CN107216352B - Mitochondrially targeted dihydrogen pyridine derivative and preparation method and application - Google Patents
Mitochondrially targeted dihydrogen pyridine derivative and preparation method and application Download PDFInfo
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- CN107216352B CN107216352B CN201710436442.4A CN201710436442A CN107216352B CN 107216352 B CN107216352 B CN 107216352B CN 201710436442 A CN201710436442 A CN 201710436442A CN 107216352 B CN107216352 B CN 107216352B
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- China
- Prior art keywords
- mitochondrially targeted
- pyridine derivative
- dihydrogen pyridine
- preparation
- dihydrogen
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 dihydrogen pyridine derivative Chemical class 0.000 title claims description 86
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 10
- 229910052740 iodine Chemical group 0.000 claims description 10
- 239000011630 iodine Chemical group 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 4
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 229960003966 nicotinamide Drugs 0.000 claims description 3
- 235000005152 nicotinamide Nutrition 0.000 claims description 3
- 239000011570 nicotinamide Substances 0.000 claims description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 3
- 230000003537 radioprotector Effects 0.000 claims description 2
- 230000006378 damage Effects 0.000 abstract description 14
- 150000003254 radicals Chemical class 0.000 abstract description 13
- 201000010099 disease Diseases 0.000 abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 10
- 239000001301 oxygen Substances 0.000 abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 abstract description 10
- 230000005855 radiation Effects 0.000 abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 5
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 abstract 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 13
- 210000003470 mitochondria Anatomy 0.000 description 12
- 239000008363 phosphate buffer Substances 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
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- 239000012043 crude product Substances 0.000 description 8
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
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- 229930192474 thiophene Chemical group 0.000 description 6
- KVYRCBOUKXJXDK-UHFFFAOYSA-N 3,4-dimethylphenazine-1,2-diamine hydrochloride Chemical compound Cl.C1=CC=CC2=NC3=C(C)C(C)=C(N)C(N)=C3N=C21 KVYRCBOUKXJXDK-UHFFFAOYSA-N 0.000 description 5
- PYVUTBASRBNWKO-UHFFFAOYSA-N 3-[bromo(triphenyl)-$l^{5}-phosphanyl]propan-1-ol Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(CCCO)C1=CC=CC=C1 PYVUTBASRBNWKO-UHFFFAOYSA-N 0.000 description 5
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
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- 125000001246 bromo group Chemical group Br* 0.000 description 4
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
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- 230000003595 spectral effect Effects 0.000 description 4
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 3
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- XDFNWJDGWJVGGN-UHFFFAOYSA-N 2-(2,7-dichloro-3,6-dihydroxy-9h-xanthen-9-yl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1C2=CC(Cl)=C(O)C=C2OC2=CC(O)=C(Cl)C=C21 XDFNWJDGWJVGGN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses the preparation method and application of Mitochondrially targeted dihydropyridine compounds, Mitochondrially targeted dihydropyridine compounds have structure shown in formula (I) and (II):
Description
Technical field
The present invention relates to Mitochondrially targeted dihydrogen pyridine derivative and Preparation method and uses, belong to field of medicaments.
Background technique
In recent years, due to the fast development of nuclear science and radiating medical, ionising radiation is more and more closer from our life, by
Risk to ionization radiation injury is also higher and higher, is especially engaged in the mistake of core relevant staff, medical inspection and treatment
Patient in journey causes the ionization radiation injury of body due to touching excessive ray, causes body normal function to be lacked of proper care, body
Internal oxidition stress, or even induce many chronic diseases and eventually lead to aging and death.Ionization radiation injury is mainly high-energy ray
The damage that body generates function macromolecular is penetrated, harm is divided into coup injury and indirect injury, and coup injury is due to big agent
Amount ray directly acts in the intracorporal eucaryotic cell structure of machine, leads to the DNA damage of nucleus, induces body oxidative stress and each
Class chronic disease；Indirect injury is also ionization common during we live as the main damage of one kind of effect of low dose radiation
Damage, principle are because high-energy ray ionizes intracorporal water and oxygen, a large amount of free radicals of generation, the excessive freedom in this part
Cannot effectively removing for base will damage the intracorporal macro-molecular protein of people, lipid and nucleic acid, these macromolecular biology function
The obstacle or missing of energy will lead to body dysfunction or disease.Ionising radiation be because the intracellular water of ray ionization simultaneously
It generating free radicals, radical damage large biological molecule causes ionization radiation injury, still, the radical life pole that ionizing water generates
Its is of short duration, will disappear after a few minutes, and most duration ionization damages rely primarily on internal delay active oxygen radical
Generation be persistently damaged so as to cause intracorporal functional molecular, cause response to oxidative stress.
