CN112279778A - Substituted phenoxyamide derivative, application and medicine for treating Parkinson's disease - Google Patents

Substituted phenoxyamide derivative, application and medicine for treating Parkinson's disease Download PDF

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CN112279778A
CN112279778A CN202011340794.8A CN202011340794A CN112279778A CN 112279778 A CN112279778 A CN 112279778A CN 202011340794 A CN202011340794 A CN 202011340794A CN 112279778 A CN112279778 A CN 112279778A
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岳千奥
史宇悰
周琥
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Beijing Zhongyuan Hengkang Biotechnology Co.,Ltd.
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Abstract

The invention belongs to the field of biomedicine, and discloses a substituted phenoxyamide derivative, application and a medicament for treating Parkinson's disease. The substituted phenoxyamide derivative provided by the invention has excellent MAO-B (monoamine oxidase) -resisting activity.
Figure DDA0002798532100000011

Description

Substituted phenoxyamide derivative, application and medicine for treating Parkinson's disease
Technical Field
The invention relates to the field of biological medicines, and particularly relates to a substituted phenoxyamide derivative, application thereof and a medicament for treating Parkinson's disease.
Background
The description of the background of the invention pertaining to the related art to which this invention pertains is given for the purpose of illustration and understanding only of the summary of the invention and is not to be construed as an admission that the applicant is explicitly or implicitly admitted to be prior art to the date of filing this application as first filed with this invention.
Parkinson's Disease (PD) is a common chronic degenerative disease of the central nervous system of middle-aged and elderly people, has the incidence rate second to Alzheimer's disease, and is one of difficult diseases determined by the world health organization. Levodopa has been the most effective drug for the treatment of parkinson's disease for many years, and is taken by most parkinson patients. However, long-term use of levodopa runs the risk of potential impaired motor ability and motor fluctuations. This fluctuation occurs in two diametrically opposed phases, during the "on" phase, the patient's motor function is all normal; during the "off" period, the patient's motor capacity is significantly reduced, and even walking with difficulty.
At present, specific therapeutic drugs are lacking clinically, so that the search for new therapeutic drugs for parkinson's disease is urgent.
Disclosure of Invention
The embodiment of the invention aims to provide a substituted phenoxyamide derivative, application and a medicament for treating Parkinson's disease.
The purpose of the invention is realized by the following technical scheme:
the invention provides a substituted phenoxyamide derivative, which is a compound shown as a molecular formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002798532080000021
in structural formula I:
R1is hydrogen atom, electron withdrawing group or electron donating group; r2Is hydrogen atom, electron withdrawing group or electron donating group; r3Is hydrogen atom, electron withdrawing group or electron donating group; r4Is hydrogen atom, electron withdrawing group or electron donating group; r5Is hydrogen atom, electron withdrawing group or electron donating group; r is a hydrogen atom or C1-C5A linear or branched alkyl group of (a); the structure of the chiral carbon connected with R is R type or S type.
Optionally, R1、R2、R3、R4And R5At least one is selected from an electron withdrawing group or an electron donating group; preferably, R1、R2、R3、R4And R5One or two of which are selected from electron withdrawing groups or electron donating groups.
Optionally, the electron withdrawing group comprises: -NO2，-CN,-SO3H,-CF3，-CCl3Halogen, -CHO and-COOH; the halogen is preferably fluorine, chlorine or bromine;
the electron donating group comprises: -NH2，-OH，-OCH3，-OC2H5，-CH3and-C2H5。
Optionally, the electron-withdrawing group is selected from fluorine or chlorine, and the electron-donating group is selected from-OCH3；
Preferably, R is methyl.
Alternatively, the compound has the formula Ia:
Figure BDA0002798532080000022
optionally, the compound is selected from compounds represented by the following structural formula:
Figure BDA0002798532080000031
Figure BDA0002798532080000041
alternatively, the compound has the formula Ib:
Figure BDA0002798532080000042
optionally, the compound is selected from compounds represented by the following structural formula:
Figure BDA0002798532080000043
Figure BDA0002798532080000051
the invention also provides application of the substituted phenoxyamide derivative in preparing a medicament for treating Parkinson's disease.
The invention also provides a pharmaceutical composition for treating Parkinson's disease, which comprises the substituted phenoxyamide derivative; preferably, the pharmaceutical composition further comprises other active ingredients, and the other active ingredients are levodopa.
