Nitrogen-containing Derivative of Substituted Phenol Hydroxy Acid Ester, and Preparation and Use Thereof

Abstract

A nitrogen-containing derivative of substituted phenol hydroxyl acid ester is represented by formula (I). A salt of the compound of formula (I) has good water solubility, and in vivo, can rapidly and completely release substituted phenols having a pharmacological effect, which can improve the water solubility of substituted phenols, rapidly exert the pharmacological effects of substituted phenols in vivo, and has good safety. The method for preparing the above-mentioned compound is provided. This compound can also be used in the preparation of drugs that produce anaesthesia and/or sedative and hypnotic effects on humans and animals.

##STR00001##

Claims

1. A compound having the structure of formula (I): ##STR00141## wherein, R.sub.1-R.sub.5 are each independently selected from the group consisting of H, C.sub.1-6 linear or branched or cyclic hydrocarbyl, halogen, C.sub.1-4 alkoxy, cyano, nitro, ester group, etc.; R.sub.6-R.sub.9 are each independently selected from the group consisting of H, and C.sub.1-8 linear or branched or cyclic hydrocarbyl; when R.sub.7 and R.sub.8 are covalently linked, R.sub.7 and R.sub.8 can also be C.sub.1-3 alkylenes; H in the skeleton of R.sub.1-9 can be substituted with halogen, hydroxyl, sulfhydryl, carbamoyl, guanidyl, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, β-indolyl, etc.; R.sub.1-9 skeleton can contain O, S, N and other heteroatoms.

2. The salt of the compound of formula (I) according to claim 1, including but not limited to the group consisting of acetate, adipate, alginate, 4-aminosalicylate, ascorbate, aspartate, glutamate, pyroglutamate, benzenesulfonate, benzoate, butyrate, camphorate, camphorsulfonate, carbonate, cinnamate, citrate, cyclohexaminesulfonate, cyclopentanepropionate, decanoate, 2,2-dichloroacetate, digluconate, dodecylsulphate, ethane-1,2-disulfonate, ethanesulfonate, formate, fumarate, mucate, gentisate, glucoheptanate, gluconate, glucuronate, glycerophosphate, hydroxyacetate, semisulfate, heptanoate, caproate, hippurate, hydrochloride, hydrobromide, hydroiodate, 2-hydroxyethanesulfonate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, naphthalene-1,5-disulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, 2-oxoglutarate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, sebacate, bisebacate, stearate, succinate, sulfate, tannate, tartrate, bitartrate, thiocyanate, toluenesulfonate or undecylate, hydrogen sulfate, sodium, ammonium.

3. The compound of formula (I) according to claim 1, characterized in that R.sub.1-R.sub.5 are each independently selected from the group consisting of H, and C.sub.1-6 linear or branched or cyclic hydrocarbyl; R.sub.6-R.sub.9 are each independently selected from the group consisting of H, and C.sub.1-8 linear or branched or cyclic hydrocarbyl; H in the skeleton of R.sub.1-9 can be substituted with hydroxyl, sulfhydryl, carbamoyl, guanidyl, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, β-indolyl, etc.; R.sub.1-9 skeleton can contain O, S, N and other heteroatoms.

4. The compound of formula (I) according to claim 1, characterized in that R.sub.1-R.sub.5 are each independently selected from the group consisting of H, and C.sub.1-6 linear or branched or cyclic hydrocarbyl; R.sub.6 and R.sub.7 are covalently linked, and R.sub.6 and R.sub.7 are C.sub.1-3 alkylenes; R.sub.8 and R.sub.9 are each independently selected from the group consisting of H, and C.sub.1-8 linear or branched or cyclic hydrocarbyl.

5. The compound of formula (I) according to claim 1, characterized in that R.sub.1-R.sub.5 are each independently selected from the group consisting of H, and C.sub.1-6 linear or branched or cyclic hydrocarbyl; R.sub.7 and R.sub.8 are covalently linked, and R.sub.7 and R.sub.8 are C.sub.1-3 alkylenes; R.sub.6 and R.sub.9 are each independently selected from the group consisting of H, and C.sub.1-8 linear or branched or cyclic hydrocarbyl.

6. The compound of formula (I) according to claim 1, characterized in that R.sub.1 and R.sub.5 are isopropyl; R.sub.2-R.sub.4 are H; R.sub.6-R.sub.9 are each independently selected from the group consisting of H, and C.sub.1-8 linear or branched or cyclic hydrocarbyl; when R.sub.6 and R.sub.7 are covalently linked, R.sub.6 and R.sub.7 can also be C.sub.1-3 alkylenes; when R.sub.7 and R.sub.8 are covalently linked, R.sub.7 and R.sub.8 can also be C.sub.1-3 alkylenes; H in the skeleton of R.sub.1-9 can be substituted with halogen, hydroxyl, sulfhydryl, carbamoyl, guanidyl, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, β-indolyl, etc., and R.sub.1-9 skeleton can contain O, S, N and other heteroatoms.

7. The compound of formula (I) according to claim 1, characterized in that R.sub.1 is isopropyl; R.sub.5 is ##STR00142## R.sub.2-R.sub.4 are H; R.sub.6-R.sub.9 are each independently selected from the group consisting of H, and C.sub.1-8 linear or branched or cyclic hydrocarbyl; when R.sub.6 and R.sub.7 are covalently linked, R.sub.6 and R.sub.7 can also be C.sub.1-3 alkylenes; when R.sub.7 and R.sub.8 are covalently linked, R.sub.7 and R.sub.8 can also be C.sub.1-3 alkylenes; H in the skeleton of R.sub.1-9 can be substituted with halogen, hydroxyl, sulfhydryl, carbamoyl, guanidyl, carboxyl, 4-imidazolyl, phenyl, hydroxyphenyl, β-indolyl, etc., and R.sub.1-9 skeleton can contain O, S, N and other heteroatoms.

8. The compound of formula (I) according to claim 1, characterized in that said compound is preferably selected from the group consisting of: ##STR00143## ##STR00144## ##STR00145##

9. The compound of formula (I) according to claim 1, characterized in that said compound is preferably selected from the group consisting of: ##STR00146## ##STR00147##

10. Use of a formulation obtained by a compound of formula (I) according to-claim 1, and a stereoisomer, an isotopically substituted compound, a pharmaceutically acceptable salt, a solvate, a pharmaceutical composition thereof, and pharmaceutically acceptable excipients/carriers/adjuvents, etc., in the preparation of a medicament that has central sedative actions and/or anesthetic effects on humans or animals.