Place of the mitochondria as intracellular oxidation breathing, and the intracellular only possible subcellular generated free radicals
Structure, studies have shown that ionising radiation leads to structure of mitochondria dysfunction, and continual generate free radicals generates cell
Damage.And the aging either mitochondrial function damage as caused by extraneous certain chemical factors can also generate it is same from
By base, therefore mitochondria is protected not to be damaged and remove the Intramitochondrial free radical of damage, aging as mitochondrial function barrier
Hinder the top priority of disease.
Currently, dihydropyridine compounds, since its hypotoxicity is clinically used as Ca2+Antagonist is as drop
Pressing, there are nicotinamide-adenine dinucleotide phosphate (NADPH) in organism, as a kind of important dihydropyridine endogenous
Antioxidant can remove the oxidation materials such as endogenic free radical, but the particularity of NADPH structure can not efficiently gather
Collect the active oxygen radical removed in mitochondria in mitochondria, therefore, need to be gathered in mitochondria effectively play it is clear
Except the effect of free radical, mitochondria is assisted to remove the compound of the free radical of excess generation.
Summary of the invention
The purpose of the present invention is overcome the deficiencies of the prior art and provide Mitochondrially targeted dihydrogen pyridine derivative.
A second object of the present invention is to provide the preparation methods of Mitochondrially targeted dihydrogen pyridine derivative.
Third object of the present invention is to provide the applications of Mitochondrially targeted dihydrogen pyridine derivative.
Technical solution of the present invention is summarized as follows:
Mitochondrially targeted dihydrogen pyridine derivative, has following structure
Wherein: R is hydrogen atom, phenyl ring or thiophene；X is chlorine, bromine or iodine.
The preparation method of Mitochondrially targeted dihydrogen pyridine derivative (I), includes the following steps:
1) triphenylphosphine is reacted to generation (3- hydroxypropyl) triphenyl phosphonium halides with 3- halogen propyl alcohol；
2) by ammonium hydrogen carbonate, ethyl acetoacetate withThe back flow reaction in ethanol water obtains compound 7, changes
Object 7 is closed to hydrolyze to obtain compound 8, compound 8 and (3- hydroxypropyl) triphen obtained with step 1) by sodium hydrate aqueous solution
Base phosphorus Halides is anti-under 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole catalysis
It answers, obtains dihydrogen pyridine derivative shown in Formulas I；
Reaction equation are as follows:
Wherein: R is hydrogen atom, phenyl ring or thiophene；X is chlorine, bromine or iodine.
The preparation method of Mitochondrially targeted dihydrogen pyridine derivative (II), includes the following steps:
Triphenylphosphine is reacted to generation (3- hydroxypropyl) triphenyl phosphonium halides with 3- halogen propyl alcohol；By (3- hydroxypropyl) triphenyl
Phosphorus Halides reacts to obtain (3- bromopropyl) triphenyl phosphonium halides with HBr；(3- bromopropyl) triphenyl phosphonium halides and niacinamide are anti-
Compound 14 should be obtained, under conditions of pH=8~9, by sodium hydrosulfite reducing compound 14, obtains dihydro pyrrole shown in formula II
Piperidine derivatives；
Reaction equation are as follows:
Wherein: X is chlorine, bromine or iodine.
Above-mentioned Mitochondrially targeted dihydrogen pyridine derivative is in the application for preparing drug for treating Alzheimer's disease.
Application of the above-mentioned Mitochondrially targeted dihydrogen pyridine derivative in preparation treatment Parkinsonian drugs.
Above-mentioned Mitochondrially targeted dihydrogen pyridine derivative is in the application for preparing radioprotector.
Advantages of the present invention:
It is demonstrated experimentally that Mitochondrially targeted dihydrogen pyridine derivative of the invention can effectively be gathered in mitochondria and remove electricity
From active oxygen (ROS) caused by radiation, therefore the related disease caused by free radical, such as Alzheimer's disease and ionization are damaged
There is purposes in terms of hurting disease treatment.This preparation method is simple, and product is easy to get, pollution-free.
