AU2013385618B2 - Multifunctional quinoline derivatives as anti-neurodegenerative agents - Google Patents

Multifunctional quinoline derivatives as anti-neurodegenerative agents Download PDF

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AU2013385618B2
AU2013385618B2 AU2013385618A AU2013385618A AU2013385618B2 AU 2013385618 B2 AU2013385618 B2 AU 2013385618B2 AU 2013385618 A AU2013385618 A AU 2013385618A AU 2013385618 A AU2013385618 A AU 2013385618A AU 2013385618 B2 AU2013385618 B2 AU 2013385618B2
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quinolin
undecan
methoxyquinolin
chloro
hydrogen
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Pei-Teh Chang
Ji-Wang Chern
Chen-Wei Huang
Rahul Subhash Talekar
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Annji Pharmaceutical Co Ltd
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    • 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
    • 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
    • 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
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    • 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
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    • 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

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 QUINOLINE DERIVATIVES AS ANTINEURODEGENERATIVE AGENTS
BACKGROUND OF THE INVENTION US Patent Nos. 7,439,243 and 7,452,888 describe a series of quinoline derivatives useful for the treatment of CNS disorders, including Alzheimer’s disease. US Patent No. 7,009,053 describes a series of quinoline derivatives useful for treatment of Alzheimer's disease, Huntington's disease, Parkinson's disease, amylotrophic lateral sclerosis, stroke, ischemia, traumatic brain injury, spinal cord injury, and osteoarthritis.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
Formula (I) (I) wherein R1 is hydrogen, (Ci-Cs)alkyl, (Ci-C8)alkylene(C3-Cs)cycloalkyl, (Ci-Cs)haloalkyl, or (Ci-Cs)alkylene(C6-C2o)aryl; R2 is hydrogen or halogen; R3 is hydrogen, halogen, (Ci-Cs)alkyl, or (Ci-Cs)alkoxy; R4 is hydrogen, halogen, (Ci-Cs)alkyl, (Ci-Cs)alkoxy, or (Ci-Cs)haloalkyl; R5 is hydrogen or (Ci-C2o)alkanol; R6 is hydrogen; and R7 is (C6-C2o)alkanol, CH2(N(CH2CH2)2N)CH2CH2OH, (Cio-Ci3)alkyleneOCOCH3, (Ci-C8)alkylene(Ci-C6)alkylamino(Ci-C6)alkynyl, (Ci-C8)alkyleneamino(C3-C2o)alkanol, or (Ci-C8)alkyleneamino(Ci-C2o)alkanol(Ci-C8)alkylene(8-methoxyquinolin-2-yl); or (II) wherein: R1, R2, R3, R4 and R6 are each as defined in (I) above; R5 is (C5-C2o)alkanol; and R7 is hydrogen, (C6-C2o)alkanol, CH2(N(CH2CH2)2N)CH2CH2OH, (Cio-Ci3)alkyleneOCOCH3, (Ci-C8)alkylene(Ci-C6)alkylamino(Ci-C6)alkynyl, (Ci-C8)alkyleneamino(C3-C2o)alkanol, or (Ci-C8)alkyleneamino(Ci-C2o)alkanol(Ci-C8)alkylene(8-methoxyquinolin-2-yl).In one embodiment, R2 is hydrogen;
In another embodiment, R1 is hydrogen, (Ci-Cs)alkyl, (Ci-C8)alkylene(C3-Cs)cycloalkyl, or (Ci-Cs)haloalkyl.
Described herein is a method for preparing the compound of the invention, the method comprising: (1) reacting the compound of Formula (II)
Formula (II) wherein: R2, R3, R4, R5, and R6 are each independently hydrogen; or R2, R4, R5, and R6 are each independently hydrogen and R3 is CH3; or R2, R3, R5, and R6 are each independently hydrogen and R4 is CH3, F, Cl, or Br; or R2, R5, R6 are each independently hydrogen, R3 is OCH3, and R4 is Cl; or R2, R4 is Cl and R3, R5, R6 are each independently hydrogen, with benzyl bromide, methyl iodide, ethyl iodide, 2-bromopropane, or methylenecyclopropyl bromide in a basic solution at about room temperature to about 80°C to obtain the compound of Formula (III)
Formula (III) wherein: R1 is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, or benzyl; and R2, R3, R4, R5, and R6 are each independently hydrogen; or R2, R4, R5, and R6 are each independently hydrogen and R3 is CH3; or R2, R3, R5, and R6 are each independently hydrogen and R4 is CH3, F, Cl, or Br; or R2, R5, R6 are each independently hydrogen, R3 is OCH3, and R4 is Cl; or R2, R4 is Cl and R3, R5, R6 are each independently hydrogen; (2) reacting the compound of Formula (III) with lithium bis(trimethylsilyl)amide and a bromo(CiC2o)alkanol in tetrahydrofuran at 0°C to obtain the compound of Formula (I)
Formula (I) wherein: R1 is CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, or benzyl; R2, R3, R4, R5, and R6 are each independently hydrogen; or R2, R4, R5, and R6 are each independently hydrogen and R3 is CH3; or R2, R3, R5, and R6 are each independently hydrogen and R4 is CH3, F, Cl, or Br; or R2, R5, R6 are each independently hydrogen, R3 is OCH3, and R4 is Cl; or R3 is Cl, and R4 is OCH3 or R2, R4 is Cl and R3, R5, R6 are each independently hydrogen; and R7 is (CH2)9OH, (CH2)ioOH, (CH2)hOH, (CH2)i20H, (CH2)i3OH, (CH2)i50H, (3) reacting the compound of Formula (I), wherein R1 is benzyl, with hydrogen gas under pressure with palladium on carbon at room temperature in methanol or with boron trichloride in dichloromethane at 0°C to obtain the compound of Formula (I)
Formula (I) R1, R2, R3, R4, R5, and R6 are each independently hydrogen; or R1, R2, R4, R5, and R6 are each independently hydrogen and R3 is CH3; or R1, R2, R3, R5, and R6 are each independently hydrogen and R4 is CH3, F, Cl, or Br; or R1, R2, R5, R6 are each independently hydrogen, R3 is OCH3, and R4 is Cl; or R2, R4 is Cl and R1, R3, R5, R6 are each independently hydrogen; and R7 is (CH2)9OH, (CH2)ioOH, (CH2)hOH, (CH2)i2OH, (CH2)i3OH, (CH2)i5OH; or (4) reacting the compound of Formula (I), wherein R1, R2, R3, R4, R5, and R6 are each independently hydrogen and R7 is (CH2)nOH, with N-chlorosuccinimide in methylene chloride at room temperature to afford the compound of Formula (I), wherein R1, R3, R5, and R6 are each independently hydrogen, R2 and R4 are each independently chlorine, and R7 is (CH2)nOH; or (5) reacting the compound of Formula (I), wherein R1 is methyl, R2, R3, R4, R5, and R6 are each independently hydrogen and R7 is (CH2)nOH, (CH2)i2OH or (CH2)i30H with concentrated hydrochloric acid, ICI3, and glacial acetic acid to afford the compound of Formula (I), wherein R1 is methyl, R2, R3, R5, and R6 are each independently hydrogen, R4 is Cl, and R7 is (CH2)i0OH, (CH2)hOH, (CH2)i2OH, (CH2)i3OH, (CH2)i5OH, (CH2)i0OCOCH3, (CH2)hOCOCH3, (CH2)i2OCOCH3, (CH2)i3OCOCH3; or (6) reacting 2-aminophenol with methylvinyl ketone in hydrochloric acid to obtain the compound of Formula (INT-1)
Formula (INT-1); (7) reacting the compound of Formula (INT-1) with methyl iodide, ethyl iodide, 2-bromopropane, methylenecyclopropyl bromide, or benzyl bromide in basic solution to afford the compound of Formula (III),
Formula (III) wherein R10 is methyl, ethyl, 2-propyl, methylenecyclopropyl, or benzyl; (8) reacting the compound of Formula (III), wherein R10 is methyl, ethyl, 2-propyl, methylenecyclopropyl, or benzyl, with lithium bis(trimethylsilyl)amide and 10-bromo-l-decanol or 11 -bromo-1 -undecanol in tetrahydrofuran at 0°C to obtain the compound of Formula (I), wherein R1 is methyl, ethyl, 2-propyl, methylenecyclopropyl, or benzyl; R2, R3, R4, R6, and R7 are each independently hydrogen; and R5 is (CH2)nOH or (CFk)i20Fl; (9) reacting the compound of Formula (I), wherein R1 is benzyl; R2, R3, R4, R6, and R7 are each independently hydrogen; and R5 is (CH2)nOH or (CFb)i20FI, with hydrogen gas under pressure with palladium on carbon at room temperature in methanol to obtain the compound of Formula (I), wherein R1 is hydrogen; R2, R3, R4, R6, and R7 are each independently hydrogen; and R5 is (CH2)nOH or (CFh)i20Fl; or (10) reacting 2-trifluoromethoxyanaline with crotonaldehyde to obtain 2-methyl-8-trifluormethoxyquinoline, which is treated with lithium bis(trimethylsilyl)amide and a bromo(CiC2o)alkanol in tetrahydrofuran at 0°C to obtain the compound of Formula (I), wherein R1 is trifluoroemethyl; R2, R3, R4, R5, and R7 are each independently hydrogen; and R7 is (CH2)ioOH, (CH2)hOH, (CH2)i2OH, (CH2)i30H, or (CH2)i50H; or (11) reacting an 8-hydroxy-2-methylquinoline compound of Formula (IV), wherein R1 is hydrogen, methyl, ethyl, 2-propyl, or methylenecyclopropyl,
Formula (V) with selenium dioxide in dioxane at elevated temperature to afford a compound of Formula (VI), R1 is hydrogen, methyl, ethyl, 2-propyl, or methylenecyclopropyl.
Formula (VI) (12) reacting the compound of Formula (VI), wherein R1 is hydrogen, methyl, ethyl, 2-propyl, or methylenecyclopropyl, with N-methylpropagylamine to obtain a compound of Formula (I), wherein R1 is hydrogen, CFF, CH2CH3, CFkCF[(CF[3)2, CFbCFI(CFl2)2, or CH(CH3)2, R2, R3, R4, R5, and R6 are each independently hydrogen; and R7 is CH2N(CH3)CH2OCH; or (13) reacting the compound of Formula (VI), R1 is hydrogen, methyl, ethyl, 2-propyl, or methylenecyclopropyl, with 2(piperazin-1-yl) ethanol to obtain a compound of Formula (I), wherein R1 is hydrogen, CH3, CH2CH3, CH2CH(CH3)2, CH2CH(CH2)2, or CH(CH3)2, R2, R3, R4, R5, and R6 are each independently hydrogen; and R7 is CH2(N(CH2CH2)2N)CH2CH20H; or (14) reacting compound of Formula (VI) with an amino(Ci-C2o)alkanol to obtain a compound of Formula (I), wherein R1 is hydrogen, CH3, CFhCFF, CFkCFl(CF[3)2, CH2CH(CH2)2, or CH(CH3)2; R2, R3, R4, R5, and R6 are each independently hydrogen; and R7 is CH2NH(CH2)sOH, or CH2N((CH2)60H)CH2(8-methoxyquinolin-2-yl). In another aspect, the invention relates to a composition comprising a a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
Further in another aspect, the invention relates to a method for the treatment of Alzheimer’s disease, brain traumatic injury, and/or spinal cord injury, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of the invention.
Also disclosed is use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of Alzheimer’s disease, brain traumatic injury, and/or spinal cord injury.
Alternatively, the invention relates to a use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Alzheimer’s disease, brain traumatic injury, and/or spinal cord injury.
The invention is also related to a method for improving learning and/or memory performance in a patient of Alzheimer's disease, comprising administering a therapeutically effective amount of the composition of the invention to the patient with Alzheimer's disease. Alterantively, the invention relates to a compound of the invention or a pharmaceutically acceptable salt thereof, when used in improving learning and/or memory performance in a patient with Alzheimer’s disease.
Also disclosed is use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving learning and/or memory performance in a patient with Alzheimer’s disease.
In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identified by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims.
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 invention. Wherever 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. 1A-B show morphological analysis of the effects of compound C12 on ίΑβ formation and dissociation of fAps in the presence or absence of zinc ions. FIG. 2 shows compound C12 inhibiting polymerization of Αβ in the absence of zinc ions. FIGs. 3 A-B show compound C12 acting as a neuroprotective agent targeting ίΑβ. FIG. 4 shows quinoline derivatives-induced neurite outgrowth. FIG. 5 shows quinoline 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 ίΑβ level in memory-deficit ίΑβ-lesioned mice after compound C12 treatment.
DETAILED DESCRIPTION OF THE INVENTION
The term “comprising” as used in this specification and claims means “consisting at least in part of’. When interpreting statements in this specification and claims which include “comprising”, other features besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise” and “comprised” are to be interpreted in a similar manner.
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 -CONFh is attached through the carbon atom.
The term “amino” refers to -NFh. The amino group can be optionally substituted as defined herein for the term “substituted.” The term “alkylamino” refers to -NR2, wherein at least one R is alkyl and the second R is alkyl or hydrogen. The term “acylamino” refers to N(R)C(=0)R, wherein each R is independently hydrogen, alkyl, or aryl.
The term “alkyl” refers to a Ci-Cis hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-l-propyl (iso-butyl, -CH2CH(CH3)2), 2-butyl (sec-butyl, -CF^CFyCFbCFF), 2-methyl-2-propyl (tert-butyl, -C(CH3)3), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl. The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., alkylene). The alkyl can optionally be substituted with one or more alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulflnyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfmyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfmamoyl, sulflno, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. The alkyl can optionally be interrupted with one or more non-peroxide oxy (-0-), thio (-S-), amino (-N(H)-), methylene dioxy (-OCH2O-), carbonyl (-C(=0)-), carboxy (-0(=0)0-), carbonyldioxy (-00(=0)0-), carboxylato (-00(=0)-), imino (C=NH), sulfinyl (SO) or sulfonyl (SO2). Additionally, the alkyl can optionally be at least partially unsaturated, thereby providing an alkenyl.
The term “alkylene” refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (-CH2-) 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene can optionally be substituted with one or more alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulflnyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfmyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfmamoyl, sulflno, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, the alkylene can optionally be interrupted with one or more non-peroxide oxy (-0-), thio (-S-), amino (-N(H)-), methylene dioxy (-OCH2O-), carbonyl (-C(=0)-), carboxy (-0(=0)0-), carbonyldioxy (-00(=0)0-), carboxylato (-0C(=0)-), imine (C=NH), sulfinyl (SO) or sulfonyl (SO2). Moreover, the alkylene can optionally be at least partially unsaturated, thereby providing an alkenylene.
The term “alkynyl” refers to a monoradical branched or unbranched hydrocarbon chain, having a point of complete unsaturation (i.e., a carbon-carbon, sp triple bond). In one embodiment, the alkynyl group can have from 2 to 10 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, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1-octynyl, and the like. The alkynyl can be unsubstituted or substituted.
The term “alkoxy” refers to the group alkyl-Ο-, where alkyl is defined herein. Preferred alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, fvo-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. The alkoxy can optionally be substituted with one or more halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
The term “alkanol” refers to a compound of a general formula ROH, where R is alkyl, as defined herein.
The term “aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferred aryls include phenyl, naphthyl and the like. The aryl can optionally be a divalent radical, thereby providing an arylene. The aryl can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfmamoyl, sulflno, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
The terms “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 alkyl moeity. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
The term “carbocycle” refers to a saturated, unsaturated or aromatic ring having 3 to 8 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 30 carbon atoms as a polycycle. Monocyclic carbocycles typically have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl. The carbocycle can be optionally substituted as described above for alkyl groups.
When a substituent is specified to be an atom or atoms of specified identity, “or a bond”, a configuration is referred to when the substituent is “a bond” that the groups that are immediately adjacent to the specified substituent are directly connected to 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 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, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfmamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy. The cycloalkyl can optionally be at least partially unsaturated, thereby providing a cycloalkenyl. Additionally, the cycloalkyl can optionally be a divalent radical, thereby providing a cycloalkylene.
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 fluoro, chloro, bromo, and iodo. Similarly, the term “halogen” refers to fluorine, chlorine, bromine, and iodine.
The term “haloalkyl” refers to alkyl substituted by 1-4 halo groups, which may be the same or different. Representative haloalkyl groups include trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl, 2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.
The term “heteroaryl” is a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted. The heteroaryl can optionally be a divalent radical, thereby providing a heteroarylene. Examples of heteroaryl groups include, but are not limited to, 2//-pyrrolyl, 3//-indolyl, 4//-quinolizinyl, 4H-carbazolyl, acridinyl, benzo[b]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl. In one embodiment the term “heteroaryl” denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from the group non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, phenyl, or benzyl. In another embodiment heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, or tetramethylene diradical thereto.
The heteroaryl can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
The term “heterocycle” or “heterocyclyl” refers to a saturated or partially unsaturated ring system, containing at least one heteroatom selected from the group oxygen, nitrogen, and sulfur, and optionally substituted with alkyl, or C(=0)0Rb, wherein Rb is hydrogen or alkyl. Typically heterocycle is a monocyclic, bicyclic, or tricyclic group containing one or more heteroatoms selected from the group oxygen, nitrogen, and sulfur. A heterocycle group also can contain an oxo group (=0) attached to the ring. Non-limiting examples of heterocycle groups include 1,3-dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, 2//-pyran, 2-pyrazoline, 4//-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, and thiomorpholine. The heterocycle can optionally be a divalent radical, thereby providing a heterocyclene. The heterocycle can optionally be substituted with one or more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulflnyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulflnyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfmamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles.