Description

EXAMPLES

Example 1

[0035] ##STR00010##

[0036] Propofol (178 mg, 1 mmoL) and chloroacetyl chloride (124 mg, 1.1 mmoL) were dissolved in 10 mL of dichloromethane, to which was added pyridine (237 mg, 3 mmoL) in an ice bath, and then the reaction solution was warmed to room temperature and stirred for 2 h. The solvent was evaporated to dry, and the residue was subjected to silica gel column chromatography (cyclohexane/ethyl acetate=20/1) to obtain the intermediate b as colorless oils (180 mg), with a yield of 70.6%.

[0037] Intermediate b (180 mg, 71 mmoL) and BOC-glycine (140 mg, 80 mmoL) were mixed in 10 mL of DMF, to which was added anhydrous potassium carbonate (290 mg, 210 mmoL), and then the reaction solution was stirred at room temperature for 8 h and filtered. The filtrate was poured into 100 mL of water, and then extracted with 50 mL of ethyl acetate. The organic layer was separated out, dried overnight with anhydrous sodium sulfate, and filtered the next day. The filtrate was evaporated to dry under reduced pressure, and the residue was subjected to column chromatography (cyclohexane/ethyl acetate=5/1) to yield 183 mg of white solid powder, i.e. intermediate c, with a yield of 66%. 183 mg of intermediate c was dissolved in 10 mL of ethyl acetate, and then excess dry HCl gas was purged. The reaction solution was stirred for 1 h at room temperature, and the solvent was evaporated to dry under reduced pressure, to obtain the crude product. The crude product was rinsed with cyclohexane for 3 times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain 115 mg of target compound 1 as a white solid, with a yield of 75%.

[0038] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.52 (s, 3H), 7.23-7.31 (m, 3H), 5.29 (s, 2H), 4.00 (s, 2H), 2.94 (hept, J=6.9 Hz, 2H), 1.13 (d, J=6.8 Hz, 12H).

Example 2

[0039] ##STR00011##

[0040] The intermediate b was prepared as described in Example 1. Intermediate b (180 mg, 71 mmoL) and BOC-sarcosine (151 mg, 80 mmoL) were mixed in 10 mL of DMF, to which was added anhydrous potassium carbonate (290 mg, 210 mmoL), and then the reaction solution was stirred at room temperature for 8 h and filtered. The filtrate was poured into 100 mL of water, and then extracted with 50 mL of ethyl acetate. The organic layer was separated out, dried overnight with anhydrous sodium sulfate, and filtered the next day. The filtrate was evaporated to dry under reduced pressure, and the residue was subjected to column chromatography (cyclohexane/ethyl acetate=5/1) to yield 186 mg of white solid powder, i.e. intermediate c, with a yield of 64.5%. 186 mg of intermediate c was dissolved in 10 mL of ethyl acetate, and then excess dry HCl gas was purged. The reaction solution was stirred for 1 h at room temperature, and the solvent was evaporated to dry under reduced pressure, to obtain the crude product. The crude product was rinsed with cyclohexane for 3 times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain 113 mg of target compound 2 as a white solid, with a yield of 72%.

[0041] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.46 (s, 2H), 7.23-7.31 (m, 3H), 5.31 (s, 2H), 4.17 (s, 2H), 2.94 (hept, J=6.8 Hz, 2H), 2.59 (s, 3H), 1.13 (d, J=6.8 Hz, 12H).

Example 3

[0042] ##STR00012##

[0043] The intermediate b was prepared as described in Example 1. Intermediate b (180 mg, 71 mmoL) and N,N-dimethylglycine (82.4 mg, 80 mmoL) were mixed in 10 mL of DMF, to which was added anhydrous potassium carbonate (290 mg, 210 mmoL), and then the reaction solution was stirred at room temperature for 8 h and filtered. The filtrate was poured into 100 mL of water, and then extracted with 50 mL of ethyl acetate. The organic layer was separated out, dried overnight with anhydrous sodium sulfate, and filtered the next day. The filtrate was evaporated to dry under reduced pressure, and the residue was subjected to column chromatography (cyclohexane/ethyl acetate=30/1) to yield 123 mg of compound 3 as free base. 123 mg of compound 3 as free base was dissolved in 10 mL of ethyl acetate, and then excess dry HCl gas was purged for 1 h. The reaction solution was stirred for 2 h at room temperature, and the solvent was evaporated to dry under reduced pressure, to obtain the crude product. The crude product was rinsed with cyclohexane for 3 times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain 87.6 mg of target compound 3 as a white solid, with a yield of 64%.

[0044] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.78 (s, 1H), 7.23-7.31 (m, 3H), 5.32 (s, 2H), 4.42 (s, 2H), 2.94 (hept, J=6.9 Hz, 2H), 2.85 (s, 6H), 1.13 (d, J=6.8 Hz, 12H).

Example 4

[0045] ##STR00013##

[0046] Boc-L-alanine (1.49 g, 7.87 mmol) and propofol chloroacetate (2 g, 7.85 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 40 min, to which was then added K.sub.2CO.sub.3 (1.19 g, 8.6 mmol). The reaction solution was stirred at 70° C. for 4 h and then filtered. The filtrate was extracted with ethyl acetate (100 mL) and water (50 mL). The organic layer was washed several times with water (3×50 mL) and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (cyclohexane/ethyl acetate, from 40:1 to 20:1) to give 2.18 g of intermediate a as a white solid, with a yield of 68%. Intermediate a (2.18 g, 5.35 mmol) was dissolved in 50 mL of ethyl acetate, and then dry HCl gas was purged for 1 h. Then, the reaction solution was stirred and reacted for 4 h at room temperature. Ethyl acetate was removed by evaporation under reduced pressure, to obtain a crude product. The crude product was rinsed with cyclohexane for 3 times, and then subjected to suction filtration. The filter cake was dried at 65° C. to obtain 1.28 g of target compound 4 as a white solid, with a yield of 69.6%.

[0047] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.66 (s, 3H), 7.23-7.31 (m, 3H), 5.29 (d, J=2.4 Hz, 2H), 4.26 (q, J=7.1 Hz, 1H), 2.93 (hept, J=6.9 Hz, 2H), 1.48 (d, J=7.2 Hz, 3H), 1.13 (d, J=6.8 Hz, 12H).

