CN113754711B - Fennlafaxine 21-position metabolite and preparation and application thereof - Google Patents
Fennlafaxine 21-position metabolite and preparation and application thereof Download PDFInfo
- Publication number
- CN113754711B CN113754711B CN202010504572.9A CN202010504572A CN113754711B CN 113754711 B CN113754711 B CN 113754711B CN 202010504572 A CN202010504572 A CN 202010504572A CN 113754711 B CN113754711 B CN 113754711B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- water
- methanol
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Toxicology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a Fennlafaxine 21-position metabolite and preparation and application thereof. The Fennlafaxine 21-site metabolite has good antioxidant activity, anti-neuroinflammation and neuroprotective activity. The 21-position metabolite of the phentermine is shown in the following formula (I):
Description
Technical Field
The invention relates to the field of medicines, in particular to a Fennlamine 21-site metabolite and preparation and application thereof.
Background
Fenton amine is a derivative of annonaceous acetogenins, and its compound structure is disclosed in chinese patent CN1445211 (publication No.), which describes "new annonaceous acetogenins derivative and its preparation method, and its pharmaceutical composition and use" invented by the national academy of medical science and drug research.
Fennlamine (chemical name: trans-2- (2, 5-dimethoxyphenyl) -3- (4-hydroxy-3-methoxyphenyl) -N- (4-hydroxyphenylethyl) acrylamide) has the following molecular structural formula:
the pharmacodynamics effect of the phentermine for treating Parkinsons Disease (PD) is similar to that of the known positive drug levodopa, and the activity of the phentermine is stronger than that of the levodopa. The action mechanism of the phentermine is novel, can resist nerve cell apoptosis, and has neuroprotective effect. However, the effect of phentermine on neuroprotection is not satisfactory, and therefore, development of new substitution products of phentermine is a current urgent problem to be solved.
Disclosure of Invention
It is an object of the present invention to provide a 21-metabolite of phentermine;
another object of the present invention is to provide a process for the preparation of the metabolite at position 21 of phentermine;
it is a further object of the present invention to provide a pharmaceutical composition;
it is a further object of the present invention to provide the use of the metabolite at position 21 of phentermine.
To achieve the above object, in one aspect, the present invention provides a metabolite at position 21 of phentermine, wherein the metabolite at position 21 of phentermine is represented by the following formula (I):
on the other hand, the invention also provides a preparation method of the Fennlamine 21-position metabolite, wherein the method comprises the steps of taking a compound of formula (7) as a raw material to prepare the Fennlamine 21-position metabolite shown in formula (I):
according to some embodiments of the invention, wherein the method further comprises preparing a compound of formula (7) starting from a compound of formula (6) and a compound of formula (3):
according to some embodiments of the invention, wherein the method further comprises preparing a compound of formula (6) starting from a compound of formula (5) and a compound of formula (5A):
according to some embodiments of the invention, wherein the method further comprises preparing a compound of formula (5) starting from a compound of formula (4) and a compound of formula (4A):
according to some embodiments of the invention, wherein the method further comprises a compound of formula (2) and CCl 3 CN is used as a raw material to prepare a compound of formula (3):
according to some embodiments of the invention, wherein the method further comprises reacting a compound of formula (1) with (NH) 2 NH 2 ) 2 COCH 3 Preparing a compound of formula (2) as a starting material:
according to some embodiments of the invention, the method comprises the steps of:
according to some embodiments of the invention, wherein the solvent of step 1 is selected from the group consisting of DMF, dichloromethane, acetonitrile, 1, 4-dioxane, DMSO, and tetrahydrofuran.
According to some embodiments of the invention, wherein the solvent of step 2 is selected from the group consisting of dichloromethane, DMF, acetonitrile, 1, 4-dioxane, DMSO, and tetrahydrofuran.
According to some embodiments of the invention, wherein the solvent of step 3 is acetic anhydride.
According to some embodiments of the invention, wherein the solvents of step 4 and step 5 are each independently selected from the group consisting of dichloromethane, DMF, acetonitrile, 1, 4-dioxane, DMSO, and tetrahydrofuran.