The embodiment of the invention has the following beneficial effects:
the substituted phenoxyamide derivative has excellent MAO-B resisting activity, has obvious cell proliferation promoting effect and has positive significance on the recovery of PD neuron cells.
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FIG. 1 shows the cell flow results of compound Ia-12 (200. mu.g/ml) on MPP + (0.1M) induced apoptosis of Pc12 cells;
FIG. 2 is a graph of a statistical analysis of the effect of Ia-12 (200. mu.g/ml) on MPP + (0.1M) induced apoptosis of PC12 cells (n-3,. beta.P < 0.001, vs. saline group,. beta.P < 0.01,. beta.P < 0.05 vs. MPP +);
FIG. 3 is a roadmap for spontaneous activity of compound Ia-12(20mg/kg) on an MPTP (30mg/kg) induced mouse model of Parkinson's disease;
FIG. 4 is a statistical analysis of the effect of compound Ia-12(20mg/kg) on the spontaneous activity of the MPTP (30mg/kg) induced mouse model of Parkinson's disease (n 8, P < 0.001, vs. saline group, & & P < 0.01, & P < 0.05 vs. MPTP group);
FIG. 5 is a statistical analysis of compound Ia-12(20mg/kg) versus the time to induce the mouse model of Parkinson's disease by MPTP (30mg/kg) (n 8, P < 0.001, compare saline group, & & P < 0.01, & P < 0.05 compare MPTP group);
FIG. 6 is a statistical analysis of compound Ia-12(20mg/kg) versus MPTP (30mg/kg) induced PD mouse striatum Tyrosinases (TH) (n 8, P < 0.001, vs. saline set, & & P < 0.01, & P < 0.05 vs. MPTP set);
FIG. 7 is a graph showing the results of compound Ia-12(20mg/kg) on MPTP (30mg/kg) induced Tyrosine Hydroxylase (TH) protein expression in striatum of PD mice;
FIG. 8 is a statistical analysis of the induction of intrastriatal Tyrosinhydroxylase (TH) by MPTP (30mg/kg) by compound Ia-12(20mg/kg), (n-8, P < 0.001, vs. saline group, & & P < 0.01, & P < 0.05 vs. MPTP group).
Detailed Description
The present application is further described below with reference to examples.
In the following description, different "one embodiment" or "an embodiment" may not necessarily refer to the same embodiment, in order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art. Various embodiments may be replaced or combined, and other embodiments may be obtained according to the embodiments without creative efforts for those skilled in the art.
The embodiment of the invention provides a substituted phenoxyamide derivative, a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002798532080000061
in formula I:
R1selected from hydrogen atoms, electron withdrawing groups or electron donating groups; r2Selected from hydrogen atoms, electron withdrawing groups or electron donating groups; r3Selected from hydrogen atoms, electron withdrawing groups or electron donating groups; r4Selected from hydrogen atoms, electron withdrawing groups or electron donating groups; r5Selected from hydrogen atoms, electron withdrawing groups or electron donating groups;
r is selected from hydrogen atom or C1-C5A linear or branched alkyl group of (a); the structure of the chiral carbon connected with R is R type or S type.
Optionally, R1、R2、R3、R4And R5At least one is selected from an electron withdrawing group or an electron donating group; preferably, R1、R2、R3、R4And R5One or two of which are selected from electron withdrawing groups or electron donating groups.
Optionally, the electron withdrawing group comprises: -NO2，-CN,-SO3H,-CF3，-CCl3Halogen, -CHO and-COOH; halogen is preferably fluorine, chlorine or bromine; electron donating groups include: -NH2，-OH，-OCH3，-OC2H5，-CH3and-C2H5。
Preferably, the electron-withdrawing group is selected from fluorine or chlorine, and the electron-donating group is selected from-OCH3；
Preferably, R is methyl.
In the embodiments of the present invention, the substituted position of the substituted phenoxyalkyl group and the middle benzene ring in the compound shown in formula i is para, and the structural formula thereof is shown in formula Ia:
Figure BDA0002798532080000071
in the embodiment of the invention, the substituted position of the substituted phenoxyalkyl and the middle benzene ring in the compound shown in the formula I is a meta position, and the structural formula is shown as Ib:
Figure BDA0002798532080000072
the compounds of the embodiments of the present invention may be compounds described by the following structural formula:
Figure BDA0002798532080000081
Figure BDA0002798532080000091
the embodiment of the invention also relates to application of the substituted phenoxyamide derivative in preparing a medicament for treating Parkinson's disease.
