CN113004180B - N-acetylcysteine derivative or pharmaceutically acceptable salt thereof, preparation method and application - Google Patents

N-acetylcysteine derivative or pharmaceutically acceptable salt thereof, preparation method and application Download PDF

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CN113004180B
CN113004180B CN202110258859.2A CN202110258859A CN113004180B CN 113004180 B CN113004180 B CN 113004180B CN 202110258859 A CN202110258859 A CN 202110258859A CN 113004180 B CN113004180 B CN 113004180B
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甄乐
王广基
许亚文
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China Pharmaceutical University
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Abstract

The invention discloses an N-acetylcysteine derivative with a structure shown as a formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and application. The derivatives have excellent in vitro stability, are remarkably superior to NAC, show ideal drug effect in an oxidative stress model and are superior to NAC.
Figure DDA0002966799280000011

Description

N-acetylcysteine derivative or pharmaceutically acceptable salt thereof, preparation method and application
Technical Field
The invention relates to the field of biomedicine, in particular to an N-acetylcysteine derivative or pharmaceutically acceptable salt thereof, a preparation method and application.
Background
N-acetylcysteine (NAC) has been shown to be a well-defined class of antioxidants and is widely used in the treatment of diseases such as respiratory, liver, thyroid, and even tumors. NAC deacetylates in the cell to Cys; the latter is a key raw material for synthesizing reduced Glutathione (GSH) in vivo, and the GSH is an important non-enzyme antioxidant in cells and is also a substrate of a plurality of antioxidant enzymes; NAC can also directly play an anti-oxidation role by utilizing free sulfydryl in the structure; in addition, NAC has been reported to be involved in S-oversulfurization of proteins in vivo, thereby regulating the fate and function of a portion of proteins and affecting oxidative stress signaling pathways. It is noteworthy, however, that free thiols are themselves poorly stable and prone to dimerization or oxidation, which affects the pharmacological effects of NAC administration. Therefore, a proper prodrug strategy can be selected to protect the sulfhydryl group first, so that the sulfhydryl group has ideal stability in vitro; and can release active sulfhydryl products in vivo.
Disclosure of Invention
The purpose of the invention is as follows: the object of the present invention is to provide an N-acetylcysteine derivative or a pharmaceutically acceptable salt thereof.
The invention also aims to provide a preparation method and medical application of the N-acetylcysteine derivative or the pharmaceutically acceptable salt thereof.
The technical scheme is as follows: the invention provides an N-acetylcysteine derivative with a structure shown as a formula (I) or a medicinal salt thereof,
Figure BDA0002966799260000011
R1selected from: h or C1-C8 alkyl;
R2selected from: h or methyl;
R3selected from: h or methyl;
R4selected from: h or C1-C4 alkyl;
ar is selected from: phenyl, X-substituted phenyl, 1-naphthyl or 2-naphthyl;
x is selected from: fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or methylsulfonyl.
Further, R1Selected from: H. methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl;
R2selected from: h or methyl;
R3selected from: h or methyl;
R4selected from: H. methyl or ethyl;
ar is selected from: phenyl or X-substituted phenyl;
x is selected from: fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or methylsulfonyl.
Further, the air conditioner is provided with a fan,
the N-acetylcysteine derivative with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof is any one of the following:
Figure BDA0002966799260000021
a pharmaceutical composition comprises a therapeutically effective amount of the N-acetylcysteine derivative with the structure shown in the formula (I) or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or auxiliary material.
The preparation method of the N-acetylcysteine derivative with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof has the following synthetic route:
Figure BDA0002966799260000031
wherein, R is1、R2、R3、R4Ar and X are defined as before; y is selected from: chlorine, bromine or iodine; g is selected from:
Figure BDA0002966799260000032
(1) performing halogenation reaction on the compound II to obtain a compound III;
(2) carrying out thiourea substitution reaction on the compound III to obtain a compound IV;
(3) carrying out deprotection reaction on the compound IV to obtain a compound V;
(4) and coupling the compound V with a compound VI to obtain a compound I.