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 (I) 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 in 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 hydrolyzed 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 that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, 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 Enzymology, 112:309 323 (1985); Bodor, N., “Novel Approaches in Prodrug Design,” Drugs of the 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. (1985); Burger’s Medicinal Chemistry and Drug Chemistry,
Fifth Ed., Vol. 1, pp. 172 178, 949 982 (1995).
The term “solvate” refers to a complex of variable stoichiometry formed by a solute (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 activity 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 30°C.
The term “substituted” is intended to indicate that 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., alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, acyloxy, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyanato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NRxRy and/or COORx, wherein each Rx and Ry are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy. When a substituent is oxo (i.e., =0) or thioxo (i.e., =S) group, then two hydrogens on the atom are replaced.
The terms “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 neurondegenerative disease involving neuronal toxicity or dysfunction induced by oxidative stress and other disorders associated with misfolding protein aggregation. In animal model, quinoline derivatives (B3 or Cl2) at 1 to 100 mg/kg, preferable 1 to 10 mg/kg, i.p. daily) were found to improve memory of micewithout causing significant toxicity.
In one aspect, the invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
Formula (I) (I) wherein R1 is hydrogen, (Ci-Cs)alkyl, (Ci-C8)alkylene(C3-Cs)cycloalkyl, (Ci-Cs)haloalkyl, or (Ci-Cs)alkylene(C6-C2o)aryl; R2 is hydrogen or halogen; R3 is hydrogen, halogen, (Ci-Cs)alkyl, or (Ci-Cs)alkoxy; R4 is hydrogen, halogen, (Ci-Cs)alkyl, (Ci-Cs)alkoxy, or (Ci-Cs)haloalkyl; R5 is hydrogen or (Ci-C2o)alkanol; R6 is hydrogen; and R7 is (C6-C2o)alkanol, CH2(N(CH2CH2)2N)CH2CH2OH, (Cio-Ci3)alkyleneOCOCH3, (Ci-C8)alkylene(Ci-C6)alkylamino(Ci-C6)alkynyl, (Ci-Cs)alkyleneamino(C3-C2o)alkanol, or (Ci-C8)alkyleneamino(Ci-C2o)alkanol(Ci-C8)alkylene(8-methoxyquinolin-2-yl); or (II) wherein: R1, R2, R3, R4 and R6 are each as defined in (I) above; R5 is (C5-C2o)alkanol; and R7 is hydrogen, (C6-C2o)alkanol, CH2(N(CH2CH2)2N)CH2CH2OH, (Cio-Ci3)alkyleneOCOCH3, (Ci-C8)alkylene(Ci-C6)alkylamino(Ci-C6)alkynyl, (Ci-C8)alkyleneamino(C3-C2o)alkanol, or (Ci-C8)alkyleneamino(Ci-C2o)alkanol(Ci-Cs)alkylene(8-methoxyquinolin-2-yl).
In one embodiment of the invention, (A) wherein: R1 is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH2)2, CH2CH(CH3)2, CF3, or benzyl; R2 is hydrogen, F, or Cl; R3 is hydrogen, F, Cl, CH3, or OCH3; R4 is hydrogen, F, Cl, Br, CH3, OCH3, or CF3; R5 is hydrogen, (CH2)nOH, or (CH2)i20H; R6 is hydrogen; and R7 is hydrogen, (CH2)9OH, (CH2)ioOH, (CH2)nOH, (CH2)i20H, (CH2)i3OH, (CH2)i40H, (CH2)i5OH, (CH2)ioOCOCH3, (CH2)hOCOCH3, (CH2)i20C0CH3, (CH2)i3OCOCH3, CH2(N(CH2CH2)2N)CH2CH2OH, CH2N(CH3)CH2C=CH, CH2NH(CH2)80H, or CH2N((CH2)60H)CH2(8-methoxyquinolin-2-yl); or (B) wherein: R1, R2, R3, R4 and R6 are each as defined in (A) above; R5 is (CH2)nOH, or (CH2)i20H; and R7 is hydrogen, (CH2)9OH, (CH2)ioOH, (CH2)nOH, (CH2)i20H, (CH2)i3OH, (CH2)i4OH, (CH2)i5OH, (CH2)ioOCOCH3, (CH2)hOCOCH3, (CH2)i20C0CH3, (CH2)i3OCOCH3, CH2(N(CH2CH2)2N)CH2CH2OH, CH2N(CH3)CH2C=CH, CH2NH(CH2)80H, or CH2N((CH2)60H)CH2(8-methoxyquinolin-2-yl).
In another embodiment of the invention, wherein R1 is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH(CH2)2, CF3, or benzyl; R2, R3, R4, R5, and R6 are each independently hydrogen; and R7 is (CH2)9OH, (CH2)ioOH, (CH2)hOH, (CH2)i20H, (CH2)i3OH, (CH2)i40H, (CH2)i50H, CH2(N(CH2CH2)2N)CH2CH2OH, or CH2N(CH3)CH2C=CH.
In another embodiment of the invention, wherein R1 is hydrogen, CH3, CH2CH3, CH2CH(CH3)2, CH2CH(CH2)2, or CH(CH3)2; R2, R3, R5, and R6 are each independently hydrogen; R4 is CH3, F, Cl, Br, CF3, or OCH3; and R7 is (CH2)9OH, (CH2)ioOH, (CH2)hOH, (CH2)i20H, (CH2)i3OH, (CH2)i50H, (CH2)ioOCOCH3, (CH2)iiOCOCH3, (CH2)i20C0CH3, (CH2)i3OCOCH3, CH2NH(CH2)80H, CH2(N(CH2CH2)2N)CH2CH2OH, or CH2N(CH3)CH2 C^CH.
In another embodiment of the invention, wherein R1 is hydrogen, CH3, CH2CH3, CH(CH2)2, or CH2CH(CH2)2; R2,R4 are each independently Cl; R3, R5, and R6 are each independently hydrogen; and R7 is (CH2)nOH, CH2NH(CH2)80H, or CH2N(CH3)CH2C=CH.
In another embodiment of the invention, wherein R1 is hydrogen, CH3, CH2CH3, CH2CH(CH3)2, CH2CH(CH2)2, CH(CH3)2, or benzyl; R2, R3, R4, R6, and R7 are each independently hydrogen; and R5 is (CH2)nOH or (CH2)i20H.
In another embodiment of the invention, wherein R1 is CH3; R2, R5, and R6 are each independently hydrogen; R3 and R4 are each independently OCH3 or Cl; and R7 is (CH2)nOH.
In another embodiment of the invention, the compound is selected from the group consisting of 9-(8-(benzyloxy)quinolin-2-yl)nonan-l-ol,10-(8-(benzyloxy)quinolin-2-yl)decan-l-ol, 11-(8-(benzyloxy)quinolin-2-yl)undecan-1 -ol, 12-(8-(benzyloxy)quinolin-2-yl)dodecan-1 -ol, 13-(8-(benzyloxy)quinolin-2-yl)tridecan-1 -ol, 14-((8-(benzyloxy)quinolin-2-yl)tetradecan-1 -ol, 15-(8-(benzyloxy)quinolin-2-yl)pentadecan-1 -ol, 11 -(8-(benzyloxy)-5-methylquinolin-2-yl)undecan-1 -ol, 1 l-(8-(benzyloxy)-6-methylquinolin-2-yl)undecan-l-ol, 1 l-(8-(benzyloxy)-5-fluoroquinolin-2-yl)undecan-l-ol, 1 l-(8-(benzyloxy)-5-chloroquinolin-2-yl)undecan-l-ol, 2-(9-hydroxynonyl)quinolin-8-ol, 2-(10-hydroxydecyl)quinolin-8-ol, 2-(11-hydroxyundecyl)quinolin-8-ol, 2-(12-hydroxydodecyl)quinolin-8-ol, 2-(13-hydroxytridecyl)quinolin-8-ol, 2-(14-hydroxytetradecyl)quinolin-8-ol, 2-(15-hydroxypentadecyl)quinolin-8-ol, 2-(1 l-hydroxyundecyl)-5-methylquinolin-8-ol, 2-(11-hydroxyundecyl)-6-methylquinolin-8-ol, 5-chloro-2-(l l-hydroxyundecyl)quinolin-8-ol, 9-(8-methoxyquinolin-2-yl)nonan-1-ol, 10-(8-methoxyquinolin-2-yl)decan-l-ol, 11-(8-methoxyquinolin-2-yl)undecan-1 -ol, 12-(8-methoxyquinolin-2-yl)dodecan-1 -ol, 13-(8-methoxyquinolin-2-yl)tridecan-1 -ol, 14-((8-methoxyquinolin-2-yl)tetradecan-1 -ol, 15-(8-methoxyquinolin-2-yl)pentadecan-1 -ol, 11 -(8-methoxy-5-methylquinolin-2-yl)undecan-1 -ol, 1 l-(5-fluoro-8-methoxyquinolin-2-yl)undecan-l-ol, 12-(5-fluoro-8-methoxyquinolin-2-yl)dodecan-l-ol, 9-(5-chloro-8-methoxyquinolin-2-yl)nonan-l-ol, 1 l-(5-chloro-8-methoxyquinolin-2-yl)undecan-l-ol, 15-(5-chloro-8-methoxyquinolin-2-yl)pentadecan-l-ol, 11-(5-bromo-8-methoxyquinolin-2-yl)undecan-l-ol, 1 l-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-l-ol, 1 l-(5,8-dimethoxyquinolin-2-yl)undecan-l-ol, 1 l-(8-methoxy-6-methylquinolin-2-yl)undecan-l-ol, 1 l-(6-fluoro-8-methoxyquinolin-2-yl)undecan-l-ol, 11-(6-chloro-8-methoxyquinolin-2-yl)undecan-1 -ol, 11 -(7-fluoro-8-methoxyquinolin-2-yl)undecan-1 -ol, 1 l-(7-chloro-8-methoxyquinolin-2-yl)undecan-l-ol, 1 l-(5-chloro-6,8-dimethoxyquinolin-2-yl)undecan-l-ol, 1 l-(6-chloro-5,8-dimethoxyquinolin-2-yl)undecan-l-ol, 1 l-(5,7-dichloro-8-methoxyquinolin-2-yl)undecan-1 -ol, 9-(8-ethoxyquinolin-2-yl)nonan-1 -ol, 10-(8-ethoxyquinolin-2-yl)decan-l-ol, 11 -(8-ethoxy quinolin-2-yl)undecan-1-ol, 12-(8-ethoxyquinolin-2-yl)dodecan-1 -ol, 13 -(8-ethoxyquinolin-2-yl)tridecan-1 -ol, 14-((8-ethoxyquinolin-2-yl)tetradecan-l-ol, 15-(8-ethoxyquinolin-2-yl)pentadecan-l-ol, 1 l-(8-ethoxy-5-methylquinolin-2-yl)undecan-l-ol, 1 l-(8-ethoxy-5-fluoroquinolin-2-yl)undecan-l-ol, 9-(5-chloro-8-ethoxyquinolin-2-yl)nonan-l-ol, 1 l-(5-chloro-8-ethoxyquinolin-2-yl)undecan-l-ol, 15-(5-chloro-8-ethoxyquinolin-2-yl)pentadecan-l-ol, 1 l-(5-bromo-8-ethoxyquinolin-2-yl)undecan-Ιοί, 1 l-(5,7-dichloro-8-ethoxyquinolin-2-yl)undecan-l-ol, 9-(8-isopropoxyquinolin-2-yl)nonan-1 -ol, 10-(8-isopropoxyquinolin-2-yl)decan-l-ol, 1 l-(8-isopropoxyquinolin-2-yl)undecan-l-ol, 12-(8-isopropoxyquinolin-2-yl)dodecan-l-ol, 13-(8-isopropoxyquinolin-2-yl)tridecan-l-ol, 14-((8-isopropoxyquinolin-2-yl)tetradecan-l-ol, 15-(8-isopropoxyquinolin-2-yl)pentadecan-l-ol, 1 l-(8-isopropoxy-5-methyl quinolin-2-yl)undecan-l-ol, 1 l-(5-fluoro-8-isopropoxyquinolin-2-yl)undecan-l-ol, 9-(5-chloro-8-isopropoxyquinolin-2-yl)nonan-l-ol, 1 l-(5-chloro-8-isopropoxyquinolin-2-yl)undecan-1 -ol, 15-(5-chloro-8-isopropoxyquinolin-2-yl)pentadecan-1 -ol, 1 l-(5-bromo-8-isopropoxyquinolin-2-yl)undecan-l-ol,, 11-(5,7-dichloro-8-isopropoxyquinolin-2-yl)undecan-1 -ol, 9-(8-(cyclopropylmethoxy)quinolin-2-yl)nonan-1 -ol, 10-(8-(cyclopropylmethoxy)quinolin-2-yl)decan-1 -ol, 11 -(8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1 -ol, 12-(8-(cyclopropylmethoxy)quinolin-2-yl)dodecan-1 -ol, 13-(8-(cyclopropylmethoxy)quinolin-2-yl)tridecan-1 -ol, 14-((8-(cyclopropylmethoxy)quinolin-2-yl)tetradecan-l-ol, 15-(8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-l-ol, 11-(8-(cyclopropylmethoxy)-5-methylquinolin-2-yl)undecan-1 -ol, 11 -(8-(cyclopropylmethoxy)-5-fluoroquinolin-2-yl)undecan-l-ol, 9-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)nonan-Ιοί, 1 l-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-l-ol, 15-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-l-ol, 1 l-(5-bromo-8- (cyclopropylmethoxy)quinolin-2-yl)undecan-l-ol, 1 l-(5,7-dichloro-8- (cyclopropylmethoxy)quinolin-2-yl)undecan-l-ol, 5,7-dichloro-2-(l 1-hydro xyundecyl)quinolin- 8-ol, 10-(5-chloro-8-methoxyquinolin-2-yl)decan-l-ol, acetic acid 10-(5-chloro-8-methoxyquinolin-2-yl)decyl ester, 1 l-(5-chloro-8-methoxyquinolin-2-yl)undecan-l-ol, acetic acid 1 l-(5-chloro-8-methoxyquinolin-2-yl)undecyl ester, 12-(5-chloro-8-methoxyquinolin-2-yl)dodecan-l-ol, acetic acid 12-(5-chloro-8-methoxyquinolin-2-yl)dodecyl ester, 13-(5-chloro- 8- methoxyquinolin-2-yl)tridecan-l-ol, acetic acid 13-(5-chloro-8-methoxyquinolin-2-yl)tridecyl ester, 1 l-(8-methoxyquinolin-4-(-yl)undecan-l-ol, 1 l-(8-ethoxyquinolin-4-(-yl)undecan-l-ol, 1 l-(8-isopropoxyquinolin-4-(-yl)undecan-l-ol, 1 l-(8-(cyclopropylmethoxy)quinolin-4-(-yl)undecan-l-ol, 1 l-(8-(benzyloxy)quinolin-4-(-yl)undecan-l-ol, 12-(8-(benzyloxy)quinolin-4-(-yl)dodecan-l-ol, 4-((1 l-hydroxyundecyl)quinolin-8-ol, 4-((12-hydroxydodecyl)quinolin-8-ol, 9- (8-(trifluoromethoxy)quinolin-2-yl)nonan-1 -ol, 11 -(8-(trifluoromethoxy)quinolin-2-yl)undecan-1 -ol, 14-((8-(trifluoromethoxy)quinolin-2-yl)tetradecan-1 -ol, 15-(8-(trifluoromethoxy)quinolin-2-yl)pentadecan-l-ol, 2-((4-((2-hydroxyethyl)piperazin-l-yl)methyl)quinolin-8-ol, 2-(4-(((5-chloro-8-methoxyquinolin-2-yl)methyl)piperazin-1 -yl)ethanol, 2-(4-(((5-chloro-8-ethoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol, 2-(4-(((5-chloro-8-isopropoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol, 2-(4-(((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol, 2-(4-(((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-1 -yl)ethanol, 2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol, 5-chloro-2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol, N((5-chloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1 -amine, N((5-chloro-8-ethoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1 -amine, N((5-chloro-8-isopropoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine, N((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-1 -amine, N((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine, N((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine, 8-((5-chloro-8-methoxyquinolin-2-yl)methylamino)octan-l-ol, 8-((5-chloro-8-ethoxyquinolin-2-yl)methylamino)octan-1 -ol, 8-((5-chloro-8-isopropoxyquinolin-2-yl)methylamino)octan-1 -ol, 8-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1 -ol, 8-((5,7-dichloro-8-methoxyquinolin-2-yl)methylamino)octan-1 -ol, 8-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1 -ol, and 6-(bis((8-methoxyquinolin-2-yl)methyl)amino)hexan-1 -ol.
In another aspect, the invention relates to a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier for use in treating a neurodegenerative disease, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, brain traumatic injury, and spinal cord injury.