According to some embodiments of the invention, the solvent of step 6 is selected from methanol, or from one of the following mixed solutions: methanol/water, ethanol/water, acetonitrile/water, 1, 4-dioxane/water, DMF/water, tetrahydrofuran/water, and DMSO/water.
According to some embodiments of the invention, wherein step 2 is performed in the presence of an organic base as a compound of formula (2) and CCl 3 CN is used as a raw material to prepare a compound of formula (3).
According to some embodiments of the invention, step 3 is the preparation of the compound of formula (5) starting from the compound of formula (4) and the compound of formula (4A) in the presence of a catalyst.
According to some embodiments of the invention, step 4 is the preparation of the compound of formula (6) starting from the compound of formula (5) and the compound of formula (5A) in the presence of an organic base.
According to some embodiments of the invention, step 5 is the preparation of the compound of formula (7) starting from the compound of formula (6) and the compound of formula (3) in the presence of a catalyst.
According to some embodiments of the invention, step 6 wherein, when the solvent is selected from one of methanol/water, ethanol/water, acetonitrile/water, 1, 4-dioxane/water, DMF/water, tetrahydrofuran/water and DMSO/water, step 6 is to prepare the compound of formula (I) starting from the compound of formula (7) in the presence of a basic substance.
Alternatively, step 6 when the solvent is selected from methanol, step 6 is to prepare the compound of formula (I) starting from the compound of formula (7) in a methanol/sodium methoxide system or a sodium tert-butoxide/methanol system.
According to some embodiments of the invention, wherein the organic base of step 2 is selected from one of DBU (1, 8-diazabicyclo undec-7-ene), triethylamine, diisopropylethylamine and N-methylimidazole.
According to some embodiments of the invention, wherein the catalyst of step 3 is selected from triethylamine or diisopropylethylamine.
According to some embodiments of the invention, wherein the organic base of step 4 is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylimidazole and N-methylmorpholine.
According to some embodiments of the invention, wherein the catalyst of step 5 is selected from the group consisting of BF 3 .Et 2 O, TMSOTf (trimethylsilyl triflate) and BF 3 One of THF.
According to some embodiments of the invention, wherein the alkaline substance of step 6 is selected from the group consisting of sodium carbonate, potassium carbonate and sodium hydroxide.
According to some embodiments of the invention, step 1 is performed at a temperature of 10℃to 30 ℃.
According to some embodiments of the invention, step 1 is performed at room temperature.
According to some embodiments of the invention, step 2 is performed at a temperature of 10℃to 30 ℃.
According to some embodiments of the invention, step 2 is performed at room temperature.
According to some embodiments of the invention, step 3 is performed under reflux.
According to some embodiments of the invention, step 4 is performed at a temperature of 5 ℃ to 15 ℃.
According to some embodiments of the invention, step 5 is performed at-30℃to-10 ℃.
According to some embodiments of the invention, step 5 is performed at-20 ℃.
According to some embodiments of the invention, step 6 is performed at a temperature of 10℃to 30 ℃.
According to some embodiments of the invention, step 6 is performed at room temperature.
In yet another aspect, the present invention provides a pharmaceutical composition comprising a metabolite of the present invention at position 21 of phentermine, and one or more pharmaceutically acceptable carriers and/or excipients.
In still another aspect, the invention also provides the use of the metabolite at position 21 of phentermine in the preparation of antioxidant, anti-neuroinflammatory and neuroprotective agents.
The invention also provides application of the Fenoleamine 21-bit metabolite in preparing medicines for preventing and treating Parkinson's disease, improving learning and memory disorder, and treating hypomnesis and Alzheimer's disease.
In summary, the invention provides a Fennlafaxine 21-position metabolite and preparation and application thereof. The Fennlafaxine 21-metabolite has the following advantages:
the Fennlafaxine 21-site metabolite has good antioxidant activity, anti-neuroinflammation and neuroprotective activity.
Detailed Description
The following detailed description of the invention and the advantages achieved by the embodiments are intended to help the reader to better understand the nature and features of the invention, and are not intended to limit the scope of the invention.