Detailed description of the invention
Fig. 1 is the survival rate that Mitochondrially targeted dihydrogen pyridine derivative can obviously increase cell after irradiation.
Fig. 2 is that Mitochondrially targeted dihydrogen pyridine derivative Scavenging ability obviously increases.
Fig. 3 is that Mitochondrially targeted dihydrogen pyridine derivative protects DNA double chain ability increased.
Fig. 4 can effectively be gathered in mitochondria for Mitochondrially targeted dihydrogen pyridine derivative and play a role.
The Mitochondrially targeted dihydrogen pyridine derivative of 1- (I -1) in Fig. 4；The Mitochondrially targeted dihydrogen pyridine derivative (I-of 2-
2)；The Mitochondrially targeted dihydrogen pyridine derivative of 3- (I -3)；The Mitochondrially targeted dihydrogen pyridine derivative of 4- (II).
Specific embodiment
Determining instrument: nuclear magnetic resonance VARIAN INOVA 500MHz type Nuclear Magnetic Resonance.Mass spectrum Waters 3100
Level four bars mass spectrograph.
The present invention is further illustrated combined with specific embodiments below, and the embodiment of the present invention is to make this field
Technical staff better understood when the present invention, but the present invention is not imposed any restrictions.
Embodiment 1
The preparation method of Mitochondrially targeted dihydrogen pyridine derivative (I-1), includes the following steps:
(1) triphenylphosphine (9.4g, 35.9mmol) is sequentially added in the 50ml single port vial equipped with spherical condensation tube,
Bromo- 1 propyl alcohol (0.5g, 3.6mmol) of 3- and 10ml n,N-Dimethylformamide (DMF), 100 DEG C are stirred at reflux 10h, reaction knot
Shu Houyong is cooled to room temperature, depressurizes the solid being precipitated in suction filtration system and is simultaneously washed solid 3 times with cold DMF, obtains white solid, and 50
It DEG C is dried overnight, obtains white powdery solids (3- hydroxypropyl) tri-phenyl-phosphorus bromide；
(2) NH is separately added into the 100ml there-necked flask equipped with magnetic agitation4HCO3(7.9g, 0.1mol), 40% formaldehyde
Aqueous solution (containing formaldehyde 0.1mol) and ethyl acetoacetate (26g, 0.2mol) and 60ml volumetric concentration are 50% ethanol water,
Under nitrogen protection, it is heated to reflux 20h, until there is yellowish precipitating, reaction system is cooled to room temperature, filters solid and with cold
Ethanol washing twice, is dried to obtain compound 7 (wherein R is hydrogen) faint yellow solid (20.32g), weighs 2.53g (0.01mol)
100ml single port vial is added in compound 7, is then successively separately added into 30ml methanol, the NaOH aqueous solution 10ml of 4mol/L adds
Heat reflux 5h or so.Reaction solution is poured into 200ml cold water, is filtered under diminished pressure, hydrochloric acid tune pH=2.5 of the filtrate with 1mol/L, analysis
Solid out is filtered under diminished pressure and is dried to obtain faint yellow solid compound 8 (wherein R is hydrogen) (1.52g).
(3) compound 8 (450mg, 2.0mmol), 1- hydroxy benzenes are added in the 100ml round-bottomed flask equipped with magnetic agitation
And triazole (HOBT) (162mg, 1.2mmol) and DMF (15mL) stir half an hour, add 1- ethyl-(3- dimethylamino
Propyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) (230mg, 1.2mmol), step 1) obtain (3- hydroxypropyl) tri-phenyl-phosphorus bromide
(514mg, 1mmol) and triethylamine (202mg, 2mmol).It is protected from light under nitrogen protection overnight, decompression steams most
DMF, by the NaHCO of saturation3Aqueous solution (20mL) is added in reaction system, and faint yellow solid is precipitated, and decompression collected by suction is solid
Body obtains faint yellow solid (390mg, yield 36.9%) by the method for column chromatographic purifying after drying.Solvent (petroleum
Ether: ethyl acetate).