CHEMISTRY
Example 1 - Preparation of (8-benzyloxyquinolin-2-yl) and (8-hydroxyquinolin-2-yl)alkyl alcohol
R=H n= 9-15 A1-A7 R=5-CH3 n= 11 A8 R= H n= 9-15 B1-B7 R= 6-CH3 n= 11 A9 R=5-CH3 n=11 B8 R= 5-F n= 11 A10 (d) R= 6-CH3 n=11 B9 R= 5-CI n= 11 A11 -- R= 5-CI n= 11 B10
Reagents and conditions: (a) BnBr, KOH, EtOH, reflux, 15 h.; (b) 1) LHMDS, THF, 0 °C, 1 h.; 2) Br(CH2)„-iOH, rt, 16 - 36 h.; (c) H2, Pd/C, MeOH, rt, 6 to 10 h.; (d) BC13, CH2C12, 0 °C to rt, 3 h.
Method: The benzylation was performed as described by G. Serratrice et al. [Tetrahedron, 1996, 52, 4659-4672]. Benzyl bromide (6.45 g, 37.7 mmol) was added to a stirred solution of 2-methylquinaldine (5.0 g, 31.4 mmol) and KOH (1.95 g, 34.8 mmol) in 60 ml EtOH under reflux condition. After 15 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 Br(CH2)n-iOH (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 chromatography with Hex/EA (3:1 to 2:1) or DCM/EA (15:1 to 9:1) and recrystallized 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 610 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 All (0.65g, 1.4 mmol) in 20 ml CH2C12 was added 1M BCb (2.8 ml, 2.8 mmol) at an ice bath for 3 h. The reaction mixture was poured into an ice bath and extracted by 50 ml CH2C12. The organic layer was concentrated in vacuum and residue purified by flash column chromatography (EA) to afford the product (0.3 lg, 60%). 9-(8-(benzyloxy)quinolin-2-yl)nonan-l-ol (Al)
Yield (YD): 53%. *HNMR (400 MHz, ί/4-MeOD) 58.15 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 6.8 Hz, 2H), 7.31 ~ 7.41 (m, 5H), 7.29 (d, J= 2.0 Hz, 1H), 7.15 (dd, J= 7.6, 2.0 Hz, 1H), 5.40 (s, 2H), 3.52 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 8.0 Hz, 2H), 1.80 (quin, J= 6.8 Hz, 2H), 1.50 (t, J= 7.2 Hz, 2H), 1.28-1.42 (br, 11H); MS. m/z 400.0, [M+Na]+. 10- (8-(benzyloxy)quinolin-2-yl)decan-l-ol (A2) YD: 41%. 'HNMR (400 MHz, ί/4-MeOD) 58.14 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 7.6 Hz, 2H), 7.32- 7.42 (m, 5H), 7.28 (t, J= 12 Hz, 1H), 7.14 (dd, J= 7.6, 1.2 Hz, 1H), 5.38 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.98 (t, J= 8.0 Hz, 2H), 1.79 (quin, J= 12 Hz, 2H), 1.49 (t, J= 6.8 Hz, 2H), 1.29-1.40 (br, 13H); MS. m/z 414.0, [M+Na]+. 11- (8-(benzyloxy)quinolin-2-yl)undecan-l-ol (A3) YD: 42%. lH NMR (400 MHz, CDCb) 58.02 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 12 Hz, 2H), 7.27 7.39 (m, 6H), 7.02 (d, J= 7.6 Hz, 1H), 5.46 (s, 2H), 3.63 (t, J= 6.8 Hz, 2H), 3.05 (t, J= 8 Hz, 2H), 1.84 (q, J= 7.6 Hz, 3H), 1.56 (t, J= 12 Hz, 2H), 1.29-1.46 (m, 12H); MS. m/z 428.3, [M+Na]+. 12- (8-(benzyloxy)quinolin-2-yl)dodecan-l-ol (A4) YD: 44%. lH NMR (400 MHz, ί/4-MeOD) 58.13 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 7.6 Hz, 2H), 7.31-7.40 (m, 5H), 7.26 (d, J=7.6Hz, 1H), 7.13 (dd, .7=7.6, 0.8 Hz, 1H), 5.37 (s, 2H), 3.51 (t,J = 6.8 Hz, 2H), 2.98 (t, J= 7.6 Hz, 2H), 1.78 (quin, J= 12 Hz, 2H), 1.49 (quin, J= 12 Hz, 2H), 1.25-1.41 (m, 17H); MS. m/z 442.3, [M+Na]+. 13- (8-(benzyloxy)quinolin-2-yl)tridecan-l-ol (A5) YD: 40%.¾ NMR (400 MHz, CDCb) 57.95 (d, J= 8.4 Hz, 1H), 7.45 (d, J= 7.6 Hz, 2H), 7.19 7.30 (m, 5H), 6.93 (d, J= 7.6 Hz, 1H), 5.40 (s, 2H), 3.55 (t, J= 6.8 Hz, 2H), 2.99 (t, J= 7.6 Hz, 2H), 1.77 (quin, J= 7.6 Hz, 2H), 1.46 (t, J= 6.8 Hz, 2H), 1.19-1.38 (br, 19H); MS. m/z 456.3, [M+Na]+. 14- (8-(benzyloxy)quinolin-2-yl)tetradecan-l-ol (A6) YD: 51%. 'HNMR (400 MHz, ί/4-MeOD) 58.14 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 12 Hz, 2H), 7.33- 7.42 (m, 5H), 7.28 (t, J= 12 Hz, 1H), 7.14 (d, J= 6.8 Hz, 1H), 5.38 (s, 2H), 3.52 (t, J= 6.4 Hz, 2H), 2.98 (t, J= 8.0 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.47 (t, J= 6.8 Hz, 2H), 1.22-1.41 (br, 21H); MS. m/z 447.3, [M+H]+. 15- (8-(benzyloxy)quinolin-2-yl)pentadecan-l-ol (A7) YD: 42%. lH NMR (400 MHz, ί/4-MeOD) 58.15 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 12 Hz, 2H), 7.35-7.43 (m, 5H), 7.28-7.33 (m, 1H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 5.39 (s, 2H), 3.52 (t, J= 6.8 Hz, 2H), 2.99 (t, J= 8.0 Hz, 2H), 1.79 (quin, J= 6.8 Hz, 2H), 1.51 (quin, J= 6.8 Hz, 2H), 1.221.41 (br, 23H); MS. m/z 462.3, [M+H]+. ll-(8-(benzyloxy)-5-methylquinolin-2-yl)undecan-l-ol (A8) YD: 47%. lH NMR (400 MHz, ί/4-MeOD) 58.30 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 12 Hz, 2H), 7.44 (d, J= 8.8 Hz, 1H), 7.26-7.36 (m, 3H), 7.17 (d, J= 8.0 Hz, 2H), 7.02 (d, J= 8.0 Hz, 2H), 5.36 (s, 2H), 3.52 (t, J= 6.4 Hz, 2H), 3.00 (t, J= 7.6 Hz, 2H), 2.55 (s, 3H), 1.80 (quin, J= 7.2 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.28-1.41 (m, 15H); MS. m/z 420.3, [M+H]+. ll-(8-(benzyloxy)-6-methylquinolin-2-yl)undecan-l-ol (A9) YD: 40%. l¥i NMR (400 MHz, ί/4-MeOD) 58.03 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 7.2 Hz, 2H), 7.33-7.37 (m, 3H), 7.:26-7.30 (m, 1H), 7.16 (s, 1H), 7.00 (d, J= 1.2 Hz, 2H), 5.36 (s, 2H), 3.51 (t, J= 6.8 Hz, 2H), 2.95 (t, J= 7.6 Hz, 2H), 2.40 (s, 3H), 1.76 (q, J= 7.6 Hz, 2H), 1.56 (t, J= 12 Hz, 2H), 1.29-1.46 (m, 15H); MS. m/z 442.3, [M+Na]+. ll-(8-(benzyloxy)-5-fhioroquinolin-2-yl)undecan-l-ol (A10) YD: 43%. Ή NMR (400 MHz, CDCb) 58.28 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 7.2 Hz, 2H), 7.33 7.40 (m, 3H), 7.28 (t, J= 8.0 Hz, 1H), 6.89 ~ 6.98 (m, 2H), 5.42 (s, 2H), 3.61 (t, J= 6.4 Hz, 2H), 3.07 (t, J= 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, [M+Na]+. ll-(8-(benzyloxy)-5-chloroquinolin-2-yl)undecan-l-ol (All) YD: 43%. H NMR (400 MHz, ί/4-MeOD) 58.48 (d, J= 8.8 Hz, 1H), 7.52-7.57 (m, 3H), 7.46 (d, J= 8.4 Hz, 1H), 7.35 -7.39 (m, 2H), 7.31 (d, ./= 7.2 Hz, 1H), 7.14 (d,J= 8.4 Hz, 1H), 5.40 (s, 2H), 3.52 (t, J= 6.8 Hz, 2H), 3.03 (t, J= 7.6 Hz, 2H), 1.81 (quin, J= 7.2 Hz, 2H), 1.49 (t, J= 6.8 Hz, 2H), 1.28-1.41 (m, 15H); MS. m/z 462.2, [M+Na]+. 2-(9-hydroxynonyl)quinolin-8-ol (Bl) YD: 85%. l¥i NMR (400 MHz, ί/4-MeOD) 57.86 (d, J= 8.4 Hz, 1H), 7.22 (t, J= 7.6 Hz, 1H), 7.03-7.13 (m, 3H), 3.50 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 8.0 Hz, 2H), 1.58 (quin, J= 6.8 Hz, 2H), 1.44 (quin, J= 6.8 Hz, 2H), 1.10-1.20 (m, 11H); HRMS (ESI): Calcd for [CisHisNCb-Naf: 310.1778, Found: 310.1779. 2-(10-hydroxydecyl)quinolin-8-ol (B2) YD: 85%. Ή NMR (400 MHz, CDCb) 58.01 (d, J= 8.4 Hz, 1H), 7.35 (t, J= 6.8 Hz, 1H), 7.26 7.28 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H), 3.60 (t, J= 6.4 Hz, 2H), 2.92 (t, J= 7.6 Hz, 2H), 1.79 (quin, J= 6.8 Hz, 2H), 1.53 (quin, J= 6.8 Hz, 2H), 1.27-1.33 (br, 14H); MS. m/z 302.2, [M+H]+. 2-(ll-hydroxyundecyl)quinolin-8-ol (B3) YD: 77%. Ή NMR (400 MHz, CDCb) 58.04 (d, J= 8.4 Hz, 1H), 7.38 (t, J= 7.8 Hz, 1H), 7.27 7.31 (m, 2H), 7.14 (dd, J = 1.2, 7.6 Hz, 1H), 3.64 (t, J= 6.8 Hz, 2H), 2.95 (t, J= 7.8 Hz, 2H), 1.83 (quin, J= 7.8 Hz, 2H), 1.55 (m, 2H), 1.28-1.36 (br, 17H); 1 MS. m/z 316.2, [M+H]+. 2-(12-hydroxydodecyl)quinolin-8-ol (B4) YD: 76%. Ή NMR (400 MHz, CDCb) 58.03 (d, J= 8.4 Hz, 1H), 7.36 (t, J= 8 Hz, 1H), 7.25 7.30 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 3.62 (t, J= 6.4 Hz, 2H), 2.94 (t, J= 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, [M+H]+. 2-(13-hydroxytridecyl)quinolin-8-ol (B5) YD: 84%. l¥i NMR (400 MHz, CDC13) 58.03 (d, J= 8.4 Hz, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.26 7.30 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 3.62 (t, J= 6.8 Hz, 2H), 2.95 (t, J= 7.6 Hz, 2H), 1.81 (quin, J= 7.2 Hz, 2H), 1.54 (quin, J= 6.8 Hz, 2H), 1.25-1.34 (br, 20H); MS. m/z 344.3, [M+H]+. 2-(14-hydroxytetradecyl)quinolin-8-ol (B6) YD: 87%. Ή NMR (400 MHz, CDCI3) 58.02 (d, J= 8.8 Hz, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.25 7.29 (m, 2H), 7.12 (d, J = 7.2 Hz, 1H), 3.61 (t, J= 6.4 Hz, 2H), 2.94 (t, J= 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. m/z 358.3, [M+H]+. 2-(15-hydroxypentadecyl)quinolin-8-ol (B7) YD: 83%. 'HNMR (400 MHz, CDCI3) 58.04 (d, J= 8.4 Hz, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.26 7.29 (m, 2H), 7.13 (d, J = 7.2 Hz, 1H), 3.62 (t, J= 6.8 Hz, 2H), 2.95 (t, J= 7.6 Hz, 2H), 1.80 (quin, J= 7.2 Hz, 2H), 1.54 (quin, J= 7.2 Hz, 2H), 1.24-1.37 (br, 24H); MS. m/z 372.3, [M+H]+. 2-(ll-hydroxyundecyl)-5-methylquinolin-8-ol (B8) YD: 83%. Ή NMR (400 MHz, ί/4-MeOD) 58.26 (d, J= 8.4 Hz, 1H), 7.39 (d, J= 8.8 Hz, 1H), 7.15 (d, J= 12 Hz, 1H), 6.93 (d, J= 3.2 Hz, 1H), 3.52 (t, J= 6.4 Hz, 2H), 2.95 (t, J= 8.0 Hz, 2H), 2.53 (s, 3H), 1.81 (quin, J= 12 Hz, 2H), 1.48 (quin, J= 6.8 Hz, 2H), 1.13-1.37 (m, 15H); MS. m/z 330.3, [M+H]+. 2-(ll-hydroxyundecyl)-6-methylquinolin-8-ol (B9) YD: 83%. l¥i NMR (400 MHz, ί/4-MeOD) 57.99 (d, J= 8.4 Hz, 1H), 7.29 (d, J= 8.8 Hz, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 3.51 (t, J= 6.4 Hz, 2H), 2.90 (t, J= 8.0 Hz, 2H), 2.41 (s, 3H), 1.77 (quin, J= 6.4 Hz, 2H), 1.49 (quin, J= 6.8 Hz, 2H), 1.25-1.37 (m, 19H); MS. m/z 352.2, [M+Na]+. 5-chloro-2-(ll-hydroxyundecyl)quinolin-8-ol (BIO) 'HNMR (400 MHz, ί/4-MeOD) 58.39 (d, J= 8.8 Hz, 1H), 7.49 (d, J= 8.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 3.51 (t, J = 6.4 Hz, 2H), 2.98 (t, J= 8.0 Hz, 2H), 1.81 (quin, J= 12 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.27-1.35 (m, 15H); MS. m/z 350.2, [M+H]+. Example 2 - Preparation of (8-methoxyquinol-2-yl)alkyl alcohols
Reagents and conditions: (a) Mel, K2CO3, acetone, r.t, 10 h.; (b) 1) LHMDS, THF, 0 °C, 1 h.; 2) Br(CH2)„-iOH, rt, 12 - 30 h.
