCH3!
(CH2)J2OCOCH3, (CHa) 50COCH3; or
(6) reacting 2-aminophenol with raethy lvinyl ketone in hydrochloric acid to obtain the compound of Formula (INT-1)
Figure imgf000006_0003
Formula (ΪΝΤ-'l);
(7) reacting the compound of Formula (INT-1) with methyl iodide, ethyl iodide, 2- bi'omopropane, me ylenecyclopropyl bromide, or benzyl bromide in basic solution to afford the compound of Formula (01),
Figure imgf000006_0004
Formula (111) wherein RUl is methyl, ethyl, 2-propyl, methylenecyclopropyl, or benzyl;
(8) reacting the compound of Formula (111), wherein R5V is methyl, ethyl, 2-propyL methylenecyclopropyl, or benzyl, with lithium bis(trimeih Isily I )ami de and 1 ( uomo-l -decanol or
I l-bromo-l-undecanol in tetrahydrof uran at 0¾C to obtain the compound of Formula (I), wherein Rl is methyl, ethyl, 2 -propyl, niethylenecyciopropyt or benzyl; R", R\ R4 R\ and R7 are each independently hydrogen; and R'1 is (€¾)»011 or
Figure imgf000006_0005
(9) reacting the compound of Formula (1), wherein R! is benzyl; , R-\ K Kb f and R' are each independently hydrogen; and R* is {(¾ υΟΗ or (Ο¾)ΐ20Η, with hydrogen gas under pressure with palladium on carbon at room temperature in methanol to obtain the compound of Formula (I), wherein R} is hydrogen; R2, R3, R , , and R' are each independently hy drogen: and R5 is (a¾)j-iOH or (CH2)i20H; or (ID) reacting 2-trif1uoromeihoxyanaline with crotonaldehyde to obtain 2-meihyl-8- trifluormethoxyqiiinoliiie, which is treated with lithium bis(trimethylsiiyl.)aniide and a
bromo(Cit½)alkanol hi tetiahydrofuran at ( C to obtain the compound of Formula (1), vvlterein R3 is trifluoroemethyl; R\ R\ R4, R\ and R' are each independently hydrogen; and R7 is (0¾)ιοΟΚ
(C¾)uOH, (CH2)j20H, (CH2)i.,OH, or (CH2)iSOH; or
(1 J ) reacting an ound of Formula (IV), wherein Rs is hydrogen, methyl, ethyl 2
Figure imgf000007_0001
Formula (V)
with selenium dioxide in dsoxane at elevated temperature to afford a compound of Formula (VI), R is hydrogen, methyl ethyl, 2-propyl or inethySenecyclopropyi.
Figure imgf000007_0002
Formula < VI )
02) reacting the compound of Formula (VI), wherein R1 is hydrogen, methyl, ethyl, 2- propyl, or methyienecyciopropyl, with N-methylpropag lamine to obtam a compound of Formula (I), wherein R* is hydrogen, CH3, CH2CH?5 CB2CH(a-}j)2, Cil2CFl(CH2)2; or CH(t%)& R2,
Figure imgf000007_0003
R4, R3, and R6 are each independently hydrogen; and R7 is C¾N(C¾)CH2CsCH; or
(13) reacting the compound of Formula (VI), R1 is hydrogen, methyl, ethy l, 2-propyl, or methylenecyclopropyl., with 2(piperazin-l-yl) ethanol to obtain a compound of Formula (1), wherein R3 is hydrogen, CHh C¾CH3, CHsCHgCti fe. Cl fcCHiClfek or CFi(CFi3)¾ R2, R3, R R\ and R6 are each independently hydrogen: and R ' is CH2(N(CH2Ci-i2)2 )CH2CFi20H; or
(14) reacting compound of Formula (VI) with an aniino(C rC¾)aikanoi to obtam a compound of Formula (I), wherein R1 is hydrogen, Cl¼ CH2CH3, CHaCHCCHj CHaCHiCHfefe, or CH(CH >2; R2, R . 5- and R6 are each independently hydrogen; and R7 is CH2NH<CH2)*OR or CH2N((CH2)sOH)CH2(8-memoxyqu!noHn-2-yl).
In another aspect, the invention reiates to a composition comprising a therapeutically effective amount of the compound as aforementioned, or a pharmaceutically acceptable salt a solvate or hydrate, a prodrug, or a metabolite thereof, and a pharmaceutically acceptable diluent or carrier. Further in another aspect, the invention relates to a composition comprising a compound as aforementioned, or a pharmaceutically acceptable salt a solvate or hydrate, a prodrug, or a
metabolite thereof, and a pharmaceutically acceptable diluent or carrier for use in treating a neurodegenerati ve disease.
Yet in another aspect, the invention relates to a use of a compound as aforementioned in the manufacture of a medicament for treating a neurodegenerative disease. In one embodiment; the medicament is for treating Alzheimer's disease.
These and other aspects will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.
The accompanying drawings illustrate one or more embodiments of the invention and, together with the written description, serve to explain the principles of the in vention. Whereve possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.
BRIEF DESCRIPTION OF THE DRAWINGS
FiGs. lA-B show morphological analysis of the effects of compound C I 2 on fAf¾ formation and dissociation of fAfis in the presence or absence of zinc ions.
FIG. 2 shows compound C12 inhibiting polymerization of Αβ in the absence of zinc ions.
FiGs. 3A-B show compound C 1 2 acting as a neuroprotective agent targeting f Αβ.
FIG. 4 shows qtii.noli.iie derivatives-induced neurite outgrowth.
FIG, 5 shows quinolme derivatives increased expression of GAP43 (a marker for neurite outgrowth).
FIG. 6 shows the results of rotarod test.
FiGs. 7A-.D show the results of Morris water maze test.
FIG. 8 shows an increase in GAP43 level and decrease in fAp level in memory-deficit fA|?>- lesioned mice after compound CI.2 treatment
DETAILED DESCRIPTION OF THE INVENTION
The singular forms "a," "an." and "the" include plural reference unless the context clearly dictates otherwise,
A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a moiety or substituent For example, the moiety -CONH2 is attached through the carbon atom.
The term "amino" refers to -NHj. The amino group can be optionally substituted as defined herein for the term "substituted."' The term ''alkyiamino" refers to -M 2, wherein at least one R is alky i arid the second is alkyl or hydrogen. The term "ac i amino" refers to N(R)C{ :::0)R, wherein each R is independently hydrogen, alky I . or aryl.
The term "alky!" refers to Cj-Ci¾ hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl, ethyl, 1 -propyl, 2-propyi, J -butyl, 2-methyl-l -propyl (iso- butyl -CH2CH(CH3)2), 2~butyl (sec-butyl. ~CH(CH CH2CH3}, 2-methyl-2-prop>'l (tert-butyk ~ C(CHs)s), 1-pent 2~pentyl, 3-peniyl, 2-methyl-2-butyl, 3~methyl~2-butyl, 3~methvl~l~butyl, 2---raetb T -- 1 -- butyl 1-hexyL 2-hexyL 3-hexyl. 2-rnethyl-2-pentylf 3 --methyl--2--peMyL 4-methyl- 2-pem I 3-methy 1 -3 -pentyl, 2-methy !-3~penty 1, 2,3-di metlry l-2-butyl 3,3 - di methyl~2~butyl . The a!kyi can be a monovalent hydrocarbon radical, as described arid exemplified above, or it can be a divalent hydrocarbon radical (i.e., alkylene). The alky can optionally be substituted with one or more alkoxy, halo, haloalkyl, hydroxy, h droxy alkyl, ar iJieteroaryl heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylammo, acylamino, nitro, tri.fluoromethy.1,
trifluoromethoxy, carboxy. carboxy alkyl, keto, thioxo, alkyl thio, alkylsuliinyl, alkylsuifon 1, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesdfonyl, benzenesulfonyS amino,
Figure imgf000009_0001
benzoyloxy, benzyl, benzyloxy, benzyloxy carbonyl, benzyl thio, carbamoyl, carbamate, isocyannato, suifamoyl, sulfirtamoyi sulfino, sulfo, sulfoamino, thiosulfo, R'"'Ry and/or COOR ;, wherein each Rs and R are independently H, alkyl, alkenyl, and, heteroaryl, heterocycle, cycloalkyl or hydroxy. The alkyl can optionally be interrupied with one or more non-peroxide oxy (-0-), thio (-S-), imino (- (H)-), methylene dioxy (-tX¾0~), carbon l (~C(=OH carboxy (-C(O)O-). carbonyl dioxy (~ C(=0)0-), carboxylato i~OC(=0> -), imino (€:::::NH), su!fisiy! (SO) or suifonyl (SO?). Additionally, the alkyl can optionally be at least partially unsaturated, thereby providing art alken l.
The term "alky lene5" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 cai'bon atoms, and having two monovalent radical centers deri ved by the removal of two hydrogen atoms from the same or different carbon atoms of a parent alkane. Typicai alk lene radicals include, but are not limited to: methylene (~CHr-) -ethyiene (-CH2CH2-), U-propylene (~CH2CH2CHr-X 1 ,4- butylene and the like. The alkylene can optionally be substituted with one or more alkoxy, halo, haloalkyl, hydroxy, hydroxy alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxy carbon l, amino, imino, alkylamino, acylamino, nitro, trilluoromethyi,
trifluoromethoxy, carboxy, carboxy alk l keto, thioxo, alkylthio, alkylsuliinyl, alk lsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesuifinyl, benzenesulfonamido, enzenesuif nyl, benzenesulfonylamino, benzoyl,, benzoylamino, benzoyloxy, benzyl benzyloxy, benzxloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, suifamoyl, sulfinamo sulfino, sulfo, sulfoamino, thiosulfo, NR¾y and/or COORx. wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl heteroar k heterocycle. cyc!oalkyl or hydroxy. Additionally, the alkylerie can optionally be interrupted with one or more non-peroxide oxy (-0-), thio f-S-}, imino C-- (H)---}, methyiene dioxy f-OCH20-}, carbonyl (-C(=0>-)5 carboxy (--€(=0)0-), carbonyldioxy ( -OC(=0)0 ), carboxy lata i-OC(":0)-), imine (C~NH), sulfinyl (SO) or sulfonyl (SO2). Moreover, the aikykne can optionally be at least partially unsaturated, {hereby providing an alkenyierie.
The term "alkynyl" refers to a morsoradical branched or unbranched hydrocarbon chain, having a. point of complete unsaturauon (i.e., a carbon-carbon, sp triple bond), in one embodiment, the alkynyl group can have from 2 to 1 carbon atoms, or 2 to 6 carbon atoms. In another embodiment the alkynyl group can have from 2 to 4 carbon atoms. This term is exemplified by groups such as ethynyl, l-propynyl. 2-propynyl, t-butyny!, 2-biitynyi, 3-lurtynyt, 1-hexynyl, 2-hexynyI, 3-hexynyl, 1-octynyl, and the like. The alkynyl can be unsubstituted or substituted.
The term "alkoxy" refers to the group alky 1-0-, where alky), is defined herein. Preferred alkoxy groups include, e.g., methoxy, ethoxy, »-propoxy. .i'o-propoxy, ?i-buioxy, tert-bvtoxy, .ve -butoxy, n-penioxy, »-hexoxy, l ,2---dimethylbutoxys and the like. The alkoxy can optionally be substituted with one or more halo, haloalkyl, hydroxy, hydroxyalkyl. aryl, heteroaryl, heterocycle, cycloalkyL aikanoyl, alkoxycarbonyl, amino, imino, alkylamirto, acylamino, nitro, triffuoromethyJ,
trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo. alkylthio. alkylsuifmyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzanrido, benzenes uifin I, benmiesulfonamido, henzenesulfon l. benzenesidfonyianii.no, benzoyl, benzo l amino, benzovioxv, benzyl, benzyloxy, benzyloxycarbonyl, benz lthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfa sulfoamino, thiosulfo, NR Ry and'or COQR*, wherein each R* and R are independently H, alkyl, aikenyl, aryl, heteroaryl. heterocycle. cyc!oalkyl, or hydroxy .
The term "alkanot" refers to a compound of a general formula ROR where R is alkyl, as defined herein.
The term "ary P refers to an unsaturated aromatic earbocycSic group of from 6 to 20 carbon atoms having a single ring (e.g. , phen l) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fiuorenyi, or anthryl}. Preferred aryls include phenyl, naphihyi and the like. The aryl can optionally be a divalent radical, thereby providing an arylene. Tire ar l can optionally be substituted with one or more alkyl, aikenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl aikanoyl,
alkoxycarbonyl amino, imino. alkylammo, acylamino, nitro, irifluoromeihyl, trifluoromethoxy, carboxy. carboxyalkyl, keto, thioxo, alkylthio, alkyisulfinyi, alkylsulfonyl. cyano, acetamido, acetoxy, acetyl, benzamido, betizenesulfinyl, benzenesulfonamido, benzenesulfonyi,
benzenesulfonyiamino, benzoyl, benzoylamino. benzovioxv, benzyl, benzyloxy, benzyloxycarbonyl, be zylthio, carbamoyl carbamate, isocyannato, su!famoyl, sulfinamoyl, suifino, sulfo, sulfoamino, thiosulfo, NR*Ry and/or CQOR\ wherein each Rx and W are independently H, alkyl alkenyl aryl, heteroaryf heterocycle, cycloalkyl or hydroxy.
The terms 4iaryloxy" and ''arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alky! mostl . Examples include but are not limited to phenoxy, naphthyloxy, and benzyioxy.
The term "carbocyele" refers to a saturated, unsaturated or aromatic ring having 3 to 8 carbon atoms as a raonocycle, 7 to 12 carbon atoms as a bicycle, and up to about 30 carbon atoms as a pot cycle. Monocyclic carbocycles typically have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bieyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a icyclo [4,5], (5,5}, {5,6} or [6,6] system, or 9 or 10 ring atoms arranged as a bicycio {5.6} or [6.6} system. Examples of carbocycles include eyclopropyl. cyclobutyl, cyclopenlyl, l-cyclopent-l-eoyk l - ydopent-2-enyl, 1- eyelopeni-3-enyl, eyctohexyl l-cyclohex-l-enyi, l-cye!ohex-2-enyi, 1 -cyclohex-3-enyl, phenyl, spiryi and naphthyi. The carbocycle can be optionally substituted as described above for aikyl groups.
When a substituent is specified io be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond"' thai the groups that are immediately adjacent to the specified substituent are directly connected io each other by a chemically feasible bonding configuration.
The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as eyclopropyl, cyclobutyl, cyclopenlyl. cyclooetyi. and the like, or multiple ring structures such as adamantanyl, and the like. The cycloalkyl can optionally be substituted with one or more alkyl alkenyl, aJkoxy, halo, haloalkyl, hydroxy, hydroxy alkyl aryl, heteroary 1, heterocycle, cycloalkyl, alkanovl, aikoxycaxbony), amino, imino, alkylaroino, acyiarairio, riitro, triOuorometh l. trill norometho y, carboxy, earboxyalkyl, keto, ihioxo, alkylthio, a!k lsuifinyl, alkylsulfonyl, cyano. acetamido, acetoxy, acetyl benzamido, benzenesulfm l benzenesulf namido, benzenesulfonyi, benzenesulionyl amino, benzoyl benzoyl ammo, benzo l oxy, benzyl benzyioxy, benzyioxy carbo T henzylthio, carbamoyl, carbamate, isoeyannato, siiliamovl, sulfinamoyl, sulfino, sulfo, suifoamino, thiosulfo, NRxRy and or COORs, wherein each Rx and Ry are independently H, alkyl, alkenyl, and, heteroary I. heterocycle, cycloalkyl of hydroxy. The cycloalkyl can optionally be at least partially unsaturated, thereby providing a cycioalkenyl. Additionally, the cycloalkyl can optionally be a divalent radical, thereb providing a cycloalky!ene. The term "an effective amount" refers to an amount sufficient to effect beneficial or desired results. Determination of an effective amount for a given administration is well within the ordinary skill in the pharmaceutical arts.
The term "halo" refers to fiuoro, chSoro, bromo, and iodo. Similarly, the term ''halogen" refers to fluorine, chlorine, bromine, and iodine.
The term "haioalky refers to alky! substituted by 1-4 halo groups, which may be the same or different. Representative haloa!kyl groups include trill uoromethyl, 3-fluorododecyL 12,12,12- trifiuorododecyl, 2-brornooctyI, 3 --bromo---6--chioiOheptyl. and the like.
The term '"heieroaryP is a monocyclic, bicyclie, or tricyclic ring system containing one, two, or three aromatic rings aid containing at least one nitrogen, oxygen, or sulfur atom i an aromatic ring, and which can be unsubstituted or substituted. The heteroaryl can optionally be a divalent radical, thereby providing heteroarylene. Examples of heteroar l groups include, but are not limited to, 2H-pyrroiyl, 3H-indo'lyI, 4H~qumoIizinyk 4nH---carbazolyl, acridinyl, benzo[d|thienyi,
benzothiazoS i, β- arboiinyl, carbazoi l, chromen l, cinnaoiinyl, dibenzo{b,d)furanyl, furazanyl, fury I, imidazoiyl, imidizoi l, indazolyl, indoiisin l, indoiyl, isobenzofuranyl, isoindoiyl, isoquinolyl, isotliiazoly!, isoxazolyS, naphrayridinyl, napthoj 2,3-6], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolrayl, phenarsazin l, phenazinyl, phenothiazinyS, phenoxaihiim , phenoxa inyi,