Example 1
Step 1:
in a three-necked flask, tetraacetylglucuronic acid (15.0 g,39.9 mmol), DMF (150 mL), hydrazine acetate (4.4 g,47.9 mmol) under the protection of ice-bath nitrogen, stirring for 4 hours at room temperature and naturally returning to the temperature, TLC showed complete reaction, pouring the system into water (500 mL), EA (ethyl acrylate) (300 mL) was extracted, the organic phase was washed three times with water, saturated brine once, dried over anhydrous sodium sulfate, and spun dry to give compound 2 (11 g, yield 83%).
1 HNMR CDCl 3 δ:5.61-5.55(m,2H),5.23-5.16(m,1H),4.93-4.90(m,1H),4.61-4.58(d,1H,J＝10.0Hz),3.74(s,3H),2.05-2.04(m,9H)。
Step 2:
in a three-necked flask, compound 2 (12.0 g,35.9 mmol), methylene chloride (150 mL), trichloroacetonitrile (25.8 g,180 mmol), DBU (2.18 g,14.4 mmol) were added under the protection of ice-bath nitrogen, the solution turned brown, and the reaction was stirred for 6 hours at room temperature after natural temperature return, TLC showed complete reaction, and triethylamine was added to terminate the reaction. Direct wet silica gel column chromatography (silica gel column is first wetted with 0.5% triethylamine/petroleum ether eluent) purification (petroleum ether/ethyl acetate=5:1-3:1-1:1), rapid column passing afforded crude compound 3 (12 g, 70% yield).
1 HNMR CDCl 3 δ:8.75(s,1H),6.66-6.65(d,1H,J＝2.8Hz),5.67-5.62(m,1H),5.29-5.26(m,1H),5.18-5.15(m,1H),4.53-4.51(d,1H,J＝10.4Hz),3.77(s,3H),2.10-2.03(m,9H)。
Step 3:
in a single port flask, compound 4 (20.0 g,102 mmol), compound 4A (15.5 g,102 mmol), acetic anhydride (47.8 g,469 mmol), triethylamine (6.9 g,68.4 mmol), heating and refluxing at 130-140℃for 15 hours, stopping the reaction, cooling to 90℃and refluxing with water (26 mL) for 1 hour, distilling off the solvent under reduced pressure, diluting the residue with dichloromethane (100 mL), 1N hydrochloric acid (50 mL), extracting the aqueous layer with dichloromethane (100 mL), combining the organic phases, washing the organic phases with 1N hydrochloric acid (50 mL), drying over anhydrous sodium sulfate, filtering, distilling off the solvent, refluxing and dissolving with toluene, refrigerating overnight in a refrigerator, filtering, washing the filter cake with diethyl ether to give pale yellow Compound 5 (30 g, yield 79%).
1 HNMR d6-DMSOδ:12.50-12.46(m,1H),7.71(s,1H),7.10-6.92(m,3H),6.90-6.66(m,2H),6.62-6.61(d,1H,J＝2.8Hz),3.84-3.73(m,6H),3.53(s,3H,),3.77(s,3H),2..27(s,3H)。
Step 4:
in a three-necked flask, compound 5 (10.0 g,26.9 mmol), DCM (dichloromethane) (200 mL), compound 5A (3.70 g,26.9 mmol), HOBT (1-hydroxybenzotriazole) (4.40 g,32.3 mmol), EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide) (7.70 g,40.3 mmol), triethylamine (6.80 g,67.2 mmol) and stirring at 10deg.C for 7 hours, TLC showed complete reaction. The reaction system was washed with water (50 ml×3), saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was distilled off to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 6 (6.00 g, yield 45%).
1 HNMR CDCl 3 δ:7.81(s,1H),6.93-6.87(m,5H),6.79-6.72(m,3H),6.63-6.59(m,1H),5.80-5.66(m,2H),3.71(s,3H),3.62(s,3H),3.54-3.31(m,2H),3.45(s,3H),2.73-2.69(m,2H),2..28(s,3H)。
Step 5:
in a three-necked flask, compound 6 (5.00 g,10.2 mmol), compound 3 (9.70 g,20.4 mmol), molecular sieves 4A (24.0 g), anhydrous dichloromethane (1500 mL), and BF dropwise added under nitrogen at 20deg.C 3 .Et 2 O (2.89 g,20.4 mmol), -after stirring at 20℃for 2 hours, TLC showed complete reaction and reaction was terminated by adding 1 drop of triethylamine. Filtration, washing of the filter cake with dichloromethane, successive water washing (30 mL), washing with saturated sodium chloride (30 mL), drying over anhydrous sodium sulfate, filtration, evaporation of the solvent, column chromatography on silica gel (petroleum ether: ethyl acetate=6:1) gives compound 7 (6 g, yield 73%).