Method: Methyl iodide (10.8 g, 76.3 mmol) was added to a stirred solution of 2-methylquinaldine (1.0 g, 6.3 mmol) and K2CO3 (5.0 g, 36.2 mmol) in 30 ml 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 recrystallized with Hexane/EA to give 8-methoxy-2-methylquinoline 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 Br(CH2)n-iOH (1.0 to 1.2 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 recrystallized by Hex/EA to afford series of compounds C. 9- (8-methoxyquinolin-2-yl)nonan-l-ol (Cl) YD: 50%. l¥i NMR (400 MHz, CDCb) 58.05 (d, J= 8.4 Hz, 1H), 7.33-7.42 (m, 3H), 7.04 (d, J = 6.8 Hz, 1H), 4.08 (s, 3H), 3.62 (t, J= 6.4 Hz, 2H), 3.07 (t, J= 7.6 Hz, 2H), 1.79 (br, 2H), 1.53 (br, 2H), 1.30-1.42 (br, 11H); MS. m/z 324.0, [M+Na]+. 10- (8-methoxyquinolin-2-yl)decan-l-ol (C2) YD: 38%. l¥i NMR (400 MHz, CDCb) 5 8.01 (d, J= 8.4 Hz, 1H), 7.36 (t, J= 7.6 Hz, 1H), 7.307.33 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H), 3.60 (t, J= 6.8 Hz, 2H), 3.01 (t, J= 7.6 Hz, 2H), 1.79 (quin, J= 8 Hz, 2H), 1.52 (quin, J= 6.8 Hz, 2H), 1.30-1.43 (br, 12H); MS. m/z 316.2, [M+H]+. 11- (8-methoxyquinolin-2-yl)undecan-l-ol (C3) YD: 42%. Ή NMR (400 MHz, CDCb) 58.02 (d, J= 8.8 Hz, 1H), 7.38 (t, J= 7.8 Hz, 1H), 7.317.34 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H), 3.61 (t, J= 6.8 Hz, 2H), 3.02 (t, J= 7.8 Hz, 2H), 1.79 (quin, J= 7.6 Hz, 2H), 1.54 (quin, J= 6.8 Hz, 2H), 1.31-1.42 (br, 15H); MS. m/z 352.2, [M+Na]+. 12- (8-methoxyquinolin-2-yl)dodecan-l-ol (C4) YD: 38%. Ή NMR (400 MHz, CDCb) 58.01 (d, J= 8.8 Hz, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.30 7.32 (m, 2H), 7.01 (d, J = 7.2 Hz, 1H), 4.05 (s, 3H), 3.61 (t, J= 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, [M+H]+. 13- (8-methoxyquinolin-2-yl)tridecan-l-ol (C5) YD: 38%. Ή NMR (400 MHz, CDCb) 58.01 (d, J= 8.4 Hz, 1H), 7.37 (t, J= 7.6 Hz, 1H), 7.30 7.33 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 4.05 (s, 3H), 3.61 (t, J= 12 Hz, 2H), 3.01 (t, J= 8 Hz, 2H), 1.80 (quin, J= 7.6 Hz, 2H), 1.54 (quin, J= 6.8 Hz , 2H), 1.36-1.43 (br, 19H); MS. m/z 358.3, [M+H]+. 14- (8-methoxyquinolin-2-yl)tetradecan-l-ol (C6) YD: 38%. Ή NMR (400 MHz, CDCb) 58.02 (d, J= 8.4 Hz, 1H), 7.31-7.38 (m, 3H), 7.01 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H), 3.61 (t, J= 6.8 Hz, 2H), 3.02 (t, J= 8 Hz, 2H), 1.79 (quin, J= 7.6 Hz, 2H), 1.54 (quin, J= 6.8 Hz , 2H), 1.23-1.40 (br, 21H); MS. m/z 394.3, [M+Na]+. 15-(8-methoxyquinolin-2-yl)pentadecan-l-ol (C7) YD: 31%. !H NMR (400 MHz, CDC13) 58.01 (d, ./= 8.4 Hz, 1H), 7.31-7.39 (m, 3H), 7.01 (d, J = 7.2 Hz, 1H), 4.06 (s, 3H), 3.63 (t, J= 6.8 Hz, 2H), 3.02 (t, J= 8 Hz, 2H), 1.79 (quin, J= 7.6 Hz, 2H), 1.54 (quin, J= 6.8 Hz , 2H), 1.32-1.43 (br, 23H); MS. m/z 408.3, [M+H]+. ll-(8-methoxy-5-methylquinolin-2-yl)undecan-l-ol (C8) YD: 30%. l¥i NMR (400 MHz, ί/4-MeOD) 58.29 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 8.8 Hz, 1H), 7.24 (dd, J= 8.0, 0.8 Hz, 1H), 7.01 (d, J= 8.0 Hz, 1H), 4.00 (s, 3H), 3.51 (t, J= 6.8 Hz, 2H), 2.97 (t, J= 8.0 Hz, 2H), 2.56 (s, 3H), 1.76 (quin, J= 7.6 Hz, 2H), 1.50 (quin, J= 7.2 Hz, 2H), 1.27-1.40 (br, 15H); MS. m/z 366.2, [M+Na]+. 11- (5-fhioro-8-methoxyquinolin-2-yl)undecan-l-ol (C9) 'HNMR (400 MHz, ί/4-MeOD) 58.34 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 8.8 Hz, 1H), 7.15 (d, J = 12 Hz, 1H), 6.93 (d, J= 3.2 Hz, 1H), 4.02 (s, 3H), 3.52 (t, J= 6.8 Hz, 2H), 2.95 (t, J= 8.0 Hz, 2H), 1.81 (quin, J= 12 Hz, 2H), 1.48 (quin, J= 6.8 Hz, 2H), 1.13-1.37 (m, 15H); MS. m/z 370.2, [M+Na]+. 12- (5-fluoro-8-methoxyquinolin-2-yl)dodecan-l-ol (CIO) YD: 38%. Ή NMR (400 MHz, ί/4-MeOD) 58.36 (d, J= 8.8 Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H), 7.17 (d, J= 8.8 Hz, 1H), 7.08 (dd, J= 8.4, 4.8 Hz, 1H), 4.04 (s, 3H), 3.53 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 8.0 Hz, 2H), 1.78 (quin, J= 12 Hz, 2H), 1.51 (quin, J= 12 Hz, 2H), 1.28-1.42 (m, 17H); MS. m/z 384.2, [M+Na]+. 9-(5-chloro-8-methoxyquinolin-2-yl)nonan-l-ol (Cll) YD: 38%. Ή NMR (400 MHz, ί/4-MeOD) 58.47 (d, J= 8.8 Hz, 1H), 7.55 (d, J= 8.8 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.11 (d, J=8.8Hz, 1H), 4.04 (s, 3H), 3.51 (t, .7= 6.8 Hz, 2H), 3.00 (t,J = 8.0 Hz, 2H), 1.77 (quin, J= 7.6 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.30-1.37 (m, 11H); MS. m/z 336.2, [M+H]+. ll-(5-chloro-8-methoxyquinolin-2-yl)undecan-l-ol (C12) YD: 35%. Ή NMR (400 MHz, ί/4-MeOD) 58.46 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 4.04 (s, 3H), 3.51 (t, J= 6.8 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.76 (quin, J= 7.6 Hz, 2H), 1.49 (quin, J= 6.8 Hz, 2H), 1.27-1.38 (br, 15H); MS. m/z 386.2, [M+Na]+. 15-(5-chloro-8-methoxyquinolin-2-yl)pentadecan-l-ol (C13) YD: 39%. l¥i NMR (400 MHz, ^-MeOD+CDCb) 58.44 (d, J= 8.4 Hz, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.01 (dd, J= 8.4, 4.0 Hz, 1H), 4.03 (s, 3H), 3.52 (t, J= 6.8 Hz, 2H), 2.99 (t, J= 8.0 Hz, 2H), 1.76 (quin, J= 7.6 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.22-1.38 (m, 23H); MS. m/z 442.3, [M+Na]+. ll-(5-bromo-8-methoxyquinolin-2-yl)undecan-l-ol (C14) YD: 46%. l¥i NMR (400 MHz, CDC13) 58.40 (d, J= 8.4 Hz, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.63 (t, J= 6.8 Hz, 2H), 3.07 (t, J = 8.0 Hz, 2H), 1.79 (quin, J= 7.6 Hz, 2H), 1.55 (quin, J= 6.8 Hz , 2H), 1.30-1.45 (br, 15H); MS. m/z 430.2, [M+Na]+. ll-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-l-ol (C15) YD: 36%. Ή NMR (400 MHz, ^-MeOD+CDCb) 58.40 (dq, J= 10.4, 1.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.58 (d, J= 8.8 Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 4.11 (s, 3H), 3.51 (t, .7= 6.8 Hz, 2H), 3.00 (t, J= 8.0 Hz, 2H), 1.78 (quin, J= 7.6 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.27-1.43 (m, 15H); MS. m/z 420.2, [M+Na]+. 11-(5,8-dimethoxyquinolin-2-yl)undecan-l-ol (C16) YD: 31%; Ή NMR (400 MHz, ί/4-MeOD) 58.46 (d, J= 8.4 Hz, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.51 (t, J= 6.8 Hz, 2H), 2.95 (t, J= 8.0 Hz, 2H), 1.73 (quin, J= 7.6 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.27-1.35 (br, 15H); MS. m/z 360.2, [M+H]+. ll-(8-methoxy-6-methylquinolin-2-yl)undecan-l-ol (C17) YD: 41%. Ή NMR (400 MHz, CDCI3) 57.96 (d, J= 8.4 Hz, 1H), 7.30 (t, J= 8.4 Hz, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 4.06 (s, 3H), 3.63 (t, J= 6.8 Hz, 2H), 3.05 (t, J= 7.6 Hz, 2H), 2.50 (s, 3H), 1.79 (quin, J= 8.0 Hz, 2H), 1.55 (quin, J= 6.8 Hz, 2H), 1.27-1.41 (br, 15H); MS. m/z 366.2, [M+Na]+. ll-(6-fhioro-8-methoxyquinolin-2-yl)undecan-l-ol (C18) YD: 41%; 'HNMR (400 MHz, ί/4-MeOD) 58.12 (d, J= 8.4 Hz, 1H), 7.44 (d, J= 8.8 Hz, 1H), 7.07 (dd, J= 9.2, 2.4 Hz, 1H), 7.01 (dd, J= 10.8, 2.8 Hz, 1H), 4.06 (s, 3H), 3.52 (t, J= 6.8 Hz, 2H), 2.95 (t, J= 8.0 Hz, 2H), 1.75 (quin, J= 7.6 Hz, 2H), 1.48 (quin, J= 7.2 Hz, 2H), 1.19-1.35 (m, 15H); MS. m/z 348.2, [M+H]+. ll-(6-chloro-8-methoxyquinolin-2-yl)undecan-l-ol (C19) YD: 39%; Ή NMR (400 MHz, <74-MeOD) 58.11 (d, J= 8.4 Hz, 1H), 7.44-7.47 (m, 2H), 7.13 (d, J= 2.0 Hz, 1H), 4.05 (s, 3H), 3.52 (t, J= 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. m/z 360.2, [M+H]+. ll-(7-fhioro-8-methoxyquinolin-2-yl)undecan-l-ol (C20) YD: 32%; Ή NMR (400 MHz, ί/4-MeOD) 58.20 (d, J= 8.8 Hz, 1H), 7.60 (dd, J= 8.8, 5.6 Hz, 1H), 7.39 (dd, J= 8.8, 1.6 Hz, 1H), 7.01 (d, J= 8.8 Hz, 1H), 4.13 (d, J= 1.2 Hz, 3H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t, J= 7.6 Hz, 2H), 1.80 (quin, J= 7.6 Hz, 2H), 1.48 (quin, J= 6.8 Hz, 2H), 1.29-1.42 (m, 15H); MS. m/z 348.2, [M+H]+. ll-(7-chloro-8-methoxyquinolin-2-yl)undecan-l-ol (C21) YD: 17%; Ή NMR (400 MHz, ί/4-MeOD) 58.20 (d, J= 8.4 Hz, 1H), 7.60 (d, J= 8.8 Hz, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.42 (d, J= 8.4 Hz, 1H), 4.08 (s, 3H), 3.52 (t, J= 6.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.82 (quin, J= 7.2 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.28-1.42 (br, 15H); MS. m/z 360.2, [M+H]+. ll-(5-chloro-6,8-dimethoxyquinolin-2-yl)undecan-l-ol (C22) YD: 32%; Ή NMR (400 MHz, ί/4-MeOD) 58.40 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 8.8 Hz, 1H), 7.07 (s, 1H), 4.08 (s, 3H), 4.02 (s, 3H), 3.51 (t, J= 6.8 Hz, 2H), 2.94 (t, J= 7.6 Hz, 2H), 1.74 (quin, J= 7.6 Hz, 2H), 1.50 (quin, J= 6.8 Hz , 2H), 1.27-1.34 (br, 15H); MS. m/z 394.2, [M+H]+. ll-(6-chloro-5,8-dimethoxyquinolin-2-yl)undecan-l-ol (C23) YD: 35%; 'HNMR (400 MHz, ί/4-MeOD) 58.38 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.12 (s, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 3.52 (t, J= 6.4 Hz, 2H), 2.97 (t, J= 7.6 Hz, 2H), 1.74 (quin, J= 7.6 Hz, 2H), 1.50 (quin, J= 6.8 Hz , 2H), 1.34-1.41 (br, 15H); MS. m/z 394.2, [M+H]+. 11-(5,7-dichloro-8-methoxyquinolin-2-yl)undecan-l-ol (C24) YD: 40%. l¥i NMR (400 MHz, CDC13) 58.40 (d, J= 8.4 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.19 (s, 3H), 3.63 (t, J= 6.8 Hz, 2H), 3.04 (t, J= 7.6 Hz, 2H), 1.84 (quin, J= 7.2 Hz, 2H), 1.55 (quin, J= 6.8 Hz , 2H), 1.27-1.40 (br, 15H); MS. m/z 420.2, [M+Na]+.
Example 3 - Preparation of (8-ethoxyquinol-2-yl) and (8-Isopropoxyquinol-2-yl)alkyl alcohols
Reagents and conditions: (a) Ethyl iodide or 2-bromopropane, K2CO3, DMF, 60 °C, 14 h.; (b) 1) LHMDS, THF, 0 °C, 1 h.; 2) Br(CH2)n-iOH, RT, 12 - 30 h.
