Y-type discrete polyethylene glycol derivative and preparation method thereof
10858479 ยท 2020-12-08
Assignee
Inventors
Cpc classification
A61K47/10
HUMAN NECESSITIES
C08G65/48
CHEMISTRY; METALLURGY
C08G2650/50
CHEMISTRY; METALLURGY
International classification
C08G65/48
CHEMISTRY; METALLURGY
C08G65/332
CHEMISTRY; METALLURGY
A61K47/10
HUMAN NECESSITIES
Abstract
The present invention relates to a Y-type discrete polyethylene glycol derivative as shown by Formula (I). The Y-type discrete polyethylene glycol derivative has the advantages of a determined molecular weight and number of segments in the chain, and can avoid the defects where the polyethylene glycol derivative itself is a mixture and the molecular weight is not homogeneous. The Y-type polyethylene glycol of the present invention can solve the problem of insufficient water solubility caused by an increase in the loading capacity when the discrete polyethylene glycol modifies an insoluble drug while increasing the drug loading capacity. ##STR00001##
Claims
1. A Y-type discrete polyethylene glycol derivative having the structure of formula (IV), (V), (VI), (VII), (IX): ##STR00030## wherein: E.sub.1 is a discrete polyethylene glycol group with a structure of (CH.sub.2CH.sub.2O).sub.j, j is an integer from 1 to 20; E.sub.2 is a discrete polyethylene glycol group with a structure of (CH.sub.2CH.sub.2O).sub.k, k is an integer from 1 to 20; E.sub.3 is a discrete polyethylene glycol group with a structure of (CH.sub.2CH.sub.2O).sub.l, l is an integer from 0 to 204-04; and r, s and t are 0.
2. The Y-type discrete polyethylene glycol derivative of claim 1, wherein j is an integer from 1 to 12; and/or, k is an integer from 1 to 12; and/or, l is an integer from 1 to 12.
3. The Y-type discrete polyethylene glycol derivative of claim 1, wherein j is 1, 2, 3, 4, 5, 6, 7 or 8; and/or, k is 1, 2, 3, 4, 5, 6, 7 or 8; and/or, l is 1, 2, 3, 4, 5, 6, 7 or 8.
4. A The Y-type discrete polyethylene glycol derivative is (N.sub.3-EG.sub.4).sub.2-OH with a structure of: ##STR00031## or, the Y-type discrete polyethylene glycol derivative is (tBuOOC-EG.sub.4).sub.2-NH-Boc with a structure of: ##STR00032##
5. A preparation method of the Y-type discrete polyethylene glycol derivative of claim 1, including: (1) halogenating or sulfonating one or more end-group-modified discrete polyethylene glycol derivatives; (2) reacting any of the products obtained in step (1) with at least one hydroxyl group of a core compound; and, (3) optionally, modifying the end group(s) of the product of step (2) to give a Y-type discrete polyethylene glycol derivative having the structure of formula (I), or, modifying the end group(s) of the product of step (2) into a hydroxyl group, then reacting with any of the products obtained in step (1), modifying the end group(s) of the obtained product to give a Y-type discrete polyethylene glycol derivative having the structure of formula (I); the end-group-modified discrete polyethylene glycol derivative in step (1) has a structure of ZX(CH.sub.2).sub.n-E-OH, wherein: X is a linking group selected from the group consisting of (CH.sub.2).sub.i, (CH.sub.2).sub.iNH, (CH.sub.2).sub.iOCOO, (CH.sub.2).sub.iOCONH, (CH.sub.2).sub.iNHCONH, OC(CH.sub.2).sub.iCOO, (CH.sub.2).sub.iCOO and (CH.sub.2).sub.iCONH, i is an integer from 0 to 10; Z is selected from the group consisting of the active end groups defined by Y in the structure of formula (I), or, Z is selected from the group consisting of methyl ester group, ethyl ester group, tert-butyl ester group, aldehyde acetal group, benzyloxy, tert-butoxy, imidogen, halogen and hydroxy; the Y is: hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, hydroxy, amino, aminomethyl, maleimido, carboxyl, sulfydryl, succinimide carbonate, succinimide acetate, succinimide propionate, succinimide succinate, succinimide, dithiopyridinyl, propionic acid group, aldehyde group, thioester group, acryloxy, azido, glutaric acid group, hydrazide, alkynyl, p-nitrophenyl carbonate, isocyanato, o-dithiopyridinyl, silane, carboxymethyl, vinyl sulfone group or vitamin H; E is a discrete polyethylene glycol group with a structure of (CH.sub.2CH.sub.2O).sub.a, a is an integer from 0 to 100; the core compound in step (2) has a structure of formula (X): ##STR00033## wherein: r, s, and t are independently selected from 0, 1, 2, 3; R.sub.1, R.sub.2 and R.sub.3 are selected from the group consisting of hydroxy, allyloxy, benzyloxy, tert-butoxy, azido, imino, ester, halogen, methoxy, ethoxy, amino, sulfydryl, carboxyl, aldehyde group, acryloxy, maleimide, vinyl sulfone group and vitamin H, and at least one of R.sub.1, R.sub.2 and R.sub.3 is hydroxy.
