CN110041291B - Macamide derivative and preparation method thereof - Google Patents
Macamide derivative and preparation method thereof Download PDFInfo
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- CN110041291B CN110041291B CN201810036189.8A CN201810036189A CN110041291B CN 110041291 B CN110041291 B CN 110041291B CN 201810036189 A CN201810036189 A CN 201810036189A CN 110041291 B CN110041291 B CN 110041291B
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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Abstract
The invention discloses a novel macamide derivative and a preparation method thereof; the invention also discloses the use of the novel macamide derivatives for preventing or treating depression and nervous system diseases. The macamide derivatives are compounds with a structure shown in a formula (I) or pharmaceutically acceptable salts thereof. A large number of experiments show that the compounds can inhibit the activity of Fatty Acid Amide Hydrolase (FAAH) and excite the level of 5-hydroxytryptamine (5-TH) receptors in vitro, and can improve anxiety symptoms and motor behaviors of various depression animal models in vivo.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a novel macamide derivative and a preparation method thereof; the invention also relates to the use of novel macamide derivatives for the prevention and treatment of depression and neurological diseases.
Background
Depression is a mental disease that has been a great threat to human health for a long time, and its incidence rate worldwide has increased year by year in recent years with the pace of life of people. According to the statistics of the world health organization, the number of depression patients in the world reaches 3.5 hundred million at present, the depression patients are predicted to become the second largest disease in the world in 2020, and the number of deaths due to suicide in depression is up to 100 ten thousand every year. In china, depression patients have reached 9000 million and approximately 28 million suicides annually, most of which are diagnosed with depression.
For depression, there is still a lack of satisfactory treatment at present, and the problems are mainly: (1) symptoms are manifested variously: the main manifestations are emotional obstacles such as depressed mood, decreased interest, etc.; cognitive disorders such as diminished energy, reduced thinking, and reduced concentration, and physical disorders such as sudden weight loss or weight gain, insomnia or sleepiness, agitation or retardation, and fatigue. (2) The pathogenesis is not clear: the prevailing pathogenesis hypothesis for depression today is the hypothesis of hypofunction of 5-hydroxytryptamine. Also, scientists believe that depression is caused by a deficiency of catecholamines in the brain. (3) The therapeutic effect of the medicine is not obvious: commonly used antidepressants are mainly divided into three groups: one is serotonin reuptake inhibitors (SSR class drugs); the second class is serotonin reuptake inhibitors (SNR class drugs); the third class is tricyclic antidepressants (TCA class drugs). Although these antidepressants can improve the symptoms of depression patients to a certain extent, on one hand, about one third of patients have no curative effect on various medicines, on the other hand, different adverse reactions occur after long-term use, and the phenomenon of relapse rate after drug withdrawal is also prominent.
In recent years, there has been increasing evidence that dysfunction of cannabinoid receptors may be implicated in the development of depression. Activation of cannabinoid receptors results in adenylate cyclase activity, inhibition of calcium influx and increased potassium influx, which cause a decrease in presynaptic neuronal excitability, inhibition of neurotransmitter release, and thus amelioration of depression and other psychiatric symptoms.
Cannabinoid receptors include mainly the CB1 and CB2 receptors, both of which belong to G protein-coupled receptors. Among them, CB1 receptor is mainly located in the brain, spinal cord and peripheral nervous system, and is also called central cannabinoid receptor. The intracerebral CB1 receptors are distributed primarily in the basal ganglia (substantia nigra, globus pallidus, lateral striatum), hippocampal CA pyramidal cell layer, cerebellum and cerebral cortex. Cannabinoids, both endogenous and exogenous, act as psychoactive substances by activating cannabinoid receptor 1 (CB 1). The major endogenous cannabinoid-like substances in the brain are anandamide (AEA) and 2-arachidonylglycerol (2-AG). AEA is degraded in brain by Fatty Acid Aminohydrolase (FAAH), so that the degradation of AEA is reduced by inhibiting FAAH, the content of brain AEA is increased, cannabinoid receptors are indirectly excited, and the antidepressant effect is exerted.
