Tetradentate chelating monoquinoline derivative, manufacturing method thereof, and application of same as metal ion regulator for neurodegenerative disease

Abstract

A tetradentate chelating monoquinoline derivative with a structure as shown in formula (I) is able to specifically chelate redox active metal ions like copper ions that are dis-regulated in neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis), or copper accumulation disease like Wilson's disease. The binding constants of these derivatives for zinc are 6-10 orders of magnitude below that ones for copper, and these derivatives have a good capability of reducing an oxidative stress. The method for preparing the derivative is simple and the derivatives have good application prospects in manufacturing drugs for neurodegenerative diseases and diseases related to disorder of copper metabolism.

Claims

1. A tetradentate chelating monoquinoline derivative, wherein a structure of the derivative is as shown in formula (I): ##STR00014## X represents a NRR group; Y represents a group with the following formula: (CH.sub.2).sub.nNR.sub.6(CH.sub.2).sub.mNR.sub.7R.sub.8; n represents 1 or 2 or 3 or 4 or 5, m represents 1 or 2 or 3 or 4 or 5; R and R are the same or different and independently represent a hydrogen atom, or C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl or CF.sub.3, or a halogen atom, or CN, or OH; R.sub.6 represents hydrogen atom, or C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl, or CF.sub.3 or an halogen atom; the definition of R.sub.7 or R.sub.8 is the sane as that of R.sub.6; R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are the same or different and independently represent a group or an atom selected from H or a halogen atom, or CN, or CF.sub.3, or OH, or C.sub.1-6 alkyl, or C.sub.3-6 cycloalkyl.

2. The tetradentate chelating monoquinoline derivative of claim 1, wherein X represents an NH.sub.2.

3. A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof of formula (I) as claimed in claim 1 and a pharmaceutically acceptable diluent.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is an UV-visible spectrum of copper complexes of compound TDMQ-5, associated with other competing ligands; and

(2) FIG. 2 is the inhibition of production of H.sub.2O.sub.2 induced by the copper complexes of amyloid- associated to ascorbate, in the presence of TDMQ-5 (indicated as Q5) or TDMQ-10 (indicated as Q10).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

(3) The present disclosure will be further described in detail with reference to the accompanying drawings and preferred embodiments below. It should be understood that embodiments described here are only for explaining the present disclosure and the disclosure, however, should not be constructed as limited to the embodiment as set forth herein. Reagents, methods and devices described in the present disclosure are all conventional ones in the art unless the context clearly dictates otherwise.

(4) Reagents and materials used in the following examples are all purchased from the market.

Example 1: Synthesis of TDMQ-5

(5) Synthetic route is shown as follows.

(6) ##STR00003##

(7) The specific steps are described below.

5,7-dichloro-2-methylquinoline (1)

(8) To a solution of 3,5-dichloroaniline (3.24 g, 20 mmol) in concentrated HCl (12 mL) at 0 C. was added dropwise with stirring acetaldehyde. The reaction medium was kept at 0 C. for 15 min, and the temperature was gradually raised to 75 C. The mixture was stirred at 75 C. for 4 h. The reaction mixture was poured into ice-cold water and neutralized with aqueous ammonium hydroxide. After extraction with CH.sub.2Cl.sub.2, the organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel flash column chromatography (ethyl acetate/petroleum ether, 1:20, v/v). After evaporation of the eluent, compound 1 was obtained as a light yellow solid (2.93 g, 69%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.40 (d, J=8.0 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 2.76 (s, 3H).

5,7-dichloro-2-methyl-8-nitroquinoline (2)

(9) To a stirred solution of compound 1 (2.12 g, 10 mmol) in neat sulfuric acid (10 mL) was added fuming nitric acid (2.0 mL) dropwise over a 1 h period at ambient temperature. The resulting mixture was stirred for an additional hour, and was then poured onto ice. The mixture was allowed to warm to ambient temperature, neutralized with aqueous ammonium hydroxide. After extraction with CH.sub.2Cl.sub.2, the organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel flash column chromatography (ethyl acetate/petroleum ether, 1:10, v/v). Evaporation of the solvent afforded compound 2 as a yellow solid (2.34 g, 91%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.43 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 2.76 (s, 3H).

5,7-dichloro-2-methylquinolin-8-amine (3)

(10) Iron (1.34 g, 24 mmol) and acetic acid (18 mL) were added to a solution of compound 2 (2.06 g, 8 mmol) in ethanol (50 mL). The mixture was stirred at reflux for 4 h. The mixture was added dropwise over a saturated aqueous solution of NaHCO.sub.3 (400 mL) and extracted with CH.sub.2Cl.sub.2 (3200 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ethyl acetate/petroleum ether, 1:10, v/v). Evaporation of the solvent afforded compound 3 as a light yellow solid (1.62 g, 89%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.31 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 5.36 (brs, 2H), 2.76 (s, 3H).

