CN117304109A - Dextromethorphan nitrate compound and application thereof in preparation of medicines with vascular dementia preventing and/or treating effects - Google Patents
Dextromethorphan nitrate compound and application thereof in preparation of medicines with vascular dementia preventing and/or treating effects Download PDFInfo
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- CN117304109A CN117304109A CN202311185322.3A CN202311185322A CN117304109A CN 117304109 A CN117304109 A CN 117304109A CN 202311185322 A CN202311185322 A CN 202311185322A CN 117304109 A CN117304109 A CN 117304109A
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- dextromethorphan
- nitrate compound
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- 229960001985 dextromethorphan Drugs 0.000 title claims abstract description 70
- -1 Dextromethorphan nitrate compound Chemical class 0.000 title claims abstract description 45
- 229910002651 NO3 Inorganic materials 0.000 title claims abstract description 41
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 201000004810 Vascular dementia Diseases 0.000 title claims abstract description 11
- 229940079593 drug Drugs 0.000 title abstract description 17
- 230000000694 effects Effects 0.000 title abstract description 12
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims abstract description 27
- 210000002569 neuron Anatomy 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 11
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- 230000000304 vasodilatating effect Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
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- 238000011160 research Methods 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
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- 238000002474 experimental method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 5
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
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- 238000007157 ring contraction reaction Methods 0.000 description 3
- MISZALMBODQYFT-URVXVIKDSA-N 125-69-9 Chemical compound Br.C([C@@H]12)CCC[C@]11CCN(C)[C@H]2CC2=CC=C(OC)C=C21 MISZALMBODQYFT-URVXVIKDSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
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- 210000003710 cerebral cortex Anatomy 0.000 description 2
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- 230000013016 learning Effects 0.000 description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- 230000004083 survival effect Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 210000000115 thoracic cavity Anatomy 0.000 description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 1
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 description 1
- DKEGCUDAFWNSSO-UHFFFAOYSA-N 1,8-dibromooctane Chemical compound BrCCCCCCCCBr DKEGCUDAFWNSSO-UHFFFAOYSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 206010058558 Hypoperfusion Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 1
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000008809 cell oxidative stress Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000003788 cerebral perfusion Effects 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
-
- 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
- A61P25/28—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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of biological medicines, and particularly discloses a dextromethorphan nitrate compound and application thereof in preparation of a medicament with a vascular dementia preventing and/or treating effect. The dextromethorphan nitrate compound has a structure shown in a formula I. Research shows that the dextromethorphan nitrate compound has the function of protecting nerve cells, and the function of protecting nerve cells is stronger than that of dextromethorphan; in addition, the dextromethorphan nitrate compound also has the function of dilating blood vessels. Therefore, the dextromethorphan nitrate compound serving as an active ingredient is used for preparing medicines with the function of protecting nerve cells, or is used for preparing medicines with the function of dilating blood vessels, or is used for preparing medicines with the function of preventing and/or treating vascular dementia, and has important application value.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a dextromethorphan nitrate compound and application thereof in preparing a medicament for preventing and/or treating vascular dementia.
Background
Vascular dementia (Vascular dementia, VD) refers to severe cognitive dysfunction syndrome caused by cerebral vascular diseases with hypo-perfusion in brain areas such as memory, cognition and behavior. About 30% of dementia patients are VD, the most frequently occurring cognitive disorder disease following alzheimer's disease. The prevalence of VD in the 65-year old population is 1% -4%, and the risk of developing VD increases with age by 1-fold every 5.3 years, and it is expected that the dementia patient of year 2050 will reach 3500 ten thousand, and VD has become one of the most significant diseases affecting the health of all humans. However, VD treatment does not have any effective drugs, and various large-scale clinical experiments prove that the drugs originally used for treating VD, such as cholinesterase inhibitors, lipid-lowering drugs or neurotrophic drugs, cannot significantly improve symptoms of VD, and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine can improve cognitive functions of VD patients with partial small blood vessels, but has limited overall efficacy. Therefore, there is an urgent need for effective drugs for VD treatment.
Numerous studies have demonstrated that VD patients have insufficient local cerebral perfusion, while decreased cerebral blood flow supply can cause disorder of neural cell function network and cognitive impairment through mechanisms such as blood brain barrier damage, neural cell oxidative stress, calcium overload, inflammatory response, etc. Therefore, how to improve the cerebral blood supply of VD patients becomes one of the keys to break through in VD treatment. Endothelial cell-derived gas signaling molecule NO plays a central role in maintaining cerebral vascular blood perfusion stability, and NO causes cGMP to increase and vasodilation by activating guanylate cyclase (Soluble guanylate cyclase, sGC) within vascular smooth muscle cells.