phthalazinyl, pteridin l. purin l, pyranyl, pyrazinvL pyrazolyl, pyridazinyl, pyridyi. pyrimidinyl, pyrimddinyl, pyrroiyL qumazolmyl, quino!yl. quinoxaUnyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazoly'l. and xaothenyl. In one embodiment die terra "heteroary denotes a monocyclic aromatic ring containing fi e or six ring atoms containing carbon and 1 , 2, 3, or 4 heteroatoms independently selected from the group non-peroxide oxygen, sulfur, and ( ) wherein is absent or is H, O, alky I. phenyl, or benzyl In another embodiment heteroaryl denotes an ortho-fused bicyclie heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz -derivative or one derived by fusing a propylene, or tefiramethylene diradieal thereto.
The heteroaryl can optionally be substituted with one or more alkyl, a!ken l, alkoxy, halo, haloalkyi, hydroxy, hydroxy alkyl, aryl heteroaryl, heterocycle, cycioalkyl, alkanoyi,
alkox earhonyl, amino- iniino, alkylamino. acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxya!kyl, keto, thioxo, alkylmio, alkylsulfinyl, alkylsulfonyl. cyano. acetamido.
acetoxy. acetyl, benzamido, benzenesulfmyl, benzenesulfonamido, benzenesulfonyl,
benzenesulfoiiySaniino, benzoyl, benzoyl amino, ben/.oyloxy, benzyl, benzyloxv. benzyloxy carbonyi, benzylthio, carbamoyl, carbamate, isoeyann&to. sulfamoyl, sulfinamoyl, suiiwo. sulfo, sulfoamino, thiosulfo, NR*Ry and/or COOR ;, wherein each Rs and R are independently H, alkyl, a!kenyl, and, heteroaryl heterocycle, cycioalkyl, or hydroxy. The term heterocycle" or '"heterocyclv * refers to a saturated or partially unsaturated ring system, containing at least one heteroatom selected from ihe group oxygen, nitrogen, and sulfur, and optionally substituted with alky I, or ΟΧ^ΟΧ^, wherein Rh is hydrogen or alfcyl. Typically
heterocycle is a monocyclic, bicyclk, or tricyclic group containing one or more heteroatoms selected from the group oxygen, nitrogen, a d sulfur, A heteroc cle group also can contain an oxo group (=0) attached to the ring. Non-limiting examples of heterocycle groups include 1,3- dilrydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, l ,4-- 3ithiane, 2H--pyran, 2-py-raxoline, 4 /-p ran, chromanyl, imidazolidmyl, imidazolinyi, indolinyl, isochromanyl, isoindolinyl, morpholine, piperazinyi, piperidine, piperidyl, pyrazolidine, pyrazoiidinyi, pyrazoUnyl, pyrrolidine, pyrroiine, quinuclidine, and tliiomorpholine. The heterocycle can optionally be a div alent radical, thereby providing a heterocyciene. The heterocycle can optionally be substituted with one or more aJkyl, alkenyl, alkoxy, halo, haloalkyi, hydroxy, hydroxy alky I, ar l, heteroar l, heterocycle, cyeloalkyi, alkanoyl, a!koxycarbonyl, amino, imino. alkylamino, aeylaniino, nitro, triiluoromethyl,
trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylihio, aikylsulfmyl, aikylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, henzenesuifonamido, ben/enesuifooyi. benzenesulfonyiamino, benzoyl, benzoyl amino, benzoyloxy, benzyl, benz loxy, teroyloxycarbonyl, benzy!thio, carbamoyl carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfmo, sulfo, snlfoammo, thiosu!fo, NR*R-V and/or COOR*, wherein each R and R5 are independently !L alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
Examples of nitrogen heteroeycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole. pyridine, pyra ine, pyrimidme, pyridazine, indoiizine, isoindole, indole, indazoie, purine, quino!izioe, isoquinoline, quinoiine, phthalaane, naphthylpyridine. quinoxaline, quinazoline, cinnoiine, pteridine, carbazole. carboline, phenanthridine, acridine. phenanthroline, isothiazoie, phenazine, isoxazole, phenoxazme, phenothiazine, rmidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyL teirahydrofuranyl, and roe like as well as N-aikox -nitrogen containing heterocy cl es.
The term "hydrate" refers to the complex where the solvent molecule is water.
The terms '"individual," '"host," '"subject," and "patient'" are used interchangeably, and refer to a mammal, including, but not limited to, primates, including simians and humans.
The term '"metabolite'' refers to any compound of the Formula.0) produced in vivo or in 'vitro from the parent drug, or its prodrugs.
The pharmaceutically acceptable salts of the compounds described herein can be synthesized from the parent compound, which contains a. basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid m water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of many suitable salts are found in Remington: The Science and Practice of Pharmacy. 21st edition, Lippincott Williams & Wilkins, (2005).
Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydroi zed or oxidized, in the host to form a compound of the Formula (I). Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds thai can be oxidized, reduced, animated, deaminated, hydroxylated, dehydroxylaied. hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated. dephosphorylated to produce the active compound.
The prodrug can be readily prepared from the compounds of Formula (I) using methods known in the art. See, e.g. See Notari, R E., "Theory and Practice of Prodrug Kinetics," Methods in E ymo gy, 1 12:309 323 (1985); Bodor, N., "Novel Approaches in Prodrug Design/* Drugs of (he Future, 6(3): 165 182 (1981 ); and Bundgaard, H., '"Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities.'' in Design of Prodrugs (H. Bundgaard, ed. ),
Elsevier, N.Y. (1 85); Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 1.72 178, 949 982 (1995).
The term "sol vate" refers to a complex of variable stoichiometry formed by a solut (in this invention, a compound of Formula I, or a salt or physiologically functional derivative thereof) and a solvent. Such solvents, for the purpose of the invention, should not interfere with the biological acti vity of the solute. Non-limiting examples of suitable solvents include, but are not limited to water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid.
The phrase "room temperature" refers to a temperature in the range of about 20° C to about 30T. The term "substituted" is intended to indicate thai one or more hydrogens on the atom indicated is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Suitable indicated groups include, e.g., alky I, alkenyl, alkyiidenyi, alkenyiidenyl, aikoxy, halo, haloalkyl, hydroxy, hydroxy alky .1, arvl, heteroaryl, heterocycJe, cycloalkyl, alkanoyl, acyloxy, aikox carbonyl, amino, imino, alkylarnino, acyl amino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo. alkylthio, alkyisulfinyl, alkyisulfonyi cyano, acetamido, aeetoxy, acetyl, benzamido, benzenesulfinyl, berrzenesidfonaniido, benzenesu!fony 1, benxenesulfonylamino, benzoyl, ben oylaniino, benzoyloxy, benzyl, benzyloxy, benzyloxy carbonyl, henzylthio, carbamoyl, carbamate, isocyanato, sulfamoyk sulfinanwy sulfmo, sulfo, sitlfoaimno, thiosulfo, RsRy and/or COOR* wherein each Rs and Ry are independently H, alkyl, aikenyl, aryi, heteroaryl, heieroeyele, cycloalkyt or hydroxy. When a substituem is oxo (i.e., =0) or thioxo (i.e., -$) group, then two hydrogens on the atom are replaced.
The term "treating" or "treat" or "treatment" refer to obtaining a desired pharmacologic and or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease.
The invention relates to multifunctional quinoline derivatives having following properties: metal chelation, clearance of reactive oxygen species, anti-aggregation, neurite outgrowth and neuron proliferation. They are useful for treating neurondegeneratrve disease involving neuronal toxicity or dysfunction induced by oxidative stress and other disorders associated with misfokling protein aggregation, in animal model, quinoline derivatives (B3 or C I 2) at 1 to 100 mg/kg, preferable 1 to 10 mg/kg, i.p. daily) were found to improve memory of micewithout causing significant toxicit .
In one aspect, the invention relates to a compound of Formula (i) or a. pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof:
Figure imgf000015_0001
Formula (1)
wherein
R5 is hydrogen, (Ci-C8)alkyl_ (CrCs)ajkylene(C3'Cs)wcloalkyi, iC Cs)teloalkyl, or (C Cs)alkylene(C6-C¾))aiyi;
R'; is hydrogen or halogen;
R"! is hydrogen, halogen, (CVCs)aikyL or (Ci-Cs)alkoxy;
R4 is hydrogen, halogen, (Cj-Cs)aikyL (Ci-Cs)alkoxy, or (CrCyjhaloalkyl;
R5 is hydrogen or (C.t-C.¾))aJkanol;
Rft is hydrogen; and R7 is hydrogen, ( Qjo)aikarioS, fC i-Cs}aikylerie (C^-C^etero^dyliCj-CaoJaikiaiol, (Cj- Cg)a!kylene (C j-Cs)heterocyc1 yi (C rCa aik l t (Cr g)alkyl ie(Ci- Cclalky iaminoCC 3 -C¾)al kynyi, (C j - C½)a!kyleneamino(CrC2o}alkancsl5 or (Cr ¼)a!kyleneamsno{Ci-C2o)aIkaooI(CrCs)alk\1eite sutetituted(C C2o)heteroaryi.
In one embodiment of the invention, wherein
R' is hydrogen,€H3, CH-2CH3, CH(CH^, ClfeCitfCHsfe, CF3, or benzyl;
R2 is hydrogen, F, or CI;
R3 is hydrogen, F. CI, CH3f or OCH ;
R4 is hydrogen. F, CI, Br, C¾, OC¾. or CF3;
R5 is hydrogen. (CH2)„GH, or (CH2)l20H;
Rft is hydrogen; id
R7 is hydrogen, (CH2)90H? (CH2)u>OH5 ((¾)ηΟΗ, {C¾)»2OH, (CH2)13OH, (CH^^OH,
(CH2)jSOH, CH2(>3iCH2Ce2)2 )CHaCH20H,
Figure imgf000016_0001
CH2NH(CH2.)80H, or CH2N((CH2^OH)CH2(8-methoxyquinolin-2-yl).
In another embodiment of the invention, wherein
R ! is hydrogen, CHS, CH2CH3, C.H(C¾>2, CB2CH(CH,)2, C¾CH(CH2)¾ C ¾ or benzyl;
R . R" , R4, R\ and R" are each independently hydrogen; and
R7 is (OfefeOH, (CH2)u>OH, (CH2)nOH5 (CH2)i2OH, <CH2)iiOH, (CH2)l40H,
Figure imgf000016_0002
CH2i (CH2CH2)2N)CH2CH20H, or CH2N<CH3)CH.2C^H.
In another embodiment of the invention, wherein
R' is hydrogen, O F, CH2CHs, CrfjCf!fCHsk C%CBiCB2)¾ or CH(CH3>2;
R"?, R3, R', and Re are each independently hydrogen;
R* is CHj, F. CI, Br, Cf 3, or OCH3; and
R7 is (CH2)i>OH, (CB2)K'(OH, (CH^nOH, (CH2}J2OB, (C ^DOH. (CH2)lsOH}
(CB2)ioOCOCH3, (Ci feJi iOCOCHj, (CB2)nOCOCH3. (CH2>,3OCOCffc, CB2 W(CH2)sOH,
C 2( (CH2CH2)2N)CH2CH20H, CH^Cl^C ^^CH^Hr,, or CH2N(CBj)CB2 C-CB.
In another embodiment of the invention, wherein
R* is hydrogen, CB3, CH2C¾, CH(CH2>2, or C¾CH(CH2)2;
R , R4 are each independently CI;
R."', R' and R" are each independently hydrogen; and
R7 is (CH2)uOH, CH2NH(CH2)sOH. or C¾N(C¾)CH2C-CH.
In another embodiment: of the invention, wherein
RJ is hydrogen, <¾, CH2CH. CHsCHiCH a, CB2CH(CH2)2, CH(CH3}2, or benzyl;
R'", R\ R4, R(>. and R' are each independently hydrogen; and ' is «¾)uGH or (CH2}I2OH.
In another embodiment of the invention, wherein
R* is C¾;
R\ R5, and R6 are each independently hydrogen;
R"1 and R4 are each independently OCH3 or CI; and
Figure imgf000017_0001
In another erabodimerii of the invention, the compound is selected from the group consisting of 9-( 8-(benzy I oxy )q uinolin-2-yj)n onan- 1 -oL 10-(8-(benzy loxy)q uinol in-2-y !)decatv 1 -ol, 1 1 -(8 - (benzy!oxy)qninolin-2-y!)ur)decan-t -ol. I2-(8-(ben; 1oxy)qmnoHn-2-y1)dodecan-l -ol- 13-(8- (ben yioxy) 3ianoiin-2-yi)tridecaii-l-oi, 14-((8-(bmzyloxy)quinolm-2-yl)ietradec.Mi-l-ol, 15-(8- (henzyioxy)qmnoIin-2-yi)pentadeci!jti-I-oi, 1 1 -(8-(ben¾dox> -5-methsdqu}no!in-2-y})undeci«i- 1 -ol, I H'S-Cbe iCTiox ^. ne J^^ uinolin^ylJundec^-'l-ol,, i t-(S-Cben»'"loxy}-5-fIift>roqui.tiolin-2- yl )undecan- 1 -ol, 1 .1 -(8-(benzy!ox )-5-chloroqninolin-2-yl)undec n- 1 -ol, 2-(9- hydroxynonyl)quinolin-8-ol, 2-(10-hydroxydecyl)quinolin-8-ols 2-(l I -hydroxy undeeyl)quinolin-8- ol, 2 1 ~h droxy dodecy 1 ) uinoiin~8-o! , 2413 -h droxy tridecy I )q uinol in-8-oS , 24.14~(- hydroxytettadecyl)qumolin-8-ol52415-hy droxypentadecy1)quino1m-8-o1, 2-( S ί -h droxy undecy!)-5- methyfqumofin-S-of. 2-(l l-hydroxj'undecjrl)>6-methyIq«moHn-8-ol. 5~chloro~2~(l l- hydroxyundecYl)quinolin~8~ol, 9-{8-nietl }xyqirinoiin-2-yl)'ffflnaii-l-oL 10-(8~ ethoxyqu ioi»i-2- yl)decan-l -ol 1 1 -{S-methoxyqianoiin-2-yi)iindecan-l -ol, 1.2-(8-methoxyquinolin-2-yl)dodecan-l - ol, 13-{8-methoxyq«moHn-2-yl)tridecan-l -of 14-((8-n^thoxyquinolin-2-yl)tetradecan- 1 -ol. 15-(8- meihoxyquinolin-2-y 1)pentadecan- i -ol, 11 -(8-methoxy-5-raethyiqiiinoijn-2-yI)undec.an-l -ol, l l-(5- fl oro-8-methoxyquinohn-2-yi)undecaii-I-ol, .l 2-(5-iluoro-8-raeftoxyquirioliri-2-y!)dodecari-i -oi, 9-(5-chloro-8-methoxyqumoHn-2-yI)nonan-i-oi, 1 1 -(5-chloro-8-.methoxyquinolin-2-y l)undecan-l - ol. 15-(5-chloro-8-methoxyquinolin-2-yj)pentadeean- 1 -of 1 1 -(5-broriK>-8-methoxyq moltn-2- yi)iindecan- 1 -ol, 1 1 -{8-rae†hoxy-5-itriilL»rome -ol, 1 1 -{5,8- dimelhoxy qumolin-2-y l)undecan- 1 -ol, i l-(8~methoxy-6-methy"lquinoii.n-2-yi}uf i can-l -of 1 ! -(6- fluoro-8-methoxyqumoHn-2-yl)undecan- 1 -ol 11 -(6-chloro-8-methoxyquinolin-2-y!)undecan- 1 -ol 1 i -(7-fluoro-8-meihoxyquinolin-2-y l)undecan- 1 -ol, 1 1 -i7-chloro-8-methoxyquinolin-2-y l)iindecan-
1 - oL I H ^h!oro^6,8-dinieihoxyquinoHn-2-yl)undecan- 1 -ol, ri-(6-chioro-5J-dlniethoxyquino!in~
2- yi)undecan-l -ol n^5>7^idiloro-8-nTeihoxyqumolm-2-yJ)iindecan-l -o1, 9~(8~ethoxyquinolin-2- yi)nonan-l-oL K)-(8-eihoxyqumolin-2-yl)decan-l-ol, 11 -(8-edioxyquinolin-2-yl)undecan-l -ol? 12- (8-ethoxyquinolin-2-y I )dodecan- 1 -ol, 13~( 8-etlioxyquinoiin-2-yi)tridecan- 1 -of 14-((8- ethoxyquinolin-2-y iMetradecati- 1 -ol , 15-( 8-ethoxy q uinol in-2-y l)pentadecan~l -ol , 1148~ethoxy ~5~ meihyiquinoiin-2-y! }uiidecan-l-oi, 1 1 -i8-ethoxy-5-fl oroqyinolin-2-yl)undecan- 1 -ol, 9-{5-chloro-8- ethoxyquinoIin-2-yl)nonan-l-oL, I l-(5-cJ\]oro-8-et oxyquinoliT^2-yl)uiidec∞-l-oL 15-(5-cWoro-8- ethoxyq inolm-2-yl)peniadecan-l -oi, 11 -(5-bromo-8-eihoxyquinol.in-2-y l)«ndecan-l-oL 11 -(5.7- dichioro-8-ethoxyquitiolin-2-yl)undecan- 1 -oi. -(8-isopropoxyquinoUn-2-yl^ionan- 1 -ol, 1 G-(8- is pr opoxy qtsinoIm-2-yl)decan- 1 -ol, 1 1 -(8-isopfopoxyqumolin-2-yl)undecan-J -oL 12~{8- isopropoxyqu)nolin-2-vl)dodecan-I-oL 13^8-isopropoxyquinoIm-2-yI)tridecan-.l -oi, 14~((8~ isopropoxy quinolin~2~yl )tetradecan- I -ol , i 5-(8~isopropoxyquinol -2-yl)pentadecan- 1 -ol, 1 f ~<S~ jsopropoxy-5-i«ethylquinolin-2-yi)undecaii-l-oL I l-(5-fluoro-8-isopropoxyquinoIin-2-yi)ur iecan-
1 - oL 9-(5-c loro-8-isopropoxyquinoHn-2-yI)nonan-l-ol, 11 -(5-cftIoro-8-isopropoxyquinolin-2- y))undecan-l-ol, 15-(5-di!oro-S-isopropoxyqyinolin-2-yl)pentadecan-l -ol. 1 l-(5-bromo-8- isopropoxyq inoIin-2-yl)undecan-l-oI!, 15-(5-cWoro-8-isopropoxyq«iftoIin-2-yI)paatadecaii-l-oL 11 -{5 -bromo-8 -i sopr opoxy qui noHn-2-y i)undecan- 1 -ol, 1 1 -(5 , 7-di chl oro-8-isopropoxy quinolin-2- yl)undecaii-l-ol, -(8-(c^; lopropylmethoxy)quino1m-2-y1)nonan-l-oi, 10-(8- (c> iopropylmeihoxy}qiiinolin-2-yl)decaii-l-oL Ϊ l -(8-(cyclopropylmeiiioxy)quinoliii-2-yl)iii-idecan- 1 -ol , 12-f 8 -(cy ciopropy imethoxy )quinoii n-2-y i)dodecan- 1 -ol, 13-(8-(cy clopropy i methoxy )qirinolm-
2- yl)tndecan-i~ot \ 4-((8-(c> loprop lnw&o ) uimiIm-2- I)teli'adecaii-'1 -o!. 15-<8~