Further, the preparation of the compound II in the step (1) can be referred to the prior documents CN 110305036; the solvent used was: n-hexane, cyclohexane, benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate or a mixed solvent optionally composed of these solvents; the adopted halogenated reagent is hydrogen chloride, thionyl chloride, phosphorus trichloride, hydrogen bromide, phosphorus tribromide or hydrogen iodide; the equivalent weight of the halogenating agent is 0.1 to 10 equivalents, preferably 1 to 3 equivalents; the reaction temperature is-20 ℃ to 60 ℃, preferably 0 ℃ to 40 ℃.
Further, the solvent used in the step (2): dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, 2-butanone, methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, water, or a mixed solvent optionally composed of these solvents; the reaction temperature is from-20 ℃ to 100 ℃, preferably from 0 ℃ to 50 ℃.
Further, the solvent used in the step (3): dichloromethane, ethyl acetate, chloroform, acetonitrile, tetrahydrofuran, acetone, 2-butanone, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, water, or a mixed solvent optionally composed of these solvents; the adopted deprotection reagent is ammonia water, ethanolamine, n-butylamine, n-hexylamine, triethylamine, diisopropylethylamine, sodium thiosulfate, sodium pyrosulfate, sodium sulfite, sodium bisulfite, sodium hydrosulfite or a mixed reagent optionally composed of the reagents; the reaction temperature is from-20 ℃ to 100 ℃, preferably from 20 ℃ to 80 ℃.
Further, the compound IV in the step (4) can be prepared by referring to the prior documents ACSMaco Lett.2020, 9, 606-; the solvent used was: dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, 2-butanone, methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, water, or a mixed solvent optionally composed of these solvents; the adopted additives are as follows: ammonia, ethanolamine, n-butylamine, n-hexylamine, triethylamine, diisopropylethylamine, acetic acid, propionic acid, butyric acid, or benzoic acid; additive equivalent weight is 0 to 10 equivalents, preferably 0 to 3 equivalents; the reaction temperature is from-20 ℃ to 100 ℃, preferably from 0 ℃ to 50 ℃.
The application of the N-acetylcysteine derivative with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof in the medicine for resisting oxidative stress.
Has the advantages that: the derivatives have excellent in vitro stability, are obviously superior to NAC, show ideal drug effect in an oxidative stress model and are superior to NAC; the invention also provides a preparation method of the derivative and an intermediate thereof, a pharmaceutical composition and medical application thereof.
Drawings
FIG. 1 is a 1H NMR spectrum of compound I-4;
FIG. 2 is a 1H NMR spectrum of Compound I-6.
Detailed Description
Example 1
Figure BDA0002966799260000041
Synthesis of Compound III-1: II-1(640mg, 2.51mmol) was placed in a dry round bottom flask (50mL), dichloromethane (15mL) was added and PBr was added dropwise under ice bath conditions3(339mg, 1.25 mmol). After the reaction of the starting materials was completed, saturated sodium bicarbonate solution (30mL) was added, and the mixture was extracted with DCM (3X 20mL), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Column chromatography (petroleum ether: ethyl acetate 2: 1) of the crude product afforded a pale yellow solid (702mg, 88% yield) which was used directly in the next reaction.
Synthesis of Compound V-1: compound III-1(636mg, 2mmol), thiourea (183mg, 2.4mmol) and THF (20mL) were placed in a dry round bottom flask (50mL) and stirred at room temperature for 5 h. The crude product IV-1 is obtained by suction filtration and is directly carried out in the next step without purification. Putting the IV-1 crude product into a sealed tube, and adding Na2S2O5(760mg, 4mmol), dichloromethane (15mL) and H2O (15 mL). The oil bath was heated to 50 ℃ to TLC to monitor the completion of the IV-1 reaction. Extract with DCM (3X 20mL), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Column chromatography of the crude product (petrol ether: ethyl acetate 2: 1) gave V-1 as a yellow solid (449mg, 89% yield).