N-acetyl-N-(5,7-dichloro-2-methylquinolin-8-yl)acetamide (4)

(11) To a solution of compound 3 (1.29 g, 5 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added acetyl chloride (1.1 mL) and N,N-diisopropylethylamine (5 mL) at 0 C. The reaction medium was kept at 0 C. for 15 min, and was gradually raised to reflux. The mixture was stirred at reflux for 4 h and then the solvent was removed under reduced pressure. The crude mixture was purified by silica gel flash column chromatography (ethyl acetate/petroleum ether, 1:20, v/v). After evaporation of the eluent, compound 4 was obtained as a light yellow solid (1.09 g, 70%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.41 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 2.71 (s, 3H), 2.29 (s, 6H).

N-acetyl-N-(5,7-dichloro-2-formylquinolin-8-yl)acetamide (5)

(12) To a solution of compound 4 (0.93 g, 3 mmol) in 1,4-dioxane (7 mL) was added selenium dioxide (0.5 g, 4.5 mmol). The reaction mixture was heated at 85 C. and stirred for 12 h. The reaction mixture was filtered through a celite column and selenium metal was washed with dichloromethane. The combined filtrates were evaporated to dryness under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate/petroleum ether, 1:20, v/v). After evaporation of the eluent, compound 5 was obtained as a light yellow solid (0.69 g, 71%). .sup.1H NMR (400 MHz, CDCl.sub.3): 10.13 (s, 1H), 8.76 (d, J=8.0 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.92 (s, 1H), 2.32 (s, 6H).

N.SUP.1.-((8-amino-5,7-dichloroquinolin-2-yl)methyl)-N.SUP.2.,N.SUP.2.-dimethylethane-1,2-diamine (TDMQ-5)

(13) To a solution of compound 5 (622 mg, 2 mmol) in 1,2-dichloroethane (30 mL) was added N,N-dimethyl-1,2-ethanediamine (352 mg, 4 mmol) under argon. The reaction mixture was stirred at room temperature for 1 h, and sodium triacetoxyborohydride (848 mg, 4 mmol) was added. The resulting mixture was stirred for an additional 12 h, diluted with CH.sub.2Cl.sub.2 (100 mL), followed by the addition of saturated aqueous sodium bicarbonate solution (40 mL). The organic phase was separated. The aqueous phase was added to 2 mL of ammonium hydroxide, and extracted with CH.sub.2Cl.sub.2 (330 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. To the crude product in CH.sub.2Cl.sub.2 (5 mL) was added 6M HCl (2 mL), which was stirred at room temperature for 4 h. Water (50 mL) was added, followed by addition of aqueous 25% ammonium hydroxide. The mixture was extracted with CH.sub.2Cl.sub.2 (330 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ethyl acetate/isopropanol/ammonium hydroxide (25%), 8:2:0.5, v/v/v). Evaporation of the solvent afforded TDMQ-5 as a light yellow solid (488 mg, 78%).

(14) The structural formula of the compound TDMQ-5 is as follows:

(15) ##STR00004##

(16) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.35 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 5.38 (brs, 2H), 4.10 (s, 2H), 2.75 (t, J=6.0 Hz, 2H), 2.55 (brs, 1 H), 2.48 (t, J=6.0 Hz, 2H), 2.22 (s, 6H).

(17) ESI.sup.+-MS: m/z (relative intensity) 313.1 (MH.sup.+, 100), 314.1 (18), 315.1 (65), 316.1 (11), 317.1 (11), 318.1 (2). Minor peaks due to fragmentation in the mass spectrometer were detected at m/z 268.0 {M=[M(CH.sub.3).sub.2N].sup.+, 9}, 224.9 {M=[M(CH.sub.3).sub.2N(CH.sub.2).sub.2NH].sup.+, 15}, 190.0 (MCl, 5), 155.0 (M2 Cl, 3). Isotopic patterns are consistent. HRMS (ESI.sup.+) for C.sub.14H.sub.19N.sub.4Cl.sub.2: Calcd, 313.0987; Found, 313.0987.

(18) Calculated log P=2.42 (ChemDraw Pro, v. 14.0).

Example 2: Synthesis of TDMQ-9

(19) Synthetic route is shown as follows.

(20) ##STR00005##

(21) The specific steps are described below.

6-fluoro-2-methyl-8-nitroquinoline (6)

(22) The procedure was similar to that described for the preparation of compound 1. Compound 6 was obtained as a light yellow solid (73%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (d, J=8.4 Hz, 1H), 7.70 (dd, J=8.0, 2.8 Hz, 1H), 7.55 (dd, J=8.0, 2.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 2.69 (s, 3H).