Method: Ethyl iodide (3.9 g, 25.0 mmol) or 2-bromopropane (2.4 g, 19.2 mmol) was added to a stirred solution of 2-methylquinaldine (3.0 g, 18.8 mmol) and K2CO3 (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 H2O (200 ml) and extracted with EtOAc (50 ml 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 recrystallized with Hexane/EA to give 8-ethoxy-2-methylquinoline as intermediate (2.75g, 78%) in solid but liquid form for 8-isopropoxy-2-methylquinoline (2.92g, 77%). LHMDS (2.2 equiv.) was treated with a stirred solution of different intermediates in THF solution at 0 °C for 1 h. Corresponding Br(CH2)n-iOH (1.1 - 1.2 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 recrystallized by Hexane/EA to afford compound D and E. 9- (8-ethoxyquinolin-2-yl)nonan-l-ol (Dl) YD: 45%. l¥i NMR (400 MHz, CDCb) 58.07 (d, J= 8.0 Hz, 1H), 7.34-7.42 (m, 3H), 7.06 (d, J = 8.4 Hz, 1H), 4.35 (q, J= 6.8 Hz, 2H), 3.63 (t, J= 6.8 Hz, 2H), 3.11 (br, 2H), 1.83 (quin, J= 7.6 Hz, 2H), 1.52-1.64 (m, 5H), 1.26-1.46 (br, 11H); MS. m/z 338.0, [M+Na]+. 10- (8-ethoxyquinolin-2-yl)decan-l-ol (D2) YD: 36%. Ή NMR (400 MHz, ί/4-MeOD) 58.16 (d, J= 8.4 Hz, 1H), 7.38-7.44 (m, 3H), 7.14 (dd, J= 12, 1.6 Hz, 1H), 4.29 (q, J= 6.8 Hz, 2H), 3.52 (t, J= 6.8 Hz, 2H), 2.99 (t, J= 7.6 Hz, 2H), 1.78 (quin, J= 7.6 Hz, 2H), 1.57 (t, J= 7.6 Hz, 3H), 1.50 (t, J= 7.6 Hz, 2H), 1.30-1.43 (br, 13H); MS. m/z 352.0, [M+Na]+. 11- (8-ethoxyquinolin-2-yl)undecan-l-ol (D3) YD: 43%. 'HNMR (400 MHz, CDCb) 58.03 (d, J= 7.6 Hz, 1H), 7.31-7.41 (m, 3H), 7.04 (d, J = 12 Hz, 1H), 4.33 (q, J= 12 Hz, 2H), 3.62 (t, J= 6.4 Hz, 2H), 3.06 (br, 2H), 1.81 (quin, J= 8.0 Hz, 2H), 1.51-1.61(m, 6H), 1.38-1.51 (br, 14H); MS. m/z 344.3, [M+H]+. 12- (8-ethoxyquinolin-2-yl)dodecan-l-ol (D4) YD: 33%.¾ NMR (400 MHz, CDCb) 58.03 (d, J= 8.4 Hz, 1H), 7.31-7.39 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 4.33 (q, J= 6.8 Hz, 2H), 3.62 (t, J= 6.4 Hz, 2H), 3.05 (t, J= 8.0 Hz, 2H), 1.82 (quin, J= 12 Hz, 2H)„ 1.53-1.62 (m, 5H), 1.27-1.42 (br, 17H); MS. m/z 380.3, [M+Na]+. 13- (8-ethoxyquinolin-2-yl)tridecan-l-ol (D5) YD: 43%. l¥i NMR (400 MHz, CDCb) 58.04 (d, J= 8.4 Hz, 1H), 7.32-7.40 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 4.34 (q, J= 6.8 Hz, 2H), 3.62 (t, J= 6.4 Hz, 2H), 3.07 (t, J= 8.0 Hz, 2H), 1.82 (quin, J= 7.6 Hz, 2H), 1.52-1.62 (m, 5H), 1.19-1.46 (br, 19H); MS. m/z 394.0, [M+Na]+. 14- (8-ethoxyquinolin-2-yl)tetradecan-l-ol (D6) YD: 35%. l¥i NMR (400 MHz, CDCb) 58.00 (d, J= 8.4 Hz, 1H), 7.28-7.35 (m, 3H), 7.02 (d, J = 12 Hz, 1H), 4.32 (q, J= 6.8 Hz, 2H), 3.61 (t, 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, 21H); MS. m/z 408.3, [M+Na]+. 15- (8-ethoxyquinolin-2-yl)pentadecan-l-ol (D7) YD: 33%. Ή NMR (400 MHz, ί/4-MeOD) 58.21 (d, J= 8.4 Hz, 1H), 7.40-7.47 (m, 3H), 7.17 (dd, J= 12, 1.6 Hz, 1H), 4.30 (q, J= 12 Hz, 2H), 3.52 (t, J= 6.8 Hz, 2H), 3.01 (t, J= 7.6 Hz, 2H), 1.78 (quin, J= 7.6 Hz, 2H), 1.57 (t, J= 6.8 Hz, 3H), 1.51 (quin, J= 6.8 Hz, 2H), 1.26-1.43 (br, 23H); MS. m/z 400.4, [M+Na]+. ll-(8-ethoxy-5-methylquinolin-2-yl)undecan-l-ol (D8) YD: 34%. 'HNMR (400 MHz, CDC13) 58.20 (d, J= 8.8 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 7.6 Hz, 1H), 6.94 (d, J= 8.0 Hz, 1H), 4.31 (q, J= 6.8 Hz, 2H), 3.63 (t, J= 6.4 Hz, 2H), 3.08 (t, J= 8.0 Hz, 2H), 2.57 (s, 3H), 1.83 (quin, J= 7.6 Hz, 2H), 1.83 (t, J= 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+Na]+. ll-(8-ethoxy-5-fluoroquinolin-2-yl)undecan-l-ol (D9) YD: 49%. l¥i NMR (400 MHz, ί/4-MeOD) 58.33 (d, J= 8.4 Hz, 1H), 7.49 (d, J= 8.8Hz, 1H), 7.12 (t, J= 9.2 Hz, 1H), 7.05 (dd, J= 8.4, 4.8 Hz, 1H), 4.25 (q, J= 7.2 Hz, 2H), 3.51 (t, J= 6.8 Hz, 2H), 2.99 (t, J= 8.0 Hz, 2H), 1.77 (quin, J= 7.2 Hz, 2H), 1.55 (t, J= 7.2 Hz, 3H), 1.48-1.52 (m, 2H), 1.28-1.46 (br, 15H); MS. m/z 384.2, [M+Na]+. 9-(5-chloro-8-ethoxyquinolin-2-yl)nonan-l-ol (DIO) YD: 34%. Ή NMR (400 MHz, ί/4-MeOD) 58.47 (d, J= 8.8 Hz, 1H), 7.55 (d, J= 8.8 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.10 (d, J= 8.8 Hz, 1H), 4.28 (q, J= 6.8 Hz, 2H), 3.51 (t, J= 6.4 Hz, 2H), 3.01 (t, J= 8.0 Hz, 2H), 1.76 (quin, J= 7.6 Hz, 2H), 1.56 (t, J= 6.8 Hz, 3H), 1.48-1.51 (m, 2H), 1.31-1.46 (br, 11H); MS. m/z 350.2, [M+H]+. ll-(5-chloro-8-ethoxyquinolin-2-yl)undecan-l-ol (Dll) YD: 38%. 'HNMR (400 MHz, CDCI3) 58.35 (d, J= 8.8 Hz, 1H), 7.36 (dd, J= 8.4, 3.6 Hz, 1H), 7.19 (d, J= 2.4 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 4.25 (q, J= 7.2 Hz, 2H), 3.56 (t, 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. m/z 400.2, [M+Na]+. 15-(5-chloro-8-ethoxyquinolin-2-yl)pentadecan-l-ol (D12) YD: 38%. 'HNMR (400 MHz, ^-MeOD+CDCb) 58.47 (d, J= 8.8 Hz, 1H), 7.53 (d, J= 8.8 Hz, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.08 (d, J= 8.4 Hz, 1H), 4.28 (q, J= 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.01 (t, J= 8.0 Hz, 2H), 1.79 (quin, J= 7.6 Hz, 2H), 1.57 (t, 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]+. ll-(5-bromo-8-ethoxyquinolin-2-yl)undecan-l-ol (D13) YD: 33%.¾ NMR (400 MHz, ί/4-MeOD) 5 8.41 (d, J= 8.8 Hz, 1H), 7.67 (d, J= 8.4Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H), 7.04 (d, J= 8.4 Hz, 1H), 4.27 (q, J= 12 Hz, 2H), 3.52 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 8.0 Hz, 2H), 1.77 (quin, J= 7.6 Hz, 2H), 1.56 (t, J= 12 Hz, 3H), 1.47-1.57 (m, 2H), 1.27-1.39 (br, 15H); MS. m/z 444.2, [M+Na]+. 11-(5,7-dichloro-8-ethoxyquinolin-2-yl)undecan-l-ol (D14) YD: 34%. Ή NMR (400 MHz, ί/4-MeOD) 58.43 (d, J= 8.8 Hz, 1H), 7.64 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.39 (q, J= 6.8 Hz, 2H), 3.52 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 12 Hz, 2H), 1.84 (quin, J= 12 Hz, 2H), 1.45-1.49 (m, 5H), 1.27-1.36 (br, 15H); MS. m/z 434.2, [M+Na]+. 9-(8-isopropoxyquinolin-2-yl)nonan-l-ol (El) YD: 28%. 'HNMR (400 MHz, ί/4-MeOD) δ 8.07 (d, J= 8.8 Hz, 1H), 7.33-7.36 (m, 1H), 7.31 7.33 (m, 2H), 7.09 (d, J= 12 Hz, 1H), 4.79 (m, 1H), 3.49 (t, J= 6.8 Hz, 2H), 2.93 (t, J= 7.6 Hz, 2H), 1.71 (quin, J= 7.6 Hz, 2H), 1.45-1.49 (m, 2H), 1.41 (d,J=6Hz, 6H), 1.20-1.35 (br, 11H); MS. m/z 330.2, [M+H]+. 10- (8-isopropoxyquinolin-2-yl)decan-l-ol (E2) YD: 36%. 'HNMR (400 MHz, ί/4-MeOD) δ 8.14 (d, J= 8.8 Hz, 1H), 7.40-7.43 (m, 1H), 7.377.39 (m, 2H), 7.16 (dd, J= 6.8, 2.0 Hz, 1H), 4.83 (m, 1H), 3.51 (t, J= 6.8 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 1.77 (quin, J= 12 Hz, 2H), 1.45-1.49 (m, 2H), 1.41 (d, J= 6 Hz, 6H), 1.20-1.35 (br, 11H); MS. m/z 366.0, [M+Na]+. 11- (8-isopropoxyquinolin-2-yl)undecan-l-ol (E3) YD: 45 %. l¥i NMR (400 MHz, CDCb) 51.99 (d, J= 8.4 Hz, 1H), 7.34 (d, J= 4.4 Hz, 2H), 7.247.27 (m, 1H), 7.09 (t, J= 4.4 Hz, 1H), 4.82 (sept, J= 6 Hz, 1H), 3.60 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 7.6 Hz, 2H), 1.81 (quin, J= 7.6 Hz, 2H), 1.51-1.56 (m, 2H), 1.47 (d, J= 6 Hz, 6H), 1.33-1.43 (br, 15H); MS. m/z 380.3, [M+Na]+. 12- (8-isopropoxyquinolin-2-yl)dodecan-l-ol (E4) YD: 34 %. 'HNMR (400 MHz, CDCb) δ8.05 (d, J= 7.6 Hz, 1H), 7.30-7.39 (m, 3H), 7.13 (dd, J = 6.4, 2.4 Hz, 1H), 4.85 (sept, J= 6 Hz, 1H), 3.63 (t, J= 6.8 Hz, 2H), 3.09 (br, 2H), 1.84 (quin, J = 7.6 Hz, 2H), 1.56 (quin, J= 12 Hz, 2H), 1.48 (d, J= 6 Hz, 6H), 1.27-1.47 (br, 17H); MS. m/z 394.3, [M+Na]+. 13- (8-isopropoxyquinolin-2-yl)tridecan-l-ol (E5) YD: 34%. !H NMR (400 MHz, ί/4-MeOD) δ 8.11 (d,J= 8.4 Hz, 1H), 7.35-7.41 (m, 3H), 7.14 (d, J= 12 Hz, 1H), 4.81 (br, 1H), 3.52 (t, J= 6.8 Hz, 2H), 2.96 (t, J= 8.0 Hz, 2H), 1.75 (quin, J = 12 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+Na]+. 14- (8-isopropoxyquinolin-2-yl)tetradecan-l-ol (E6) YD: 36%. Ή NMR (400 MHz, ί/4-MeOD) 68.13 (d, J= 8.8 Hz, 1H), 7.37-7.43 (m, 3H), 7.16 (dd, J= 12, 1.6 Hz, 1H), 4.86 (br, 1H), 3.52 (t, J= 6.8 Hz, 2H), 2.98 (t, J= 7.6 Hz, 2H), 1.78 (quin, J= 7.6 Hz, 2H), 1.49-1.52 (m, 2H), 1.46 (d, J= 6.4 Hz, 6H), 1.26-1.41 (br, 21H); MS. m/z 422.3, [M+Na]+. 15- (8-isopropoxyquinolin-2-yl)pentadecan-l-ol (E7) YD: 36%. 'HNMR (400 MHz, CDCb) 68.01 (d, J= 8.4 Hz, 1H), 7.27-7.36 (m, 3H), 7.10-7.13 (m, 1H), 4.82 (sept, J= 4.1 Hz, 1H), 3.61 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 6.4 Hz, 2H), 1.81 (quin, J= 7.6 Hz, 2H), 1.52-1.55 (m, 2H), 1.48 (d, J= 2 Hz, 6H), 1.31-1.47 (br, 21H); MS. m/z 436.3, [M+Na]+. ll-(8-isopropoxy-5-methylquinolin-2-yl)undecan-l-ol (E8) YD: 48%. 'HNMR (400 MHz, CDC13) 58.09 (d, J= 8.4 Hz, 1H), 7.26 (d, J= 8.8 Hz, 1H), 7.12 (d, J= 8.0 Hz, 1H), 6.97 (t, J= 7.6 Hz, 1H), 4.75 (sept, J= 6 Hz, 1H), 3.55 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 7.6 Hz, 2H), 2.51 (s, 3H), 1.81 (t, J= 12 Hz, 2H), 1.23-1.49 (br, 23H); MS. m/z 394.3, [M+Na]+. ll-(5-fluoro-8-isopropoxyquinolin-2-yl)undecan-l-ol (E9) YD: 46%. l¥i NMR (400 MHz, ί/4-MeOD) 58.30 (d, J= 8.8 Hz, 1H), 7.44 (d, J= 8.4 Hz, 1H), 7.09 (d, J= 4.8 Hz, 1H), 4.79 (m, 1H), 3.51 (t, J= 6.8 Hz, 2H), 2.97 (t, J= 8.0 Hz, 2H), 1.74 (quin, J= 7.6 Hz, 2H), 1.45-1.51 (m, 2H), 1.42 (d, J= 6.4 Hz, 6H), 1.12-1.39 (br, 15H); MS. m/z 398.2, [M+Na]+. 9-(5-chloro-8-isopropoxyquinolin-2-yl)nonan-l-ol (E10) YD: 46%. l¥i NMR (400 MHz, ί/4-MeOD) 58.45 (d, J= 8.8 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.12 (d, J= 8.4 Hz, 1H), 4.85 (m, 1H), 3.51 (t, J= 6.4 Hz, 2H), 3.01 (t, J= 8.0 Hz, 2H), 1.78 (quin, J= 7.6 Hz, 2H), 1.49 (quin, J= 6.4 Hz, 2H), 1.45 (d, J= 6.0 Hz, 6H), 1.30-1.42 (br, 11H); MS. m/z 364.2, [M+H]+. ll-(5-chloro-8-isopropoxyquinolin-2-yl)undecan-l-ol (Ell) YD: 46%. l¥i NMR (400 MHz, ί/4-MeOD) 58.47 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 4.89 (m, 1H), 3.52 (t, J= 6.4 Hz, 2H), 3.01 (t, J= 12 Hz, 2H), 1.79 (quin, J= 7.6 Hz, 2H), 1.48 (quin, J= 6.8 Hz, 2H), 1.41 (d, J= 5.6 Hz, 6H), 1.21 ~ 1.39 (br, 15H); MS. m/z 414.2, [M+Na]+. 15-(5-chloro-8-isopropoxyquinolin-2-yl)pentadecan-l-ol (E12) YD: 46%. Ή NMR (400 MHz, d4-MeOD +CDCI3) 58.46 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 8.8 Hz, 1H), 7.48 (d, J= 8.8 Hz, 1H), 7.11 (d, J= 8.4 Hz, 1H), 4.85 (m, 1H), 3.52 (t, J= 6.8 Hz, 2H), 3.01 (t, J= 8.0 Hz, 2H), 1.79 (quin, J= 12 Hz, 2H), 1.51 (quin, J= 6.8 Hz, 2H), 1.46 (d, J = 6.0 Hz, 6H), 1.25-1.39 (m, 23H); MS. m/z 448.3, [M+H]+. ll-(5-bromo-8-isopropoxyquinolin-2-yl)undecan-l-ol (E13) YD: 40%. l¥i NMR (400 MHz, ί/4-MeOD) 58.43 (d, J= 8.8 Hz, 1H), 7.69 (d, J= 8.8 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.10 (d, J= 7.6 Hz, 1H), 4.86 (br, 1H), 3.52 (t, J= 6.8 Hz, 2H), 3.02 (t, J= 7.6 Hz, 2H), 1.79 (quin, J= 12 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+Na]+. 11-(5,7-dichloro-8-isopropoxyquinolin-2-yl)undecan-l-ol (E14) YD: 37%. Ή NMR (400 MHz, CDCI3) 58.36 (d, J= 8.4 Hz, 1H), 7.56 (d, J= 3.2 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 5.13 (m, 1H), 3.63 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 7.6 Hz, 2H), 1.86 (quin, J = 6.8 Hz, 2H), 1.52-1.59 (m, 4H), 1.27-1.44 (br, 20H); MS. m/z 448.4, [M+Na]+.
Example 4- Preparation of (8-cyclopropylmethoxyquinol-2-yl)alkyl alcohol derivatives
Reagents and conditions: (a) Methylenecyclopropyl bromide, K2CO3, DMF, 60 °C, 13 h.; (b) 1) LHMDS, THF, 0 °C, 1 h.; 2) Br(CH2)n-iOH, rt, 12 - 20 h.
Method: Methylenecyclopropyl bromide (1.0 g, 6.3 mmol) was added to a stirred solution of 2-methylquinaldine (1.0 g, 6.3 mmol) and K2CO3 (2.5 g, 18.1 mmol) in 25 ml DMF at 60 °C for 13 h. The reaction mixture was quenched by H2O (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-(cyclopropylmethoxy)-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 °C for 1 h.