(cyclopropylmethox )quino!in-2- i)pentadecan- 1 -ol, 1 1 -(8-(cyclopropyln½thoxy)-5- mgthylqumoUn-2-yl)«ndecan-.I-oU 11 -(8-(cyxiopropylrr-ethoxy)-5 luoroquinolin-2-yl)ijridecan-l~ ol, <^5-ddoro-8-(c> lopi >p>!lmetboxy)quinolm-2-yl)noni«i-l -ol, 1 1 -(5-chloro-8- (c5'dopropyl.raethoxy)qirinolm-2-yl)imdecaii-l-ol, 15-(5-chioro-8-icydopropyimet oxy)quitioHn--2- yl )pentadecan-l-oi, ί 1 -{5-bromo-8-(c cloprop lmethoxy)quiiiolin-2-yi)undecan-l -ol, 11 -(5,7- did oro-8-(c>xlopfopylnietiiioxy)q\ji.nolin-2-yl)undeciai-l-oIJ S,7-dicliloro-2-(I I- hydroxyundecyi)quinoiin-8-oL 10-(5-diloro-8-meihoxyqoinoliT^2-yl)decaii-l -oi. acetic acid ί 0-(5- cb.loro-8-nietiK xyquinolin-2-yl)decyi ester, 1 i -(5-chlorcv8-medioxyquinolin-2- l)mdecan-l-oi, acetic acid 1 1 -(5-diioro-8-meti oxyquinolin-2-yi)undec>:l ester, l2~{5-chloro-8-niethoxyquinoHn-2- yl)dodecari- 1 -ol, acetic acid 12-(5-chiofo-8-raethoxyquiiiolin-2-y !)dodecyi ester, 13-(5-diIoro-8- meihoxyquinolin-2-yl}tridecari-l -ol, acetic acid .13-(5^loro-8-methoxyq inolin-2-yl)tridec>''l ester l l-(8-niethoxyqu oiin-4-(-yi)uiidecan-l-o!, 1 i-{8-ethoxyquinolin-4-(-yl)imdecan-i-oL 1 1 -(8- isopropoxy q uinoli«-4-(-yl)undecan- 1 -oi, 11 -(8 -icy clopropylmethoxy )quinol in -4-{-y 1 )undecan- 1. -oi, 1.1 -(8-(ben/ !ox )qomolm-4-(-yl)ondecari-i -ol, 12-(8-(benzydoxy}qusnoii1i-4-(-yl)dodecati-l -ol, 4- ((] 1 -hydroxyundecylJqiiinol -S-oi, 4-((l 2 -hydrox dodec l)quino)in~8-ol, -(8- (trit]uoroined oxy)quinolsa-2yi)nona-l-ol, l H8^trifluororaetiiox>;)quinolm-2-y'l)undecan-l-ol, 14 ((8-(trifl oinethoxy)quinoim-2-y i)tetradecan-l -oi,. 15-(8-(trifluoromeihoxy)quinolin~2~ y.l)pe.ntadecan-l~ol, 2-((4-((2-hydroxyethyl)piper&^ 2-(4-(((5-chloro-8- me^oxyquinolin^-yilraethy piperazm-l -y ethanoi, 2-(4-({{5-chloro-8-ethoxyqumolin-2- i)nieiiTyl)pi erazm-l-yi)eiha3;ioL 2-i4-(((5-cMo-ro-8-iso
yl)ethanol, 2-{4-(ii5-cMoro-8-(^ 2- (4-(((5 -dich!oro-8-melhoxyquinolin-2-yi^^^ 2-(4-{{{5,7-dichloro-8- <cy cl opropy 1 me oxy )qirinolm-2-yl)me&y l)pipera£in~ 1 ~y )ethanol, 2-((meilTvI(prop-2- ynyl)animo).mefljyl)quinoIjn- -oi, 5-chloro-2-((methyl(prop-2-ym^
((5~chioro~8~meihoxygum^ ((5-chloro-8- e^oxyqianolm-2-yl)m^hy!)-N-n^iyIprop-2-yn-J-an¾ne, N((5-diioro-8-isopropoxyqianolm-2- y i)niethy l)-N-metliy { prop-2-yn- .1 -amine, ((5-chloro-8-(cy cl opropyi methoxy )q uinol in-2- y'l)meihyl)-N-meihyiprop-2-yn-l -amine., N((5J-dicWoro-8-methoxyq«inolin-2-yl)methyl)-N- me yiprop-2-yn-l -amine, N((5,7-dic orQ-8-(c.yciopropylme ox
methylprop-2-yn-l -amine, 8-( -chloio-8-raethoxyqiimolin-2-yl)me&yIar»irio)aet i-l-oL 8-((5- ι).θΓθ-8-<ηΚθλ^ώηοΙίη-2^1). κ^ν lamino)octan- .1 -ol, 8 \5-chloro~8 sopropoxyqiunolin-2- yl)meihylammo)octan-l-ol, 8-((5-chloro-8-(cyciopropy^methoxy)quitiolin-2-yl)niethy
I -ol , 8-((5 , 7-dich! oro-8-meihox quinoli -2 -y l )memy l amino'joctan - 1 -ol, 8-((5,7-dichloro-8-
Figure imgf000019_0001
and 6-( is(<8-meihoxyquino in-2~ y])methy l)amino)hexan- 1 -ol.
In another aspect, the invention relates to a composition comprising a compound as
aforementioned, or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof, and a pharmaceutically acceptable diluent or carrier for use in treating a neurodegetierati v e disease.
In one embodiment of the invention, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, amyotrophic lateral scierosis (ALS), cataract cognitive disorder, cerebral ischaemia stroke, cerebral palsy; stroke, haemorrhagie stroke, Creotzfeldt-Jacob disease, spongiform encephalopathy, Mad Cow disease, dementia, depression. Down's syndrome, epilepsy, post- traumatic epilepsy, frontolemporal dementia.. Gilles de ia Tourette's syndrome, Haiierhoden- Spaiz disease, Huntington's disease, Levvy body disease, Parkinson's disease, cognitive impairment, learning deficit, macular degeneration, memory deficit, multiple sclerosis, multiple system atrophy, motor neuron disease. Pick's disease, progressive supranuclear palsy, pseudo dementia, retinopathy, senile dementia, schizophrenia transient anoxial induced neurodegeneration, pain, brain traumatic- injury, and spinal cord injury.
CHEMISTRY
Example 1 - Preparation of (8-benzyIoxyquinol-2-yi) and (8-hydroxyquinol-2-yl)alkyi alcohol
Figure imgf000020_0001
R= H O= 9-1S A1-A7
R= 5-CHS AS R= H n= 9-15 81 -S?
R= S-CH3 AS R= 5-CH3 n= 11 BS
~ 5 F (1= 1 A10 ,d} R« e-CHj «= 11 BS
R= 5-CS n= 11 A11 - R= 5-Ci fi¾ 11 B10
Reagents and conditions; (a) BnBr, KOH, EiOlL reflux, 15 h.; (b) 1) LHMDS, THF. 0 °C, 1 h.; 2) Br(C¾)Jj-5OH, rt, 16 - 36 h.; Cc) ¾ Pd/C, MeOH, rt, 6 to 10 h.; (d) BCh, C¾Ch, 0 °C to rt, 3 h.
Method: The benzylation was performed as described by G. Serrairice ei al. XFetrahedron, 1996, 52, 4659-4672}. Benzyl bromide (6.45 g, 37.7 mmol) was added to a stirred solution of 2- metbyiquinaidine (5.0 g, 31.4 mmol) and KOH (1.95 g, 34.8 mmol) in 60 ml EiOH under reflux condition. After J 5 h, the reaction, mixture was filtered and filtrate removed in. vacuo. The residue was purified by flash column chromatography with Hex/EA (6: 1) and recrystallized in Hexane to give intermediate. LHMDS (2.2 to 2.5 equiv.) was treated with a stirred solution of (1 equiv.) in 20 ml THF at 0 °C for .1 h. Corresponding BriCH-VjOH (1.0 to 1.2 equiv.) was added to a reaction mixture and the temperature was recovered to room temperature (RT) for further 15 to 36 h. The solvent was removed under a reduced pressure. The brown oily residue was purified by flash column chromatograph with Hex/EA (3: 1 to 2: 1 ) or DCM/EA (.15: 1 to 9:1) and reerystaUized by
Hexane/EA to afford series of compounds A. Removal of benzyl group of series of compounds A was carried out in the presence of 10% Pd/C under hydrogen at RT for 6-10 h. The reaction mixture was filtered off and the filtrate purified by flash column chromatography by Hex/EA (4: 1 to 3: 1) to give series compound of B. To a stirred solution of AH (0.65g, 1.4 mmol) in 20 ml Cf¾C¾ was added 1M BCI3 (2.8 nil, 2.8 mmol) at an ice bath for 3 h. The reaction mixture was poured into an ice bath and extracted by 50 ml CH2CI2. The organic lay er was concentrated in vacuum and residue purified by flash column chromatography (EA) to afford the product (0.31g, 60%).
9- (S-(betizyIoxy)quinoIin-2-yl)nonan-i-oI (Al)
Yield (YD): 53%, *HNMR (400 MHz, iW-MeOD) 68, 15 (d, J~ 8.4 Hz, lH), 7.52 (d, J~ 6.8 Hz, 2H), 7.3.1 - 7.41. (m, 5H), 7.29 (d, J - 2.0 Hz, IH), 7.15 (dd, ,/- 7.6, 2.0 Hz, 1H), 5.40 (s, 2H), 3.52 (t, ,7 - 6.8 Hz, 2H), 3.00 (t, J = 8,0 Hz, 2H). 1.80 (qiiin, J= 6.8 Hz, 2H), 1.50 (t, J = 7.2 Hz, 2H), 1.28-1.42 (br, 1 1H); MS. mfz 400.0, f +NaJ\
10- (S-f benzylox )quinolin-2-y I )de an- 1 -el (Λ2)
YD: 41%. 5H .R (400 MHz, Λ-MeOD) 58, .14 (d, 8.4 H/, I.H). 7,52 (d, J ~ 7,6 Hz, 2H), 7.32- 7.42 (m, 5H), 7.28 (t. J = 7.2 Hz, IH), 7.14 (dd, ./ = 7.6, 1.2 Hz, 1H). 5.3 (s, 2H). 3,51 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.79 (qirin, J = 7.2 Hz. 2H), 1.49 it J = 6.8 Hz, 2H), 1.29- 1.40 (br, 13H) ; MS. m/z 414.0, [M÷NaJ \ 11 ~(8-( benz ioxy)quinoiin~2~yl)undecan- f -of (A3)
YD: 42%. 5H NMR (400 MHz, CDCIs) 68.02 id, J = 8.4 Hz, 1H), 7.53 (d, J = 7,2 Hz, 2H), 7.27-7.39 (m. 6H), .02 (d, J - 7.6 Hz, i H), 5.46 (s, 2H), 3.63 (t, J = 6.8 Hz, 2H)5 3.05 (t J = 8 Hz, 2H), 1.84 (q, J - 7.6 Hz. 3H 1.5 (t, J ::: 7.2 ¾ 2H), 1.29-1.46 (m, 12H); MS. m/z 428.3, [M+Naf.
12-(8-(be«zy!oxy)q«inolin-2-yi)dodec-ti»-l-ol (A4)
YD: 44%. l N R (400 MHz, <&~MeOD) 58.13 (d, J 8.4 Hz, IH), 7.52 (d, = 7.6 Hz, 2H), 7.31- 7.40 (m, 5H)S 7.26 (d, 7= 7.6 Hz, IH), 7.13 (dd, J - 7.6, 0.8 Hz, 1H), 5.37 (s, 2H), 3.51 (t ./ === 6.8 Hz, 2H), 2.98 (t, .7 - 7.6 Hz. 2H). 1.78 (qui J - 7.2 Hz, 2ΪΪ), 1.49 (quin, ,/ === 7.2 Hz, 2H), 1.25-1.41 (m, 17H); MS. ra/z 442.3, [M- Naf'.
13-($-{beiizy ioxy)qu«io!in-2-yi)trideca»-l- i (AS)
YD: 40%. lH NMR (400 MHz, CDCI3) 37.95 (ds J === 8.4 Hz, 1H), 7.45 (d, ./ - 7.6 Hz, 2H), 7.19-7.30 (m, 5H), 6.93 (d. ,/ - 7.6 Hz, ΪΗ) 5.40 (s, 2H), 3.55 (t J - 6.8 Hz, 2H), 2.99 (i, J 7.6 Hz, 2H), 1.77 (quia, J = 7.6 Hz, 2H). 1.46 (t ,/ = 68 Hz, 2H), 1. 9-1.38 (br, 19H); MS. ffl/z 456.3, j M+Na) \ 1 -(S-(beiizyloxy)quin«lin-2-yl)tt,trade aH-l-ol (A6)
YD: 51%. 5H NM (400 MHz, tU-M OD) 88.14 (d, ../ :::: 8.4 Hz, IH), 7.52 (d, J ::: 7.2 Hz, 2H). 7.33-
7.42 (m, 5H), 7.28 (t. J = 7.2 Hz, IH), 7.14 (d, J = 6.8 Hz, !H), 5.38 (s, 2H), 3.52 (t ./ = 6,4 Hz, 2H),
2.98 (t, ,/ = 8.0 Hz, 2H), 1.5 (quirt, ,/ = 6.8 Hz. 2H), 1.47 (t J = 6.8 Hz, 2H), 1.22-1.41 (br, 21H); MS. m/z 447.3, [M +Hf .
15~(8-(be« .y! xy)qtiinolin-2-yi)pe!iiadecaH-f -ol (A?)
YD: 42%. lH NMR (400 MHz, ί -MeOD) 68.15 id. J= 8,4 Hz, IH), 7.53 (d, ,/ = 7,2 Hz, 2H), 7.35-
7.43 (m, 5H), 7.28-7.33 (ra, IH), 7.15 (dd, ,/ - 7.6, 1.6 Hz, IH), 5.39 (s, 2H), 3.52 (t, J=- 6.8 Hz, 2H),
2.99 (t, J ::: 8.0 Hz. 2H). 1.79 (qum, J - 6.8 Hz, 2H), 1 ,51 (quio 6.8 Hz, 2H), 1.22-1.41 (br, 23H); MS. m/z 462.3, {M÷H}!.
1 l-(8- >e»zyioxv)-5-methylqumoU«-2-yl) iHiec;m- l -oi (AS)
YD: 47%. ¾ NMR (400 MHz, rf¥-M.eOD) 68.30 (d, J === 8.4 Hz, 1 H), 7.52 (d, J = 7.2 Hz, 2H), 7.44
(d, j» 8.8 Hz, IH), 7.26-7.36 (m, 3H). 7, 17 (d, 8.0 Hz, 2H). 7.02 (d, J~ 8.0 Hz. 2H), 5.36 (s,
2H), 3.52 (t, ,/ = 6,4 Hz, 2H), 3.00 (t, </ = 7.6 Hz, 2H), 2.55 (s, 3H), 1.80 (quin, J= 7.2 Hz, 2H), 1.50
(quiii, J » 6.8 Hz, 2H), 1.28-1.41 (ni 15H); MS. m/z 420.3, |M+Hf ,
l.lr(8'( ^loxy -6'tt}etfa l uinolltt> -> l)andecan'l-c^ (A9)
YD: 40%. 5H NMR (400 MHz, t/-/-MeOD) §8.03 (d, J~ 8.4 Hz, IH), 7.53 (d, J~ 7.2 Hz, 2H), 7.33-
7.37 (m, 3H), 7.26-7.30 (to, IH), 7.16 (s, IH), 7.00 (d, J~ 1.2 Hz, 2H), 5.36 (s, 2H), 3.51 (t, J= 6.8
Hz, 2H), 2.95 (t, ./ === 7.6 Hz, 2H), 2.40 (s, 3H), 1.76 (q, 7.6 Hz, 2H), 1.56 ø, /=== 7.2 Hz, 2H),
1.29-1.46 (m, 15H); MS. m z 442.3, [M+Naf .
n-(S-(benzy!oxy)-S-fitioroquinoIki-2-yl)uiidecmi-l-ol (A 10) YD: 43%. H'N (400 MHz, CDC¾) 58.28 (d,J::: 8.8 HA 111), 7.51 (d, J-7.2 Hz, 2B\ 7.33-7.40 (m, 3H).7.28 (t J = 8,0 Hz, IH), 6.8 ~ 6.98 (m, 2H), 5.42 is, 211), 3.61 (I, J = 6.4 H , 2H), 3.07 it, /» 8 Hz, 2H), 1.83 (q,J ~ 7.6 Hz, 2H).1.51-1.54 (m, 2H), 1.21-1.45 (m, 15H): MS. m/z 446.2, 1 l-{8-(bwizyloxy)-5-chl r«tuin H»-2-yr)undecan-l- l (A 11)
YD: 43%. H NMR (400 MHz, ί/ -MeOD) 58.48 (d, J = 8. Hz, 1H), 7.52-7.57 (1113H), 7.46 (el J = 8.4 Hz, IH), 7.35 - 7.30 (ra, 2H), 7.31 id../ 7 Hz, ill), 7.1 id../ 8.4 Hz, IH), 5.40 (s, 2H>, 3.52 J- 6.8 Hz.2HK 3,03 <(J - 7.6 H*, 2H), 1.81 (quirt. J■■■■■■ 7.2 Hz, 2H), 1.49 (i,/::: 6.8 Hz, 2H), 1.28-1. 1 (m, 15H); MS. rn/z 462.2, [M+Na]".
2»(9>hydroxyno»yi)4 i»oI-n>$*oi (B I )
YD: 85%.5H NMR (400 MHz, < -MeOD) 67.86 (d, J - 8.4 Hz, HI), 7.22 (L J - 7.6 Hz, IH), 7.03- 7.13 (ra, 3H), 3.50 ({, J- 6.8 Hz, 2H), 2.75 (t, J™ 8.0 Hz, 2H), 1.58 (quin, ,/ - 6.8 Hz, 2H), 1.44 (quia, J - 6.8 Hz, 2H), 1.10-1.20 (m, 1 IH); HRMS (ES ): Caicd for iCisH25NO : 310.1778, Found: 310,1779.
2-(10~hydro.xydecyi)quinoiin~$~ol (B2)
YD: 85%.5H NMR (400 MHz, CDCI3) 58.01 (d« .7=8.4 Hz, IH), 7.35 (t, J~ 6.8 Hz, IH), 7.26-7.28 fm, 2H), 7.11 (d, J » 7.2 Hz, IH), 3.60 (t, J » 6.4 Hz, 2H>, 2.92 (I. J- 7,6 Hz, 2H)51.79 (quin, J - 6.8 Hz, 2H), 1.53 (qui«,J=== 6.8 Hz, 2H), 1.27-1.33 (br, 14H); MS. mz 302.2, {M+Hf.
2~(ll- ydroxyundetyl)q«inoiiii~8~oi (B3)
YD: 77%. lH NMR (400 MHz, CDC¾) § . 4 (d, J =8.4 Hz, I H), 7.38 (t, J = 7.8 Hz, 1 ), 7, 27-7.31 (ra, 2H), 7.14 (dd, i - 1.2.7.6 Hz, IH), 3.64 it..7-6.8 Hz, 2H), 2.950,·/ 7.8 Hz, 2H), 1,83 (quin,
7.8 Hz, 2H) 1.55 ( .2H>, 1.28-1.36 (br, 17H); 1 MS. m/z 316.2, jM+Hf .
2-( 12-hydroxydodecyt)quinotin-S- l (B4)
YD: 76%. Ή NMR (400 MHz, CDCb) 58.03 id, J = 8.4 Hz, IH), 7.36 (t, J= 8 Hz, 1 H), 7.25-7.30 (m,2H),7.13(d, J - 7.6 Hz. IH), 3.62 (t, J ::: 6.4 Hz, 2H), 2.94 (I ,/:::: 7.6 Hz, 2H), .1.81 (quin, J- 7.6 Hz, 2H), 1.54 (quin, J- 6.8 Hz, 2H), 1.29-1.38 (br.18H) MS. m/z 330.3, JM+H]\
2-( 13-hyd roxytridecyl )qiiinoiitt-S-oi ( 5)
YD: 84%. XE NMR (40 MHz, CDCI3) 68.03 (d, ./= 8.4 Hz, 1 H), 7.36 (t, J '= 7.6 Hz, IH), 7.26-7.30 (m, 2H), 7.13 (d, j === 7.6 Hz, IH), 3.62 (t, J ::: 6.8 Hz, 2H), 2.95 (t </ - 7.6 Hz, 2H), 1.81 (quin,./ - 7.2 Hz.2H), 1.54 (quin, ./ - 6.8 Hz, 2H), 1.25-1.34 (br, 20H); MS. m/z 344.3, M+H)r.
2-( 14-hydroxytetradecyl)qulnoli«-8-ol (B6)
YD: 87%. ¾ NMR (40 MHz, CDCl?) 58.02 (d, J■■■ 8.8 Hz, IH), 7.36 (1, 7.6 Hz, H).7.25-7.29 (m, 2H), 7.12 (d, j = 7.2 Hz, 1.H), 3.61 ((.. - 6.4 Hz, 2H), 2,940,./- 7,6 Hz, 2H), .1.80 (quin, J- 7.2 Hz,2H), 1.54 (quin, J= 6.8 Hz, 2H), 1.24-1.34 (br, 24H); MS. mz 358.3, [M+Hf. 2-{15~h droxypeiitadec l) uino!ln~8~oi (B7)
YD: 83%. JH NMR (400 MH , CDC!;;) 58.04 id, J = 8.4 Hz, IH), 7.35 (t, J= 7.6 Hz, IH), 7.26-7.29 (m. 2H), 7.13 (d, J » 7.2 Hz, IH), 3.62 (t, J = 6.8 Hz, 2H), 2.95 (t, j~ 7,6 Hz, 2H)5 1.80 (quin, J - 7.2 Hz, 2H 1.54 (quift, J ^ 7.2 Hz, 2H), 1.24-1.37 (br, 24H); MS. m z 372.3, {MR-Hf .
2-(l i- ydr xyundecylJ-S-t etiiy!quiiioiiii-S-o! (.88)
YD: 83%. lH NMR (400 MHz, <&~MeOO) 58.26 (d, ./ = 8.4 Hz, IH), 7.39 (d, ,/ = 8.8 H , I H), 7. 15 (d, J 7.2 H IH), 6.93 (d../ 3.2 Hz, IH), 3.52 (t, J - 6.4 Hz. 2H)f 2.95 (t ·/ 8.0 Hz, 211 ), 2.53 (s, 3H)5 1 .81 (quin, J - 7.2 Hz. 2H), 1.48 (quin, ,/ - .8 Hz, 2H); 1.13-1.37 (m, 15H); MS, m/z 330.3, [M+H]\
2-{ i l-hydr xyiuidecyl)-6-tiiettiyiqiiiii iin-S-oI
YD: 83%. 5H NMR (400 MHz, </ -MeOD) 67.99 (& J === 8. Hz, 1 H), 7.29 (d, J - 8.8 Hz, 1 H), 7.06 (s, IH). 6. 1 (s. IH), 3,51 ( ί, ,/' 6.4 Hz. 2H), 2.90 (t, ,/ - 8,0 Hz, 2Π) 2,41 (s, 3H), 1.77 (quin, ./ - 6.4 Hz, 2H), 1.49 (quin, 7= 6.8 Hz, 2H), 1.25-1.37 (m, I H); MS. /z 352.2, [M+Naf.
5-cliloro-2-(l l-liydroxy«n<iecyl)qtii«t>lin-8-fjl (BIO)
Ή NMR (400 MHz. iW- OD) 58.39 (d, J === 8.8 Hz, I H), 7.49 (d, 8.8 Hz, IH), 7.41 (d, J === 8.4 Hz, IH), 7.01 (d, J = 8.0 Hz, IH). 3.5.1 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 1.81 (quin, J = 7.2 ¾ 2H), 1.50 (quin, J = 6.8 Hz, 2H). 1 .27-1.35 (ill 1SH); MS. m/z 350.2, {M+Hf.
Example 2 - Preparation of (S-inetiioxyquinoI~2~yl aiky! alcohols
Figure imgf000023_0001
C1-C23
Reagents and conditions: (a) Mel, K2CO acetone, r.t 10 h.; (b) 1 ) LHMDS, THF, 0 DC, 1 h.;
Figure imgf000023_0002
Method: Methyl iodide ( 10.8 g, 76.3 rtiraol) was added to a stirred solution of 2~
methylquinaldine ( 1 .0 g, 6.3 mmol) and 2CO3 (5.0 g, 36.2 mmoi) in 30 mi acetone at RT for 10 h. The reaction mixture was filtered and filtrate removed under a reduced pressure. The residue was purified by flash column chromatography with Hex EA (3: 1) and recrystal!ized with Hexane/EA to give 8-methoxy-2-methylauinoline as intermediates. LHMDS (2.2 to 2.5 equiv.) was treated with a stirred solution of intermediate (.1 equiv.) in THF at 0 °C for 1 h. Corresponding Brt'CHa tOH (1.0 to .2 equiv.) was added to a reaction mixture and recover to RT for further 12 to 30 h. The solvent was removed under a reduced pressure. The brown oily residue was purified by flash column chromatography with Hex/EA or DCM/EA and recrystalhzed by Hex/EA to afford series of compounds C.
9-(8-methoxyquiaotin-2-yt)nonan-■ l-ol ( C 1 ) YD: 50%. H 'N (400 MHz, CDC¾) 58.05 (d, ::: 8.4 Hz, IH), 7.33-7.42 (m, 3HX 7.04 (d J :::: 6.8 Hz, IH), 4.08 is, 3H), 3.62 (I, J = 6.4 Hz, 2H), 3.07 (i, ,/ = 7.6 Hz, 2H), 1 , 79 (br, 2H), 1.53 (br, 2H), 1.30-1.42 (br, 1 IH); MS. m z 324.0, [M+Naf .
10~(8-metlioxy q«i«oiiti-2~ l)decaJi- 1 ~oi (C2 )
YD: 38%. 5H NMR (400 Hz. CDCU) S 8.01. (d, 8.4 Hz, IH), 7.36 (\, J ~ 7.6 Hz, IH), 7.30-7.33 (ra, 2H), 7.00 (d, J = 7.6 Hz, IH), 4.05 (s, 3.H), 3.60 (t, J- 6. Hz. 2H), 3.01 (i, J = 7.6 Hz, 2H), 1.79 (quin, J - 8 Hz, 2H), 1.52 (qirirt ./ =- 6.8 Hz, 2H), 1.30-1.43 (br, I 2H): MS. m/z 316.2, [M+Hf.
11- (S-meihoxyqtiinoiin-2-yf)tinilecaii-l-o! (C3)
YD: 42%. !H NMR (400 MHz, CDCI3) S8.02 id, - 8. Hz, 1 H), 7.38 (t, J = 7.8 Hz, IH), 7.31 -7.34 (ra 2H), 7.15 (d, j - 7.2 Hz, IH), 4.06 (s. 3H), 3.6! it J === 6.8 Hz, 2H), 3.02 it. ./ 7.8 Hz, 2H), 1.79 (quiii, ./- 7.6 Hz, 2H)? 1 .54 (quin, ,/ - 6.8 Hz, 2H), 1.31-1.42 (br, 15H); MS. m/z 352.2, |M÷Naj ' ,
12- (S-tncIhoxyquin Hn-2-yl)(l«decan- l- l (C4)
YD: 38%. lH NMR (400 MHz. CDC¾) §8.01 (d, ./= 8.8 Hz, IH), 7.35 (t, .7 = 7.6 Hz, IH), 7.30-7.32 (ill, 2H), 7.01 (d5 j - 7.2 Hz, I H). 4,05 (s, 3H), 3.61 (t, ,/= 6.4 Hz, 2H), 3.01 (t J = 8 Hz, 2H), 1.78 (quin, J - 7.6 Hz. 2H), 1.36-1.41 (m, 2H), 1.24-1.33 (br, 16H): MS. m/z 344.3, [ H}÷.
13- (8-methoxyqHinolin-2-yi)tiid can- l-ol (C5)