6-fluoro-2-methylquinolin-8-amine (7)

(23) The procedure was similar to that described for the preparation of compound 3. Compound 7 was obtained as a light yellow solid (92%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.87 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.95 (dd, J=10.8, 2.8 Hz, 1H), 6.63 (dd, J=10.8, 2.8 Hz, 1H), 5.13 (brs, 2H), 2.69 (s, 3H).

tert-butyl (6-fluoro-2-methylquinolin-8-yl)carbamate (8)

(24) To a solution of compound 7 (1.76 g, 10 mmol) in 1,4-dioxane (20 mL) was added di-tert butyl dicarbonate (3.27 g, 15 mmol). The reaction mixture was stirred at reflux for 12 h. After removal of the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (ethyl acetate/petroleum ether, 1:20, v/v). After evaporation of the eluent, compound 8 was obtained as a white solid (2.58 g, 89%).

(25) .sup.1H NMR (400 MHz, CDCl.sub.3) 9.08 (s, 1H), 8.21 (d, J=10.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.8, 2.8 Hz, 1H), 2.72 (s, 3H), 1.59 (s, 9H).

tert-butyl (6-fluoro-2-formylquinolin-8-yl)carbamate (9)

(26) The procedure was similar to that described for the preparation of compound 5. Compound 9 was obtained as a light yellow solid (50%). .sup.1H NMR (400 MHz, CDCl.sub.3): 10.23 (s, H), 9.04 (s, 1H), 8.36 (d, J=10.8 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.11 (dd, J=8.4, 2.4 Hz, 1H), 1.62 (s, 9H).

tert-butyl(2-(((2-(dimethylamino)ethyl)amino)methyl)-6-fluoroquinolin-8-yl)carbamate (10)

(27) To a solution of compound 9 (580 mg, 2 mmol) in 1,2-dichloroethane (30 mL) was added N,N-dimethyl-1,2-ethanediamine (352 mg, 4 mmol) under argon. The reaction mixture was stirred at room temperature for 1 h, and sodium triacetoxyborohydride (848 mg, 4 mmol) was added. The resulting mixture was stirred for an additional 12 h and diluted with 100 mL CH.sub.2Cl.sub.2, followed by the addition of saturated aqueous sodium bicarbonate solution (40 mL). The organic phase was separated. The aqueous phase was added to 2 mL of ammonium hydroxide, and extracted with CH.sub.2Cl.sub.2 (330 mL). The organic phases were combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. After removal of the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (ethyl acetate/isopropanol/ammonium hydroxide (25%), 8:2:0.5, v/v/v). After evaporation of the eluent, compound 10 was obtained as a light yellow solid (660 mg, 91%). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.07 (s, 1H), 8.25 (d, J=10.0 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.0 (dd, J=8.8, 2.8 Hz, 1H), 4.11 (s, 2H), 2.76 (t, J=6.0 Hz, 2H2), 2.49 (t, J=6.0 Hz, 2H), 2.24 (s, 6H), 1.60 (s, 9H).

N.SUP.1.-((8-amino-6-fluoroquinolin-2-yl)methyl)-N.SUP.2.,N.SUP.2.-dimethylethane-1,2-di amine (TDMQ-9)

(28) To compound 10 (725 mg, 2 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added trifluoroacetic acid (5 mL), which was stirred at room temperature for 4 h. After the removal of extra trifluoroacetic acid, the crude residue was diluted with CH.sub.2Cl.sub.2, followed by addition of 50 mL water and aqueous 25% ammonium hydroxide (2 mL). The mixture was extracted with CH.sub.2Cl.sub.2 (330 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ethyl acetate/isopropanol/ammonium hydroxide (25%), 8:2:0.5, v/v/v). After evaporation of the eluent, TDMQ-9 was obtained as a light yellow solid (451 mg, 86%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.93 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 6.71 (dd, J=10.4, 2.8 Hz, 1H), 6.64 (dd, J=10.4, 2.8 Hz, 1H), 5.20 (brs, 2H), 4.07 (s, 2H), 2.85 (brs, 1H), 2.78 (t, J=6.0 Hz, 2H), 2.49 (t, J=6.0 Hz, 2H), 2.23 (s, 6H).

Example 3: Synthesis of TDMQ-10

(29) Synthetic route is shown as follows.

(30) ##STR00006##

(31) The specific steps are described below.

5,6-dichloro-2-methyl-8-nitroquinoline (11)

(32) The procedure was similar to that described for the preparation of compound 1. Compound 11 was obtained as a light yellow solid (54%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.51 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 8.16 (d, J=8.8 Hz, 1H), 2.79 (s, 3H).