Synthesis of Compound I-1: compound V-1(273mg, 1.06mmol) and compound VI-1(288mg, 1.06mmol) were placed in a two-necked flask, methanol (10mL) and triethylamine (10mg, 10%) were added, and the mixture was stirred at room temperature overnight; the solvent was directly distilled off under reduced pressure, and the crude product was subjected to column chromatography (dichloromethane: methanol 10: 1) to give compound I-1(292mg, yield 64%) as a pale yellow solid.1H NMR(300MHz，DMSO)δ12.88(s，1H)，10.95(s，1H)，8.26(d，J＝8.0Hz，1H)，8.12-7.99(m，2H)，7.90-7.52(m，5H)，7.35(d，J＝8.2Hz，2H)，4.48(t，J＝7.6Hz，1H)，3.97(s，2H)，3.03(dd，J＝13.6，4.6Hz，1H)，2.83(dd，J＝13.5，9.0Hz，1H)，1.87(s，3H).
Example 2
Figure BDA0002966799260000051
Compound I-2 was obtained by substituting the starting material II-1 in example 1 with II-2 in accordance with the procedure of example 1.1H NMR(300MHz，DMSO-d6)δ12.85(s，1H)，10.99(s，1H)，8.32(d，J＝8.1Hz，1H)，8.06-7.96(m，2H)，7.89-7.79(m，2H)，7.76-7.59(m，2H)，7.44-7.26(m，2H)，4.50(td，J＝8.6，4.5Hz，1H)，3.97(s，2H)，3.01(dd，J＝13.6，4.7Hz，1H)，2.82(dd，J＝13.6，9.1Hz，1H)，1.88(s，3H).
Example 3
Figure BDA0002966799260000052
Referring to the procedure of example 1, starting material II-1 in example 1 was replaced with II-3, triethylamine was replaced with acetic acid in step (4), and the solvent was replaced with a mixed solvent of methanol and tetrahydrofuran (1: 1v/v), to finally obtain compound I-3.1H NMR(300MHz，DMSO-d6)δ11.01(s，1H)，8.22(dd，J＝9.4，2.9Hz，3H)，8.06(d，J＝8.3Hz，2H)，7.73(d，J＝8.4Hz，2H)，7.35(d，J＝8.2Hz，2H)，4.46(td，J＝8.5，4.6Hz，1H)，3.97(s，2H)，3.03(dd，J＝13.5，4.7Hz，1H)，2.84(dd，J＝13.5，8.9Hz，1H)，1.87(s，3H).
Example 4
Figure BDA0002966799260000061
Compound IV-4 was prepared by substituting the starting material II-1 in example 1 with II-4 in accordance with the procedure of example 1.
Synthesis of Compound V-4: crude compound IV-4 (445mg, ca. 1mmol) was placed in a round bottom flask and n-butylamine (176mg, 2mmol) and dichloromethane (15mL) were added. Stir at room temperature until TLC monitors IV-4 reaction completion. Extract with DCM (3X 20mL), combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Column chromatography of the crude product (petrol ether: ethyl acetate 2: 1) gave V-4(228mg, 72% yield) as a yellow solid.
Synthesis of Compound I-1: compound V-4(220mg, 0.7mmol) and compound VI-1(190mg, 0.7mmol) were placed in a two-necked flask, ethanol (10mL) was added, and the mixture was stirred at room temperature overnight; the solvent was directly distilled off under reduced pressure, and the crude product was subjected to column chromatography (dichloromethane: methanol 10: 1) to give compound I-1(194mg, yield 58%) as a pale yellow solid.1H NMR(300MHz，DMSO-d6)δ12.89(s，1H)，11.03(s，1H)，8.45-8.24(m，5H)，7.79-7.71(m，2H)，7.42-7.31(m，2H)，4.51(t，J＝8.7，4.6Hz，1H)，3.99(s，2H)，3.03(dd，J＝13.5，4.7Hz，1H)，2.84(dd，J＝13.5，9.3Hz，1H)，1.88(s，3H).