Example 5

[0048] ##STR00014##

[0049] Boc-D-alanine (1.49 g, 7.87 mmol) and propofol chloroacetate (2 g, 7.85 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 40 min, to which was then added K.sub.2CO.sub.3 (1.19 g, 8.6 mmol). The reaction solution was stirred at 70° C. for 4 h and then filtered. The filtrate was extracted with ethyl acetate (100 mL) and water (50 mL). The organic layer was washed several times with water (3×50 mL) and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (cyclohexane/ethyl acetate, from 40:1 to 20:1) to give 2.01 g of intermediate a as a white solid, with a yield of 62.8%. Intermediate a (2.01 g, 4.93 mmol) was dissolved in 50 mL of ethyl acetate, and then dry HCl gas was purged for 1 h. Then, the reaction solution was stirred and reacted for 4 h at room temperature. Ethyl acetate was removed by evaporation under reduced pressure, to obtain a crude product. The crude product was rinsed with cyclohexane for 3 times, and then subjected to suction filtration. The filter cake was dried at 65° C. to obtain 1.15 g of target compound 5 as a white solid, with a yield of 62.5%.

[0050] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.69 (s, 3H), 7.21-7.30 (m, 3H), 5.24 (d, J=2.4 Hz, 2H), 4.29 (q, J=7.2 Hz, 1H), 2.91 (hept, J=6.9 Hz, 2H), 1.44 (d, J=7.2 Hz, 3H), 1.11 (d, J=6.8 Hz, 12H).

Example 6

[0051] ##STR00015##

[0052] (R)-2-cyclopropylethyl-6-isopropylphenol (CAS: 1637741-58-2, 204 mg, 1 mmoL) and chloroacetyl chloride (124 mg, 1.1 mmoL) were dissolved in 10 mL of dichloromethane, to which was added pyridine (237 mg, 3 mmoL) in an ice bath, and then the reaction solution was warmed to room temperature and stirred for 2 h. The solvent was evaporated to dry. The residue was subjected to silica gel column chromatography (cyclohexane/ethyl acetate=20/1) to yield 186 mg of intermediate a as colorless oil, with a yield of 66%. Intermediate a (186 mg, 0.66 mmoL) and morpholin-4-ylacetic acid (96 mg, 0.66 mmoL) were dissolved in DMF (20 mL) and stirred for 40 min at room temperature, to which was then added K.sub.2CO.sub.3 (97 mg, 0.7 mmol). The reaction solution was stirred at 70° C. for 4 h and cooled. Then, water (100 mL) was added, and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water (3×100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration the next day, the filtrate was evaporated to remove the solvent and obtain the crude product, which was subjected to silica gel column chromatography (cyclohexane/ethyl acetate, 30:1), to provide 141 mg of intermediate b as colorless oil, with a yield of 55%. 141 mg of intermediate b was dissolved in 3 mL of trifluoroacetic acid, and stirred at room temperature for 30 min. The excess trifluoroacetic acid was removed by evaporation under reduced pressure, to which was added 20 mL of cyclohexane, and then the solid was precipitated. The solution was filtered, and the filter cake was dried at 65° C., to obtain 114.7 mg of white solid, with a yield of 63%.

[0053] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.23 (s, 1H), 7.30-7.36 (3H, m), 5.36 (2H, s), 4.41 (2H, s), 3.82-3.89 (m, 4H), 3.21-3.28 (m, 5H), 2.55-2.58 (m, 1H), 1.31 (d, J=7.2 Hz, 3H), 1.26 (d, J=7.2 Hz, 6H), 1.03-1.07 (m, 1H), 0.42-0.52 (m, 2H), 0.17-0.25 (m, 2H).

Example 7

[0054] ##STR00016##

[0055] Equimolar amounts of 4-methyl-1-piperazineacetic acid (CAS: 54699-92-2) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 3, intermediate a was prepared, and the yield was 46-68% based on the amount of propofol chloroacetate.

[0056] Intermediate a was dissolved in ethyl acetate, to which was purged dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. Ethyl acetate was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 7 as a white solid, with a yield of 71-84%.

[0057] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.07 (s, 1H), 7.20-7.27 (m, 3H), 5.19 (s, 2H), 3.85 (s, broad, 2H), 3.42-3.47 (m, 2H), 3.14-3.23 (m, 4H), 2.89-2.98 (m, 4H), 2.75 (s, 3H), 1.13 (d, J=6.9 Hz, 12H).

Example 8

[0058] ##STR00017##

[0059] Equimolar amounts of N,N-dimethylalanine (CAS: 19701-89-4) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 3, intermediate a was prepared, and the yield was 51-63% based on the amount of propofol chloroacetate.

[0060] Intermediate a was dissolved in ethanol, to which was added 0.5-fold molar amount of sulfuric acid, and then the reaction solution was stirred at room temperature for 30 min. Ethanol was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 8 as a white solid, with a yield of 61-71%.

[0061] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.91 (s, 1H), 7.25-7.33 (m, 3H), 5.21 (s, 2H), 4.27 (q, J=7.2 Hz, 1H), 2.95 (hept, J=6.8 Hz, 2H), 2.83 (s, 6H), 1.88 (d, J=7.2 Hz, 3H), 1.13 (d, J=6.8 Hz, 12H).

Example 9

[0062] ##STR00018##

[0063] Equimolar amounts of 4-methyl-3-morpholinecarboxylic acid (CAS: 1240518-88-0) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 3, intermediate a was prepared, and the yield was 52-71% based on the amount of propofol chloroacetate.

[0064] Intermediate a was dissolved in ethyl acetate, to which was purged excess dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. Ethyl acetate was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 9 as a white solid, with a yield of 49-71%.

[0065] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.91 (s, 1H), 7.31-7.36 (m, 3H), 5.16 (s, 2H), 4.61-4.64 (m, 1H), 3.91-4.13 (m, 4H), 3.32-3.41 (m, 2H), 2.85 (s, 3H), 1.15 (d, J=6.8 Hz, 12H).

Example 10

[0066] ##STR00019##

[0067] Equimolar amounts of 1-methylpiperidine-2-carboxylic acid (CAS: 7730-87-2) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 3, intermediate a was prepared, with a yield of 36-61%.