YD: 38%, Ή NMR (400 MHz, CDCI3) 58.01 (d, , - 8.4 Hz, IH), 7.37 0, = 7.6 Hz, I H), 7.30-7.33 (m, 2H), 7.01 (d, J === 7.6 Hz. IH), 4.05 (s, 3H), 3.61 (l, J 7.2 Hz, 2H), 3.01 (\, 8 Hz, 2H), 1.80 (quin, J - 7.6 Hz, 2H), 1.54 (quia. ,/ - 6.8 Hz , 2H), 1.36-1.43 (br, 9H); MS. m/z 358.3, [MtHf . 14-(S-nietlioxyquiiioIiii-2-yl)tetra(le i-l-ol (C6)
YD: 38%, XB NMR (400 MHz, CDCk) 68.02 (d, ./ 8.4 Hz, Hi), 7.31-7.38 (m, 3H). 7.01 (d, J - 7.2 Hz, IH), 4.06 (s. 3H), 3. 1 it J - 6.8 Hz. 2H). 3.02 (l, j- 8 Hz, 2H), 1 .79 (quin, J - 7.6 Hz, 2H), 1 .54 (quin, 6.8 Hz , 2H), 1 .23-1.40 (br, 21 H); MS. /z 394.3, jM+Naf.
15-(8-methoxyq«inolio-2-yi)pentadecaii-i -οϊ (C7)
YD: 31 %. ¾ NMR (400 MHz, CDCU) 58.01 (d, J- 8.4 Hz, IH), 7.3.1-7.39 (ra, 3H), 7.01 (d, j - 7.2 Hz, I H), 4.06 (s, 3H), 3.63 (t. - 6, 8 Hz, 2H), 3.02 (i, J ~ 8 Hz. 2H). 1.79 (quia, ./ - 7.6 Hz, 2H), 1.54 (quia ,7 = 6.8 Hz , 2H), 1.32-1.43 (br, 23H); MS. m/z 408.3, [M+Hf.
1 l-(8-methoxy-5-methyl uinc)lin-2-yi)ui}decan-i -ol (CS)
YD: 30%. !H NMR (400 MHz, ώΜ- eOD) δ8.29 (ά, J 8.4 Hz, IH), 7.43 (d, J === 8.8 Hz. IH). 7.24 (dd, ./ - 8.0, 0.8 Hz. H). 7.01 (d, ,/ 8.0 Hz, ί H), 4,00 (s, 3H), 3.51 (I, J- 6.8 Hz, 21 ί }. 2.97 (I, J - 8.0 Hz, 2H), 2.56 (s, 3H), 1.76 (quin, ,/ = 7.6 Hz, 2H), L50 (quin, J~ 7.2 Hz, 2H), 1,27-1 ,40 (br, 15H); MS. m/z 366.2, [Mf Na .
1 l~(5-fluoro~8-t«ethoxyq um iin-2~yi )tind can~ l-ol ( C9) Ή NMR (400 MHz. 44-MeOD) 58.34 (d. J- 8.8 Hz I H), 7.51 ( l ■■■■■■■■ 8.8 I¼ I H), 7.15 (d, J■■■■■■ 7.2 Hz, I H), 6.93 (d, J = 3.2 Hz, IH), 4.02 is, 3H), 3.52 (i, J " = 6.8 Hz, 2H), 2.95 (i, J= 8,0 Hz, 2H), 1.81 (quin, 7.2 Hz, 2H), 1.48 (quin, / - 6.8 Hz. 2H); 1.13-1.37 (m, 15H); MS. m'z 370.2, (M+Naj\ 12~(5-fluoro~8~methoxyquiiioliii-2~j,l)dodecan- I-ol (CIO)
YD: 38%. 5H NMR (400 MHz. d4~MtiOD) 58.36 {<! ./ = 8.8 Hz, IH), 7.52 (d, 8.8 Hz, 1H), 7. 17 (d, J= 8.8 Hz, IH), 7.08 (dd. J - 8.4, 4.8 Hz, IH), 4.04 {s, 3H), 3.53 (t J- .8 Hz, 2H), 3.00 (t, J = 8.0 Hz, 2HX 1.78 (quin, J— .2 Hz, 2E\ 1.51 (quia, J - 7.2 Hz, 2H). 1.28-1.42 (m, 17H); MS. /z 384.2, [M+Naf .
9-{5-chloro-8-inethoxyq«ino n-2-y!)iioiiaii-l-ol (Cll)
YD: 38%. Ή NMR (400 MH . </ -MeOD) §8.47 (d\ J- 8.8 Hz. H), 7.55 (d, — 8.8 Hz, IH), 7.52 (ds J ::: 8.4 Hz. IH), 7.1 1 id, J === 8.8 Hz, I H), 4.04 (s, 3H), 3.51 (t J === 6.8 Hz, 2H), 3.00 (t, J - 8.0 Hz, 2H), 1.77 (quin, J = 7.6 Hz, 2H), 1.50 (quin, 6.8 Hz, 2H>, 1.30-1.37 fm, I IH); MS. m/z 336.2, [M+H) \
l l-(5-chloro-$-methoxyquhi lin-2-y!)iiiideciin-l-ol (CI 2)
YD: 35%. 5H NMR (400 MHz, cW-MeOD) δ8.46 (ά, J = 8.4 Hz, IH), 7.54 (d, J - 8.8 Hz. IH). 7.51 (d, ./ = 8.4 Hz, IH), 7.10 (d, J '= 8.4 Hz, IH), 4.04 (s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.99 (t J = 8.0 Hz, 2.H), 1.76 (quin, ,7 - 7.6 Hz. 2H), 1.49 (quin, J = 6.8 Hz, 2H), 1 .27-1.38 (br, i 5H); MS. m/z 386.2, (M+Naj*.
15~{5-chloro-8-meili xyq«inoiiii~2-yr)pentadeciHi~l~ol (C13)
YD: 39%. lH NMR (400 MHz, ί -MeOD+CDCij) 68.44 id. J = 8.4 Hz, IH), 7.47 {d, J = 8.4 Hz, I H), 7.46 (d, 8.4 Hz, IH), 7.01 (dd. 8.4, 4.0 Hz, H), 4.03 is, 3H), 3.52 it J 6.8 Hz, 2H), 2.99 (t, J ::: 8.0 Hz. 2H>. 1.76 (quin, J - 7.6 Hz, 2H), 1.50 (quin, « 6.8 Hz, 2H), 1 .22-1.38 (ra. 23H); MS. m/z 442.3, |M+Na]+.
1 l-(5-bromo-8-meth xyc|ui»oliii-2-yl)unflecan-l- l (CI 4)
YD: 46%. 5H NMR (400 MHz, CDCh) 58,40 (d, J = 8.4 Hz, IH), 7.65 id, J- 8.4 Hz, IH), 7.44 id, J - 8.8 Hz, IH), 6.91 (d, j - 8.4 Hz, IH), 4.0 (s, 3H), 3.63 (t, ./~ 6.8 Hz, 2H), 3.07 (i, J- 8.0 Hz, 2H), 1.79 (quin, J = 7,6 Hz, 2H), Ϊ .55 (quin. J = 6.8 Hz , 2H), 1.30-1.45 (br, 15H); MS. m/z 430.2, |M÷Naf .
Figure imgf000025_0001
YD: 36%. 5H NMR (400 MHz, t/4-MeOD+CDCU) §8.40 (dq, J~ 10.4, 1 .6 Hz, IH), 7.86 id, ,/ = 8.4 Hz, IH), 7,58 (d, J~ 8,8 Hz, LH), 7.20 (ά, J - 8.0 Hz, IH), 4.1 1 is, 3H), 3.51 it J~ 6.8 Hz, 2H), 3.00 (i, J- 8.0 Hz, 2H), 1.78 (quin, J■■■ 7.6 Hz, 2H)„ 1.50 (quin, .8 Hz, 2H), 1.27-1.43 (m, 15H); MS. m/z 420.2, [M+Naf.
l l-(5,S-dimethoxyquinoiiii-2-yI)undecan-l-oi (CI 6) YD: 31%; Ή NMR (400 MHz, aW- eOD) 8.46 (d, J■■■ 8.4 Hz, IH), 7.38 (d, J - 8.4 H/: IH), 7.03 (d, - 8.4 Hz, IH), 6.82 (cLJ= 8.4 H¾, IH), 3.98 (s, 3H), 3,94 (s, 3H).3.51 (t,J = 6.8 Hz, 2H).2,95 ft, J- 8.0 Hz, 2H), 1.73 (quin, J- 7.6 Hz, 2H), Ϊ.50 <quh%J = 6.8 Hz, 2H), 1.27-1.35 ibr, 15H); MS. m/z 360.2, [M+H .
1 l-{8-ineihoxy-6-iiH>tfjylquin«Un-2-yl)undecan-f-«l (C17)
YD: 41 %. -lH NMR (400 MHz, CDCK) 57.96 (d5 J = 8.4 Hz, I Ml 7.30 (t, J - 84 i f/. IH), 7, i 2 (s, 3 H), 6.87 (s. I HI 4.06 (s.3H), 3.63 (t J - 6.8 Hz, 2H), 3.05 (t J = 7.6 Hz, 2H), 2.50 (s, 3H).3.79 (quin, J■■■■■■ 8.0 Hz.2H), 1.55 (quin, J- 6.8 Hz, 2H), 1,27-1.4! <¼ 15H); MS. m/ 366.2, [M+Naf. 11 -(6-¾iore-8-nieihoxyquiiioliifi-2-yJ)iititlecan-l -oi (C 18)
YD: 43%; ¾ NMR (400 MHz, cW-MeOD) §8.12 (clJ - 8.4 Hz, iH), 7.44 (d, J - 8.8 Hz, IH), 7.0? (ddsJ-9.2f 2.4 Hz, JH), 7.01 (dd. J- 10.8.2.8 Hz, lH)f 4.06 (s, 3H)f 3.52 (t J- 6.8 Hz, 2H), 2.95 (t,./-S.0Hz, 2HX 1.75 (quin, ./ « 7.6 Hz, 2H), 1.48 (quin, J = 7.2Hz,2H), 1.1.9-1.35 (m, 1.5H); MS.
Figure imgf000026_0001
l1-(6-chloro-8-methoxyquiii lin-2-y!)iiiideciin-l-ol (CI 9)
YD: 39%; ¾ NMR (400 MHz, ctt- eOD) 68.13 (d,J~- 8.4 Hz, IH), 7.44-7.47 (m, 2H), 7.13 (d, J- 2.0 Hz, IH), 4.05 (s, 3H), 3.52 (i, ./= 6.8 Hz.2H), 2.96 (t, J = 8.0 Hz, 2H), 1.76 (quin, J = 7.2 Hz, 2H), 1.50 (quin, J - 6.8 Hz, 2H), 1.28-1.36 (br, 15H): MS. mix 360.2. [M+H]\
n~(7-fluoiO~8~t«eihoxyqtihioim-2~yJ)titidecaH~l-oi (C2 )
YD: 32%; }H NMR (400 MHz, d4-MeOO) 58.20 (d, J - 8. Hz, IH), 7.60 (dd, J - 8.8, 5.6 Hz, IH), 7.39 (dd, J = 8.8, 1.6 Hz, IH), 7.01 (d, J = 8.8 Hz, iH), 4.3361 J = 3 ,2 Hz, 3H), 3.52 (t J = 6.8 Hz, 2H), 2.99 it J 7.6 Hz, 2H), 3,80 (quia,,/- 7.6 Hz, 2H), 1.48 {'quin,■/ 6.8 Hz, 2H), 1.29-1.42 (m, 35H); MS. m/z 348.2, M-i-Hf.
I l-(7-€hloro-8-iiiethoxyqiiiiiotiii-2-yi)iHidec¾n- l-ol (C21)
YD: 17%; !H NMR (400 MHz, tW-MeOD) 58.20 (d,J = 8.4 Hz, IH), 7.60 (d, J - 8.8 Hz, IH), 7.50 id, J ::: 8.8 Hz. IH), 7.42 (dtJ - 8.4 Hz, 3H), 4.08 (s, 3H), 3.52 (LJ - 6.8 Hz, 2H), 2.99 (t, ■■■ 7.6 Hz, 2H), 1.82 (quin,,/- 7.2 Hz, 2H), 3.50 (quin, J~ 6.8 Hz.2H).1.28-1.42 (br.15H): MS. m/z 360.2, |\1ill|
I I -(5-chIoro-6,8-diiwetiiOxyq uinoiin-2-y.)iindecan- l-ol (€22)
YD: 32%; *H NMR (400 ΜΗζ,ί/ -MeOD) 68.40 (d, J === 8.8 Hz, IH), 7.46 id, J === 8.8 Hz, 3H), 7.07 (s, .IH), 4.08 (s, 3H), 4.02 (s, 3H), 3.51 (t ,/ - 6. Hz, 2H), 2.94 (t, ,/ = 7.6 Hz, 2H), 1.74 (quin, J- 7.6 Hz, 2H), 1.50 (quin, </ = 6.8 Hz, 2H)S 1.27-1.34 (br, 15H);MS. m/z 394.2, M+Hj*.
n~(6-chloro-5,8~ditneihoxyqtiinoiiii-2-y!)tuidec.ui~l-ii (C23) YD: 35%; Ή NMR (400 MHz, rf^-MeOD) 58.38 (dsJ- 8.8 Hz, IHk 7.5.1 4 J - 8.4 Hz, 1H), 7.12 (s, !HX 4.02 (s, 3H), 3.94 (s, 3H), 3.52 (t J = 6.4 Hz, 2H), 2.97 ( J= 7.6 Hz, 2H), 1.74 (quilt, J = 7,6 Hz, 2M)s 1.50 (qusn5 J - 6. H 5 2eX 1.34-1.41 (br, 15H); MS. m/z 394.2, M+Hj+.
YD: 40%. ]H NMR {400 MHz, CDCS3) 58.40 (<L ,/ - 8,4 Hz, 1 H), 7.59 (d, ,/ - 8.0 Hz, 1 H), 7.56 (s, 1.H). 7.39 (d, J = 8.8 Hz, IH). 4. 19 (s, 3H). 3.63 (t, 6.8 Hz, 2H), 3.04 (I J - 7.6 Hz, 2H), 1.84 (quia, J - 7.2 Hz, 2H), 1.55 (qura../ - .8 Hz , 2H). 1.27-1.40 (br, 15H): MS. m/z 420.2. [M Naf . Example 3 - Preparation of (8~ethovyqiiinol-2-vl} and
Figure imgf000027_0001
alcohols
Figure imgf000027_0002
Reagents and conditions: (a) Ethyl iodide or 2-bronropropan.e, ¾Ci¾, DMF, 60 '"'C. 14 h. (b) 1) LHMDS, THE 0 1 h.; 2)
Figure imgf000027_0003
RT, 12 - 30 h.
Method: Ethyl iodide (3,9 g, 25.0 mmol) or 2~broroopropane (2.4 g, 19.2 mmoi) was added to a stirred solution of 2-mewy Iquinaldine (3.0 g, 18.8 mmol) and K3CQ3 (6,5g? 47 mmol; 5,2 g, 37,6 mmol) in 30 ml DMF at.60 °C for .14 h, The reaction mixture was quenched by H20 (200 ml) and extracted with EtOAc (50 nil X 2), The organic layer was concentrated by evaporation in vacuum. The residue was purified by flash column chromatography with Hex/EA (6:1) and reerystaiiized with Hexane/EA to give 8-e¾ioxy-2-metIiylqi«noline as intermediate (2.75g, 78%) in solid but liquid form for 8-isopropopxy-2-n«thyiqtiitioHfie (2.92g, 77%). LHMDS (2.2 equiv.) was treated with a stirred solution of different intermediates in Ti !F solution ai °C for 1 h. Corresponding BriCHz iOH ( 1. 1
- 1 .2 equiv.) was added to a reaction mixture and recover to RT for further 1 to 30 h. The solvent was removed under a reduced pressure. The brown oily residue was purified by flash column chromatography with Hex/E A or DCM EA and reerysiallized by Hexane/EA to afford compound I) and E.
9- (8-t*thoxy(}uiHolin-2-yl)iu>nan- 1 -ol (Dt )
YD: 45%. lH NMR (400 MHz, COCK) 88,07 (d, J~ 8. Hz, IB). 7.34-7.42 (m, 3H), 7.06 (d, 8.4 Hz, 1H), 4,35 (q, J = 6.8 Hz. 2H), 3.63 (1 J = 6.8 Hz, 2H), 3.11 (br, 2H), 1 .83 iquin, J= 7.6 Hz, 2H), 1.52- 1.64 (m, 5H), 1.26-1.46 (br, 11H); MS. m z 338.0, (M+Naf .
10- iS^thoxyqumolin-i-yjldecan-t-o! (D2)
YD; 36%. SH NMR (400 MHz, oW-MeOD) 58.16 (d, J~ 8.4 Hz, W). 7.38-7.44 (m, 3H), 7.14 (dd5 J
- 7.2, 1.6 Hz, lH)f 4.29 (q../ 6.8 Hz, 2Π), 3.52 i :,■/ 6.8 Hz, 2H). 2.99 (t J™ 7,6 Hz, 2H) 1.78 (quirt, J 1:: 7.6 Hz, 2H); 1.57 (t, J~- 7.6 Hz, 3H1 1.50 (t J™ 7.6 Hz, 2H), 1.30-1.43 (br, 13H); MS. m/z 352.0, [M÷Naf.
1 l-(8-ethoxyquiiioliii-2-yi)iiii(tecai»- ί-οϊ 1)3) YD: 43%. Ή NMR (400 MHz, CDC¾) 58.03 ( L ::: 7.6 Hz, IH), 7.31-7.41 (m, 3H>„ 7.04 ( J === 7.2 Hz, I H), 4.33 (q, J = 7.2 Hz, 2H), 3.62 it J = 6.4 Hz, 2H), 3.06 (br, 2H). 1.81 (quin, = 8,0 Hz, 2H), i .51-1.6 i (m, 6H), 1 ,38-1.51 (br, 14H); MS. m/z 344.3, (M Hf.
12~(8-ethoxyquhioHn~2~yl)dodecan-l-oi (D4)
YD: 33%. !B NMR (400 MHz, CDCfe) 58.03 (d, ,7 = 8.4 Hz, IH), 7.3 1-7.39 (m, 3H), 7.04 (d, J™ 7.6 Hz, IH). 4,33 (q, ,7 - 6.8 Hz. 2H), 3.62 (t, ,7 = 6.4 Hz, 2H), 3.05 (t J = 8.0 Hz, 2H), 1 .82 (quin, ./ = 7.2 Hz, 2H)„ 1.53-1.62 (m, 5H), 1.27-1.42 (br, 17H); MS. mte 380.3, (M-HMa)*.
13-(8~ei hosyqiiHioM«-2-yl)tridecaii~ 1 ~oi (D5)
YD: 43%. !H NMR (400 MHz, CDCI3) 58.04 id, ,/ - 8.4 Hz, 1 H), 7.32-7.40 (m, 3H), 7.04 (d, J - 7.6 Hz, IB), 4.34 (q. J- 6.8 Hz, 2H), 3.62 ft J- .4 Hz, 2H), 3.07 (1, J™ 8,0 Hz, 2H), 1.82 (quin, ,7 = 7.6 Hz, 2H), 1.52-1.62 (m. 5H). 1 , 1 9-1 .46 (br, 19H); MS. tn/x. 394.0, [M+Naf.
14~(8-ethoxyq «oliii~2~yl )tetradecan-l -ol (D6)
YD: 35%. lH NMR (400 MHz. CDC¾) §8,00 (d, ./= 8.4 Hz, IH), 7,28-7.35 (m, 3H), 7.02 (d, J = 7.2 Hz, IH). 4.32 (q, ,/ = 6.8 Hz, 2H), 3.61 (i, J = 6.4 Hz. 2H), 3.01 (t, J - 8,0 Hz, 2H). 1.80 (quin, J - 7.6 Hz, 2H), 1.52-1.60 (m, 5H), 1.24-1.41 (br, 2,1 H); MS, m/z 408,3, M+Naf .
lS-(8-ethosyquiiioliii-2-y1)peiitadec3ii- 1-oi (I>7)
YD: 33%, Ή NMR (400 MHz, t/4-MeOD) §8.21 (d, J- 8.4 Hz, I H). 7.40-7.47 (m, 3Hj, 7.17 (dd, J === 7.2. 1.6 Hz, I H), 4.30 (q, J- 7.2 Hz, 2H), 3.52 (t, J === 6.8 Hz, 2H), 3.01 ( /=== 7.6 Hz, 2H), 1 .78 (quin, J - 7.6 Hz, 2H), 1.57 (t. ,/ - 8 Hz, 3H), 1 .51 (quin, J = 6.8 Hz, 211), .26-1 .43 (br, 23H); MS.
Figure imgf000028_0001
YD: 34%. 5H NMR (400 MHz, CDCb) §8.20 (d, J === 8.8 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.19 (d, ./ - 7.6 Hz, 1 H), 6.94 (d, J— 8.0 Hz, IH). 4.31 (q, J - 6.8 Hz. 2H), 3.63 it, J- 6.4 Hz, 2H), 3.08 (t, J - 8.0 Hz, 2H)S 2.57 (s5 3H)S 1.83 (quin, J » 7.6 Hz. 2H), 1.83 (t, 7.6 Hz, 3H). 1.57 (quin, J - 7.2 Hz, 2H), 1 .41-1.45 (m. 2H), 1.28- 1.33 (br. 13H), MS. m/z 380,2. (M+Naj*.
1 l-(8-ethoxy-5-nuoroqHiiioliii-2-yl)tiiidecan- l-ol (D9)
YD: 49%. lH NMR (400 MHz, <&-MeOD) 58.33 (d, J = 8,4 Hz, IH), 7.49 (d, J = 8,8Hz, IH), 7. 12 (t, ,/ '= 9.2 Hz, IH), 7.05 (dd, J= 8.4. 4.8 Hz, IH), 4.25 {¾ J = 7.2 Hz, 2H), 3.51 (1, J - 6.8 Hz, 2H), 2.99 (t, J■■■■■■ 8.0 Hz. 2H). 1.77 (quin, .7 - 7.2 Hz, 2H), 1.55 (1 ,7 - 7.2 Hz, 3H), 1.48-1.52 (m. 2H), 1.28- 1.46 (br, 15H); MS. m z 384.2, {M+Naf.
9-(5-chI ro-8-ethoxyqHi» Iin-2-yl)nonan- Noi (1)10)
YD: 34%, ¾ NMR (400 MHz, d4~MeOD) 58.47 (d, ./ = 8.8 Hz, 1 H), 7.55 (d, ,7 === 8.8 Hz, 1 H), 7.50 (d, 8.4 Hz, IH), 7.10 (d J - 8.8 Hz, IH), 4.28 (q, J - 6.8 Hz, 2H), 3.51 (t J - 6.4 Hz, 2H), 3.01 (L J - 8.0 Hz, 2H), 1.76 (quin, J::: 7. ¾ 2H). 1.56 0, ,/ - 6.8 Hz, 3H); 1,48-1.51 ( , 2H), 1.31-1.46
(br, 1 1H); MS. ffi/z 350.2, (M+Hf .
1 l-(5-chloro-8-etboxy<jai»oli»-2- ! )H»deca»-l-oI (Dl 1)
YD: 38%. ¾ NMR (400 MHz. CDCK) 88.35 <d5 J™ 8.8 Hz, 111), 7.36 <dd, J™ 8.4, 3.6 Hz, I B), 7.19 (d, J- 2.4 Hz. IH). 6,88 (d, J~ 8.4 Hz, iH), 4,25 (q, J~ 7.2 Hz, 2H), 3.56 (L J - 6.4 Hz, 2H), 2.98 (t, J = 8,0 Hz, 2H), 1.76 (quin. J = 8.0 Hz, 2H), 1.45-1 ,54(m} 5H), 1.19-1.39 (br, 15H); MS. ra z 400.2, [ +Naf .
lS~(5~chloro~S~etho. q^ (012)
YD: 38%. !H NMR (400 MHz, < ¥-MeOD+CDCl?) 68.47 (d, ./ = 8.8 Hz, IH), 7.53 (d, J - 8.8 Hz, IH), 7.49 (d, ./ 8.4 Hz, IH), 7.08 (d, J - 8.4 Hz. 1H), 4.28 (q, J~ 6.8 Hz, 2H). 3.52 (t. 6.8 Hz, 2H)f 3.01 (i, 8.0 Hz, 2H), 1.79 (quin, J - 7.6 Hz, 2H), 1.57 (L J - 6.8 Hz, 3H), 1.49 (quin, J- 6.8 Hz, 2H), 1.25-1.41 (br, 23H); MS, m/z 434.3, [M+H] \
1 l-(5-bt oino-8-ethoxyqujnoHH-2-y )unde an-I-ol (l>13)
YD: 33%, Ή NMR (400 MHz, <*¥-MeOD) 0 8.41 (d J = 8.8 Hz, IH), 7.67 (d, J 8.4Hz, I H), 7.52 (d. ,/- 8.8 Hz, I H), 7.04 (d, ./ - 8,4 Hz, IH), 4.2? (q, J - 7.2 Hz, 2H), 3.52 (i, 6.8 Hz, 2H), 3.00 (t J = 8.0 Hz, 2H>, 1.77 (quin, ,/ = 7.6 Hz, 2H), 1.56 (i, J = 7.2 Hz, 3H), 1.47-1.57 (m, 2H), 1.27-1.39 (br, I5H); MS. miz 444.2, [M+Naj''.
ll'CS^Hlkbloro^-^hoxyq in^itt-Z'- Ou decati l'O (D14)
YD: 34%. !H NMR (400 MHz. tW-MeOD) S8.43 (d, ./ - 8.8 Hz, IH), 7.64 (s, IH), 7.51 (d, J - 8.4 Hz, 1 H), 4.39 (q , .7 = 6,8 Hz, 2H), 3.52 (t ,/ = 6,8 Hz, 2H), 3.00 (t J = 7.2 Hz, 2H), 1. 4 (quin, J = 7.2 Hz, 2H), 1.45-1.49 (in, 5H), 1.27-1.36 (br, 15H); MS. miz 434.2, [M+Naf.
9- (8-i<> pi O|> xy uin<>Hn-2-yl)n«nan-l-ol (EI)
YD: 28%. ]H NMR (40 MHz, tW-M OD) δ 8.07 (d, J - 8.8 Hz, IH), 7.33-7.36 ( , IH), 7,31-7.33 (m. 2H), 7.09 (d,J = 7.2 Hz, I H), 4.79 (ni IH), 3.49 (t, J = 6.8 Hz, 2H), 2.93 = 7.6 Hz, 2H), 1.71 (guin, ./=== 7.6 Hz, 2H), 1.45-1.49 (m, 2H), 1.41 (d, J~ 6 Hzf 6H); 1,20-1.35 (br, 1 1 H); MS. ro/z 330.2, | M l l|
10- (S-iso rogioxyq uitioHn-2-yl )decan-l -ol (E2)
YD: 36%, ¾ NMR (400 MHz, fiW-MeOD) S 8.14 (d, j = 8.8 Hz, I H), 7.40-7.43 (m, IH), 7.37-7.39 (m, 2H), 7. 16 (dd, J :::: 6.8, 2.0 Hz, IH), 4.83 (m, I H), 3.51 (t, </ - 6,8 Hz, 2H), 2.98 (t, J = 7.6 Hz. 2H), .1.77 (quin, J'~ 7.2 Hz. 2H), 1.45-1.49 (m, 2H), 1.41 (d, J - 6 Hz, 6H), 1.20-1.35 (br, 1 H); MS, m/z 366.0, [M÷Naf .
n~(S-isopropoxyqtihioH«-2-yl)titidecai»~l-0l (E3)
YD: 45 %. 1H NMR (40 MHz, CDC!3) 67.99 (d. ,/ - 8,4 Hz, IH), 7.34 (d, J - 4.4 Hz, 2H), 7.24- 7.27 (m, IH), 7,09 (i, J = 4.4 Hz, IH), 4.82 (sept J = 6 Hz, IH), 3.60 (i, J = 6.8 Hz, 2H), 3.00 {i, J = 7.6¾2H 1.81 (quin, J- 7.6 Hz 2B), 1.51-1.56 (ra 2ί ϊ 1.47 df,/=== 6 Hz, 61-1), 1.33-1.43 (br, 15H); MS. mfz 380.3, [M+Naf.
12- (8«iso fopovyquinolin-2-yl)dodeciUJ- l-ol (E4)
YD: 34 %. Ή NMR (400 MHz, CDC¼> 68.05 (d, ,/ === 7.6 ¾ IH), 7.30-739 (m, 3H>.7.13 <dd, J === 6.4, 2.4 Hz, IH), 4.85 (sepL J - 6 H , 1H), 3.63 ({,,7-6.8 Hz, 2H), 3,09 (br, 2H)? 1.84 (quin, J - 7.6 Hz, 2H\ 1.56 (quin. J = 7.2 Hz, 2H), i .48 (d, J = 6 Hz.6B), 1.27-.! .47 (br, 17H); MS. mfz 3943, M+Naf.
13- (8~isoproposyquiii Mn-2-y!)iri(leciin~l~ol (E5)
YD: 34%. ¾ NMR (400 MHz, </¥-MeOD) §8.11 id, J - 8,4 Hz, 1 H), 7.35-7. 1 (m, 3H), 7.14 (d, J - 7.2 Hz, IH), 4.81 (br, 1H), 3.52 { J- 6.8 Hz, 2H), 2.96 it. J- 8.0 Hz, 2H), 1.75 (quin, J === 7.2 Hz, 2H), 1.45-1.52 (m, 2H), 1.43 (d, J:::: 6.0 Hz, 6H), 1.25-1,42 (br, 19H); MS. m/z 408.0, [M+Naf.
14- (8-is«|irop«xyquiri liH-2-yl)ti'lradeciin-l-r>l (E6)
YD: 36%. lH NMR (400 MHz. i#- eOD) 58.13 id, J = 8. Hz, 1 H), 7.37-7.43 (l 3H), 7.1 (dd, J
- 7.2, 1.6 Hz, 1H), 4.86 (br.1H), 3.52 (t, ,/ - 6.8 Hz, 2M), 2.98 (tJ » 7.6 Hz, 2H), 1.78 (quin, 7.6 Hz.2H), 1.49-1.52 (in, 2H), 1.46 (d,J- 6.4 Hz, 6H), 1.26-1.41 (hi; 21 H); MS. m/z 422.3, [M*Naj \
15- {S-iso|)ropo\y uinoiiii-2-yr)pentadecan-l- l (E7)