The NMDA receptor is an important excitatory amino acid receptor in the central nervous system, plays an extremely important role in regulating the survival of neurons, regulating the development of dendrites and axon structures of neurons and participating in the formation of synaptic plasticity, and is a vital receptor in learning and memory processes. In ischemia, alzheimer's diseaseUnder pathological conditions such as diseases, excessive activation of NMDA receptors can lead to intracellular calcium overload, OH, O 2·- And ONOO – The number of isofree radicals increases, resulting in neuronal cell damage or death, learning and memory and cognitive dysfunction; on the other hand, excessive activation of NMDA receptor channels can release excessive NO through the formation of a triple complex of NMDA receptor-PSD 95-nNOS, but NO rapidly becomes O in an oxidative stress state 2·- Forming the ONOO with extremely strong oxidation – Not only does NO lose physiological function, but also exacerbates the damage to nerve cells, ultimately leading to cognitive dysfunction. Inhibition of NMDA receptor channel activity is therefore effective in protecting neuronal cell damage.
In view of the above, development of a compound capable of dilating blood vessels in the brain to increase cerebral blood flow and protecting brain nerves has been one of the viable routes for treating vascular dementia.
Disclosure of Invention
In order to overcome at least one technical problem existing in the prior art, the invention firstly provides a dextromethorphan nitrate compound.
The technical scheme of the invention is as follows:
the invention firstly provides a dextromethorphan nitrate compound, which has a structure shown in a formula I:
the inventor finds that the dextromethorphan nitrate compound has the function of protecting nerve cells, and the function of protecting nerve cells is stronger than that of dextromethorphan.
Further researches show that the dextromethorphan nitrate compound also has the function of dilating blood vessels.
Preferably, n.gtoreq.1 in formula I.
Further preferably, 1.ltoreq.n.ltoreq.10 in the formula I.
Most preferably, 1.ltoreq.n.ltoreq.7 in the formula I.
Preferably, the dextromethorphan nitrate compound is selected from compounds with any structure of formulas a-e:
the invention also provides a composition comprising a compound of the structures shown in formula d and formula e.
The inventors have surprisingly found in the study that a composition formed by combining compounds of the structures of formula d and formula e can produce a synergistic vasodilating effect; the vasodilation effect is significantly higher than that of the compound of the structure shown in the formula d alone or the compound of the structure shown in the formula e alone.
Preferably, the molar ratio of the compounds of the structures shown in the formula d and the formula e is 1-3:1-3;
most preferably, the molar ratio of the compounds of the structures of formula d and formula e is 1:1.
The invention also provides a preparation method of the dextromethorphan nitrate compound, which comprises the following steps:
(1) Taking dextromethorphan as a raw material, and adding an HBr solution for reaction to obtain reduced dextromethorphan;
(2) Reacting the reduced dextromethorphan with dibromoalkane to obtain brominated dextromethorphan;
(3) And (3) reacting the bromo dextromethorphan with silver nitrate to obtain dextromethorphan nitrate compounds.
Preferably, the reaction in step (1) is carried out by heating at 100-120℃for 1.5-3 hours.
Most preferably, the reaction in step (1) is conducted by heating at 110℃for 2 hours.
Preferably, the reaction in the step (2) means reflux reaction at 70-90 ℃ for 4-12 hours.
Most preferably, the reaction in step (2) is reflux reaction at 80℃for 6 to 10 hours.
The reaction in the step (3) is that stirring is carried out for 4 to 10 hours under the protection of light shielding at the temperature of between 60 and 80 ℃;
most preferably, the reaction in step (3) is stirred for 6 hours at 70 ℃ under protection from light.
The invention provides a brand new preparation method of dextromethorphan nitrate compounds; the method has simple preparation steps and high yield, and is suitable for large-scale industrialized production.
The invention also provides application of the dextromethorphan nitrate compound or the composition in preparation of a medicament with a nerve cell protecting effect.
The invention also provides application of the dextromethorphan nitrate compound or the composition in preparation of a medicament with a vasodilation effect.
The invention also provides application of the dextromethorphan nitrate compound or the composition in preparing medicines with the effect of preventing and/or treating vascular dementia.