Corresponding Br(CH2)n-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 recrystallized by Hex/EA to afford compound F. 9- (8-(cyclopropylmethoxy)quinolin-2-yl)nonan-l-ol (FI) YD: 49%. 'HNMR (400 MHz, ί/4-MeOD) 58.15 (d, J= 8.4 Hz, 1H), 7.38-7.43 (m, 3H), 7.14 (dd, J= 5.6, 3.2 Hz, 1H), 4.06 (d, J= 12 Hz, 2H), 3.51 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 8.0 Hz, 2H), 1.77 (quin, J= 7.6 Hz, 2H), 1.48-1.52 (m, 3H), 1.32-1.47 (m, 11H), 0.65-0.70 (m, 2H), 0.340.45 (m, 2H); MS. m/z 342.2, [M+H]+. 10- (8-(cyclopropylmethoxy)quinolin-2-yl)decan-l-ol (F2) YD: 43%. 'HNMR (400 MHz, ί/4-MeOD) 58.16 (d, J= 8.4 Hz, 1H), 7.40 ~ 7.43 (m, 3H), 7.15 (dd, J= 5.6, 3.2 Hz, 1H), 4.07 (d, J= 12 Hz, 2H), 3.52 (t, J= 6.4 Hz, 2H), 3.01 (t, J= 8.0 Hz, 2H), 1.80 (quin, J= 7.6 Hz, 2H), 1.47-1.53 (m, 3H), 1.31-1.44 (m, 13H), 0.67-0.69 (m, 2H), 0.440.46 (m, 2H); MS. m/z 356.2, [M+H]+. 11- (8-(cyclopropylmethoxy)quinolin-2-yl)undecan-l-ol (F3) YD: 45%. l¥i NMR (400 MHz, CDCI3) 58.02 (d, J= 8.4 Hz, 1H), 7.30 ~ 7.38 (m, 2H), 7.05 (dd, J= 6.4, 2.4 Hz, 1H), 4.11 (d, J= 6.8 Hz, 1H), 3.63 (t, J= 6.4 Hz, 2H), 3.04 (t, J= 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. m/z 392.2, [M+Na]+. 12- (8-(cyclopropylmethoxy)quinolin-2-yl)dodecan-l-ol (F4) YD: 36%. 'HNMR (400 MHz, CDCI3) 58.01 (d, J= 8.4 Hz, 1H), 7.29-7.38 (m, 3H), 7.06 (dd, J = 6.0, 2.4 Hz, 1H), 4.11 (d, J= 6.8 Hz, 1H), 3.63 (t, J= 6.4 Hz, 2H), 3.04 (t, J= 12 Hz, 2H), 1.83 (quin, J= 7.6 Hz, 2H), 1.48-1.59 (m, 3H), 1.27-1.47 (br, 17H), 0.67 (dd, J= 13.2, 5.6 Hz, 2H), 0.42-0.48 (m, 2H); MS. m/z 384.3, [M+H]+. 13- (8-(cyclopropylmethoxy)quinolin-2-yl)tridecan-l-ol (F5) YD: 42%. 'HNMR (400 MHz, ί/4-MeOD) 58.14 (d, J= 8.4 Hz, 1H), 7.38 ~ 7.41 (m, 3H), 7.05 (dd, J= 5.6, 3.2 Hz, 1H), 4.05 (d, J= 6.8 Hz, 2H), 3.52 (t, J= 6.4 Hz, 2H), 2.99 (t, J= 8.0 Hz, 2H), 1.78 (quin, J= 7.6 Hz, 2H),1.44-1.52 (m, 3H), 1.26-1.40 (m, 19H), 0.67 (dd, J= 13.2, 5.6 Hz, 2H), 0.40-0.47 (m, 2H); MS. m/z 420.0, [M+Na]+. 14- (8-(cyclopropylmethoxy)quinolin-2-yl)tetradecan-l-ol (F6) YD: 37%. 'HNMR (400 MHz, ί/4-MeOD) 58.15 (d, J= 8.8 Hz, 1H), 7.39 ~ 7.42 (m, 3H), 7.13 (dd, J= 5.6, 3.2 Hz, 1H), 4.05 (d, J= 6.8 Hz, 2H), 3.52 (t, 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 (m, 3H), 1.26-1.43 (m, 21H), 0.65-0.69 (m, 2H), 0.42 (dd, J= 10.0, 4.8 Hz, 2H); MS. m/z 434.3, [M+Na]+. 15- (8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-l-ol (F7) YD: 69%. 'HNMR (400 MHz, ί/4-MeOD+CDCb) 58.13 (dd, J= 8.4, 2.0 Hz, 1H), 7.38 (br, 3H), 7.11 (d, J= 2.4 Hz, 1H), 4.05 (d, J= 6.8 Hz, 2H), 3.52 (t, J= 6.8 Hz, 2H), 2.99 (t, J= 8.0 Hz, 2H), 1.78 (quin, J= 7.2 Hz, 2H),1.46-1.52 (m, 3H), 1.25-1.44 (m, 23H), 0.63-0.69 (m, 2H), 0.400.46 (m, 2H); MS. m/z 426.4, [M+H]+. ll-(8-(cyclopropylmethoxy)-5-methylquinolin-2-yl)undecan-l-ol (F8) YD: 45%. 'HNMR (400 MHz, ί/4-MeOD) 58.31 (d, J= 8.8 Hz, 1H), 5 7.44 (d, J= 8.8 Hz, 1H), 7.22 (d, J= 8.0 Hz, 1H), 7.02 (d, J= 8.0 Hz, 1H), 4.02 (d, J= 12 Hz, 2H), 3.52 (t, J= 6.4 Hz, 2H), 3.00 (t, J= 8.0 Hz, 2H), 2.57 (s, 3H), 1.79 (quin, J= 12 Hz, 2H), 1.29-1.52 (m, 18H), 0.65 -0.68 (m, 2H), 0.40-0.43 (m, 2H); MS. m/z 406.3, [M+Na]+. ll-(8-(cyclopropylmethoxy)-5-fhioroquinolin-2-yl)undecan-l-ol (F9) YD: 46%. 'HNMR (400 MHz, ί/4-MeOD) 58.36 (d, J= 8.8 Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H), 7.07-7.15 (m, 2H), 4.05 (d, J= 6.8 Hz, 2H), 3.53 (t, J= 6.8 Hz, 2H), 3.02 (t, J= 7.6 Hz, 2H), 1.79 (quin, J= 7.6 Hz, 2H), 1.42-1.49 (m, 3H), 1.22-1.40 (m, 15H), 0.65-0.69 (m, 2H), 0.42 (dd, J= 10.4, 4.8 Hz, 2H); MS. m/z 410.2, [M+Na]+. 9-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)nonan-l-ol (F10) YD: 33%. 'HNMR (400 MHz, ί/4-MeOD) 58.48 (d, J= 8.8 Hz, 1H), 7.55 (d, J= 8.8 Hz 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.11 (d, ./= 8.4 Hz, 1H), 4.06 (d, J= 6.8 Hz, 2H), 3.51 (t, ./= 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, 15H), 0.67-0.71 (m, 2H), 0.43-0.46 (m, 2H); MS. m/z 376.2, [M+H]+. ll-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-l-ol (Fll) YD: 34%. 'HNMR (400 MHz, CDC13) 58.41 (d, J= 8.8 Hz, 1H), 7.43 (d, J= 2.4Hz 1H), 7.41 (d, J= 2.4 Hz, 1H), 6.97 (d, J= 8.4 Hz, 1H), 4.09 (d, J= 12 Hz, 2H), 3.63 (t, J= 6.4 Hz, 2H), 3.05 (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, 15H), 0.670.71 (m, 2H), 0.43 -0.46 (m, 2H); MS. m/z 426.2, [M+Na]+. 15-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-l-ol (F12) YD: 28%. l¥i NMR (400 MHz, ^-MeOD+CDCb) 58.47 (d, J= 8.8 Hz, 1H), 7.54 (d, J= 8.8 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 4.06 (d, J= 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.02 (t, J= 7.6 Hz, 2H), 1.79 (quin, J= 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, [M+Na]+. ll-(5-bromo-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-l-ol (F13) YD: 35%. l¥i NMR (400 MHz, ί/4-MeOD) 58.42 (d, J= 8.8 Hz, 1H), 5 7.67 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 8.8 Hz, 1H), 7.06 (d, J= 8.4 Hz, 1H), 4.05 (d, J= 12 Hz, 2H), 3.51 (t, J= 6.4 Hz, 2H), 3.02 (t, J= 8.0 Hz, 2H), 1.77 (quin, J= 7.6 Hz, 2H), 1.46-1.52 (m, 3H), 1.28-1.44 (m, 15H), 0.65-0.70 (m, 2H), 0.42-0.45 (m, 2H); MS. m/z 470.2, [M+Na]+. 11-(5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-l-ol (F14) YD: 53%. Ή NMR (400 MHz, ί/4-MeOD) 58.47 (d, J= 8.8 Hz, 1H), 5 7.67 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.06 (d, J= 8.4 Hz, 1H), 4.23 (d, J= 12 Hz, 2H), 3.53 (t, J= 6.4 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.86 (quin, J= 12 Hz, 2H), 1.48-1.53 (m, 2H), 1.29-1.38 (m, 16H), 0.62 (dd, J = 12.8, 5.2 Hz, 2H), 0.31 (dd, J= 10.8, 5.2 Hz, 2H); MS. m/z 460.2, [M+Na]+.
Example 5 - Preparation of (5,7-dichloro-8-hydroxyquinol-2-yl)alkyl alcohol
Reagents and conditions: (a) NCS, CHCb, rt, 48 h.
Method: N-chlorosuccinimide (0.3 g, 2.25 mmol) 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 recrystallized to give compound G1 (0.18g, 49%). 5,7-dichloro-2-(ll-hydroxyundecyl)quinolin-8-ol (Gl) YD: 49%. Ή NMR (400 MHz, CDCI3) 58.38 (d, J= 8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 3.63 (t, J= 6.8 Hz, 2H), 3.00 (t, J= 7.6 Hz, 2H), 1.82 (quin, J= 12 Hz, 2H), 1.56 (quin, J= 7.6 Hz , 2H), 1.27-1.38 (br, 15H); MS. m/z 382.0, [M-H]+.
Example 6 - Preparation of (5-chloro-8-methoxyquinol-2-yl)alkyl alcohol or alkylacetate
Reagents and conditions: (a) HC1, ICI3, glacial HOAc, H2O, 6 h, rt.
Method: To a various long chain substituted (8-methoxyquinolin-2-yl)-ol (1.0 eq.) was added cone. HC1 (0.5 mL/mmol) at RT and the reddish yellow mixture was stirred for 5 minutes. To this mixture was added dropwise a solution of ICI3 (1.5 eq.) in cone. HC1 (2 mL). The yellow gummy mixture was stirred at RT for 6 h. Water was added to it and partitioned with EA.
Organic layer was washed with brine, drying on anhydrous MgS04 and filtered followed by solvent removal, yielded oily residue purified by flash column chromatography using CHCI3 to yield HI to H5. 10-(5-Chloro-8-methoxyquinolin-2-yl)decan-l-ol (Hla) and acetic acid 10- (5-chloro-8-methoxyquinolin-2-yl)decyl ester (Hlb). YD: 61% and 10%. Hla: Ή NMR (200 MHz, CDCI3) 58.41 (d, J = 8.68 Hz, 1H), 7.42 (dd, J = 8 Hz , J = 2 Hz , 2H), 6.91 (d, J = 8 Hz , 1H), 4.03 (s, 3H), 3.59 (t, J = 6 Hz , 2H), 3.59 (t, J = 4 Hz , 2H), 1.73 (m, 2H), 1.48 (m, 2H), 1.25 (br, 12H); HRMS (El): Calcd for C2oH28C1N02:349.1803, Found:349.1781. Hlb: Ή NMR (400 MHz, CDCI3) 58.41 (d, J = 8 Hz, 1H), 7.42 (dd, J = 8 Hz , J = 4Hz , 2H), 6.92 (d, J = 8 Hz , 1H), 4.06 (t, J = 8 Hz , 2H), 4.02 (s, 3H), 3.03 (t, J = 8 Hz, 2H), 2.02 (s, 3H), 1.79 (m, 2H), 1.59 (m, 2H), 1.40 (m, 2H), 1.23 (br, 12H); HRMS (FAB, M + H): Calcd for C22H31CINO3 392.1992, Found 392.1983. 11- (5-Chloro-8-methoxyquinolin-2-yl)undecan-l-ol (H2a) and acetic acid ll-(5-chloro-8-methoxyquinolin-2-yl)undecyl ester (H2b) YD: 60% and 12%. H2a: Ή NMR (400 MHz, CDCI3) 58.43 (d, J = 8.72 Hz, 1H), 7.44 (dd, J = 13.5 Hz , J = 5.3 Hz , 2H), 6.94 (d, J = 8.3 Hz , 1H), 4.05 (s, 3H), 3.62 (t, J = 6.6 Hz,2H), 3.07 (t, J = 5.2 Hz , 2H), 1.80 (m, 2H), 1.54 (m, 2H), 1.39 (m, 2H), 1.26 (br, 12H); HRMS (El): Calcd for C21H30CINO2 363.1960, Found 363.1941. H2b: Ή NMR (400 MHz, CDCI3) 58.41 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.3 Hz, J = 3.8 Hz, 2H), 6.91(d, J = 8.4 Hz, 1H), 4.06 (t, J = 7.8 Hz, 2H), 4.02 (s, 3H), 3.02 (t, J = 7.8 Hz, 2H), 2.01 (s, 3H), 1.78 (m, 2H), 1.58 (m, 2H), 1.39 (m, 2H), 1.22 (br, 12H); HRMS (El): Calcd for C23H32CINO3 405.2065, Found 405.2044. 12- (5-Chloro-8-methoxyquinolin-2-yl)dodecan-l-ol (H3a) and acetic acid 12-(5-chloro-8-methoxyquinolin-2-yl)dodecyl ester (H3b) YD: 57% and 27%. H3a: Ή NMR (400 MHz, CDCI3) 58.46 (d, J = 8.6 Hz, 1H), 7.44 (dd, J = 8.3 Hz, J = 6.9 Hz, 2H), 6.94(d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 1.78 (m, 2H), 1.50 (m, 2H), 1.40 (m, 2H), 1.23 (br, 14H); HRMS (El): Calcd for C22H32CINO2 377.2116, Found 377.2106. H3b: Ή NMR (200 MHz, CDCI3) 58.38 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 4.03 (t, J = 7.8 Hz, 2H), 4.01 (s, 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 C24H35CINO3 420.2305, Found 420.2310. 13-(5-Chloro-8-methoxyquinolin-2-yl)tridecan-l-ol (H4a) and acetic acid 13-(5-chloro-8-methoxyquinolin-2-yl)tridecyl ester (H4b) YD: 64% and 14%. H4a: Ή NMR (400 MHz, CDC13) 58.46 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.3 Hz, J = 6.9 Hz, 2H), 6.94(d, J = 8.4 Hz, 1H), 4.04 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 1.78 (m, 2H), 1.50(m, 2H), 1.40 (m, 2H), 1.23 (br, 16H); HRMS (El): Calcd for C23H34CINO2 391.2273, Found 391.2249. H4b: Ή NMR (400 MHz, CDCI3) 5 8.38 (d, J = 8.6 Hz, 1H), 7.40 (dd, J = 8.5 Hz, J = 5.8 Hz, 2H), 6.89(d, J = 8.4 Hz, 1H), 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, 2H), 1.38 (m, 2H), 1.22 (br, 16H); HRMS (FAB, M + H): Calcd for C25H37CINO3 434.2462, Found 434.2459. Example 7 - Preparation of (8-hydroxyquinol-4-yl) or (8-alkoxyquinol-4-yl) alkyl alcohols
Reagents and conditions: (a) methyl vinyl ketone, HC1, reflux, (b) Mel, K2CO3, acetone, rt, 8h; EtI or 2-bromopropane or methylenecyclopropyl bromide, K2CO3, DMF, 60 °C, (c) 1) LHMDS, THF, 0 °C, 1 h.; 2) Br(CH2)„-iOH, rt, (d) BnBr, KOH, EtOH, reflux, (e) H2, Pd/C, MeOH, rt, 24 h.
Method: The intermediate INT 1 was synthesized through ring closure from 2-aminophenol reacted with methylvinyl ketone. INT 1 was reacted with various alkyl halides to afford 8-alkoxy-4-methylquinoline derivatives as intermediates. Corresponding Br(CH2)n-iOH was reacted with intermediates to synthesize series of compounds J and I. The protective group J was removed by hydrogenation (method illustrated in example 1) to obtain compound K. ll-(8-methoxyquinolin-4-yl)undecan-l-ol (II) YD: 34%. 'HNMR (400 MHz, CDCI3) 58.80 (dd, J= 4.4, 0.6 Hz, 1H), 7.59 (dd, J= 8.4, 0.8 Hz, 1H), 7.44-7.49 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.08 (s, 3H), 3.63 (t, J= 6.8 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 1.74 (quin, J= 7.6 Hz, 2H), 1.55 (quin, J= 7.2 Hz, 2H), 1.23-1.45 (br, 15H); MS. m/z 329.9, [M+H]+. ll-(8-ethoxyquinolin-4-yl)undecan-l-ol (12) YD: 42%. H NMR (400 MHz, ί/4-MeOD) 58.66 (d, J= 8.4 Hz, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.51 (t, J= 8.0 Hz, 1H), 7.37 (d, J= 8.4 Hz, 1H), 7.15 (d, J= 7.6 Hz, 1H), 4.27 (q, J= 6.8 Hz, 2H), 3.52 (t,J= 6.8 Hz, 2H), 3.08 (d, J= 7.6 Hz, 2H), 1.75 (quin, J= 7.6 Hz, 2H), 1.50-1.57 (m, 5H), 1.21-1.49 (br, 15H); MS. m/z 366.2, [M+Na]+. ll-(8-isopropoxyquinolin-4-yl)undecan-l-ol (13) YD: 48%. l¥i NMR (400 MHz, ί/4-MeOD) 5 8.65 (d, J= 8.4 Hz, 1H), 7.63 (d,J= 7.6 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 4.4 Hz, 1H), 7.17 (d, J= 8.0 Hz, 1H), 4.84 (br, 1H), 3.52 (t, J= 6.4 Hz, 2H), 3.07 (d, J= 7.6 Hz, 2H), 1.74 (br, 2H), 1.43-1.50 (br, 9H), 1.29-1.34 (br, 14H); MS. m/z 380.3, [M+Na]+. ll-(8-(cyclopropylmethoxy)quinolin-4-yl)undecan-l-ol (14) YD: 53%. l¥i NMR (400 MHz, ί/4-MeOD) 58.66 (d, J= 8.4 Hz, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.49 (t, J= 8.4 Hz, 1H), 7.36 (d, J= 4.8 Hz, 1H), 7.13 (d, J= 7.6 Hz, 1H), 4.03 (d, J= 6.8 Hz, 1H), 3.52 (t, J= 6.8 Hz, 2H), 3.06 (d, J= 7.6 Hz, 2H), 1.69-1.75 (m, 2H), 1.28-1.52 (br, 18H), 0.65-0.68 (m, 2H), 0.42-0.43 (m, 2H); MS. m/z 392.2 [M+Na]+. 11- (8-(benzyloxy)quinolin-4-yl)undecan-l-ol (Jl) YD: 46%. l¥i NMR (400 MHz, ί/4-MeOD) 5 8.66 (d, J= 8.4 Hz, 1H), 7.64 (d,J = 8.4 Hz, 1H), 7.52 (d,J= 7.2 Hz, 2H), 7.45 (t, J= 8.0 Hz, 1H), 7.30-7.38 (m, 3H), 7.26-7.28 (m, 1H), 7.17 (d, J= 7.6 Hz, 1H), 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, J= 7.2 Hz, 2H), 1.28-1.48 (m, 15H); MS. m/z 428.3, [M+Na]+. 12- (8-(benzyloxy)quinolin-4-yl)dodecan-l-ol (J2) YD: 46%. l¥i NMR (400 MHz, ί/4-MeOD) 5 8.67 (d, J= 4.4 Hz, 1H), 7.65 (d,J = 8.4 Hz, 1H), 7.52 (d,J= 7.2 Hz, 2H), 7.45 (t, J= 8.0 Hz, 1H), 7.30-7.39 (m, 3H), 7.27-7.30 (m, 1H), 7.18 (d, J= 8.0 Hz, 1H), 5.38 (s, 2H), 3.52 (t, J= 6.4 Hz, 2H), 3.08 (t, J= 7.6 Hz, 2H), 1.74 (q, J= 7.6 Hz, 2H), 1.49 (t, J= 7.2 Hz, 2H), 1.23-1.45 (m, 17H); MS. m/z 442.3, [M+Na]+. 4-(ll-hydroxyundecyl)quinolin-8-ol (Kl) YD: 84%. l¥i NMR (400 MHz, ί/4-MeOD) 5 8.63 (d, J= 4.4 Hz, 1H), 7.51 (d,J = 8.4 Hz, 1H), 7.40 (t,J= 8.0 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 7.06 (d, J= 7.6 Hz, 1H), 3.51 (t, J= 6.8 Hz, 2H), 3.02 (t,J= 8.0 Hz, 2H), 1.71 (t,J= 7.6 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.12-1.31 (br, 15H); MS. m/z 316.2, [M+H]+. 4-(12-hydroxydodecyl)quinolin-8-ol (K2) YD: 86%. lYi NMR (400 MHz, CDCb) 58.52 (d, J= 4.4 Hz, 1H), 7.36 (dd, J= 8.4, 0.8 Hz, 1H), 7.31 (d, J= 7.6 Hz, 1H), 7.13 (d, J = 4.4 Hz, 1H), 6.99 (dd, J= 7.6, 1.2 Hz, 1H), 3.43 (t, J= 6.8 Hz, 2H), 2.89 (t, J= 7.6 Hz, 2H), 1.61 (quin, J= 7.6 Hz, 2H), 1.40 (quin, J= 6.8 Hz, 2H), 1.12 1.31 (br, 17H); MS. m/z 352.2, [M+Na]+.