YD: 36%, Ή NMR (400 MHz, CDC!j) 58.01 (dJ = 8.4¾ IH), 7.27-7.36 (m.3H), 7.10-7.13 m, 1H), 4.82 (sept,J=== 4.1 Hz, IH), 3.61 ø,</=== 6.8 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 1.81 (qum, J- 7.6 Hz, 2H), 1.52-1.55 (m, 2H), 1.48 (d,,/=== 2 Hz, 6H), 1.31-1.47 (br, 21H): MS. mfz 436.3, fM+ af . 11 -(8-iso r p«xy-5-i« thyIqiMnolni-2-yl)uu(icca»- 1-oi (ES)
YD: 48%, XB NMR (400 MHz, CDC¾) 68.09 (d, ,/=== 8.4 Hz, IH), 7.26 (d. ,/- 8.8 Hz, IH), 7.12(d, ./
- 8.0 Hz, 1 H), 6.97 (1 J « 7.6 Hz, 1 H), 4.75 (sept J === 6 Hz, IH), 3.55 (t ,/ - 6. Hz, 2H), 3.00 (t ./ = 7.6 Hz, 2H), 2.51 (s, 3H), 1.81 (i,,/- 7.2 Hz, 2H), 1.23-1.49 (br, 23H): MS. m/z 394.3, [Μ+ΝβΓ. ll-(5-fiuoro-8-isopropoxyquiHoli»-2-y!)un(lecati-l-oI (ΈΒ)
YD: 46%. ¾ NMR (400 Ml-iz, <#-M.eOD ) 68.30 (d, === 8.8 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7. 9 (d, j» 4.8 Hz, IH), 4.79 (m, 1 H), 3.5 (t ./ - 6.8 Hz, 2H), 2.97 (t, J~ 8.0 Hz, 2H), 1.74 (quin, J-7.6 Hz, 2H), 1.45-1.5] (m, 2H), 1.42 (d, J = 6.4 Hz, 6H), 1.12-1.39 (br, i5H); MS. m'z 398.2, [M-*-Na*. 9-(5-chIoro-S-i sopropoxyq uiitolin-2- l)noiian- 1-oi (E 10)
YD: 46%. !H NMR (400 MHz, -MeOD) 68.45 (d, 8.8 Hz, IH), 7.52 (d, J = 8.4 Hz. IH).7.49 (d, J - 8.4 Hz, IH), 7.12 (d, J- 8.4 Hz, IH), 4.85 (in. ill).3.51 it../ 6.4 Hz, 21! ).3.01 (t, ./ 8.0 Hz, 2H), 1,78 (quin, </= 7.6 Hz, 2H).1.49 (quin, J -6.4 Hz, 2H), 1.45 (d, J = 6.0 Hz, 6H). L30-1.42 (br, 11 H): MS. mfz 364.2, [M+ Hf■
1 l-(5- hh)ro-8-isoproposyqu!fH»liH-2~yl )undecan- f -ol (E l l) YD: 46%. Ή NMR (400 MHz, «'-/-MeOD) 68.47 (d, J- 8.4 H ; IH), 7.53 (d, J ::: 8.4 Ez, ill), 7.50 (d, J = 8.4 Hz, IH), 7. i 3 (d, J '= 8.4 H IH), 4.89 (m, IH), 3.52 (t, J= 6.4 Hz, 2H), 3.01 (I, J~ 7.2 Hz, 2H), 1.79 (quin, /» 7.6 Hz, 2H), 1 .48 (qum, J - 6.8 Hz, 2H), 1.41 id, J = 5.6 Hz. 6H), 1.21. - 1.39 (br, 15H); MS. m z 414.2, [M+Na .
15-(5-cMoi¾-8-i«opropoxyqumolin-2-yl)pe^ (E12)
YD: 46%. 5H NMR (400 MHz, d4~MeOD -fCDCI3) 58.46 (d,■/» 8.8 Hz, IH). 7.51 (d, J ' = 8.8 Hz, I H), 7.48 (d, J~ 8.8 Hz, IH), 7.11 (d .7 - 8.4 Hz, IH), 4.85 (m, IH), 3.52 t 6.8 Hz, 2H), 3.01 (t. ./ - 8.0 Hz, 2H): 1.79 (quin. ./::: 7.2 Hz, 2H), 1 .51 (quin, J- 6.8 Hz. 2H), 1.46 (d, </ === 6.0 Hz, 6H), 1.25- 1.39 (m, 23H); MS. ro/z 448.3, |M+H] \
1 l-(5-bromo*S>isopropoxy(|utnoiin-2-yt)imdecan-i-ol (E 13)
YD: 40%. 5H NMR (400 MHz, < -MeOD) 68.43 0± J - 8.8 Hz, HI), 7.69 (d, J - 8.8 Hz, I H), 7.52 (d, J 8.4 Hz, IH), 7.10 (d J - 7.6 Hz, IH), 4.86 (br, I H ) 3.52 ( i. 6.8 Hz, 21 ί > 3.02 (t J~ 7.6 Hz, 2H), 1 .79 (quia J - 7.2 Hz, 2H), 1.50-1 .52 (m, 2H), 1.46 (d, J = 6.0 Hz, 6H), 1.28-1 .41 (br, 15H): MS. m/z 458.2, [M+Naf .
11-(5 ,7-dk'h!oi'«-8-isopropoxyquinofin-2-yl)uiidet,an-:l-ol (EI 4)
YD: 37%. 5H NMR (400 MHz, CDC ) 58.36 (d, J = 8.4 Hz, IH), 7.56 (d, J = 3.2 Hz, IH), 7.35 (d, i = 8.4 Hz. IH). 5.13 (ra I H), 3.63 (t ,/= 6.8 Hz, 2H), 3.00 (t, ,/ = 7.6 Hz, 2H), 1.86 (quin, J™ 6.8 Hz, 2H)? 1.52-1.59 (m, 411), ί .27-1.44 (br, 20H); MS. m/z 448.4, jM-f-Naf .
Example 4- Preparation of (S-cyclopiOpylmethylenoxyqumoi-2~y!)iiikyl alcohol derivatives
Figure imgf000031_0001
Reagents and conditions: (a) Meth enecyclopropoyl bromide, KjCO?, DMF, 60 °C, 13 h.; (b) 1 ) LHMDS, THF, 0 °C, 1 h.; 2) Br(CH2)«-iOH, ft, 1.2 - 20 h.
Method: Methylenecyclopropyl bromide (1.0 g, 6.3 mniol) was added to a stirred solution of 2- meth lquina!dliie (i . g, 6.3 mniol) and 2C<¾ (2.5 g, 18.1 mmoi) in 25 ml DMF at 60 for .13 h. The reaction mixture was quenched by ¾0 (200 ml) and extracted with EtOAc (30 ml X 3). The organic layer was concentrated by evaporation in vacuum and the residue purified by flash column chromatography with Hex/EA (8: 1 to 6: 1) to give 5-chloro-8-(cycloprop *Imethoxy)-2- methylquinoline as intermediate, LHMDS (2.2 equiv.) was treated with a stirred solution of
intermediate (0.5 g, 2.3 mmol) in THF solution at 0 X for 1 h. Corresponding BriCHa iOH (1 .1 - 1.2 equiv.) was added to reaction mixture and recover to RT for further 12 to 20 h. The solvent was removed under a reduced pressure. The brown oily residue was purified by flash column
chromatography with Hex/EA or DCM/EA and recrysiallized by Hex/EA to afford compound F. 9- {S-{cyi,!opr pyimetii xy)q«kio!in~2~yl)Ho«-Mi~l~ol (Ft)
YD: 49%. 5H NMR (400 MHz, <**-MeOD) §8.15 (d, ./= 8.4 Hz, ΊΗ), 7.38-7.43 (m, 3H), 7.14 (dd, J » 5.6, 3.2 Hz, I H), 4.06 (d, J = 7.2 Hz, 2H), 3.51 ( J 6.8 Hz, 2H), 3.00 (f, J= 8,0 Hz, 2H), 1 .77 (qum. J™ 7.6 Hz, 2H),1.48- 1.52 (m, 3H), 1.32-1.47 (m, 1 IH), 0.65-0.70 (ni 2H), 0.34-0.45 (m, 2H); MS. m/z 342.2. j M Hlf.
10- (8-(cy€lopropylmetlioxy)qiiinolm-2-yl)decan-l-ol (F2)
YD: 43%, lH NMR (400 MHz. i#-MeOD) 88.16 fd. ./ - 8.4 Hz, 111 ), 7.40 - 7.43 (m, 3H)f 7.15 (dd.
5.6, 3.2 Hz. H). 4.07 (d, J = 7.2 Hz, 2H), 3.52 (t, J - 6.4 Hz. 2H), 3.01 (t J - 8.0 Hz, 2H). 1.80 (qum, J~ 7.6 Hz, 2H),1.47- I,5 (m, 3H), 1.31 -1 .44 (m, 13H), 0.67-0,69 (m, 2H), 0.44-0.46 (m, 2H); MS. m/z 356.2, [M+Hf .
11- (8-{cyclopropyfiBtHtioxy)< uhit>im-2-yi)undecaji-i-ol (F3)
YD: 45%. Ή NMR (400 MHz. CDC!. §8.02 (d, ../ - 8.4 Hz, I H), 7.30 - 7.38 (m, 2H), 7.05 (dd, 6.4, 2,4 Hz, 1 H), 4, 1 1 (d, ./= 6.8 Hz, IH), 3,63 (t, J = 6,4 Hz, 2H), 3.04 (t, ,/ = 8,0 Hz, 2H), 1.83 (quin, J » 7.6 Hz, 2H), 1.48-1 .59 (m„ 3H), 1.26-1.46 (br, 15H), 0.67 (dd, J - 13.2, 5.6 Hz, 2H), 0.44 (dd. J 13.2, 5.6 Hz, 2H); MS. mte 392.2, [M+Naf'.
1 2- (8-<cyclopropy{itutftoxy) uHiol»»-2-yl)do<lecan- I- l (F4)
YD: 36%, Ή NMR (400 MHz, CDCI3) 58.01 (d, ,/ - 8.4 Hz, IH), 7.29-7.38 (m. 3H), 7.06 (dd, J = 6.0. 2.4 Hz, IH), 4.1 1 (d, J :::: 6.8 Hz, IH), 3.63 (t, J- 6,4 Hz, 2H), 3.04 (t 7.2 Hz, 2H), 1 83 (quiii, J - 7.6 Hz, 2H), 1.48-1.59 (m, 3H), 1.27- 1.47 (br, 17.H), 0,67 (dd, J = 1 .2, 5.6 Hz, 2H), 0.42- 0.48 (m, 2H); MS, /z 384.3, [M+Hj \
13*($^(^elopmpyIim^ox ) ttinoiin»2<>yi)tHdeciin>]->oI (F5)
YD: 42%. 5H NMR (400 MHz, CU-MQOU) 58, 14 (d ./ - 8.4 Hz, IH), 7.38 - 7.41 (m, 3H), 7.05 (dd, J ~ 5.6, 3.2 Hz, IH), 4.05 id, ,/ - 6. S Hz, 2H), 3.52 it, J~ 6.4 Hz, 2H), 2.99 it, J - 8.0 Hz. 2H). 1.78 (quin, 7.6 Hz, 2H}J .44-i ,52 (n% 3H), 1.26-1.40 (m, 19H), 0.67 (dd, J= 13,2, 5.6 Hz, 2H), 0.40- 0.47 (m, 2H); MS, /z 420,0. [M+Naj*.
14- (8-(cyciopropy!iiiethoxy)quiii lin-2-y1)(etri»decan-:l-ol (F6)
YD: 37%. lH NMR (400 MHz, i#-MeOD) 58.1 (d, J = 8.8 Hz, IH), 7.39 - 7.42 (m, 3H), 7.13 (dd, J - 5.6, 3.2 Hz, IH), 4.05 (d, J = 6,8 Hz, 2H), 3.52 (†, J = 6.8 Hz. 2H), 2.99 (t, J - 7.6 Hz, 2H), 1.78 (quin, J■■■■■■ 7.6 Hz. 2H>,1.44- 1.52 Cm, 3H), .1.26-1 .43 (m, 21 H), 0.65-0.69 (m, 2H), 0.42 (dd. J - 10.0, 4.8 Hz, 2H); MS. m/ 434.3. (M+Naf.
15- (8 €ytlopiOpyl!ttetlioxy)qu ioIin-2-yi)i}e«tadecai»-l-ot (F?)
YD: 69%. ¾ NMR (400 MHz, t -MeOD+CDCh) 68.13 (dd, /=== 8.4, 2.0 Hz, I H), 7.38 (br, 3H), 7.1 1 (d, . - 2.4 Hz. IH). 4.05 (d, J = 6.8 Hz, 2H), 3.52 (t, . 6.8 Hz, 2H). 2.99 (t, J~ 8.0 Hz, 2H), 1 .78 (qmn, J
Figure imgf000033_0001
3H), 1.25-1.44 ( , 23H), 0.63-0.69 (m, 2H), 0.40-0.46 (m, 2H); MS. m 426.4, [M÷H] * .
1 l-(8-{cy lopropylniethox )-5-merhyiqMinoH»-2-yl}undecan- l-ol (F8)
YD: 45%. ¾ NMR (400 MHz. t/ -MeOD) 58.31 (d../"· 8.8 ϊ¾ 111), δ 7.44 (d, J :::: 8. 1¾ IH), 7.22 (d, J - 8.0 Hz, IH), 7.02 id. J - 8.0 Hz, IH), 4.02 (d. J - 7.2 Hz, 2H), 3.52 (t, J - 6.4 Hz, 2H), 3.00 (t, ,7 = 8.0 Hz. 2H), 2.57 (s, 3H>, 1.79 (quirt, J - 7.2 Hz, 2H), ! .29-1.52 (ni. 18H), 0.65 -0,68 (ox 2H), 0.40-0.43 (ra, 2H); MS. m 406.3, (M+Naj*.
ll~(8~(cydopropyimetho.xy)~5^^ (F9)
YD: 46%. !H NMR (400 MHz, </¥-MeOD) §8.36 (d, ./~ 8.8 Hz, Ί.Η), 7.52 (d, J - 8.8 Hz, IH), 7.07- 7.15 (m, 2H), 4.05 ( J - 6,8 f¾ 2H), 3.53 (t, J - 6.8 H . 2H), 3.02 (t, J - 7.6 Hz, 2H), 1.79 (quin, J === 7.6 Hz, 2H),L42-1.49 im, 3H), 1 .22-1.40 (m, I5H) 0.65-0.69 Cm, 2H), 0.42 (dd, 10.4, 4.8 Hz, 2H); MS. m z 410.2. (M+Naf .
9-(5-ch1oro-8-(cyctopropyi-ttethoxy)quittolm-2-yI)nonan-l-oI (Fltf)
YD: 33%. lE NMR (400 MHz, fiW-MeOD) 88.48 (d, J- 8.8 Hz, IH), 7.55 (d, J = 8.8 Hz IH), 7.49 (d. ,/- 8.4 Hz, IB), 7.1 1 (d, ./ - ,4 Hz, IH), 4.06 (d, J■■■ 6.8 Hz, 2H), 3.51 (i, 6.4 Hz, 2H), 3.03 (t J = 8.0 Hz, 2H>, 1.83 (t J= 7.6 Hz, 2H), 1.54- 1.69 (m, 3H), 1,27-1 ,48 (br, 1 H), 0.67-0, 71 (m, 2H), 0.43-0.46 (m, 2H); M.S. mfe 376,2, [M+H]\
1 l~(5-ehioro-8-(cydopropy Itiief hox )q uim>lm-2~yi)undecan~ l-ol ( I' l l )
YD: 34%. !H NMR (400 MHz. CDC!. §8.41 (d, ../ - 8.8 Hz, Hi), 7.43 (d, J ~ 2.4Hz IH), 7.41 (d, ,/ = 2.4 Hz, IH), 6.97 id, ,7 = 8.4 Hz, IH), 4.09 (d, ./ - 7.2 Hz, 2H), 3.63 (i .7 = 6,4 Hz, 2H), 3.05 (t J = 8.0 Hz, 2H), 1.83 ( 7,6 Hz, 2H), 1.54-1.69 (m, 3H), 1 .27-1.48 (br, 15H), 0.67-0.71 (m, 2H), 0.43 -0.46 (m. 2H) MS. m/z 426.2, [M+Naf.
15-(5-ihloiO-8-(cyclopropylme<ho\ )quiaoJin-2-y p nlade ;tn- 1 -of (F12)
YD: 28%. Ή NMR (400 MHz, <3f¥-MeOD+CDC ) 38.47 (d, .7 = 8.8 Hz, 1 H), 7.54 (d, J - 8.8 Hz, IH), 7.48 (d, J- 8.4 Hz. IH). 7, 10 i J - 8.4 Hz. IH), 4.06 ( ,7 - 6.8 Hz, 2H), 3.52 (L J - 6.8 Hz, 2H), 3.02 (1, J - 7 6 Hz, 2H), 1.79 (quin, ,/ - 7.6 Hz, 2H), 1 .46-1.52 (m, 2H). 1.25-1.44 (br, 24H), 0.65-0.69 (m, 2H), 0.41 -0.43 (m, 2H); MS. m/z 460.3, Μ+Νδ '.
l l-(5-bfO«io-8-(€ycIopropyl«iethoxy)qiiiiioiin-2-yl)uiideca«-l-ol (F13)
YD: 35%. !H NMR (400 MHz, -MeOD) 58.42 (d, J 8.8 Hz, IH), 5 7.67 ( J === 8.4 Hz, IH), 7.53 (d, J - 8.8 Hz, I H), 7.06 (d, J - 8.4 Hz. IH). 4.05 (d, J - 7.2 Hz, 2H), 3.51 < i. J - 6.4 Hz, 2H), 3.02 (L J - 8.0 Hz, 2H), 1.77 {quin, J- 7.6 Hz, 2H), 1.46-1.52 (m, 3H), 1.28-1.44 (m, 1 SH), 0.65-0.70 (m, 2H), 0.42-0.45 (m. 2H>; MS. m z 470.2, [M+Naf.
1 l-(5?7-djcidor ~8-(cyclopr pyhiM h \y){^HiH)li«-2-yI)i}^ (F I4) YD: 53%. H 'N (400 MHz, «'- -MeOD) 68.47 (d 8.8 Hz, IH), δ 7.67 (S> IH), 7.53 (dt < - 8.8 Hz, IH), 7.06 (4 J = 8.4 Hz, IH), 4.23 (ά, J = 7.2 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.02 0, J = 7.6 Hz, 2B), 1 ,86 <qum, /= 7.2 Bz, 2H), 1 .48-1 .53 (m, 2H), 1.29-1.38 m, 16H), 0.62 (dd, ./= 12,8, 5.2 Hz, 2H), 0.31 (dd, J :::: 1 .8, 5.2 Hz, 2H); MS, mfe 460.2, {M+Na}\
Example S - Preparation of (S^-dicfaloro-S'-b droxyqttin -yOiilk^ alcohol
C!
0H OH
Reagents and conditions: (a) NCS, CHCb. ri, 48 h.
Method: N-chlorosuccini raids (0.3 g, 2.25 mmoi) was added to a stirred solution of compounds B in CHCI3 (20 ml) for 48 h. The reaction mixture was poured into crushed ice and extracted with CH2CI2 (20ml X 2). The extract was purified by column, chromatography with Hex/EA (3: 1) and recrystai Sized to gi ve compound (0.1 g, 49%).
5,7-dichloro~2-( 11-byd roxytmdecy l)qniiiotm-8-el (Ci 1)
YD: 49%. lH NMR (400 MHz, CDCK) 68.38 (d, J - 8.8 Hz, IH). 7.5 (s. IH). 7.42 (d, J - 8.8 Hz, I H), 3.63 (t, J - 6.8 Hz, 2H), 3.00 (i, ./ 7.6 Hz, 2H), 1.82 (quin, J - 7.2 Hz, 2H), i 56 iqum, ./ 7.6 H 2H)? 1 .27-1,38 (or, 15H); MS. ro/z 382.0, [M-Hf .
Example 6 - Preparation of (5-chloro-8-metho¾yquiiiol-2-yi)alk>'l alcohol or alky!acetate
Figure imgf000034_0001
n~ 19 - 3 (t= 10 - 13 n= 10 - 13
H1a - H4a H1b - 84t>
Reagents and conditions: (a) HQ. iCI.?, glacial HOAe, 1 i;;0. 6 h, rt.
Method: To a various long chain substituted (8-metftoxyquinoiin-2-yl)-ol (1.0 eq.) was added cone. HC1 (0.5 mL/rontof) at RT and the reddish yello mixture was stirred for 5 minutes. To this mixture was added dropwise a solution of ids (1.5 eq.) in cone. HO (2 mL). The yellow gummy mixture was stirred at RT for 6 h. Wate was added lo it and partitioned with EA. Organic layer was washed with brine, drving on anhvdrous MgSiXj and filtered .followed bv solvent removal, vielded oily residue purified by flash column chromatography using CHCb to yield HI to HS.
10-(5-Chloro-8-methoxyquiiiolin-2-yl)decaii-l-ol (H la) and acetic acid
i0-(5~chloro~S~inethoxyquiiiolin-2-yi)decyl ester (HI b).
YD: 61% and 10%. Hla: JH NMR (200 MHz, CDClj) 68. 1 (dj = 8.68 Hz, IH), 7.42 (dd, j = 8 Hz
, j - 2 Hz , 2H), 6.91 (d, S - 8 Hz , IH), 4.03 (S, 3M), 3.59 (t J = 6 Hz , 2H), 3.59 (t, j = 4 Hz , 2H),
1,73 (m, 2H>. 1.48 (m, 2H), 1.25 (or, 12H); HRMS (EI): Caicd for C3»i½aNO2:349.J 03.
Found:349.1781. Hlb: Ή NMR (400 MHz, CDC¾) 38.41 (d, J = 8 Hz, IH), 7.42 (dd, j ~ 8 Hz , j - 41-fe , m 6.92 (d, J - 8 Hz , I H), 4.06 (t J - 8 Hz , 2H), 4.02 (s, 3H 3.03 it J - 8 Hz, 2H), 2,02 (ss 3H), 1.79 (m, 2H), 1.59 (i 2H), 1.40 (m, 2H), 1.23 (br, I 2H); H MS (FAB. M + H): Calc for CjjHjfCI Os 392.1992. Found 392, 1983.
l l~(5-Oiloro^~metivoxy tdtiolki-2-yi)iindecaii-i~ol (H2a) and acetic acid 1.l-(5-cbJoro-8~ inethoxy q tiinoHn-2-yI)iindecyt ester (H2 b)
YD: 60% and 12%. H2a; !H NMR (400 MHz, CDCU) 58.43 (d, J = 8.72 Hz, IH), 7.4 (dd, J = 13.5 Hz , J - 5,3 Hz , 2M), 6.94 (d, I - 8.3 Hz , ! ! f), 4,05 (s, 3H). 3.62 (i, 1 = 6.6 11 .2H}, 3.0? (i J = 5.2 Hz 2H)5 1 .80 (ni 2H). 1.54 (ra. 2H), 1.39 (m, 2B), 1 .26 (br. 12H); HRMS (EI): Calcd for
C21.H30CINO2 363.1960. Found 363.1 41. H2b: Ή NMR (400 MHz, CDClj) 58.41 (d, J = 8.6 Hz, IH), 7.42 (dd, J = 8.3 Hz, J - 3.8 Hz, 2H), 6.91 (d, S === 8.4 Hz. I H ), 4.06 (ΐ, j - 7.8 Hz, 211), 4.02 (s, 3Ϊ-Ι), 3.02 (i, J === 7.8 Hz, 2H), 2.01 (s, 3H), 1 .78 (m, 2H), 1.58 (ra, 2H>. 1.39 Cm, 2H), 1.22 (br, 12H); HRMS (El): Calcd for C23H.32CINO3 405.2065, Found 405,2044,
12- (S-ChIoro^-methoxyq«iiio ii-2-yl)dodecaii- ! -oi (H3a) and acetic acid 12-(5-ch_oro-8- metlioxytj«ino!tn-2-yl)dodecyl ester (H3b)
YD: 57% and 27%. H3a: ¾H NMR (400 MHz, CDCh) 38.46 (d, J === 8.6 Hz, IH), 7.44 (dd, J - 8.3 Hz, j = 6.9 Hz, 2H), 6.94(d, I = 8.4 Hz, IH). 4.04 (s, 3H), 3.59 (t j = 6.6 Hz, 2H), 3.1 1 R J = 7.8 Hz, 2H), 1.78 (m, 2H), 5 .50 (m, 2H). 1.40 (m, 2H), 1 ,23 (br, I4H); HRMS (El): Caicd for
C22H32CINO2 377.21 ! 6, Found 377.2106. H3b: Ή NMR (200 MHz, CDC¾) 58.38 (d, J === 8.7 Hz, I H), 7.40 (d, J - 8.6 Hz, 2H), 6.88 (d, J - 8.4 Hz, IH), 4.03 (t, J - 7.8 Hz, 2H), 4.01 is, 3H), 3.02 (t, J = 7.8 Hz, 2H), 1 ,99 (s, 3H), 1 ,76 (m, 2H), 1.59 (m, 2H), 1.20 (br, 16H); HRMS (FAB, M+H): Calcd for CJ ½CINO? 420,2305, Found 420.2310.
1 - (5-<rhloro-8-meth<>xyquinolin-2-y|Hridecitii-l -of (H4a) and acetic acid 13-(5~cbioro-S- methosyqumolin-2-yl)tridecyt ester (H4b)
YD: 64% and 14%. H4a: Ή NMR (400 MHz, CDCU) 58.46 (d, J - 8.6 Hz, IH), 7.45 (dd J = 8.3 Hz, J - 6,9 Hz, 2H), 6,94(d. I === 8.4 Hz. IH), 4.04 is. 3Hh 3.59 (t .1 - 6.6 IU, 2H), 3.1.1 (t .1 - 7.8 Hz, 2H), 1 .78 (m, 2H). 1 50(m, 2H), 1.40 (m. 211), 1.23 (br, 16H): HRMS (El): Calcd .for
C¾H.VJC!N02 391.2273, Found 391 .2249. H4b: lE NMR (400 MHz, CD<¾) § 8.38 ( , j = 8.6 Hz, I H), 7.40 (dd, J » 8.5 Hz, I » 5.8 Hz, 2H), 6.89(d, J = 8.4 Hz, IH), 4.01 (t, j - 9.6 Hz, 2H), 4.00 (s, 3H), 3.00 (t, J ==== 7.9 Hz. 2H), 1.99 (s, 3H), 1.75 (m, 2H), 1.58 (m, 2i¾ 1 .38 (n\ 2H), 1.22 (br, 1 H); HRMS (FAB, M + H): Calcd for C25H37CINO3 434.2462, Found 434.2459.
Example 7 - Preparation of 8-hydroxyquino -yi) or (S-alkovyquino -yl) aikyl alcohols SWT 1
Figure imgf000036_0001
11 = 11-12 n = 11-12 K1 - K2
J1 - J2
Reagents and conditions: (a) methyl vinyl ketone, HCL reflux, (b) Mel. sCCh, acetone, rt 8h; Elf or 2~bromopropane or methylenecyclopropyl bromide, K2CO3, DMF, 60 6C, (c) I) LH.MDS, THF, 0 °C, 1 h.: 2) Br(CH2)»..i H, rt. (d) BnBr. KOM, EtOH, reflux, (e) H¾ Pd/C, MeOH, rt 24 h.
Method: T¾e intermediate INT was synthesized through ring closure from 2-arninophenol reacted with methyl vin l ketone. INT I was reacled with various aJkyl halides to afford 8-alkoxy- 4methylquino.)me derivatives as intermediates. Corresponding Brt'CHs iOH was reacted with intermediates to synthesize series of compounds 3 and I. The protective group J was removed by hydrogenaiiori (method iliustraied in example I) to obtain compound K.
1 1 -(S-nietlioxyquinoIin-4-yl)imde€aii-i-oI (ϊ I)
YD: 34%. lH NMR (400 MHz, CDt¾) 88.80 (ckt J - 4.4, 0.6 Hz. IH), 7.59 (dd, J ~ 8.4, 0.8 Hz, I H), 7.44-7.49 (m, 1H 7.03 (d. J - 7.6 Hz, Hh 4.08 (3, 3H); 3.63 ( J ::: 6.8 Hz, 2H), 3.03 (t J - 7.6 Hz, 2H), 1.74 (quia - 7.6 Hz, 2H), S .55 (quin, J - 7.2 Hz, 2H), 1.23-1.45 (br, 1SH); MS. m/z 329.9, JM+Hf .