Lepidium meyenii Walp is an annual herb of the genus Lepidium L in the family Brassicaceae (Brassicaceae) S.C., native to Peru's Andes mountain area in south America. Due to the rich nutritional value and medicinal value, the edible tea has long-term planting and eating history in the Andes mountain area. China starts breeding and planting experiments in Lijiang of Yunnan in 2002 and successively plants in Sichuan, Tibet, Xinjiang, Qinghai and the like. 2011 China ministry of health approves maca powder as a new resource food. In recent 20 years, many studies prove that maca has the effects of improving the fertility of people and animals, improving sexual functions, resisting fatigue, resisting depression, improving memory and the like. Maca contains various secondary metabolites, and macamide is a special component only found in maca at present. Since 2000, 22 macamides have been isolated and identified in succession. There is increasing evidence that such compounds have significant activity in inhibiting Fatty Acid Amide Hydrolase (FAAH). Macamides act on the central nervous system by inhibiting FAAH to regulate neurotransmitter release and may have therapeutic effects on anxiety, depression, pain, and the like. Subsequent studies demonstrated FAAH inhibition of macamides of different structures, synthetic macamide analogs, and aza-alkanamides (N-alkylamides) isolated from maca and the jerusalem artichoke variety Heliopsis heliophiloides var. Among them, among many macamides, compounds having unsaturated double bonds have high FAAH inhibitory effects, which show significant time and dose dependence, and the inhibition is irreversible or extremely slow to reverse.
The invention aims to provide a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof and a preparation method thereof; the invention aims to provide a pharmaceutical application of a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof. The purpose of the invention is realized by the following technical scheme:
a compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein:
R1selected from fatty acids, wherein the fatty acid is a linear saturated or unsaturated fatty acid, preferably any 1 or a combination of at least 2 selected from palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, 5-oxo-6 trans, 8 trans-octadecadienoic acid.
R2Selected from aryl or heteroaryl groups containing from 5 to 20 carbon atoms (e.g. from 5 to 15 carbon atoms, further e.g. from 5 to 10 carbon atoms), preferably said aryl or heteroaryl group is selected from phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolinyl, benzopyranyl, benzopyrimidinyl, quinoxalinyl, benzpyridazinyl, benzotriazinyl and purinyl.
X is a saturated or partially saturated alkylene group containing 0 to 6 carbon atoms, optionally wherein the alkylene group is substituted with a substituent selected from hydroxyl or methyl.
Y is-N-or-C (R) -, wherein the R group is selected from hydrogen, hydroxyl, amino, C1-6 alkyl.
Z is a saturated or partially saturated alkylene group containing 0 to 6 carbon atoms, optionally wherein the alkylene group is substituted with a substituent selected from hydroxyl or methyl.
More preferably, the compound or a pharmaceutically acceptable salt thereof, wherein R1Selected from the group consisting of any 1 or a combination of at least 2 of the fatty acids which are linear saturated or unsaturated, preferably palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, 5-oxo-6 trans, 8 trans-octadecadienoic acid. Wherein R is2Selected from aryl or heteroaryl groups containing from 5 to 20 carbon atoms (e.g. from 5 to 15 carbon atoms, further e.g. from 5 to 10 carbon atoms), preferably said aryl or heteroaryl group is selected from phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolyl, benzoquinoxalyl, benzisoxazolyl, and the likePyranyl, benzopyrimidinyl, quinoxalinyl, benzopyrazinyl, benzotriazinyl and purinyl.
More preferably, the compound is selected from:
1- (4- (2-methoxyphenyl) piperazin-1-yl) hexadecan-1-one;
1- (4- (2-methoxyphenyl) piperazin-1-yl) octadecan-1-one;
(Z) -1- (4- (2-methoxyphenyl) piperazin-1-yl) octadec-9-en-1-one;
(Z, Z) -1- (4- (2-methoxyphenyl) piperazin-1-yl) octadeca-9, 12-dien-1-one;
1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) hexadecan-1-one;
1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadecan-1-one;
(Z) -1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadec-9-en-1-one;
(Z, Z) -1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadeca-9, 12-dien-1-one.
The pharmaceutical composition of the compound of the formula I or the pharmaceutically acceptable salt thereof comprises the compound of the formula I or the pharmaceutically acceptable salt thereof and/or pharmaceutically acceptable auxiliary materials (such as a carrier and/or an excipient and the like).