Example 5
Figure BDA0002966799260000062
Referring to the procedure of example 4, compound 1-5 was prepared by substituting II-5 for the starting material II-4 in example 4.1H NMR(300MHz，Chloroform-d)δ8.31(d，J＝8.8Hz，2H)，8.06(d，J＝8.8Hz，2H)，7.30-7.20(m，2H)，7.16-7.03(m，2H)，6.51(d，J＝7.3Hz，1H)，4.74-4.65(m，1H)，3.81(s，2H)，3.51(s，3H)，2.76(dd，J＝14.1，5.0Hz，1H)，2.65(dd，J＝14.1，6.0Hz，1H)，2.06(s，3H).
Example 6
Figure BDA0002966799260000071
Synthesis of Compound I-6: compound V-4(220mg, 0.7mmol) and CompoundThe substance VI-2(388mg, 1.05mmol) was placed in a two-necked flask, diisopropylethylamine (13mg, 10%) and ethanol (10mL) were added, and the mixture was stirred at room temperature overnight; the solvent was directly distilled off under reduced pressure, and the crude product was subjected to column chromatography (dichloromethane: methanol 10: 1) to give compound I-6(181mg, yield 49%) as a pale yellow solid.1H NMR(300MHz，DMSO-d6)δ11.05(s，1H)，8.44-8.26(m，5H)，7.79-7.68(m，2H)，7.34(d，J＝8.1Hz，2H)，4.63(dd，J＝8.7，3.0Hz，1H)，3.96(s，2H)，3.65(s，3H)，1.92(s，3H)，1.35(s，3H)，1.33(s，3H).
The solvent, the reducing agent, the acylating agent, the alkylating agent, and the like in the above examples may be replaced as necessary.
Example 7
Determination of in vitro stability
The experimental method comprises the following steps:
10 μ L of compound stock solution (100mM) was added to each of the artificial gastric juice, intestinal juice, plasma, and PBS (980 μ L), and the blank control was PBS. After shaking and mixing, incubating at 37 ℃ (n-3). 100 mul samples were taken at different time points ( t 0, 5, 15, 30, 60min), 500 mul acetonitrile (containing 2ng/mL of warfarin as internal standard) was added, the mixture was shaken for 30s, centrifuged at 18000rpm x 10min at 4 ℃, 200 mul supernatant was taken, centrifuged twice (18000rpm x 10min), the precipitate was discarded, and 80 mul supernatant was sampled.
Chromatographic conditions are as follows:
a chromatographic column: agilent ZORBAX SB-C18column (5 μm, 4.6X 250 mm); column temperature: 40 ℃; aqueous phase (a): ultrapure water (0.1% formic acid), organic phase (B): methanol; flow rate: 0.8 mL/min;
gradient elution procedure is as follows:
Figure BDA0002966799260000072
mass spectrum conditions:
Figure BDA0002966799260000073
Figure BDA0002966799260000081
the experimental results are as follows:
Figure BDA0002966799260000082
the experimental results are as follows: compared with NAC, the derivatives disclosed by the invention have better in vitro stability.
Example 8
In vitro determination of antioxidant stress Activity
The experimental method comprises the following steps: HepG2 cells were grouped: blank control group, model group and administration group. The blank control group was cultured in normal cell culture medium, and the model group was cultured in 400. mu.M H2O2Culturing for 12H, adding compound to the administration group for pretreatment for 24H, and adding 400 μ M H2O2Culturing for 12 h.
Cell culture: HepG2 cells were harvested at 8X 10 in logarithmic growth phase4Perml was inoculated into 96-well plates at 100. mu.L per well. Adding 10 mu LCCK-8 stock solution into the culture medium, continuously incubating in an incubator, and measuring the optical density value at 450nm by using an enzyme-labeling instrument at the specified time; the cell viability was calculated.
The results of the experiment are as follows: (n is 6)
Figure BDA0002966799260000083
Figure BDA0002966799260000091
The experimental results are as follows: the compound shows antioxidant stress activity with different degrees, and the activity is superior to NAC; especially, the compounds I-4 and I-6 have very obvious antioxidant stress activity.

