CN110938014A - Substituted phenoxyamide derivative, application and medicine for treating Parkinson's disease - Google Patents
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Abstract
The invention belongs to the field of biomedicine, and discloses a substituted phenoxyamide derivative, application and a medicament for treating Parkinson's disease, wherein the substituted phenoxyamide derivative is a compound shown as a molecular formula I or a pharmaceutically acceptable salt thereof: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; 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. The substituted phenoxyamide derivative provided by the invention has excellent MAO-B (monoamine oxidase) -resisting activity.
Description
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 is difficult.
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:
embodiments of the first aspect of the present invention provide a substituted phenoxyamide derivative, which is a compound represented by formula I or a pharmaceutically acceptable salt thereof:
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.
Furthermore, the substituted position of the substituted phenoxyalkyl and the middle benzene ring in the compound is para; the compound has a formula shown as Ia:
furthermore, the substituted position of the substituted phenoxyalkyl and the middle benzene ring in the compound is a meta position; the molecular formula of the compound is shown as Ib:
further, the electron withdrawing group includes: -NO2,-CN,-SO3H,-CF3,-CCl3Halogen, -CHO and-COOH;
the electron donating group comprises: -NH2,-OH,OCH3,-OC2H5,-CH3and-C2H5。
The embodiment of the second aspect of the invention provides application of a substituted phenoxyamide derivative in preparing a medicament for treating Parkinson's disease, wherein the substituted phenoxyamide derivative is the substituted phenoxyamide derivative.
Furthermore, the substituted phenoxyamide derivative is independently used as an active ingredient.
Furthermore, the application is the combined application of the substituted phenoxyamide derivative and the active compound.
Further, the active compound is levodopa.
The embodiment of the third aspect of the invention provides a medicament for treating Parkinson's disease, wherein the active component of the medicament comprises a substituted phenoxyamide derivative, and the substituted phenoxyamide derivative is the substituted phenoxyamide derivative.
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.
Drawings
FIG. 1 shows substituted phenoxyamide derivatives Ia-12 (200. mu.g/ml) vs. MPP in examples of the present invention+(0.1M) effect of induction of Pc12 apoptosis;
FIG. 2 is a graph showing the effect of substituted phenoxyamide derivatives Ia-12(20mg/kg) on MPTP (30mg/kg) induced spontaneous activity in a mouse model of Parkinson's disease according to an embodiment of the present invention;
FIG. 3 is a graph showing the effect of substituted phenoxyamide derivatives Ia-12(20mg/kg) on MPTP (30mg/kg) induced rod drop time in a mouse model of Parkinson's disease according to an embodiment of the present invention;
FIG. 4 is a graph showing the effect of substituted phenoxyamide derivatives Ia-12(20mg/kg) on MPTP (30mg/kg) induced striatum Tyrosinases (TH) in PD mice according to an embodiment of the present invention;
FIG. 5 is a graph showing the effect of substituted phenoxyamide derivatives Ia-12(20mg/kg) on MPTP (30mg/kg) induced Tyrosine Hydroxylase (TH) in the striatum of PD mice according to an embodiment of the present invention.
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.
A substituted phenoxyamide derivative is a compound shown as a molecular formula I or a pharmaceutically acceptable salt thereof:
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.
In some embodiments of the invention, the substituted position of the substituted phenoxyalkyl group and the middle phenyl ring in the compound is para; the compound has a formula shown as Ia:
in some embodiments of the invention, the substituted position of the substituted phenoxyalkyl group and the intermediate phenyl ring in the compound is meta; the molecular formula of the compound is shown as Ib:
in some embodiments of the invention, the electron withdrawing group comprises: -NO2,-CN,-SO3H,-CF3,-CCl3Halogen (III)Elements, -CHO and-COOH. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine. In other embodiments, the halogen is bromine. The electron donating group comprises: -NH2,-OH,OCH3,-OC2H5,-CH3and-C2H5。
The application of the substituted phenoxyamide derivative in preparing the medicine for treating the Parkinson disease is disclosed.