5,6-dichloro-2-methylquinolin-8-amine (12)

(33) The procedure was similar to that described for the preparation of compound 3. Compound 12 was obtained as a light yellow solid (86%). .sup.1H NMR (400 MHz, CDCl.sub.3) 10.25 (s, H), 8.91 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.93 (s, 1H), 2.71 (s, 3H).

tert-butyl(5,6-dichloro-2-methylquinolin-8-yl)carbamate (13)

(34) The procedure was similar to that described for the preparation of compound 8. Compound 13 was obtained as a white solid (84%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.98 (s, 1H), 8.50 (s, 1H), 8.40 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 2.75 (s, 3H), 1.59 (s, 9H).

tert-butyl(5,6-dichloro-2-formylquinolin-8-yl)carbamate (14)

(35) The procedure was similar to that described for the preparation of compound 5. Compound 14 was obtained as a light yellow solid (56%). .sup.1H NMR (400 MHz, CDCl.sub.3) 10.25 (s, 1H), 8.91 (s, 1H), 8.69 (d, J=8.4 Hz, 1H), 8.65 (s, 1H), 8.16 (d, J=8.4 Hz, 1H), 1.62 (s, 9H).

tert-butyl(5,6-dichloro-2-(((2-(dimethylamino)ethyl)amino)methyl)quinolin-8-yl)carbamate (15)

(36) The procedure was similar to that described for the preparation of compound 10. Compound 15 was obtained as a light yellow solid (92%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.97 (s, 1H), 8.54 (s, 1H), 8.48 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 4.14 (s, 2H), 2.75 (d, J=6.0 Hz, 2H), 2.48 (d, J=6.0 Hz, 2H), 2.24 (s, 6H), 1.59 (s, 9H).

tert-butyl(5, dichloro-2-(((2-(dimethylamino)ethyl)amino)methyl)quinolin-8-yl) carbamate (TDQM-10)

(37) The procedure was similar to that described for the preparation of TDMQ-9. TDMQ-10 was obtained as a light yellow solid (92%).

(38) The structural formula of the compound TDMQ-10 is as follows:

(39) ##STR00007##

(40) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.41 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 6.94 (s, 1H), 5.06 (s, 2H), 4.10 (s, 2H), 2.76 (d, J=6.0 Hz, 2H), 2.48 (d, J=6.0 Hz, 2H), 2.23 (s, 6H).

(41) ESI.sup.+-MS: m/z ESI.sup.+-MS: m/z (relative intensity) 313.1 (MH.sup.+, 100), 314.1 (18), 315.1 (65), 316.1 (11), 317.1 (11), 318.1 (2). Minor peaks due to fragmentation in the mass spectrometer were detected at m/z 268.0 {M=[M(CH.sub.3).sub.2N]+, 10}, 224.9 {M=[M(CH.sub.3).sub.2N(CH.sub.2).sub.2NH].sup.+, 18}, 190.0 (MCl, 6), 155.0 (M2 Cl, 3). Isotopic patterns are consistent. HRMS (ESI.sup.+) for C.sub.14H.sub.19N.sub.4Cl.sub.2: Calcd, 313.0987; Found, 313.0990.

(42) Calculated log P=2.42 (ChemDraw Pro, v. 14.0).

Example 4: Synthesis of TDMQ-12

(43) Synthetic route is shown as follows.

(44) ##STR00008##

(45) The specific steps are described below.

6-chloro-2-methyl-8-nitroquinoline (16)

(46) The procedure was similar to that described for the preparation of compound 1. Compound 11 was obtained as a light yellow solid (54%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.04 (d, J=8.4 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 2.76 (s, 3H).

6-chloro-2-methylquinolin-8-amine (17)

(47) The procedure was similar to that described for the preparation of compound 3. Compound 17 was obtained as a light yellow solid (81%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.84 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H), 5.05 (brs, 2H), 2.68 (s, 3H).

N-(6-chloro-2-formylquinolin-8-yl)acetamide (18)

(48) The procedure was similar to that described for the preparation of compound 8. Compound 11 was obtained as a light yellow solid (81%). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.79 (s, 1H), 8.75 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J=8.0 Hz, 1H), 2.73 (s, 3H), 2.36 (s, 3H).

N-(6-chloro-2-formylquinolin-8-yl)acetamide (19)

(49) The procedure was similar to that described for the preparation of compound 5. Compound 19 was obtained as a light yellow solid (45%). .sup.1H NMR (400 MHz, CDCl.sub.3): 10.23 (s, 1H), 9.71 (s, 1H), 8.90 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 2.42 (s, 3H).

N.SUP.1.-((8-amino-6-chloroquinolin-2-yl)methyl)-N.SUP.2.,N.SUP.2.-dimethylethane-1,2-dia mine (TDMQ-12)

(50) The procedure was similar to that described for the preparation of TDMQ-5. TDMQ-12 was obtained as a light yellow solid (91%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.89 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H), 5.14 (brs, 2H), 4.06 (s, 2H), 2.81 (brs, 1H), 2.77 (t, J=6.0 Hz, 2H), 2.48 (t, J=6.0 Hz, 2H), 2.22 (s, 6H).

Example 5: Synthesis of TDMQ-13

(51) Synthetic route is shown as follows.

(52) ##STR00009##

(53) The specific steps are described below.

7-chloro-2-methyl-8-nitroquinoline (20)

(54) The procedure was similar to that described for the preparation of compound 1. Compound 20 was obtained as a light yellow solid (80%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.08 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.52 (d J=8.8 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 2.74 (s, 3H).