The beneficial effects are that: the invention provides a dextromethorphan nitrate compound with a brand new structure, and researches show that the dextromethorphan nitrate compound has the function of protecting nerve cells, and the function of protecting nerve cells is stronger than that of dextromethorphan; in addition, the dextromethorphan nitrate compound also has the function of dilating blood vessels. Therefore, the dextromethorphan nitrate compound serving as an active ingredient is used for preparing medicines with the function of protecting nerve cells, or is used for preparing medicines with the function of dilating blood vessels, or is used for preparing medicines with the function of preventing and/or treating vascular dementia, and has important application value.
Detailed Description
The present invention is further explained below with reference to specific examples, which are not intended to limit the present invention in any way.
The preparation method of the dextromethorphan nitrate compound comprises the following steps:
(1) Into the reaction flask was added dextromethorphan (1.25 g,4.555 mmol), 50 ml of HBr solution. Heated at 110℃for 2 hours. After cooling, 125 ml of chloroform and 40 ml of ammonium hydroxide solution (25%) were added dropwise to the reaction mixture (ph=9). The organic layer was separated, dried (sodium sulfate) and then evaporated in vacuo. The residue was dissolved in an ethanol-ethyl acetate mixture. Acidifying hydrochloric acid to pH=2 in ethyl acetate to obtain hydrochloride crystal, and obtaining the reduced dextromethorphan with the yield of 90% -93%.
(2) To the reaction flask was added reduced dextromethorphan (0.16 mmol), potassium carbonate (0.96 mmol), and 2mL of acetone, dibromoalkane (0.96 mmol), under nitrogen protection, was added. Reflux overnight at 80 ℃. Post-treatment: suction filtration, washing the precipitate 3 times with DCM, drying the organic phase, and rotary evaporating under reduced pressure to obtain the crude product dextromethorphan bromide.
(3) To the reaction flask, dextromethorphan bromide (10 mmol), silver nitrate (20 mmol) and acetonitrile (12 ml) were added and stirred at 70℃for 6 hours under protection from light. The resulting mixture was washed with 10% hydrochloric acid, water and brine in this order, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Purifying by column chromatography (50:1 petroleum ether: acetone) to obtain the dextromethorphan nitrate compound with 75-81% yield.
EXAMPLE 1 preparation of dextromethorphan nitrate
Referring to the method, dibromoethane is specifically selected as dibromoalkane in the step (2), and a compound with a structure shown in a formula a is prepared;
the structural analysis of the compound of the structure shown in formula a is as follows: chemical Formula C 19 H 26 N 2 O 4 ,Molecular Weight:346.4270； 1 H NMR(400MHz,CDCl 3 )δ7.07(d,J＝8.4Hz,1H),6.82(d,J＝2.7Hz,1H),6.72(dd,J＝8.4,2.6Hz,1H),4.82(dd,J＝5.8,3.5Hz,2H),4.28–4.20(m,2H),3.12(dd,J＝5.9,3.2Hz,1H),3.03(d,J＝18.7Hz,1H),2.85(dd,J＝18.7,5.9Hz,1H),2.75(ddd,J＝12.3,4.8,1.8Hz,1H),2.59(s,3H),2.32(qd,J＝12.5,11.8,3.4Hz,2H),2.14(dt,J＝12.8,3.2Hz,1H),2.00(td,J＝13.2,4.6Hz,1H),1.69–1.56(m,2H),1.54(s,1H),1.51–1.28(m,5H),1.28–1.17(m,1H),1.10(qd,J＝12.6,3.9Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ21.97,23.83,26.03,26.34,35.90,36.75,40.35,41.93,43.20,47.40,58.82,64.09,71.13,111.98,112.02,128.65,128.93,140.86,157.15.