1H NMR(500MHz,DMSO-d6) δ=8.41 (s, 4H ,-OH), δ=7.91-7.70 (m, 15H ,-CH2-P+ Ph 3),
δ=7.39 (d, J=15.8Hz, 1H=CH- Ph), δ=7.11 (s, 1H, benzene), δ=6.90 (d, J=8.1Hz, 1H,
), benzene δ=6.73 (d, J=8.1Hz, 1H, benzene), δ=6.68 (s, 1H, benzene), δ=6.55 (d, J=
8.0Hz, 1H, benzene), δ=6.43 (d, J=8.1Hz, 1H, benzene), δ=6.22 (d, J=15.8Hz, 1H ,=CH-
), COO- δ=5.12 (dd, J=6.9,5.7Hz, 1H, COO-CH- COO), δ=4.16 (t, J=5.5Hz, 2H ,-COO-CH 2-
CH2), δ=3.54 (dd, J=6.3Hz, 2H, Ph-CH 2- CH-), δ=3.00-2.90 (m, 2H ,-P+-CH 2), 1.81 (d, J=
7.3Hz,2H,-P+-CH2-CH 2-).13C NMR(500MHz,DMSO-d6): δ=18.365,22.157,36.783,64.520,
73.569,115.913,116.298,116.729,117.733,118.427,119.110,120.582,122.265,
125.408,127.048,130.882,131.065,134.171,134.251,135.712,135.735,145.234,
(146.107,146.920,147.370,150.445,166.875,170.102.ESI-MS m/z)=663.5 [M]+.
After nuclear magnetic resonance and mass spectral characteristi, obtain Mitochondrially targeted dihydrogen pyridine derivative crude product (shown in Formulas I,
In: R is hydrogen atom, and X is bromine)
It is demonstrated experimentally that the 3- substituted in the present embodiment step (1) with chloro- 1 propyl alcohol of equimolar 3- or iodo- 1 propyl alcohol of 3- is bromo-
1 propyl alcohol, other same the present embodiment, preparing Mitochondrially targeted dihydrogen pyridine derivative crude product shown in formula (I), (wherein: R is that hydrogen is former
Son, X are chlorine or iodine).
Embodiment 2
A kind of preparation method of Mitochondrially targeted dihydrogen pyridine derivative (I-2), includes the following steps:
(1) with (1) of embodiment 1；
(2) with the formaldehyde in equimolar benzaldehyde alternate embodiment (2), the other the same as in Example 2；
(3) be added in the 100ml round-bottomed flask equipped with magnetic agitation compound 8 (wherein R be phenyl) (600mg,
2.0mmol), HOBT (162mg, 1.2mmol) and DMF (15mL) stir half an hour, add EDCI (230mg,
1.2mmol), step 1) obtain (3- hydroxypropyl) tri-phenyl-phosphorus bromide (514mg, 1mmol) and triethylamine (202mg,
2mmol).It is protected from light under nitrogen protection overnight, decompression steams most DMF, by the NaHCO of saturation3Aqueous solution
(20mL) is added in reaction system, and faint yellow solid is precipitated, and is depressurized collected by suction solid, is passed through column chromatographic purifying after dry
Method obtains faint yellow solid (640mg, 52.9%).Solvent (petroleum ether: ethyl acetate).
1H NMR(500MHz,DMSO-d6): δ=9.08 (s, 1H ,-NH), δ=7.98-7.57 (m, 15H ,-PPh 3), δ=
7.09 (d, J=7.2Hz, 2H, benzene), δ=6.99 (t, J=7.6Hz, 2H, benzene), δ=6.86 (t, J=
7.3Hz, 1H, benzene), δ=4.80 (s, 1H ,-CH), δ=4.18-3.98 (m, 2H ,-CH 2-CH2-CH2-PPh3), δ=
3.97–3.89(m,2H,-CH2 CH3), δ=3.47-3.35 (m, 2H ,-CH2-CH2-CH 2-PPh3), δ=2.25 (s, 3H ,-
CH 3), δ=2.22 (s, 3H ,-CH 3), δ=1.75 (m, J=14.6,7.3Hz, 2H ,-CH2-CH 2-CH2), δ=1.08 (t, J=
7.1Hz,3H,-CH2CH 3).13C NMR(500MHz,DMSO-d6): δ=14.09,18.08,18.19,38.74,58.92,
100.69,102.18,117.59,118.27,127.11,127.73,130.15,130.25,133.37,133.45,134.97,
(145.06,146.82,148.15,166.42,166.83.ESI-MS m/z)=604.6 [M]+
After nuclear magnetic resonance and mass spectral characteristi, obtain Mitochondrially targeted dihydrogen pyridine derivative crude product (shown in Formulas I,
In: R is phenyl ring, and X is bromine)
It is demonstrated experimentally that the 3- substituted in the present embodiment step (1) with chloro- 1 propyl alcohol of equimolar 3- or iodo- 1 propyl alcohol of 3- is bromo-
1 propyl alcohol, other same the present embodiment, preparing Mitochondrially targeted dihydrogen pyridine derivative crude product shown in formula (I), (wherein: R is benzene
Ring, X are chlorine or iodine).