6. The preparation method of claim 5, wherein the Z is methyl ester group, ethyl ester group, tert-butyl ester group, azido, aldehyde acetal group or benzyloxy.
7. The preparation method of claim 5, wherein in the core compound (X), two of R.sub.1, R.sub.2 and R.sub.3 in the core compound are hydroxy.
8. The preparation method of claim 5, wherein the reaction for sulfonating the end-group-modified discrete polyethylene glycol derivative in the step (1) is as follows: ##STR00034## wherein, the G is methyl or p-tolyl.
9. The preparation method of claim 5, wherein the reaction in the step (2) of the preparation method is as follows: ##STR00035## wherein, W is OMs, OTs, Cl, Br, or I; Z.sub.1 and Z.sub.2 are independently selected from the group consisting of the reactive end groups defined by the Z; and E.sub.1 and E.sub.2 are independently selected from the group consisting of discrete polyethylene glycol groups defined by the E.
10. The preparation method of claim 5, wherein the step (1) is: adding methylene chloride in a volume ratio of 1 to 100 times and triethylamine in a molar ratio of 1 to 5 times to one end-group-modified discrete polyethylene glycol derivative, then dissolving methane chloride or p-toluenesulfonyl chloride in a molar ratio of 1-3 times in methylene chloride in a volume ratio of 1 to 30 times and adding dropwise into a reaction flask, reacting at room temperature for 1 to 48 hours, washing the reaction solution with water 1-3 times, drying the organic phase with anhydrous sodium sulfate, filtering to remove the sodium sulfate, evaporating the solvent to dryness and concentrating to give a product, i.e., the sulfonylated product of the end-group-modified discrete polyglycol derivative.
11. The preparation method of claim 5, wherein the step (2) is: adding toluene in a volume ratio of 1 to 50 times to the core compound, adding 60% sodium hydride with a mass-to-volume ratio of 0.5-1.0 g/mL under an ice-water bath, reacting for 1 to 3 hours at room temperature, adding dropwise the product of step (1) in a mass ratio of 5-10 times to sodium hydride, and toluene in a volume ratio of 1 to 50 times reacting at 60-70 C. for 1 to 48 hours, evaporating the toluene to dryness, adding dichloromethane and water, each washing once, evaporating the dichloromethane to dryness, and column-purifying with mobile phase being 1-3% methanol/dichloromethane to give a product.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF THE INVENTION
Example 1: Synthesis of (mEG.SUB.3.).SUB.2.-OH (1)
(8) The synthetic route is shown in
(9) 1. Synthesis of mEG.sub.3-OMs
(10) TEA (32 mL, 230 mmol) and DCM (150 mL) were added to mEG.sub.3-OH (32 mL, 200 mmol), the resulting mixture was placed in a reaction flask in an ice-water bath. MsCl (17.5 mL, 220 mmol) was dissolved with DCM (50 mL), and when dissolved completely, the resulting mixture was dropwise added into the reaction flask in ice-water bath. The reaction was performed at room temperature for 3 hours. The completeness of the reaction was checked by thin layer chromatography (TLC). The reaction mixture was washed three times with water (150 mL). The organic phase was dried over anhydrous sodium sulfate and then the sodium sulfate was removed by filtration. About 52 g product was obtained after concentration.
