Compounds as HIF-1α inhibitors and manufacturing process thereof

Abstract

The present invention relates to novel compounds as HIF-1α inhibitors, manufacturing process thereof, and a pharmaceutical compositions. The compounds according to the present invention having inhibition activity against HIF-1α, can be used as a therapeutic prevention and/or treatment for various solid cancers such as colon cancer, liver cancer, stomach cancer and breast cancer. Also, the compounds according to the present invention are useful in the treatment of diabetic retinopathy and rheumatoid arthritis, which are aggravated by HIF-1α-mediated VEGFA expression.

Claims

1. A method of treating colon cancer in a subject in need thereof, comprising administering an effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of: 2-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (“I-3”); 2-(4-(Adamantan-1-yl)-2-methylphenoxy)-1-morpholinoethanone (“I-6”); 3-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one (“I-8”); 4-(2-(4-(Adamantan-1-yl)-2-methylphenoxy)acetyl)-1,1-dimethylpiperazin-1-ium iodide (“I-16”); 4-(4-(4-(Adamantan-1-yl)phenoxy)butanoyl)-1,1-dimethylpiperazin-1-ium iodide (“I-22”); and 2-(4-(Adamantan-1-yl)phenoxy)-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one (“I-23”), or a pharmaceutically acceptable base or acid addition salt, hydrate, or solvate thereof.

2. The method of claim 1, wherein the compound is I-3.

3. The method of claim 1, wherein, the compound suppresses the growth and metastasis of colon cancer.

4. A method of treating rectal cancer in a subject in need thereof, comprising administering an effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of: 2-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (“I-3”); 2-(4-(Adamantan-1-yl)-2-methylphenoxy)-1-morpholinoethanone (“I-6”); 3-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one (“I-8”); 4-(2-(4-(Adamantan-1-yl)-2-methylphenoxy)acetyl)-1,1-dimethylpiperazin-1-ium iodide (“I-16”); 4-(4-(4-(Adamantan-1-yl)phenoxy)butanoyl)-1,1-dimethylpiperazin-1-ium iodide (“I-22”); and 2-(4-(Adamantan-1-yl)phenoxy)-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one (“I-23”), or a pharmaceutically acceptable base or acid addition salt, hydrate or solvate thereof.

5. The method of claim 4, wherein the compound is I-3.

6. A method of treating cancer in a subject in need thereof, comprising administering an effective amount of a pharmaceutical composition comprising I-3, wherein the cancer is selected from the group consisting of pro static cancer, renal cell carcinoma, and pancreatic cancer.

Description

BRIEF DESCRIPTION OF DRAWING

(1) FIG. 1 shows the inhibitory activity of the compounds according to the present invention against HIF-1α expression.

(2) FIG. 2 shows the results of CAM (chick embryo chorioallantoic membrane) assay of the compounds prepared in the present invention.

DETAILED DESCRIPTION OF THE INVENTION

(3) The present invention will be described more particularly by the Examples but the present invention is not limited at all by these examples.

2-(4-(Adamantan-1-yl)phenoxy)-N,N-dimethylacetamide (I-1)

(4) A suspension of 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol), dimethylamine (0.031 g, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDCI) (0.16 g, 0.83 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (0.11 g, 0.83 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (DIPEA) (0.106 mL, 1.74 mmol) and stirred at room temperature under nitrogen overnight. Reaction mixture was diluted with ethyl acetate and subsequentially washed with aqueous sodium hydroxide and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)phenoxy)-N,N-dimethylacetamide as a white solid (0.198 g, 90.3% yield).

(5) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.23 (2H, d, aromatic-H), 6.82 (2H, d, aromatic-H), 4.73 (2H, s, OCH.sub.2), 2.98 (3H, s, CH.sub.3), 2.83 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-N-cyclopropylacetamide (I-2)

(6) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and cyclopropylamine (0.039 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-cyclopropylacetamide as a white solid (0.198 g, 87.4% yield).

(7) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 8.07 (1H, s, (C═O)NH), 7.25 (2H, d, aromatic-H), 6.85 (2H, d, aromatic-H), 4.38 (2H, s, OCH.sub.2), 2.67 (1H, m, cyclopropyl), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H), 0.61 (2H, m, cyclopropyl), 0.48 (2H, m, cyclopropyl).

2-(4-(Adamantan-1-yl)phenoxy)-1-(4-piperazin-1-yl)ethanone (I-3)

(8) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (2.0 g, 6.98 mmol) and 1-methylpiperazine (0.69 g, 6.98 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (2.4 g, 93.3% yield).

(9) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.23 (2H, d, aromatic-H), 6.82 (2H, d, aromatic-H), 4.74 (2H, s, OCH.sub.2CO), 3.40 (4H, m, piperazine), 2.74 (4H, m, piperazine), 2.17 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium chloride (I-4)

(10) A suspension of 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (0.4 g, 1.08 mmol), prepared from example 3, and 1.0 M HCl solution in diethyl ether (0.047 g, 1.30 mmol) in diethyl ether (4 mL) was stirred at room temperature overnight. The reaction mixture was filtered and dried in vacuum to afford a 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium chloride as a crystalline white solid (0.43 g, 97.9% yield).

(11) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.24 (2H, d, aromatic-H), 6.86 (2H, d, aromatic-H), 4.82 (2H, s, OCH.sub.2CO), 4.20 (2H, m, piperazine), 3.38 (3H, m, piperazine), 3.05 (3H, m, piperazine), 2.77 (3H, s, CH.sub.3), 2.04 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone (I-5)

Step 1: 1-(4-Methoxy-3-methylphenyl)adamantan

(12) To a solution of 1-bromoadamantane (3.25 g, 15.25 mmol) and potassium carbonate (1.05 g, 7.62 mmol) in 1-methoxy-2-methylbenzene (10 mL) was added 10 wt. % Pd/C (2.22 g) and stirred at 150° C. under nitrogen for 24 hours. The reaction mixture was cooled to room temperature and filtered. Solvent was evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 1-(4-methoxy-3-methylphenyl)adamantane as a white solid (4.9 g, 82.3% yield).

(13) .sup.1H-NMR (CDCl.sub.3, 300 MHz) δ 7.15 (2H, m, aromatic-H), 6.78 (1H, d, aromatic-H), 3.81 (3H, s, OCH.sub.3), 2.23 (3H, s, CH.sub.3) 2.08 (3H, s, adamantyl-H), 1.90 (6H, m, adamantyl-H), 1.76 (6H, m, adamantyl-H).

Step 2: 4-(Adamantan-1-yl)-2-methylphenol

(14) 1-(4-methoxy-3-methylphenyl)adamantane was dissolved in dichloromethane (90 mL) and cooled to −10° C. Boron tribromide (BBr.sub.3) (1.97 g, 8.31 mmol) was slowly added at −10° C. under nitrogen and stirred for 30 minutes at same temperature to 1.5 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 4-(Adamantan-1-yl)-2-methylphenol as a white solid (1.58 g, 100% yield).

(15) .sup.1H-NMR (CDCl.sub.3, 300 MHz) δ 7.07 (2H, s, aromatic-H), 6.72 (1H, d, aromatic-H), 4.52 (1H, s, OH), 2.25 (3H, s, CH.sub.3) 2.08 (3H, s, adamantyl-H), 1.88 (6H, m, adamantyl-H), 1.76 (6H, m, adamantyl-H).

Step 3: Ethyl 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetate

(16) To a solution of 4-(adamantan-1-yl)-2-methylphenol (2.0 g, 8.76 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (3.63 g, 23.29 mmol) and ethyl chloroacetate (1.29 g, 10.51 mmol), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give ethyl 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetate as a white solid (2.6 g, 95.9% yield).

(17) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.06 (2H, m, aromatic-H), 6.72 (1H, m, aromatic-H), 4.73 (2H, s, OCH.sub.2CO), 4.15 (2H, q, OCH.sub.2CH.sub.3), 2.18 (3H, q, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.81 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H), 1.2 (3H, t, CH.sub.3).

Step 4: 2-(4-(Adamantan-1-yl)-2-methylphenoxy)acetic acid

(18) To a solution of ethyl 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetate (1.1 g, 3.50 mmol) in H.sub.2O/THF (1 mL/1.20 mL) was added lithium hydroxide monohydrate (0.29 g, 7.00 mmol), and stirred at room temperature overnight. The reaction mixture was adjusted to acidic solution with 1 N aqueous HCl and extracted with dichloromethane. The organic layer was washed with H.sub.2O and brine, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid as a white solid (0.54 g, 96.7% yield).

(19) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 12.91 (1H, bs, COOH), 7.13 (1H, s, aromatic-H), 7.05 (1H, m, aromatic-H), 6.70 (1H, d, aromatic-H), 4.63 (2H, s, OCH.sub.2CO), 2.17 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.90 (6H, m, adamantyl-H), 1.76 (6H, m, adamantyl-H).