[0068] Intermediate a was dissolved in ethyl acetate, to which was purged excess dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. Ethyl acetate was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 10 as a white solid, with a yield of 45-68%.

[0069] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.21 (s, 1H), 7.27-7.36 (m, 3H), 5.28 (s, 1H), 4.38-4.32 (m, 1H), 3.13-3.25 (m, 2H), 2.97 (hept, J=6.8 Hz, 2H), 2.91 (s, 3H), 2.01-2.18 (m, 2H), 1.71-1.75 (m, 2H), 1.13-1.35 (m, 14H).

Example 11

[0070] ##STR00020##

[0071] Equimolar amounts of 1-BOC-piperidin-2-carboxylic acid (CAS: 98303-20-9) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 5, intermediate a was prepared, with a yield of 56-71%.

[0072] Intermediate a was dissolved in excess trifluoroacetic acid, and then the reaction solution was stirred at room temperature for 6 h. Trifluoroacetic acid was removed by evaporation under reduced pressure, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 11 as a white solid, with a yield of 55-63%.

[0073] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.83 (s, 2H), 7.23-7.30 (m, 3H), 5.23 (s, 1H), 4.33-4.30 (m, 1H), 3.14-3.26 (m, 2H), 2.94 (hept, J=6.8 Hz, 2H), 2.03-2.16 (m, 2H), 1.72-1.77 (m, 2H), 1.12-1.34 (m, 14H).

Example 12

[0074] ##STR00021##

[0075] Equimolar amounts of 4-BOC-morpholine-3-carboxylic acid (CAS: 212650-43-6) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 5, intermediate a was prepared, with a yield of 61-74%.

[0076] Intermediate a was dissolved in ethyl acetate, to which was purged excess dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. Ethyl acetate was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 12 as a white solid, with a yield of 55-78%.

[0077] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.45 (s, 2H), 7.29-7.34 (m, 3H), 5.19 (s, 2H), 4.63-4.65 (m, 1H), 3.92-4.15 (m, 4H), 3.30-3.39 (m, 2H), 2.95 (hept, J=6.8 Hz, 2H), 1.13 (d, J=6.8 Hz, 12H).

Example 13

[0078] ##STR00022##

[0079] Equimolar amounts of N,N-bis(2-methoxyethyl)ammonium acetate (CAS: 3235-71-0) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 3, intermediate a was prepared, with a yield of 41-61%.

[0080] Intermediate a was dissolved in ethyl acetate, to which was purged excess dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. Ethyl acetate was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed with cyclohexane for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 13 as a white solid, with a yield of 65-69%.

[0081] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.95 (s, 1H), 7.32-7.37 (m, 3H), 5.22 (s, 2H), 4.25 (s, 2H), 3.73-3.81 (m, 4H), 3.42-3.47 (m, 4H), 3.24 (s, 6H), 2.94 (hept, J=6.8 Hz, 2H), 1.13 (d, J=6.8 Hz, 12H).

Example 14

[0082] ##STR00023##

[0083] Equimolar amounts of BOC-L-valine (CAS: 13734-41-3) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 5, intermediate a was prepared, with a yield of 54-61%.

[0084] Intermediate a was dissolved in ethyl acetate, to which was purged excess dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. Ethyl acetate was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed with cyclohexane for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 14 as a white solid, with a yield of 51-68%.

[0085] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.91 (s, 3H), 7.31-7.35 (m, 3H), 5.22 (s, 2H), 4.16 (d, J=6.8 Hz, 1H), 2.96-3.04 (m, 3H), 1.13 (d, J=7.2 Hz, 12H), 0.96 (d, J=7.2 Hz, 6H).

Example 15

[0086] ##STR00024##

[0087] Equimolar amounts of BOC-L-cysteine (CAS: 20887-95-0) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 5, intermediate a was prepared, with a yield of 49-72%.

[0088] Intermediate a was dissolved in ethyl acetate, to which was purged excess dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. Ethyl acetate was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed with cyclohexane for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 15 as a white solid, with a yield of 67-73%.

[0089] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.56 (s, 3H), 7.28-7.33 (m, 3H), 5.26 (s, 2H), 4.70 (t, J=6.8 Hz, 1H), 3.46-3.64 (m, 3H), 2.93 (hept, J=6.8 Hz, 2H), 1.16 (d, J=7.2 Hz, 6H).

Example 16

[0090] ##STR00025##

[0091] Equimolar amounts of BOC-N-methyl 2-aminopropionic acid (CAS: 13734-31-1) and propofol chloroacetate were dissolved in DMF, to which was added two-fold excess of potassium carbonate, and then the reaction solution was stirred at 40° C. for 6 h. Following the work-up procedure in Example 5, intermediate a was prepared, with a yield of 52-66%.

[0092] Intermediate a was dissolved in ethyl acetate, to which was purged excess dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. Ethyl acetate was removed by evaporation, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 16 as a white solid, with a yield of 61-69%.

[0093] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.71 (s, 2H), 7.26-7.32 (m, 3H), 5.25 (s, 2H), 4.24 (q, J=7.2 Hz, 1H), 2.95 (hept, J=6.8 Hz, 2H), 2.84 (s, 3H), 1.88 (d, J=7.2 Hz, 3H), 1.13 (d, J=6.8 Hz, 12H).

Example 17

[0094] ##STR00026##

[0095] Intermediate b mentioned in Example 6 was dissolved in ethyl acetate, to which was purged excess dry HCl gas, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and subjected to suction filtration. The solid was rinsed with cyclohexane for three times and filtered by suction. The filter cake was dried at 65° C. to obtain target compound 17 as a white solid, with a yield of 51-64%.

[0096] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.91 (s, 1H), 7.28-7.33 (3H, m), 5.29 (2H, s), 4.44 (2H, s), 3.78-3.85 (m, 4H), 3.22-3.27 (m, 5H), 2.55-2.59 (m, 1H), 1.34 (d, J=7.2 Hz, 3H), 1.24 (d, J=7.2 Hz, 6H), 1.01-1.06 (m, 1H), 0.41-0.51 (m, 2H), 0.18-0.24 (m, 2H).

Example 18

[0097] ##STR00027##

[0098] Intermediate b mentioned in Example 6 was dissolved in absolute ethanol, to which was added equimolar benzenesulfonic acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 18 as a white solid, with a yield of 70-84%.