In some embodiments of the present invention, the substituted phenoxyamide derivatives of the embodiments of the present invention are used alone as active ingredients. In some embodiments of the invention, substituted phenoxyamide derivatives that are used in embodiments of the invention are used in combination with an active compound. In some embodiments of the invention, the active compound is levodopa.
The embodiment of the invention also relates to a medicament for treating the Parkinson disease, and the active component of the medicament comprises the substituted phenoxyamide derivative.
The following are detailed descriptions of the preparation methods of Ia and Ib in the above examples:
synthesizing target compound shown as formula Ia or Ib takes terephthalaldehyde (I-1) or isophthalaldehyde (I-2) as initial raw materials, and generates p-hydroxymethyl benzaldehyde (II-1) or isophthalaldehyde (II-2) through reduction reaction, wherein II-1 or II-2, N-bromosuccinimide (NBS) and triphenylphosphine (PPh)3) Reaction to generate p-bromomethylbenzaldehyde (III-1) or m-bromomethylbenzaldehydeThe aldehyde (III-2), III-1 or III-2 is further reacted with a substituted phenol, K2CO3Or Cs2CO3KI reaction to generate para-substituted ether intermediate (IV-1) or meta-substituted ether intermediate (IV-2), IV-1 or IV-2 and alpha-amino amide hydrochloride, sodium cyanoborohydride, triethylamine,
Figure BDA0002798532080000101
The type molecular sieve is subjected to a reductive amination reaction to obtain a target product Ia or Ib. The synthetic route is as follows:
Figure BDA0002798532080000102
Figure BDA0002798532080000111
in the above synthetic scheme, R1、R2、R3、R4、R5And R is as defined above.
In the present embodiments, "pharmaceutically acceptable salts" refer to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
The dosage and method of administration of the compounds of the embodiments of the present invention will depend upon a variety of factors including the age, weight, sex, physical condition, nutritional status, the activity intensity of the compound, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The preferred dosage is between 0.001-1000mg/kg body weight/day. The amount to be used is administered in a single dose per day or in several sub-doses per day, for example 2,3, 4, 5 or 6 doses per day. Alternatively, the administration may be intermittent, such as once every other day, once a week, or once a month. A therapeutically effective amount of a salt or solvate or the like may be determined as a ratio of therapeutically effective amounts of the compounds themselves.
In some embodiments, the pharmaceutical composition may optionally further comprise one or more additional pharmaceutically active compounds.
According to the invention, the pharmaceutical composition comprises a compound of the invention and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition can be administered, for example, orally or parenterally. The pharmaceutical composition of the present invention can be prepared into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections according to conventional methods in the art, and administered by routes such as oral or parenteral routes.
The pharmaceutical compositions of the present invention may be presented in unit dosage form containing a predetermined amount of active ingredient per unit dose. Such units may contain 0.001-1000mg, e.g., 0.05mg, 0.1mg, 0.5mg, 1mg, 10mg, 20mg, 50mg, 80mg, 100mg, 150mg, 200mg, 250mg, 300mg, 500mg, 750mg or 1g of a compound of the invention, depending on the disease to be treated, the route of administration and the age, weight and condition of the subject, or the pharmaceutical composition may be presented in unit dosage form containing a predetermined amount of the active ingredient per unit dose. In another embodiment, the unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of the active ingredient described herein. In addition, such pharmaceutical compositions may be prepared by any method known to those skilled in the art.
Example 1 Synthesis of (2S) -2- (4- (3, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ia-12)
Figure BDA0002798532080000121
Synthesis of 1.14-hydroxymethylbenzaldehyde (II-1)
A500 mL eggplant-shaped bottle was taken, 20g of terephthalaldehyde (0.15mol, 4.0equiv), 100mL of ethanol and 150mL of tetrahydrofuran were sequentially added to the bottle, and the mixture was stirred and dissolved uniformly. Then 1.7g sodium borohydride solid (9.3mmol, 1.0equiv) was slowly added to the flask in one portion under ice bath conditions and reacted for more than 6h, followed by thin layer TLC spot plate and uv analyzer (254nm) to monitor the progress of the reaction. And stopping the reaction after the point of the terephthalaldehyde raw material completely disappears, dropwise adding a 2mol/L hydrochloric acid solution prepared in advance for quenching, adjusting the pH value to 4-5, then carrying out rotary evaporation on the reaction liquid until the reaction liquid is dry, re-dissolving the obtained residue with water and ethyl acetate, and adding the re-dissolved residue into a separating funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 30g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate is 3:1, collecting the obtained monoaldehyde group reduction reaction product, and obtaining 17.6g of II-1 white solid, wherein the yield is as follows: 86.1 percent.