7-chloro-2-methylquinolin-8-amine (21)

(55) The procedure was similar to that described for the preparation of compound 3. Compound 21 was obtained as a light yellow solid (86%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.84 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.06 (s, 1H), 6.83 (s, 1H), 5.05 (brs, 2H), 2.68 (s, 3H).

N-(7-chloro-2-methylquinolin-8-yl)acetamide (22)

(56) The procedure was similar to that described for the preparation of compound 8. Compound 22 was obtained as a light yellow solid (42%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.04 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 2.688 (s, 3H), 2.298 (s, 6H).

N-(7-chloro-2-formylquinolin-8-yl)acetamide (23)

(57) The procedure was similar to that described for the preparation of compound 5. Compound 23 was obtained as a light yellow solid (64%). .sup.1H NMR (400 MHz, CDCl.sub.3): 10.13 (s, 1H), 8.39 (d, J=8.8 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 2.330 (s, 6H).

N-(7-chloro-2-(((2-(dimethylamino)ethyl)amino)methyl)quinolin-8-yl)aceta mide (24)

(58) The procedure was similar to that described for the preparation of compound 10. Compound 24 was obtained as a light yellow solid (94%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.08 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.11 (s, 2H), 2.79 (t, J=6.0 Hz, 2H), 2.50 (t, J=6.0 Hz, 2H), 2.239 (s, 6H).

N.SUP.1.-((8-amino-7-chloroquinolin-2-yl)methyl)-N.SUP.2.,N.SUP.2.-dimethylethane-1,2-dia mine (TDMQ-13)

(59) The procedure was similar to that described for the preparation of TDMQ-5. TDMQ-13 was obtained as a light yellow solid (97%). TDMQ-13: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.99 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 5.35 (brs, 2H), 4.09 (s, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.48 (t, J=6.0 Hz, 2H), 2.46 (brs, 1H), 2.23 (s, 6H).

Example 6: Synthesis of TDMQ-16

(60) Synthetic route is shown as follows.

(61) ##STR00010##

(62) The specific steps are described below.

2-methyl-8-nitro-6-(trifluoromethyl)quinoline (25)

(63) The procedure was similar to that described for the preparation of compound 1. Compound 25 was obtained as a light yellow solid (59%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.28 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.12 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 2.81 (s, 3H).

2-methyl-6-(trifluoromethyl)quinolin-8-amine (26)

(64) The procedure was similar to that described for the preparation of compound 3. Compound 26 was obtained as a light yellow solid (74%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.02 (d, J=8.4 Hz, 1H), 7.39 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 5.15 (brs, 2H), 2.74 (s, 3H).

N-(2-methyl-6-(trifluoromethyl)quinolin-8-yl)acetamide (27)

(65) The procedure was similar to that described for the preparation of compound 8. Compound 27 was obtained as a light yellow solid (78%). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.85 (s, 1H), 8.97 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 2.79 (s, 3H), 2.38 (s, 3H).

N-(2-formyl-6-(trifluoromethyl)quinolin-8-yl)acetamide (28)

(66) The procedure was similar to that described for the preparation of compound 5. Compound 28 was obtained as a light yellow solid (50%). .sup.1H NMR (400 MHz, CDCl.sub.3): 10.28 (s, 1H), 9.77 (s, 1H), 9.12 (s, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 2.43 (s, 3H).

N-(2-(((2-(dimethylamino)ethyl)amino)methyl)-6-(trifluoromethyl)quinolin-8-yl)acetamide (29)

(67) The procedure was similar to that described for the preparation of compound 10. Compound 29 was obtained as a light yellow solid (96%). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.92 (s, 1H), 9.00 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 4.17 (s, 2H), 2.77 (t, J=6.0 Hz, 2H), 2.50 (t, J=6.0 Hz, 2H), 2.36 (s, 3H), 2.24 (s, 6H).

N.SUP.1.-((8-amino-6-(trifluoromethyl)quinolin-2-yl)methyl)-N.SUP.2.,N.SUP.2.-dimehyletha ne-1,2-diamine (TDMQ-16)

(68) The procedure was similar to that described for the preparation of TDMQ-5. TDMQ-16 was obtained as a light yellow solid (99%). TDMQ-16: .sup.1H NMR (400 MHz, CDCl.sub.3) 8.07 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.39 (s, 1H), 7.01 (s, 1H), 5.23 (brs, 2H), 4.11 (s, 2H), 2.77 (t, J=6.0 Hz, 2H), 2.55 (brs, 1H), 2.48 (t, J=6.0 Hz, 2H), 2.23 (s, 6H).

Example 7: Synthesis of TDMQ-19

(69) Synthetic route is shown as follows.

(70) ##STR00011##

(71) The specific steps are described below.

N.SUP.1.-((8-amino-5,7-dichloroquinolin-2-yl)methyl)-N.SUP.3.,N.SUB.3.-dimehypropane-1,3-diamine (TDMQ-19)

(72) The procedure was similar to that described for the preparation of TDMQ-5. TDMQ-19 was obtained as a light yellow solid (87%). .sup.1H NMR (400 MHz, D.sub.2O): 8.49 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 4.58 (s, 2H), 3.25 (t, J=8.0 Hz, 2H), 3.19 (t, J=8.0 Hz, 2H), 2.82 (s, 6H), 2.23-2.15 (m, 2H).