In some embodiments of the invention, the substituted phenoxyamide derivative is used alone as an active ingredient. In some embodiments of the invention, the use is of a substituted phenoxyamide derivative in combination with an active compound. In some embodiments of the invention, the active compound is levodopa.
The active component of the medicine comprises a substituted phenoxyamide derivative, wherein the substituted phenoxyamide derivative is the substituted phenoxyamide derivative.
The compounds of the embodiments of the present invention may be compounds described by the following structural formula:
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 by using terephthalaldehyde (I-1) or isophthalaldehyde (I-2) as initial raw material and performing reduction reaction to generate p-hydroxymethyl benzaldehyde (II-1) or isophthalaldehyde (II-2), II-1 or II-2, N-bromosuccinimide (NBS) and triphenyl benzenePhosphine (PPh)3) Reaction to generate p-bromomethylbenzaldehyde (III-1) or m-bromomethylbenzaldehyde (III-2), III-1 or III-2, and further reacting with substituted phenol and K2CO3Or Cs2CO3KI reaction to generate para-substituted ether intermediate (IV-1) or meta-substituted ether intermediate (IV-2), reacting IV-1 or IV-2 with α -aminoamide hydrochloride, sodium cyanoborohydride, triethylamine,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:
synthetic route to Compounds Ia
Synthetic route to compound Ib
Structural formula Ia or Ib: r1、R2、R3、R4、R5Each independently a hydrogen atom, or an electron withdrawing group, including but not limited to-NO2,-CN,-SO3H,-CF3,-CCl3Halogen (F, Cl, Br), -CHO, -COOH, etc., or electron donating groups including but not limited to-NH2,-OH,OCH3,-OC2H5,-CH3,-C2H5Etc., R is a hydrogen atom or C1-C5Linear or branched alkyl groups of (a).
In certain embodiments, in structural formula I, the configuration of the chiral carbon to which R is attached is R-type or S-type.
As used herein, "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits 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 present invention will depend upon a variety of factors including the age, weight, sex, physical condition, nutritional status, the strength of the activity 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.
MAO inhibition and MAO-B selectivity studies
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 study on the inhibitory effect of the above compounds on MAO activity revealed that (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 determining the activity of MAO-A and MAO-B, 50um of chlorogeiline (MAO-A inhibitor) and pargyline (MAO-B inhibitor) solutions were added in A ratio of 1: 100, respectively, and reacted in A water bath at 37 ℃ for 30min to obtain MAO-B and MAO-A, and the activity of MAO-B and MAO-A was determined as described above. As a result, it was found that the compounds represented by Ia and Ib exhibited relatively strong selectivity for MAO-B. 2.45 times and 2.46 times of the positive control drug Sal. 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
Research on MPTP (Multi-Point transfer protocol) cytotoxicity protection effect
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, MPTP), a metabolite in vivo, 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. In this study, we utilized MPP+Inducing PC12 cell damage into PD cell model, observing Ia-12 to MPP+The intervention of (2) and the possibility of new use in the treatment of PD.
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+After 24 hours of incubation, the growth activity and apoptosis of the cells were detected by Annexin V-FITC/PI apoptosis detection kit (purchased from Roch) and FACSCaliur flow cytometer, and data were obtained and analyzed by CellQuest Pro.
Results
MPP+After the (0.1M) concentration is acted for 24 hours, the cell flow detection shows that the percentage of apoptotic cells of a 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, and the 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, apoptosis was significantly reduced (P < 0.05, n ═ 3) (see table 1.a and 1. B).