Synthesis of 1.24-bromomethylbenzaldehyde (III-1)
A500 mL eggplant-shaped bottle was peeled and 10.0g of intermediate II-1(0.073 mol; 1.0equiv) was weighed, dissolved in 150mL of methylene chloride, and then charged with 19.6g N-bromosuccinimide solid under stirring. Subsequently, triphenylphosphine solid was added to the eggplant-shaped bottle in four portions under ice-bath conditions, and a total amount of 38.5g (0.146 mol; 2.0equiv) was added, and at half an hour intervals for each portion, the ice-bath was removed after the addition of triphenylphosphine was completed, the reaction was continued at room temperature for more than 3 hours, and the progress of the reaction was monitored by a thin-layer TLC plate and an ultraviolet analyzer (254 nm). Stopping the reaction after the II-1 raw material point basically disappears, pouring the reaction solution into a beaker filled with 150ml of cold water, pouring the mixed solution of the organic phase and the aqueous phase into a separating funnel for extraction, extracting the aqueous phase with 150ml of dichloromethane, combining dichloromethane layers, and adding saturated sodium chloride aqueous solution for washing. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 15g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry prepared sand, and carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether: ethyl acetate 99:1, the resulting benzylic alcohol hydroxy bromination reaction product was collected to give III-1 as a white solid 8.5g, yield: 58.0 percent.
1.3 preparation of 34- (3, 4-Difluoroxyphenoxymethyl) -benzaldehyde (IV-3)
A250 mL eggplant-shaped bottle was taken, and 1.0g of intermediate III-1(5.0 mmol; 1.0equiv), 0.65g of 3, 4-difluorophenol (5.0 mmol; 1.0equiv), 2.1g of potassium carbonate (15.0 mmol; 3.0equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv) and 60mL of acetone were weighed into the bottle, stirred uniformly, followed by heating to 58 ℃ for reflux reaction for 24 hours, thin-layer TLC plates, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry prepared sand, and carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether: ethyl acetate 10:1, and the resulting ether-forming reaction product was collected to give 0.46g of IV-3 as a pale yellow solid in total, yield: 36.5 percent. Preparation of 4- (2S) -2- (4- (3, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ia-12)
A250 mL eggplant-shaped bottle was taken and 0.68g L-alaninamide hydrochloride (5.4 mmol; 1.0equiv), 0.26g sodium cyanoborohydride (4.3 mmol; 0.8equiv), 1g
Figure BDA0002798532080000142
Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.34g of intermediate IV-3(5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). After the reaction was completed, the solution was filtered, then the reaction solution was rotary evaporated to dryness, and the resulting residue was redissolved with water, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry prepared sand, and carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (by gradient elution, methanol)The volume ratio to dichloromethane was gradually increased from 0% to 5% over 50 min), and the final product Ia-12 was obtained as a white solid amounting to 0.49g with a yield of 36.5%. MS (ESI) M/z (M + H)+)320.1；1H-NMR(400MHz,DMSO-d6):9.14(s,2H),7.91(s,1H),6.80-7.63(m,7H),5.08(s,2H),4.02-4.11(m,2H),3.72-3.74(m,1H),1.39(d,3H,J＝6.7Hz).
Example 2 Synthesis of (2S) -2- (3- (3, 4-difluorophenoxymethyl) benzyl) amino-propionamide (Ib-6)
Figure BDA0002798532080000141
Preparation of 2.13-hydroxymethylbenzaldehyde (II-2)
A500 mL eggplant-shaped bottle was taken, 20g of isophthalaldehyde (0.15 mol; 4.0equiv), 100mL of ethanol and 150mL of tetrahydrofuran were sequentially added to the bottle, and the mixture was stirred and dissolved uniformly. Then 1.7g of sodium borohydride solid (9.3 mmol; 1.0equiv) was slowly added to the flask in one portion under ice bath conditions and reacted for more than 6h, followed by thin layer TLC spot plate and monitoring the progress of the reaction with UV analyzer (254 nm). And stopping the reaction after the point of the terephthalaldehyde raw material completely disappears, dropwise adding a 2mol/L hydrochloric acid solution prepared in advance for quenching, adjusting the pH value to 4-5, then carrying out rotary evaporation on the reaction liquid until the reaction liquid is dry, re-dissolving the obtained residue with water and ethyl acetate, and adding the re-dissolved residue into a separating funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined and washed with saturated aqueous sodium chloride solution. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 30g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry sand making, carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether and ethyl acetate is 3:1, collecting the obtained monoaldehyde group reduction reaction product, and obtaining 16.4g of II-2 white solid with yield: 80.2 percent.
Preparation of 4.23-bromomethylbenzaldehyde (III-2)
A500 mL eggplant-shaped bottle is taken, 10.0g of intermediate II-2(0.073 mol; 1.0equiv) is weighed out after peeling, 150mL of dichloromethane is added to dissolve 1b, and 19.6g N-bromosuccinimide solid is added under stirring. Subsequently, triphenylphosphine solid was added to the eggplant-shaped bottle in four portions under ice-bath conditions, and a total amount of 38.5g (0.146 mol; 2.0equiv) was added, and at half an hour intervals for each portion, the ice-bath was removed after the addition of triphenylphosphine was completed, the reaction was continued at room temperature for more than 3 hours, and the progress of the reaction was monitored by a thin-layer TLC plate and an ultraviolet analyzer (254 nm). Stopping the reaction after the II-2 raw material point basically disappears, pouring the reaction solution into a beaker filled with 150ml of cold water, pouring the mixed solution of the organic phase and the aqueous phase into a separating funnel for extraction, extracting the aqueous phase with 150ml of dichloromethane, combining dichloromethane layers, and adding saturated sodium chloride aqueous solution for washing. Subsequently, the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 15g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry prepared sand, and carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether: ethyl acetate 99:1, the resulting benzylic alcohol hydroxy bromination reaction product was collected to give III-2 as a white solid 6.8g, yield: 46.8 percent.
2.3 preparation of (3, 4-Difluoroxyphenoxymethyl) -benzaldehyde (IV-4)
A150 mL eggplant-shaped flask was taken, and 1.0g of intermediate III-2(5.0 mmol; 1.0equiv), 0.56g of 3, 4-difluorophenol (5.0 mmol; 1.0equiv), 2.5g of cesium carbonate (7.5 mmol; 1.5equiv), 0.6g of potassium iodide (3.0 mmol; 0.6equiv), and 40mL of N, N-dimethylformamide were weighed into the flask, stirred well, then heated to 40 ℃ for reaction overnight, thin layer TLC plates were spotted, and the progress of the reaction was monitored by an ultraviolet analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 5g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry prepared sand, and carrying out silica gel column chromatography separation, wherein the selected elution system is petroleum ether: ethyl acetate 10:1, and the resulting ether-forming reaction product was collected to give 0.37g of IV-4 as a pale yellow solid in total, yield: 30.0 percent.
2.2 preparation of (2S) -2- (3- (3, 4-Difluoroxyphenoxymethyl) benzyl) amino-propionamide (Ib-6)
Take one 250mL of eggplant-shaped bottle, 0.68g 0.68g L-alaninamide hydrochloride (5.4 mmol; 1.0equiv), 0.26g sodium cyanoborohydride (4.3 mmol; 0.8equiv), 1g
Figure BDA0002798532080000161
Type molecular sieve, 0.5ml triethylamine and 50ml methanol were added to a flask, stirred at room temperature for 20min, followed by the rapid addition of 1.24g of intermediate IV-4(5.4 mmol; 1.0equiv), heated to 40 deg.C and continued for 12h, thin layer TLC plates, and the progress of the reaction was monitored by UV analyzer (254 nm). The reaction was then filtered and evaporated to dryness and the resulting residue was redissolved with 2mol/L aqueous NaOH, ethyl acetate and added to a separatory funnel. The aqueous phase was extracted 2 to 3 times with an equal volume of ethyl acetate, the ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then the organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight. Filtering out the drying agent, weighing about 4g of silica gel powder with the specification of 60-100 meshes, adding the silica gel powder into the filtrate, carrying out rotary evaporation to dry prepared sand, and carrying out silica gel column chromatography separation, wherein the selected elution system is dichloromethane: methanol (methanol to dichloromethane volume ratio gradually increased from 0% to 5% in 50min by gradient elution) provided the final product Ib-6 as a white solid totaling 0.49g, yield 30.1%. MS (ESI) M/z (M + H)+)302.1；1H-NMR(400MHz,DMSO-d6):7.36-7.39(m,6H),7.12(s,2H),6.77-6.91(m,2H),5.09(s,2H),3.52-3.70(m,2H),2.99-3.01(m,1H),1.13(d,3H,J＝6.7Hz).
EXAMPLE 1 MAO inhibition and MAO-B selectivity study
Preparing rat liver monoamine oxidase (MAO), oxidizing monoamine substances under the action of the MAO, simultaneously generating a byproduct hydrogen peroxide, oxidizing 4-aminoantipyrine by the hydrogen peroxide in the presence of peroxidase, and reacting the generated oxidation product with vanillic acid to generate red dye with absorption at 490 nm. If the enzyme is inhibited, less red dye is produced and the absorbance value is small. The inhibitory activity of the test substance on the enzyme is determined by the change in the absorbance.
Study on inhibition effect of compounds shown as Ia and Ib on MAO activity
The research on the inhibition effect of the compound on the MAO activity discovers(10-5M) Ia and Ib show the effect of inhibiting MAO activity, and the activity of MAO can be reduced by about 45 +/-3.2 percent and 55 +/-6.7 percent respectively, and the difference is significant compared with that of an untreated group.
Study of the Selective Effect of MAO-A/MAO-B
When the activity of MAO-A and MAO-B is determined, 1: 100 um of A50 um solution of clorgoline (MAO-A inhibitor) and pargyline (MAO-B inhibitor) were reacted in A water bath at 37 ℃ for 30min to obtain MAO-B and MAO-A, and the activities of MAO-B and MAO-A were measured as described above. As shown in table 1:
TABLE 1 comparative study of the inhibition of MAO-B and MAO-B/MAO-A selectivity by IA and Ib series of compounds
Figure BDA0002798532080000171
As a result, the compounds Ia and Ib show relatively strong selectivity for MAO-B. 2.45 times and 2.46 times of the positive control drug Sal.
Example 2 MPTP cytotoxicity protection Studies
PC12 cells are rat adrenal pheochromocytoma cells that express tyrosine hydroxylase and synthesize dopamine and are therefore also referred to as dopaminergic cells. MPP + is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPP), a metabolite in vivo, expressed as MPP+The cell model established by acting on the PCI2 cell is well recognized by the academic circles at home and abroad and is widely used for the experimental research of the Parkinson's disease. Utilizing MPP+Inducing PC12 cell damage into PD cell model, observing compound Ia-12 to MPP+The intervention of (2) and the possibility of new use in the treatment of PD.
1. Using MPP+(100mM) PC12 apoptosis induction model, combined with the cell flow technology, the ZBH-LHT-series was observed to protect MPP + induced cell damage and apoptosis. The method comprises adding the drug Ia-12(200 μ g/ml) to be detected half an hour in advance, and adding MPP into PC12+Incubated for 24 hours, and assayed for apoptosis using Annexin V-FITC/PIThe kit (purchased from Roch company) detects the growth activity and apoptosis of cells by FACSCAlIur flow cytometer, and the CellQuest Pro acquires and analyzes the data. The results of the experiment are shown in FIGS. 1 and 2.
MPP+After the (0.1M) concentration is acted for 24h, as shown in the cell flow test of FIG. 1, the percentage of apoptotic cells in the normal saline parallel control group is 23.5 +/-2.75%, the drug Ia-12 to be tested (200 mu g/mL) is singly incubated with PC12 cells, the percentage of apoptotic cells is 28.47 +/-3.17%, and compared with the normal saline group, the difference is not significant, which indicates that Ia-12(200 mu g/mL) has no significant cytotoxic effect. And MPP+The percentage of apoptosis in the model group was 49.5 ± 10.12%, and the apoptotic cells in the model group were significantly increased (P < 0.001, n ═ 3). PC12 cells were incubated with Ia-12 (200. mu.g/ml) for half an hour before and then MPP+(0.1M) incubation for 24 hours, the percentage of apoptotic cells is reduced to 35.9 +/-2.19%, and MPP is added+Compared with the model group, the apoptosis is obviously reduced (P < 0.05, n is 3).
2. The MPTP dose is 30mg/kg, the continuous intraperitoneal injection is carried out for 7 days, a C57/BL mouse Parkinson disease model is established, and the experimental results are shown in figures 3 and 4.
As shown in the spontaneous activity results of fig. 3 and 4, the total movement distance of the normal saline parallel control mice was 31.4 ± 4.41 (m). The total movement distance of the mice in the MPTP group is 15.6 +/-1.66 (m), and compared with the normal saline group, the difference is significant (P is less than 0.001, and n is 8). The test drug Ia-12(20mg/kg) is given to the mice for 7 days by intraperitoneal continuous injection, the total movement distance of the mice is 28.8 +/-4.23 (m), and compared with a normal saline group, the difference is not significant, which indicates that Ia-12(20mg/kg) has no influence on the movement capacity of the mice. The test drug Ia-12(20mg/kg) was administered to an MPTP-induced mouse model of Parkinson's disease by intraperitoneal injection for 7 days. The total movement distance of the mouse is 23.9 +/-2.66 (m), and compared with an MPTP model group, the difference is significant (P is less than 0.01, n is 8),
3. the MPTP dose is 30mg/kg, and the injection is continuously carried out in the abdominal cavity for 7 days, so as to establish a C57/BL mouse Parkinson disease model. The results of the rotarod experiments are shown in FIG. 5.
As shown in the results of FIG. 5, the rod drop time of the normal saline level parallel control group mice was 15.3. + -. 2.11(min) in exercise. The rod drop time of the mice in the MPTP group is 3.5 +/-0.86 (min), and compared with the mice in the normal saline group, the difference is significant (P is less than 0.001, and n is 8). The test drug Ia-12(20mg/kg) is given to the mice for 7 days by intraperitoneal continuous injection, the rod dropping time of the mice is 13.8 +/-5.23 (m), and compared with the normal saline group, the difference is not significant, which indicates that Ia-12(20mg/kg) has no influence on the movement capacity of the mice. The test drug Ia-12(20mg/kg) was administered to an MPTP-induced mouse model of Parkinson's disease by intraperitoneal injection for 7 days. The rod drop time of the mice is 11.9 +/-2.12 (m), and compared with the MPTP model group, the difference is significant (P < 0.01, and n is 8).
4. The results of compound Ia-12(20mg/kg) on MPTP (30mg/kg) induced Tyrosine Hydroxylase (TH) protein expression in striatum of PD mice are shown in fig. 6 (immunohistochemical assay), the TH positive cells in the striatum of MPTP induced PD mice were significantly reduced, and the difference compared to the control group was statistically significant (P < 0.05, n ═ 3). When the test drug Ia-12(20mg/kg) is administered to an MPTP-induced PD mouse model and is injected into the abdominal cavity for 7 days continuously, TH positive cells in striatum of the mouse are increased remarkably, and compared with an MPTP group, the difference has statistical significance (P is less than 0.05, and n is 3).
5. Compound Ia-12(20mg/kg) induced Tyrosine Hydroxylase (TH) protein expression in the striatum of PD mice by MPTP (30mg/kg) as shown in fig. 7 and 8 (Western blot assay), with lower levels of TH expression in MPTP-induced striatum of PD mice, with statistical differences compared to the control group (P < 0.05, n ═ 3). When the drug Ia-12(20mg/kg) to be tested is administered to an MPTP-induced PD mouse model and is injected into the abdominal cavity for 7 days continuously, the TH expression in the striatum of the mouse is obviously increased, and compared with the MPTP group, the difference has statistical significance (P is less than 0.05, and n is 3).
Example 3 MPTP-induced C57/BL mouse Parkinson's disease model pharmacodynamic evaluation results
Injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into primates and some rodents causes degenerative changes in the nigrostriatal dopaminergic neurons to varying degrees and produces manifestations that mimic PD in biochemical, pathological and clinical features. The MPTP injury model is a commonly used animal model in PD research, and in rodents, particularly C57/BL mice are most sensitive to MPTP, and the MPTP model becomes an optimal tool for researching PD pathogenesis, neurobiochemistry, pathological anatomy, movement and mental disorder, drug action and the like.
Among various behavioral testing methods for this animal model, the spontaneous motility and rotarod method (rotarod) are two more commonly used testing methods. In the experiment, an MPTP dose is 30mg/kg, intraperitoneal injection is performed for 7 days, and a C57/BL mouse Parkinson disease model is established. The method comprises the following steps of finishing a behavioural experiment, killing the broken ends of experimental animals, carrying out immunohistochemistry and Westblot quantitative analysis on changes of striatal dopaminergic neurons so as to determine the action basis of Ia-12 on MPTP Parkinson disease animal pharmacodynamics. As shown in table 2:
TABLE 2
Figure BDA0002798532080000201
The compound has the MAO activity inhibiting effect of 10 concentration-5M, about 10% of the screened molecules were found to exhibit MAO activity inhibition, which decreased MAO activity by about 30%.
And candidate drug molecules with MAO-B selectivity comprise Ia-12, Ia-13 and Ia-15, which can obviously inhibit PC12 cell apoptosis induced by MPP +, immunohistochemistry and WB experimental results prove that Ia-12 can obviously inhibit MPTP-induced specific apoptosis of C57/BLc mouse substantia nigra and striatum dopaminergic neurons, which shows that Ia-12 has a protective effect on MPTP/MPP + neurotoxins, and behavioral research (spontaneous activity, swimming experiments and rolling axis experiments) results prove that Ia-12 can obviously improve and correct behavioral disorders of MPTP/C57/BLc Parkinson's disease models, and improve the movement promotion capability of sick mice. Suggesting that the compound has potential therapeutic effect on Parkinson's disease.
The result of the embodiment of the invention determines that the novel substituted phenoxyamide derivative Ia-12 has a protective effect on MPTP/MPP + neurotoxins from the cellular level, the in vitro level and the in vivo level, can obviously improve and correct the behavioral disturbance of an MPTP/C57/BLc Parkinson disease model, improves the motor lifting capacity of sick mice, and has a potential therapeutic effect on Parkinson disease.
It should be noted that the above embodiments can be freely combined as necessary. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A substituted phenoxyamide derivative is characterized in that the substituted phenoxyamide derivative is a compound shown as a molecular formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0002798532070000011
in structural formula I:
R1is hydrogen atom, electron withdrawing group or electron donating group;
R2is hydrogen atom, electron withdrawing group or electron donating group;
R3is hydrogen atom, electron withdrawing group or electron donating group;
R4is hydrogen atom, electron withdrawing group or electron donating group;
R5is hydrogen atom, electron withdrawing group or electron donating group;
r is a hydrogen atom or C1-C5A linear or branched alkyl group of (a); the structure of the chiral carbon connected with R is R type or S type.
2. The substituted phenoxyamide derivative according to claim 1, wherein R is1、R2、R3、R4And R5At least one of them being selected from electron withdrawing groups or electron donating groupsAn electron group;
preferably, R1、R2、R3、R4And R5One or two of which are selected from electron withdrawing groups or electron donating groups.
3. The substituted phenoxyamide derivative according to claim 1 or 2, wherein the electron-withdrawing group comprises: -NO2，-CN,-SO3H,-CF3，-CCl3Halogen, -CHO and-COOH; the halogen is preferably fluorine, chlorine or bromine;
the electron donating group comprises: -NH2，-OH，-OCH3，-OC2H5，-CH3and-C2H5。
4. The substituted phenoxyamide derivative according to claim 1 or 2, wherein the electron-withdrawing group is selected from fluorine or chlorine, and the electron-donating group is selected from-OCH3；
Preferably, R is methyl.
5. The substituted phenoxyamide derivative according to any one of claims 1 to 4, wherein the formula of the compound is shown as Ia:
Figure FDA0002798532070000021
6. the substituted phenoxyamide derivative according to claim 5, wherein the compound represented by Ia is selected from the compounds represented by the following structural formulae:
Figure FDA0002798532070000022
Figure FDA0002798532070000031
Figure FDA0002798532070000041
7. the substituted phenoxyamide derivative according to any one of claims 1 to 4, wherein the molecular formula of the compound is shown as Ib:
Figure FDA0002798532070000042
8. the substituted phenoxyamide derivative according to claim 7, wherein the compound represented by formula Ib is selected from the compounds represented by the following structural formulas:
Figure FDA0002798532070000043
Figure FDA0002798532070000051
9. use of a substituted phenoxyamide derivative according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of parkinson's disease.
10. A pharmaceutical composition for treating parkinson's disease, comprising the substituted phenoxyamide derivative of any one of claims 1 to 8;
preferably, the pharmaceutical composition further comprises other active ingredients, and the other active ingredients are levodopa.
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