Example 8 Preparation of (8-trifluoromethoxyquinol-2-yl)alkyl alcohols.
Method: The intermediate was synthesized through ring closure from 2-trifluoromethoxyaniline reacted with crotonaldehyde. Intermediate was reacted with corresponding Br(CH2)n-iOH (as illustrated above) to synthesize series compounds L. 9-(8-(trifhioromethoxy)quinolin-2-yl)nonan-l-ol (LI) YD: 41%. 'HNMR (400 MHz, CDCb) 58.06 (dd, J= 8.4, 1.2 Hz, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.56 (d, J= 7.6 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.34 (dd, J= 8.4, 1.2 Hz, 1H), 3.61 (t, J= 6.4 Hz, 2H), 3.01 (t, J= 6.4 Hz, 2H), 1.81-1.85 (br, 2H), 1.53-1.56 (br, 2H), 1.21-1.35 (m, 15H); MS. m/z 355.9, [M+H]+. ll-(8-(trifhioromethoxy)quinolin-2-yl)undecan-l-ol (L2) YD: 41%. 'HNMR (400 MHz, ί/4-MeOD) 58.26 (t, J= 8.0 Hz, 1H), 7.86 (d, J= 7.6 Hz, 1H), 7.64 (t, J= 7.2 Hz, 1H), 7.47-7.56 (m, 2H), 3.51 (t, J= 6.8 Hz, 2H), 2.99 (t, J= 6.4 Hz, 2H), 1.79 (quin, 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+Na]+. 14- (8-(trifluoromethoxy)quinolin-2-yl)tetradecan-l-ol (L3) YD: 37%. l¥i NMR (400 MHz, ί/4-MeOD) 5 8.27 (d, J= 8.4 Hz, 1H), 7.87 (d, J= 8.0 Hz, 1H), 7.65 (t, J= 7.2 Hz, 1H), 7.49-7.56 (m, 2H), 3.52 (t, J= 6.8 Hz, 2H), 3.01 (t, J= 7.6 Hz, 2H), 1.82 (quin, J= 7.2 Hz, 2H), 1.51 (quin, J= 6.8 Hz, 2H), 1.27-1.37 (m, 21H); MS. m/z 448.2, [M+Na]+. 15- (8-(trifluoromethoxy)quinolin-2-yl)pentadecan-l-ol (L4) YD: 32%. l¥i NMR (400 MHz, J4-MeOD+CDCb) 58.21 (d, J= 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.46 (t,J= 8.4 Hz, 1H), 3.52 (t, J = 6.8 Hz, 2H), 2.99 (t,J= 7.6 Hz, 2H), 1.80 (quin, J= 7.6 Hz, 2H), 1.50 (quin, J= 7.2 Hz, 2H), 1.15-1.41 (br, 23H); MS. m/z 462.2, [M+Na]+.
Example 9 - Preparation of 2-N-substitutedalcohol-8-hydroxyquinoline
Reagents and conditions: (a) SeCb, dioxane, 50 to 80 °C; (b) N-methylpropagylamine or 2-(piperazin-l-yl) ethanol or NH2(CH2)n-1 OH, NaBH(OAc)3, 1,2-dichloroethane, rt.
Method: A solution of 8-hydroxy-2-methylquinoline (6.0 g, 37.7 mmol) in dioxane (15 ml) was added to a stirred solution of Se02 (6.3 g, 56.8 mmol) in dioxane (80 ml) dropwise at 50 °C and the 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/EA = (15:1 to 10:1) to give 8-hydroxyquinoline-2-carboxaldehyde (2.45g, 38 %) derivatives as intermediates. Intermediate was converted into A'-substi luted compounds by reductive amination with aminoalcohol, aminoalkyne or other heterocycles to give series of compounds. 8-alkoxy-2-methyl quinoline were oxidized to give 8-alkoxyquinoline-2- carboxaldehyde derivatives and followed by the same method to give compounds M to O. 2-((4-(2-hydroxyethyl)piperazin-l-yl)methyl)quinolin-8-ol (Ml) YD: 76%. l¥i NMR (400 MHz, CDCb) 58.02 (d, J= 8.4 Hz, 1H), 7.43 (d, J= 8.4 Hz, 1H), 7.34 (t, J= 8.0 Hz, 1H), 7.22 (d, J= 7.6 Hz, 1H), 7.10 (d, J= 6.8 Hz, 1H), 3.73 (s, 2H), 3.61 (t, J = 6.8 Hz, 2H), 2.51 (t, J= 5.6 Hz, 10H); HRMS (ESI): Calcd for [M+Na]+: 310.1526, Found: 310.1527. 2-(4-((5-chloro-8-methoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol (M2) YD: 76%. Ή NMR (400 MHz, CDCb) 58.23 (d, J= 8.8 Hz, 1H), 7.59 (d, J= 8.8 Hz, 1H), 7.21 (d, J= 8.4 Hz, 1H), 6.68 (d, J= 8.8 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 2H), 3.44 (t, J= 4.8 Hz, 2H), 2.35-2.38 (m, 10H); MS. m/z 336.1, [M+H]+. 2-(4-((5-chloro-8-ethoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol (M3) YD: 53%. NMR (400 MHz, CDCb) 58.36 (d, J= 8.8 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 6.83 (d, J= 8.4 Hz, 1H), 4.18 (q, J= 6.8 Hz, 3H), 3.84 (s, 2H), 3.54 (t, J = 5.2 Hz, 2H), 2.45-2.50 (br, 10H), 1.49 (t, J= 6.8 Hz, 3H); MS. m/z 350.1, [M+H]+. 2-(4-((5-chloro-8-isopropoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol (M4) YD: 61%. Ή NMR (400 MHz, ί/4-MeOD) 58.52 (d, J= 8.8 Hz, 1H), 7.81 (d, J= 8.8 Hz, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.14 (d, J= 8.4 Hz, 1H), 4.87 (m, 1H), 3.89 (s, 2H), 3.67 (t, J= 6.0 Hz, 2H), 2.54-2.62 (br, 10H), 1.45 (t, J= 6.0 Hz, 6H); MS. m/z 364.1, [M+H]+. 2-(4-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-l-yl)ethane (M5) YD: 76%. l¥i NMR (400 MHz, ί/4-MeOD) 58.40 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.42 (d, J= 8.4 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 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 (br, 8H), 2.51 (t, J= 4.8 Hz, 2H), 1.37-1.43 (m, 1H), 0.62-0.66 (m, 2H), 0.37-0.40 (m, 2H); MS. m/z 376.2, [M+H]+. 2-(4-((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol (M6) YD: 39%. 'HNMR (400 MHz, ί/4-MeOD) δ 8.53 (d, J= 8.8 Hz, 1H), 7.80 (d, J= 8.8 Hz, 1H), 7.70 (s, 1H), 4.11 (s, 3H), 3.89 (s, 2H), 3.67 (t, J= 6.0 Hz, 2H), 2.63 (br, 8H), 2.55 (t, J= 6.0 Hz, 2H), 1.93 (s, 1H); MS. m/z 370.1, [M+H]+. 2-(4-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-l-yl)ethanol (M7) YD: 82%. 'HNMR (400 MHz, CDCb) 58.43 (d, J= 8.8 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.58 (s, 1H), 4.22 (d, J= 12 Hz, 2H), 3.88 (s, 2H) 3.61 (t, J= 6.4 Hz, 2H), 2.56 (t, J= 5.2 Hz, 10H), 1.41-1.44 (m? in), 0.57-0.62 (m, 2H), 0.33-0.37 (m, 2H); MS. m/z 410.1, [M+Na]+. 2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol (Nl) YD: 49%. l¥i NMR (400 MHz, CDCb) 58.08 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), 7.40 (t, J= 8.0 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.15 (d, J= 7.6 Hz, 1H), 3.90 (s, 2H), 3.41 (d, J = 2.0 Hz, 2H), 2.39 (s, 3H), 2.31 (d, J= 2.0 Hz, 1H); MS. m/z 249.1, [M+H]+. 5-chloro-2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol (N2) YD: 38%. 'HNMR (400 MHz, CDCb) 58.47 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.08 (d, J= 8.4 Hz, 1H), 3.93 (s, 2H), 3.42 (d, J= 2.0 Hz, 2H), 2.40 (s, 3H), 2.31 (t, J= 2.0 Hz, 1H); MS. m/z 261.0, [M+H]+. N-((5-chloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine (N3) YD: 52%. l¥i NMR (400 MHz, CDCb) 58.48 (d, J= 8.8 Hz, 1H), 7.80 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 8.4 Hz, 1H), 6.93 (d, J= 8.4 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 2H), 3.42 (d, J= 2.0 Hz, 2H), 2.37 (s, 3H), 2.27 (t, J= 2.0 Hz, 1H), MS. m/z 297.0, [M+Na]+. N-((5-chloro-8-ethoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine (N4) YD: 64%. lYi NMR (400 MHz, CDCb) 58.48 (d, J= 8.8 Hz, 1H), 7.79 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 8.8 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 4.32 (t, J= 6.8 Hz, 2H), 4.01 (s, 2H), 3.45 (d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 2.28 (t, J= 2.0 Hz, 1H), 1.59 (t, J= 6.8 Hz, 3H); MS. m/z 289.1, [M+H]+. N-((5-chloro-8-isopropoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine (N5) YD: 76%. lYi NMR (400 MHz, CDCb) 58.47 (d, J= 8.8 Hz, 1H), 7.73 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 4.80 (m, 1H), 3.99 (s, 2H), 3.44 (d, J= 2.4 Hz, 2H), 2.41 (s, 3H), 2.28 (t, J= 2.4 Hz, 1H), 1.48 (d, J= 6.4 Hz, 6H); MS. m/z 303.1, [M+H]+. N-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine (N6) YD: 58%. l¥i NMR (400 MHz, CDCb) 58.48 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 8.8 Hz, 1H), 7.45 (d, J= 8.4 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 4.09 (d, J= 12 Hz, 2H), 4.01 (s, 2H), 3.45 (d, J = 2.0 Hz, 2H), 2.41 (s, 3H), 2.28 (t, J= 2.0 Hz, 1H), 1.42 ~ 1.50 (m, 1H), 0.65-0.70 (m, 2H), 0.420.45 (m, 2H); MS. m/z 337.1, [M+Na]+. N-((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine (N7) YD: 58%. ln NMR (400 MHz, CDC13) 58.47 (d, J= 8.8 Hz, 1H), 7.74 (d, J= 8.8 Hz, 1H), 7.60 (s, 1H), 4.20 (s, 3H), 3.99 (s, 2H), 3.43 (d, J= 2.0 Hz, 2H), 2.41 (s, 3H), 2.29 (t, J= 2.0 Hz, 1H); MS. m/z 309.0, [M+H]+. N-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine (N8) YD: 76%. Ή NMR (400 MHz, CDCI3) 58.45 (d, J= 8.8 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.59 (s, 1H), 4.25 (d, J= 7.6 Hz, 2H), 3.95 (s, 2H), 3.40 (d, J= 2.0 Hz, 2H), 2.40 (s, 3H), 2.28 (t, J = 2.0 Hz, 1H), 1.41-1.45 (m, 1H), 0.57-0.62 (m, 2H), 0.36 (dd, J = 10.0, 4.8 Hz, 2H); MS. m/z 371.0, [M+Na]+. 8-((5-chloro-8-methoxyquinolin-2-yl)methylamino)octan-l-ol (Ol) YD: 44%. l¥i NMR (400 MHz, ί/4-MeOD) 58.55 (d, J= 8.8 Hz, 1H), 7.69 (d, J= 8.8 Hz, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.16 (d, J= 8.4 Hz, 1H), 4.07 (s, 5H), 3.50 (t, J= 6.8 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.56 (quin, J= 7.2 Hz, 2H), 1.50 (quin, J= 6.8 Hz, 2H), 1.29-1.32 (br, 10H); MS. m/z 351.2, [M+H]+. 8-((5-chloro-8-ethoxyquinolin-2-yl)methylamino)octan-l-ol (02) YD: 41%. l¥i NMR (400 MHz, ί/4-MeOD) 58.51 (d, J= 8.8 Hz, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.12 (d, J= 8.4 Hz, 1H), 4.29 (q, J= 6.8 Hz, 2H), 4.07 (s, 2H), 3.51 (t, J= 6.8 Hz, 2H), 2.64 (t, J= 7.2 Hz, 2H), 1.47-1.58 (m, 7H), 1.31 (br, 9H); MS. m/z 365.2, [M+H]+. 8-((5-chloro-8-isopropoxyquinolin-2-yl)methylamino)octan-l-ol (03) YD: 31%. Ή NMR (400 MHz, ί/4-MeOD) 58.55 (d, J= 8.8 Hz, 1H), 7.66 (d, J= 8.8 Hz, 1H), 7.56 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 4.89 (m, 1H), 4.15 (s, 2H), 3.52 (t, J= 6.4 Hz, 2H), 2.71 (t, J= 12 Hz, 2H), 1.59 (quin, J= 6.8 Hz, 2H) 1.46-1.50 (m, 8H), 1.33 (br, 9H); MS. m/z 379.2, [M+H]+ .8-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-l-ol (04) YD: 29%. l¥i NMR (400 MHz, ί/4-MeOD) 58.54 (d, J= 8.4 Hz, 1H), 7.67 (d, J= 8.8 Hz, 1H), 7.54 (d, J= 8.4 Hz, 1H), 7.15 (d, J= 8.4 Hz, 1H), 4.09 (s + d, J= 6.8 Hz, 4H), 3.51 (t, J= 6.8 Hz, 2H), 2.67 (t, J= 12 Hz, 2H), 1.59 (quin, J= 12 Hz, 2H), 1.43-1.51 (m, 3H), 1.29-1.42 (br, 10H), 0.66-0.89 (m, 2H), 0.44 (dd, J= 10.4, 4.8 Hz, 2H); MS. m/z 391.2, [M+H]+. 8-((5,7-dichloro-8-methoxyquinolin-2-yl)methylamino)octan-l-ol (05) YD: 37%. Ή NMR (400 MHz, ί/4-MeOD) 58.54 (d, J= 8.8 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 4.14 (s, 3H), 4.12 (s, 2H), 3.52 (t, J= 6.8 Hz, 2H), 2.70 (t, J= 12 Hz, 2H), 1.60 (quin, J= 6.8 Hz, 2H), 1.50 (m, 2H), 1.33 (br, 9H); MS. m/z 385.1, [M+H]+. 8-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-l-ol (06) YD: 56%. 'HNMR (400 MHz, ί/4-MeOD) 58.51 (d, J= 8.4 Hz, 1H), 7.69 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 4.22 (d, J= 12 Hz, 2H), 4.10 (s, 2H), 3.52 (t, J= 6.8 Hz, 2H), 2.68 (t, J= 12 Hz, 2H), 1.59 (quin, J= 12 Hz, 2H), 1.51 (quin, J= 6.8 Hz, 2H), 1.28-1.42 (br, 11H), 0.55-0.60 (m, 2H), 0.30-0.33 (m, 2H); MS. m/z 425.2, [M+H]+. 6-(bis((8-methoxyquinolin-2-yl)methyl)amino)hexan-l-ol (PI) 'HNMR (400 MHz, (74-MeOD) 58.18 (d, J= 8.4 Hz, 2H), 7.80 (d, J= 8.4 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.38 (d, J= 8.0 Hz, 2H), 7.13 (d, J= 12 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 (quin, J= 6.8 Hz, 2H), 1.41 (quin, J= 6.8 Hz, 2H), 1.27 (quin, J= 7.6 Hz, 2H), 1.18 (quin, J= 6.8 Hz, 2H); MS. m/z 482.3, [M+Na]+. FIG. 1A shows C12 inhibited Αβ aggregation in the presence or absence of zinc ions using a microscopy analysis after Congo red staining. FIG.IB and FIG.2 show that C12 dissolved preformed Αβ aggregates. FIGs. 3A-B show that compounds Cl2, CQ and C12 intermediate protected neuron cells from zinc-induced ίΑβ. Only compound C12 was effective toward zinc-free aggregates (FIG. 3B). FIG. 4 shows induction of neurite outgrowth triggered by compounds B3, C3, and D3, respectively, on undifferentiated PC 12 cells. FIG. 5 shows quinoline derivatives increased expression of GAP43. FIG. 6 shows compound C12 and B3 improved performance of learning in fAβ-induced memory-deficit mice. C12 and B3 (10 mg/kg) increased riding time of fAβ-lesioned mice in a rotarod test. FIGs. 7A-D show compound C12 improved learning of memory-deficit fAβ-lesioned mice in the Morris water maze test. Mice were assessed for the total duration of movement (FIG. 7A) and total duration of distance (FIG. 7B) to climb onto the hidden platform; and also quantified the appearance to target zone (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 ίΑβ level in memory-deficit fAβ-lesioned mice by compound Cl2.