[0099] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.73 (s, 1H), 7.68-7.79 (m, 5H), 7.31-7.35 (3H, m), 5.29 (2H, s), 4.44 (2H, s), 3.81-3.89 (m, 4H), 3.22-3.26 (m, 5H), 2.57-2.59 (m, 1H), 1.32 (d, J=7.2 Hz, 3H), 1.28 (d, J=7.2 Hz, 6H), 1.04-1.07 (m, 1H), 0.41-0.52 (m, 2H), 0.16-0.23 (m, 2H).

Example 19

[0100] ##STR00028##

[0101] Intermediate b mentioned in Example 6 was dissolved in absolute ethanol, to which was added 0.5 molar equivalents of sulfuric acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 19 as a white solid, with a yield of 80-88%.

[0102] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.24 (s, 1H), 7.31-7.35 (3H, m), 5.33 (2H, s), 4.43 (2H, s), 3.83-3.89 (m, 4H), 3.19-3.26 (m, 5H), 2.53-2.57 (m, 1H), 1.29 (d, J=7.2 Hz, 3H), 1.25 (d, J=7.2 Hz, 6H), 1.02-1.07 (m, 1H), 0.39-0.51 (m, 2H), 0.18-0.26 (m, 2H).

Example 20

[0103] ##STR00029##

[0104] Intermediate b mentioned in Example 6 was dissolved in absolute ethanol, to which was added equimolar p-toluenesulfonic acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 20 as a white solid, with a yield of 75-86%.

[0105] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.89 (s, 1H), 7.68-7.79 (m, 2H), 7.45-7.49 (m, 2H), 7.28-7.32 (3H, m), 5.24 (2H, s), 4.41 (2H, s), 3.80-3.87 (m, 4H), 3.19-3.23 (m, 5H), 2.53-2.55 (m, 1H), 2.43 (s, 3H), 1.33 (d, J=7.2 Hz, 3H), 1.25 (d, J=7.2 Hz, 6H), 1.02-1.05 (m, 1H), 0.40-0.51 (m, 2H), 0.17-0.23 (m, 2H).

Example 21

[0106] ##STR00030##

[0107] Intermediate b mentioned in Example 6 was dissolved in absolute ethanol, to which was added equimolar methanesulfonic acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 21 as a white solid, with a yield of 75-86%.

[0108] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.21 (s, 1H), 7.28-7.32 (3H, m), 5.25 (2H, s), 4.43 (2H, s), 3.81-3.87 (m, 4H), 3.31 (s, 3H), 3.15-3.22 (m, 5H), 2.54-2.58 (m, 1H), 2.42 (s, 3H), 1.32 (d, J=7.2 Hz, 3H), 1.26 (d, J=7.2 Hz, 6H), 1.01-1.05 (m, 1H), 0.40-0.51 (m, 2H), 0.18-0.23 (m, 2H).

Example 22

[0109] ##STR00031##

[0110] Morpholin-4-ylacetic acid (2.29 g, 15.8 mmol), NaI (1.18 g, 15.8 mmol) and propofol chloroacetate (4 g, 15.8 mmol) were dissolved in DMF (20 ml), to which was added K.sub.2CO.sub.3 (2.25 g, 16.2 mmol), and then the reaction solution was stirred at 40° C. for 6 h. The reaction solution was cooled, and then extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (3×100 mL) for several times. The organic layers were separated, dried over anhydrous sodium sulfate, and filtered the next day. The filtrate was evaporated to dryness under reduced pressure to obtain the crude product, which was purified by column chromatography (cyclohexane/ethyl acetate 30:1) to obtain 3.16 g of intermediate a as colorless oil, with a yield of 55.34%.

[0111] Intermediate a (1.02 g, 2.8 mmol) was dissolved in 30 mL of ethyl acetate, to which was purged dry HCl gas for 30 min, and then the reaction solution was stirred at room temperature for 1 h. Ethyl acetate was removed by evaporation under reduced pressure, to provide the crude product, which was rinsed with cyclohexane for many times and then subjected to suction filtration. Then, the filter cake was dried at 65° C. to obtain 0.78 g of target compound 22 as a white solid, with a yield of 70.91%.

[0112] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.29 (s, 1H), 7.24-7.29 (m, 3H), 5.32 (s, 2H), 4.43 (s, 2H), 3.86 (s, broad, 4H), 3.25 (s, broad, 4H), 2.93 (hept, J=6.8 Hz, 2H), 1.13 (d, J=6.8 Hz, 12H).

Example 23

[0113] ##STR00032##

[0114] Intermediate a mentioned in Example 22 was dissolved in absolute ethanol, to which was added 0.5 molar equivalents of sulfuric acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 23 as a white solid, with a yield of 70-85%.

[0115] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.10 (s, 1H), 7.25-7.31 (m, 3H), 5.31 (s, 2H), 4.41 (s, 2H), 3.87 (s, broad, 4H), 3.26 (s, broad, 4H), 2.94 (hept, J=6.8 Hz, 2H), 1.14 (d, J=6.8 Hz, 12H).

Example 24

[0116] ##STR00033##

[0117] Intermediate a mentioned in Example 22 was dissolved in absolute ethanol, to which was added equimolar benzenesulfonic acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 24 as a white solid, with a yield of 71-79%.

[0118] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.32 (s, 1H), 7.63-7.76 (m, 5H), 7.28-7.32 (m, 3H), 5.28 (s, 2H), 4.37 (s, 2H), 3.88 (s, broad, 4H), 3.28 (s, broad, 4H), 2.92 (hept, J=6.8 Hz, 2H), 1.13 (d, J=6.8 Hz, 12H).

Example 25

[0119] ##STR00034##

[0120] Intermediate a mentioned in Example 22 was dissolved in absolute ethanol, to which was added equimolar p-toluenesulfonic acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 25 as a white solid, with a yield of 75-89%.

[0121] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.04 (s, 1H), 7.65-7.77 (m, 2H), 7.46-7.51 (m, 2H), 7.27-7.30 (m, 3H), 5.22 (s, 2H), 4.38 (s, 2H), 3.85 (s, broad, 4H), 3.23 (s, broad, 4H), 2.93 (hept, J=6.8 Hz, 2H), 1.15 (d, J=6.8 Hz, 12H).

Example 26

[0122] ##STR00035##

[0123] Intermediate a mentioned in Example 22 was dissolved in absolute ethanol, to which was added equimolar methanesulfonic acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 26 as a white solid, with a yield of 72-88%.