Example 8: Synthesis of TDMQ-20

(73) Synthetic route is shown as follows.

(74) ##STR00012##

(75) The specific steps are described below.

5,7-dichloro-8-nitro-2-vinylquinoline (30)

(76) TBHP (0.6 mmol, 70% aqueous solution) was added to a mixture of FeCl.sub.3 (3.2 mg, 0.02 mmol), compound 2 (51.4 mg, 0.2 mmol), and N,N-dimethylacetamide (1 mL). Subsequently, the reaction mixture was heated to 140 C. and stirred at this temperature for 4 h under air. The resulting mixture was then cooled to room temperature, diluted with water, and extracted with dichloromethane. The organic phase was washed with brine and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (EtOAc/petroleum ether, 1:10, v/v) to give compound 30 as a white solid (17.7 mg, 67% based on the conversion of starting material; 51% of the starting material was recovered unchanged). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.52 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 6.97 (dd, J=17.6, 10.8 Hz, 1H), 6.46 (d, J=17.6 Hz, 1H), 5.79 (d, J=10.8 Hz, 1H).

N.SUP.1.-(2-(5,7-dichloro-8-nitroquinolin-2-yl)ethyl)-N.SUP.2.,N.SUP.2.-dimethylethane-1,2-d iamine (31)

(77) A mixture of compound 30 (1.08 g, 4 mmol), N,N-dimethyl-1,2-ethanediamine (352 mg, 4 mmol), and acetic acid (4 mmol) in methanol (15 mL) was refluxed for 12 h. After removal of the solvent by evaporation, the resulting residue was dissolved in CH.sub.2Cl.sub.2 (30 mL), and the CH.sub.2Cl.sub.2 solution was washed with 10% aqueous NaOH three times, and dried over anhydrous K.sub.2CO.sub.3. After removal of K.sub.2CO.sub.3 by filtration and evaporation of the organic solvent, compound 31 was isolated by silica gel flash chromatography (ethyl acetate/isopropanol/ammonium hydroxide (25%), 8:2:0.5, v/v/v) as a light yellow solid (75%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.46 (d, J=8.8 Hz, 1H), 7.66 (s, 1H), 7.54 (d, J=8.8 Hz, 1H), 3.22 (t, J=6.0 Hz, 2H), 3.12 (t, J=6.0 Hz, 2H), 2.74 (t, J=6.4 Hz, 2H), 2.43 (t, J=6.4 Hz, 2H), 2.23 (s, 6H).

N.SUP.1.-(2-(8-amino-5,7-dichloroquinolin-2-yl)ethyl)-N.SUP.2.,N.SUP.2.-dimethylethane-1,2-diamine (TDMQ-20)

(78) The procedure was similar to that described for the preparation of compound 3. TDMQ-20 was obtained as a light yellow solid (90%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.33 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 5.40 (brs, 2H), 3.19-3.12 (m, 4H), 2.77 (t, J=6.0 Hz, 2H), 2.44 (t, J=6.0 Hz, 2H), 2.22 (s, 6H).

Example 9: Synthesis of TDMQ-22

(79) Synthetic route is shown as follows.

(80) ##STR00013##

(81) The specific steps are described below.

8-nitro-6-(trifluoromethyl)-2-vinylquinoline (32)

(82) To a solution of compound 25 (1.0 g, 3.9 mmol) in DMA (5 mL) was added FeCl.sub.3 (19.0 mg, 0.117 mmol) and K.sub.2S.sub.2O.sub.8 (1.05 g, 7.8 mmol). The mixture was stirred at 110 C. for 15 min and quenched with water. After extraction with CH.sub.2Cl.sub.2, the organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel flash column chromatography (dichloromethane/hexane, 1:5, v/v). After evaporation of the eluent, compound 32 was obtained as a brown solid (470.7 mg, 45%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm: 8.30-8.28 (m, 2H), 8.15 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.02 (dd, J=17.6 Hz, 10.8 Hz, 1H), 6.52 (d, J=17.6 Hz, 1H), 5.82 (d, J=10.8 Hz, 1H).