The foregoing description of the exemplary 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. Many modifications and variations are possible in light of the above teaching.
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 rather 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. All 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 individually incorporated by reference.
In this specification where reference has been made to external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

Claims (17)

  1. CLAIMS What is claimed is:
    1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
    Formula (I) (I) wherein: R1 is hydrogen, (Ci-Cs)alkyl, (Ci-C8)alkylene(C3-Cs)cycloalkyl, (Ci-Cs)haloalkyl, or (Ci-Cs)alkylene(C6-C2o)aryl; R2 is hydrogen or halogen; R3 is hydrogen, halogen, (Ci-Cs)alkyl, or (Ci-Cs)alkoxy; R4 is hydrogen, halogen, (Ci-Cs)alkyl, (Ci-Cs)alkoxy, or (Ci-Cs)haloalkyl; R5 is hydrogen or (Ci-C2o)alkanol; R6 is hydrogen; and R7 is (C6-C2o)alkanol, CH2(N(CH2CH2)2N)CH2CH2OH, (Cio-Ci3)alkyleneOCOCH3, (Ci-Cs)alkylene(Ci-C6)alkylamino(Ci-C6)alkynyl, (Ci-Cs)alkyleneamino(C3-C2o)alkanol, or (Ci-C8)alkyleneamino(Ci-C2o)alkanol(Ci-C8)alkylene(8-methoxyquinolin-2-yl); or (II) wherein: R1, R2, R3, R4 and R6 are each as defined in (I) above; R5 is (C5-C2o)alkanol; and R7 is hydrogen, (C6-C2o)alkanol, CH2(N(CH2CH2)2N)CH2CH2OH, (Cio-Ci3)alkyleneOCOCH3, (Ci-C8)alkylene(Ci-C6)alkylamino(Ci-C6)alkynyl, (Ci-Cs)alkyleneamino(C3-C2o)alkanol, or (Ci-C8)alkyleneamino(Ci-C2o)alkanol(Ci-Cs)alkylene(8-methoxyquinolin-2-yl).
  2. 2. The compound of claim 1, (A) wherein: R1 is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH2)2, CH2CH(CH3)2, CF3, or benzyl; R2 is hydrogen, F, or Cl; R3 is hydrogen, F, Cl, CH3, or OCH3; R4 is hydrogen, F, Cl, Br, CH3, OCH3, or CF3; R5 is hydrogen, (CFh)iiOFl, or (CH2)i20H; R6 is hydrogen; and R7 is (CH2)9OH, (CH2)ioOH, (CH2)hOH, (CH2)i20H, (CH2)i30H, (CH2)i4OH, (CH2)i5OH, (CH2)ioOCOCH3, (CH2)iiOCOCH3, (CH2)i20C0CH3, (CH2)i30C0CH3, CH2(N(CH2CH2)2N)CH2CH2OH, CH2N(CH3)CH2C^CH, CH2NH(CH2)80H, or CH2N((CH2)60H)CH2(8-methoxyquinolin-2-yl); or (B) wherein: R1, R2, R3, R4 and R6 are each as defined in (A) above; R5 is (CH2)nOH, or (CH2)i20H; and R7 is hydrogen, (CH2)9OH, (CH2)ioOH, (CH2)nOH, (CH2)i20H, (CH2)i30H, (CH2)i40H, (CH2)i5OH, (CH2)ioOCOCH3, (CH2)iiOCOCH3, (CH2)i20C0CH3, (CH2)i30C0CH3, CH2(N(CH2CH2)2N)CH2CH2OH, CH2N(CH3)CH2C^CH, CH2NH(CH2)80H, or CH2N((CH2)60H)CH2(8-methoxyquinolin-2-yl).
  3. 3. The compound of claim 2, wherein R1 is hydrogen, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH2CH(CH2)2, CF3, or benzyl; R2, R3, R4, R5, and R6 are each independently hydrogen; and R7 is (CH2)9OH, (CH2)ioOH, (CH2)hOH, (CH2)i20H, (CH2)i30H, (CH2)i40H, (CH2)i50H, CH2(N(CH2CH2)2N)CH2CH2OH, or CH2N(CH3)CH2C=CH.
  4. 4. The compound of claim 2, wherein R1 is hydrogen, CH3, CH2CH3, CH2CH(CH3)2, CH2CH(CH2)2, or CH(CH3)2; R2, R3, R5, and R6 are each independently hydrogen; R4 is CH3, F, Cl, Br, CF3, or OCH3; and R7 is (CH2)9OH, (CH2)ioOH, (CH2)hOH, (CH2)i20H, (CH2)i30H, (CH2)i5OH, (CH2)ioOCOCH3, (CH2)iiOCOCH3, (CH2)i20C0CH3, (CH2)i30C0CH3, CH2NH(CH2)80H, CH2(N(CH2CH2)2N)CH2CH2OH, or CH2N(CH3)CH2 C^CH.
  5. 5. The compound of claim 2, wherein R1 is hydrogen, CH3, CH2CH3, CH(CH2)2, or CH2CH(CH2)2; R2,R4 are each independently Cl; R3, R5, and R6 are each independently hydrogen; and R7 is (CH2)nOH, CH2NH(CH2)80H, or CH2N(CH3)CH2C=CH.
  6. 6. The compound of claim 2, wherein R1 is hydrogen, CH3, CH2CH3, CH2CH(CH3)2, CH2CH(CH2)2, CH(CH3)2, or benzyl; R2, R3, R4, R6, and R7 are each independently hydrogen; and R5 is (CH2)nOH or (CH2)i20H.
  7. 7. The compound of claim 2, wherein R1 is CH3; R2, R5, and R6 are each independently hydrogen; R3 and R4 are each independently OCH3 or Cl; and R7 is (CH2)nOH.
  8. 8. The compound of claim 2, which is selected from the group consisting of: 9- (8-(benzyloxy)quinolin-2-yl)nonan-1 -ol, 10- (8-(benzyloxy)quinolin-2-yl)decan-1 -ol, 11 -(8-(benzyloxy)quinolin-2-yl)undecan-1 -ol, 12- (8-(benzyloxy)quinolin-2-yl)dodecan-l-ol, 13- (8-(benzyloxy)quinolin-2-yl)tridecan-l-ol, 14- ((8-(benzyloxy)quinolin-2-yl)tetradecan-l-ol, 15- (8-(benzyloxy)quinolin-2-yl)pentadecan-l-ol, I l-(8-(benzyloxy)-5-methylquinolin-2-yl)undecan-l-ol, II -(8-(benzyloxy)-6-methylquinolin-2-yl)undecan-1 -ol, 11 -(8-(benzyloxy)-5-fluoroquinolin-2-yl)undecan-1 -ol, 11 -(8-(benzyloxy)-5-chloroquinolin-2-yl)undecan-1 -ol, 2-(9-hydroxynonyl)quinolin-8-ol, 2-(10-hydroxydecyl)quinolin-8-ol, 2-(1 l-hydroxyundecyl)quinolin-8-ol, 2-(12-hydroxydodecyl)quinolin-8-ol, 2-(13-hydroxytridecyl)quinolin-8-ol, 2-(14-hydroxytetradecyl)quinolin-8-ol, 2-(15-hydroxypentadecyl)quinolin-8-ol, 2-(1 l-hydroxyundecyl)-5-methylquinolin-8-ol, 2-(11 -hydroxyundecyl)-6-methylquinolin-8-ol, 5-chloro-2-(l l-hydroxyundecyl)quinolin-8-ol, 9- (8-methoxyquinolin-2-yl)nonan-1 -ol, 10- (8-methoxyquinolin-2-yl)decan-1 -ol, 11 -(8-methoxyquinolin-2-yl)undecan-1 -ol, 12- (8-methoxyquinolin-2-yl)dodecan-l-ol, 13- (8-methoxyquinolin-2-yl)tridecan-l-ol, 14- ((8-methoxyquinolin-2-yl)tetradecan-1 -ol, 15- (8-methoxyquinolin-2-yl)pentadecan-l-ol, I l-(8-methoxy-5-methyl quinolin-2-yl)undecan-l-ol, II -(5-fluoro-8-methoxyquinolin-2-yl)undecan-1 -ol, 12-(5-fluoro-8-methoxyquinolin-2-yl)dodecan-l-ol, 9-(5-chloro-8-methoxyquinolin-2-yl)nonan-1 -ol, 1 l-(5-chloro-8-methoxyquinolin-2-yl)undecan-l-ol, 15-(5-chloro-8-methoxyquinolin-2-yl)pentadecan-1 -ol, I l-(5-bromo-8-methoxyquinolin-2-yl)undecan-l-ol, II -(8-methoxy-5 -(trifluoromethyl)quinolin-2-yl)undecan-1 -ol, I l-(5,8-dimethoxyquinolin-2-yl)undecan-l-ol, II -(8-methoxy-6-methylquinolin-2-yl)undecan-1 -ol, 11 -(6-fluoro-8-methoxyquinolin-2-yl)undecan-1 -ol, 11 -(6-chloro-8-methoxyquinolin-2-yl)undecan-1 -ol, 11 -(7-fluoro-8-methoxyquinolin-2-yl)undecan-1 -ol, I l-(7-chloro-8-methoxyquinolin-2-yl)undecan-l-ol, II -(5-chloro-6,8-dimethoxyquinolin-2-yl)undecan-1 -ol, 11 -(6-chloro-5,8-dimethoxyquinolin-2-yl)undecan-1 -ol, 11 -(5,7-dichloro-8-methoxyquinolin-2-yl)undecan-1 -ol, 9- (8-ethoxyquinolin-2-yl)nonan-1 -ol, 10- (8-ethoxyquinolin-2-yl)decan-1 -ol, 11 -(8-ethoxy quinolin-2-yl)undecan-1 -ol, 12- (8-ethoxyquinolin-2-yl)dodecan-l-ol, 13- (8-ethoxy quinolin-2-yl)tridecan-l-ol, 14- ((8-ethoxyquinolin-2-yl)tetradecan-l-ol, 15- (8-ethoxyquinolin-2-yl)pentadecan-l-ol, I l-(8-ethoxy-5-methyl quinolin-2-yl)undecan-l-ol, II -(8-ethoxy-5-fluoroquinolin-2-yl)undecan-1 -ol, 9-(5-chloro-8-ethoxyquinolin-2-yl)nonan-1 -ol, 1 l-(5-chloro-8-ethoxyquinolin-2-yl)undecan-l-ol, 15-(5-chloro-8-ethoxyquinolin-2-yl)pentadecan-l-ol, I l-(5-bromo-8-ethoxyquinolin-2-yl)undecan-l-ol, II -(5,7-dichloro-8-ethoxyquinolin-2-yl)undecan-1 -ol, 9- (8-isopropoxyquinolin-2-yl)nonan-1 -ol, 10- (8-isopropoxyquinolin-2-yl)decan-1 -ol, 11 -(8-isopropoxyquinolin-2-yl)undecan-1 -ol, 12-(8-isopropoxyquinolin-2-yl)dodecan-l-ol, 13- (8-isopropoxyquinolin-2-yl)tridecan-l-ol, 14- ((8-isopropoxyquinolin-2-yl)tetradecan-1 -ol, 15- (8-isopropoxyquinolin-2-yl)pentadecan-l-ol, 11 -(8-isopropoxy-5-methyl quinolin-2-yl)undecan-1 -ol, 11 -(5-fluoro-8-isopropoxyquinolin-2-yl)undecan-1 -ol, 9-(5-chloro-8-isopropoxyquinolin-2-yl)nonan-1 -ol, 11 -(5-chloro-8-isopropoxyquinolin-2-yl)undecan-1 -ol, 15-(5-chloro-8-isopropoxyquinolin-2-yl)pentadecan-1 -ol, I l-(5-bromo-8-isopropoxyquinolin-2-yl)undecan-l-ol, II -(5,7-dichloro-8-isopropoxyquinolin-2-yl)undecan-1 -ol, 9- (8-(cyclopropylmethoxy)quinolin-2-yl)nonan-1 -ol, 10- (8-(cyclopropylmethoxy)quinolin-2-yl)decan-1 -ol, 11 -(8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1 -ol, 12- (8-(cyclopropylmethoxy)quinolin-2-yl)dodecan-1 -ol, 13- (8-(cyclopropylmethoxy)quinolin-2-yl)tridecan-1 -ol, 14- ((8-(cyclopropylmethoxy)quinolin-2-yl)tetradecan-1 -ol, 15- (8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-1 -ol, 1 l-(8-(cyclopropylmethoxy)-5-methylquinolin-2-yl)undecan-l-ol, I l-(8-(cyclopropylmethoxy)-5-fluoroquinolin-2-yl)undecan-l-ol, 9- (5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)nonan-l-ol, II -(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1 -ol, 15-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-1 -ol, 11 -(5-bromo-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1 -ol, 1 l-(5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-l-ol, 5,7-dichloro-2-(l l-hydroxyundecyl)quinolin-8-ol, 10- (5-chloro-8-methoxyquinolin-2-yl)decan-l-ol, acetic acid 10-(5-chloro-8-methoxyquinolin-2-yl)decyl ester, I l-(5-chloro-8-methoxyquinolin-2-yl)undecan-l-ol, acetic acid 1 l-(5-chloro-8-methoxyquinolin-2-yl)undecyl ester, 12- (5-chloro-8-methoxyquinolin-2-yl)dodecan-l-ol, acetic acid 12-(5-chloro-8-methoxyquinolin-2-yl)dodecyl ester, 13- (5-chloro-8-methoxyquinolin-2-yl)tridecan-l-ol, acetic acid 13-(5-chloro-8-methoxyquinolin-2-yl)tridecyl ester, II -(8-methoxyquinolin-4-(-yl)undecan-1 -ol, 11 -(8-ethoxy quinolin-4-(-yl)undecan-1 -ol, 11 -(8-isopropoxyquinolin-4-(-yl)undecan-1 -ol, 11 -(8-(cyclopropylmethoxy)quinolin-4-(-yl)undecan-1 -ol, 11 -(8-(benzyloxy)quinolin-4-(-yl)undecan-1 -ol, 12-(8-(benzyloxy)quinolin-4-(-yl)dodecan-1 -ol, 4-(( 11 -hydroxyundecyl)quinolin-8-ol, 4- (( 12-hydroxydodecyl)quinolin-8-ol, 9-(8-(trifluoromethoxy)quinolin-2-yl)nonan-1 -ol, 11 -(8-(trifluoromethoxy)quinolin-2-yl)undecan-1 -ol, 14- ((8-(trifluoromethoxy)quinolin-2-yl)tetradecan-1 -ol, 15- (8-(trifluoromethoxy)quinolin-2-yl)pentadecan-1 -ol, 2-((4-((2-hydroxyethyl)piperazin-1 -yl)methyl)quinolin-8-ol, 2-(4-(((5-chloro-8-methoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol, 2-(4-(((5-chloro-8-ethoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol, 2-(4-(((5-chloro-8-isopropoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol, 2-(4-(((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)piperazin-l-yl)ethanol, 2-(4-(((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-l-yl)ethanol, 2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol, 5- chloro-2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol, N((5-chloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine, N((5-chloro-8-ethoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine, N((5-chloro-8-isopropoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine, N((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine, N((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-l-amine, N((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-l- amine, 8-((5-chloro-8-methoxyquinolin-2-yl)methylamino)octan-l-ol, 8-((5-chloro-8-ethoxyquinolin-2-yl)methylamino)octan-l-ol, 8-((5-chloro-8-isopropoxyquinolin-2-yl)methylamino)octan-l-ol, 8-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-l-ol, 8-((5,7-dichloro-8-methoxyquinolin-2-yl)methylamino)octan-l-ol, 8-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1 -ol, and 6- (bis((8-methoxyquinolin-2-yl)methyl)amino)hexan-1 -ol.
  9. 9. The compound of claim 1, wherein R2 is hydrogen.
  10. 10. The compound of claim 1, wherein R1 is hydrogen, (Ci-Cs)alkyl, (Ci-Cs)alkylene(C3-C8)cycloalkyl, or (Ci-Cs)haloalkyl.
  11. 11. A composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  12. 12. A method for the treatment of Alzheimer’s disease, brain traumatic injury, and/or spinal cord injury, comprising administering to a subject in need thereof a therapeutically effective amount of a composition as claimed in claim 11.
  13. 13. A compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, when used in treating Alzheimer’s disease, brain traumatic injury, and/or spinal cord injury.
  14. 14. Use of a compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of Alzheimer’s disease, brain traumatic injury, and/or spinal cord injury.
  15. 15. A method for improving learning and/or memory performance in a patient of Alzheimer's disease, comprising administering a therapeutically effective amount of composition as claimed in claim 11 to the patient with Alzheimer's disease.
  16. 16. A compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, when used in improving learning and/or memory performance in a patient with Alzheimer’s disease.
  17. 17. Use of a compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving learning and/or memory performance in a patient with Alzheimer’s disease.
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