(11) 2. Synthesis of (mEG.sub.3).sub.2-O-Allyl
(12) Toluene (75 mL) was added to 3-allyloxy-1,2-propanediol (3.01 mL), NaH (60%, 2.05 g) was added under ice-water bath. The reaction was performed at room temperature for 2 hours. A solution of mEG.sub.3-OMs (13 g) in toluene (80 mL) was added dropwise and the reaction was continued overnight at 60 C. The reaction mixture was detected by HPLC, the toluene was evaporated to dryness, the resulting mixture was washed once each with DCM and water, the DCM was evaporated to dryness to give a crude product. The crude product was purified with a column (mobile phase: 1% MeOH/DCM) to give a product (8.8 g, yield: 85%).
(13) 3. Synthesis of YType Small Molecule 1
(14) Pd/C (0.8 g) and TsOH (1.6 g) were added to the product of the previous step (8 g), and methanol (80 mL)/water (16 mL) was added, the resulting mixture was refluxed for 24 hours. Upon completion of the reaction detected by HPLC, the reaction mixture was filtered to recover Pd/C and concentrated to give a crude product. The crude product was purified with a column (3% MeOH/DCM) to give a product (5.8 g, yield: 80.2%).
(15) NMR (CDCl.sub.3) : 3.89-3.50 (m, 29H), 3.38 (s, 6H); ESI-MS: 385.4 (M+H).sup.+, 407.2 (M+Na).sup.+.
Example 2: Synthesis of (mEG.SUB.5.).SUB.2.-OH (2)
(16) The synthetic route is shown in
(17) 1. Synthesis of mEG.sub.5-OMs
(18) TEA (6.86 mL) and DCM (60 mL) were added to mEG.sub.5-OH (10.08 g), the resulting mixture was placed in a reaction flask in an ice-water bath. MsCl (3.56 mL) was dissolved with DCM (50 mL), the resulting mixture was dropwise added into the reaction flask in ice-water bath. The reaction was performed at room temperature for 3 hours. The completeness of the reaction was checked by TLC. The reaction mixture was washed three times with water. The organic phase was dried over anhydrous sodium sulfate and then the sodium sulfate was removed by filtration. About 9.8 g product was obtained after concentration.
(19) 2. Synthesis of (mEG.sub.5).sub.2-O-Allyl
(20) Toluene (40 mL) was added to 3-allyloxy-1,2-propanediol (1.22 mL), NaH (60%, 0.79 g) was added under ice-water bath. The reaction was performed at room temperature for 2 hours. A solution of mEG.sub.5-OMs (6.9 g) in toluene (40 mL) was added dropwise and the reaction was continued overnight at 60 C. The reaction mixture was detected by HPLC, the toluene was evaporated to dryness, the resulting mixture was washed once each with DCM and water, the DCM was evaporated to dryness to give a crude product. The crude product was purified with a column (mobile phase: 1% MeOH/DCM) to give a product (4.7 g, yield: 83%).
(21) 3. Synthesis of Y-Type Small Molecule 2
(22) Pd/C (0.4 g) and TsOH (0.8 g) were added to the product of the previous step (4 g), and methanol (40 mL)/water (8 mL) was added, the resulting mixture was refluxed for 24 hours. Upon completion of the reaction detected by HPLC, the reaction mixture was filtered to recover Pd/C and concentrated to give a crude product. The crude product was purified with a column (3% MeOH/DCM) to give a product (3.0 g, yield: 82%).
(23) NMR (CDCl.sub.3) : 3.89-3.50 (m, 45H), 3.38 (s, 6H); ESI-MS: 561.4 (M+H).sup.+.
Example 3: Synthesis of (HO-EG.SUB.4.).SUB.2.-OH (3)
(24) The synthetic route is shown in
(25) 1. Synthesis of (HO-EG.sub.4).sub.2-O-Allyl
(26) Toluene (75 mL) was added to 3-allyloxy-1,2-propanediol (2.43 mL), NaH (60%, 1.57 g) was added under ice-water bath. The reaction was performed at room temperature for 2 hours. A solution of HO-EG.sub.4-Br (10.6 g) in toluene (80 mL) was added dropwise and the reaction was continued overnight at 70 C. The reaction mixture was detected by HPLC, the toluene was evaporated to dryness, the resulting mixture was washed once each with DCM and water, the DCM was evaporated to dryness to give a crude product. The crude product was purified with a column (mobile phase: 1% MeOH/DCM) to give a product (7.3 g, yield: 80%).