N.SUP.1.,N.SUP.1.-dimethyl-N.SUP.2.-(2-(8-nitro-6-(trifluoromethyl)quinolin-2-yl)ethyl)ethan e-1,2-diamine (33)

(83) To a mixture of compound 32 (388.9 g, 1.45 mmol) and K.sub.2CO.sub.3 (240.5 g, 1.74 mmol) in 1,4-dioxane (5 mL) was added N,N-dimethyl-1,2-ethanediamine (255.6 mg, 2.9 mmol). The reaction mixture was stirred at room temperature for 1 h, and quenched with water. After extraction with CH.sub.2Cl.sub.2, the organic phase was dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel flash column chromatography (ethyl acetate/isopropanol/ammonium hydroxide (25%), 50:1:1, v/v/v). After evaporation of the eluent, compound 33 was obtained as yellow solid (416 mg, 80%). .sup.1H NMR (400 MHz, CDCl.sub.3) ppm: 8.29 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.16 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 3.26 (t, J=6.4 Hz, 2H), 3.16 (t, J=6.4 Hz, 2H), 2.77 (t, J=6.4 Hz, 2H), 2.44 (t, J=6.4 Hz, 2H), 2.22 (s, 6H).

N.SUP.1.-(2-(8-amino-6-(trifluoromethyl)quinolin-2-yl)ethyl)-N.SUP.2.,N.SUP.2.-dimethyletha ne-1,2-diamine (TDMQ-22)

(84) To a mixture of compound 33 (142.5 mg, 0.4 mmol), SnCl.sub.2.2H.sub.2O (270.8 mg, 1.2 mmol) in ethanol (5 mL) was added concentrated HCl (1 mL) dropwise at room temperature, and the mixture was stirred at 50 C. for 1 h. Water (50 mL) was added, followed by addition of extra aqueous 25% ammonium hydroxide. The mixture was extracted with CH.sub.2Cl.sub.2 (330 mL). The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (ethyl acetate/isopropanol/ammonium hydroxide (25%), 50:1:1, v/v/v). Evaporation of the solvent afforded TDMQ-22 as a light yellow solid (96.6 mg, 74%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.04 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 5.24 (brs, 2H), 3.21-3.11 (m, 4H), 2.78 (t, J=6.0 Hz, 2H), 2.45 (t, J=6.0 Hz, 2H), 2.21 (s, 6H).

Example 10: Experiment of the Derivatives Specifically Chelating Copper Ions

(85) Estimation of affinity constants of compounds of general formula (I) with metal ions:

(86) Affinity Constants for Cu.sup.2:

(87) The following mother solutions were prepared: (A) ligand L=TDMQ-n, 300 M in 20 mM Tris.HCl pH 7.4, 150 mM NaCl; (B) Competing ligands (namely NTA, EDTA, EDDA, EGTA, or CDTA), 300 M in 20 mM Tris.HCl pH 7.4, 150 mM NaCl; (C) CuCl.sub.2, 15 mM in H.sub.2O. In the UV/Vis cuvette, 100 L of (A), 100 L of (B), 1800 L of 20 mM Tris.HCl pH 7.4, 150 mM NaCl, and 2 L of (C) were added in that order. The final concentrations of L, Competing ligand (L.sub.C), and Cu.sup.2+ were 15 M. The spectrum of the mixture was recorded from 250 to 600 nm at room temperature as shown in FIG. 1.

(88) The spectrum of the ligand L (2 L of H.sub.2O instead of 2 L of (C)) was recorded according to above conditions; and the spectrum of [Cu.sup.2+L] (100 L of 20 mM Tris.HCl pH 7.4, 150 mM NaCl, instead of 100 L of (B)) was recorded according to above conditions. All ligands and complexes studied followed the Beer-Lambert law in the experimental conditions used.

(89) The equations of complexation are as follows:

(90) $L+{\mathrm{Cu}}^{2+}\mathrm{Cu}-L,\mathrm{with}{K}_{\mathrm{app}\left[\mathrm{Cu}-L\right]}=\frac{\left[\mathrm{Cu}-L\right]}{\left[\mathrm{Cu}\right]\left[L\right]}$$L_C+{\mathrm{Cu}}^{2+}\mathrm{Cu}-L_C,\mathrm{with}{K}_{\mathrm{app}\left[\mathrm{Cu}-\mathrm{Lc}\right]}=\frac{\left[\mathrm{Cu}-L_C\right]}{\left[\mathrm{Cu}\right]\left[L_C\right]}$

(91) It can be deduced that at the equilibrium:

(92) $K_{\mathrm{app}\left[\mathrm{Cu}-L\right]}=K_{\mathrm{app}\left[\mathrm{Cu}-\mathrm{Lc}\right]}\frac{\left[L_C\right]\left[\mathrm{Cu}-L\right]}{\left[L\right]\left[\mathrm{Cu}-L_C\right]}$

(93) UV/Vis monitoring at 383 nm allowed to determine the absorbance of the competitive chelation mixture (A.sub.mix), the absorbance of L in the absence of Cu.sup.2+ (A.sub.L), and the absorbance of CuL in the absence of competing ligand (A.sub.Cu-L). The proportion of Cu.sup.2+ chelated by L was calculated as x=(A.sub.L-A.sub.mix)/(A.sub.L-A.sub.Cu-L). Experiments were performed in triplicate.