The compound of the formula I or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the invention can be used for preparing medicines for treating or preventing depression or nervous system diseases. The nervous system diseases are selected from anxiety disorders, neuropathic pain, schizophrenia, manic-depressive psychotic disorder (bipolar disorder), cognitive disorders, stress-related disorders, attention deficit and hyperactivity disorder, tic disorders, and psychotic disorders accompanied by various organic disorders
A process for the preparation of said compound or a pharmaceutically acceptable salt thereof, which comprises linking a fatty acid moiety to a substituted phenyl or 1, 2-benzisoxazolyl-substituted piperazinyl or piperidinyl group, wherein each group or symbol is as defined above;
the method comprises the following steps: a. the synthesis method comprises the steps of using 1-1.5 equivalent of N, N '-dicyclohexylcarbodiimide as a dehydrating agent and 0.1-0.5 equivalent of 4-dimethylaminopyridine as a catalyst for synthesis, placing the 4-dimethylaminopyridine in a catalytic amount in a reaction kettle, dissolving the 4-dimethylaminopyridine in a dichloromethane solution, stirring the mixture at room temperature for 15 minutes, adding the N, N' -dicyclohexylcarbodiimide, 1.5-2.5 equivalent of fatty acid and 1-1.2 equivalent of piperidine or piperazine substances, and continuing stirring the mixture at room temperature for reaction for 24 hours;
b. and (3) purification: after the reaction is finished, silica gel powder is mixed into the reaction liquid, the mixture is subjected to reduced pressure evaporation to dryness, and then is subjected to chromatographic separation and purification by using a silica gel column, and is eluted by using a petroleum ether-ethyl acetate (50:1-10:1) system to remove unreacted reactants and a catalyst, so that the macamide derivative is obtained.
The invention obtains a compound with a novel structure by carrying out structural modification on the macamides compound, and the compound can simultaneously act on the target points of a cannabinoids system and a 5-hydroxytryptamine system. In the embodiment of the invention, the compound has excellent inhibition of Fatty Acid Amide Hydrolase (FAAH) activity, improves the behavioral changes of various depression animal models, shows that the compound has the effect of preventing and treating depression and nervous system diseases, and provides a new idea for treating related diseases.
The inventor of the invention researches the biological activity and pharmacological action of a novel macamide derivative by synthesizing the novel macamide derivative, finds that the macamide derivative has the functions of inhibiting Fatty Acid Amide Hydrolase (FAAH) and exciting 5-hydroxytryptamine (5-TH) receptor activity, antagonizes symptoms of eyelid ptosis and body temperature reduction of an animal model caused by reserpine, reduces the immobility time in a forced swimming experiment and a tail suspension experiment of a mouse, and can be used for preventing or treating depression and nervous system diseases.
The following experimental examples and examples are intended to further illustrate but not limit the invention.
Experimental example 1: in vitro Activity test of Compounds of the present invention (NMC-1 to NMC-6 prepared in examples 1 to 6, respectively) against Fatty Acid Amide Hydrolase (FAAH)
Experimental principle and purpose: fatty Acid Amide Hydrolase (FAAH) can hydrolyze arachidonic Acid Ethanolamine (AEA) to Arachidonic Acid (AA) and ethanolamine (MEA). When a molecule having an inhibitory effect on FAAH is added to the reaction system, the ability of FAAH to degrade AEA is reduced, and arachidonic acid, a hydrolysis product thereof, is also reduced, so that the amount of the substrate hydrolyzed by AEA can be compared between the control group to which no inhibitor is added and the experimental group to which the inhibitor is added, whereby the inhibitory ability of the compound on FAAH can be obtained.
The experimental method comprises the following steps: in the study, the content of arachidonic acid, a hydrolysate, was measured by a liquid chromatography-mass spectrometry (LC-MS) technique to evaluate the inhibitory activity of the compounds of the present invention on FAAH. The experiment is divided into three groups, wherein the first group is a substrate group ((Blank)) which is used for eliminating the influence of arachidonic acid generated by the decomposition of arachidonic Acid Ethanolamine (AEA) on the experiment; the second group was a FAAH and AEA co-addition group (Vihicle) for determining the amount of arachidonic acid produced by FAAH catalyzed AEA decomposition in the absence of inhibitor; the third group, Test, was a group of FAAH, AEA plus inhibitor, and was used to determine the amount of arachidonic acid produced by decomposition of AEA catalyzed by FAAH in the presence of the inhibitor.