(27) 2. Synthesis of Y-Type Small Molecule 3
(28) Pd/C (0.6 g) and TsOH (1.2 g) were added to the product of the previous step (6 g), methanol (60 mL)/water (12 mL) was added, the resulting mixture was refluxed for 24 hours. Upon completion of the reaction detected by HPLC, the reaction mixture was filtered to recover Pd/C and concentrated to give a crude product. The crude product was purified with a column (3-4% MeOH/DCM) to give a product (4.3 g, yield: 78%).
(29) NMR (CDC.sub.3) : 3.89-3.50 (m, 36H), 3.25 (m, 1H); ESI-MS: 445.4 (M+H).sup.+, 467.4 (M+Na).sup.+.
Example 4: Synthesis of (NHrEG.SUB.4.).SUB.2.-OH (4)
(30) The synthetic route is shown in
(31) 1. Synthesis of N.sub.3-EG.sub.4-OH
(32) EG.sub.4 (36 mL, 210 mmol), DCM (100 mL) and TEA (25 mL) were added to a reaction flask which was placed in an ice-water bath. A solution of MsCl (5.81 mL, 75 mmol) in DCM (100 mL) was added dropwise. The reaction was performed at room temperature for 4 hours. The reaction mixture was washed once with water (100 mL) and evaporated to dryness to give a crude product.
(33) To the crude product of the previous step, 95% ethanol (150 mL) and sodium azide (6.5 g, 100 mmol) were added, and the resulting mixture was refluxed at room temperature for 16 hours. The reaction mixture was filtered to remove solids and the resulting solution was evaporated to dryness. The resulting solid was added with DCM (150 mL) and washed three times with water (100 mL). The DCM phase was evaporated to dryness to give a crude product. The crude product was purified with a column (mobile phase: PE/EA=50-0%) to give a product (13.1 g, yield: 28.4%).
(34) 2. Synthesis of N.sub.3-EG.sub.4-OMs
(35) To the N.sub.3-EG.sub.4-OH prepared in above Step 1 (11 g, 50.2 mmol), TEA (8.6 mL, 60.3 mmol) and DCM (150 mL) were added and placed in an ice-water bath. MsCl (4.5 mL, 57.8 mmol) was dissolved in DCM (50 mL) and added dropwise to the reaction flask in ice-water bath. The reaction was performed at room temperature overnight. The completeness of the reaction was checked by TLC. The reaction mixture was washed three times with water (100 mL). The organic phase was dried over anhydrous sodium sulfate and then the sodium sulfate was removed by filtration. About 14.2 g product (yield: 95%) was obtained after concentration.
(36) 3. Synthesis of (N.sub.3-EG.sub.4).sub.2-O-Allyl
(37) Toluene (40 mL) was added to 3-allyloxy-1,2-propanediol (1.22 mL), NaH (60%, 0.79 g) was added under an ice-water bath. The reaction was performed at room temperature for 2 hours. A solution of N.sub.3-EG.sub.4-OMs (6.1 g) in toluene (80 mL) was added dropwise and the reaction was continued overnight at 60 C. The reaction mixture was detected by HPLC, the toluene was evaporated to dryness, the resulting mixture was washed once each with DCM and water, the DCM was evaporated to dryness to give a crude product. The crude product was purified with a column (mobile phase: 1% MeOH/DCM) to give a product (4.3 g, yield: 85%).
(38) 4. Synthesis of (N.sub.3-EG.sub.4).sub.2-OH
(39) To the product (4 g) of the previous step, Pd/C (0.4 g), TsOH (0.8 g) were added, methanol (40 mL)/water (8 mL) was added, the resulting mixture was refluxed for 24 hours. Upon completion of the reaction detected by HPLC, the reaction mixture was filtered to recover Pd/C and concentrated to give a crude product. The crude product was purified with a column (mobile phase: 3% MeOH/DCM) to give a product (3.0 g, yield: 82%).