Embodiment 3
A kind of preparation method of Mitochondrially targeted dihydrogen pyridine derivative (I-3), includes the following steps:
(1) with (1) of embodiment 1；
(2) with the formaldehyde in equimolar thiophene 2- formaldehyde alternate embodiment (2), the other the same as in Example 2；
(3) be added in the 100ml round-bottomed flask equipped with magnetic agitation compound 8 (wherein R be thienyl) (307mg,
1.0mmol), HOBT (162mg, 1.2mmol) and DMF (15mL) stir half an hour, add EDCI (230mg,
1.2mmol), step 1) obtain (3- hydroxypropyl) tri-phenyl-phosphorus bromide (514mg, 1mmol) and triethylamine (202mg,
2mmol).It is protected from light under nitrogen protection overnight, decompression steams most DMF, by the NaHCO of saturation3Aqueous solution
(20mL) is added in reaction system, and faint yellow solid is precipitated, and is depressurized collected by suction solid, is passed through column chromatographic purifying after dry
Method obtains faint yellow solid (470mg, 77%).Solvent (petroleum ether: ethyl acetate).
1H NMR(500MHz,DMSO-d6): δ=9.33 (s, 1H ,-NH), 7.80 (dq, J=19.1,7.4Hz, 15H ,-
PPh 3), 7.04 (d, J=6.0Hz, 1H, thiophene), 6.68-6.61 (m, 1H, thiophene), 6.58 (d, J=
3.3Hz,1H,thiophene),5.13(s,1H,-CH), 4.15 (dd, J=38.2,33.0Hz, 2H ,-CH 2-CH2-CH2-
PPh3),4.04–3.95(m,2H,-CH2 CH3), 3.40 (t, J=13.2Hz, 2H ,-CH2-CH2-CH 2-PPh3),2.26(s,
3H,-CH 3),2.23(s,3H,-CH 3),1.87–1.75(m,2H,-CH2-CH 2-CH2), 1.12 (t, J=7.1Hz, 3H ,-
CH2CH 3).13C NMR(500MHz,DMSO-d6): δ=14.97,18.84,18.88,22.35,34.5,59.90,63.01,
63.16,101.00,102.40,118.40,119.09,123.13,124.12,127.07,130.96,131.06,134.17,
134.25,135.74,135.76,146.50,148.07,152.70,166.97,167.36. ESI-MS (m/z)=610.5 [M]+
After nuclear magnetic resonance and mass spectral characteristi, obtain Mitochondrially targeted dihydrogen pyridine derivative crude product (shown in Formulas I,
In: R is thiphene ring, and X is bromine)
It is demonstrated experimentally that the 3- substituted in the present embodiment step (1) with chloro- 1 propyl alcohol of equimolar 3- or iodo- 1 propyl alcohol of 3- is bromo-
1 propyl alcohol, other same the present embodiment, preparing Mitochondrially targeted dihydrogen pyridine derivative crude product shown in formula (I), (wherein: R is thiophene
Ring, X are chlorine or iodine).
Embodiment 4
A kind of preparation method of Mitochondrially targeted dihydrogen pyridine derivative (II), includes the following steps:
(1) with (1) of embodiment 1；
(2) (3- hydroxypropyl) tri-phenyl-phosphorus bromide 2.0g is added in the 100ml there-necked flask equipped with magnetic agitation
Hydrobromic acid (Han Liang≤40% is added dropwise in (5mmol) at 108 DEG C) to just dissolving, back flow reaction 24 hours.It is cooled to room temperature,
Solution is slowly dropped in 50 times of v aqueous solutions, there is white precipitate precipitation.It is filtered under diminished pressure, cold water is washed, and drying obtains white solid
Body (3- bromopropyl) tri-phenyl-phosphorus bromide (1.9g, yield 83%).