Claims (9)

1. An N-acetylcysteine derivative or its medicinal salt with the structure shown in formula (I),
Figure FDA0003610357920000011
R1selected from: h or C1-C8 alkyl;
R2selected from: h or methyl;
R3selected from: h or methyl;
R4selected from: h or C1-C4 alkyl;
ar is selected from: phenyl, X-substituted phenyl, 1-naphthyl or 2-naphthyl;
x is selected from: fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or methylsulfonyl.
2. The N-acetylcysteine derivative according to claim 1 having the structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein:
R1selected from the group consisting of: H. methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl;
R2selected from: h or methyl;
R3selected from the group consisting of: h or methyl;
R4selected from: H. methyl or ethyl;
ar is selected from: phenyl or X-substituted phenyl;
x is selected from: fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or methylsulfonyl.
3. The N-acetylcysteine derivative according to claim 1 having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, which is any one of the following:
Figure FDA0003610357920000012
Figure FDA0003610357920000021
4. a process for the preparation of an N-acetylcysteine derivative or a pharmaceutically acceptable salt thereof according to claim 1 having the structure of formula (I), wherein: the method comprises the following steps:
Figure FDA0003610357920000022
wherein, R is1、R2、R3、R4Ar and X are defined in accordance with claim 1;
y is selected from: chlorine, bromine or iodine; g is selected from:
Figure FDA0003610357920000023
(1) performing halogenation reaction on the compound II to obtain a compound III;
(2) carrying out thiourea substitution reaction on the compound III to obtain a compound IV;
(3) carrying out deprotection reaction on the compound IV to obtain a compound V;
(4) and coupling the compound V with a compound VI to obtain a compound I.
5. A process for the preparation of N-acetylcysteine derivatives or pharmaceutically acceptable salts thereof according to claim 4 having the structure of formula (I), wherein: the solvent adopted in the reaction of the step (1) is any one or a mixture of several of n-hexane, cyclohexane, benzene, toluene, dichloromethane, chloroform, tetrahydrofuran or ethyl acetate; the adopted halogenated reagent is hydrogen chloride, thionyl chloride, phosphorus trichloride, hydrogen bromide, phosphorus tribromide or hydrogen iodide; the equivalent weight of the halogenating agent is 0.1 to 10; the reaction temperature is-20 ℃ to 60 ℃.
6. A process for the preparation of N-acetylcysteine derivatives or pharmaceutically acceptable salts thereof according to claim 4 having the structure of formula (I), wherein: the solvent adopted in the reaction of the step (2) is any one or a mixture of more of dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, 2-butanone, methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or water; the reaction temperature is-20 ℃ to 100 ℃.
7. A process for the preparation of N-acetylcysteine derivatives or pharmaceutically acceptable salts thereof according to claim 4 having the structure of formula (I), wherein: the solvent adopted in the reaction of the step (3) is any one or a mixture of more of dichloromethane, ethyl acetate, chloroform, acetonitrile, tetrahydrofuran, acetone, 2-butanone, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or water; the adopted deprotection reagent is any one or a mixture of more of ammonia water, ethanolamine, n-butylamine, n-hexylamine, triethylamine, diisopropylethylamine, sodium thiosulfate, sodium pyrosulfate, sodium sulfite, sodium bisulfite or sodium hydrosulfite; the reaction temperature is-20 ℃ to 100 ℃.
8. A process for the preparation of N-acetylcysteine derivatives or pharmaceutically acceptable salts thereof according to claim 4 having the structure of formula (I), wherein: the solvent adopted in the reaction of the step (4): dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, 2-butanone, methanol, ethanol, isopropanol, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or a mixture of more of water; the adopted additives are ammonia water, ethanolamine, n-butylamine, n-hexylamine, triethylamine, diisopropylethylamine, acetic acid, propionic acid, butyric acid or benzoic acid; additive equivalent weight is 0 to 10 equivalent weight; the reaction temperature is-20 ℃ to 100 ℃.
9. Use of an N-acetylcysteine derivative as defined in claim 1 having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for resisting oxidative stress.
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