1 l~(8-ethoxyqutiiolin-4~yl)undecai»~l-ol (12)
YD: 42%. H NMR (400 MHz, d4-M&OD) 08.66 (d. J - 8.4 Hz, IH), 7.64 (d, J - 8.4 Hz, 1H)_ 7. 1 (t J - 8,0 Hz, iH), 7.37 (d, , - 8.4 ffe 1H), 7..15 (d, J = 7.6 Hz, iH), 4.27 iq, = 6,8 Hz, 2H), 3.5.2 (t ,/ - 6.8 Hz, 2H), 3.08 (d, 7.6 Hz, 2M), 1.75 Ujum. J - 7.6 Hz, 2H), 1.50-1.57 (m, 5H), 1.21-1.49 (br. 15H); MS. m/z 366.2. j M-t-Na] *.
il-(8~isoproposyquiiiolin-4-yl}undei'an-l-oi (13)
YD: 48%. SH N.MR (400 MHz, a'-Z-MeO'D) 5 8.65 (d, ./ = 8.4 Hz, IH), 7.63 (d, J = 7.6 Hz, IH), 7.51 (d, ■■■■■■ 8.0 Hz, IH). 7.35 (d. J ::: 4.4 Hz, I H), 7.17 (d, J = 8.0 Hz, IH), 4.84 (hr, IH). 3.52 (t, J - 6.4 Hz, 2H), 3.07 (d, J = 7.6 Hz. 2H), 1.74 (br, 2M), 1.43-1.50 (br, 9H), 1.29-1.34 (br, 14H); MS. m z
Figure imgf000036_0002
1 ί -(8-(cy€lopropyimethoxy)qiiinolin-4-yl)undecan- l-ol (14)
YD: 53%. Ή NMR (400 MHz, f«»Me()D) 08.66 (d, J« 8,4 Hz, LH), 7.63 (d, ,/:::: 8.4 Hz, IH), 7.49 (t, J - 8.4 Hz, 1 H), 7.36 (d, ~ 4.S Hz, IH), 7..13 (d, ./ - 7.6 Hz, IH), 4.03 (d, J - 6.8 Hz, I H), 3,52 (t - 6.8 H¾ 2H). 3.06 (d, J ==== 7.6 Hz, 2H), 1.69-1.75 (m, 2H), 1, 28-1.52 (brt 18H), 0.65-0.68 (m5 2H), 0.42-0.43 (m, 2H); MS. nVz 392.2 |M+Naf ,
11 -(8-{ }>e»zyioxy)quinoli»-4-yl)u»(fecaii- 1 -οϊ (J l
YD: 46%. *H NMR (400 MHz, dtf- eOD) δ 8.66 (d, J - 8.4 Hz, IH), 7.64 (d, J - 8.4 Hz. IH), 7.52 (d, J - 7.2 Hz, 2H), 7.45 (t, J - 8.0 Hz, IH), 730-7,38 (m, 3H), 7.26-7.28 (m, IH), 7.17 (d, J = 7.6 Hz, IH), 5.37 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.06 (t J = 8 Hz, 2H), 1.73 (q, J = 7.6 Hz. 2H), 1.50 (t, ,7 - 7.2 Hz, 2H). 1.28-1.48 (m, I5H); MS. m/z 428.3, (M+Na)\
i2-(8~{beii¾ytoxy)q«inol!n~4~yl)dodei'aii-J-ol (,12)
YD: 46%. lH NMR (400 MHz, «'-/-MeOD) § 8.67 ( J = 4.4 Hz, IH), 7.65 (d, J ~ 8.4 Hz, I H), 7.52 (d, · 7.2 Hz, 2B), 7.45 (t J 8.0 Hz. IH), 7.30-7.39 (m, 311). 7.27-7.30 fm, IH), 7. 18 id, J ~ 8.0 Hz, 1 H)? 5.38 (s, 2H), 3.52 (1 J - 6,4 Hz, 2H), 3.08 (t J- 7,6 Hz, 2H); 1.74 (q, J = 7.6 Hz, 2H), 1.49 (l, J - 7.2 Hz, 2HX 1.23-1 ,45 <ro, .! 7H); MS. m/z 442,3, [M+Naf.
4-(ll-hydroxyundecyi)quinoiiti-8- l (Kl)
YD: 84%. {H NMR (400 MHz, d4-MeOD) S 8.63 (d, J ~ 4.4 Hz, 1 M), 7.51 (d, J = 8.4 Hz, I H), 7.40 (t, === 8.0 Hz, IH), 7.28 (d, I === 4.0 Hz, I H), 7.06 (d, J === 7.6 Hz, I H), 3.51 (t, J === 6.8 Hz, 2H), 3.02 (t, .7 = 8.0 Hz, 2H), 1.71 0, ./ = 7,6 Hz, 2H), 1 .50 (quin, J— 6.8 Hz, 2H), 1 , 12-1, 1 (br, 5H); MS. m/z 316.2, f +H f .
4~(i2-hydroxydodecyl)qu.ttoHn~8-oi (Kl)
YD: 86%. }H NMR (400 MHz, CDC Is) §8.52 (d J™ 4.4 Hz, IH), 7.36 (dd, J™ 8.4, 0.8 Hz, IH), 7.31 (d, J = 7,6 Hz, IH), 7, 1 (d, j = 4.4 Hz, I H). 6,99 (dd, J = 7,6, 1 .2 Hz, IH), 3.43 (t J = 6.8 Hz, 2H), 2.89 (1 7.6 Hz, 21 1 ). 1.61 (quin, ,7 = 7.6 Hz, 2H), 1.40 (quin, J - 6.8 Hz, 2Π). 1. 12-1.31 (br, 17H); MS. m/z 352,2, | -;-Naf .
Example 8 Preparation of (g-trifluoromethoxyquinol-2-yl)aikyl alcohols.
Figure imgf000037_0001
Method: TSie intermediate was synthesized through ring closure from 2 rifluoromethoxy aniline reacied with crotoiialdehyde. Intermediate was reacted with corresponding Br(Ci¾)tl.,iOH (as illustrated above) to synthesize series compounds L.
9-(S-(tiilluoromethoxy)qtiHio ii-2-y!)nona-l-o! (LI)
YD: 41%, :lH NMR (400 MHz, CEX¾) §8.06 (dd, J = 8.4, 1.2 Hz, IH), 7.70 (d, J = 8.4 Hz, IH), 7.56 ( ,/■■■■■■ 7.6 Hz, ! H), 7.43 (d. J— 8.0 Hz, I H), 7.34 (dd, 8.4, i .2 Hz, IH), 3.61 (t, 6.4 Hz, 2H), 3.01 (I, J— 6.4 Hz, 2H), . .81 -1.85 (br, 2H), 1 53-1.56 (br. 2H), 1.21-1.35 (m, 15H); MS. m/z 355,9, [M+Hf ,
1 1-<8-(triflu roHielhoxv)quinoHii-2-yi)unde aH- t-ol (L2) YD: 41%. Ή NMR (400 MHz, CU-MQOU) 68.26 (1 J - 8.0 Hz, ! H)f 7.86 (d, ./ - 7.6 Hz, IH), 7.64 ( = 7.2 Hz, IH), 7.47-7.5 ( ID. 2H). 3.51 (t, ,/ = 6.8 Hz, 2f t ) 2.99 (t J = 6,4 Hz, 2Π). 1.79 (qyin, J » 6.8 Hz, 2H 1.50 (quin, J™ 6.8 Hz, 2H), 1.21 -1.35 (m, 15H); MS. m/z 406.2, M+Naf .
14- (8^tdflttot^}etkoxy)qatHolitt-2-yi)t ^r^ecan>.l*oi (L3)
YD: 37%. 5H NMR (400 MHz. ^4-M.eOD) o 8.27 (d, 8.4 H*, IH). 7,87 (d, J ~ 8.0 Hz, IH), 7.65 (t, ,7 - 7.2 Hz, IH), 7.49-7.56 (m, 2H), 3.52 (t. J— 6.8 Hz, 2H), 3.01 (i, J = 7.6 Hz, 2H), 1.82 (quio, J - 7.2 Hz, 211 ). 1.51 <quin, J 6.8 Hz, 211 ). ί 27· I 37 (ra, 21H); MS. m/ 448,2, {M+Na]+.
15- (8~iiriflti r«inelhoxy)q«HH»Hn-2~ l}pentatlecan- l~ l (1.4)
YD: 32%. !H NMR (400 MHz.
Figure imgf000038_0001
8.4 Hz. IH), 7, 81 (d, J - 8.0 Hz, IH), 7.61 (d, J™ 7,6 Hz, IH), 7.51 (d, J - 8.0 Hz. IH), 7.46 (t J - 8.4 Hz. IH), 3.52 (t J - 6.8 Hz, 2H)f 2.99 (t, J === 7.6 Hz, 2H), 1,80 (quin, J - 7.6 Hz. 2H), 1.50 (quin, J === 7.2 I¾ 2H), L I 5- 1.41 (br, 23H); MS. m/z 462.2. fM+Naf .
Example 9 - Preparation of 2- -stifostit«tedalcohol-S-hydiroxyqiiiiioiiiie
Figure imgf000038_0002
Reagents and conditions: (a) SeO¾ dioxane, 50 to 80 °C; (b) N-methy!propagylaraine or 2- (pipera .in-1 -yl) ethano! or NHaiCHa )n-i OH, NaBH(OAc);;, l,2~dkhloroeihane, rt.
Method: A solution of 8-hydroxy-2«raethy!quinolme (6.0 g, 37, 7 mrnoJ) in dioxane (15 ml) was added to a stirred solution of SeOs (6.3 g, 56.8 mmol) in dioxane (80 ml) drop ise at 50 °C and tiie mixture was heated up to 80 "C for further 20 h. The resulting mixture was filtered. The filtrate was concentrated and the residue purified by column chromatography with Hex/BA - (15: 1 to 10: 1 ) to give 8-hydroxyquinoline-2-carboxaldehyde (2.45g, 38 %) derivatives as intermediates. Intermediate was converted into N-substituted compounds by reductive aminat on with aminoaicohoL aminoalkyne or other lieterocycles to give series of compounds. 8~alkoxy~2-methyl quinoline were oxidized to give 8-alkoxyquinoline-2- carboxaldehyde derivatives and followed by tire same method to gi e compounds M to O.
2-((4-(2-liydroxyetliyl)piperazin-l-yi)inethyl)quiiio!in-8-ol (Ml) YD: 76%. H'N (400 MHz, CDC¾) 58.02 (d,J::: 8.4 HA IH), 7.43 (d ./-8.4 Hz, 1H 7.34 (1/ = 8,0 Hz, IH), 7.22 (dJ= 7. Hz, IH).7.10 (d, J= 6.8 Hz, IH), 3.73 (s, 2H), 3.61 (t,J=6.8Hz, 2H), 2.51 (I■/ ~ 5.6 Hz, 10H); HUMS (ESI): Calcd for jM-HMaf: 310.1526, Found: 310.1527.
2~(4~((5-chl0re-8-methoxyquino^^ (M2)
YD: 76%.5H NMR (400 MHz. CDCU) §8.23 (d, 8.8 Hz, IB), 7,59 (d, J - 8.8 Hz, IH), 7.21 (d, «/ - 8.4 Hz, IH), 6.68 (d,J= 8.8 Hz, IH), 3.81 (s, 3H), 3.72 (s, 2H), 3.44 (t, J ~ 4.8 Hz, 2H), 2.35-2.38 (m, 10H); MS. m-/ 336,1, i.VMfj
2-(4-{{5~diiore~8~eihoxyquiiiolin^ (M3)
YD: 53%. Ή NMR (400 MHz, CDCI3) 58.36 (d, J™ 8.8 Hz, IH), 7.68 (d, J~ 8.4 Hzf B), 7.34 (d, J - 8.4 Hz, IH), 6.83 (d. J = 8,4 Hz, IH), 4. 8 (q, J - 6.8 Hz, 3H), 3.84 (s, 2H), 3.54 (t = 5,2 Hz, 2H), 2.45-2,50 (br, KM), 1.49 (t, J = 6.8 Hz, 3H); MS, mz 350.1, |M÷H .
2-(4-((5-chler0-S-iso|M*ojK},^ (M4)
YD: 61%. !H NMR (40 MHz, tW-MeOD) 88.52 (d, J- 8.8 Hz I I).7.8! (d, J~ 8.8 Hz, IH), 7.53 (d, = 8.4 Hz, IH), 7.14 (d, ,7-8.4 Hz, IH), 4.87 (m, IH), 3.89 (s, 2.H), 3.67 (i, J 6.0 Hz, 2H), 2.54-2,62 (br.10H), 1.450,./ 6.0 Hz, 6H); MS. m/z 364.1, |MH|
2~(4~((5-chioro-S-(cy opropyt e^ (MS)
YD: 76%.5H NMR (400 MHz. tW-MeOD) S8.40 (d, ./ - 8,4 Hz, IH), 7.71 (d, J - 8.8 Hz, 1 H), 7.42 (d, J = 8.4 Hz, IH), 6.99 id, J = 8.4 Hz, IH), 3.97 (d, J » 6.8 Hz, 2H), 3.84 (s, 2H), 3.65 (t J = 6.0 Hz, 2H), 3.44 <t,J- 4.8 Hz.2H).2.56 ibf, 8H), 2.51 (1J- 4,8 Hz, 2H), 1.37-1.43 (ra, IH), 0.62- 0.66 (m, 2H), 0. 7-0, 40 (m, 2H); MS . m/z 376.2, [M+Bf .
2-(4-CC5,?-dichIoiO-8-meth0xy (M6)
YD: 39%. M NMR (400 MHz, <*¥-MeOD) 08.53 (d, J - 8.8 Hz, IH), 7.80 id, ./ = 8.8 Hz, IH), 7.70 (s, IH).4.11 (s, 3H).3.89 is, 2H), 3.67 (t, J - 6.0 Hz, 2B), 2.63 (br, 8H), 2.55 (t,J = 6.0 Hz, 2H), 1.93 (s, IH): MS. m/z 370.1. [M+Hf
2-(4-((5,7-dichloro^-(€ycl0propyimethoxy (M7) YD: 82%, }H NMR (400 MHz. CDCk) 58.43 (d, J= 8.8 Hz. IH), 7.71 (d,,/-8.8Hz, IB), 7.58 (s, IH), 4.22 (d, J - 7.2 Hz, 2H), 3.88 ($, 2H) 3.61 (i, 6.4 Hz, 2H), 2.56 (i,J~ 5.2 Hz, 10H), 141- 1.44 (.m, IH), 0.57-0.62 (m, 2H), 0.33-0.37 (rti, 2H); MS. m/z 410.1 [M+Naf.
i^tmethyK roii^ ny tmno^etli qamoHtt^ol (Nl)
YD: 49%. Ή NMR (400 MHz, CDC!3) 58.08 (d, .7 - 8.4 Hz; IB), 7.55 (d, J- 8.4 Hz, IH), 7.40 (t, J -8.0 Hz, IH), 7.28 (A ,/ = 8.0 Hz, IH), 7.15 (d, J - 7.6 Hz, IH), 3.90 (s, 2H), 3.41 (d, J =2.0 Hz, 2H), 2.39 (s, 3H), 2.3.1 (d, J = 2.0 Hz, IH); MS. m/z 249.1 [M+H]\
S-cldoro-2-((meibyI(prop-2-ynyi)aRiino)methyt)quiRoiitt>$>ot ( 2) YD: 38%. H'NMR (400 MHz, CDC¾) 58.47 (d, ~- 8.4 HA IH), 7.71 (d,J- 8.8 Hz, IH), 7.4? (d,J = 8.0 Hz, IH), 7.08 (dJ = 8.4H IH), 3,93 (st 2H), 3,42 (d, J= 2.0 Hz, 2H), 2.40 (s, 3H), 2.31 (i, J = 2.0 Hz. IH : MS. m/z 261.0, [M- Hf .
~((5~chIo 0~8Hmcfhex umoiin-^^
YD: 52%.5H NMR (400 MHz. CDCU) §8.4 (d, 8.8 Hz, IH), 7, 80 (d, J - 8.8 Hz, IH), 7.46 (d, «/
- 8.4 Hz, IH), 6.93 (d. J = 8,4 Hz, IH), 4.05 (s, 3H), 4.00 (s, 2H), 3.42 (d, J = 2.0 Hz, 2H), 2.37 (s, 3H), 2.27 (l. 2.0 Hz, IH), MS. m/z 297.0, |Μ+Να]÷.
N-((5-chioro-8^ttto^^ (N4)
YD: 64%. !H NMR (400 MHz, CDCI3) 38.48 id, ,/ - 8.8 Hz, IH), 7.79 (d, J - 8, 8 Hz, I H), 7.46 (d, J - 8.8 Hz. IH).6.96 (d,J=- 8.4 Hz, iH), 4,32 (t,J- 6.8 Hz, 2H), 4,01 (s, 2H), 3.45 (d, J -2.0 Hz, 2Η),2.4ί (s 3B),2.28 (1, J- 2.0 Hz, IH), 1.59 (i, J- 6,8 Hz, 3H); MS, m/z 289, 1, [M+H]'.
-ftS-chtoro-S-tsopropoxyquinotm^^ ( S)
YD: 76%. lH NMR (400 MHz. CDC¾) §8.47 (d, ./= 8.8 Hz, H), 7.73 (d, J = 8.8 Hz, IH), 7,46 (d, J
- 8.0 Hz, IH), 7,03 (d, J - 8.4 Hz, IH), 4.80 (m, IH"), 3.9 (S, 2H),.3,44 (d, J - 2.4 Hz, 2H), 2.41 (s, 3H), 2.28 (t, ,/ === 2.4 Hz. IH), 1.48 (d, J === 6,4 Hz, 6H); MS, m/z 303.1 , | +H)\
-((5-chloro-8-(cyci pi*0|)ylmet oxy)q«iii liii-2-yI)m ( 6) YD: 58%, Ή NMR (400 MHz, CDCI3) 38.48 (d, ,/ - 8.4 Hz, IH), 7.77 (d, J = 8. Hz, I H), 7.45 (d, ■■■■■■ 8.4 Hz, IH), 6.98 (&./=== 8.4 Hz, IH), 4.09 (d, J- 7.2 Hz, 2H), 4.01 (s, 2H), 3.45 (d, ./-2.0 Hz, 2H), 2.41 (s, 3H), 2.28 (i, J - 2.0 Hz, H), 1.42 ~ 1.50 (m, IH), 0.65-0.70 (m, 2H), 0.42-0.45 (m, 2H); MS. m/z 337.1, |M÷Naj *.
N«{{5,?-dielil0ro»$«tnei exyc^ ( 7)
YD: 58%.1 H'NMR (400 MHz, CDCb) 58.47 (dsJ=== 8.8 Hz, IH), 7.74 (d ./- 8.8 Hz, IH), 7.60 (s, IH), 4.20 (s, 3H), 3.99 (s, 2H), 3.43 (d. J ~ 2.0 Hz, 2H), 2.41 (s, 3H), 2.29 (L ./ - 2.0 Hz, IH); MS.
Figure imgf000040_0001
N-((5,7-dicWoro-S-(cyckiproiylmeih0xy)<juinotiii-2-yt)rn
(NS)
YD: 76%.5H NMR (400 MHz, CDCI3) 58.45 (d, J = 8.8 Hz, IH), 7.71 (d, = 8,8 Hz, IH), 7,59 (s, IH), 4.25 (d, J - 7.6 Hz, 2H), 3.95 (s, 2H), 3.40 (d. 2,0 Hz, 2H).2.40 (S, 3H), 2,28 (t, 2.0 Hz, IH), 1.41-1,45 (m, IH). 0.57-0.62 (m, 2H), 0.36 (dd, J = 10,0, 4.8 Hz, 2H); MS. mz 371.0,
8-((5-chl0i'0-8-meth«xy<j»jn0tHi-2-yl)inerhyiamin<»)0cta (01.)
YD: 44%. ]H NMR (400 MHz, ί/ -MeOD) §8.55 (d, J - 8.8 Hz, H), 7.69 (d, J = 8.8 Hz, H i), 7.58 (d, J - S.4 Hz, ill) 7.16 (d, J = 8.4 Hz. IH), 4.07 (s.5H), 3.50 (t J - 6.8 Hz, 2H), 2.63 it, J - 7.2 H/, 2H):, 1 .56 (quin, J - 7.2 ¾ 2H) 1 .50 (quia J - 6.8 Hz, 2H), 1.29-1.32 (br, KM); MS. ro/z 3 1 .2, [M+H f.
S-({5-chloro-S-ethoxyqiiiiioyii-2-yl)inetiiylai«in )octaii-l-ol (02)
YD: 41 %. Ή NM (400 MHz, ί/ -MeOD) 58.31 (d, J - 8.8 Hz, IH), 7.66 (d, J™ 8.4 Hz, IH). 7.53 (d, J - 8.4 Hz, IH), 7.12 <d, J = 8.4 Hz, ?H), 4.29 (q, ,/ - 6.8 Hz, 2H), 4.07 (a, 2H) 3.51 (t J - 6.8 Hz, 2H), 2,64 (t, J = 7.2 Hz, 2H), 1.47-1.58 (m, 7H)S 1.31 (br, 9H); MS. m/z 365.2, jM-HH]\
8-((5-chloro-8-isopro|Joxyq uln olii!i-2-yl )methyIamino)ocfan" i-ol (03)
YD: 31%. SH NMR (400 MHz, CU-MQOU) 68.55 {d, J - 8.8 Hz, IH), 7.66 <d, J- 8.8 Hz, IH), 7.56 (d J - 8.4 Hz, IH). 7.1 (d, J - 8.4 H¾, IH). 4.89 (m, IH), 4.15 (s, 2H), 3.52 (t, J 6.4 Hz, 2H), 2.71 (t, J - 7.2 Hz, 2H), 1.59 (quia, J ~ 6.8 Hz, 2H) 1.46-1.50 (m, 8H), 1.33 (br, 9H); MS. m/z 379.2,
8-((5-chIoro-8<eyclopr0pylineih0x^^ (04)
YD: 29%. - H NMR (400 MHz, fiW-MeOD) 88.54 (d, J- 8,4 Hz, IH), 7.67 (d, J = 8.8 Hz, IH), 7.54 (d, ../ - 8.4 Hz, IB), 7.15 (d. ./ ~ 8,4 Hz, IH), 4.09 (s + d. ··· 6.8 Hz, 4H), 3.51 (t J === 6.8 Hz, 2H), 2.67 (i, "= 7.2 Hz, 2H), 1.59 (quin, J = 7,2 Hz. 2H), 1 .43-1, 1 (m, 3H), 1 .29-1.42 (br, H), 0.66- 0.89 (.m, 2H), 0.44 (dd, J = 10.4, 4.8 Hz, 2H); MS. m/z 391.2. [M+Hf.
5- CCS^-didiioTO-S-nieihox uhio^ (OS)
YD: 37%. !H NMR (400 MHz. tW-MeOD) S8.54 (d, ./ - 8.8 Hz, IH), 7.71 (s, IH), 7.65 (d, J - 8.8 Hz, IH), 4. 14 (s, 3H). 4.12 (s, 2H). 3.52 (t ,7 = 6.8 Hz, 2H), 2.70 (t J = 7.2 Hz, 2H), 1.60 (quin, J— 6.8 Hz, 2H), 1.50 (m. 2H), 1.33 (br, 9H): MS. m z 385.1, {M+Hf.
$- 5^-dkhi0r0-S-(c> ¼pTOp (06)
YD: 56%. 5H NMR (40 MHz, tW-MeOD) 58,51 (d, J ~ 8.4 H IH). 7.69 <s. I H). 7.61 (d, J ~ 8.8 Hz, I H), 4,22 (d J - 7.2 Hz, 2H), 4.10 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.68 = 7.2 Hz, 2H), 1.59 (quin, ./"■■■ 7.2 Hz, 2H), 1 .51 (quin, J === 6.8 Hz, 2H), 1.28-1 .42 (br, 1 IH), 0.55-0.60 (ro, 2H), 0.30-0.33 (m, 2H); MS. m/z 425.2, [M-Hif .
6- (bis((8-niethoxyqiiitioHii-2-yl )me†hyl)a-tt-no)hexan- 1 -ol (P t )
*H NMR {400 MHz, < -MeOD) §8.18 (d, J= 8.4 Hz, 2H), 7.80 (d, 8.4 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz. 2H), 7.13 id, J = 7.2 Hz, 2H), 4.02 (s, 6H), 3.99 (s, 4H), 3.40 (t J = 6.8 Hz, 2H), 2.59 (t, J:~ 6.8 Hz, 2H). 1 .56 (qum, - 6.8 Hz, 2H), 1 .41 (quin, 6.8 Hz, 2H), .27 {quin, J- 7.6 Hz, 2H), 1 , 1 (quin, J == 6.8 Hz, 2H): MS, m/z 482.3, fM+Na|'!.
FIG. lA shows C12 inhibited Α aggregation in the presence or absence of zinc ions using a microscopy analysis after Congo red staining. FIG. IB and F1G.2 show that C1.2 dissolved preformed Αβ aggregates. HQs. 3A-B show that compounds C I 2, CQ and€12 intermediate protected neuron cells from zinc-induced ί'Αβ. Only compound C 12 was effective toward zinc-tree aggregates (FIG, 3B). FIG. 4 shows induction of neurite outgrowth triggered by compound C 12 on undifferentiated PCI 2 cells. FIG, 5 shows quinoline derivatives increased expression of GAF43. FIG, 6 shows compound C 12 and B3 improved performance of learning in ιΆβ-induced memor -deficit mice. C 12 and B3 (10 mg kg) increased riding time of fAp-lesioned mice in a rota rod test. FiGs, 7A-D show compound C I 2 improved learning of memory -deficit fAp-lesioned mice in the Morris water maze test. Mice were assessed for the total duration of movement (FIG, 7 A) and total duration of distance (FIG, 7B) to climb onto the hidden platform; and also quantified the appearence to target zone f FIG. 7C) indicating the relative time (compared to total time in swimming) to entry into a zone around the hidden platform; and for average swimming velocity (FIG. 7D) to discriminate enhanced memory from enhanced motor activity. FIG. 8 shows an increase in GAP43 level and decrease in fAp level in memory-deficit fAp-lesioned mice by compound CI 2.
The foregoing description of the exemplar}' embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Marry modifications and variations are possible in light of the abov e teach ing.
The embodiments and examples were chosen and described in order to explain the principles of the invention and their practical application so as to enable others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the present invention pertains without departing from its spirit and scope. Accordingly, the scope of the present invention is defined by the appended claims rattier than the foregoing description and the exemplary embodiments described therein.
Some references, which may include patents, patent applications and various publications, are cited and discussed in the description of this invention. The citation and/or discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any such, reference is "prior art'* to the invention described, herein. Ail references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was indi vidually incorporated by reference.