(40) 5. Synthesis of Y-Type Small Molecule 4
(41) THF (20 mL) and triphenylphosphine (1.5 g) were added to the reaction product of the previous step (2 g). After the mixture was reacted overnight at room temperature, water (0.1 mL) was added and the reaction was continued overnight. The THF was evaporated to dryness, water (50 mL) was added, the resulting mixture was washed twice with toluene (40 mL), then twice with DCM (30 mL), the water was evaporated to dryness to give a product (1.5 g, yield: 86%).
(42) NMR (D.sub.2O) : 3.5-3.8 (m, 33H), 2.8 (m, 4H); ESI-MS: 443.4 (M+H).
Example 5: Synthesis of (HOOC-EG.SUB.4.).SUB.2.-NH.SUB.2 .(5)
(43) The synthetic route is shown in
(44) 1. Synthesis of MsO-EG.sub.4-COOtBu
(45) DCM (350 mL) and TEA (22.7 mL) were added to HO-EG.sub.4-COOtBu (39.4 g). A solution of MsCl (11.4 mL) in DCM (150 mL) was added under ice-water bath. The reaction was performed overnight at room temperature. The reaction mixture was washed 3 times with water (200 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by evaporation to give a product (45.5 g, yield: 93%).
(46) 2. Synthesis of (tBuOOC-EG.sub.4).sub.2-NH-Boc
(47) Toluene (75 mL) was added to 3-Boc-NH1,2-propanediol (2 g), NaH (60%, 0.92 g) was added under an ice-water bath. The reaction was performed at room temperature for 2 hours. A toluene solution (80 mL) containing MsO-EG.sub.4-COOtBu (9.2 g) was added dropwise, and the reaction was continued overnight at 60 C. The reaction mixture was detected by HPLC, the toluene was evaporated to dryness, the resulting mixture was washed once each with DCM and water, the DCM was evaporated to dryness to give a crude product. The crude product was purified with a column (mobile phase: 1-2% MeOH/DCM) to give a product (6.4 g, yield: 75%).
(48) 3. Synthesis of Y-Type Small Molecule 5
(49) To the (tBuO-EG.sub.4).sub.2-NH-Boc (2.3 g) prepared in Step 2 above, DCM (20 mL) and trifluoroacetic acid (TFA) (8 mL) were added, the reaction was performed overnight at room temperature. The solvent was evaporated to dryness, the resulting mixture was added with water, washed twice with EA, and the aqueous phase was evaporated to give a product (1.5 g, yield: 92.0%).
(50) NMR (CDC.sub.3) : 3.5-3.8 (m, 39H), 2.78 (n, 2H), 2.4 (t, 4H); ESI-MS: 588.4 (M+H).sup.+, 600.3 (M+Na).sup.+.
Example 6: Synthesis of (mEG.SUB.3.).SUB.2.-EG.SUB.4.-OH (6)
(51) The synthetic route is shown in
(52) Toluene (50 mL) was added to (mEG.sub.3).sub.2-OH (1) (2 g), the mixture was azeotroped to remove water. The toluene (about 20 mL) was distilled off. NaH (60%, 220 mg) was added under ice-water bath and stirred at room temperature for 2 hours. A solution of HO-EG.sub.4-Br (1.47 g) in toluene (10 mL) was added dropwise. After the addition was complete, the mixture was heated to 60 C. and reacted overnight. Toluene is evaporated to dryness to give a crude product. The crude product was purified with a column (4% MeOH/DCM) to give a product (2.1 g, yield: 72.0%).
(53) NMR (CDCl.sub.3) : 3.5-3.8 (m, 45H), 3.37 (s, 6H); ESI-MS: 561.4 (M+H).sup.+, 583.4 (M+Na).sup.+.
Example 7: Synthesis of Three Derivatives of (mEG.SUB.3.)-OH (1)
(54) THF (20 mL) and pyridine (1.26 mL) were added to (1) (2 g) prepared in Example 1, and then cholesteryl chloroformate (2.46 g) was dissolved in THF (30 mL) and added dropwise to the reaction flask. The mixture was stirred at room temperature overnight. The completeness of the reaction was checked by TLC. The reaction mixture was washed once with water, spin-dried to give a crude product, and purified by column (2% MeOH/DCM) to give a cholesterol derivative (2.8 g, yield: 67.4%).
(55) NMR (CDCl.sub.3) : 5.45-5.55 (m, 1H), 4.50-4.65 (m, 1H), 4.0-4.1 (m, 2H), 3.5-3.8 (m, 27H), 3.38 (s, 6H), 0.80-2.50 (m, 40H), 0.60-0.65 (m, 3H).
(56) DCM (20 mL) and pyridine (0.32 mL) were added to (1) (0.5 g) prepared in Example 1, and then hexadecyl chloroformate (0.86 mL) was dissolved in DCM (10 mL) and added dropwise to the reaction flask. The mixture was stirred at room temperature overnight. The completeness of the reaction was checked by TLC. The reaction mixture was washed with water, spin-dried to give crude product, and purified by column (2% MeOH/DCM) to give a hexadecanol derivative (0.65 g, yield: 76.6%).
(57) NMR (CDCl.sub.3) : 4.0-4.3 (m, 4H), 3.5-3.8 (m, 27H), 3.38 (s, 6H), 1.65 (m, 2H), 1.2-1.3 (m, 26H), 0.88 (t, 3H).
(58) DCM (20 mL) and pyridine (0.32 mL) were added to (1) (0.5 g) prepared in Example 1, and then menthol chloroformate (0.41 mL) was dissolved in DCM (10 mL) and added dropwise to the reaction flask. The mixture was stirred at room temperature overnight. The completeness of the reaction was checked by TLC. The reaction mixture was washed with water, spin-dried to give crude product, and purified by column (2% MeOH/DCM) to give a menthol derivative (0.58 g, yield: 78.6%).
(59) NMR (CDCl.sub.3) : 4.4-4.6 (m, 1H), 4.1-4.3 (m, 2H), 3.5-3.8 (m, 27H), 3.38 (s, 6H), 1.9-2.1 (m, 2H), 1.0-1.7 (m, 7H), 0.7-0.9 (m, 9H).
Example 8: Synthesis of Three Derivatives of mEG.SUB.7.-OH
(60) Commercially available mEG.sub.7-OH was used for preparation of three derivatives of mEG.sub.7-OH under the same conditions as in Example 7.
(61) Cholesterol derivative: NMR (CDCl.sub.3) : 5.45-5.55 (m, 1H), 4.50-4.65 (m, 1H), 4.0-4.1 (m, 2H), 3.5-3.8 (m, 26H), 3.37 (s, 3H), 0.80-2.50 (m, 40H), 0.60-0.65 (m, 3H).
(62) Hexadecanol derivative: NMR (CDCl.sub.3) : 4.27 (t, 2H), 4.12 (t, 2H), 3.5-3.8 (m, 26H), 3.38 (s, 3H), 1.65 (m, 2H), 1.25 (m, 26H), 0.88 (t, 3H).
(63) Menthol derivative: NMR (CDCl.sub.3) : 4.4-4.6 (m, 1H), 4.2-4.3 (m, 2H), 3.5-3.8 (m, 26H), 3.38 (s, 3H), 1.9-2.1 (m, 2H), 1.0-1.7 (m, 7H), 0.7-0.9 (m, 9H).
Example 9: Comparison Test of Dispersibility of Cholesterol and Cholesterol Derivatives in Water
(64) 20 mg the cholesterol derivative of (1) prepared in Example 7, 20 mg the cholesterol derivative of mEG.sub.7-OH prepared in Example 8 and 20 mg cholesterol were respectively placed in a 50 mL volumetric flask, which was then added with water to the scale, and placed in 20 C. water bath, shaken vigorously for 30 s every 5 min. The disperse state of the two cholesterol derivatives and cholesterol in water are shown in
Example 10: Comparison Test of Solubility of Cholesterol Derivatives in Water
(65) 20.0 mg cholesterol derivative of (l) prepared in Example 7 was dispersed in 50 mL water, 5 mL was taken out therefrom and added with 1.5 mL water, the resulting mixture was placed in a 20 C. water bath, and shaken vigorously for 30 s every 5 min. After 30 min, the solution was turbid; another 1.5 mL water was added, the resulting mixture was vigorously shaken for 30 s every 5 min until 14 mL water was added, and the solution became clear.
(66) 24.2 mg cholesterol derivative of mEG.sub.7-OH prepared in Example 8 was dispersed in 50 mL of water, 5 mL was taken out therefrom and added with 5 mL water, the resulting mixture was shaken vigorously for 30 s every 5 min. After 30 mmin, the solution was turbid; another 5 mL water was added, the resulting mixture was vigorously shaken for 30 s every 5 min until 25 mL water was added. 5 mL solution was taken from the dilute solution, the same procedure was carried out until 10 mL water was added, and the solution became clear.
(67) The results are shown in Table 1. From the analysis of the results, the cholesterol derivative of (1) has a solubility of 10.5 mg/100 g H.sub.2O, which is 3.90 times the solubility of the cholesterol derivative of mEG.sub.7-OH (2.69 mg/100 g H.sub.2O), and 52.5 times the solubility of cholesterol (<0.2 mg/100 g H.sub.2O).
Example 11: Comparison Test of Solubility of Hexadecanol Derivative in Water
(68) 111.0 mg the hexadecanol derivative of (1) prepared in Example 7 was dispersed in 25 L of water and shaken vigorously for 30 s every 5 min. After 30 min, the solution was clear; another 50 L water was added, the resulting mixture was vigorously shaken for 30 s every 5 min until 1.025 mL of water was added, and the solution remained clear.
(69) 112.9 mg the hexadecanol derivative of mEG.sub.7-OH prepared in Example 8 was dispersed in 50 L of water and shaken vigorously for 30 s every 5 min. After 30 min, the solution was turbid; another 50 L water was added, the resulting mixture was vigorously shaken for 30 s every 5 min until 250 L was added, and the solution became clear.
(70) The results are shown in Table 1. From the analysis of the results, the hexadecanol derivative of (1) can be miscible with water in any proportion at room temperature, while the hexadecanol derivative of mEG.sub.7-OH has a solubility of 45.2 g/100 g H.sub.2O and hexadecanol has a solubility of <1 mg/100 g H.sub.2O.
Example 12: Comparison Test of Solubility of Menthol Derivative in Water
(71) 106.7 mg the menthol derivative of (1) prepared in Example 7 was dispersed in 25 L of water and shaken vigorously for 30 s every 5 min. After 30 min, the solution was clear; another 50 L water was added, the resulting mixture was vigorously shaken for 30 s every 5 min until 1.025 mL water was added, and the solution remained clear.
(72) 101.3 mg the menthol derivative of mEG.sub.7-OH prepared in Example 8 was dispersed in 50 L of water and vigorously shaken for 30 s every 5 min. After 30 min, the solution was turbid; another 50 L of water was added, the resulting mixture was vigorously shaken for 30 s every 5 min. After 30 min, the solution became clear.
(73) The results are shown in Table 1. The menthol derivative of (1) can be miscible with water in any proportion at room temperature, while the menthol derivative of mEG.sub.7-OH has a solubility of 67.5 g/100 g of H.sub.2O and menthol has a solubility of <100 mg/100 g H.sub.2O.
(74) TABLE-US-00001 TABLE 1 The solubility of three derivatives Modifier Cholesterol Hexadecanol Menthol <0.2 mg/100 g H.sub.2O <1 mg/100 g H.sub.2O <100 mg/100 g H.sub.2O mEG.sub.7-OH 2.69 mg/100 g H.sub.2O 45.2 g/100 g H.sub.2O 67.5 g/100 g H.sub.2O Y-type 10.5 mg/100 g H.sub.2O miscible with miscible with small water in water in mole- any proportion any proportion cule 1
(75) According to the above experimental results, taking cholesterol, hexadecanol and menthol as poorly soluble drug models, the modification with the discrete polyethylene glycol can greatly increase their solubility in water, and under the same conditions, the modification with Y-type discrete polyethylene glycol gives a higher degree of water solubility improvement than the linear discrete polyethylene glycol.