[0124] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.16 (s, 1H), 7.29-7.31 (m, 3H), 5.22 (s, 2H), 4.37 (s, 2H), 3.84 (s, broad, 4H), 3.25-3.35 (m, 7H), 2.95 (hept, J=6.8 Hz, 2H), 1.13 (d, J=6.8 Hz, 12H).

Example 27

[0125] ##STR00036##

[0126] Intermediate a mentioned in Example 22 was dissolved in excess trifluoroacetic acid, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then the residue was dispersed in cyclohexane and filtered. The solid was rinsed with cyclohexane for three times and subjected to suction filtration. The filter cake was dried at 65° C. to obtain target compound 27 as a white solid, with a yield of 68-79%.

[0127] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.16 (s, 1H), 7.27-7.33 (m, 3H), 5.32 (s, 2H), 4.43 (s, 2H), 3.88 (s, broad, 4H), 3.25 (s, broad, 4H), 2.92 (hept, J=6.8 Hz, 2H), 1.13 (d, J=6.8 Hz, 12H).

Example 28

[0128] ##STR00037##

[0129] (R)-2-cyclopropylethyl-6-isopropylphenol (CAS: 1637741-58-2, 204 mg, 1 mmoL) and chloroacetyl chloride (124 mg, 1.1 mmoL) were dissolved in 10 mL of dichloromethane, to which was added pyridine (237 mg, 3 mmoL) in an ice bath, and then the reaction solution was warmed to room temperature and stirred for 2 h. The solvent was evaporated to dry. The residue was subjected to silica gel column chromatography (cyclohexane/ethyl acetate=20/1) to yield 176 mg of intermediate a as colorless oil. Intermediate a (176 mg, 0.62 mmoL) and morpholin-4-ylacetic acid (90 mg, 0.66 mmoL) were dissolved in DMF (20 mL) and stirred for 40 min at room temperature, to which was then added K.sub.2CO.sub.3 (97 mg, 0.7 mmol). The reaction solution was stirred at 70° C. for 4 h and cooled. Then, water (100 mL) was added, and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water (3×100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration the next day, the filtrate was evaporated to remove the solvent and obtain the crude product, which was subjected to silica gel column chromatography (cyclohexane/ethyl acetate, 30:1), to provide 138 mg of intermediate b as colorless oil, with a yield of 54%. 138 mg of intermediate b was dissolved in 3 mL of ethyl acetate, to which was purged excess HCl gas, and then the reaction solution was stirred at room temperature for 30 min. The solvent was evaporated to dry under reduced pressure, and then 20 mL of cyclohexane was added to the residue. The solid was precipitated and collected by filtration, followed by rinsing with cyclohexane for 3 times and filtering. The filter cake was dried at 65° C., to obtain 101.2 mg of white solid, with a yield of 55.6%.

[0130] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.61 (s, 1H), 7.31-7.38 (3H, m), 5.32 (2H, s) 4.39 (2H, s), 3.83-3.92 (m, 4H), 3.20-3.26 (m, 5H), 2.57-2.59 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.28 (d, J=7.2 Hz, 6H), 1.02-1.09 (m, 1H), 0.41-0.53 (m, 2H), 0.17-0.26 (m, 2H).

Example 29

[0131] ##STR00038##

[0132] Piperidin-1-acetic acid (2.26 g, 15.8 mmol), NaI (1.18 g, 15.8 mmol) and propofol chloroacetate (4 g, 15.8 mmol) were dissolved in DMF (20 ml), to which was added K.sub.2CO.sub.3 (2.25 g, 16.2 mmol), and then the reaction solution was stirred at 40° C. for 6 h. The reaction solution was cooled, and then extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (3×100 mL) for several times. The organic layers were separated, dried over anhydrous sodium sulfate, and filtered the next day. The filtrate was evaporated to dryness under reduced pressure to obtain the crude product, which was purified by column chromatography (cyclohexane/ethyl acetate 30:1) to obtain 3.31 g of intermediate a as colorless oil, with a yield of 58.1%.

[0133] Intermediate a (1.02 g, 2.8 mmol) was dissolved in 30 mL of ethyl acetate, to which was purged dry HCl gas for 30 min, and then the reaction solution was stirred at room temperature for 1 h. Ethyl acetate was removed by evaporation under reduced pressure, to provide the crude product, which was rinsed with cyclohexane for many times and then subjected to suction filtration. Then, the filter cake was dried at 65° C. to obtain 0.82 g of target compound 29 as a white solid, with a yield of 73.6%.

[0134] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.53 (s, 1H), 7.2′-7.28 (m, 3H), 5.33 (s, 2H), 4.40 (s, 2H), 3.45-3.48 (m, 2H), 2.90-3.04 (m, 4H), 1.68-1.80 (m, 5H), 1.33-1.36 (m, 1H), 1.13 (d, J=6.9 Hz, 12H).

Example 30

[0135] ##STR00039##

[0136] Intermediate a (176 mg, 0.62 mmoL) and piperidine-1-acetic acid (89 mg, 0.66 mmol) were dissolved in DMF (20 mL) and stirred at room temperature for 40 min, to which was then added K.sub.2CO.sub.3 (97 mg, 0.7 mmol). The reaction solution was stirred at 70° C. for 4 h, to which was added water (100 mL), and then extracted with ethyl acetate (200 mL). The organic layer was washed with water (3×100 mL), separated out, and dried over anhydrous sodium sulfate. The resultant solution was filtered the next day, and the filtrate was evaporated to remove the solvent and obtain the crude product, which was subjected to silica gel column chromatography (cyclohexane/ethyl acetate, 30:1), to provide 145 mg of intermediate b as colorless oil, with a yield of 60.4%. 145 mg of intermediate b was dissolved in 3 mL of ethyl acetate, to which was then purged excess HCl gas. Then, the reaction solution was stirred for 30 min at room temperature. The solvent was evaporated to dry under reduced pressure, and then 20 mL of cyclohexane was added to the residue. The solid was precipitated and collected by filtration, followed by rinsing with cyclohexane for 3 times and filtering. The filter cake was dried at 65° C., to obtain 110.2 mg of white solid, with a yield of 69.4%.