Claims

CLAIMS What is claimed is;
1 . A compound of Formula (!) or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof:
Figure imgf000043_0001
Formula (Ϊ)
wherein
R is hydrogen, (CrCs)a5kyi, (CrCsialk lene Cs-Csic clo lkyl 'C Csl io lkyl, or (C r C s)a! ky leneit C ;
R2 is hydrogen or halogen,
R~! is hydrogen, halogen, (CrCg kyi, or (CrCs)a1koxy;
R* is hydrogen, halogen, (CVCs)alkyl. (C rCgJaikoxy, or (tVCs)haloalkyS;
R5 is hydrogen or (CrC2o)alkanoi;
R6 is hydrogen; and
R7 is hydrogen, (CrC¾>)alkatioi5 (Ci-Cs)alkylene (C3-C8)heterocyclyl(CrC2o)alkanol., (Cj- Cs)a!kylene (CyCsJheieroc cl KCrCa^alk h (Ci^s^lWeneCCi-C^ lk lairanoiCi^^k njl, (Cr Cs)aik leneamino(C rC¾>)al kanol, or (C■ i- Cs)aikyleneamifio(C i.-C 2o)aikanol(C j-C»)alkylene su bs ti tuiedCC C2o)heieroary I .
2. The compound of claim 1 , wherein
R5 is hydrogen, CH¾ CH2CH3, CH{C¾)2, CH2CH(C¾)2! CF or benzyl;
R2 is hydrogen, F, or Ci;
R" is hydrogen, F, CI, CH3, or OCH3;
R4 is hydrogen, F, CL Br, CH¾ OCH3, or CF3;
Rs is hydrogen, (CH^uOH, or {CHjJnOH;
Rc> is hydrogen: and R7 is hydrogen, (Cil^OfL (Cf¾)f i>OiI (C¾)uOR (Cl¾)uOH, (Cl¾)BOH; (CH2)i.fOR (CH2)}5OH, CH2(NiCH2CH2¾N ¾CH20H5 CH2{ (C¾CH2>2N)CH2CH3! CH2 (CH3)CH2C^CH, CH2NH(CH2 OH, or CH2N((CH2)60H)CH2(8-metho\7quinolin-2-yl).
3. The compound of claim 2. wherein
R5 is ydrogen, CJ¾ CH2C¾ CH(CH3)2, CH2CH(CH3)¾ CH2CH(CH;>}:>, Cf> or benzyl;
R2, R\ JR.4, R5. and R6 are each independently hydrogen: and
R7 is (CH^OH, (CH oOH, (CH I IOH, (CB2}nOH. <CH2)wQH, (CH2)f OR (CRitsOR a-i2(N(CH2CB2)2N)Ci-i:2CI-i2OH? or CH2 (CR}Ci¾O R
4. 'line compound of claim 2, wherein
RJ is hydrogen, Ci¾ CH2CH3, Ce2CH(CH?)2, CH2CH(CH2)2, or CH<CF¼)2;
R2, R~\ R% and Rf> are each independently hydrogen;
R4 is CH3, F, CL Br, CF3? or OCH.v and
R7 is (CR^OH, (CH^wOH, iCR)iiOH, (CH2)j2OH, (CH2)BOR iCH2)! 5OR
(CH2),oOCOCH3, (C¾)nOCOCH3, (CH2)t2OCOCH5, iCR)nOOX¾ CH2NMiCH2)8OR CH2(N(CH2CH2)2N)CH2CH2O CH2iN(CH2CH2)2 )CH2CH5! or CH2N(CH3)CH2 C-CH.
5. The compound of claim 2, wherein
R* is hydrogen. Cf¾. CH2CH3, CH(CH2 , or CH2CH(CH2)2;
R2„ R"! are each independently CI;
RJ, R\ and R.6 are each independently hydrogen; and
R7 is (CH2)i i OH, CH2NH(CH2)aOH, or C i3N(CHi)CH2C-CH,
6. The compound of claim 2, wherein
R1 is hydrogen, CHj, CH2CH3, CH2CB(CH3k CRCHfCRk CH<CH3)¾ or beuyi;
". R R4, R", and R' are each independently hydrogen; and
R5 is (CH2)uOH or (CH2)r2OH.
7. The compound of claim 2. wherein
RJ is CH3;
R'", R% and R6 are each independently hydrogen;
R' and R4 are each independently OC¾ or CI; and
R7 is (CH2)„OR
8. The compound of claim 2, which is selected from the group consisting of:
9-(8-(ben¾1oxy) uinolin-2-yi)nonan- l-oi,
.10-(8-(benz ! oxy } uinoliit-2-y 1 )decan- 1 -ol ,
1 -(8-(ben/yU>xy)qu olin-2-y1)undecan-l -ol,
12-(8-(benzy !oxy )quinolin-2-yl)dodecan- i -ol 13- i8-{bm¾'ioxy)quinoljn-2-yl)tridecan-'l-oi, i4 (8-(ben^'lo>-y) uirio1m-2-yl)t£*radecan-l-ol5 i 5-(8-(benz ! oxy )q uitiolm-2-yi)pentadecan- 1 -ol.
1 .1 -(8-(beft¾-ioxy)-5-m^ylquinoHn-2-y l)mdec.m- J -ol,
.1 .1 -(8-(ben/yk>xy)-6-meil¾-1qumolin-2-y!)undecaii-i -ol, 5 5.-(8-{beii¾-1ox r)-5-'fluoroqiiinolin-2-yl)undecaa-j -ol:,
11- (8-(benzj ox)\)-5-dilor0quiiio!rn-2-yi)ufldeca{i- 1-oL 2-{ 9-hy droxy riorry ί )q ui noi in-8-οί ,
2-( 10- hy droxy decy 1 ) q uinolin-8-ol,
2-( 1 1 -hydroxy undecy I)qitiiioiin-8-oi,
2-(12-hydroxydodea )quinolm-8-ol,
2-(] 3-hydK)xyiridecyi)q«i.noiiti-8-o!,
2-(] 4-(-hydroxyietradecyl)qoiiioliii-8-oL
2-( 15-hy droxypeniadecy])quinoiin-8-o!s
2-i l l~hydroxyuiidecy!)~5~methylquinolin-8-ol,
Figure imgf000045_0001
5-chl oro~2~( 1 1 -hy droxy undecy I )qui nol in-8-οί ,
-(8-methoxyquino!tn-2-y !)nonaa- 1 -ol,
I 0-(8-m thoxyqu!.iioUn-2-yi)d can-] -ol,
{ 1 -(8-methoxyqu olm-2-yi)undecan-l -ol,
12 -{ 8 -methoxy qui no! in -2 - ! dodecan- i -ol
l3^8-methoxyquinolin-2-yi)tridecan-l-ol5
14- ((8-meihoxyquir!olirt~2-yl)ieti"ad caii-.J -oli i 5-(8-methoxyquinoltn-2- l)pentadecan- 1 -ol,
.1 .1 -(8-rnethoxy-5-meihy !quino!rn-2- i)undecan-l -ol i 1 -(5-tluoro-8-ra^hox\fquino1in-2-yi)imdecan-l -ol,
12- (5-t uoro-8-methoxyqiiino1iii-2-y1)dodecan- 1 -ol, 9-i5-ch!oro-8-meihoxyquinoiin-2-yi)noRan-l -oi,
I I ~f 5 -chS or o~8-meihoxy quinol in~2-y 1 )undecan~l -ol, 15 5-<-hloro-8-n½ihoxyquinolin-2-> )pentadecan- 1 -o!, i i-(5-bromo-8-methoxyquinolvn-2-yl)uiidecan-l -olt
.1 i -(8-methoxy~5~(irilliiorometliyl)qionoii.n
I I -(5,8-dimetlK>xyqu!.iioiiti-2-yl)undecaii- -oi,
I I -(8-methox>--6-raethylqoinoliri-2-y1)undecaii- 1 -ol I l-(6-fluoro-8-n¾eti50xyqujiioiin-2-yi)ijndecajn-l-ol,
I l-(6-diioro-8-meihoxyqunio1in-2-yl)undecan- 1 -ol, i 1 -(7-i uoro-8-meihoxyqiiinoiin-2-y!)undecan-l -oi,
I I -(7-d oro-8-mei oxy qujnolia-2-yl}undecaii-l -ol, .1 .1 -(5-chioro-6,8-di meihoxy qui«oliii-2-yf)uttdeean- 1 -ol,
11- (6-ΛΙθΓθ-5,8-ΛηιβίΗο ^^ωηο1}η-2^Ι)υηά6θ8η-1-οΙ, 11 -(5s7-di<^lofo-8-i«ethoxyquinolin-2-yl)undecaii- 1 -ol,
9- {8-ethoxyqu!i oUn-2-yi)iionan- l-oL,
10- (8-eihoxyq ol -2-yl)decan-l-ol.
11 -(8-eihoxyqu oiin-2-yi)imdecan-l -ol.
ί 2-(8-eihoxyquH5oIi«-2-y l)dodeciTO- 1 -ol
.13-(8-eihoxy quinoiin-2-y i)iiidecan- 1 -ol,
.14-((8-ethoxy uinolm-2-yI)tetradecan-l-ol,
15-f 8-ethoxyquinolin-2-y l)pentadecan- 1 -ol,
I l~(8-eihoxy -5-niel y !quino!in-2-y i)undecan- 1 -ol, 1 ! -(8-eihoxy-5-fl uoroquinolin-2-yl)imdecan- 1 -ol
^S-ch!oro-S-ethoxy uinolm^- ^nonan-l-ol,
.1 .1 -(5-diloro-8-elhoxyquinoHn-2-yl)undecan- 1 -ol,
.l5-(5-c ioro-S-ethoxy iu olin-2-yl)pemadecari-l -ol, { 1 -(5-bromo-8-ethoxyquinoIin-2-y i)undecan- 1 -ol , l l 5,7-di<^lofo-8^tlioxyq\iinoIm-2-yl)undeciKi-l-ol5 9-{8-isopropoxyquii5oli«-2-yS)iio.naf\-1 -o!i
H'8-isopropoxyquinol in-2-y i)decan~l ~ol,
i i -(8-i sopropox uinolin-2- l)undecan- 1 -ol,
1 2- (8-isopropoxy qui.noliii-2-y!)dodecaii- 1 -ol, i 3-(8-i sopropoxy q umoliii-2-y ί )iri decan- 1 -ol
.14-((8-iSopropoxyq«inoliii-2-yl)ieiradecan- 1 -ol.
15-(8-isopK>poxyquinolin-2-yl)peHtadecan- 1 -ol,
I H'S^so ro o y-S-awtliyiquinolin- - lJu decaEi-l'Ol, !. !. -(5-fiuoro- 8-i sopropoxy quinoim-2-y ί )undecan- 1 -ol, 9-(3-chloro-8-isopropoxyquinolin-2-yl)non i-l-ol, .1 i -(5-ddoro-8-isopropoxyqiiHioiin-2-yl)iHidecan-l-oL, J5-(5-(^loro-8-isopropoxyquinolm"2-yi)penladecan-'l-ol,
I I -(5 -bromo-8-isopropoxyqoinolin-2-yl)undecan- 1 -ol. 15^5-chlofo-8-isopropowquinolin-2-yl)pentadecan- 1 -oL
I l-(5-bromo-8-i$opropoxyquinohn-2-y i)undecan-1 ~oi ,
i i -(5,7-dichioro-8-isopropoxyquinoiiR-2-yl)undecan-l -ot.
-(8-(<^ lo f opyltmftoxy)quinoHn-2-yl)nonaft- 1 -ol,
0-(8-(cyck>propylmeihoxy)quiiioUii-2-yl)decan-i-ol,
I I -(8-{cy cl opropy I methoxy )quin.ol in-2-y 1 )undecan- 1-oJ,
12K8-(cycloprop 1methoxy)quinoUn-2-yl)dodecaa-l-ol,
13- i 8-(cy dopropy I methoxy )q ui n oii n-2-y l)tridecati- 1 -ol ,
14- ((8-(c clopropsdraeihoxy)q inolin-2-yI)t«¾radecan-l-ol!.
15-(8-(c5!doprop> methoxy)quinoHn-2'-yl)pwtadecaii- 1 -ol,
.1 .1 -(8-(c^TJopfop> raethoxy)-5-imthylqdnolin-2-yl)utidecan-.l -oif .1 J-CS-C 'dopro lmetho y'^S-fiuoro umolm^-y iOTdecan-l-ol, <H5-chioro-8-{cydopropy1 methoxy )quinolin-2-yl)nonan-l -oi, 11 -( 5 -c¾!oro-8-{cydopropylmelhoxy )quinol in-2-y i)undecan-1 -ol , 15~{5~ch!orQ~8~(cydopropyimelhoxy)quw^
l l-(5-bromo-8-( 5' lopropj methoxy )quinolin-2-\ )undecar)-'l-oi, 1 l-(5,7^idiloro>8-(c¾'dopropy'lmethoxy )quinolin-2-yl)undecan- 1 -ol 5 ,7~dichloro-2-( 1 1 - ydroxy undecy i)quif ioiin-8-oJ ,
I 0-(5-c oro-8-.methoxy q«moHii-2-yl)decaii- 1 -ol,
acetic acid 10-(5-diloro-8-methoxyqiiinolin-2-yl)decyi ester.
11- (5-dxlofo-8-«¾ethoxyquinolin-2-yl)undecan-l>ol5
acetic, acid 1 -(5-dUoro-8-nieti^ umolm-2-yI)undecy I ester,
12- (5-chk>ro-8-meihoxy uinolir!-2-y])dodecan~l -ol.
acetic acid 12-(5-chioro-8-methox>'qumohn-2-yi)dodecyl ester. .13-(5-chloro-8-meihoxyqoinoliii-2-yl)tridecaTi-l -oh
acetic acid i.3K5-chloro-8-metiioxyqiaT>olin-2-y!)trsdecy! ester, n-(8-methoxyquinoHn-4-(-yl)inidecan-l-ol,
11-f 8-ethoxyquinoiin-4-(-yl)undecan- 1 -ol,
lH'8 sopropoxyquinolin~4-(-yl)undecaii-l-ol,
l l~(8-(cyxtoprop\dmeihoxy)quinolin~4-(~yi)undecari-l-oL
1 i -(8-(beazyloxy)quinolm-4 -yl)undecan-l-ol.
.12-(8-(heii yk xy} uinolin-4-(-yl)dodecan-l-oi,
4-((! 1 -hydroxy undecyl)quinohn~8~ol,
4-((l 2-hydroxydodecyi)qumoim-8-ol, 9-{8-(iriiluororaeiiroxy)quinoiin-2-y l)nona- 1 -ol,
1 l-(8-(trifluoromethoxy)qianolin-2-yl)undecan- 1 -ol,
i 4-((8-(ii fltioromeihoxy )qifiiioiio-2-yi)teiradecan- i -oi,
15-(8-(trifl uoromethoxy )quinolio -2-y l)pentadecan~ 1 -oi ,
2-((4-((2~hydroxyeihyi>^
2-(4-({{5 ioro~8-m
2 4^((5-chIoro-8-e^oxyq moIin-2-yI)melhyl)p^era»n-l-yJ)ethaii L
2-(4-{{(3-cMoro-8-isopropoxyqumolm-2-y l)methy I >piperazin-l -y I)ethanoI,
2-(4-(((5-€hloro-8-(tyclopropyta
2-(4-(((5;7-dic.hioro-8-metl¾oxyqiiinoIm-2-yI)mei
2-(4-(((5,7-dichl oro-8-(cy clopropy i metiioxy )qiiinolijn-2-y l)meihyl)pipera jn-l -yi)ei a«oL 2-((niethyl(prop-2-yftyl)am
5^hloro-2^(meth\ (prop-2-ynyl)amino)metiiyl)q moim-8-ol5
N((5-chloro-8-methoxyquinoIiR-2-yl)m^
N((5-c ioro-8-emoxyquinoi «2«y l)roethy i)-N«m^ylprop«2«yn- 1 -amine,
N((S-ch!oro-8-isopropoxyquinolin-2-yl)methy
.N{{5 ]oro-8~(cyck)pTopytmeihoxy)q^u
N((5.7-dichiofO-8-methoxyquInoli
N((5J~dic loro-8-(cvclopropyiraeihoxy)q
8^(5-<¾loro-8-niethoxyq inolm-2-yl)me{h> an'ano)octan-l-ol:,
8-(( 5 -chi or o-8-ethox quiool in-2-vl)methy Ianiino)ocian-l-oi.
8 -{{5 -chi of o-8-isopropoxyq uinolin-2-y i )methy laniino)ocian- 1 -oL
8~((5-chi oro-8-(cy ciopropylmeihoxy )qui n oHn-2-y l)methyIamino)oclan-l -ol,
8-((5,7-dichiofO-8-meAo\yquinolin-2-yi)memy lamino)octan- 1 -olf
8-((5.7-di oro-8-(cyciopropylmemoxy)quj^ and
6-(bis((8-jmeihoxyqdnolin-2-yi)methyi)amino)hexan-l -o3.
A method for preparing die compound of claim 1 , comprising;
(15) reacting the compound of Formui a (II)
Figure imgf000048_0001
Formula (11) wherein:
RA R\ R4, R5, and are each independently h dronem or
Figure imgf000049_0001
and R* are each independently hydrogen and R* is C¾; or
R\ R;. R5, and S axe each independently hydrogen and R is Cl-fe, F, Ci. or Br; or
R^ R3, R6 are each independently hydrogen. R" is OCHb and R4 is CI; or
R2, R4 is CI and R"'. *, R* are each independently hydrogen,
with benzyl bromide, .methyl iodide, ethyl iodide, 2-broroopropane, or methylenecyciopropyl bromide in a basic solution at about room temperature to about 80°C to obtain the compound of Formula (111)
Figure imgf000049_0002
Formula (ill)
wherein:
R5 is CHs, C¾CH.Si CH(CHs)2 ¾CH(CH.;)i; r benzyl; and
R2„ R\ R4, R5, and R° are each independently hydrogen; or
R2, R4, R:\ and R6 are each independently hydrogen and R* is CH ; or
R'", R\ R"\ and R6 are each independently hydrogen and R4 is C¾, F, CI, or Br; or
R':, R\ Rft are each independently hydrogen, R'' is OCFij, and R4 is CI; or
R2, R4 is CI and R\ R\ R* are each independently hydrogen:
(16) reacting the compound of Formula (111) with lithium bis(tTimeihylsily1)amide and a bromo(C{-C2o)alkanol in ietrahydrofuran at 0°C to obtain the conipound of Formula (1)
Figure imgf000049_0003
Formula (Ϊ) wherein:
RJ is CH5 H2 H,, CH(CH5}2, C.H2CH<CH3>2, or benzyl;
R Rl 4. R\ and Rft are each independently hydrogen; or
RJ, R . R\ at¾d Rft are each independently hydrogen and R? is CM;, or R% Rl R5, and R6 are each independently hydrogen and R* is C¾ F, Ci, or Br; or
R", R5, R° are each independently hydrogen, R* is OCHj, and R4 is CI; or R' is CI, and R4 is OC¾ or
R\ R4 is CI and R R\ Rft are each independently hydrogen; and
R7 is
Figure imgf000050_0001
(17) reacting the compound of Formula (I). wherein Rl is benzyl, with hydrogen gas under pressure with palladium on carbon at room temperature in methanol or with boron trichloride in diehiorometharie at 0°C to obtain the compound of Fonnuia (i)
Figure imgf000050_0002
Formula (I)
R\ R2 t R R\ R\ and R° are each independently hydrogen; or
Figure imgf000050_0003
and R<; are each independently hydrogen and R"' is CH3; or
R!. R2, R3, R5, and R* are each independently hy drogen and R* is C¾ F, CL or Br; or
R1, ^ R5, 6 are each independently hydrogen, R* is OCH¾, and R4 is CI; R"' is CL and R4 is OC¾ or
R2. R4 is CI and R!. R\ R5, R6 are each independently hydrogen; and
R7 is (CH2)aOHf (CH j)KiOi-L (CH2)»OH5 (C¾), GH; <CH2)i*OR (CH3)i5OH; or
(18) reacting the compound of Formula (I), wherein Rl, R* R~ R*, R3 5 and R" are each independently hydrogen and R' is <Ο¾)π0Η, with -chlorosuccinimide in methyl chloride at room temperature to afford the compound of Formula (Ϊ), wherein R1 , R"\ R\ and R6 are each
independently hydrogen, R~ and R4 are each independently chlorine, and R' is (C¾)uOH; or
( 19) reacting the compound of Formula (i), w herein Rf is methyl R*", R\ R4, R5, and RB are each independently hydrogen and R' is (CH2)yOH, (CH2)t2OH or {Ci¾)jsOH with concentrated hydrochloric acid, ICb, and glacial acetic acid to afford the compound of Formula (I), wherein R* is methyl, R' R~\ R5, and R" are each independently hydrogen, R4 is Ci and R7 is (Ο¾)ι(>0Η, (CH2), ,OH, (CH2)J ?.OH, (CH2).l3OH, (CM2)f JOR (CH2)ioOCOCH¾ (CH2.)uOCOCH3!
(CH2)i2OCOCH3; iC¾)J 3OCOCR, or
(20) reacting 2-aminophenol with ethytvinyl ketone in hydrochloric acid to obtain the compound of Formula (I T-i)
Figure imgf000051_0001
Formula (ΪΝΤ-1):
(21) reacting the compound of Formula (i"NT-l ) with methyl iodide, ethyl iodide, 2- bromopropane, methyienecyciopropyl bromide, or benzyl bromide in basic solution to afford the compound of Formula fill),
Figure imgf000051_0002
Formula (III ) wherein RK! is methyl, ethyl, 2-propyi, melhyienecydopropyL or benzyl;
(22) reacting the compound of Formula (III), w herein R!L is methyl ethyl 2-propyl, methyienecyciopropyl, or benzyl, with lithium bis(trimethyisiiyl)amide and 11 -bromo-undecanol or 12-bromododecanol in tetrahydrofuran at 0¾C to obtain the compound of FoniRila (I), wherein R! is methyl, ethyl, 2-prop l. methyienecyciopropyl, or benzyl; , R' R4, R6, and R' are each independently hydrogen; and R* is (CHs uOH or (CHa^aOH;