FAAH enzymatic hydrolysis process: to the reaction system, 50. mu.L of FAAH protein solution, 150. mu.L of AEA-containing buffer solution and 2. mu.L of the objective compound DMSO solution or DMSO blank solution were added, and after incubation in a shaking water bath at 37 ℃ for 30 minutes, 200. mu.L of stop buffer (1 nmol of fatty acid as an internal standard in 200. mu.L of methanol) was added and stored in a freezer at-20 ℃. The amount of arachidonic acid produced was analyzed by LC/MS.
LC/MS detection conditions: the liquid chromatography column is ZORBAX Eclipse XDB-C18 column (4.6X50mm, 1.8 mm, Agilent, USA); the column temperature was kept at 40 ℃; the sample injection amount is 5 mu L; mobile phase A: water (0.25% acetic acid and 5mmol/L ammonium acetate), mobile phase B: methanol (containing 0.25% acetic acid and 5mmol/L ammonium acetate) at flow rate of 0.6mL/min, and eluting with 95% B for 4 min; mass spectrum is ESI negative ion source; the drying gas is N2; the temperature is 350 ℃; curtain air 20 psi; the scanning molecular weight range is 50-400D. The FAAH hydrolysate arachidonic acid [ M-H ] -M/z 303 was quantitatively analyzed.
Inhibition rate calculation formula:
inhibition [ (% Vihicle-Blank) - (Test-Blank) ]/(Vihicle-Blank) × 100.
Experimental results and conclusions: as shown in Table 1, when FAAH and AEA were added alone, FAAH efficiently hydrolyzed AEA, and Arachidonic Acid (AA) was significantly increased, indicating that FAAH had hydrolytic activity. The relative content of hydrolysate arachidonic acid can be reduced to different degrees under the dosage of 10 mu M, which shows that the medicine composition has the function of inhibiting FAAH activity, wherein the inhibition rate of NMC-4 can reach 92.3 percent, and the medicine composition has obvious effect.
TABLE 1 inhibition of FAAH by some of the compounds of the invention
Experimental example 2: effect of Compounds of the invention (NMC-1, NMC-2, NMC-4, NMC-5 are compounds prepared in example 1, example 2, example 4 and example 5, respectively) on the immobility time of forced swimming in mice
The experimental principle and purpose are as follows: the forced swimming model of the mouse belongs to a stress depression model, and the immobility state of the mouse in the model reflects the despair behavior of animals and can simulate the depression state of human beings. In the experiment, a mouse forced swimming model is adopted to evaluate the in vivo activity of the compounds NMC-1, NMC-2, NMC-3 and NMC-4.
The experimental method comprises the following steps: selecting male mice of SPF-grade Kunming species without special pathogens, weighing (20 +/-2) g, and randomly dividing the mice into a normal control group, a positive medicament fluoxetine hydrochloride group and a medicament group. The method comprises the steps of adapting to a breeding environment for 1 week, continuously performing gavage administration for 6 days, after the gavage administration for 1 hour on the 7 th day, putting the mouse into a glass jar with the diameter of 18cm and the water depth of 20cm, keeping the water temperature at 23-25 ℃, timing for 6min after the mouse enters water, and recording the cumulative immobility time(s) within 4 min. By immobile, it is meant that the mouse stops struggling in the water, or the animal is in a floating state with only small limb movements to keep the head floating on the water.
The experimental results are as follows: the forced swimming experiment of the mouse shows that the positive drug fluoxetine hydrochloride group can remarkably shorten the immobility time of the forced swimming of the mouse (P is less than 0.01) under the dosage of 20 mg/Kg; the drug group can obviously shorten the immobility time of forced swimming of mice at the dose of 40mg/Kg, has obvious difference (P <0.05) compared with a blank control group, proves that the drug has the immobility behavior of a stress depression model for improving forced swimming of mice, and has the most obvious NMC-4 effect (P <0.01) through comparison, and the result is shown in a table 2.
TABLE 2 influence of partial compounds of the invention on immobility time in forced swimming of mice
Data are expressed as Mean ± SE, each set n being 12; p <0.05, P <0.01, dosing groups compared to controls
Experimental example 3: effect of the Compounds of the present invention (NMC-1, NMC-2, NMC-4, NMC-5 are the compounds prepared in example 1, example 2, example 4 and example 5, respectively) on the immobility time of the tail suspension of mice
Purpose of the experiment: in the experiment, another stress depression model mouse tail suspension experiment is adopted to evaluate the antidepressant effect of the compound. The immobility state of the mouse in the tail suspension experiment model reflects the despair behavior of animals and can simulate the depression state of human beings.
The experimental method comprises the following steps: selecting male mice of SPF-grade Kunming species without special pathogens, weighing (20 +/-2) g, and randomly dividing the mice into a normal control group, a positive medicament fluoxetine hydrochloride group and a medicament group. The mice are adapted to the breeding environment for 1 week, the continuous gavage administration is carried out for 6 days, on the 7 th day, after the last gavage administration is carried out for 1 hour, the tail part of the mouse is about 2cm away from the tail end, and the tail part of the mouse is stuck and fixed on a horizontal rod by using medical adhesive plaster, so that the mouse is suspended in an open box, and the head part of the mouse is about 5cm away from the bottom of the box. And (5) hanging for timing 6min, and recording the accumulated motionless time(s) within 4 min.
The experimental results are as follows: the result of a mouse tail suspension experiment shows that the 20mg/Kg dose of the positive drug fluoxetine hydrochloride group can remarkably shorten the mouse tail suspension immobility time, and has remarkable difference (P <0.01), the drug group of the invention can also remarkably shorten the mouse tail suspension immobility time at the 40mg/Kg dose, wherein NMC-1, NMC-3 and NMC have remarkable difference (P <0.05) compared with a blank control group, and the result is shown in Table 3.
TABLE 3 influence of partial compounds of the invention on immobility time in forced swimming of mice
Data are expressed as Mean ± SE, each set n being 12; p <0.05, P <0.01, dosing groups compared to controls
Experimental example 4: effect of Compounds of the invention (NMC-1, NMC-2, NMC-4, NMC-5 are compounds prepared in example 1, example 2, example 4 and example 5, respectively) on reserpine-induced depression models in mice
Purpose of the experiment: reserpine antagonizes the depression model, which is a more applied and more mature pharmacological model. Reserpine can deplete monoamine neurotransmitters in the brain, induce phenomena such as catalepsy, drooping eyelids, diarrhea, bradycardia, etc. in mice, and also cause the body temperature of rodents to drop. These behavioral manifestations have a relationship with clinical depression and can be reversed by treatment with antidepressants.
The experimental method comprises the following steps: selecting male mice of SPF-grade Kunming species without special pathogens, weighing (20 +/-2) g, and randomly dividing the mice into a normal control group, a model group, a positive medicament fluoxetine hydrochloride group and a medicament group of the invention. The mice are adapted to the breeding environment for 1 week, the continuous gavage administration is carried out for 6 days, the basal body temperature of the mice is firstly measured after the last gavage administration for 30min on the 7 th day, and then the intraperitoneal injection of reserpine is carried out for 2.5 mg/kg. Mice were placed on the rack 1h after injection of reserpine, respectively, and the number of mice above the eyelid closure 1/2 was recorded 15s after observation. Meanwhile, a thermometer probe is inserted into the anus of the mouse for 2cm after injection of reserpine respectively, and the anal temperature of the mouse is measured.
The experimental results are as follows: the effect of reserpine on body temperature in the antagonistic depression model is shown in Table 3, where there was essentially no difference in basal body temperature (P > 0.05) between the groups of mice before injection of reserpine. The body temperature of the model group is obviously lower than that of the control group (P is less than 0.05) after the injection of the reserpine for 2 hours, and the body temperature of each administration group is obviously higher than that of the model group after the injection of the reserpine for 2 hours, wherein the fluoxetine hydrochloride, NMC-4 and NMC-5 groups have obvious difference (P is less than 0.05). In addition, in an eyelid observation experiment, compared with a normal control group, the eyelid ptosis incidence rate of the model group is also obviously increased (P is less than 0.01), and each administration group can relieve the eyelid ptosis incidence rate of mice, wherein fluoxetine hydrochloride and NMC-4 are most obviously expressed, and the result is shown in a table 5. The medicine has a certain antidepressant effect on reserpine model mice.
TABLE 4 Effect of some of the compounds of the invention on the body temperature of mice with a reserpine model
Data are expressed as Mean ± SE, each set n being 12; # P <0.05, model group vs control; p <0.05, dosed groups compared to control
TABLE 5 Effect of some compounds of the invention on Lepidemic model mouse eyelid droop
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used are conventional products which are commercially available or may be prepared in accordance with known teachings, without reference to the manufacturer.
Example 1: synthesis of 1- (4- (2-methoxyphenyl) piperazin-1-yl) hexadecan-1-one (NMC-1)
N, N' -Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), dichloromethane
The reaction process is as follows: weighing 1.0g of 1- (2-methoxyphenyl) piperazine, dissolving the 1.0g of 1- (2-methoxyphenyl) piperazine in 30ml of dichloromethane, adding 1.2g of N, N' -Dicyclohexylcarbodiimide (DCC) and 100mg of 4-Dimethylaminopyridine (DMAP), stirring the mixture at room temperature for 14 hours to finish the reaction, directly stirring the reaction solution by silica gel, and separating and purifying the mixture by a silica gel column (200-300 meshes) to obtain petroleum ether: ethyl acetate (20:1) as eluent to obtain 1.86g of white powder solid; elution was carried out in 83.1% yield.
ESI+-MS：431.4[M+H]+
1H NMR(300MHz，CDCl3)：δ＝7.05(m,1H,Ar-H),6.92(m,3H,Ar-H), 3.91(s,3H,-OC 3H),3.82(t,2H,J＝5.1Hz,-N 2H),3.68(t,2H,J＝4.8 Hz,-N 2H),3.05(m,4H,2×-N 2H),2.39(m,2H,-NC＝O-C 2H),1.98-1.18(m, 26H,13×-C 2H),0.87(t,3H,J＝9.6Hz,-C 3H).
Example 2: synthesis of (Z) -1- (4- (2-methoxyphenyl) piperazin-1-yl) octadec-9-en-1-one (NMC-2)
N, N' -Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), dichloromethane
The procedure is as in example 1, using oleic acid as a reactant in the procedure, the product NMC-2 being obtained as a colorless oily liquid.
ESI+-MS：457.3[M+H]+
1H NMR(300MHz，CDCl3)：δ＝7.06(m,1H,Ar-H),6.93(m,3H,Ar-H), 5.36(m,2H,-CH＝CH-),3.89(s,3H,-OC 3H),3.83(t,2H,J＝5.1Hz,-N 2H), 3.67(t,2H,J＝5.1Hz,-N 2H),3.05(m,4H,2×-N 2H),2.34(t,2H,J＝ 7.8Hz),2.00(m,4H),1.67(m,2H),1.42-1.26(m,20H,),0.90(t,3H, J＝9.6Hz,-C 3H).
Example 3: synthesis of (3Z,6Z,9Z) -1- (4- (2-methoxyphenyl) piperazin-1-yl) octadeca-3, 6, 9-trien-1-one (NMC-3)
N, N' -Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), dichloromethane
The procedure is as in example 1, using linoleic acid as a reactant in the procedure, the product NMC-3 obtained is a colorless oily liquid.
ESI+-MS：453.3[M+H]+
1H NMR(300MHz，CDCl3)：δ＝7.04(m,1H,Ar-H),6.91(m,3H,Ar-H), 5.62(m,2H,-CH＝CH-),5.18(m,4H,2×-CH＝CH-),3.88(s,3H,-OC 3H),3.83 (t,2H,J＝4.8Hz,-N 2H),3.66(t,2H,J＝5.1Hz,-N 2H),3.03(m,4H,2×-N 2H), 2.78(m,2H,-CH2-),2.43(m,4H,2×-CH2-),2.00(m,2H),1.51-1.24(m, 16H,),0.87(t,3H,J＝9.3Hz,-CH3).
Example 4: synthesis of (Z) -1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadec-9-en-1-one (NMC-4)
N, N' -Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), dichloromethane
The procedure is as in example 1, using 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole as a reactant in the synthesis procedure, the product NMC-4 is obtained as a white powdery solid.