1 HNMR CDCl 3 δ:7.78(s,1H),6.99-6.97(m,2H),6.93-6.85(m,5H),6.76-6.71(m,1H),6.60-6.57(m,2H),5.60-5.57(m,1H),5.35-5.25(m,3H),5.10-5.08(d,1H,J＝7.6Hz),4.19-4.09(m,1H),3.78-3.69(m,6H),3.59(s,3H),3.54-3.46(m,2H),3.43(s,3H),2.74-2.67(m,2H),2..25(s,3H),2.07-2.05(m,9H)。
Step 6:
compound 7 (6.00 g,7.44 mmol) was dissolved in methanol/water (135 mL, v/v=2:1) and Na was added 2 CO 3 (12.3 g,119 mmol) was stirred overnight at room temperature. LCMS monitored completion of the reaction. Spin-drying the reaction solution, and mixing with waterDissolving, adjusting pH of the reaction solution to be between 5 and 6 by using 1N hydrochloric acid, filtering, and purifying a filter cake which is a crude product by using prep-HPLC to obtain a compound I (Target 1, T1) (1.1 g, yield 23%).
1 HNMR CD 3 ODδ:7.56(s,1H),7.03-7.05(m,4H),6.96-6.98(m,2H),6.70-6.73(m,1H),6.62-6.67(m,2H),6.44-6.48(m,2H),4.93-4.95(m,1H),3.99-4.01(d,1H),3.73(s,3H),3.61-3.67(m,4H),3.46-3.53(m,4H),3.43(s,3H),2.72-2.75(t,2H).
LC-MS:m/z＝626(M+1)。
Test example 1
This test example evaluates and compares the in vitro antioxidant, anti-neuroinflammatory and neuroprotective activity of the Felbamine (FLZ) and the felbamine 21-position metabolites of the invention.
1. Experimental method
1.1 determination of the content of Malondialdehyde (MDA) as a lipid peroxidation product
Preparation of liver microsomes: after the rat liver tissue was weighed, 10% homogenate was prepared with Tris-HC1 buffer, and liver microsomes were isolated by differential centrifugation.
The experiments were performed in blank, model, FLZ and FLZ21 metabolite groups, each group being provided with 3 duplicate wells. PBS buffer, liver microsomes, cysteine and test drug solution were added to each tube. The final concentration of each tube of the test group added with FLZ or FLZ21 metabolite is 1×10 respectively -4 、1×10 -5 And 1X 10 -6 M, blank, model groups add the same volume of DMSO per tube. Shaking in 37deg.C water bath for 15min, adding 1×10 for each tube of model group and drug adding group -2 M FeSO 4 The solution, blank, was added with the same volume of PBS buffer and continued to oscillate in a 37℃water bath for 15min. Then TCA solution and TBA solution are added into each tube, and water bath is carried out for 10min at the temperature of 100 ℃. Centrifuge at 8000rpm for 10min. The supernatant was taken and absorbance (OD) was measured at 532 nm.
1.2 anti-neuroinflammatory drug administration and detection of Nitric Oxide (NO) content
BV 2 Cells were placed in DMEM medium containing 10% fetal calf serum at 37℃with 5% CO 2 Is cultured in an incubator of (a). Cells in the logarithmic growth phase are selected and divided into a blank group, a model group, an FLZ group and an FLZ21 metabolite group, and 3 compound wells are arranged in each group. Different concentrations of FLZ or FLZ21 metabolite (final concentration 1X 10) -5 ，1×10 -6 ，1×10 -7 M), the blank group and the model group are added with the DMSO with the same volume, and after 1h, the model group and the dosing group are added with the LPS with the concentration of 500ng/mL for 24h, and the blank group is added with the PBS buffer with the same volume. 100 mu L of culture medium is sucked up from each hole, the prepared Griess reagent is added, and the mixture is kept stand for 20min at room temperature. The absorbance (OD) was measured at 540nm for each group. And converting the absorbance into a concentration value of NO by using a standard curve and carrying out formula calculation.