[0137] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.12 (s, 1H), 7.29-7.37 (3H, m), 5.30 (2H, s) 4.35 (2H, s), 3.81-3.91 (m, 4H), 3.15-3.19 (m, 1H), 2.56-2.59 (m, 1H), 1.55-1.71 (m, 6H), 1.34 (d, J=7.2 Hz, 3H), 1.26 (d, J=7.2 Hz, 6H), 1.01-1.07 (m, 1H), 0.40-0.52 (m, 2H), 0.18-0.25 (m, 2H).

Example 31

[0138] According to the method described in Examples 1-30, the general preparation method of the target compound of formula (I) according to the present invention was as follows: equimolar amounts of substituted phenol chloroacetate and N-BOC-protected amino acids (the amino of amino acids whose amino hydrogen had been completely substituted did not need to be protected) were mixed in DMF, and then the reaction solution was stirred and reacted for 4-12 h at the temperature of r.t. to 70° C. (equimolar NaI could be added to promote the reaction). Then, the reaction solution was cooled, to which was added water to dissolve the inorganic salt, and then the solution was diluted with DMF. The resultant solution was extracted with ethyl acetate, and the organic layer was washed three times with water. The organic layers were separated, and dried over anhydrous sodium sulfate. The solution was filtered the next day. The filtrate was evaporated to remove the solvent and obtain a crude product, which was subjected to silica gel column chromatography, to obtain the free base of the target compound represented by formula (I), with a yield of 15%-80%. The free base and a suitable organic or inorganic acid are allowed to react in ethyl acetate or ethanol, to provide the corresponding salt. After the solvent was removed, the water-soluble salt of compound of formula (I) was obtained, with a yield of 35%-85%. The salts of the target compound of formula (I) that could be prepared by the above method (together with the main starting materials and the molecular ion peaks of products) included, but were not limited to:

TABLE-US-00001 TABLE 1 Structures and MS data of some compounds. Com- pound No. Structure Main starting materials [M + H].sup.+ Com- pound 31 [00040] [00041] [00042] 350.4 Com- pound 32 [00043] [00044] [00045] 368.5 Com- pound 33 [00046] [00047] [00048] 384.4 Com- pound 34 [00049] [00050] [00051] 334.4 Com- pound 35 [00052] [00053] [00054] 324.2 Com- pound 36 [00055] [00056] [00057] 324.3 Com- pound 37 [00058] [00059] [00060] 334.4 Com- pound 38 [00061] [00062] [00063] 322.3 Com- pound 39 [00064] [00065] [00066] 322.3 Com- pound 40 [00067] [00068] [00069] 336.2 Com- pound 41 [00070] [00071] [00072] 336.2 Com- pound 42 [00073] [00074] [00075] 348.4 Com- pound 43 [00076] [00077] [00078] 338.3 Com- pound 44 [00079] [00080] [00081] 334.3 Com- pound 45 [00082] [00083] [00084] 354.3 Com- pound 46 [00085] [00086] [00087] 366.2 Com- pound 47 [00088] [00089] [00090] 382.2 Com- pound 48 [00091] [00092] [00093] 350.3 Com- pound 49 [00094] [00095] [00096] 334.2 Com- pound 50 [00097] [00098] [00099] 350.2 Com- pound 51 [00100] [00101] [00102] 364.3 [00103] Com- pound 52 [00104] [00105] [00106] 390.2 [00107] Com- pound 53 [00108] [00109] [00110] 388.2 Com- pound 54 [00111] [00112] [00113] 374.2 Com- pound 55 [00114] [00115] [00116] 374.2 Com- pound 56 [00117] [00118] [00119] 320.4 Com- pound 57 [00120] [00121] [00122] 334.2 Com- pound 58 [00123] [00124] [00125] 348.3 Com- pound 59 [00126] [00127] [00128] 334.2 Com- pound 60 [00129] [00130] [00131] 334.2 Com- pound 61 [00132] [00133] [00134] 388.3 Com- pound 62 [00135] [00136] [00137] 320.4 Com- pound 63 [00138] [00139] [00140] 334.2

Example 32

[0139] The prodrug to be tested was prepared into a saline solution of 10 mg/mL. 10 μL of drug-containing solution was added to 990 μL of mouse plasma, vortexed for 30 s, and then incubated at 37° C. At 30 s, 1 min, 5 min, 10 min, 30 min, 60 min and 120 min, 50 μL of drug-containing plasma was collected, to which was immediately added 150 μL of acetonitrile to terminate the enzymatic reaction, and then centrifuged at 20000 rpm and 4° C. for 10 min. 50 μL of supernatant was taken out and injected into HPLC, to determine the concentration of propofol by internal standard method. The decomposition rate of the prodrug was calculated from the concentrations of propofol or other substituted phenols. Chromatographic conditions: Agilent Zorbax XdB C.sub.18 column (150 mm)×4.6 mm, 5 μm); column temperature 30° C.; the mobile phase, water:acetonitrile (40:60, v/v); fluorescence wavelength: excitation wavelength (Ex) at 276 nm, emission wavelength (EM) at 310 nm; flow rate: 1.2 mL/min; retention time: internal standard (thymol) 3.9 min, propofol 7.4 min. Linear range of propofol or other substituted phenols: 50-35000 ng/mL. Instruments: Waters 2695 high performance liquid chromatograph, Waters 2475 fluorescence detector. The experimental results for the breakdown of some prodrugs in plasma are shown in Table 2.

TABLE-US-00002 TABLE 2 The decomposition rates of prodrug molecules in plasma. Decomposition rates of prodrugs Drugs 30 s 1 min 5 min 10 min 30 min 60 min 120 min fospropofol — — — —   3%  16%  38% Compound 1 97% 100% 100% 100% 100% 100% 100% Compound 2 87%  98% 100% 100% 100% 100% 100% Compound 3 51%  67% 80%  90%  97% 100% 100% Compound 4 94% 100% 100% 100% 100% 100% 100% Compound 7 91% 100% 100% 100% 100% 100% 100% Compound 17 55%  63%  78%  85% 100% 100% 100% Compound 22 58%  66%  80%  89% 100% 100% 100% Compound 23 89% 100% 100% 100% 100% 100% 100% Compound 27 60%  65%  79%  86% 100% 100% 100% Compound 29 88% 100% 100% 100% 100% 100% 100% Compound 37 75 92 100% 100% 100% 100% 100% Compound 41 89 100% 100% 100% 100% 100% 100% Compound 42 91 100% 100% 100% 100% 100% 100% Compound 48 92 100% 100% 100% 100% 100% 100%

[0140] The in vitro decomposition experiment in plasma showed that the prodrug molecules of the present invention had a very fast decomposition rate in mouse plasma. After co-culturing with plasma for 30 s, 51%-98% of these prodrug molecules were decomposed in average, while the marketed drug fopropofol was still not decomposed significantly after co-culturing with plasma for 10 min, and only 38% was decomposed after co-culturing for 2 h, indicating that the decomposition rate of fospropofol in plasma was slow. The prodrug molecules prepared in the present invention could be rapidly decomposed in plasma to obtain propofol or other substituted phenols.