EXAMPLE 2 preparation of dextromethorphan nitrate
Referring to the method, specifically selecting 1, 4-dibromobutane from dibromoalkane in the step (2) to prepare a compound with a structure shown in a formula b;
the structural analysis of the compound of the structure shown in formula b is as follows: chemical Formula C 21 H 30 N 2 O 4 ,Molecular Weight:374.4810； 1 H NMR(400MHz,Chloroform-d)δ7.04(d,J＝8.4Hz,1H),6.80(d,J＝2.6Hz,1H),6.69(dd,J＝8.3,2.6Hz,1H),4.56(t,J＝6.3Hz,2H),3.99(t,J＝5.7Hz,2H),3.00(d,J＝18.2Hz,1H),2.87(dd,J＝5.8,3.2Hz,1H),2.64(dd,J＝18.3,5.8Hz,1H),2.50(ddd,J＝11.9,4.8,1.8Hz,1H),2.44(s,3H),2.40–2.32(m,1H),2.13(td,J＝12.3,3.3Hz,1H),2.02–1.85(m,5H),1.79(td,J＝12.7,4.8Hz,1H),1.70–1.62(m,1H),1.58–1.51(m,1H),1.43(dt,J＝10.3,3.4Hz,1H),1.39–1.32(m,3H),1.27(d,J＝2.7Hz,1H),1.14(qd,J＝13.4,12.7,4.0Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ22.24,23.42,23.91,25.66,26.51,26.74,36.55,37.20,41.84,42.68,45.08,47.31,58.09,66.82,73.01,111.37,111.57,128.57,129.78,141.66,157.42.
EXAMPLE 3 preparation of dextromethorphan nitrate
Referring to the method, specifically selecting 1, 8-dibromooctane from dibromoalkane in the step (2), and preparing a compound with a structure shown in a formula c;
the structural analysis of the compound of the structure shown in formula c is as follows: chemical Formula C 25 H 38 N 2 O 4 ,Molecular Weight:430.5890； 1 H NMR(400MHz,CDCl 3 )δ7.01(d,J＝8.4Hz,1H),6.79(d,J＝2.5Hz,1H),6.69(dd,J＝8.4,2.6Hz,1H),4.44(t,J＝6.7Hz,2H),3.91(t,J＝6.7Hz,2H),3.63(s,1H),2.98(d,J＝18.4Hz,2H),2.71(dd,J＝18.4,6.0Hz,1H),2.59(dd,J＝12.1,3.3Hz,1H),2.49(s,3H),2.35(d,J＝13.1Hz,1H),2.20(td,J＝12.5,3.2Hz,1H),1.98(d,J＝12.5Hz,1H),1.86(td,J＝13.1,4.7Hz,1H),1.79–1.69(m,4H),1.58(dd,J＝12.1,12.2Hz,2H),1.49–1.23(m,15H),1.11(dddd,1H). 13 C NMR(101MHz,CDCl 3 )δ22.14,23.59,25.59,25.99,26.32,26.58,26.73,29.05,29.18,29.34,36.27,36.97,41.20,42.34,44.29,47.42,58.52,67.82,73.41,111.64,111.69,128.60,141.05,157.99.
EXAMPLE 4 preparation of dextromethorphan nitrate
Referring to the method, specifically selecting 1, 5-dibromopentane from dibromoalkane in the step (2) to prepare a compound with a structure shown in a formula d;
the structural analysis of the compound of the structure shown in formula d is as follows: chemical Formula C 22 H 32 N 2 O 4 ,Molecular Weight:388.5080； 1 H NMR(400MHz,CDCl 3 )δ7.01(d,J＝8.4Hz,1H),6.77(d,J＝2.5Hz,1H),6.66(dd,J＝8.4,2.6Hz,1H),4.48(t,J＝6.6Hz,2H),3.93(t,J＝6.2Hz,2H),2.97(d,J＝18.2Hz,1H),2.80(dd,J＝5.4,3.2Hz,1H),2.58(dd,J＝18.1,5.8Hz,1H),2.43(dd,J＝12.3,3.2Hz,1H),2.39(s,3H),2.34(d,J＝9.4Hz,1H),2.27(s,1H),2.07(td,J＝12.3,3.2Hz,1H),1.81(dq,J＝6.2,3.4Hz,5H),1.73(td,1H),1.62(dd,J＝6.6,4.6Hz,2H),1.59(t,1H),1.51(d,J＝9.4Hz,1H),1.43–1.24(m,6H),1.13(td,1H). 13 C NMR(101MHz,CDCl 3 )δ22.28,22.53,23.37,26.57,26.63,26.79,28.93,36.63,37.26,42.03,42.78,45.32,47.30,58.00,67.29,73.21,111.27,111.61,128.52,129.87,141.75,157.54.
EXAMPLE 5 preparation of dextromethorphan nitrate
Referring to the method, specifically selecting 1, 6-dibromohexane from dibromoalkane in the step (2) to prepare a compound with a structure shown in a formula e;
the structural analysis of the compound of formula e is as follows: chemical Formula C 23 H34N 2 O 4 ,Molecular Weight:402.5350； 1 H NMR(400MHz,CDCl 3 )δ7.00(d,J＝8.4Hz,1H),6.77(d,J＝2.5Hz,1H),6.67(dd,J＝8.4,2.6Hz,1H),4.45(t,J＝6.6Hz,2H),3.92(t,J＝6.6Hz,2H),2.97(d,J＝18.2Hz,1H),2.84(dd,J＝5.3,3.2Hz,1H),2.61(dd,J＝18.2,5.8Hz,1H),2.47(dd,J＝12.9,3.1Hz,1H),2.41(s,3H),2.34(d,J＝12.4Hz,1H),2.11(td,J＝12.4,3.2Hz,1H),1.85(dt,J＝12.9,2.8Hz,1H),1.76(ddd,J＝17.1,9.3,4.7Hz,5H),1.63(d,J＝11.2Hz,1H),1.54–1.46(m,5H),1.44(dd,J＝9.3,2.6Hz,1H),1.41–1.37(m,1H),1.35(d,J＝2.7Hz,1H),1.34–1.31(m,1H),1.30(s,1H),1.13(td,J＝12.4,3.6Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ22.25,23.42,25.52,25.75,26.51,26.73,29.20,36.53,37.18,41.81,42.67,45.07,47.34,58.15,67.51,73.28,111.37,111.62,128.53,129.44,141.53,157.70.
Example 6 preparation of the composition
And (3) uniformly mixing the compound with the structure shown in the formula d and the compound with the structure shown in the formula e according to a molar ratio of 1:1 to obtain the composition.
Experimental example 1MTT method for detecting protection effect of dextromethorphan nitrate compound on primary cerebral cortex cells induced by glutamic acid
SD pregnant mice (pregnant for 16-18 days) were extracted from cerebral cortex cells. Inoculating cells into a 96-well plate, culturing for 11 days, and respectively adding a compound to be tested of 10 mu m, dextromethorphan or an equivalent amount of neuron culture medium according to the sequence of a dosing group, a Control group and a Glutamate (Glu) group; after 2h of pre-protection of the drug, 200. Mu.M of Glutamate was added to the Glutamate group and the drug-added group, after 24h of incubation, MTT solution was added for 4h of incubation, MTT solution was then aspirated, 100. Mu.L of DMSO was added to each well, and OD (570 nm) was measured by an ELISA reader. Cell viability = test group OD value 100%/model group OD value; the experimental results are shown in Table 1.
TABLE 1 test results of dextromethorphan nitrate compounds of the invention for protecting nerve cells
| Test compounds | Cell viability | |
| Blank control group | - | 100％ |
| Glu group | Glutamate | 52.1％ |
| Positive control group | Dextromethorphan | 63.5％ |
| Experiment group 1 | Compounds of the structure shown in formula a | 69.3％ |
| Experiment group 2 | Compounds of the structure shown in formula b | 72.2％ |
| Experiment group 3 | Compounds of the structure shown in formula c | 68.8％ |
| Experiment group 4 | Compounds of the structure shown in formula d | 82.7％ |
| Experiment group 5 | Compounds of the structure shown in formula e | 71.4％ |
As can be seen from the experimental data in Table 1, the cell viability of the compounds of the structures represented by formulas a-e of the present invention is greater than that of dextromethorphan; this illustrates: the dextromethorphan nitrate compound has the function of protecting nerve cells, and the function of protecting nerve cells is stronger than that of dextromethorphan.
As can be seen from the experimental data in Table 1, the compounds of the structures shown in formulas a-e of the present invention all have different cell viability; wherein the cell survival rate of the compound with the structure shown in the formula d is obviously higher than that of dextromethorphan nitrate compounds with other structures; and is also substantially higher than dextromethorphan. This shows that, in the dextromethorphan nitrate compound with the parent nucleus structure shown in the formula I, n is different in value, and the sizes of the functions of protecting nerve cells are different; the effect of protecting nerve cells of the compound with the structure shown in the formula d obtained when n takes 5 is greatly higher than that of the compound obtained when n takes other values.
Experimental example 2 Effect of dextromethorphan nitrate Compounds on rat thoracic aortic vascular ring Shu Chang
After the rat is anesthetized, the thoracic cavity is cut off, the thoracic aorta is rapidly taken out, the thoracic aorta is placed in a culture dish, the aorta is separated, and the thoracic aorta below the aortic arch is cut into a plurality of arterial annular sections with the length of 4mm for standby. The stainless steel triangle hook is gently penetrated into the vascular ring, the other triangle stainless steel hook is also gently penetrated into the vascular ring, the stainless steel hook is hung in the bath tube, the lower part of the stainless steel triangle hook is fixed on the fixed hook, the upper part of the stainless steel triangle hook is connected with the tension transducer through a thin steel wire hook, mixed gas is introduced, and the ventilation amount is adjusted until small bubbles escape one by one. The temperature in the bath should be maintained at 37.+ -. 0.5 ℃. The initial tension of the vascular ring was adjusted to 1g 15 minutes before, 2g 15 minutes after, and the tension was equilibrated for 60 minutes with each 15 minute change. Contracting vascular ring with final concentration of 60mmol KCl (100 μm compound to be tested is added into the solution), acting for 15min to induce vascular ring contraction, activating the contraction activity, eluting with preheated Krebs after the contraction is stabilized, repeatedly flushing until the tension is restored to the initial value; the same concentration of KCl was repeatedly added and the samples were repeatedly rinsed with Krebs solution to observe the contraction curve waveform and restore the tension signal to its original value. After 30min of stabilization, a subsequent experiment is carried out, and the numerical value of the change of the vascular ring tension is recorded. Tension changes are expressed as percent (%) of the relative value of the change in the magnitude of vascular ring contraction.
The compound to be tested is dextromethorphan, a compound with a structure shown in formulas a-e and the composition prepared in example 6; the test results are shown in Table 2.
TABLE 2 vasodilation test results of dextromethorphan nitrate compounds of the invention
As can be seen from the test data in table 2, the relative value of the change in vascular ring contraction amplitude of dextromethorphan was 0%; this suggests that dextromethorphan has no vasodilating effect; the compounds of the structures of formulas a-e of the present invention all exhibit vasodilatory effects.
It can also be seen from the test data in Table 2 that the composition prepared in example 6 (composition consisting of compounds of the structures of formulas d and e) has a significantly higher percentage of the relative values of the change in the magnitude of the vasoconstrictor than the compounds of either the structures of formulas d and e. This illustrates: a composition formed by combining the compounds of the structures of formula d and formula e, which produces a synergistic vasodilating effect; the vasodilation effect is significantly higher than that of the compound of the structure shown in the formula d alone or the compound of the structure shown in the formula e alone.
Claims (10)
1. The dextromethorphan nitrate compound is characterized by having a structure shown in a formula I:
2. the dextromethorphan nitrate compound according to claim 1, wherein n is greater than or equal to 1;
further preferably, 1.ltoreq.n.ltoreq.10 in the formula I;
most preferably, 1.ltoreq.n.ltoreq.7 in the formula I.
3. The dextromethorphan nitrate compound according to claim 1, wherein the dextromethorphan nitrate compound is selected from the group consisting of compounds having any one of the structures of formulas a-e:
4. a composition comprising a compound having the structure of formula d and formula e.
5. The method for preparing dextromethorphan nitrate compound according to claim 1, comprising the steps of:
(1) Taking dextromethorphan as a raw material, and adding an HBr solution for reaction to obtain reduced dextromethorphan;
(2) Reacting the reduced dextromethorphan with dibromoalkane to obtain brominated dextromethorphan;
(3) And (3) reacting the bromo dextromethorphan with silver nitrate to obtain dextromethorphan nitrate compounds.
6. The method for preparing dextromethorphan nitrate compound according to claim 4, wherein the reaction in the step (1) is heating at 100-120 ℃ for 1.5-3 hours;
most preferably, the reaction in step (1) is conducted by heating at 110℃for 2 hours.
7. The method for preparing dextromethorphan nitrate compound according to claim 4, wherein the reaction in the step (2) is reflux reaction for 4-12 hours at 70-90 ℃;
most preferably, the reaction in the step (2) is reflux reaction at 80 ℃ for 6-10 hours;
the reaction in the step (3) is that stirring is carried out for 4 to 10 hours under the protection of light shielding at the temperature of between 60 and 80 ℃;
most preferably, the reaction in step (3) is stirred for 6 hours at 70 ℃ under protection from light.
8. Use of a dextromethorphan nitrate compound or composition according to any one of claims 1-4 in the preparation of a medicament having a neuronal cell protective effect.
9. Use of a dextromethorphan nitrate compound or composition according to any one of claims 1 to 3 in the preparation of a medicament having vasodilating effect.
10. Use of a dextromethorphan nitrate compound or composition according to any one of claims 1 to 3 in the preparation of a medicament for preventing and/or treating vascular dementia.
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