NO inhibition rate= [1- (C) Test compounds -C Blank space )/(C Model -C Blank space ]×100％
1.3, neuroprotective administration and determination of cell viability
SH-SY5Y nerve cells were cultured in DMEM medium containing 10% fetal bovine serum, and incubated at 37℃with 5% CO 2 Is cultured in an incubator of (a). And selecting cells in the logarithmic growth phase for experiments. SH-SY5Y cells were divided into a blank group, a model group, an FLZ group and an FLZ21 metabolite group, each group being provided with 3 multiplex wells. Different concentrations of FLZ or FLZ21 metabolite (final concentration 1X 10) -5 ，1×10 -6 ，1×10 -7 M), model group and dosing group added 8mM MPP after 1h + Incubation was performed for 24h, and the blank was added with the same volume of PBS buffer. The supernatant was pipetted off, 100. Mu.L of MTT (0.5 mg/mL) was added to each well, incubation was continued for 4h, and absorbance (OD) was measured on a microplate reader at 570 nm.
Effective percent= (OD Test compounds -OD Model )/(OD Blank space -OD Model )×100％
2. Experimental results
2.1 Effect of FLZ21 Metabolic acid on lipid peroxidation
In an in vitro liver microsomal lipid antioxidant experiment, the metabolite T1 at the FLZ21 position has a certain inhibition effect on MDA generation and has a certain dose effect relationship (table 1).
TABLE 1 results of in vitro antioxidant Activity of FLZ21 Metabolic substances
2.2, FLZ and Effect of FLZ21 Metabolic acid on NO Release
After LPS stimulates BV2 microglial cells, the level of NO in the culture medium is obviously increased, FLZ and its FLZ21 metabolite T1 have a certain inhibition effect on BV2 cells to release NO, and the inhibition effect of T1 on NO release is stronger than that of FLZ (Table 2).
TABLE 2 results of in vitro anti-neuritic Activity of FLZ and FLZ21 Metabolic
2.3, FLZ and Effect of FLZ21 Metabolic acid on cell viability
SH-SY5Y cells added MPP + The survival rate of the cells is obviously reduced, and the FLZ has a certain protection effect on cell injury and has a dose-response relationship. T1 also showed some protection and T1 was better than FLZ (Table 3).
TABLE 3 results of in vitro neuroprotective Activity of FLZ and FLZ21 Metabolic acid
3. Conclusion(s)
The FLZ21 metabolite has certain antioxidant, anti-neuroinflammatory and neuroprotective activities, wherein the high concentration effect is good, and the FLZ21 metabolite has dose dependency. The FLZ21 metabolite has higher efficacy in resisting neuroinflammation and neuroprotective activity than FLZ.
Claims (16)
1. A method for preparing a metabolite at position 21 of phentermine shown in formula (I), wherein the method comprises the steps of preparing the metabolite at position 21 of phentermine shown in formula (I) by taking a compound shown in formula (7) as a raw material:
the solvent is selected from methanol or one of the following mixed solutions: methanol/water, ethanol/water, acetonitrile/water, 1, 4-dioxane/water, DMF/water, tetrahydrofuran/water, and DMSO/water;
when the solvent is selected from one of methanol/water, ethanol/water, acetonitrile/water, 1, 4-dioxane/water, DMF/water, tetrahydrofuran/water and DMSO/water, the compound of formula (7) is used as a raw material to prepare the compound of formula (I) in the presence of alkaline substances;
alternatively, when the solvent is selected from methanol, the compound of formula (I) is prepared from the compound of formula (7) as a starting material in a methanol/sodium methoxide system or a sodium tert-butoxide/methanol system.