FIG. 1 shows the effect of substituted phenoxyamide derivatives Ia-12 (200. mu.g/M1) on MPP + (0.1M) induced Pc12 apoptosis in accordance with an embodiment of the present invention. A: (ii) a cell flow result; b: the effect of Ia-12 (200. mu.g/M1) on MPP + (0.1M) induction of PC12 apoptosis was quantified. (n ═ 3,. X.P < 0.001, compare with saline group, & P < 0.01, & P < 0.05 compare with MPP +)
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 spontaneous activity results showed that the total movement distance of 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 distance of movement of the mice was 23.9 ± 2.66(m), and the differences were significant compared to the MPTP model group (P < 0.01, n ═ 8) (see fig. 2.a and 2. B).
FIG. 2 is a graph showing the effect of the substituted phenoxyamide derivative Ia-12(20mg/kg) on MPTP (30mg/kg) induced spontaneous activity in a mouse model of Parkinson's disease in accordance with an embodiment of the present invention. A: an autonomous activity roadmap; b: the effect of Ia-12(20mg/kg) on MPTP (30mg/kg) induced spontaneous activity in a mouse model of Parkinson's disease was quantified. (n-8, P < 0.001, compared to saline group, & & P < 0.01, & P < 0.05 compared to MPTP group).
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 rod rotation show that the rod falling time of the normal saline level control group mouse is 15.3 +/-2.11 (min). 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 was 11.9 ± 2.12(m), and the difference was significant compared to the MPTP model group (P < 0.01, n ═ 8) (see fig. 3).
FIG. 3 shows the effect of substituted phenoxyamide derivatives Ia-12(20mg/kg) on MPTP (30mg/kg) induced rod drop time in a mouse model of Parkinson's disease. A: the effect of Ia-12(20mg/kg) on the stick-drop time of the MPTP (30mg/kg) induced mouse Parkinson's disease model was statistically analyzed. (n-8, P < 0.001, compared to saline group, & & P < 0.01, & P < 0.05 compared to MPTP group).
Ia-12(20mg/kg) induced Tyrosine Hydroxylase (TH) protein expression in striatum of PD mice induced by MPTP (30mg/kg) as shown in figure 3 (immunohistochemical detection), TH positive cells were significantly reduced in striatum of MPTP-induced PD mice, and the difference compared with a control group had statistical significance (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).
FIG. 4 shows the effect of substituted phenoxyamide derivatives Ia-12(20mg/kg) on MPTP (30mg/kg) induced striatal Tyrosine Hydroxylase (TH) in PD mice (immunohistochemical analysis) in accordance with an embodiment of the present invention. A: statistical analysis of the effect of Ia-12(20mg/kg) on MPTP (30mg/kg) induced the expression of Tyrosine Hydroxylase (TH) in the striatum. (n-8, P < 0.001, compared to saline group, & & P < 0.01, & P < 0.05 compared to MPTP group).
Ia-12(20mg/kg) induced Tyrosine Hydroxylase (TH) protein expression in striatum of PD mice induced by MPTP (30mg/kg) as shown in figure 3(Western blot assay), TH expression is at a lower level in the striatum of MPTP-induced PD mice, and the difference is statistically significant compared with a control group (P < 0.05, n is 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).
FIG. 5 shows the effect of substituted phenoxyamide derivatives Ia-12(20mg/kg) on MPTP (30mg/kg) induced Tyrosine Hydroxylase (TH) in striatum of PD mice according to an embodiment of the present invention. A: statistical analysis of the effect of Ia-12(20mg/kg) on MPTP (30mg/kg) induced the striatal Tyrosinyl Hydroxylase (TH). (n-8, P < 0.001, compared to saline group, & & P < 0.01, & P < 0.05 compared to MPTP group).