(3) by (3- bromopropyl) tri-phenyl-phosphorus bromide 0.92g (20mmol) in 50ml round-bottomed flask, 0.24g is added
The niacinamide (13) of (20mmol).10ml DMF is added at 100 DEG C.After reflux 5 hours, it is cooled to room temperature.It is evaporated under reduced pressure out
Suitable quantity of water (10ml) dissolution is added in most DMF solvent.Use ethyl acetate (40ml × 6), methylene chloride (40ml respectively again
× 6) extracting and washing is evaporated under reduced pressure out most of water, adds a small amount of methanol dissolution residue and is added to 50-100 times of volumes of acetic acid
In ethyl ester, there is white solid precipitation.Filtering, cold ethyl acetate are washed, and are dried, are obtained white solid 3- carbamyl -1- (3- (triphen
Base phosphine) propyl) pyridiniujm (14) 0.76g.(yield 65%).
(4) take 3- carbamyl -1- (3- (triphenylphosphine) propyl) pyridiniujm (14) 0.58g (1mmol) in round-bottomed flask
In, the sodium dithionite of 0.52g (3mmol) is added.It is dissolved with sodium carbonate liquor and adjusts PH to 8-9 (after stable reaction
PH), it is protected from light room temperature reaction 4h, decompression filters solid, and with massive laundering, drying obtains faint yellow solid 0.36g (yield
70%).
1H NMR(500MHz DMSO-d6): δ=8.00-7.65 (m, 15H ,-+PPh 3): δ=6.87 (s, 1H,
), pyridine δ=6.56 (s, 2H ,-NH 2), 5.84 (d, J=8.0Hz, 1H, pyridine), δ=4.61-4.54 (m, 1H,
), pyridine δ=3.57-3.44 (m, 2H ,-CH2-+PPh3), δ=3.26 (t, J=6.9Hz, 2H ,-CH2-CH2-CH 2-N),δ
=2.92 (d, J=1.0Hz, 2H, pyridine-CH 2), δ=1.69 (dd, J=14.8,7.4Hz, 2H ,-CH2-CH 2-
CH2) .ESI-MS (m/z)=427.8 [M]+
After nuclear magnetic resonance and mass spectral characteristi, Mitochondrially targeted dihydrogen pyridine derivative crude product shown in formula (II) is obtained
(wherein: X is bromine)
It is demonstrated experimentally that in chloro- 1 propyl alcohol of equimolar 3- or 3-1 iodine propyl alcohol (11-3) substitution the present embodiment step (1)
Bromo- 1 propyl alcohol of 3-, other same the present embodiment, Mitochondrially targeted dihydrogen pyridine derivative crude product shown in preparation formula (II) is (wherein: X
For chlorine or iodine)
Experimental example 1
Dimethyl diaminophenazine chloride method measures cell survival rate
1, cell culture
CHO-K1 cell (National Laboratory cell shared resource platform is bought) is 5%CO in volumetric concentration237 DEG C culture
It is cultivated in case, the DMEM culture solution culture containing 10% dual anti-fetal calf serum to logarithmic phase.
2, cell survival rate is measured
The CHO-K1 cell of culture to logarithmic phase is layered in 96 orifice plates for 4000 with every hole, cultivates adherent overnight, irradiation
Preceding 30min gives Mitochondrially targeted dihydro shown in Mitochondrially targeted dihydrogen pyridine derivative (I-1, I-2, I-3) and formula (II) respectively
Pyridine derivate medical fluid (1 μm of ol/L, solvent are containing serum and dual anti-DMEM culture medium) every 100 μ L of hole, is placed in incubator
Middle culture 30min is irradiated with 4Gy gamma-rays, is then continued culture 24 hours in incubator, is removed culture solution, then every hole
The dimethyl diaminophenazine chloride culture solution that 100 μ L saturation is added cultivates 2h in incubator, and cell is made sufficiently to absorb dimethyl diaminophenazine chloride, and dimethyl diaminophenazine chloride training is sucked out
Nutrient solution is washed 2 times with 150 μ L phosphate buffers (PBS), washes away unabsorbed residual dimethyl diaminophenazine chloride, dries PBS, is added in 150 μ L
Property red lysate (acetic acid: ethyl alcohol: volume ratio=1:50:49 of water), shake 3min, measure absorbance in 544nm with microplate reader.
Experimental result: Mitochondrially targeted dihydrogen pyridine derivative can obviously increase the survival rate of cell after irradiation (see Fig. 1).
Experimental example 2
The measurement of ROS elimination effect
1. with 1 step 1 of experimental example；
2. the CHO-K1 cell of culture to logarithmic phase is layered in 6 orifice plates, every hole 1x104It is a, two groups of controls are respectively set
Group and four groups of dosing groups, dosing group 30min before irradiation, be separately added into Mitochondrially targeted dihydrogen pyridine derivative (I-1, I-2,
I-3 (1 μm of ol/L, solvent are containing serum and dual anti-for Mitochondrially targeted dihydrogen pyridine derivative medical fluid) and shown in formula (II)
DMEM culture medium) every hole 1mL, control group 30min before irradiation is only added the fresh of equivalent and cultivates containing serum with dual anti-DMEM
Base, while being placed in incubator and cultivating 30min.Then it is irradiated with 4Gy gamma-rays, then cultivated 24 hours in the incubator, removed
2', 7'- dichlorofluorescin diethylester (DCFH-DA) (sigma is bought) (5 μM, culture medium dissolution) culture is added in culture solution
Liquid 1ml is protected from light 37 DEG C of incubation 20min, removes DCFH-DA culture solution, washed 3 times with PBS, with collected by trypsinisation cell, enzyme
Mark instrument measures fluorescence intensity under the conditions of 488nm excitation wavelength, 525nm launch wavelength.
Experimental result: Mitochondrially targeted dihydrogen pyridine derivative Scavenging ability obviously increases (see Fig. 2).
Experimental example 3
DNA double chain fracture measurement
1. with 1 step 1 of experimental example；
2. one group of non-irradiation group and four groups of irradiation groups, four groups of irradiation groups are respectively set in the Chinese hamster ovary celI of culture to logarithmic phase
30min before irradiating, respectively to Mitochondrially targeted shown in Mitochondrially targeted dihydrogen pyridine derivative (I-1, I-2, I-3) and formula (II)
Dihydrogen pyridine derivative medical fluid (1 μm of ol/L, solvent be containing serum and dual anti-DMEM culture medium) and it is fresh containing serum and pair
500 μ L of the every hole of anti-DMEM culture medium, non-irradiation group are added the fresh containing serum and dual anti-DMEM culture medium of equivalent, and four
Group irradiation group uses 4Gy gamma-rays to irradiate respectively.Culture 1 is small in the incubator simultaneously for four groups of cells and non-irradiation group after irradiation
When, culture solution is removed, 500 μ L mass fraction, 4% paraformaldehyde aqueous solution is added, fixed 15min, PBS is washed 3 times, with 500 μ L
Mass fraction 0.2%, 100 solution of Triton-X, (solvent of 100 solution of Triton-X is PBS) broken cell film 15min are used
PBS is washed 3 times, and sheep blood serum working solution closes 2h, and (abcom is bought 200 μ L rabbit polyclonal γ-H2AX, and 1:1000 blood of goats is thin
Release) hatch 4 DEG C overnight, PBS is washed 3 times, and 200 μ L goat-anti rabbit fluorescence secondary antibodies (abcom is bought, 1:2000PBS dilution) are protected from light room
Temperature is incubated for 1h, and PBS is washed 3 times, and DAPI (Suo Laibao is bought) dyes 5min, and PBS is washed 3 times, anti-quencher mounting (Suo Laibao purchase
), it is taken pictures with AMG evo fluorescence microscope, Image Pro Plus6.0 software focus counts.
Experimental result: Mitochondrially targeted dihydrogen pyridine derivative protection DNA double chain ability increased.(see Fig. 3).
Experimental example 4
1. with 1 step 1 of experimental example；
2. by 106A cell inoculation is into laser co-focusing culture dish, after cell is adherent, gives Mitochondrially targeted dihydro respectively
Mitochondrially targeted dihydrogen pyridine derivative medical fluid (drug concentration 10 shown in pyridine derivate (I-1, I-2, I-3) and formula (II)- 5Mol/L) 37 DEG C of incubation 1h in the incubator, remove cell culture fluid, and washed 3 times with PBS, are added 37 DEG C and contain
Mitotracker Red@The cell culture fluid of (life company buys) (20nmol/L) is incubated for 20min under the conditions of 37 DEG C, discards
Former culture medium is added PBS and washs 3 times, and the paraformaldehyde for being added 4% is fixed, using in confocal laser scanning microscope cell
Drug and Mitotracker Red@Distribution.
Experimental result: tentatively conclude that Mitochondrially targeted dihydrogen pyridine derivative can be effectively gathered in mitochondria.(see
Fig. 4).
In our daily normal vital movements, body has Free-radical ring opening polymerization, including superoxide dismutase,
Catalase, glutathione reductase etc. remove the large biological molecule of free radical.But on the one hand due to people itself aging
Leading to the decline of Free-radical ring opening polymerization, the superoxide anion that mitochondrial oxidation breathing generates, which cannot access, effectively to be removed,
Be diffused into cell and be converted to more active oxygens, cause vivo oxidation stress, to generate Parkinson's disease and Alzheimer
The disease relevant to active oxygen such as disease；On the other hand due to the effect by ionising radiation, mitochondrial oxidation respiratory chain and coding
The DNA of oxidation-respiration chain is damaged, and will become the main place of active oxidative burst, if the active oxygen of excess generation obtains not
The functional large biological molecule of tool will be damaged to effectively removing, and then leads to the Free-radical ring opening polymerization obstacle of human body, is made
Cellular oxidation stress.It can be seen that the Mitochondrially targeted active oxygen radical of our exogenous intakes is removed under these conditions
These diseases relevant with active oxygen radical of drug energy effectively preventing and dysfunction disease.And this research is due to mitochondria target
It can be effectively gathered in scavenging capacity oxygen radical in mitochondria to dihydrogen pyridine derivative, therefore such compound can be used as
The medicine of Parkinson's disease, Alzheimer's disease, while can also be given treatment to as tumour radiotherapy clinic and Nuclear Accident Emergency
When radiation injury protection medicine.
The inclusion compound of Mitochondrially targeted dihydrogen pyridine derivative (I) or Mitochondrially targeted dihydrogen pyridine derivative (II), altogether
Brilliant, polycrystalline or solid dosage forms, liquid dosage form or semisolid dosage form containing said derivative belong to protection model of the invention
It encloses.
Solid dosage forms can be tablet (including ordinary tablet, dispersible tablet, effervescent tablet, chewable tablets etc.)；
Liquid dosage form can be solution (including true solution or colloidal solution), emulsion (including o/w type, w/o type and multiple
Cream), suspension, injection (powder needle, liquid drugs injection)；
Semisolid dosage form can be paste etc..
Common system is made in Mitochondrially targeted dihydrogen pyridine derivative (I) or Mitochondrially targeted dihydrogen pyridine derivative (II)
Agent, sustained release preparation, controlled release preparation and various particulate delivery systems.
Claims (5)
1. Mitochondrially targeted dihydrogen pyridine derivative, it is characterized in that having following structure
Wherein: X is chlorine, bromine or iodine.
2. the preparation method of the Mitochondrially targeted dihydrogen pyridine derivative (II) of claim 1, it is characterized in that including the following steps:
Triphenylphosphine is reacted to generation (3- hydroxypropyl) triphenyl phosphonium halides with 3- halogen propyl alcohol；By (3- hydroxypropyl) triphenyl phosphonium halides with
HBr reacts to obtain (3- bromopropyl) triphenyl phosphonium halides；By (3- bromopropyl) triphenyl phosphonium halides and niacinamide reaction
It closes object (14) and, by sodium hydrosulfite reducing compound (14), obtains dihydropyridine shown in formula (II) under conditions of pH=8~9
Derivative；
Reaction equation are as follows:
Wherein: X is chlorine, bromine or iodine.
3. the Mitochondrially targeted dihydrogen pyridine derivative of claim 1 is in the application for preparing drug for treating Alzheimer's disease.
4. the Mitochondrially targeted dihydrogen pyridine derivative of claim 1 is in the application of preparation treatment Parkinsonian drugs.
5. the Mitochondrially targeted dihydrogen pyridine derivative of claim 1 is in the application for preparing radioprotector.
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| CN108969504A (en) * | 2018-06-22 | 2018-12-11 | 中国人民解放军第四军医大学 | The preparation method of Mitochondrially targeted nm radiation protection medicine |
| US20210395280A1 (en) * | 2018-11-01 | 2021-12-23 | The Medical College Of Wisconsin, Inc. | Targeting Redox-Active Pyridinium Cations to Mitochondria to Inhibit Proliferation of Drug-Resistant Cancer Cells |
| TWI706780B (en) * | 2019-03-27 | 2020-10-11 | 台灣粒線體應用技術股份有限公司 | Use of mitochondria for the manufacture of a medicament for treating alzheimer's disease |
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