Example 33

[0141] For each drug, 10 male Kunming mice weighing 20-35 g were included, and the dose of each drug was 2×ED.sub.50 in mice. After the compound of the present invention and fospropofol were respectively dissolved in saline, the resultant solutions were injected via the mouse tail vein. For propofol, a glucose dilution (5 mg/mL) of a commercially available emulsion of diprivan was selected and injected via the mouse tail vein; while, for another substituted phenol molecule (CAS:1637741-58-2), its 30% fat emulsion was prepared as a medicated emulsion. The concentration of the injectable solution of the compound according to the present invention was 10-15 mg/mL, and the concentration of the injectable solution of fospropofol was 55 mg/mL, while the concentration of the injectable solution of another substituted phenol molecule (CAS:1637741-58-2) was 1 mg/mL. After injection of tested drug, the occurrence time T1 of righting reflex after its disappearance, the duration T2 for the disappearance of righting reflex (i.e. anesthesia time) and the time T3 required for the animal to recover completely after waking up were recorded. Complete recovery refers to the recovery of autonomous activities of animals to the level before administration. In the experiment, animals were not given respiratory support such as oxygen inhalation or intubation.

TABLE-US-00003 TABLE 3 Anesthetic experiment of drugs. Propofol Dose intake T1 T2 T3 Drugs mg/kg mg/kg min min min Propofol 25 25 Immediate   5-11.5 1-2 Fospropofol 168 90 1.5-2 28-45  5-8 Compound 1 50 27 Immediate 6-12 1-2 Compound 2 54 28 Immediate 7-15 1-2 Compound 3 49 24.4 Immediate 5-10 1-2 Compound 4 48 25 Immediate 5-13 1-2 Compound 7 65.9 28.4 Immediate 6-13 1-2 Compound 22 58 26 Immediate 4.5-10.5 1-2 Compound 23 63.3 27.3 Immediate 5-13 1-2 Compound 27 66 24.6 Immediate 4-12 1-2 Compound 29 58.6 26.2 Immediate 5-14 1-2 Compound 37 49.3 23.7 Immediate 4-10 1-2 Compound 41 50.8 24.3 Immediate 5-13 1-2 Compound 42 53.5 24.8 Immediate 6-12 1-2 Compound 48 59.4 27.4 Immediate 6-14 1-2 T1: the onset time after injection; T2: the duration of disappearance of righting reflex; T3: the time required for righting reflex to recover to autonomous activity.

TABLE-US-00004 TABLE 4 Anesthetic experiment of other substituted phenols and their prodrug molecules. Intake of (R)-2-cyclo- propylethyl- Dose 6-isopropyl- T1 T2 T3 Drugs mg/kg phenol mg/kg min min min (R)-2-cyclo- 3.2 3.2 Immediate 5-8   1-2 propylethyl- 6-isopropyl- phenol Compound 17 6.7 3.2 Immediate 5.5-8   1-2 Compound 19 7.9 3.3 Immediate 5.5-9    1-2 Compound 53 7.1 3.4 Immediate 5-8.5 1-2 Compound 55 7.0 3.5 Immediate 5-9   1-2 T1: the onset time after injection; T2: the duration of disappearance of righting reflex; T3: the time required for righting reflex to recover to autonomous activity.

[0142] The experimental results showed that the prodrug of the present invention had a very fast decomposition rate in plasma, and thus its onset time was equivalent to that of propofol. After injection, the animals can be anesthetized immediately. At the equivalent dose of the compound according to the present invention, the amount of propofol intaken by animals was equivalent to that intaken by animals anesthetized with propofol directly, while the amount of propofol carried by fospropofol was much higher than that intaken by animals anesthetized with propofol directly. Since the prodrugs according to the present invention carried significantly less propofol at effective doses than fospropofol, the duration of anesthesia for animals was significantly shorter than that of the marketed drug fospropofol; the time from awakening to complete recovery was also significantly shorter in the group of prodrugs according to the present invention than in fospropofol group. Similarly, the prodrug molecules of other substituted phenols according the present invention also retained the characteristics of rapid onset and recovery of the prototype drug compared with the substituted phenol molecules carried by them.

[0143] In summary, the water-soluble prodrug molecules of the present invention had maintained the advantages of the substituted phenol anesthetic drugs including propofol, which had a fast onset of action and a fast recovery after withdrawal.

Example 34

[0144] Determination of therapeutic index (TI) of prodrug molecules: by referring the method in literature (Dixon, W. Staircase bioassay: the up-and-down method. Neurosci. Biobehav. Rev. 1991, 15, 47-50), the half-effective dose (ED.sub.50) and half-lethal dose (LD.sub.50) of the molecule to be tested were determined in Kunming mice (weighing 25-30 g, half male and half female). The therapeutic index for each molecule was calculated according to the equation: TI=LD.sub.50/ED.sub.50. Results are shown in Table 5.

TABLE-US-00005 TABLE 5 Therapeutic indexes of compounds. Compound No. TI Propofol 4.4 Fospropofol 2.9 Compound 7 3.9 Compound 22 4.7 Compound 23 4.4 Compound 27 4.5 Compound 29 4.1 Compound 37 3.9 Compound 41 3.8 Compound 42 3.7 Compound 48 4.1

[0145] The therapeutic index reflects the distance between the effective dose and the lethal dose of drugs, and was one of the most basic safety indicators of drug molecules. The experimental results showed that the therapeutic index of the compound according to the present invention was similar to that of propofol, and its safety was equivalent to that of propofol, which was significantly better than the marketed drug fospropofol. Because the therapeutic index of general anesthesia drugs was generally low (3-5), and for propofol, whose therapeutic window is not wide, its water-soluble prodrug can maintain a similar therapeutic index, indicating the high safety of these molecules.