Pharmacodynamic evaluation result of MPTP-induced C57/BL mouse Parkinson's disease model
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, and a C57/BL mouse Parkinson disease model is established by intraperitoneal continuous injection for 7 days, and (1) the influence of the screened Ia-12 compound on the behavior of a model animal is analyzed by animal rotating rod test, spontaneous activity and other behavioral tests. (2) After the behavioral experiment is finished, the experimental animal is killed by decapitation, immunohistochemistry and Westblot quantitatively analyzes the change of striatal dopaminergic neurons so as to determine the action basis of Ia-12 on the pharmacodynamics of the MPTP Parkinson disease animal. As shown in table 2:
TABLE 2
The screening research of the inhibition effect of the compounds on the MAO activity, the screening concentration of the medicine is 10-5M, 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.
In conclusion, the research result determines that the novel substituted phenoxyamide derivative Ia-12 has a protective effect on MPTP/MPP + neurotoxins from the cell 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 shows that the novel substituted phenoxyamide derivative has a potential therapeutic effect on the 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 (9)
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:
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.
4. the substituted phenoxyamide derivative of claim 1, wherein the electron-withdrawing group comprises: -NO2,-CN,-SO3H,-CF3,-CCl3Halogen, -CHO and-COOH:
the electron donating group comprises: -NH2,-OH,OCH3,-OC2H5,-CH3and-C2H5。
5. Use of a class of substituted phenoxyamide derivatives in the manufacture of a medicament for the treatment of parkinson's disease, wherein the substituted phenoxyamide derivative is according to any one of claims 1 to 4.
6. The use of claim 5 wherein the substituted phenoxyamide derivative is used alone as an active ingredient.
7. The use according to claim 5 wherein the use is of a substituted phenoxyamide derivative in combination with an active compound.
8. The use according to claim 7, wherein the active compound is levodopa.
9. A medicament for treating Parkinson's disease, wherein the active component of the medicament comprises a substituted phenoxyamide derivative, and the substituted phenoxyamide derivative is the substituted phenoxyamide derivative as claimed in any one of claims 1 to 4.
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IL94466A (en) * | 1989-05-25 | 1995-01-24 | Erba Carlo Spa | Pharmaceutical compositions containing n-phenylalkyl substituted alpha-amino carboxamide derivatives, some such novel compounds and their preparation |
AR044007A1 (en) * | 2003-04-11 | 2005-08-24 | Newron Pharmaceuticals Inc | METHODS FOR THE TREATMENT OF PARKINSON'S DISEASE |
CN107522654B (en) * | 2016-06-21 | 2020-09-01 | 中国人民解放军军事医学科学院毒物药物研究所 | Novel alpha-aminoamide derivatives and medicinal use thereof |
CN107522647B (en) * | 2016-06-21 | 2022-03-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Indole group-containing alpha-aminoamide derivative and medical application thereof |
CN110938014A (en) * | 2019-11-28 | 2020-03-31 | 岳千奥 | Substituted phenoxyamide derivative, application and medicine for treating Parkinson's disease |
CN111217776A (en) * | 2020-01-19 | 2020-06-02 | 中国人民解放军军事科学院军事医学研究院 | Amide derivative containing benzo heterocyclic structure, composition and application |
-
2019
- 2019-11-28 CN CN201911212436.6A patent/CN110938014A/en active Pending
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2020
- 2020-11-25 CN CN202011340794.8A patent/CN112279778B/en active Active
- 2020-11-28 WO PCT/CN2020/132545 patent/WO2021104507A1/en active Application Filing
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112279778A (en) * | 2019-11-28 | 2021-01-29 | 岳千奥 | Substituted phenoxyamide derivative, application and medicine for treating Parkinson's disease |
WO2021104507A1 (en) * | 2019-11-28 | 2021-06-03 | 岳千奥 | Substituted phenoxyamide derivative, use thereof and drugs for treating parkinson's disease |
CN112279778B (en) * | 2019-11-28 | 2021-11-30 | 北京兰晟医药科技有限公司 | Substituted phenoxyamide derivative, application and medicine for treating Parkinson's disease |
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WO2021104507A1 (en) | 2021-06-03 |
CN112279778B (en) | 2021-11-30 |
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