Step 5: 2-(4-(Adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone

(20) The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol) and 1-methylpiperazine (0.06 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.23 g, 90.5% yield).

(21) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.12 (1H, m, aromatic-H), 7.05 (1H, m, aromatic-H), 6.74 (1H, m, aromatic-H), 4.74 (2H, s, OCH.sub.2), 3.45 (4H, m, piperazine), 2.28 (4H, m, piperazine), 2.17 (6H, s, (CH.sub.3).sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)-2-methylphenoxy)-1-morpholinoethanone (I-6)

(22) The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol), prepared from the step 4 of the example 5, and morpholine (0.058 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-1-morpholinoethanone as a white solid (0.228 g, 92.7% yield).

(23) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.12 (1H, s, aromatic-H), 7.04 (1H, m, aromatic-H), 6.76 (1H, d, aromatic-H), 4.77 (2H, t, OCH.sub.2CH.sub.2), 3.58 (4H, m, morpholine), 3.45 (4H, m, morpholine), 2.17 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)acetamide (I-7)

(24) The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)acetic acid (0.2 g, 0.66 mmol), prepared from the step 4 of the example 5, and N,N-dimethylethane-1,2-diamine (0.058 g, 0.66 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)acetamide as a white solid (0.22 g, 89.4% yield).

(25) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.73 (1H, t, (C═O)NH), 7.14 (1H, s, aromatic-H), 7.06 (1H, m, aromatic-H), 6.75 (1H, d, aromatic-H), 4.43 (2H, t, OCH.sub.2CH.sub.2), 3.22 (2H, m, NHCH.sub.2CH.sub.2), 2.50 (2H, m, NHCH.sub.2CH.sub.2), 2.30 (2H, t, OCH.sub.2CH.sub.2), 2.21 (3H, s, CH.sub.3), 2.13 (6H, s, (CH.sub.3).sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

3-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one (I-8)

(26) The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)propanoic acid (0.2 g, 0.66 mmol) and 1-methylpiperazine (0.06 g, 0.66 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one as a white solid (0.24 g, 94.4% yield).

(27) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.24 (2H, m, aromatic-H), 6.84 (2H, d, aromatic-H), 4.18 (2H, t, OCH.sub.2CH.sub.2), 3.85 (4H, m, piperazine), 3.39 (4H, m, piperazine), 3.16 (6H, s, (CH.sub.3).sub.2), 2.86 (2H, t, CH.sub.2CH.sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

3-(4-(Adamantan-1-yl)phenoxy)-1-morpholinopropan-1-one (I-9)

(28) The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)propanoic acid (0.2 g, 0.66 mmol) and morpholine (0.058 g, 0.66 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)phenoxy)-1-morpholinopropan-1-one as a white solid (0.23 g, 93.4% yield).

(29) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.24 (2H, d, aromatic-H), 6.84 (2H, d, aromatic-H), 4.16 (2H, t, OCH.sub.2CH.sub.2), 3.55 (4H, m, morpholine), 3.46 (4H, m, morpholine), 2.79 (2H, m, OCH.sub.2CH.sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

3-(4-(Adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)propanamide (I-10)

(30) The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)propanoic acid (0.2 g, 0.66 mmol) and N,N-dimethylethane-1,2-diamine (0.058 g, 0.66 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)propanamide as a white solid (0.225 g, 91.4% yield).

(31) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.88 (1H, t, (C═O)NH), 7.24 (2H, d, aromatic-H), 6.83 (2H, d, aromatic-H), 4.12 (2H, t, OCH.sub.2CH.sub.2), 3.14 (2H, m, NHCH.sub.2CH.sub.2), 2.5 (2H, m, NHCH.sub.2CH.sub.2), 2.28 (2H, t, OCH.sub.2CH.sub.2), 2.14 (6H, s, (CH.sub.3).sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

3-(4-(Adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one (I-11)

(32) The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoic acid (0.2 g, 0.63 mmol) and 1-methylpiperazine (0.063 g, 0.63 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one as a white solid (0.236 g, 93.6% yield).

(33) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.08 (2H, m, aromatic-H), 6.84 (1H, d, aromatic-H), 4.15 (2H, t, OCH.sub.2CH.sub.2), 3.47 (4H, m, piperazine), 2.78 (2H, t, CH.sub.2CH.sub.2), 2.78 (1H, m, CH.sub.2CH.sub.2), 2.28 (4H, m, piperazine), 2.17 (3H, s, CH.sub.3), 2.10 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

3-(4-(Adamantan-1-yl)-2-methylphenoxy)-1-morpholinopropan-1-one (I-12)

(34) The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoic acid (0.2 g, 0.63 mmol) and morpholine (0.055 g, 0.63 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)-2-methylphenoxy)-1-morpholinopropan-1-one as a white solid (0.22 g, 90.5% yield).

(35) .sup.1H-NMR (DMSO-d.sub.6, 500 Hz) δ 7.10 (1H, s, aromatic-H), 7.07 (1H, d, aromatic-H), 6.84 (1H, d, aromatic-H), 4.16 (2H, t, OCH.sub.2CH.sub.2), 3.55 (4H, m, morpholine), 3.46 (4H, m, morpholine), 2.79 (2H, m, OCH.sub.2CH.sub.2), 2.09 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

3-(4-(Adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)propanamide (I-13)

(36) The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoic acid (0.2 g, 0.63 mmol) and N,N-dimethylethane-1,2-diamine (0.056 g, 0.63 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)propanamide as a white solid (0.228 g, 93.4% yield).

(37) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.88 (1H, t, (C═O)NH), 7.08 (2H, t, aromatic-H), 6.83 (1H, d, aromatic-H), 4.12 (2H, t, OCH.sub.2CH.sub.2), 3.16 (2H, m, NHCH.sub.2CH.sub.2), 2.5 (2H, m, NHCH.sub.2CH.sub.2), 2.28 (2H, t, OCH.sub.2CH.sub.2), 2.13 (6H, s, (CH.sub.3).sub.2), 2.09 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

4-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)butan-1-one (I-14)

Step 1: Ethyl 4-(4-(adamantan-1-yl)phenoxy)butanoate

(38) To a solution of 4-(adamantan-1-yl)phenol (2.0 g, 8.76 mmol) in N,N-dimethylformamide was added potassium carbonate (3.63 g, 26.29 mmol) and ethyl 4-bromobutanoate (1.29 g, 10.51 mmol), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give ethyl 4-(4-(adamantan-1-yl)phenoxy)butanoate as a white solid (2.7 g, 90% yield).

(39) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.23 (2H, d, aromatic-H), 6.83 (2H, d, aromatic-H), 4.06 (2H, q, CH.sub.2CH.sub.3), 3.94 (2H, t, (CH.sub.2).sub.3), 2.43 (2H, t, (CH.sub.2).sub.3), 2.08 (3H, s, adamantyl-H), 1.92 (2H, m, (CH.sub.2).sub.3), 1.88 (6H, m, adamantyl-H), 1.76 (6H, m, adamantyl-H), 1.17 (3H, m, CH.sub.3).

Step 2: 4-(4-(Adamantan-1-yl)phenoxy)butanoic acid

(40) To a solution of ethyl 4-(4-(adamantan-1-yl)phenoxy)butanoate (1.1 g, 3.50 mmol) in H.sub.2O/THF (1 mL/1.20 mL) was added lithium hydroxide monohydrate (0.14 g, 7.00 mmol), and stirred at room temperature overnight. The reaction mixture was adjusted to acidic solution with 1 N aqueous HCl and extracted with dichloromethane. The organic layer was washed with H.sub.2O and brine, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 4-(4-(adamantan-1-yl)phenoxy)butanoic acid as a white solid (0.98 g, 97.12% yield).

(41) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 12.11 (1H, bs, COOH), 7.23 (2H, d, aromatic-H), 6.83 (2H, d, aromatic-H), 3.93 (2H, t, (CH.sub.2).sub.3), 2.36 (2H, t, (CH.sub.2).sub.3), 2.03 (3H, s, adamantyl-H), 1.91 (2H, m, (CH.sub.2).sub.3), 1.81 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

Step 3: 4(-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)butan-1-one (I-14)

(42) The title compound was prepared from 4-(4-(adamantan-1-yl)phenoxy)butanoic acid (0.2 g, 0.63 mmol) and 1-methylpiperazine (0.063 g, 0.63 mmol) according to the example 1, which was given 4-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)butan-1-one as a white solid (0.239 g, 95.0% yield).

(43) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.23 (2H, d, aromatic-H), 6.83 (2H, d, aromatic-H), 3.94 (2H, t, OCH.sub.2(CH.sub.2).sub.2), 3.42 (4H, m, piperazine), 2.43 (2H, m, CH.sub.2(CH.sub.2).sub.2), 2.22 (4H, m, piperazine), 2.15 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.90 (2H, m, CH.sub.2(CH.sub.2).sub.2), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

4-(2-(4-Adamantan-1-yl)phenoxy)acetyl)-1,1-dimethylpiperazin-1-ium iodide (I-15)

(44) A suspension of 2-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (0.2 g, 0.50 mmol), prepared from example 3, and methyl iodide (0.286 g, 2.01 mmol) in diethyl ether (2 mL) was stirred at room temperature overnight. The reaction mixture was filtered and dried in vacuum oven at 50° C. to afford a 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1,1-dimethylpiperazin-1-ium iodide as a white solid (0.27 g, 97.5% yield).

(45) .sup.1H-NMR (DMSO-d.sub.6, 500 Hz) δ 7.24 (2H, d, aromatic-H), 6.85 (2H, d, aromatic-H), 4.74 (1H, s, OCH.sub.2CO), 3.82 (1H, s, OCH.sub.2CO), 3.43 (4H, m, piperazine), 3.16 (3H, s, CH.sub.3), 2.27 (4H, m, piperazine), 2.17 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)-2-methylphenoxy)acetyl)-1,1-dimethylpiperazin-1-ium iodide (I-16)

(46) The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)ethanone (0.2 g, 0.50 mmol), prepared from the example 5, according to the example 15, which was given 4-(2-(4-(adamantan-1-yl)-2-methylphenoxy)acetyl)-1,1-dimethylpiperazin-1-ium iodide as a white solid (0.268 g, 97.8% yield).

(47) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.12 (1H, m, aromatic-H), 7.05 (1H, m, aromatic-H), 6.74 (1H, d, aromatic-H), 4.84 (1H, s, OCH.sub.2), 4.74 (1H, s, OCH.sub.2), 3.83 (2H, m, piperazine), 3.40 (4H, m, piperazine), 3.17 (3H, s, CH.sub.3), 2.25 (2H, m, piperazine), 2.17 (6H, d, (CH.sub.3).sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(2-(4-Adamantan-1-yl)-2-methylphenoxy)acetamido)-N,N,N-trimethylethanaminium iodide (I-17)

(48) The title compound was prepared from 2-(4-(adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)acetamide (0.2 g, 0.50 mmol), prepared from the example 7, according to the example 15, which was given 2-(2-(4-(adamantan-1-yl)-2-methylphenoxy)acetamido)-N,N,N-trimethylethaneaminium iodide as a white solid (0.27 g, 97.8% yield).

(49) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 8.16 (1H, t, (C═O)NH), 7.15 (1H, s, aromatic-H), 7.06 (1H, m, aromatic-H), 6.75 (1H, d, aromatic-H), 4.50 (2H, t, OCH.sub.2CH.sub.2), 3.57 (2H, m, NHCH.sub.2CH.sub.2), 3.40 (2H, t, NHCH.sub.2CH.sub.2), 3.07 (6H, s, (CH.sub.3).sub.2), 2.50 (2H, t, OCH.sub.2CH.sub.2), 2.23 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

4-(3-(4-(Adamantan-1-yl)phenoxy)propanoyl-1,1-dimethylpiperazin-1-ium iodide (I-18)

(50) The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one (0.2 g, 0.50 mmol), prepared from the example 8, according to the example 15, which was given 4-(3-(4-(adamantan-1-yl)phenoxy)propanoyl-1,1-dimethylpiperazin-1-ium iodide as a white solid (0.266 g, 97.0% yield).

(51) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.24 (2H, m, aromatic-H), 6.84 (2H, d, aromatic-H), 4.15 (2H, t, OCH.sub.2CH.sub.2), 3.45 (4H, m, piperazine), 2.77 (2H t, CH.sub.2CH.sub.2), 2.28 (4H, m, piperazine), 2.17 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(3-(4-(Adamantan-1-yl)phenoxy)propanamido)-N,N,N-trimethylethanaminium iodide (I-19)

(52) The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)propanamide (0.2 g, 0.50 mmol), prepared from the example 10, according to the example 15, which was given 2-(3-(4-(adamantan-1-yl)phenoxy)propanamido)-N,N,N-trimethylethaneaminium iodide as a white solid (0.265 g, 96.0% yield).

(53) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 8.32 (1H, t, (C═O)NH), 7.24 (2H, d, aromatic-H), 6.83 (2H, d, aromatic-H), 4.15 (2H, t, OCH.sub.2CH.sub.2), 3.51 (2H, m, NHCH.sub.2CH.sub.2), 3.37 (2H, m, NHCH.sub.2CH.sub.2), 3.09 (9H, s, (CH.sub.3).sub.3), 2.55 (2H, t, OCH.sub.2CH.sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

4-(3-(4-(Adamantan-1-yl)-2-methylphenoxy)propanoyl)-1,1-dimethylpiperazin-1-ium iodide (I-20)

(54) The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)-1-(4-methylpiperazin-1-yl)propan-1-one (0.2 g, 0.50 mmol), prepared from the example 11, according to the example 15, which was given 4-(3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoyl)-1,1-dimethylpiperazin-ium iodide as a white solid (0.261 g, 96.3% yield).

(55) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.08 (2H, m, aromatic-H), 6.84 (1H, d, aromatic-H), 4.16 (2H, t, OCH.sub.2CH.sub.2), 3.84 (2H, m, piperazine), 3.46 (4H, m, piperazine) 3.37 (1H, m, CH.sub.2CH.sub.2), 2.78 (1H, m, CH.sub.2CH.sub.2), 3.15 (3H, s, CH.sub.3), 2.28 (2H, m, piperazine), 2.10 (3H, s, (CH.sub.3).sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(3-(4-Adamantan-1-yl)-2-methylphenoxy)propanamido)-N,N,N-trimethylethanaminium iodide (I-21)

(56) The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)-N-(2-(dimethylamino)ethyl)propanamide (0.2 g, 0.50 mmol), prepared from the example 13, according to the example 15, which was given 2-(3-(4-(adamantan-1-yl)-2-methylphenoxy)propanamido)-N,N,N-trimethylethaneaminium iodide as a white solid (0.269 g, 98.5% yield).

(57) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 8.31 (1H, t, (C═O)NH), 7.08 (2H, t, aromatic-H), 6.83 (1H, d, aromatic-H), 4.15 (2H, t, OCH.sub.2CH.sub.2), 3.51 (2H, m, NHCH.sub.2CH.sub.2), 3.36 (2H, m, NHCH.sub.2CH.sub.2), 3.09 (9H, s, (CH.sub.3).sub.3), 2.57 (2H, t, OCH.sub.2CH.sub.2), 2.09 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

4-(4-(4-(Adamantan-1-yl)phenoxy)butanoyl)-1,1-dimethylpiperazin-1-ium iodide (I-22)

(58) The title compound was prepared from 4-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)butan-1-one (0.2 g, 0.50 mmol), prepared from the example 14, according to the example 15, which was given 4-(4-(4-(adamantan-1-yl)phenoxy)butanoyl)-1,1-dimethylpiperazin-1-ium iodide as a white solid (0.265 g, 97.7% yield).

(59) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.23 (2H, d, aromatic-H), 6.83 (2H, d, aromatic-H), 3.95 (2H, t, OCH.sub.2(CH.sub.2).sub.2), 3.80 (4H, m, piperazine), 3.36 (4H, m, piperazine), 3.14 (6H, s, (CH.sub.3).sub.2), 2.53 (2H, m, CH.sub.2(CH.sub.2).sub.2), 2.04 (2H, m, CH.sub.2(CH.sub.2).sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one (I-23)

Step 1: Methyl 2-(4-(adamantan-1-yl)phenoxy-2-methylpropanoate

(60) To a solution of 4-(adamantan-1-yl)phenol (0.8 g, 3.50 mmol) in N,N-dimethylformamide (8 mL) was added anhydrous potassium carbonate (1.45 g, 10.51 mmol) and methyl 2-bromo-2-methylpropanoate (1.15 g, 7.0 mmol), and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give methyl 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoate as colorless oil (1.1 g, 94.1% yield).

(61) .sup.1H-NMR (MeOH-d.sub.4, 500 MHz) δ 7.21 (2H, d, aromatic-H), 6.75 (2H, d, aromatic-H), 3.73 (3H, s, OCH.sub.3), 2.05 (3H, brs, adamantyl-H), 1.88 (6H, m, adamantyl-H), 1.77 (6H, m, adamantyl-H), 1.52 (6H, s, (CH.sub.3).sub.2).

Step 2: 2-(4-(Adamantan-1-yl)phenoxy)-2-methylpropanoic acid

(62) To a solution of methyl 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoate (1.0 g, 3.00 mmol), prepared from step 1, in H.sub.2O/THF (1:1.20 mL) was added lithium hydroxide monohydrate (0.51 g, 12.00 mmol), and stirred at room temperature overnight. The reaction mixture was adjusted to acidic solution with 1 N aqueous HCl and extracted with dichloromethane. The organic layer was washed with H.sub.2O and brine, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoic acid as a white solid (0.92 g, 96.1% yield).

(63) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 12.94 (1H, bs, COOH), 7.23 (2H, d, aromatic-H), 6.74 (2H, d, aromatic-H), 2.03 (3H, brs, adamantyl-H), 1.81 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H), 1.47 (6H, s, (CH.sub.3).sub.2).

Step 3: 2-(4-(Adamantan-1-yl)phenoxy)-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one

(64) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoic acid (0.2 g, 0.63 mmol) and 1-methylpiperazine (0.063 g, 0.63 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-2-methyl-1-(4-methylpiperazin-1-yl)propan-1-one as a white solid (0.236 g, 93.7% yield).

(65) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.23 (2H, d, aromatic-H), 6.71 (2H, d, aromatic-H), 3.71 (2H, bs, piperazine), 3.47 (2H, bs, piperazine), 2.13 (2H, bs, piperazine), 2.03 (3H, brs, adamantyl-H), 1.99 (3H, s, CH.sub.3), 1.83 (2H, bs, piperazine), 1.81 (6H, m, adamantyl-H), 1.68 (6H, m, adamantyl-H), 1.47 (6H, s, (CH.sub.3).sub.2).

2-(4-(Adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)-2-methylpropanamide (I-24)

(66) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoic acid (0.2 g, 0.63 mmol), prepared from the step 2 of example 23, and N,N-dimethylethane-1,2-diamine (0.056 g, 0.63 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)-2-methylpropanamide as a white solid (0.228 g, 93.4% yield).

(67) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.83 (1H, t, (C═O)NH), 7.23 (2H, d, aromatic-H), 6.83 (2H, d, aromatic-H), 4.08 (2H, m, NHCH.sub.2CH.sub.2), 2.26 (2H, t, NHCH.sub.2CH.sub.2), 2.12 (6H, s, (CH.sub.3).sub.2), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H), 1.47 (6H, s, (CH.sub.3).sub.2).

2-(4-(Adamantan-1-yl)-2-fluorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone (I-25)

Step 1: 1-(3-Fluoro-4-methoxyphenyl)adamantane

(68) The title compound was prepared from 1-fluoro-2-methoxybenzene (10 mL) and 1-bromoadamantane (3.25 g, 15.25 mmol) according to the step 1 of the example 5, which was given 1-(3-fluoro-4-methoxyphenyl)adamantane (5.05 g, 83.3% yield).

(69) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.25 (2H, m, aromatic-H), 6.78 (1H, d, aromatic-H), 3.82 (3H, s, OCH.sub.3), 2.03 (3H, s, adamantyl-H), 1.80 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

Step 2: 4-(Adamantan-1-yl)-2-fluorophenol

(70) The title compound was prepared from 1-(3-fluoro-4-methoxyphenyl)adamantane (3.0 g, 11.52 mmol) according to the step 2 of the example 5, which was given 4-(adamantan-1-yl)-2-fluorophenol (2.80 g, 99% yield).

(71) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 9.50 (1H, bs, COOH), 7.02 (2H, m, aromatic-H), 6.85 (1H, m, aromatic-H), 2.02 (3H, s, adamantyl-H), 1.78 (6H, m, adamantyl-H), 1.70 (6H, m, adamantyl-H).

Step 3: Ethyl 2-(4-(adamantan-1-yl)-2-fluorophenoxy)acetate

(72) The title compound was prepared from 4-(adamantan-1-yl)-2-fluorophenol (2.0 g, 8.11 mmol), prepared from the step 2, according to the step 3 of the example 5, which was given ethyl 2-(4-(adamantan-1-yl)-2-fluorophenoxy)acetate (2.54 g, 94.8% yield).

(73) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.06 (2H, m, aromatic-H), 6.98 (1H, m, aromatic-H), 4.81 (2H, s, OCH.sub.2CO), 4.15 (2H, q, OCH.sub.2CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.81 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H), 1.20 (3H, t, CH.sub.3).

Step 4: 2-(4-(Adamantan-1-yl)-2-fluorophenoxy)acetic acid

(74) The title compound was prepared from ethyl 2-(4-(adamantan-1-yl)-2-fluorophenoxy)acetate (1.1 g, 3.30 mmol), prepared from the step 3, according to the step 4 of the example 5, which was given 2-(4-(adamantan-1-yl)-2-fluorophenoxy)acetic acid (0.92 g, 91.3% yield).

(75) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 13.05 (1H, brs, COOH), 7.18 (1H, m, aromatic-H), 7.04 (1H, m, aromatic-H), 6.96 (1H, m, aromatic-H), 4.71 (2H, s, OCH.sub.2CO), 2.03 (3H, brs, adamantyl-H), 1.81 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

Step 5: 2-(4-(Adamantan-1-yl)-2-fluorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone (I-25)

(76) The title compound was prepared from 2-(4-(adamantan-1-yl)-2-fluorophenoxy)acetic acid (0.15 g, 0.49 mmol), prepared from the step 4, and 1-methylpiperazine (0.049 g, 0.49 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-fluorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.173 g, 91.3% yield).

(77) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.14 (1H, m, aromatic-H), 7.04 (1H, d, aromatic-H), 6.96 (1H, m, aromatic-H), 4.86 (2H, s, OCH.sub.2CO), 3.43 (4H, m, piperazine), 2.25 (4H, m, piperazine), 2.18 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.81 (6H, m, adamantyl-H), 1.70 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-N-(furan-2-ylmethyl)acetamide (I-26)

(78) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.3 g, 1.04 mmol) and furan-2-ylmethaneamine (0.101 g, 1.04 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(furan-2-ylmethyl)acetamide as a white solid (0.346 g, 90.8% yield).

(79) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 8.52 (1H, t, (C═O)NH), 7.55 (1H, s, aromatic-H), 7.25 (2H, d, aromatic-H), 6.88 (2H, d, aromatic-H), 6.37 (1H, m, aromatic-H), 6.18 (1H, m, aromatic-H), 4.47 (2H, s, OCH.sub.2CO), 4.32 (2H, s, CH.sub.2), 2.04 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)ethanone (I-27)

(80) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.3 g, 1.04 mmol) and 1-(4-(trifluoromethyl)benzyl)piperazine (0.255 g, 1.04 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl)ethanone as a white solid (0.501 g, 93.3% yield).

(81) .sup.1H-NMR (DMSO-d.sub.6, 500 MHz) δ 7.70 (2H, d, aromatic-H), 7.55 (2H, d, aromatic-H), 7.23 (2H, d, aromatic-H), 6.82 (2H, d, aromatic-H), 4.74 (2H, s, OCH.sub.2CH.sub.2), 3.60 (2H, s, CH.sub.2), 3.46 (4H, m, piperazine), 2.38 (4H, m, piperazine), 2.03 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.71 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-1-(4-isopropylpiperazin-1-yl)ethanone (I-28)

(82) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.23 g, 0.80 mmol) and 1-isopropylpiperazine (0.102 g, 0.80 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-isopropylpiperazin-1-yl)ethanone as a white solid (0.298 g, 93.7% yield).

(83) .sup.1H-NMR (MeOH-d.sub.4, 500 MHz) δ 7.18 (2H, d, aromatic-H), 6.78 (2H, d, aromatic-H), 4.65 (2H, s, OCH.sub.2CO), 3.50 (4H, m, piperazine), 2.61 (1H, m, CH), 2.44 (4H, m, piperazine), 1.96 (3H, brs, adamantyl-H), 1.80 (6H, m, adamantyl-H), 1.69 (6H, m, adamantyl-H), 0.96 (6H, d, CH.sub.3).

tert-Butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)piperazine-1-carboxylate (I-29)

(84) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.28 g, 0.97 mmol) and tert-butyl piperazine-1-carboxylate (0.182 g, 0.97 mmol) according to the example 1, which was given tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)piperazine-1-carboxylate as a white solid (0.399 g, 90.0% yield).

(85) .sup.1H-NMR (MeOH-d.sub.4, 500 MHz) δ 7.18 (2H, d, aromatic-H), 6.79 (2H, d, aromatic-H), 4.67 (2H, s, OCH.sub.2CO), 3.47 (4H, m, piperazine), 3.35 (4H, m, piperazine), 1.96 (3H, brs, adamantyl-H), 1.80 (6H, m, adamantyl-H), 1.69 (6H, m, adamantyl-H), 1.36 (9H, s, (CH.sub.3).sub.3).

2-(4-(Adamantan-1-yl)phenoxy)-1-(piperazin-1-yl)ethanone (I-30)

(86) To a solution of tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)piperazine-1-carboxylate (0.15 g, 0.42 mmol), prepared from the example 29, in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.15 g, 1.69 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated and diluted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)phenoxy)-1-(piperazin-1-yl)ethanone as a white solid (0.11 g, 94.8% yield).

(87) .sup.1H-NMR (MeOH-d.sub.4, 500 MHz) δ 7.18 (2H, d, aromatic-H), 6.79 (2H, d, aromatic-H), 4.66 (2H, s, OCH.sub.2CO), 3.52 (4H, m, piperazine), 2.80 (4H, m, piperazine), 1.96 (3H, brs, adamantyl-H), 1.80 (6H, m, adamantyl-H), 1.69 (6H, m, adamantyl-H).

(S)-tert-Butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate (I-31)

(88) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.139 g, 0.69 mmol) according to the example 1, which was given (S)-tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate as a white solid (0.298 g, 91.2% yield).

(89) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.30 (2H, d, aromatic-H), 6.89 (2H, d, aromatic-H), 4.84 (2H, s, OCH.sub.2CO), 4.54 (1H, m, piperazine), 4.12 (2H, m, piperazine), 3.90 (2H, m, piperazine), 2.98 (2H, m, piperazine), 2.48 (3H, d, CH.sub.3), 2.14 (3H, brs, adamantyl-H), 1.89 (6H, m, adamantyl-H), 1.78 (6H, m, adamantyl-H), 1.47 (9H, s, (CH.sub.3).sub.3).

2-(4-(Adamantan-1-yl)phenoxy)-1-((S)-2-methylpiperazin-1-yl)ethanone (I-32)

(90) The title compound was prepared from (S)-tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate (0.18 g, 0.38 mmol), prepared from the example 31, according to the example 30, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-((S)-2-methylpiperazin-1-yl)ethanone as a white solid (0.132 g, 93.6% yield).

(91) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.32 (2H, d, aromatic-H), 6.91 (2H, d, aromatic-H), 4.88 (2H, s, OCH.sub.2CO), 4.30 (2H, m, piperazine), 3.50 (2H, m, piperazine), 3.34 (2H, m, piperazine), 3.25 (1H, m, piperazine), 2.56 (3H, d, CH.sub.3), 2.10 (3H, brs, adamantyl-H), 1.89 (6H, m, adamantyl-H), 1.78 (6H, m, adamantyl-H).

(R)-tert-Butyl 4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate (I-33)

(92) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.139 g, 0.69 mmol) according to the example 1, which was given (R)-tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate as a white solid (0.297 g, 91.0% yield).

(93) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.30 (2H, d, aromatic-H), 6.89 (2H, d, aromatic-H), 4.84 (2H, s, OCH.sub.2CO), 4.54 (1H, m, piperazine), 4.12 (2H, m, piperazine), 3.90 (2H, m, piperazine), 2.98 (2H, m, piperazine), 2.48 (3H, d, CH.sub.3), 2.14 (3H, brs, adamantyl-H), 1.89 (6H, m, adamantyl-H), 1.78 (6H, m, adamantyl-H), 1.47 (9H, s, (CH.sub.3).sub.3).

2-(4-(Adamantan-1-yl)phenoxy)-1-((R)-2-methylpiperazin-1-yl)ethanone (I-34)

(94) The title compound was prepared from (R)-tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-3-methylpiperazine-1-carboxylate (0.18 g, 0.38 mmol), prepared from the example 33, according to the example 30, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-((R)-2-methylpiperazin-1-yl)ethanone as a white solid (0.129 g, 91.4% yield).

(95) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.32 (2H, d, aromatic-H), 6.91 (2H, d, aromatic-H), 4.88 (2H, s, OCH.sub.2CO), 4.30 (2H, m, piperazine), 3.50 (2H, m, piperazine), 3.34 (2H, m, piperazine), 3.25 (1H, m, piperazine), 2.56 (3H, d, CH.sub.3), 2.10 (3H, brs, adamantyl-H), 1.89 (6H, m, adamantyl-H), 1.78 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone (I-35)

(96) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.15 g, 0.52 mmol) and 2-(piperazin-1-yl)ethanol (0.068 g, 0.52 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone as a white solid (0.187 g, 90.3% yield).

(97) .sup.1H-NMR (MeOH-d.sub.4, 500 MHz) δ 7.17 (2H, d, aromatic-H), 6.78 (2H, d, aromatic-H), 4.65 (2H, s, OCH.sub.2CO), 3.58 (2H, t, CH.sub.2), 3.51 (4H, m, piperazine), 2.45 (4H, m, piperazine), 2.41 (2H, t, CH.sub.2), 1.96 (3H, brs, adamantyl-H), 1.80 (6H, m, adamantyl-H), 1.69 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-1-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethanone (I-36)

(98) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.13 g, 0.45 mmol) and 1-(prop-2-yn-1-yl)piperazine (0.056 g, 0.45 mmol) according to the example 1, which was given 2-(4-(adamantan-2-yl)phenoxy)-1-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethanone as a white solid (0.158 g, 89.3% yield).

(99) .sup.1H-NMR (MeOH-d.sub.4, 500 MHz) δ 7.17 (2H, d, aromatic-H), 6.78 (2H, d, aromatic-H), 4.66 (2H, s, OCH.sub.2CO), 3.52 (4H, m, piperazine), 3.21 (2H, s, CH.sub.2), 2.56 (1H, m, CH), 2.45 (4H, m, piperazine), 1.96 (3H, brs, adamantyl-H), 1.80 (6H, m, adamantyl-H), 1.69 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)acetamide (I-37)

(100) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.133 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)acetamide as a white solid (0.30 g, 93.4% yield).

(101) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 9.79 (1H, s, (C═O)NH), 7.45 (2H, d, aromatic-H), 7.25 (2H, d, aromatic-H), 6.88 (4H, m, aromatic-H), 4.58 (2H, s, OCH.sub.2CO), 3.04 (4H, m, piperazine), 2.48 (4H, m, piperazine), 2.19 (3H, s, CH.sub.3), 2.01 (3H, brs, adamantyl-H), 1.80 (6H, m, adamantyl-H), 1.69 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-N-(4-(1,1-dioxidothiomorpholino)phenyl)acetamide (I-38)

(102) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 4-(4-aminophenyl)thiomorpholine 1,1-dioxide (0.158 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(4-(1,1-dioxidothiomorpholino)phenyl)acetamide as a white solid (0.31 g, 89.8% yield).

(103) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 9.94 (1H, s, (C═O)NH), 7.58 (2H, d, aromatic-H), 7.34 (2H, d, aromatic-H), 7.05 (2H, d, aromatic-H), 6.98 (2H, d, aromatic-H), 4.67 (2H, s, OCH.sub.2CO), 3.77 (4H, m, thiomorpholine), 3.18 (4H, m, thiomorpholine), 2.04 (3H, brs, adamantyl-H), 1.88 (6H, m, adamantyl-H), 1.74 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone (I-39)

(104) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.08 g, 0.27 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4.3-a]pyrazine (0.053 g, 0.27 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone as a white solid (0.10 g, 78.1% yield).

(105) .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 7.28 (2H, d, aromatic-H), 6.88 (2H, d, aromatic-H), 5.17 (2H, m, pyrazine), 4.78 (2H, s, OCH.sub.2CO), 4.12 (4H, m, pyrazine), 2.08 (3H, brs, adamantyl-H), 1.86 (6H, m, adamantyl-H), 1.74 (6H, m, adamantyl-H).

N-(Adamantan-1-yl)-2-(4-adamantan-1-yl)phenoxy)acetamide (I-40)

(106) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and adamantan-1-amine (0.105 g, 0.69 mmol) according to the example 1, which was given N-(adamantan-1-yl)-2-(4-(adamantan-1-yl)phenoxy)acetamide as a white solid (0.27 g, 92.1% yield).

(107) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.24 (2H, d, aromatic-H), 6.81 (2H, d, aromatic-H), 4.32 (2H, s, OCH.sub.2CO), 2.03 (6H, brs, adamantyl-H), 1.93 (3H, m, adamantyl-H), 1.80 (6H, m, adamantyl-H), 1.70 (9H, m, adamantyl-H), 1.60 (6H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)phenoxy)-N-(3-hydroxyadamantan-1-yl)acetamide (I-41)

(108) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.2 g, 0.69 mmol) and 3-aminoadamantan-1-ol hydrate (0.129 g, 0.69 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(3-hydroxyadamantan-1-yl)acetamide as a white solid (0.275 g, 90.4% yield).

(109) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.33 (1H, s, (C═O)NH), 7.23 (2H, d, aromatic-H), 6.82 (2H, d, aromatic-H), 4.49 (1H, s, OH), 4.32 (2H, s, OCH.sub.2CO), 2.11 (2H, brs, adamantyl-H), 2.06 (3H, brs, adamantyl-H), 1.80 (12H, m, adamantyl-H), 1.73 (6H, m, adamantyl-H), 1.50 (5H, m, adamantyl-H).

2-(4-(Adamantan-1-yl)-2-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone (I-42)

Step 1: 1-(3-Chloro-4-methoxyphenyl)adamantane

(110) The title compound was prepared from 1-chloro-2-methoxybenzene (10 mL) and 1-bromoadamantane (3.25 g, 15.25 mmol) according to the step 1 of the example 5, which was given 1-(3-chloro-4-methoxyphenyl)adamantane (3.52 g, 84.4% yield).

(111) .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 7.35 (1H, d, aromatic-H), 7.18 (1H, m, aromatic-H), 6.87 (1H, d, aromatic-H), 3.87 (3H, s, OCH.sub.3), 2.08 (3H, br, adamantyl-H), 1.86 (6H, m, adamantyl-H), 1.74 (6H, m, adamantyl-H).

Step 2: 4-(Adamantan-1-yl)-2-chlorophenol

(112) The title compound was prepared from 1-(3-chloro-4-methoxyphenyl)adamantane (3.0 g, 10.83 mmol) according to the step 2 of the example 5, which was given 4-(adamantan-1-yl)-2-chlorophenol (2.70 g, 95.2% yield).

(113) .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 7.27 (1H, d, aromatic-H), 7.16 (1H, m, aromatic-H), 6.95 (1H, d, aromatic-H), 5.35 (1H, bs, OH), 2.08 (3H, s, adamantyl-H), 1.85 (6H, m, adamantyl-H), 1.76 (6H, m, adamantyl-H).

Step 3: Ethyl 2-(4-(adamantan-1-yl)-2-chlorophenoxy)acetate

(114) The title compound was prepared from 4-(adamantan-1-yl)-2-chlorophenol (2.0 g, 7.61 mmol) according to the step 3 of the example 5, which was given ethyl 2-(4-(adamantan-1-yl)-2-chlorophenoxy)acetate (2.52 g, 95.4% yield).

(115) .sup.1H-NMR (CDCl.sub.3, 400 MHz) δ 7.35 (1H, d, aromatic-H), 7.15 (1H, m, aromatic-H), 6.80 (1H, d, aromatic-H), 4.68 (2H, s, OCH.sub.2CO), 4.26 (2H, q, OCH.sub.2CH.sub.3), 2.04 (3H, brs, adamantyl-H), 1.85 (6H, m, adamantyl-H), 1.75 (6H, m, adamantyl-H), 1.29 (3H, t, CH.sub.3).

Step 4: 2-(4-(Adamantan-1-yl)-2-chlorophenoxy)acetic acid

(116) The title compound was prepared from ethyl 2-(4-(adamantan-1-yl)-2-chlorophenoxy)acetate (1.1 g, 3.15 mmol), prepared from the step 3, according to the step 4 of the example 5, which was given 2-(4-(adamantan-1-yl)-2-chlorophenoxy)acetic acid (0.92 g, 91.4% yield).

(117) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.41 (1H, d, aromatic-H), 7.30 (1H, m, aromatic-H), 6.99 (1H, d, aromatic-H), 4.81 (2H, s, OCH.sub.2CO), 2.10 (3H, brs, adamantyl-H), 1.87 (6H, m, adamantyl-H), 1.78 (6H, m, adamantyl-H).

Step 5: 2-(4-(Adamantan-1-yl)-2-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone (I-42)

(118) The title compound was prepared from 2-(4-(adamantan-1-yl)-2-chlorophenoxy)acetic acid (0.2 g, 0.62 mmol), prepared from the step 4, and 1-methylpiperazine (0.062 g, 0.62 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.231 g, 92.0% yield).

(119) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.39 (1H, d, aromatic-H), 7.28 (1H, m, aromatic-H), 6.99 (1H, d, aromatic-H), 4.95 (2H, s, OCH.sub.2CO), 3.51 (4H, m, piperazine), 2.35 (4H, m, piperazine), 2.24 (3H, s, CH.sub.3), 2.03 (3H, brs, adamantyl-H), 1.81 (6H, m, adamantyl-H), 1.70 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium methanesulfonate (I-43)

(120) To a solution of 2-(4-(Adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, in acetone (2 mL) was added methanesulfonic acid (0.18 mL, 2.7 mmol) and stirred at room temperature for 3 h. The reaction mixture was filtered and dried in vacuum to afford a 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium methanesulfonate as a crystalline white solid (1.1 g, 87% yield).

(121) .sup.1H-NMR (MeOH-d.sub.4, 400 MHz) δ 7.28 (2H, d, aromatic-H), 6.91 (2H, d, aromatic-H), 4.82 (2H, s, OCH.sub.2CO), 4.64 (1H, d, piperazine), 4.24 (1H, d, piperazine), 3.54 (3H, m, piperazine), 3.10 (3H, m, piperazine), 2.94 (3H, s, CH.sub.3S), 2.71 (3H, s, CH.sub.3), 2.06 (3H, brs, adamantyl-H), 1.89 (6H, m, adamantyl-H), 1.80 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 3-carboxy-2-(carboxymethyl)-2-hydroxypropanoate (I-44)

(122) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and citric acid (0.52 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 3-carboxy-2-(carboxymethyl)-2-hydroxypropanoate as a crystalline white solid (1.43 g, 94% yield).

(123) .sup.1H-NMR (MeOH-d.sub.4, 400 MHz) δ 7.27 (2H, d, aromatic-H), 6.90 (2H, d, aromatic-H), 4.79 (2H, s, OCH.sub.2CO), 3.85 (4H, brs, piperazine), 3.11 (4H, d, piperazine), 2.85 (2H, d, CH.sub.2), 2.76 (3H, s, CH.sub.3), 2.73 (2H, d, CH.sub.2), 2.06 (3H, brs, adamantyl-H), 1.89 (6H, m, adamantyl-H), 1.79 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (Z)-3-carboxyacrylate (I-45)

(124) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and maleic acid (0.31 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (Z)-3-carboxyacrylate as a crystalline white solid (1.01 g, 77% yield).

(125) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.25 (2H, d, aromatic-H), 6.86 (2H, d, aromatic-H), 6.06 (2H, s, CH═CH), 4.82 (2H, s, OCH.sub.2CO), 3.68 (4H, brs, piperazine), 3.15 (4H, d, piperazine), 2.77 (3H, s, CH.sub.3), 2.06 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.72 (6H, m, adamantyl-H).

4-(3-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 4-methylbenzenesulfonate (I-46)

(126) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and p-toluenesulfonic acid (0.52 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 4-methylbenzenesulfonate as a crystalline white solid (1.2 g, 82% yield).

(127) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 9.69 (1H, brs, COOH), 7.49 (2H, d, aromatic-H), 7.24 (2H, d, aromatic-H), 7.12 (2H, d, aromatic-H), 6.86 (2H, d, aromatic-H), 4.83 (2H, s, OCH.sub.2CO), 4.39 (1H, brs, piperazine), 4.05 (1H, brs, piperazine), 3.40 (3H, d, piperazine), 3.05 (3H, d, piperazine), 2.83 (3H, s, CH.sub.3), 2.29 (3H, s, PhCH.sub.3) 2.04 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.72 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (2R,3R)-3-carboxy-2,3-dihydroxypropanoate (I-47)

(128) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and L-(+)-tartaric acid (0.41 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (2R,3R)-3-carboxy-2,3-dihydroxypropanoate as a crystalline white solid (1.2 g, 85% yield).

(129) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.24 (2H, d, aromatic-H), 6.84 (2H, d, aromatic-H), 4.78 (2H, s, OCH.sub.2CO), 4.25 (2H, s, OHCHCHOH), 3.54 (4H, s, piperazine), 2.60 (4H, d, piperazine), 2.38 (3H, s, CH.sub.3), 2.04 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.72 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 3-carboxypropanoate (I-48)

(130) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and succinic acid (0.41 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 3-carboxypropanoate as a crystalline white solid (0.95 g, 72% yield).

(131) .sup.1H-NMR (MeOH-d.sub.4, 400 MHz) δ 7.28 (2H, d, aromatic-H), 6.89 (2H, d, aromatic-H), 4.77 (2H, s, OCH.sub.2CO), 3.68 (4H, d, piperazine), 2.69 (4H, d, piperazine), 2.54 (4H, s, CH.sub.2CH.sub.2), 2.45 (3H, s, CH.sub.3), 2.06 (3H, brs, adamantyl-H), 1.89 (6H, m, adamantyl-H), 1.80 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium hydrogensulfate (I-49)

(132) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and sulfuric acid (0.15 mL, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium hydrogensulfate as a crystalline white solid (1.07 g, 85% yield).

(133) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.25 (2H, d, aromatic-H), 6.87 (2H, d, aromatic-H), 4.84 (2H, s, OCH.sub.2CO), 4.45 (1H, brs, piperazine), 3.95 (1H, brs, piperazine), 3.30 (6H, brs, piperazine), 2.84 (3H, s, CH.sub.3), 2.04 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.72 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium dihydrogenphosphate (I-50)

(134) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and phosphoric acid (0.19 mL, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium dihydrogenphosphate as a crystalline white solid (0.95 g, 75% yield).

(135) .sup.1H-NMR (MeOH-d.sub.4, 400 MHz) δ 7.28 (2H, d, aromatic-H), 6.90 (2H, d, aromatic-H), 4.80 (2H, s, OCH.sub.2CO), 3.92 (4H, brs, piperazine), 3.22 (4H, d, piperazine), 2.83 (3H, s, CH.sub.3), 2.06 (3H, brs, adamantyl-H), 1.89 (6H, m, adamantyl-H), 1.79 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (E)-3-carboxyacrylate (I-51)

(136) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and fumaric acid (0.41 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium (E)-3-carboxyacrylate as a crystalline white solid (1.14 g, 87% yield).

(137) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.24 (2H, d, aromatic-H), 6.87 (2H, d, aromatic-H), 6.12 (2H, s, CH═CH), 4.82 (2H, s, OCH.sub.2CO), 3.65 (4H, brs, piperazine), 3.18 (4H, d, piperazine), 2.78 (3H, s, CH.sub.3), 2.05 (3H, brs, adamantyl-H), 1.82 (6H, m, adamantyl-H), 1.72 (6H, m, adamantyl-H).

4-(2-(4-(Adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 2,2,2-trifluoroacetate (I-52)

(138) The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and trifluoroacetic acid (0.31 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 2,2,2-trifluoroacetate as a crystalline white solid (1.22 g, 93% yield).

(139) .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) δ 7.25 (2H, d, aromatic-H), 6.86 (2H, d, aromatic-H), 4.83 (2H, s, OCH.sub.2CO), 3.67 (4H, brs, piperazine), 3.28 (4H, d, piperazine), 2.88 (3H, s, CH.sub.3), 2.06 (3H, brs, adamantyl-H), 1.84 (6H, m, adamantyl-H), 1.74 (6H, m, adamantyl-H).

(140) <Experiment 1> Assay for Inhibition of HIF-1α-Mediated Transcriptional Activity (HRE Reporter Assay)

(141) This assay was performed to determine whether the compounds according to the present invention exhibited the anti-cancer activity or not. The compounds can be developed as anti-cancer drugs, because the compounds inhibiting HIF-1α-mediated HRE transcriptional activity induced by hypoxia can suppress the growth and metastasis of cancer.

(142) Inhibitory effects of the compounds according to the present invention, from Formula I-1 to I-42, on HIF-1α-mediated transcriptional activity were evaluated using this assay. pGL3-HRE-luciferase vector was constructed as follows. Six copies of HRE (Hypoxia Responsive Element, 5′-ACGTG-3′) from human VEGF genes were inserted into the multi-cloning site of a pGL3-basic vector (Promega). A luciferase gene was used as a reporter gene.

(143) In detail, HCT116(ATCC #CCL-247) human colon cancer cells were seeded in 48-well cell culture plates. The cells were co-transfected with 25 ng of pGL3-HRE-luciferase and 2.5 ng of Renila control vectors using Polyfect reagent next day. After 24 hours of incubation, the cells were incubated for an additional 4 hours with replaced cell culture media. The cells were treated with various concentrations (0, 1, 3, 5, 10, and 20 μM) of the above compounds according to the present invention and incubated for 12 hours under hypoxia (1% O.sub.2, 94% N.sub.2, and 5% CO.sub.2). The luciferase assay was performed using a dual-luciferase reporter assay system (Promega). After cell lysate preparation with RIPA buffer, induced luciferase activity under hypoxic conditions was determined to examine inhibitory effects of the compounds according to the present invention, from Formula I-1 to I-42, on HIF-1α-mediated transcriptional activity. The results are assigned to four activity ranges and those assignments are reported in Table 1.

(144) Inhibitory activity against HIF-1α (10 μM): A(76˜100%), B(51˜75%), C(26˜50%), D(1˜25%)

(145) TABLE-US-00001 TABLE 1 Inhibition of HIF-1α-mediated HRE transcriptional activity Inhibitory activityagainst Compound HIF-1α (10 μM) I-1 B I-2 A I-3 A I-4 A I-5 A I-6 A I-7 B I-8 B I-9 A I-10 C I-11 A I-12 A I-13 B I-14 B I-15 C I-16 B I-17 C I-18 C I-19 C I-20 A I-21 C I-22 B I-23 A I-24 A I-25 B I-26 A I-27 A I-28 B I-29 B I-30 A I-31 A I-32 A I-33 A I-34 B I-35 C I-36 B I-37 D I-38 B I-39 C I-40 D I-41 A I-42 B

(146) As shown in above Table 1, the effects of the compounds according to the present invention on HIF-1α-mediated HRE transcriptional activity were determined under hypoxia. The results indicate that the compounds according to the present invention show inhibitory activity against HRE transcription. In particular, 32 compounds of 42 tested compounds exhibited more than 50% HIF-1α inhibitory activity, and 18 compounds showed HIF-1α inhibitory activity more than 75% among the 32 compounds.

(147) As mentioned above, the compounds according to the present invention can be used as effective components for cancer treatment, because the compounds inhibiting HIF-1α-mediated HRE transcriptional activity can suppress the growth and metastasis of cancer. In addition, these compounds displaying anti-angiogenic activity can be considered as effective components to develop the treatment of diabetic retinopathy and rheumatoid arthritis.

(148) <Experiment 2> In Vitro Studies for Inhibition of Hypoxia-Induced HIF-1α Accumulation

(149) Inhibition of HIF-1α accumulation by the compounds according to the present invention was determined in HCT116 human colon cancer cells. In particular, western blot analysis was used to identify the compounds, I-3, I-6, I-8, I-16, I-19, I-22˜I-24, and I-27˜I-36, which inhibited HIF-1α accumulation under hypoxia.

(150) First, HCT116 human colon cancer cells (ATCC #CCL-247) were plated at the concentration of 2×10.sup.5 cells/ml. After 24 hours, the cells were incubated under hypoxia (1% O.sub.2, 94% N.sub.2, and 5% CO.sub.2, expressed as 1% O.sub.2 in FIG. 1) for 4 hours in order to induce HIF-la accumulation. Cells were treated with the compounds at various concentrations (0, 3, 10, 20, and 30 μM) for 12 hours under hypoxia. The cells were then harvested, and lysed in RIPA buffer to obtain nuclear extracts. Cells grown at 20% O.sub.2 (normoxia) were used as control groups to compare HIF-1α-mediated gene expression under each condition. 30 μg of the nuclear extracts per sample was separated by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), and was then transferred to PVDF (polyvinylidene fluoride membrane) membranes. After membranes were probed with HIF-1α antibodies (R&D System), HIF-1α proteins were detected with HRP-conjugated secondary antibodies (Amersham-Pharmacia). GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) was used as an internal control for loading in western blot analysis. The results were shown in FIG. 1. FIG. 1 shows the potency of the compounds according to the present invention that inhibit HIF-1α accumulation.

(151) As shown in FIG. 1, the compounds according to the present invention, I-3, I-6, I-8, I-16, I-19, I-22˜I-24, and I-27˜I-36, did not affect GAPDH expression levels, but promoted HIF-1α degradation. In particular, the compounds, I-3, I-8, I-16, I-19, I-22, and I-28˜I-30, had significant inhibitory effects on HIF-1α accumulation.

(152) As mentioned above, the compounds according to the present invention can be considered as effective components to develop a new anti-cancer agent, because the compounds inhibit HIF-1α accumulation that forms malignant cancer. Furthermore, these compounds inhibiting angiogenesis can be used as effective components for the treatment of diabetic retinopathy and rheumatoid arthritis.

(153) <Experiment 3> CAM Assay

(154) CAM (Chick embryo chorioallantoic membrane) assay was conducted as an in vivo model to determine whether the compounds according to the present invention, I-3, I-6, I-19, and I-22, had anti-angiogenic effects or not. DMSO-treated groups were used as negative controls.

(155) According to the present invention, CAM assay was performed as follows.

(156) Fertilized eggs were incubated periodically rolling at 37° C. with 50% humidity for 2-3 days. When eggs were erected, approximately 3 ml of albumin was extracted from the sharp edge of the eggs using a syringe. The hole of the eggs was sealed with a tape to prevent from dryness and contamination, and the hole of the eggs was put down and incubated for 2 to 3 days. After punching a hole with 1.5 cm diameter in the round part of eggs, opaque membrane was removed carefully. The compounds (10-20 μg) according to the present invention were placed and spread on thermanox coverslip equally to dry, and then the hole in the round part of eggs put on the upper part of the fertilized eggs that vessels grew. The eggs were examined under the dissecting microscope and the results were given in FIG. 2, after covering the hole with a coverglass to protect it from contamination for 2 days.

(157) As shown in FIG. 2, CAM assay was performed to evaluate the compounds prepared in the present invention, I-3, I-6, I-19 and I-22. While many vessels were grown in negative control groups treated with vehicle, DMSO, the compounds according to the present invention inhibited formation of vessels.

(158) As the above results, the compounds according to the present invention showing anti-angiogenic activity can be considered as effective components for developing new treatment of cancer, diabetic retinopathy, and rheumatoid arthritis.

In Vivo Anti-Cancer Activity of Compounds by Oral Administration

(159) In vivo anti-cancer activity of the compounds according to the present invention, I-3, I-6, I-8, I-16, I-19, I-22, I-23, and I-24, was measured in mice to evaluate in vivo efficacy by oral administration. Specifically, the nude mice were divided into test groups and control groups, each consisting of 4 mice. In vivo efficacy was evaluated by measuring body weight, tumor volume, and tumor weight.

(160) Female nude mice 6 weeks old (BALB/c nu/nu, Charles River) were bred in germ-free breeding rooms maintained at constant temperature and humidity. After the nude mice were anesthetized, HCT116 colon cancer cells were implanted at a count of 4×10′ cells/mouse into the rectum in BALB/c nu/nu mice and then the incisions were closed with surgical clips. The size of tumor was measured by a caliper. When the size of transplanted tumor reached to 50˜60 mm.sup.3, the above compounds according to the present invention were administered. In more detail, after the above compounds in test groups were dissolved at concentration of 20 mg/kg in a solvent containing 80% of physiological saline, 10% of DMAC (dimethylacetamide), and 10% Tween 80 (hereinafter referred to as ‘Solvent A’), 15 kg/ml of dissolved compounds were orally administered once a day. Mice in control groups were treated with 15 kg/ml of Solvent A alone once daily.

(161) Tumor volume and body weight were measured to identify in vivo anti-cancer activity of the compounds according to the present invention by repetitive oral administration. Tumor volume and tumor growth inhibition (TGI) in Table 2 were calculated according to the below Mathematic FIG. 1 and FIG. 2, respectively. Tumor growth inhibition was converted to a percentage in Table 2.

(162) $\begin{array}{cc}\left[\mathrm{Math}\mathrm{Figure}1\right]& \\ \mathrm{Tumorvolume}\left({\mathrm{mm}}^3\right)=\left(\mathrm{LengthofLongAxis},\mathrm{mm}\right)\times {\left(\mathrm{LengthofShortAxis},\mathrm{mm}\right)}^2\times 0.5& \left[\mathrm{Math}.1\right]\\ \left[\mathrm{Math}\mathrm{Figure}2\right]& \\ \mathrm{Tumorgrowthinhibition}\left(\%\right)=\frac{\begin{array}{c}(\mathrm{Tumorvolume}\left(\mathrm{controlgroups}\right)-\\ \mathrm{Tumorvolume}\left(\mathrm{testgroups}\right))\end{array}}{\mathrm{Tumorvolume}\left(\mathrm{controlgroups}\right)}\times 100& \left[\mathrm{Math}.2\right]\end{array}$

(163) TABLE-US-00002 TABLE 2 in vivo anti-cancer activity of compounds by oral administration Tumor volume (mm.sup.3) Tumor Group Dose TGI(%) weight(mg) (n = 4) (mg/kg) day 0 3 5 7 10 12 14 14 vehicle 0 0.0 ± 0.0 34.0 ± 5.6 92.3 ± 17.2 174.6 ± 38.6 260.7 ± 47.6 448.6 ± 48.4 666.0 ± 76.3 2370.6 ± 205.7 Control I-3 20 0.0 ± 0.0 31.6 ± 5.0 74.8 ± 11.7 133.7 ± 14.8 237.0 ± 24.9 371.4 ± 36.2 587.8 ± 48.4 2074.2 ± 373.8 33.2% 35.0% 36.0% 41.6% 44.1% 49.2% 51.5% I-6 20 0.0 ± 0.0 25.5 ± 7.5 70.1 ± 9.7  128.4 ± 14.0 186.6 ± 15.2 322.5 ± 19.6 476.9 ± 28.1 1703.3 ± 252.2 25.0% 24.1% 26.5% 28.4% 28.1% 28.4% 28.1% I-8 20 0.0 ± 0.0 24.6 ± 5.1 65.5 ± 9.0  122.2 ± 7.9  184.3 ± 10.0 319.7 ± 22.0 471.1 ± 29.0 1634.6 ± 357.2 27.6% 29.0% 30.0% 29.3% 28.7% 29.3% 31.0% I-16 20 0.0 ± 0.0 24.2 ± 6.1 66.7 ± 14.2 125.8 ± 13.6 185.7 ± 20.2 320.4 ± 33.9 471.8 ± 26.0 1655.7 ± 288.4 28.6% 27.8% 27.9% 28.8% 28.6% 29.2% 30.2% I-19 20 0.0 ± 0.0 22.4 ± 5.6 58.8 ± 11.3 110.4 ± 11.2 162.3 ± 10.1 278.8 ± 35.0 404.7 ± 17.6 1392.4 ± 153.0 34.1% 36.4% 36.8% 37.7% 37.8% 39.2% 41.3% I-22 20 0.0 ± 0.0 20.4 ± 1.1 54.7 ± 2.8  98.9 ± 4.8 143.1 ± 6.2  246.4 ± 10.8 347.6 ± 11.8 1197.3 ± 156.3 39.8% 40.8% 43.4% 45.1% 45.1% 47.8% 49.5% I-23 20 0.0 ± 0.0 40.9 ± 8.2 98.0 ± 13.9 182.4 ± 19.9 352.7 ± 53.6 577.3 ± 74.1  987.6 ± 143.7 3659.9 ± 434.8 13.5% 14.8% 12.7% 13.1% 13.1% 14.6% 14.5% I-24 20 0.0 ± 0.0 38.1 ± 6.4 93.8 ± 21.0 176.8 ± 27.6 341.7 ± 58.8 569.1 ± 72.4  990.1 ± 140.3 3685.5 ± 357.5 19.5% 18.4% 15.4% 15.8% 14.3% 14.4% 13.9%

(164) According to the TGI results in Table 2, the compounds prepared according to the present invention, I-3, I-19, and I-22, displayed significant inhibitory effects on tumor growth.

(165) Moreover, severe side effects and statistically significant changes of body weight in all mice treated compounds were not shown for 14 days, comparing to control groups treated with vehicle. (Table 3)

(166) TABLE-US-00003 TABLE 3 Body weight change for 14 days of treatment (%) Group Dose Days after treatment (n = 4) (mg/kg) day 0 3 5 7 10 12 14 vehicle 0 100.0 ± 0.0 101.1 ± 2.1 101.1 ± 2.5 101.0 ± 3.5 100.3 ± 4.8  99.3 ± 3.9  97.9 ± 2.8 Control I-3 20 100.0 ± 0.0 103.2 ± 2.8 104.7 ± 3.0 105.1 ± 2.8 104.6 ± 2.7 103.1 ± 2.7 103.7 ± 4.0 I-6 20 100.0 ± 0.0 103.4 ± 0.6 103.6 ± 2.6 103.8 ± 3.3 105.0 ± 3.1 103.8 ± 2.9 102.4 ± 3.0 I-8 20 100.0 ± 0.0 102.2 ± 2.8 103.4 ± 2.8 102.6 ± 2.2 102.9 ± 1.5 101.9 ± 1.0 101.7 ± 2.6 I-16 20 100.0 ± 0.0 104.1 ± 1.6 104.2 ± 2.8 104.3 ± 1.9 105.8 ± 4.2 103.2 ± 3.6 102.3 ± 3.7 I-19 20 100.0 ± 0.0 104.0 ± 1.6 104.7 ± 3.1 104.6 ± 4.0 105.1 ± 4.3 103.4 ± 3.5 102.2 ± 3.8 I-22 20 100.0 ± 0.0 104.1 ± 3.5 104.1 ± 4.6 104.1 ± 3.3 105.6 ± 5.1 103.8 ± 3.6 102.7 ± 4.1 I-23 20 100.0 ± 0.0 100.8 ± 1.1 101.0 ± 1.6 100.9 ± 0.7 101.9 ± 1.1 101.6 ± 1.3 102.0 ± 2.0 I-24 20 100.0 ± 0.0 103.5 ± 3.0 104.0 ± 3.6 103.6 ± 3.6 105.0 ± 4.0 104.9 ± 4.1 106.5 ± 4.5

(167) From the results of above example 1, 2, 3, and 4, the compounds according to the present invention can be markedly effective for developing anti-cancer pharmaceutical composition, due to excellent HIF-1α inhibitory activity without severe toxicity. Moreover, the compounds can be used for developing new treatment of both diabetic retinopathy and rheumatoid arthritis.

(168) It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.

(169) The compounds, HIF-1α inhibitors, according to the present invention can be new therapeutic options to develop treatment for various solid cancers such as colon, liver, gastric, and breast cancers. In addition, the compounds can be used as diabetic retinopathy and rheumatoid arthritis aggravated by up-regulation of HIF-1α-mediated VEGFA gene expression under hypoxia.