2. The production method according to claim 1, wherein the method further comprises producing the compound of formula (7) starting from the compound of formula (6) and the compound of formula (3):
3. the production method according to claim 2, wherein the method further comprises producing the compound of formula (6) starting from the compound of formula (5) and the compound of formula (5A):
4. the production method according to claim 3, wherein the method further comprises producing the compound of formula (5) starting from the compound of formula (4) and the compound of formula (4A):
5. the process according to claim 4, wherein the process further comprises reacting the compound of formula (2) with CCl 3 CN is used as a raw material to prepare a compound of formula (3):
6. the process according to claim 5, wherein the process further comprises reacting a compound of formula (1) with (NH) 2 NH 2 ) 2 COCH 3 Preparing a compound of formula (2) as a starting material:
7. the preparation method according to claim 1, wherein the method comprises the steps of:
8. the method of manufacturing according to claim 7, wherein:
the solvent in the step 1 is selected from one or more of DMF, dichloromethane, acetonitrile, 1, 4-dioxane, DMSO and tetrahydrofuran;
the solvent in the step 2 is selected from one or more of dichloromethane, DMF, acetonitrile, 1, 4-dioxane, DMSO and tetrahydrofuran;
the solvent in the step 3 is acetic anhydride;
the solvents of step 4 and step 5 are each independently selected from the group consisting of dichloromethane, DMF, acetonitrile, 1, 4-dioxane, DMSO, and tetrahydrofuran;
the solvent in the step 6 is selected from methanol or one of the following mixed solutions: methanol/water, ethanol/water, acetonitrile/water, 1, 4-dioxane/water, DMF/water, tetrahydrofuran/water, and DMSO/water.
9. The production method according to claim 7 or 8, wherein:
step 2 is carried out in the presence of an organic base, a compound of formula (2) and CCl 3 CN is used as a raw material to prepare a compound of a formula (3);
step 3 is to prepare a compound of formula (5) by using a compound of formula (4) and a compound of formula (4A) as raw materials in the presence of a catalyst;
step 4 is to prepare a compound of formula (6) from a compound of formula (5) and a compound of formula (5A) in the presence of an organic base;
step 5 is to prepare a compound of formula (7) from a compound of formula (6) and a compound of formula (3) in the presence of a catalyst;
step 6 when the solvent is selected from one of methanol/water, ethanol/water, acetonitrile/water, 1, 4-dioxane/water, DMF/water, tetrahydrofuran/water and DMSO/water, step 6 is to prepare the compound of formula (I) starting from the compound of formula (7) in the presence of a basic substance; alternatively, step 6 when the solvent is selected from methanol, step 6 is to prepare the compound of formula (I) starting from the compound of formula (7) in a methanol/sodium methoxide system or a sodium tert-butoxide/methanol system.
10. The preparation method according to claim 9, wherein the organic base in step 2 is selected from one of DBU, triethylamine, diisopropylethylamine and N-methylimidazole.
11. The process according to claim 9, wherein the catalyst of step 3 is selected from triethylamine or diisopropylethylamine.
12. The preparation method according to claim 9, wherein the organic base in step 4 is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylimidazole and N-methylmorpholine.
13. The process according to claim 9, wherein the catalyst of step 5 is selected from the group consisting of BF 3 .Et 2 O, TMSOTf and BF 3 One of THF.
14. The preparation method according to claim 9, wherein the alkaline substance in step 6 is selected from the group consisting of a mixture of one or more of sodium carbonate, potassium carbonate and sodium hydroxide.
