Certain chemical entities, compositions, and methods

Abstract

Chemical entities that are curcumin derivatives, pharmaceutical compositions and methods of treatment of cancer are described.

Claims

1. A method of inhibiting growth of a cancer cell selected from the group consisting of a colorectal cancer cell, a liver cancer cell, a lung cancer cell, a breast cancer cell and an oral cancer cell, the method comprising administering to the cell a therapeutically effective amount of a compound of Formula I: ##STR00018## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 and R.sub.2 are independently chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R.sub.1 and R.sub.2 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and R.sub.3 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted alkoxycarbonyl, and optionally substituted phosphato.

2. The method of claim 1, wherein R.sub.1 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

3. The method of claim 1, wherein R.sub.2 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

4. The method of claim 1, wherein R.sub.1 and R.sub.2 are independently chosen from optionally substituted alkyl.

5. The method of claim 1, wherein R.sub.1 and R.sub.2 are joined together to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

6. The method of claim 5, wherein R.sub.1 and R.sub.2 are joined together to form an optionally substituted pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 1,4-diazepan-1-yl, and 1,4-diazocan-1-yl.

7. The method of claim 1, wherein R.sub.3 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aminocarbonyl, and optionally substituted phosphato.

8. The method of claim 7, wherein R.sub.3 is chosen from hydrogen, optionally substituted lower alkyl, and optionally substituted aminocarbonyl.

9. The method of claim 8, wherein R.sub.3 is hydrogen.

10. The method of claim 8, wherein R.sub.3 is optionally substituted lower alkyl.

11. The method of claim 10, wherein R.sub.3 is lower alkyl substituted with hydroxyl or amino.

12. The method of claim 8, wherein R.sub.3 is optionally substituted aminocarbonyl.

13. The method of claim 1, wherein the compound is chosen from: 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-hydroxypiperidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-aminopiperidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-hydroxypiperidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopiperidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-(hydroxymethyl)piperazine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 2-(hydroxymethyl)morpholine-4-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 2-(aminomethyl)morpholine-4-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl pyrrolidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-hydroxypyrrolidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopyrrolidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-(aminomethyl)pyrrolidine-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 1,4-diazepam-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methyl-1,4-diazepane-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl (2-aminoethyl)(methyl)carbamate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl (2-(dimethylamino)ethyl)(methyl)carbamate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate, 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopiperidine-1-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopiperidine-1-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-aminopiperidine-1-carboxylate, 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate, 4-((1E,6E)-7-(4-((dimethylcarbamoyl)oxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate, ((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2-methoxy-4, 1-phenylene)bis(piperazine-1-carboxylate), 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate, 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopyrrolidine-1-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopyrrolidine-1-carboxylate, 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 1,4-diazepane-1-carboxylate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl methyl (2-(pyrrolidin-1-yl)ethyl)carbamate, 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl methyl (2-morpholinoethyl)carbamate, 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate, 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl pyrrolidine-1-carboxylate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl (2-aminoethyl)(methyl)carbamate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl (2-(dimethylamino)ethyl)(methyl)carbamate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl methyl (2-(pyrrolidin-1-yl)ethyl)carbamate, 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl methyl (2-morpholinoethyl)carbamate, 4-((1E,6E)-7-(4-(2-aminoethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl pyrrolidine-1-carboxylate, 4-((1E,6E)-7-(4-(2-aminoethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate, 4-((1E,6E)-7-(4-(2-aminoethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate, 4-((1E,6E)-7-(4-(2-aminoethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate, 4-((1E,6E)-7-(4-(2-aminoethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate, ((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2-methoxy-4,1-phenylene)bis(4-methylpiperazine-1-carboxylate), 2-methoxy-4-((1E,6E)-7-(3-methoxy-4-((piperidine-1-carbonyl)oxy)phenyl)-3,5-dioxohepta-1,6-dien-1-yl)phenyl piperazine-1-carboxylate, 4-((1E,6E)-7-(4-((dimethylcarbamoyl)oxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate, 2-methoxy-4-((1E,6E)-7-(3-methoxy-4-((piperazine-1-carbonyl)oxy)phenyl)-3,5-dioxohepta-1,6-dien-1-yl)phenyl morpholine-4-carboxylate, 2-methoxy-4-((1E,6E)-7-(3-methoxy-4-((pyrrolidine-1-carbonyl)oxy)phenyl)-3,5-dioxohepta-1,6-dien-1-yl)phenyl piperazine-1-carboxylate, and 2-methoxy-4-((1E,6E)-7-(3-methoxy-4-((4-methylpiperazine-1-carbonyl)oxy)phenyl)-3,5-dioxohepta-1,6-dien-1-yl)phenyl morpholine-4-carboxylate, and pharmaceutically acceptable salts thereof.

14. The method of claim 1, further comprising administering a second therapeutic agent to the cell.

15. A method of treating a cancer selected from the group consisting of colorectal cancer, liver cancer, lung cancer, a breast cancer and oral cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I: ##STR00019## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 and R.sub.2 are independently chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R.sub.1 and R.sub.2 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and R.sub.3 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted alkoxycarbonyl, and optionally substituted phosphato.

16. The method of claim 15, wherein R.sub.1 and R.sub.2 are independently chosen from optionally substituted alkyl.

17. The method of claim 15, wherein R.sub.1 and R.sub.2 are joined together to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

18. The method of claim 15, wherein R.sub.3 is chosen from hydrogen, optionally substituted lower alkyl, and optionally substituted aminocarbonyl.

Description

EXAMPLES

(1) The following examples serve to more fully describe the manner of using the invention. These examples are presented for illustrative purposes and should not serve to limit the true scope of the invention.

(2) In carrying out the procedures of the methods described herein, it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.

EXAMPLES

Example 1: Preparation of 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate

(3) ##STR00003##

4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate

(4) ##STR00004##

(5) To the solution of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (368 mg, 1.0 mmol, 1.0 eq.) in dry acetone (10 mL) were added anhydrous K.sub.2CO.sub.3 (138 mg, 1.0 mmol, 1.0 eq.) and sulfuric acid dimethyl ester (176 mg, 1.0 mmol, 1.0 eq.) at rt. The reaction mixture was heated under reflux overnight, cooled, diluted with water and extracted with CH.sub.2Cl.sub.2 (30 mL3). The combined organic layers were washed with H.sub.2O, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting residue was purified by silica column chromatography using CH.sub.2Cl.sub.2 as eluent to provide (1E,6E)-1-(3,4-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (170 mg, 44%).

(6) ##STR00005##

(7) To a solution of (1E,6E)-1-(3,4-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (100 mg, 0.26 mmol, 1.0 eq.), TEA (53 mg, 0.52 mmol, 2.0 eq.) and DMAP (3 mg, 0.026 mmol, 0.1 eq.) in DCM (5 mL) was added morpholine-4-carbonyl chloride (39 mg, 0.26 mmol, 1.0 eq.) at rt. The resulting mixture stirred at rt overnight, then concentrated. The resulting residue was dissolved in EA (10 mL), washed with aqueous NaHCO3 solution, dried over Na.sub.2SO.sub.4 and concentrated. The resulting residue was purified using RP-HPLC to afford 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate (29.5 mg, 23%) as an orange solid. LRMS (M+H.sup.+) m/z calculated 496.2. found 496.1. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.59-7.65 (dd, 2H), 7.08-7.17 (m, 5H), 6.89 (d, 1H), 6.49-6.57 (dd, 2H), 5.84 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.74-3.77 (m, 4H), 3.58-3.71 (m, 4H).

Example 2: Preparation of 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate

(8) ##STR00006##

4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate

(9) 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate was prepared as described for 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate (67 mg, 51%). LRMS (M+H.sup.+) m/z calculated 509.2. found 509.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.54-7.61 (dd, 2H), 7.04-7.13 (m, 5H), 6.84 (d, 1H), 6.46-6.54 (dd, 2H), 5.81 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.60-3.72 (m, 4H), 2.41-2.55 (m, 4H), 2.36 (s, 3H).

Example 3: Preparation of 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate

(10) ##STR00007##

4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate

(11) 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate was prepared as described for 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate (43 mg, 36%) as an orange solid. LRMS (M+H+) m/z calculated 454.2. found 454.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.58-7.64 (dd, 2H), 7.08-7.16 (m, 5H), 6.88 (d, 1H), 6.48-6.56 (dd, 2H), 5.84 (s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.13 (s, 3H), 3.02 (s, 3H).

Example 4: Preparation of 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate

(12) ##STR00008##

4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate

(13) 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate was prepared as described for 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate (51 mg, 40%) as an orange solid. LRMS (M+H.sup.+) m/z calculated 494.2. found 494.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.57-7.63 (dd, 2H), 7.07-7.15 (m, 5H), 6.87 (d, 1H), 6.48-6.56 (dd, 2H), 5.84 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 3.50-3.62 (m, 4H), 1.59-1.71 (m, 6H).

Example 5: Preparation of 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate

(14) ##STR00009##

4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate

(15) ##STR00010##

(16) To the solution of (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (150 mg, 0.4 mmol, 1.0 eq.) in dry DCM (15 mL) were added TEA (81 mg, 0.8 mmol, 2.0 eq.) and dimethylcarbamic chloride (43.8 mg, 0.4 mmol, 1.0 eq.). The reaction mixture was stirred at rt overnight, then washed with water and extracted with CH.sub.2Cl.sub.2 (30 mL2). The combined organic layers were washed with H.sub.2O, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting residue was separated by Prep-HPLC to provide 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (50 mg, 28% yield). LRMS (M+H+) m/z calculated 440.2. found 440.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.56 (s, 1H), 7.52 (s, 1H), 6.98-7.07 (m, 6H), 6.87 (d, 1H), 6.40-6.49 (m, 2H), 5.76 (s, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.06 (s, 3H), 2.95 (s, 3H).

Example 6: Preparation of 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate

(17) ##STR00011##

4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate

(18) 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate was prepared as described for 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (50 mg, 25% yield). LRMS (M+H+) m/z calculated 480.2. found 480.1. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.60 (d, 2H), 7.05-7.15 (m, 6H), 6.93 (d, 1H), 6.46-6.56 (m, 2H), 5.82 (s, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.51-3.63 (m, 4H), 1.58-1.69 (m, 6H).

Example 7: Preparation of 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate

(19) ##STR00012##

4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate

(20) 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate was prepared as described for 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (50 mg, 25% yield). LRMS (M+H.sup.+) m/z calculated 482.2. found 482.1. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.54 (d, 2H), 6.98-7.10 (m, 6H), 6.86 (d, 1H), 6.40-6.50 (m, 2H), 5.76 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.51-3.70 (m, 8H).

Example 8: Preparation of 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate

(21) ##STR00013##

4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate

(22) 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate was prepared as described for 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (52 mg, 26% yield). LRMS (M+H+) m/z calculated 495.2. found 495.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.57-7.63 (dd, 2H), 7.05-7.15 (m, 6H), 6.93 (d, 1H), 6.47-6.57 (m, 2H), 5.83 (s, 1H), 4.31-4.53 (m, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.51-3.70 (m, 4H), 2.88 (s, 3H), 1.65-1.81 (m, 2H).

Example 9: Preparation of 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate

(23) ##STR00014##

4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate

(24) 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate was prepared as described for 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (28 mg, 28.2% yield). LCMS (M+H.sup.|) m/z calculated 481.2. found 481.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) 7.51 (d, 2H), 7.25 (s, 1H), 7.13 (d, 2H), 7.01-7.05 (m, 2H), 6.72 (d, 1H), 6.68 (d, 1H), 6.55 (d, 1H), 5.91 (s, 1H), 3.81-3.86 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.65-3.73 (m, 2H), 3.20-3.22 (m, 4H).

Example 10: Preparation of 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate

(25) ##STR00015##

4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate

(26) ##STR00016##

(27) The mixture of 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (88 mg, 0.2 mmol, 1.0 eq), 2-bromoethanol (37.5 mg, 0.3 mmol, 1.5 eq) and K.sub.2CO.sub.3 (110 mg, 0.8 mmol, 4.0 eq) in acetone (10 ml) was stirred under reflux for 5 h. Then the mixture was concentrated and The resulting residue was separated by Prep-HPLC to provide 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (35 mg, 36.1%). LRMS (M+H.sup.+) m/z calculated 484.2. found 484.2. .sup.1H NMR (CDCl3, 400 MHz) 7.58-7.62 (dd, 2H), 7.07-7.13 (m, 5H), 6.91 (d, 1H), 6.48-6.56 (m, 2H), 5.83 (s, 1H), 4.14-4.17 (t, 2H), 3.96-3.99 (t, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.13 (s, 3H), 3.02 (s, 3H).

Example 11: Preparation of 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate

(28) ##STR00017##

4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate

(29) 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate was prepared as described for 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate (50 mg, 28%). LRMS (M+H.sup.|) m/z calculated 524.2. found 524.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.56-7.61 (dd, 2H), 7.06-7.14 (m, 5H), 6.87 (d, 1H), 6.47-6.53 (dd, 2H), 5.82 (s, 1H), 4.11-4.13 (t, 2H), 3.94-3.97 (t, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49-3.62 (m, 4H), 1.61-1.73 (m, 6H).

Example 12: Equilibrium Solubility

(30) The equilibrium solubility of compounds was measured in aqueous buffer. Excess amount of solid compound was added into buffer solution and the sample was briefly sonicated and then shaken at rt for 24 h. The sample was filtered and the concentration was analyzed by HPLC UV. A standard solution at 0.2 mg/mL was prepared in methanol or acetonitrile for each compound and used as an external standard for quantification. Data for curcumin and illustrative compounds in NaOAc/AcOH buffer (100 mM, pH 5.0) is shown in Table 1.

(31) TABLE-US-00001 TABLE 1 Solubility of Illustrative Compounds Solubility Chemical Name (mg/mL) Curcumin <0.001 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta- 0.018 1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1- carboxylate 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6- 0.32 dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta- 1.39 1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate

Example 13: Inhibition of Cell Growth in Tumor Cells

(32) Inhibition of cell growth by compounds was measured using MTT assay (Mosmann, T., Journal of Immunological Methods, 1983, 65, 55-63). Tumor cell lines were purchased from ATCC (American Type Culture Collection, Manassas, Va.). All cell lines were maintained in RPMI 1640 (Hyclone) supplemented with 10% fetal bovine serum (FBS, Hyclone), glutamine (2 mM, Hyclone), and antibiotics (penicillin 100 U/mL and streptomycin 50 g/mL) at 37 C. in a humidified atmosphere of 5% CO.sub.2 in air. Taxol (positive control, Sigma) and compounds were dissolved in DMSO (Sigma), and the final concentration of DMSO in the medium was 1%. Tumor cells were plated in 96-well plates at densities from 4000 cells/well of a 96-well plate and allowed to adhere/grow for 24 h. They were then treated with various concentrations of drug for 72 h. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma) was used to determine the number of viable cells at the time of compound addition and the number of cells remaining after 72 h compound exposure. The number of cells remaining after 72 h was compared to the number of viable cells at the time of compound addition by measuring the absorbance at 570 nm, allowing for the calculation of growth inhibition.

(33) All concentrations of compounds were tested in triplicate and controls were averaged over 4 wells. IC.sub.50 was calculated by plotting the concentration of compound vs the percentage of inhibition in treated wells using GraphPad Prism 5. In some embodiments, the compounds described herein exhibited an IC.sub.50 for A549 cells of less than 100 uM. In some embodiments, the compounds exhibited an IC.sub.50 for A549 cells of less than 10 uM. Data for curcumin and illustrative compounds are shown in Table 2.

(34) TABLE-US-00002 TABLE 2 Inhibitory Activity of Illustrative Compounds in A549 Cells A549 cell Chemical Name IC.sub.50 (M) Curcumin >30 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta- 2.3 1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta- 8.0 1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta- 7.2 1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta- 3.8 1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1- carboxylate 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6- 4.6 dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6- 4.3 dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1- carboxylate 4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6- 10.6 dien-1-yl)-2-methoxyphenyl dimethylcarbamate 4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta- 9.2 1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5- 9.1 dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate 4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5- 10.9 dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine- 1-carboxylate

(35) While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations on the scope of the claims.