ESI+-MS：459.1[M+H]+
1H NMR(300MHz，CDCl3)：δ＝7.54(dd,1H,J＝8.4,2.1Hz,Ar-H),7.26 (m,1H,Ar-H),7.06(m,1H,Ar-H),3.11(m,4H,2×-N 2H),2.43(m,1H), 2.08(m,4H,2×-C 2H)，1.87-1.18(m,26H,13×-C 2H),0.85(t,3H,J＝9.3 Hz,-C 3H).
Example 5: synthesis of (Z) -1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadec-9-en-1-one (NMC-5)
N, N' -Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), dichloromethane
The procedure is as in example 2, using 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole as a reactant in step and the product NMC-5 is obtained as a colorless oily liquid.
ESI+-MS：485.2[M+H]+
1H NMR(300MHz，CDCl3)：δ＝7.54(m,1H,Ar-H),7.26(m,1H,Ar-H), 7.06(s,1H,Ar-H),5.31(m,2H,-CH＝CH-),3.13(m,4H,2×-N 2H),2.32(m, 1H),2.08-1.97(m,8H)，1.83-1.21(m,24H,),0.89(t,3H,J＝9.6Hz,-C 3H).
Example 6: synthesis of (3Z,6Z,9Z) -1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadeca-3, 6, 9-trien-1-one (NMC-6)
N, N' -Dicyclohexylcarbodiimide (DCC), 4-Dimethylaminopyridine (DMAP), dichloromethane
The procedure is as in example 3, using 6-fluoro-3- (4-piperidinyl) -1, 2-benzisoxazole as a reactant in step and the product NMC-6 is obtained as a colorless oily liquid.
ESI+-MS：481.2[M+H]+
1H NMR(300MHz，CDCl3)：δ＝7.58(m,1H,Ar-H),7.27(m,1H,Ar-H), 7.06(s,1H,Ar-H),5.60(m,2H,-CH＝CH-),5.23(m,4H,2×-CH＝CH-),3.13 (m,4H,2×-N 2H),2.85(m,2H),2.78(m,1H),2.69(m,4H),1.99(m,4H), 1.56-1.05(m,14H)，1.01(m,3H,-CH3).
The structures of the compounds described in the above examples were determined by conventional spectroscopic techniques (nuclear magnetic resonance or ESI-MS mass spectrometry).
Claims (6)
1. A macamide compound of formula I below or a pharmaceutically acceptable salt thereof:
wherein the compound is selected from:
1- (4- (2-methoxyphenyl) piperazin-1-yl) hexadecan-1-one;
1- (4- (2-methoxyphenyl) piperazin-1-yl) octadecan-1-one;
(E) -1- (4- (2-methoxyphenyl) piperazin-1-yl) octadec-9-en-1-one;
(E, E) -1- (4- (2-methoxyphenyl) piperazin-1-yl) octadeca-9, 12-dien-1-one;
1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) hexadecan-1-one;
1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadecan-1-one;
(E) -1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadec-9-en-1-one;
(E, E) -1- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) octadeca-9, 12-dien-1-one.
2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.
3. Use of the compounds and pharmaceutical compositions according to any one of claims 1 to 2 for the preparation of medicaments for the prophylaxis and treatment of psychiatric and neurological disorders.
4. The use according to claim 3, wherein the psychiatric disorder is depression, anxiety, neuropathic pain, attention deficit and hyperactivity disorder, schizophrenia, manic-depressive psychotic disorder, cognitive disorders, stress-related disorders, tic disorders, and psychotic disorders accompanied by various organic disorders.
5. The use according to claim 4, wherein the psychotic disorders accompanied by various organic pathologies are Alzheimer's disease, vascular dementia, psychotic disorder due to brain trauma, psychotic disorder due to intracranial infection, psychotic disorder due to brain tumor, psychotic disorder due to syphilis, epileptic psychotic disorder, psychotic disorder due to HIV/AIDS.
6. Use according to claim 3, wherein the neurological disease is Alzheimer's disease, Parkinson's disease, cerebrovascular disease, brain trauma, spinal cord injury, demyelinating diseases, multiple sclerosis, inflammatory demyelinating polyneuropathies, leukoencephalopathy caused by ischemia-hypoxia, diabetic neuropathy.
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