15. The application of the Fenoleylamine 21-position metabolite shown in the formula (I) in preparing antioxidant drugs, anti-neuroinflammation drugs and neuroprotective drugs;
16. the use according to claim 15, wherein the use is the use of a metabolite at position 21 of phentermine in the manufacture of a medicament for the prevention and treatment of parkinson's disease, improvement of learning and memory disorders, treatment of hypomnesis and alzheimer's disease.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010504572.9A CN113754711B (en) | 2020-06-05 | 2020-06-05 | Fennlafaxine 21-position metabolite and preparation and application thereof |
| PCT/CN2021/098309 WO2021244635A1 (en) | 2020-06-05 | 2021-06-04 | Metabolite at position 21 of fenlean, and preparation and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010504572.9A CN113754711B (en) | 2020-06-05 | 2020-06-05 | Fennlafaxine 21-position metabolite and preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113754711A CN113754711A (en) | 2021-12-07 |
| CN113754711B true CN113754711B (en) | 2023-09-01 |
Family
ID=78783972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010504572.9A Active CN113754711B (en) | 2020-06-05 | 2020-06-05 | Fennlafaxine 21-position metabolite and preparation and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN113754711B (en) |
| WO (1) | WO2021244635A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232293A (en) * | 2017-07-11 | 2019-01-18 | 中国医学科学院药物研究所 | Fragrant happy amine crystalline substance G type, preparation method and its composition and purposes |
| CN109232297A (en) * | 2017-07-11 | 2019-01-18 | 中国医学科学院药物研究所 | Fragrant happy amine crystal B-type, preparation method and its composition and purposes |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1308288C (en) * | 2002-03-20 | 2007-04-04 | 中国医学科学院药物研究所 | New amide ramification of sweetsop as well as its preparing method, its medication composition and usage |
-
2020
- 2020-06-05 CN CN202010504572.9A patent/CN113754711B/en active Active
-
2021
- 2021-06-04 WO PCT/CN2021/098309 patent/WO2021244635A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232293A (en) * | 2017-07-11 | 2019-01-18 | 中国医学科学院药物研究所 | Fragrant happy amine crystalline substance G type, preparation method and its composition and purposes |
| CN109232297A (en) * | 2017-07-11 | 2019-01-18 | 中国医学科学院药物研究所 | Fragrant happy amine crystal B-type, preparation method and its composition and purposes |
Non-Patent Citations (1)
| Title |
|---|
| A UHPLC-MS/MS method to determine FLZ major active metabolites in human plasma: application to a pharmacokinetic study;Wang,Teng.ect;《Bioanalysis》;20200529;第12卷(第9期);第583-596页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021244635A1 (en) | 2021-12-09 |
| CN113754711A (en) | 2021-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107056630B (en) | Indane derivative, and synthesis method and medical application thereof | |
| EP1641758B1 (en) | Diphenylpyridine derivatives, preparation and therapeutic application thereof | |
| JP2010513398A (en) | Isoquinoline carboxamide derivatives as stearoyl-CoA desaturase (SCD) inhibitors | |
| TW438746B (en) | New phenylamidine derivatives, processes for preparing them and their use as pharmaceutical compositions | |
| FR2667317A1 (en) | 2-AMINOPYRIMIDINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF | |
| CN113754711B (en) | Fennlafaxine 21-position metabolite and preparation and application thereof | |
| CN102911160B (en) | Method for preparing and purifying dabigatran etexilate intermediate | |
| CN100572378C (en) | The improved preparation method of Cinepazide Maleate | |
| CN104530002B (en) | Bilastine compound and preparation method thereof | |
| EP1678159A2 (en) | Thiophene-2-carboxamide derivatives and use thereof as cannabinoid cb-1 receptor antagonists | |
| CN113861066B (en) | Deuterated fluvoxamine maleate and synthesis method thereof | |
| JP4913389B2 (en) | Acetoxycavicol acetate analog compound, production method thereof, and antiallergic agent | |
| CN111362962B (en) | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof | |
| FR2737494A1 (en) | BENZENESULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF | |
| CN111592520B (en) | 4, 5-disubstituted piperine derivatives, and preparation method and application thereof | |
| CN109810115B (en) | Isoflavone compound and preparation method and application thereof | |
| CN108409648B (en) | Preparation method of sorafenib tosylate related intermediate | |
| EP0683775A1 (en) | Heterocyclic 4-aminomethylpiperidine derivatives, their preparation and application in therapy | |
| EP0577470B1 (en) | 2-Amino-N-[[[4-(aminocarbonyl)pyrimidin-2-yl]amino]alkyl]-pyrimidine-4-carboxamide derivates, their preparation and their use in therapeutics | |
| CN111269242A (en) | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof | |
| WO1994020466A1 (en) | Novel 2-phenoxy ethylamine derivatives, their preparation and their therapeutical use | |
| EP0522914A1 (en) | 2-Piperidinylpyrimidin-4-carboxamide derivatives, their preparation and their application in therapy | |
| CN110590760B (en) | 2, 1-benzisoxazole derivative and synthetic method and application thereof | |
| CN111233751B (en) | Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof | |
| CN102702116B (en) | 4-(3-chloro-4-methoxylanilino)-6-(3-amidophenyl)quinazoline compound or pharmaceutically-acceptable salt thereof and preparation methods and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |