Phenyl containing compound, intermediate thereof, preparation method therefor and application thereof

Abstract

A phenyl-containing compound, an intermediate thereof, a preparation method therefor and an application thereof. Provided is a compound represented by formula I or a pharmaceutically acceptable salt thereof, where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or C(═O)OR.sup.8; where R.sup.8 is C.sub.1-C.sub.4 alkyl; R.sup.6 is (II), (III) or (IV); and R.sup.7 is —OH, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2 or C.sub.1-4 alkoxy. The compound has a low critical micelle concentration (CMC) and good dilution resistance and is capable of enclosing an insoluble drug to form a small-molecule micelle having a high drug loading capacity and good stability. ##STR00001##

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, ##STR00017## wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy or C(═O)OR.sup.8; wherein R.sup.8 is C.sub.1-C.sub.4 alkyl; R.sup.6 is ##STR00018## R.sup.7 is —OH, —NH.sub.2, —NHCH.sub.3, —N(CH.sub.3).sub.2 or C.sub.1-4 alkoxy.

2. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein, in the pharmaceutically acceptable salt of the compound of formula I, R.sup.6 of the compound of formula I forms ##STR00019##  with sodium ion; or, in the pharmaceutically acceptable salt of the compound of formula I, when R.sup.7 of the compound of formula I is —OH, it forms —O.sup.−Na.sup.+ with sodium ion; or, when the R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.6 alkyl, the C.sub.1-C.sub.6 alkyl is C.sub.1-C.sub.4 alkyl; or, when the R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently C.sub.1-C.sub.6 alkoxy, the C.sub.1-C.sub.6 alkoxy is C.sub.1-C.sub.4 alkoxy; or, the R.sup.8 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; or, when the R.sup.7 is independently C.sub.1-C.sub.4 alkoxy, the C.sub.1-C.sub.4 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, or, the R.sup.6 is ##STR00020## or, the R.sup.7 is C.sub.1-4 alkoxy.

3. The compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein, the compound formula I or the pharmaceutically acceptable salt thereof is ##STR00021##

4. A preparation method of the compound of formula I according to claim 1, wherein, the method comprises the following steps: in a polar aprotic solvent, in the presence of a base, a compound of formula III and a compound of formula II are subjected to the following amine transesterification reaction, ##STR00022##

5. The preparation method of the compound of formula I according to claim 4, wherein, the method further comprises the following steps: in a polar aprotic solvent, in the presence of a base, a compound of formula IV and a compound of formula V are subjected to the following condensation reaction, ##STR00023##

6. A compound of formula III, ##STR00024## wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined in claim 1.

7. The compound of formula III according to claim 6, wherein, the compound of formula III is ##STR00025##

8. A hydrophobic drug micelles, wherein, the hydrophobic drug micelle comprises a hydrophobic drug and a substance X; the substance X is the compound of formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein the hydrophobic drug is docetaxel, doxorubicin or paclitaxel.

9. The hydrophobic drug micelles according to claim 8, wherein, the mass ratio of the hydrophobic drug to the substance X is 1.25:1 to 3:1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the determination of CMC value of carrier by pyrene fluorescence probe method.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

(2) The following embodiments further illustrate the present disclosure, but the present disclosure is not limited thereto. The experimental methods not specified in the specific conditions in the following embodiments are selected according to the conventional methods and conditions, or according to the commodity instructions.

Embodiment 1

(3) ##STR00013##

(4) Preparation of acitretin butyric anhydride: In a 25 mL three-necked flask, acitretin (0.32 g, 1 mmol), 2 mL of tetrahydrofuran, 4 mL of acetonitrile, and 0.16 mL of triethylamine were added in sequence at room temperature. The flask was put into a low temperature cooling tank with mechanical stirring, when the reaction system was cooled to −20° C., butyl chloroformate (0.14 mL, 1.1 mmol) was slowly added, after the addition was completed, the reaction was continued for 30 min. A reaction solution of acitretin butyric anhydride was obtained.

(5) ##STR00014##

(6) Preparation of carrier: In a 25 mL four-necked flask, at room temperature, L-cysteic acid methyl ester (0.33 g, 1.5 mmol), 10 mL of N,N-dimethylformamide, 0.26 mL of triethylamine were added, the mixture was mechanically stirred at room temperature until the solid in the mixture was almost dissolved, and then the reaction solution of acitretin butyric anhydride was added dropwise. After the dropwise addition was completed, the reaction was continued for 4 hours. After the reaction was completed, part of the solvent was spun off, 20 mL of water was added, and the unreacted acitretin was extracted with methyl tert-butyl ether (20 mL×3), and the reaction product was extracted with ethyl acetate (20 mL×2). The ethyl acetate phase was washed with saturated sodium chloride, and the solid was precipitated for the second time. After filtration, the solid was placed in a 40° C. vacuum drying oven to obtain 410 mg of light yellow solid. The yield of the product was 84%, and the purity was 99.78%.

(7) Preparation of sodium salt carrier: In a 25 mL four-necked flask, at room temperature, L-cysteic acid methyl ester (0.33 g, 1.5 mmol), 10 mL of N,N-dimethylformamide, 0.26 mL of triethylamine were added, the mixture was mechanically stirred at room temperature until the solid in the mixture was almost dissolved, and then the reaction solution of acitretin butyric anhydride was added dropwise. After the dropwise addition was completed, the reaction was continued for 4 hours. After the reaction was completed, part of the solvent was spun off, 6 mL of saturated sodium bicarbonate was added, the mixture was continued to stir for 1 hour, 20 mL of water was added, the unreacted acitretin was extracted with methyl tert-butyl ether (20 mL×3), and the reaction product was extracted with ethyl acetate (20 mL×2). The ethyl acetate phase was washed with saturated sodium chloride, and the solid was precipitated for the second time. After filtration, the solid was placed in a 40° C. vacuum drying oven to obtain 410 mg of light yellow solid. The yield of the product was 82%, and the purity was 99.64%.

(8) Carrier: MS (ESI) m/z 490.29 (M-H.sup.+); .sup.1H NMR (400 MHz, MeOD) δ8.00 (s, 1H, NH), 7.06 (dd, J=14.9, 11.5 Hz, 1H, CH═CH—), 6.72 (d, J=16.3 Hz, 1H, —CH═CH—), 6.65 (s, 1H, Ph-H), 6.38 (d, J=15.0 Hz, 1H, —CH═CH—), 6.32-6.19 (m, 2H, —CH═CH—), 4.58 (s, 1H, CH), 3.77 (s, 3H, C—O—CH.sub.3), 3.02 (s, 1H, CH.sub.2), 2.88 (s, 1H, CH.sub.2), 2.33 (s, 3H, CH.sub.3), 2.29 (s, 3H, CH.sub.3), 2.23 (s, 3H, CH.sub.3), 2.12 (s, 6H, CH.sub.3).

(9) Carrier: HPLC detection conditions: chromatographic column: Inertsil ODS-SP (4.6×250 mm, 5 μm); mobile phase: acetonitrile: phosphate buffer salt (43:57); buffer: 20 mmol/L potassium dihydrogen phosphate and disodium hydrogen phosphate; flow rate: 1.0 mL/min; column temperature: 40° C.; detection wavelength: 355 nm; injection volume: 10 μL; retention time of product peak: 21.234 min. See Table 1 for details of HPLC detection results.

(10) TABLE-US-00001 TABLE 1 HPLC detection results of carriers Retention Peak width Peak Peak height Relative peak Peak time min (5%) min area mV area % 1 5.069 0.306 14786 1597 0.0635 2 6.201 0.418 8840 786 0.0380 3 7.060 0.000 2837 231 0.0122 4 19.058 0.000 5918 284 0.0254 5 19.436 0.000 13409 502 0.0576 6 21.234 1.162 23215820 642027 99.7804 7 26.923 0.000 5309 157 0.0228

Embodiment 2

(11) ##STR00015##

(12) Preparation of acitretin butyric anhydride: In a 50 mL three-necked flask, acitretin (0.98 g, 3 mmol), 6 mL of tetrahydrofuran, 12 mL of acetonitrile, and 0.48 mL of triethylamine were added in sequence at room temperature. The flask was put into a low temperature cooling tank with mechanical stirring; when the reaction system was cooled to −20° C., butyl chloroformate (0.42 mL, 3.3 mmol) was slowly added; after the addition was completed, the reaction was continued for 30 min. A reaction solution of acitretin butyric anhydride was obtained.

(13) ##STR00016##

(14) Preparation of carrier: In a 100 mL four-necked flask, at room temperature, L-cysteic acid methyl ester (0.99 g, 4.5 mmol), 30 mL of N,N-dimethylformamide, 0.78 of mL triethylamine were added, the mixture was mechanically stirred at room temperature until the solid in the mixture was almost dissolved, and then the reaction solution of acitretin butyric anhydride was added dropwise. After the dropwise addition was completed, the reaction was continued for 12 hours. After the reaction was completed, part of the solvent was spun off, 60 mL of water was added, the unreacted acitretin was extracted with methyl tert-butyl ether (60 mL×3), and the reaction product was extracted with ethyl acetate (60 mL×3). The ethyl acetate phase was washed with saturated sodium chloride, and the solid was precipitated for the second time. After filtration, the solid was placed in a 40° C. vacuum drying oven to obtain 1.21 g of light yellow solid. The yield of the product was 82% and the purity was 99.69%. The MS (ESI) and .sup.1H NMR data were the same as the carrier of embodiment 1.

Embodiment 3 Determination of Critical Micelle Concentration (CMC) by Pyrene Fluorescence Probe Method

(15) 1.0 mg/mL pyrene mother liquor was diluted 100 times to 0.01 mg/mL with acetone, then 10 μL of diluent was transferred into 1.5 mL EP tube, and the acetone was evaporated in a ventilated place at room temperature and away from light. 1 mL of carrier solution with different concentrations (the carrier of embodiment 1 was dissolved in pure water and configured to different concentrations) was added, and the mixture was shaken and equilibrated for 6 hours. The fluorescence intensity values at I1 (373 nm) and I3 (384 nm) were measured by fluorescence spectrophotometer, and the CMC was measured to be 6.5 μg/mL by plotting LogC with I1/I3.

Embodiment 4 Stability Testing of Carriers

(16) The carrier of embodiment 1 was placed in solid form under normal temperature and normal light, normal temperature and away from light, 4° C. away from light and −18° C. away from light, respectively, and the residual amount of the carrier was measured after being placed for 1d, 3d, 7d, 30d, 60d, 90d and 120d, respectively, and the residual amount was determined by HPLC. The test results are shown in Table 2.

(17) TABLE-US-00002 TABLE 2 Stability data of the carrier of Embodiment 1 Normal Normal temperature temperature and and away 4° C. −18° C. normal light from light Away from Away from (%) (%) light (%) light (%)  0 d 99.87 99.87 99.87 99.87  1 d 99.24 99.34 99.57 99.7   3 d 99.11 99.13 99.3  99.69  7 d 99.09 99.12 99.25 99.61  30 d 98.99 98.97 99.26 99.54  60 d 98.91 98.93 99.16 99.51  90 d 98.85 98.55 99.05 99.45 120 d 98.84 98.19 99.04 99.21

Embodiment 5 Preparation of Docetaxel Nano Micelles by Thin Film Hydration Method

(18) Docetaxel (DTX), the carrier of embodiment 1 were weighed, the mixture was sonicated with methanol until the solid was completely dissolved, placed in a vacuum drying oven at 40° C. for 5 min to remove the solvent methanol, and then the residue was placed in vacuum drying oven at 40° C. for 2 hours to remove the residual solvent, water for injection was added for hydration, wherein hydration speed was 100 r/min, hydration time was 10 min, the mixture was filtered with 0.22 μm microporous filter membrane (PES), and freeze-dried to obtain nano micelle freeze-dried preparation. The characterization data of the preparation are shown in Table 3.

(19) TABLE-US-00003 TABLE 3 Characterization data of formulations with different mass ratios of docetaxel and carrier Water for Polymer Drug DTX Carrier Methanol injection Particle dispersion Encapsulation loading Number (mg) (mg) (mL) (mL) size index rate (%) capacity 1 20 25 5 4 14.01 0.232 99.34 42.01 2 20 30 5 4 15.41 0.199 99.78 40.02 3 20 35 5 4 13.84 0.186 99.26 35.03 4 20 40 5 4 12.31 0.173 99.76 32.46 5 20 50 5 4 12.29 0.168 99.76 27.87 6 20 60 5 4 16.64 0.464 99.90 25.38

Embodiment 6 Preparation of Docetaxel Nano Micelles by Thin Film Hydration Method

(20) 20 mg of Docetaxel (DTX), 30 mg of the carrier of embodiment 1 were weighed, the mixture was sonicated with 5 mL of methanol until the solid was completely dissolved, placed in a vacuum drying oven at 40° C. for 5 min to remove the solvent methanol, and then the residue was placed in vacuum drying oven at 40° C. for 2 hours to remove the residual solvent, water for injection was added for hydration, wherein hydration speed was 100 r/min, hydration time was 10 min, the mixture was filtered with 0.22 μm microporous filter membrane (PES), and freeze-dried to obtain nano micelle freeze-dried preparation. The characterization data of the preparation are shown in Table 4.

(21) TABLE-US-00004 TABLE 4 Characterization data of preparation under different volumes of water for injection Water for Polymer Drug injection Particle dispersion Encapsulation loading Number (mL) size index rate (%) capacity 1 2 16.93 0.185 98.70 39.09 2 3 18.98 0.235 99.72 38.50 3 4 19.18 0.187 99.81 39.71 4 5 16.87 0.277 98.79 38.15 5 6 18.62 0.200 99.72 40.34

Comparative Embodiment 1

(22) The sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl ester was placed in solid form at normal temperature and normal light, at normal temperature and away from light, at 4° C. away from light and at −18° C. away from light respectively (other conditions are the same as those in embodiment 4), and the appearance and residual amount were tested after being placed for 1d, 3d, 7d and 30d, respectively, wherein the residual amount was determined by HPLC. The test results are shown in Table 5.

(23) TABLE-US-00005 TABLE 5 Stability data of sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl ester Normal Normal temperature temperature and and away 4° C. −18° C. normal light from light Away from Away from Appearance (%) (%) light (%) light (%)  0 d Yellow powder 99.54 99.54 99.54 99.54  3 d Orange 83.71 88.91 93.76 96.16  7 d Brown viscous 64.32 78.62 89.09 94.17 30 d Dark brown viscous — — 79.69 89.98

(24) Although the above describes specific embodiments of the present disclosure, it should be understood by those skilled in the art that these are merely illustrative examples and that a variety of changes or modifications to these embodiments can be made without departing from the principles and substance of the present disclosure. Therefore, the scope of protection of the present disclosure is limited by the appended claims.