(23) reacting tlie compound of Formula (I), w herein Rl is benzyl; R2, R\ R* R", and R' are each independently hydrogen; and R~ is (CH; )HOH or (Q b jOH, with h drogen gas under pressure with palladium on carbon at room temperature in methanol to obtain the compound of Formula (I), wherein R* is hydrogen;
Figure imgf000051_0003
R4, R*, and R ' are each independently hydrogen; and R' is (CH2)i iOB or (CHii tjOi l; or
(24) reacting 2 rifiuoro.methoxyaiiali.ne with croto aldehyde to obtain 2~methyi-8- trifluonnethoxy uino'line, which is treated with lithium bis(irimethyisiSyl)amide and a
bromo(CiC2o)alkanol in tetrahydroftiran at 0°C to obtain the compound of Formula (I), wherein R1 is trill uoroemeth l R2. RJ, R4, R\ and R7 are each independently hydrogen; and R'' is (CHj oOH, (CH2)HOH, (C¾)i2OH, (CHahsOH, ΟΓ <0¾)Ι5ΟΗ; or
(25) reacting an 8-hydroxy-2-methyiquinoiine compoimd of Formula (IV), wherein Rl is hydrogen, meth l, ethyl, 2-propyl. or methyienecyciopropyl.
Figure imgf000052_0001
Formul (V)
wit selenium dioxide in diosane at elevated temperature to afford a compound of Formula (VI), R1 is hydrogen, methyl, ethyl, 2-propyl, or memylenecyclopropyi
Figure imgf000052_0002
Formula (VI)
(26) reacting the compound of Formula (VI), wherein Rs is hydrogen, methyl, ethyl, 2- propyl, or niethyienecyciGpropyl, with - eth ipropagyl amine to obtain a compound of Formula (I), wherein Rs is hydrogen, CH3( CHiCHj, CH2CH«¾)2, CH2CH(CW2)2i or CH<(¾)¾ R2, ?, 4, R\ and R6 are each independently hydrogen; and R7 is CFt2N(CH¾)CH2C≡CFl; or
(27) reacting the compound of Formula (Vi\ R1 is hydrogen, methyl, ethyl, 2-propyl. or inetiwlenecy opropyL with 2(piperazu 'l-yi) ethanol to obtain a compound of Formula (1), wherein R1 is hydrogen, C¾ CH2CH*, CH2CH(CH5;b, Cf-fc€H{a-I2)2, or CH(CF¾)¾ R R3, R4, R5, and * are each independently hydrogen; and R' is
Figure imgf000052_0003
or
(28) reacting compoimd of Formula (VI) with an amino(C.rC2o)alkanoi to obtain a compound of Formula (I ), w herein Rs is hydrogen, CH¾ (¾€Ή3. CH2CH(CF¼)2, CFi2CH(€H2)2, or CH(CH¾)2; R2, R"\ R4, and R6 are each independently hydrogen; and R7 is CH2NH(CH2)sOFL or CH2N((CH2kOH)CB2(8-rnethoxyqumolm-2-yl).
i 0, A composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt a solvate or hy drate, a prodrug, or a metabolite thereof, arid a pharmaceutically acceptable diluent or carrier.
11 , A composition for use in treating a neurodegenerati v e disease, comprising a
therapeutically effective amount of a compound as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof, and a phamiaceutica!ty acceptable diluent or carrier,
12. A composition for use in treating a neurodegenerative disease as claimed in claim 1 i, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, amylotrophic lateral sclerosis (ALS), cognitive disorder, cerebral ischaemia stroke, cerebral palsy, stroke, haemorrhagic stroke, Creuizfeldt-Jacob disease, spongiform encephalopathy. Mad Cow disease, dementia, depression, Down's syndrome, epilepsy, frontotemporal dementia, Gilles d la Tourette's syndrome, Halierboden-Spatz disease, Huntington's disease, Lewy body disease,
Parkinson's disease, cognitive impairment, learning deficit macular degeneration, memory deficit, multiple sclerosis, multiple system atrophy, motor neuron disease. Pick's disease, progressive supranuclear palsy, pseudo dementia, retinopathy, senile dementia, schizophrenia transient anoxia! induced neurodegeneration, brain traumatic injury, and spina! cord injury.
13, A composition for use in treating a neurodegenerative disease as claimed in claim ! I , wherei the neurodegenerative disease is Alzheimer's disease.
14. U se of a compound as claimed in any one of claims 1 to 8 in the manufacture of a medicament for treating a neurodegenerative disease.
.15. A use as claimed i claim 14, wherein the medicament is for treating Alzheimer's disease.
PCT/US2013/034960 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as anti-neurodegenerative agents WO2014163622A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU2013385618A AU2013385618B2 (en) 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as anti-neurodegenerative agents
CN201380075030.2A CN105452224B (en) 2013-04-02 2013-04-02 Multi-functional quinoline as anti-nerve degeneration agent
RU2015137621A RU2642466C2 (en) 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as antineurodegenerative agents
JP2016506301A JP6153179B2 (en) 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as anti-neurodegenerative agents
PCT/US2013/034960 WO2014163622A1 (en) 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as anti-neurodegenerative agents
BR112015024472A BR112015024472A2 (en) 2013-04-02 2013-04-02 multifunctional quinoline derivatives as anti-neurodegenerative agents
KR1020157026392A KR101802048B1 (en) 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as anti-neurodegenerative agents
EP13881032.0A EP2981525A4 (en) 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as anti-neurodegenerative agents
IL241295A IL241295A0 (en) 2013-04-02 2015-09-08 Multifunctional quinoline derivatives as anti-neurodegenerative agents

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2013/034960 WO2014163622A1 (en) 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as anti-neurodegenerative agents

Publications (2)

Publication Number Publication Date
WO2014163622A1 true WO2014163622A1 (en) 2014-10-09
WO2014163622A8 WO2014163622A8 (en) 2014-11-13

Family

ID=51658752

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/034960 WO2014163622A1 (en) 2013-04-02 2013-04-02 Multifunctional quinoline derivatives as anti-neurodegenerative agents

Country Status (9)

Country Link
EP (1) EP2981525A4 (en)
JP (1) JP6153179B2 (en)
KR (1) KR101802048B1 (en)
CN (1) CN105452224B (en)
AU (1) AU2013385618B2 (en)
BR (1) BR112015024472A2 (en)
IL (1) IL241295A0 (en)
RU (1) RU2642466C2 (en)
WO (1) WO2014163622A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016171533A1 (en) * 2015-04-23 2016-10-27 대한민국(관리부서:국립수산과학원) Novel microorganism having antibacterial activity and method for producing pseudane using same
EP3466931A4 (en) * 2016-05-27 2019-11-27 Guangdong University Of Technology Tetradentate chelating monoquinoline derivative, manufacturing method thereof, and application of same as metal ion regulator for neurodegenerative disease

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102281647B1 (en) * 2020-12-09 2021-07-30 메디케어제약 주식회사 Method of producing a derivative-piperazine
CN113527200B (en) * 2021-05-27 2022-12-02 北京斯利安药业有限公司 Preparation method of cloquinadol

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7009053B2 (en) 2002-04-30 2006-03-07 Yungjin Pharmaceuticals Co., Ltd. Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same
US20060089380A1 (en) * 2002-07-16 2006-04-27 Prana Biotechnology Ltd. 8-Hydroxy quinoline derivatives
WO2008014602A1 (en) * 2006-07-25 2008-02-07 Envivo Pharmaceuticals, Inc. Quinoline derivatives
US7439243B2 (en) 2003-09-25 2008-10-21 Glaxo Group Limited Piperazinyl-quinoline derivatives useful for the treatment of CNS disorders
US7452888B2 (en) 2002-03-27 2008-11-18 Glaxo Group Limited Quinoline derivatives and their use as 5-ht6 ligands
US20090227626A1 (en) * 2005-08-04 2009-09-10 Palumed S.A. Novel polyquinoline derivatives and therapeutic use thereof
US20110301163A1 (en) * 2008-10-06 2011-12-08 The Johns Hopkins University Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682927A (en) * 1968-06-15 1972-08-08 Massimo Carissimi 5,7-bichloro-8-hydroxy-2-acetylamino quinoline
GB9127306D0 (en) * 1991-12-23 1992-02-19 Boots Co Plc Therapeutic agents
US5589484A (en) * 1992-10-27 1996-12-31 Janssen Pharmaceutica N.V. 4-quinolinyl derivatives
ES2162319T3 (en) * 1996-08-13 2001-12-16 Gerolymatos P N Sa USE OF THE CLIOQUINOL CHELATING AGENT FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ALZHEIMER'S DISEASE.
WO1999002520A1 (en) * 1997-07-07 1999-01-21 Kowa Co., Ltd. Diamine derivatives and pharmaceutical containing the same
FR2819507B1 (en) * 2001-01-17 2007-09-28 Inst Rech Developpement Ird SUBSTITUTED QUINOLINES FOR THE TREATMENT OF PROTOZOAN AND RETROVIRUS CO-INFECTIONS
WO2004076386A2 (en) * 2003-02-25 2004-09-10 Topotarget Uk Limited Carbamic acid compounds comprising a bicyclic heteroaryl group as hdac inhibitors
WO2005035534A1 (en) * 2003-10-08 2005-04-21 Ono Pharmaceutical Co., Ltd. Heterocyclic bicyclo ring and heterocyclic tricyclo ring compounds and drugs comprising the same
US20050131042A1 (en) * 2003-12-11 2005-06-16 Flentge Charles A. HIV protease inhibiting compounds
AU2011258217B2 (en) * 2010-05-26 2016-12-15 Sunovion Pharmaceuticals Inc. Heteroaryl compounds and methods of use thereof
CN102526052B (en) * 2012-01-19 2013-10-09 华南师范大学 Application of 2-gylcosyl chinoline compound in preparing acetylcholine esterase resisting medicines

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7452888B2 (en) 2002-03-27 2008-11-18 Glaxo Group Limited Quinoline derivatives and their use as 5-ht6 ligands
US7009053B2 (en) 2002-04-30 2006-03-07 Yungjin Pharmaceuticals Co., Ltd. Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same
US20060089380A1 (en) * 2002-07-16 2006-04-27 Prana Biotechnology Ltd. 8-Hydroxy quinoline derivatives
US7439243B2 (en) 2003-09-25 2008-10-21 Glaxo Group Limited Piperazinyl-quinoline derivatives useful for the treatment of CNS disorders
US20090227626A1 (en) * 2005-08-04 2009-09-10 Palumed S.A. Novel polyquinoline derivatives and therapeutic use thereof
WO2008014602A1 (en) * 2006-07-25 2008-02-07 Envivo Pharmaceuticals, Inc. Quinoline derivatives
US20110301163A1 (en) * 2008-10-06 2011-12-08 The Johns Hopkins University Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT, WILLIAMS & WILKINS
See also references of EP2981525A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016171533A1 (en) * 2015-04-23 2016-10-27 대한민국(관리부서:국립수산과학원) Novel microorganism having antibacterial activity and method for producing pseudane using same
EP3466931A4 (en) * 2016-05-27 2019-11-27 Guangdong University Of Technology Tetradentate chelating monoquinoline derivative, manufacturing method thereof, and application of same as metal ion regulator for neurodegenerative disease

Also Published As

Publication number Publication date
AU2013385618A1 (en) 2015-09-24
KR20150136070A (en) 2015-12-04
JP2016515617A (en) 2016-05-30
KR101802048B1 (en) 2017-12-28
WO2014163622A8 (en) 2014-11-13
JP6153179B2 (en) 2017-06-28
RU2642466C2 (en) 2018-01-25
EP2981525A4 (en) 2016-12-21
AU2013385618B2 (en) 2017-01-05
BR112015024472A2 (en) 2017-07-18
CN105452224B (en) 2017-12-26
RU2015137621A (en) 2017-05-11
CN105452224A (en) 2016-03-30
IL241295A0 (en) 2015-11-30
EP2981525A1 (en) 2016-02-10

Similar Documents

Publication Publication Date Title
AU2012305212B2 (en) Piperazine- substituted benzothiophene derivatives as antipsychotic agents
JP2014516072A (en) Apixaban production method
US20120149735A1 (en) 1,4-Dihydropyridine Derivatives and Their Uses
WO2014163622A1 (en) Multifunctional quinoline derivatives as anti-neurodegenerative agents
WO2019120210A1 (en) Benzofuran, coumestans derivatives, preparation method and use thereof
WO2016074532A1 (en) Method for preparing alectinib
WO2014135096A1 (en) Ivacaftor preparation method and intermediate thereof
JP6371741B2 (en) Synthesis and anticancer activity of aryl and heteroaryl-quinoline derivatives
JP2010215620A (en) NEW METHOD, PURIFICATION AND CRYSTALLIZATION OF 1-(4-{[4-(DIMETHYLAMINO)PIPERIDIN-1-YL]CARBONYL}PHENYL)-3-[4-(4,6-DIMORPHOLIN-4-YL-1,3,5-TRIAZIN-2-YL)PHENYL]UREA WHICH IS PI3K/mTOR INHIBITOR
JPH0592957A (en) 2-substituted quinolines, preparation thereof, and use thereof in medicine
JP7256130B2 (en) Guanidine derivative
CN113366010A (en) Terpenoid derivative and application thereof
CN109280032B (en) Pyridazinone mother nucleus structure histone deacetylase inhibitor and preparation method and application thereof
CN105924362A (en) Aromatic cyclopropyl amine compound, pharmaceutically acceptable salts thereof, and preparation method and application thereof
MX2014014895A (en) Bendamustine derivatives and related compounds, and medical use thereof cancer therapy.
JP2022515070A (en) Amide derivative impurities and their use
CN108864132B (en) Oridonin derivatives, and preparation method and application thereof
US9302992B2 (en) Multifunctional quinoline derivatives as anti-neurodegenerative agents
CA3163243A1 (en) Sstr5 antagonists
WO2014081025A1 (en) Novel crystal form of 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-n-(2-hydroxyethoxy)-5-(3-oxo-[1,2]oxazinan-2-ylmethyl)benzamide
WO2022191092A1 (en) Quinoline compound, hnmt inhibitor, and agent for preventing/treating adhd, narcolepsy, or alzheimer&#39;s disease
WO2024061300A1 (en) Inhibitors of trex1 and uses thereof
JP2024511617A (en) Novel indoleamine-2,3-dioxygenase inhibitor, method for producing the same, and pharmaceutical composition containing the same
KR101568484B1 (en) benzotellurophene derivative
CN108864113A (en) A kind of bis- target spot inhibitor of MDM2-HDAC, pharmaceutical composition and its preparation and use

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201380075030.2

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13881032

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2013881032

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 241295

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 20157026392

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2013385618

Country of ref document: AU

Date of ref document: 20130402

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2016506301

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2015137621

Country of ref document: RU

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015024472

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112015024472

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150923