(94) Affinity Constants for Zn.sup.2+:

(95) When Ligand-Zn complex (1/1) shows very low affinity, there is equilibrium in the solution under the same reaction condition:

(96) $L+{\mathrm{Zn}}^{2+}\mathrm{Zn}-L,\mathrm{with}{K}_{\mathrm{app}\left[\mathrm{Zn}-L\right]}=\frac{\left[\mathrm{Zn}-L\right]}{\left[\mathrm{Zn}\right]\left[L\right]}$

(97) As TDMQs ligands exhibit a much lower affinity for Zn.sup.2+ compared to Cu.sup.2+, at 10-20 mM, there is equilibrium in the solution between the free ligand L and the Zn-L complex (stoichiometry L/Zn=1/1). So, K.sub.app[Zn-L] can be calculated by titration of L with sequential additions of a Zn.sup.2+ salt, without using of a competing ligand:

(98) $L+{\mathrm{Zn}}^{2+}\mathrm{Zn}-L,\mathrm{with}{K}_{\mathrm{app}\left[\mathrm{Zn}-L\right]}=\frac{\left[\mathrm{Zn}-L\right]}{\left[\mathrm{Zn}\right]\left[L\right]}$

(99) TABLE-US-00001 TABLE 1 Affinity constants of the different ligands for Cu.sup.2+ or Zn.sup.2+ ions at pH = 7.4 Ligand Log KCu.sup.2+ Log KZn.sup.2+ TDMQ-5 9.8 4.2 TDMQ-9 10.2 4.7 TDMQ-10 9.7 4.5 TDMQ-12 10.2 4.7 TDMQ-13 10.4 4.6 TDMQ-16 10.0 4.5 TDMQ-19 10.2 negligible (~0) TDMQ-20 16.5 4.2 TDMQ-22 15.1 4.1

(100) The results of Table 1 show that the binding constant of the derivatives in the present disclosure for copper log K.sub.cu.sup.2+ is higher than 9.7, and up to 16.5, while the binding constant for zinc log K.sub.zn.sup.2+ is below 4.7 according to the calculation to the binding constants of copper(II) and zinc(II) for a series of TDMQ chelators. For example, the binding constant of TDMQ-19 for zinc is negligible, namely the TDMQ-19 cannot significantly chelate zinc ions. The binding constant of TDMQ-19 for copper is 10.2. The difference between the two binding constant is 10 orders of magnitude. The affinity constants of TDMQ-20 for copper and zinc are 16.5 and 4.2, respectively, and the difference between them is 12 orders of magnitude. It shows that the derivatives in the present disclosure are able to selectively chelate copper ions with respect to zinc, and can be used for manufacturing drugs for neurodegenerative diseases and diseases related to disorder of copper metabolism.

Example 11: Quantitative Analysis of the Hydrogen Peroxide Produced by A in the Presence of Cu.SUP.2+., Reducing Agent with or without TDMQ Ligand

(101) The production of H.sub.2O.sub.2 was quantified by fluorescence, using the Red Hydrogen Peroxide Assay kit from Enzo Life Sciences (Cat.=ENZ-51004 Lot No. 10231415). Fluorescence spectra were recorded on a FLSP920 spectrometer (Edinburgh Instruments), with bandwidth for excitation and emission=2 nm, .sub.ex=540 nm, .sub.em=584 nm, acquisition range=550-700 nm), repeats: 3 scans for each acquisition.

(102) Stock solutions were: CuCl.sub.2 (10 M in water), A.sub.1-16 (10 M in water), TDMQ-5.HCl (10 M in water), TDMQ-10.HCl (10 M or 20 M in water), sodium ascorbate (100 M in water), Hepes buffer 0.1 M pH 7.4.

(103) In a typical reaction, operations were introduced in the following order: Hepes buffer (50 L), CuCl.sub.2 (10 L), A.sub.1-16 (10 L), 30 min of incubation to form the Cu.sup.2+-A.sub.1-16 complex. The solution of TDMQ was then added (10 L or 20 L for 1 or 2 mol equiv with respect to Cu.sup.2+, respectively), incubation for 30 min; ascorbate (10 L); H.sub.2O (sufficient volume to adjust final volume to 100 L), then incubation for 30 min. Final concentrations were Cu.sup.2+/A.sub.1-16/TDMQ/ascorbate/Hepes buffer=1 M/1 M/1 M or 2 M/10 M/50 mM. The production of H.sub.2O.sub.2 was then quantified by fluorescence using the Red Hydrogen Peroxide Assay kit according to the protocol of the supplier (.sub.ex=540 nm, .sub.em=550-700 nm). Reaction mixtures were incubated for 30 min, protected from light before measure.

(104) Control experiments were: Cu-A.sub.1-16ascorbate, CuCl.sub.2ascorbate, A.sub.1-16 or C.sup.2+ alone, performed in the same conditions. Results are shown in FIG. 2.

(105) Through the experiments on production of hydrogen peroxide by amyloid- in the presence of copper ions and a reducing agent, it finds that the derivatives in the present invention are able to extract copper from copper-amyloid protein and exhibit a strong capability of reducing an oxidative stress.